CN101227935A

CN101227935A - Compositions and methods for treating diverticulum disease

Info

Publication number: CN101227935A
Application number: CNA2005800510643A
Authority: CN
Inventors: 威廉·L·亨特; 菲利普·M·陶勒伊科斯; 戴维·M·格拉韦特; 鲁伊·阿韦拉尔
Original assignee: Angiotech International AG
Current assignee: Angiotech International AG
Priority date: 2005-05-12
Filing date: 2005-05-12
Publication date: 2008-07-23

Abstract

Agents, compositions, and implants are provided herein for treating diverticular disease (e.g., diverticulosis and diverticulitis). In particular, fibrosis-inducing agents, hemostatic agents, and/or anti-infective agents, or compositions containing one or more of these agents are provided for use in methods for treating diverticular disease.

Description

The compositions and the method for treatment diverticulum disease

Background of invention

Invention field

Relate generally to pharmaceutical composition of the present invention, method and implant, and more specifically, relate to compositions, implant and the method for treatment diverticulum disease (for example, diverticulitis).

Description of Related Art

Diverticulum disease is wherein to have hollow organ's mucosa and the disease that submucosal hernia forms, described hollow organ such as gastrointestinal (GI) road, urinary tract or respiratory tract, and its muscular wall by body passageway produces and turns up.Although diverticulum may reside in any pipe, diverticulum disease has maximum clinical relatedness in GI road, bottom (large intestine or colon), and wherein it can cause life-threatening inflammation and infection (diverticulitis) or hemorrhage (bottom GI is hemorrhage).Usually, this disease be medical treatment or by open surgical operation remove described diverticulum and/or fully excision contain their intestinal fragment.

Diverticulum disease (it comprises the disease such as diverticulosis and diverticulitis) is the important medical disease and is the common reason of massive hemorrhage in the colon, account for a large amount of GI hemorrhage 30% to 50%.When the folliculus in the colon (being called diverticulum) outwards protrudes by weak spot, cause diverticulum disease.About 10% 40 years old the American of surpassing has diverticulosis (that is, having the disease of diverticulum), and described disease along with age of people become more general (surpass 60 years old the crowd 33% and surpass 80 years old the people 50% have diverticulum disease).In many patients, it is asymptomatic that diverticulosis keeps.Yet in the people who suffers from diverticulosis of about 10-25%, folliculus becomes infection or inflammation.This disease is called diverticulitis, can cause that stomachache (particularly centering on the left side of lower abdomen), peritonitis, abscess formation and bottom GI are hemorrhage.Perhaps the most serious result of diverticulum disease is bottom enterorrhagia (a blood per rectum process).25% of nearly 15% to 40% the hemorrhage outbreak of diverticulosis patient experience, and those patients will have periodic bleeding episodes.After for the second time hemorrhage, hemorrhage for the third time chance approximately is 50%.The mortality rate of the merging relevant with hemorrhage of diverticulum and significant sickness rate are 10% to 20%, part because patient age and with the common morbidity of other disease, described other disease such as heart, pulmonary or kidney dysfunction.

Usually, hemorrhage of diverticulum is a large amount of, painless and from restrictive.Yet, in 5% diverticulum patient, hemorrhage be enough to cause cardiovascular instability basically and may need the transfusion.The treatment of diverticulum disease relates generally to recovery, and described recovery comprises the intravenous route of large diameter, places foley's catheter, places nasal feeding tube to get rid of the administration of Upper GI hemorrhage and intravenous fluid.If necessary, through capacity recovery (volume resuscitation), the correction of disorders of hemostasis and the supportive treatment patient that transfuses blood commonly used.Most active bottom GI is hemorrhage to be stopped spontaneous.Yet as hemorrhage result, 18% to 25% the patient with hemorrhage of diverticulum will become on the hematodinamics unsettled, although and carry out the invasive recovery, continue unstable.Under the situation of a large amount of or severe haemorrhage, may need urgent surgical operation (for example, the colectomy and the most colectomy of fragment colectomy, blind section excision, abdominal part colectomy, full abdominal part) described hemorrhage to attempt to stop.

Though described several pharmacological method that are used for the treatment of diverticulitis (see, for example, U.S. Patent number 4,837,229; 6,297,214; 6,114,304; With 4,455,305), do not have a kind ofly to be proved to be effective especially.For example, can with angiospastic material such as vassopressin treatment hematodinamics stable, enliven hemorrhage patient.The risk relevant with the vasospasm material is included in 50% the hemorrhage again rate among the patient of cancelling after the described pharmacotherapy, crown perfusion, hypertension and the cardiac arrhythmia of reduction.Alternatively, thromboembolism (with the tremulous pulse of the hemorrhage intestinal segment of the particulates plug of little local injection supply) but can stop hemorrhage relevantly sometimes with colon infarction, and preferably be only and exist the patient of bad surgical risk to keep.

Current, except supportive measurement or urgent surgical operation in severe case, do not exist reliable way to treat diverticulitis acutely.Even (that is) patient, stopped bleeding, current do not have the intervention of reliable non-surgery operation can adopt to prevent periodically hemorrhage yet for the spontaneous solution of symptom.Equally because the age, as losing blood result's weakness or other concurrent medical conditions, the patient of the surgical resection art of the many diverticulums that will benefit from them often is not operating candidate.Therefore, can eliminate the intervention of nonsurgical, the invasive (minimally invasive) of diverticulum and the M ﹠ M relevant, keep significant unsatisfied needs of medical treatment with them for exploitation.

The invention summary

Be briefly described, the invention provides reagent, implant, compositions and method, the therapeutic agent, fibre modification derivant, implant and the compositions invasive ground that are used for selecting directly are delivered to diverticulum, are used for the treatment of the patient who suffers from diverticulum disease.This paper provides compositions and implant, comprises device, and the therapeutic agent delivery that is used for selecting is to diverticulum, and the method that is provided for preparing and using these reagent, compositions and implant.In certain embodiments, provide the implant (or biomaterial) of therapeutic agent or medicine dipping, it induces adhesion or fibre modification or original position to promote " filling " of diverticulum in the diverticulum wall; Thereby remove diverticulum chamber and mitigation symptoms or reduce the risk of complication development subsequently.In multiple embodiments, by partial (intracavity) or the specific pharmacological agents of zonal release, in diverticulum, induce fibre modification, described pharmacological agents is via endoscopy or based on the intervention of conduit and be delivered to described position.

In one aspect, the invention provides compositions, described compositions comprises that (a) fibrous tissue forms agent and (b) polymer or original position form the chemical compound of cross linked polymer.

In one aspect of the method, the invention provides the compositions that comprises the compositions that contains fibrous tissue formation agent and filler.

In one aspect of the method, the invention provides the method that is used for the treatment of diverticulum disease, described method comprise will the treatment effective dose fibrous tissue form agent or comprise compositions that fibrous tissue forms agent and be incorporated in the diverticulum among the host, wherein said fibrous tissue forms agent inducing fibrosis reaction (fibrotic response) in diverticulum, therefore treats the diverticulum disease among the described host.

In another related aspect, the invention provides and be used for inducing fibrotic method at its host's diverticulum of needs, described method comprises compositions is incorporated in host's the diverticulum that described compositions comprises fibrous tissue and forms agent, and wherein said reagent is induced fibre modification in diverticulum.

In one aspect of the method, the invention provides the method that is used for the treatment of diverticulum disease, described method comprises compositions is incorporated in the diverticulum among the host, described compositions comprises that (a) fibrous tissue forms agent and (b) polymer or original position form the chemical compound of cross linked polymer, wherein said compositions is the inducing fibrosis reaction in diverticulum, therefore treats the diverticulum disease among the host.

In another related aspect, the invention provides and be used for inducing fibrotic method at host's diverticulum, described method comprises compositions is inserted into the host, described compositions comprise (a) fibrous tissue form agent and (b) polymer or original position form the chemical compound of cross linked polymer, wherein said compositions is induced fibre modification in the host.

In one aspect of the method, the invention provides the method for preparing implant, described method comprises that combination (a) fibrous tissue forms agent; (b) polymer, or comprise the compositions of polymer; (c) anti-infective, wherein said fibrous tissue form agent inducing fibrosis reaction in diverticulum.

In one aspect of the method, the invention provides the test kit that uses in the treatment diverticulum disease, described test kit comprises: the dry powder composite that (a) comprises following component: (i) have first component of the core that replaces with m nucleophilic group, wherein m 〉=2; Second component that (ii) has the core that replaces with n electrophilic group, wherein n 〉=2 and m+n＞4; Be endowed reactivity when being exposed to aqueous environments but wherein said nucleophilic and electrophilic group right and wrong in dry environment are reactive, so that described component reacts to each other in aqueous environments and forms three-dimensional compositions; (b) first buffer solution of pH in about 1.0 to 5.5 scopes; (c) second buffer solution of pH in about 6.0 to 11.0 scopes; (d) comprise the 3rd component that fibrous tissue forms agent, wherein each component is independent pack and mixing immediately before using.

In aspect each is above-mentioned; it can be following one or more that described fibrous tissue forms agent: promote the fibrous tissue of cell regeneration to form agent; the fibrous tissue that promotes blood vessel to take place forms agent; promote the fibrous tissue of fibroblast migration to form agent; promote the fibrous tissue of fibroblast proliferation to form agent; promote the fibrous tissue of extrtacellular matrix deposition to form agent; promote the fibrous tissue of tissue remodeling to form agent; fibrous tissue as diverticulum wall stimulus object forms agent; silk is (such as silkworm silk; spider silk; the recombinant silk; raw silk; the silk of hydrolysis; acid-treated silk; silk with acidylate); Talcum; chitosan; polylysine; fibronectin; bleomycin or its analog or derivant; the fibrous tissue of Connective Tissue Growth Factor (CTGF) forms agent; metallic beryllium or its oxide; copper; Sa Ransu (saracin); Silicon stone; crystalline silicate; silica flour; Pulvis Talci; ethanol; extracellular matrix components; collagen; fibrin, fibrinogen, poly-(PETP); poly-(ethylene-altogether-ethyl acetate); N-carboxybutyl chitosan, RGD protein, the polymer of vinyl chloride; cyanoacrylate; crosslinked poly-(ethylene glycol)-methylated collagen, inflammatory cytokine, TGF β; PDGF; VEGF, TNF α, NGF; GM-CSF; IGF-a, IL-1, IL-8; IL-6; growth hormone, bone morphogenetic protein, cell proliferation reagent; dexamethasone; isotretinoin, 17-, estradiol; diethylstilbestrol (diethylstibesterol); ciclosporin A is complete--trans retinoic acid or its analog or derivant, fine hair (comprises animal down; wood shavings and mineral wool); cotton; bFGF, polyurethane, politef; poly-(alkyl cyanoacrylate); activator protein, angiogenin (angiopoietin), insulinoid somatomedin (IGF); hepatocyte growth factor (HGF); colony stimulating factor (CSF), erythropoietin, interferon; endothelin-1; Angiotensin II, bromocriptine, D-lysergic acid (+)-butanolamide-(2); fibrosis albumen (fibrosin); fibrin, adhesiveness glycoprotein, Dan Baijutang; hyaluronan; acidity and the secretory protein (SPaRC) that is rich in cysteine, thrombospondin binds plain (tenacin); cell adhesion molecule; the inhibitor of matrix metalloproteinase, the tissue depressant of matrix metalloproteinase, methotrexate; carbon tetrachloride, and thioacetamide.Also operable other fibrous tissue formation agent also is disclosed in the following detailed description among the present invention.

In aspect each is above-mentioned, one or more following polymers can (form agent as fibrous tissue) separately to be used or is used in combination with each fibrous tissue formation agent above-listed or that be described in this paper in addition: copolymer, block copolymer, random copolymer, biodegradable polymer, not biodegradable polymer, hydrophilic polymer, hydrophobic polymer, polymer with hydrophilic-structure territory, polymer with hydrophobic domains, non-conductive polymer, elastomer, hydrogel, siloxane polymer, hydrocarbon polymer, styrene derived polymer, the butadiene derived polymer, macromonomer (macromer), poly-(ethylene glycol), collagen or derivatives thereof, methylated collagen, the combination of collagen or derivatives thereof and fibrinogen, the combination of collagen or derivatives thereof and thrombin, (a) collagen or derivatives thereof; (b) fibrinogen; (c) combination of thrombin, the combination of methylated collagen and poly-(ethylene glycol) or derivatives thereof, CT3, COSTASIS, poly-(ethylene glycol), COSEAL, TISSEAL, FLOSEAL, fibrin, amorphous polymer, cyanoacrylate, methyl 2-cyanoacrylate, cyanacrylate, Tisuacryl, octyl 2-cyanoacrylate, alpha-cyanoacrylate methoxyl group propyl ester, poly-(alkyl cyanoacrylate), poly-(MCA), poly-(ethyl cyanoacrylate), poly-(butyl cyanoacrylate), poly-(isobutyl cyanoacrylate), poly-(hexyl cyanoacrylate), poly-(octyl cyanoacrylate), poly-(carboxyalkyl cyanoacrylate), poly-(methoxy-propyl cyanoacrylate), cross linked polymer is with the polymer of mammalian tissues reaction, naturally occurring polymer, protein, saccharide, crosslinked and biodegradable polymer, not biodegradable polymer, methylated collagen, fibrinogen, thrombin, albumin, plasminogen, Feng's von willebrand's factor, the VIII factor (Factor VIII), Hypoallergenic collagen, the collagen of non-end peptide (atelopeptidic), the collagen of end peptide, crosslinked collagen, aprotinin, gelatin, protein conjugate, gelatin conjugate, hyaluronic acid, derivatives of hyaluronic acids, synthetic polymer is by comprising the polymer that the synthetic reactant that contains the chemical compound of isocyanates forms, the synthetic chemical compound that contains isocyanates is by comprising the polymer that the synthetic reactant that contains the chemical compound of mercaptan forms, the synthetic chemical compound that contains mercaptan, by comprising the polymer that the synthetic reactant that contains the chemical compound of at least two mercaptos forms, the synthetic chemical compound that contains at least two mercaptos is by comprising the polymer that the synthetic reactant that contains the chemical compound of at least three mercaptos forms, the synthetic chemical compound that contains at least three mercaptos is by comprising the polymer that the synthetic reactant that contains the chemical compound of at least four mercaptos forms, the synthetic chemical compound that contains at least four mercaptos, by comprising the polymer that the synthetic reactant that contains amino chemical compound forms, the synthetic chemical compound that contains amino is by comprising the polymer that the synthetic reactant that contains the chemical compound of at least two amino forms, the synthetic chemical compound that contains at least two amino, by comprising the polymer that the synthetic reactant that contains the chemical compound of at least three amino forms, the synthetic chemical compound that contains at least three amino is by comprising the polymer that the synthetic reactant that contains the chemical compound of at least four amino forms, the synthetic chemical compound that contains at least four amino, by comprising the polymer that the synthetic reactant that contains the chemical compound of carbonyl-oxygen-succinimido forms, the synthetic chemical compound that contains carbonyl-oxygen-succinimido is by comprising the polymer that the synthetic reactant that contains the chemical compound of at least two carbonyl-oxygen-succinimido forms, the synthetic chemical compound that contains at least two carbonyl-oxygen-succinimido, by comprising the polymer that the synthetic reactant that contains the chemical compound of at least three carbonyl-oxygen-succinimido forms, the synthetic chemical compound that contains at least three carbonyl-oxygen-succinimido is by comprising the polymer that the synthetic reactant that contains the chemical compound of at least four carbonyl-oxygen-succinimido forms, the synthetic chemical compound that contains at least four carbonyl-oxygen-succinimido, by comprising the polymer that the synthetic reactant that contains the chemical compound of polyalkylene oxide forms, the synthetic chemical compound that contains polyalkylene oxide is by comprising the polymer that the synthetic reactant that contains the chemical compound of polyalkylene oxide and biodegradable polyester block forms, the synthetic chemical compound that contains polyalkylene oxide and biodegradable polyester block, by comprising the polymer that synthetic reactant with chemical compound that contains polyalkylene oxide of reactive amino forms, the synthetic chemical compound that contains polyalkylene oxide with reactive amino is by comprising the polymer that synthetic reactant with chemical compound that contains polyalkylene oxide of reactive mercapto forms, the synthetic chemical compound that contains polyalkylene oxide with reactive mercapto, by comprising the polymer that synthetic reactant with chemical compound that contains polyalkylene oxide of reactive carbonyl-oxygen-succinimido forms, the synthetic chemical compound that contains polyalkylene oxide with reactive carbonyl-oxygen-succinimido is by comprising the polymer that the synthetic reactant that contains the chemical compound of biodegradable polyester block forms, the synthetic chemical compound that contains the biodegradable polyester block, the polymer that forms by the reactant that comprises the synthetic polymer that forms by lactic acid or lactide wholly or in part, the synthetic polymer that is formed by lactic acid or lactide wholly or in part is by the polymer that the reactant that comprises the synthetic polymer that is formed by glycolic or Acetic acid, hydroxy-, bimol. cyclic ester wholly or in part forms, the synthetic polymer that is formed by glycolic or Acetic acid, hydroxy-, bimol. cyclic ester wholly or in part, the polymer that forms by the reactant that comprises polylysine, polylysine is by comprising (a) protein and (b) comprise the polymer that the reactant of the chemical compound of polyalkylene oxide part forms, by comprising the polymer that (a) protein and (b) reactant of polylysine form, by comprising (a) protein and (b) having a polymer that the reactant of the chemical compound of at least four mercaptos forms, by comprising (a) protein and (b) have a polymer that the reactant of the chemical compound of at least four amino forms, by comprising (a) protein and (b) having the polymer that the reactant of the chemical compound of at least four carbonyl-oxygen-succinimido forms, by comprising (a) protein and (b) having by being selected from lactic acid, lactide, glycolic, Acetic acid, hydroxy-, bimol. cyclic ester, the polymer that the reactant of the chemical compound of the biodegradable region that forms with the reactant of 6-caprolactone forms, by comprising the polymer that the reactant of (a) collagen with the chemical compound that (b) comprises the polyalkylene oxide part forms, by comprising (a) collagen and (b) polymer that forms of the reactant of polylysine, by comprising (a) collagen and (b) have the polymer that the reactant of the chemical compound of at least four mercaptos forms, by comprising the polymer that (a) collagen and the reactant that (b) has the chemical compound of at least four amino form, by comprising (a) collagen and (b) having a polymer that the reactant of the chemical compound of at least four carbonyl-oxygen-succinimido forms, by comprising (a) collagen and (b) having by being selected from lactic acid, lactide, glycolic, Acetic acid, hydroxy-, bimol. cyclic ester, the polymer that the reactant of the chemical compound of the biodegradable region that forms with the reactant of 6-caprolactone forms is by comprising (a) methylated collagen and (b) comprise the polymer of the compound formation of polyalkylene oxide part, by comprising (a) methylated collagen and (b) polymer that forms of the reactant of polylysine, by comprising (a) methylated collagen and (b) having a polymer that the reactant of the chemical compound of at least four mercaptos forms, by comprising (a) methylated collagen and (b) have a polymer that the reactant of the chemical compound of at least four amino forms, by comprising (a) methylated collagen and (b) having the polymer that the reactant of the chemical compound of at least four carbonyl-oxygen-succinimido forms, by comprising (a) methylated collagen and (b) having by being selected from lactic acid, lactide, glycolic, Acetic acid, hydroxy-, bimol. cyclic ester, the polymer that the reactant of the chemical compound of the biodegradable region that forms with the reactant of 6-caprolactone forms, by comprising the polymer that hyaluronic reactant forms, the polymer that is formed by the reactant that comprises derivatives of hyaluronic acids is by comprising number-average molecular weight 3,000 and 30, the polymer that the reactant of poly-(ethylene glycol) ether four-sulfydryl of the tetramethylolmethane between 000 forms, the tetramethylolmethane of number-average molecular weight between 3,000 and 30,000 gathers (ethylene glycol) ether four-sulfydryl; By the polymer that the reactant that comprises poly-(ethylene glycol) ether four of the tetramethylolmethane of number-average molecular weight between 3,000 and 30,000-amino forms, the tetramethylolmethane of number-average molecular weight between 3,000 and 30,000 gathers (ethylene glycol) ether four-amino; By comprising (a) synthetic number-average molecular weight 3,000 and 30, between 000 and comprise the chemical compound of polyalkylene oxide zone and a plurality of nucleophilic groups and (b) synthetic number-average molecular weight 3, between 000 and 30,000 and comprise the polymer of reactant formation of the chemical compound of polyalkylene oxide zone and a plurality of electrophilic groups; (a) synthetic number-average molecular weight is 3,000 and 30, between 000 and comprise the chemical compound of polyalkylene oxide zone and a plurality of nucleophilic groups and (b) synthetic number-average molecular weight between 3,000 and 30,000 and comprise the mixture of the chemical compound of the regional and a plurality of electrophilic groups of polyalkylene oxide.Operable other polymer also is disclosed in the following detailed description among the present invention.

In aspect each is above-mentioned, the use of can (working) separately of one or more following anti-infectives if can form agent as fibrous tissue, form agent with above-listed (or being described in this paper's in addition) each fibrous tissue, with above-listed (or being described in this paper's in addition) each polymer, or combine use with each of polymer that the fibrous tissue of above-listed (or being described in this paper's in addition) forms agent and above-listed (or being described in this paper's in addition), described infection medicament is: anthracycline, doxorubicin, mitoxantrone, the fluorine pyrimidine, 5-fluorouracil (5-FU), antifol, methotrexate, podophyllotoxin, etoposide, camptothecine, hydroxyurea, platinum complex, cisplatin, antibiotic, doxycycline, metronidazole, trimethoprim-sulfamethoxazole, the 4th generation penicillin (for example, the urea groups penicillin, penicillin carboxy, the mezlocillin, piperacillin, Carbenicillin, and ticarcillin, and analog or derivant), first generation cephalosporin (for example, cefazolin sodium (cephazolin sodium), cefalexin, cefazolin sodium, cefaloject, and cefalotin), penicillin carboxy (for example, ticarcillin), second generation cephalosporin (for example, cefuroxime, cefotetan, and cefoxitin), third generation cephalosporin (for example, ceftiofur sodium (naxcel), cefdinir, cefoperazone, ceftazidime, ceftriaxone, and cefotaxime), the 4th generation cephalosporin (for example, cefepime), monobactam (for example, aztreonam), carbapenem (carbapenem) (for example, imipenum, Ai Tapeinan (ertapenem) and meropenem, aminoglycoside (for example, streptomycin, gentamycin, tobramycin, and amikacin), the MSL group membership (for example, macrolide, the long-acting macrolide, lincosamide, streptogramin, erythromycin, azithromycin, clindamycin, quinoline slave Pu Ding-dalfopristin (Syneroid), clarithromycin, and kanamycin sulfate), quinolinones (for example, ciprofloxacin, ofloxacin, Gatifloxacin, Moxifloxacin, levofloxacin, and trovafloxacin), the DNA synthetic inhibitor (for example, metronidazole), and sulfonamide (for example trimethoprim comprises cefixime, spectinomycin, tetracycline, nitrofurantoin, polymyxin B, and polygynax).

In aspect each is above-mentioned, one or more of following filler use of can (working) separately if can form agent as fibrous tissue, form agent with each (or being described in this paper's in addition) fibrous tissue of listing above, with each (or being described in this paper's in addition) polymer of listing above, with (or being described in this paper's in addition) fibrous tissue formation agent of listing above and each combination of (or being described in this paper's in addition) polymer of listing above, with each combination of (or being described in this paper's in addition) polymer of listing above with (or being described in this paper's in addition) anti-infective of listing above, each combination that forms agent and (or being described in this paper's in addition) anti-infective of listing above with (or being described in this paper's in addition) fibrous tissue of listing above is used in combination: the reagent or the compositions that comprise microsphere, the reagent or the compositions that comprise the gel of hydroxyapatite load, the reagent or the compositions that comprise micronized alloderm acellular substrate, comprise hyaluronic reagent or compositions, the reagent or the compositions that comprise the microballon in the hydrogel, comprise the reagent or the compositions of Hai Lan (hylan) polymer and comprise the reagent or the compositions of silicon microsphere and bioavailable polymer.The other filler that can use in the present invention is described in the following detailed description.

One aspect of the present invention relates to even dry powder composite, and described dry powder composite comprises following component: have first component of the core that replaces with m nucleophilic group, wherein m 〉=2; With second component with the core that replaces with n electrophilic group, wherein n 〉=2 and m+n＞4; Wherein said nucleophilic group and electrophilic group right and wrong in dry environment are reactive, are endowed reactivity when still being exposed to aqueous environments, so that described component reacts to each other in aqueous environments and forms three-dimensional substrate.Also can comprise pharmaceutical carrier.

In an embodiment of described even dry powder composite, nucleophilic and electrophilic group experience nucleophilic substitution, nucleophilic addition, or both.Described nucleophilic group can be selected from-NH ₂,-NHR ¹,-N (R ¹) ₂＞-SH ,-OH ,-COOH ,-C ₆H ₄-OH ,-H ,-PH ₂,-PHR ¹,-P (R ¹) ₂,-NH-NH ₂,-CO-NH-NH ₂And-C ₅H ₄N, wherein R ¹Be alkyl, and each R ¹Can be identical or different.Described electrophilic group can be selected from-CO-Cl ,-(CO)-O-(CO)-R (wherein R is an alkyl) ,-CH=CH-CH=O and-CH=CH-C (CH ₃)=O, halogen ,-N=C=O ,-N=C=S ,-SO ₂CH=CH ₂,-O (CO)-C=CH ₂,-O (CO)-C (CH ₃)=CH ₂,-S-S-(C ₅H ₄N) ,-O (CO)-C (CH ₂CH ₃)=CH ₂,-CH=CH-C=NH ,-COOH ,-(CO) O-N (COCH2) ₂,-CHO ,-(CO) O-N (COCH ₂) ₂-S (O) ₂OH and-N (COCH) ₂

In another embodiment of even dry powder composite, described nucleophilic group is amino and described electrophilic group is amine-reactive group.Described amine-reactive group can contain the carbonyl to the electrophilic reactivity of the nucleophillic attack sensitivity of primary amine or secondary amine.Described amine-reactive group can be selected from that carboxylate, acid chloride group, anhydride, ketone, aldehyde, halogen, isocyanato-, isothiocyanic acid root close, epoxide, activatory hydroxyl, alkene, carboxyl, succinimide ester, sulfosuccinimide ester, dimaleoyl imino, epoxy resin and ethylene sulfonyl.

In another embodiment of even dry powder composite, described nucleophilic group is that sulfydryl and described electrophilic group are sulfydryl-reactive groups.Can select described sulfydryl-reactive group so that form thioester, acid imide-thioester, thioether or the disulfide bond during with described sulfydryl reaction.Wherein said sulfydryl-reactive group forms disulfide bond, and they can have structure-S-S-Ar, and wherein Ar is that replace or the unsubstituted heteroaromatic moiety of nitrogen or the non-heterocyclic aryl that partly replaces with electrophilic of containing.Form at sulfydryl-reactive group under the situation of thioether bond, they can be selected from dimaleoyl imino, haloalkyl, epoxy resin, imino group, '-aziridino, alkene and the α of dimaleoyl imino, replacement, beta-unsaturated aldehyde and ketone.Sulfydryl-reactive group can be selected from mixed acid anhydride; The ester derivant of phosphorus; The ester derivant of right-nitrophenol, right-nitrothiphenol and Pentafluorophenol; The ester of the azanol that replaces comprises N-hydroxyphthalimide ester, N-hydroxy-succinamide ester, N-hydroxysulphosuccinimide ester and N-hydroxyl glutarimide ester; The ester of I-hydroxybenzotriazole; 3-hydroxyl-3,4-dihydro-phentriazine-4-ketone; 3-hydroxyl-3,4-dihydro-chinazoline-4-ketone; The carbonylic imidazole derivant; Acid chloride; Ketenes; And isocyanates.

In another embodiment of even dry powder composite, the nucleophilic group number in the described mixture is approximately equal to the electrophilic group number in the described mixture.For example, the ratio of the molal quantity of nucleophilic group mole ratio electrophilic group can be about 2: 1 to 1: 2, preferred 1: 1 ratio.

In the further embodiment of even dry powder composite, described core is selected from hydrophilic polymer, hydrophobic polymer, amphipathic polymer, C _2-14Alkyl and contain heteroatomic C _2-14Alkyl.

In described core is under the situation of hydrophilic polymer, and described core can be synthetic or naturally occurring hydrophilic polymer.Described hydrophilic polymer can be straight chain, side chain, dendritic, hyperbranched or star polymer.Described hydrophilic polymer can be selected from polyalkylene oxide; Polyhydric alcohol; Two pure and mild polyhydric alcohol of poly-(oxyalkylene)-replacement; Polyoxyethylene sorbitol; The polyoxyethylene glucose; Poly-(acrylic acid) and analog and copolymer; Poly; Polyacrylamide; Poly-(enol); Poly-(N-vinyl lactam); The Ju oxazoline; Polyvinylamine; And copolymer.Described hydrophilic polymer also can be selected from protein, carboxylated polysaccharides, and amination polysaccharide, and activated polysaccharide, such as, for example, collagen and glycosaminoglycans.

At described hydrophilic polymer is under the situation of polyalkylene oxide or polyhydric alcohol, and described hydrophilic polymer can be selected from Polyethylene Glycol and poly-(oxirane)-poly-(expoxy propane) copolymer.At described hydrophilic polymer is under the situation of polyhydric alcohol, and described hydrophilic polymer can be selected from glycerol, polyglycerol and propylene glycol.Be under the situation of polyhydric alcohol of poly-(oxyalkylene)-replace at described hydrophilic polymer, hydrophilic polymer can be selected from one-, two-and three-polyoxyethylene glycerol, one-and two-polyoxyethylene propylene glycol and-and two-polyoxyethylene 1, ammediol.At described hydrophilic polymer is under the situation of poly-(acrylic acid), its analog or copolymer, and described hydrophilic polymer can be selected from poly-(acrylic acid), poly-(methacrylic acid), poly-(hydroxyethyl meth acrylate), poly-(hydroxy ethyl methacrylate), poly-(methyl alkyl sulfoxide acrylate) and poly-(methyl alkyl sulfoxide methacrylate).At hydrophilic polymer is under the situation of polyacrylamide, and described hydrophilic polymer can be selected from polyacrylamide, poly-(Methacrylamide), poly-(DMAA), poly-(N-N-isopropylacrylamide) and copolymer thereof.At hydrophilic polymer is under the situation of poly-(enol), and described hydrophilic polymer can be selected from poly-(vinyl alcohol) and copolymer thereof.At hydrophilic polymer is under the situation of poly-(N-vinyl lactam), and described hydrophilic polymer can be selected from poly-(vinyl pyrrolidone), poly-(ethylene caprolactam) and copolymer thereof.Under the situation of hydrophilic polymer Shi Ju oxazoline, described hydrophilic polymer can be selected from poly-(Jia oxazolin) and poly-(ethyl oxazoline).

Be that described core can be selected from polylactic acid and polyglycolic acid under the situation of the hydrophobic polymer selected in core.

In core is C _2-14Under the situation of alkyl, described core can be selected from alkane, glycol, polyhydric alcohol and polyacid.

In core is to contain heteroatomic C _2-14Under the situation of alkyl, described core can be selected from two-and poly--electrophilic body.

In another embodiment of even dry powder composite, described first component has the structure of formula (I)

(I)[X-(L ¹) _p] _m-R，

And second component has the structure of formula (II)

(II)[Y-(L ²) _q] _n-R’，

Wherein m and n are integer and m+n＞4 of 2-12; R and R ' independently are selected from hydrophilic polymer, hydrophobic polymer, amphipathic polymer, C _2-14Alkyl and contain heteroatomic C _2-14Alkyl; X is a nucleophilic group; Y is an electrophilic group; L ¹And L ²It is linking group; And p and q are the integers of 0-1.Described component can react to each other and form covalent bond, non-covalent bond, or both.Non-covalent bond comprises the segmental association of ionic bond, hydrogen bond or hydrophobic molecule.In a preferred embodiment, all molecule fragment is identical.

Evenly dry powder composite can also include or not have the bioactivator of pharmaceutical carrier.Pharmaceutical carrier can be micelle, microsphere or nanometer spheroid.

At pharmaceutical carrier is that described pharmaceutical carrier can be a degradable polymer under the situation of microsphere or nanometer spheroid, and such as polyester, and described polyester can be Acetic acid, hydroxy-, bimol. cyclic ester/lactide copolymer.Described degradable polymer also can comprise one or more residues of monomers, described monomer is selected from by lactide, lactic acid, Acetic acid, hydroxy-, bimol. cyclic ester, glycolic, e-caprolactone, γ-Ji Neizhi, hydroxypentanoic acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolacton, gamma-valerolactone, γ-decalactone, δ-Gui Neizhi, trimethylene carbonate, 1,4-diox-2-ketone or 1,5-cyclic heptane dioxide-2 ketone (1, the 5-dioxepan-2one) group of Zu Chenging.

Described even dry powder composite can also comprise bioactivator.In one embodiment, described bioactivator is that fibrous tissue forms agent or comprises the compositions that fibrous tissue forms agent.In certain embodiments, described fibrous tissue forms agent in another embodiment of the invention, and described even dry powder composite also comprises the bioactivator that forms agent as fibrous tissue.Such as in the even dry powder composite use, anti-fibrous tissue forms agent can be used to promote following any: regeneration; Blood vessel takes place; The fibroblast migration; Fibroblast proliferation; The deposition of extracellular matrix (ECM); And tissue remodeling.Described fibrous tissue forms agent also can be used as diverticulum wall stimulus object.

It can be maybe can comprise following material that the fibrous tissue that can use in described even dry powder composite forms agent: silk; Silkworm silk; Spider silk; The recombinant silk; Raw silk; The silk of hydrolysis; Acid-treated silk; The silk of acidylate; Mineral grain; Talcum; Chitosan; Polylysine; Fibronectin; Bleomycin; Or CTGF.It also can be the form of microgranule that described fibrous tissue forms agent, and it can be biodegradable microgranule or not biodegradable microgranule.Biodegradable microgranule can comprise that the material that is selected from the group of being made up of polyester, poly-anhydride, poly-(anhydride ester), poly-(ester-acid amide), poly-(ester-urea), poe, poly phosphate, poly-phosphazine, polybutylcyanoacrylate, collagen, chitosan, hyaluronic acid, chromic catgut, alginate, starch, cellulose and cellulose esters forms.Not biodegradable microgranule can comprise the material that is selected from the group of being made up of polyester, polyurethane, siloxanes, polyethylene, polypropylene, polystyrene, polyacrylate, polymethacrylates and silk.The example of preferred microgranule can be by being selected from by silk, Talcum, starch, glass, silicate, Silicon stone, calcium phosphate, calcium sulfate, calcium carbonate, hydroxyapatite, synthetic mineral, polymethyl methacrylate, silver nitrate, pottery, and the member's of the group formed of other inorganic particle particulate form.

In the other embodiment of even dry powder composite, described bioactivator promote osteogenesis.In this embodiment, described fibrous tissue forms agent can promote osteogenesis.Fibrous tissue that can promote osteogenesis forms agent can comprise bone morphogenetic protein and osteogenic growth factor, and the latter can be selected from transforming growth factor, platelet derived growth factor and fibroblast growth factor.

In another embodiment of the invention, contain even dry powder composite that fibrous tissue forms agent and comprise also that to induce hardened medicament (sclerosing agent), wherein said sclerosing agent can be that surfactant or it can be selected from the group of being made up of ethanol, dimethyl sulfoxine, sucrose, sodium chloride, dextrose, glycerol, minocycline, tetracycline, doxycycline, Polidocanol, sodium tetradecyl sulfate, sodium morrhuate and Sotradecol.

In other embodiment of the present invention, the even dry powder composite that contains fibrous tissue formation agent also comprises inflammatory cytokine, and described inflammatory cytokine can be selected from the group of being made up of TGF β, PDGF, VEGF, bFGF, TNF α, NGF, GM-CSF, IGF-a, IL-1, IL-1-β, IL-8, IL-6 and growth hormone.

In another embodiment of the invention, the even dry powder composite that contains fibrous tissue formation agent also comprises the reagent that stimulates cellular proliferation, and it can be selected from the group of being made up of dexamethasone, isotretinoin (13-cis-retinoic acid), 17-, estradiol, 1-α-25 dihydroxy vitamin d3, diethylstilbestrol, ciclosporin A, L-NAME, complete-trans retinoic acid (ATRA) and analog thereof and derivant.

In the other embodiment of even dry powder composite, described bioactivator mixes with first and second components and forms mixture.

In another embodiment of even dry powder composite, described bioactivator chemistry is connected to first component or chemistry is connected to second component.

Another aspect of the present invention relates to and comprises following compositions crosslinkable: (a) have first crosslinkable component of m nucleophilic group, wherein m 〉=2; (b) have n second crosslinkable component that can form the electrophilic group of covalent bond with m nucleophilic group reaction, n 〉=2 and m+n 〉=5 wherein, described first component comprises two or more amino acid residues, described amino acid residue is selected from the group of being made up of aminoacid that comprises primary amine group and the aminoacid that comprises thiol group, described second component comprises polyalkylene glycol moiety, and first and second crosslinkable component all are biocompatible, synthetic, with non-immunogenic, and the crosslinked generation of other wherein said compositions is biocompatible, non-immunogenic, crosslinked substrate.

Following any be the preferred embodiment of the cross-linkable composition described above that is right after: m＞3, m=3, m=4, n=4, described electrophilic group are the butanimide base section, all n are identical, and all m is identical.

In a preferred embodiment, the amino acid residue of selection is a lysine.In this embodiment, following any be preferred: m＞3, m=3, m=4, n=4, described electrophilic group are the butanimide base section, all n are identical, and all m is identical.

In a further preferred embodiment, the amino acid residue of selection is a cysteine.In this embodiment, following any be preferred: m＞3, m=3, m=4, n=4, described electrophilic group are the butanimide base section, all n are identical, and all m is identical.

Another aspect of the present invention relates to the compositions crosslinkable that comprises following component: (a) have first crosslinkable component of m nucleophilic group, wherein m 〉=2; (b) have n second crosslinkable component that can form the electrophilic group of covalent bond with m nucleophilic group reaction, n 〉=2 and m+n 〉=5 wherein, described first component comprises two or more amino acid residues, described amino acid residue is selected from the group of being made up of aminoacid that comprises primary amine group and the aminoacid that comprises thiol group, described second component comprises polyalkylene glycol moiety, described electrophilic group is the butanimide base section, and first and second crosslinkable component all are biocompatible, synthetic, with non-immunogenic, and the crosslinked generation of other wherein said compositions is biocompatible, non-immunogenic, crosslinked substrate.

In a preferred embodiment, the amino acid residue of selection is a lysine.In this embodiment, following any be preferred: m＞3, m=3, m=4, n=4, described electrophilic group are the butanimide base section, all n are identical, and all m is identical.In a further preferred embodiment, the amino acid residue of selection is a cysteine.In this embodiment, following any be preferred: m＞3, m=3, m=4, n=4, described electrophilic group are the butanimide base section, all n are identical, and all m is identical.

Another aspect of the present invention relates to and comprises following compositions crosslinkable: (a) have first crosslinkable component of m nucleophilic group, wherein m 〉=2; (b) have n second crosslinkable component that can form the electrophilic group of covalent bond with m nucleophilic group reaction, n 〉=2 and m+n 〉=5 wherein, described first component comprises two or more amino acid residues, described amino acid residue is selected from the group of being made up of aminoacid that comprises primary amine group and the aminoacid that comprises thiol group, described second component comprises multifunctional activated polyglycol, and first and second crosslinkable component all are biocompatible for every kind, synthetic, with non-immunogenic, and the crosslinked generation of other wherein said compositions is biocompatible, non-immunogenic, crosslinked substrate.

Following any be the preferred embodiment of the cross-linkable composition described above that is right after: m＞3, m=3, m=4, n=4, described electrophilic group is the butanimide base section, and all n is identical, and all m is identical, described multifunctional activated polyethylene glycol is four sense activated polyglycol, and described multifunctional activated polyglycol is star-branched chair polymacrogol.

In a preferred embodiment, the amino acid residue of selection is a lysine.In this embodiment, following any be preferred: m＞3, m=3, m=4, n=4, described electrophilic group are the butanimide base section, and all n is identical, all m is identical, and described multifunctional activated polyethylene glycol is that four sense activated polyglycol or described multifunctional activated polyglycol are star-branched chair polymacrogols.

In a further preferred embodiment, the amino acid residue of selection is a cysteine.In this embodiment, following any be preferred: m＞3, m=3, m=4, n=4, described electrophilic group are the butanimide base section, and all n is identical, all m is identical, and described multifunctional activated polyethylene glycol is that four sense activated polyglycol or described multifunctional activated polyglycol are star-branched chair polymacrogols.

Another aspect of the present invention relates to the method that forms three dimensional matrix, and described method comprises the following step: compositions of the present invention (a) is provided; (b) give nucleophilic and electrophilic group reactivity to realize reacting to each other by described compositions being exposed to aqueous environments; Wherein said exposure comprises: (i) with described composition dissolves in first buffer solution of pH in about 1.0 to 5.5 scopes and form homogeneous phase solution and (ii) second buffer solution of pH in about 6.0 to 11.0 scopes is joined described homogeneous phase solution; (c) three dimensional matrix is formed.The preferred composition of the usefulness of this method of confession is even dry powder composite.The three dimensional matrix described above of the present invention that is right after can form under situation about importing without any external energy or by polymerization.

In preferred embodiments, select the pH of first buffer solution, by giving the relatively non-nucleophilicity of described nucleophilic group to hinder the reactivity of slow nucleophilic group on first component.In this preferred embodiment, the neutralize effect of first buffer solution of second buffer solution is so that the nucleophilic group of first component recovers their nucleophilic feature and reacts to each other with the electrophilic group of second component.

In a further preferred embodiment, described compositions, first buffer solution and second buffer solution are encapsulated in separately in the injector system of a plurality of compartments, and described injector system has a plurality of tubes, mixing head and outlet opening; Step (b) (i) comprise first buffer solution is joined the described compositions of encapsulation tube dissolving described compositions and to form homogeneous phase solution, and described homogeneous phase solution is expressed in the described mixing head; Step (b) (ii) comprises second buffer solution is expressed in the described mixing head simultaneously; And step (c) comprises that also the compositions that will obtain is expressed on the surface by described hole.

Another aspect of the present invention relates to the method that seals patient tissue, and described method comprises the following steps: that (a) provides compositions of the present invention; (b) give nucleophilic and electrophilic group reactivity to realize reacting to each other by described compositions being exposed to aqueous environments; Wherein said exposure comprises: (i) with described composition dissolves in first buffer solution of pH in about 1.0 to 5.5 scopes and form homogeneous phase solution and (ii) second buffer solution of pH in about 6.0 to 11.0 scopes is joined described homogeneous phase solution and forms mixture; (c) the described mixture of placement contacts with tissue and makes three dimensional matrix form and seal described tissue.The preferred composition of the usefulness of this method of confession is even dry powder composite.

Additional aspects of the present invention relate to the method that forms three dimensional matrix on the surface of device, and described method comprises the following steps: that (a) provides compositions of the present invention; (b) give nucleophilic and electrophilic group reactivity to realize reacting to each other by described compositions being exposed to aqueous environments; Wherein said exposure comprises: (i) with described composition dissolves in first buffer solution of pH in about 1.0 to 5.5 scopes and form homogeneous phase solution and (ii) second buffer solution of pH in about 6.0 to 11.0 scopes is joined described homogeneous phase solution; And described homogeneous phase solution is coated to the surface of device; And three dimensional matrix is formed.The preferred composition of the usefulness of this method of confession is even dry powder composite.

Another aspect of the present invention relates near epulotic method medical implant, and described method comprises the following steps: that (a) provides compositions of the present invention; (b) give nucleophilic and electrophilic group reactivity by described compositions being exposed to aqueous environments to realize reacting to each other; Wherein said exposure comprises: (i) with described composition dissolves in first buffer solution of pH in about 1.0 to 5.5 scopes to form homogeneous phase solution and (ii) second buffer solution of pH in about 6.0 to 11.0 scopes to be joined described homogeneous phase solution; (c) described mixture is applied to medical implant the surface and allow that three dimensional matrix is formed on the surface of described medical implant; (d) described medical implant is put into the animal reservoir, wherein the cicatrization from described substrate release fibrous tissue formation agent inhibition animal reservoir.In preferred embodiments, after described implant was used, described fibrous tissue formed agent and is discharged near the tissue of described implant.The preferred composition of the usefulness of this method of confession is to contain the even dry powder composite that fibrous tissue forms agent.

Additional aspects of the present invention relate to the test kit that uses in medical application, described test kit comprises: (a) comprise following even dry powder composite: (i) have first component of the core that replaces with m nucleophilic group, wherein m 〉=2; Second component that (ii) has the core that replaces with n electrophilic group, wherein n 〉=2 and m+n＞4; Be endowed reactivity when being exposed to aqueous environments but wherein said nucleophilic and electrophilic group right and wrong in dry environment are reactive, so that described component reacts to each other in aqueous environments and forms three dimensional matrix; (b) first buffer solution of pH in about 1.0 to 5.5 scopes; (c) second buffer solution of pH in about 6.0 to 11.0 scopes; Wherein each component is independent pack and mixing immediately before using.Certainly preferably, before using, each component is in the aseptic packaging that separates.

Another aspect of the present invention relates to the test kit that uses in medical application, described test kit comprises: (a) compositions of the present invention; (b) first buffer solution of pH in about 1.0 to 5.5 scopes; (c) second buffer solution of pH in about 6.0 to 11.0 scopes, wherein each component is independent pack and mixing immediately before using.The preferred composition of the present invention that uses in this test kit is even dry powder composite.Each component of preferred described test kit is in the aseptic packaging that separates.

Described test kit can also comprise delivery apparatus, and in one embodiment, described delivery apparatus can be the device of many compartments.The preferred multi-compartment device of the present invention is the many compartments injector system with a plurality of tubes, mixing head and outlet opening.At described test kit is under the situation of many compartments injector system, and described even dry powder composite, first buffer solution and second buffer solution are encapsulated in separately in many compartments injector system.

In another embodiment of the invention, described delivery apparatus is the pressurized delivery system.Preferred pressurized delivery system comprises: a plurality of fluid components imports, and each is suitable for being communicated with the different fluid component source; At least one carrier fluid import is suitable for being communicated with pressurization carrier current body source; Be positioned at the bubbler surface in a plurality of fluid components imports and at least one carrier fluid import downstream; Outlet by the extension of bubbler surface, wherein said bubbler surface is suitable for receiving fluid components thereon and having such shape, it is effectively with the guiding of the fluid components of each reception and remain in the different flow path of outlet, mixes by the there and distributes by the pressurization carrier fluid from least one carrier fluid import being used for.In this embodiment, the carrier fluid that preferably pressurizes is a forced air, and preferred fluid components is first buffer solution of the present invention and second buffer solution.

Another embodiment of the test kit that uses in medical application also comprises bioactivator, and described medical application relates to and sends described bioactivator.Described bioactivator can be packed with even dry powder composite, and can comprise pharmaceutical carrier and the even dry powder composite of packing with described bioactivator.Described bioactivator also can be packaged as the solution that contains first buffer or contain the solution of second buffer.Described test kit can also comprise the pharmaceutical carrier as the 4th component.Described bioactivator is packed with pharmaceutical carrier.

On reference following detailed description and accompanying drawing, these and other aspect of the present invention will become obvious.Whole lists of references disclosed herein are incorporated into this by reference in its entirety, and it all is independent bonded being equivalent to each.

The accompanying drawing summary

Fig. 1 shows the figure of ciclosporin A to the influence of human smooth muscular cells propagation.

Fig. 2 shows the figure of dexamethasone to the propagation influence of human fibroblasts.

Fig. 3 shows the figure of all-trans retinoic acid (ATRA) to the influence of human smooth muscular cells propagation.

Fig. 4 shows the figure of isotretinoin to the influence of human smooth muscular cells propagation.

Fig. 5 shows the figure of 17-to the influence of human fibroblasts propagation.

Fig. 6 shows 1 α, and 25-dihydroxy-vitamin D3 is to the figure of the influence of human smooth muscular cells propagation.

Fig. 7 shows the figure of PDGF-BB to the influence of smooth muscle cell migration.

Fig. 8 is a bar chart, and it shows with respect to being exposed to the tremulous pulse that does not wrap by the PU film, the area of the granulation tissue in the carotid artery of the blood vessel week of contact silk bag quilt polyurethane (PU) film.

Fig. 9 is a bar chart, and it shows with respect to being exposed to the tremulous pulse that does not wrap by the PU film, the area of the granulation tissue in the carotid artery of the blood vessel week of contact silk suture bag quilt PU film.

Figure 10 is a bar chart, and it shows with respect to matched group, and at the silk powder that is exposed to natural and purification and wrapped up the area of the granulation tissue in the carotid artery of blood vessel week PU film, in described matched group, tremulous pulse has only wrapped up blood vessel week PU film.

Figure 11 is a bar chart, and it shows with respect to matched group, is spraying Pulvis Talci and is wrapping up the area of the granulation tissue (at 1 month and 3 months) in the carotid artery of blood vessel week PU film, and in described matched group, tremulous pulse has only wrapped up all PU films of blood vessel.

Figure 12 is explicit declaration passes through the area of granulation tissue of quantized blood vessel week of area of computer aided MORPHOMETRIC ANALYSIS OF EXFOLIATED in rat carotid artery a bar chart, and described carotid artery does not wrap by the PU film with in order to the PU film that comes unstuck and unworn silk thread is handled with contrast and handles.As shown in FIG., two types silk significantly is increased in the growth of circumvascular granulation tissue with identical degree.

Figure 13 is presented at the representative Histological section in the rat carotid artery, described carotid artery with bag by to come unstuck and the PU film of unworn silk thread is handled.As shown in FIG., two types silk is induced processed circumvascular significant tissue reaction.Movat dyeing, 100X.

Figure 14 is presented at the representative Histological section in the rat carotid artery, and described carotid artery by to come unstuck and the PU film of unworn silk thread is handled, shows the granulation tissue of growth around processed blood vessel with bag.Described silk thread be broken down into by giant cell and macrophage around granule.Described granulation tissue is by the height vascularization and comprise many inflammatory cells and fibroblast.Extrtacellular matrix deposition also is a large amount of.H ﹠amp; E dyeing, 200X.

The release profiles that Figure 15 shows as analyzes by HPLC from the ciclosporin A of polyurethane film.

Detailed Description Of The Invention

The invention provides the step of Wicresoft, in chamber and endoscope, by the administration of pharmacology composition, described step can be used for temporarily or for good and all closing diverticulum, and described composition is induced the cicatrization in diverticulum chamber and eliminated the diverticulum capsule.

As described herein, provide implant, step and treatment group compound, utilize the intervention with the imaging guiding of endoscope to be used for the treatment of diverticulum. For example, described herein is the medicament that promotes one or more aspects of the generation of fibroid (scar) tissue or regeneration. And,, for using fibre modification derivant and drug delivery composition, described composition and method, thereby be enough to occur to send described medicament with treatment level in the cycle of fibre modification and healing. Described many concrete implants, described implant produces superior clinical effectiveness by cicatrization and the healing that promotes diverticulum.

Definition

Before illustrating the present invention, the definition of at first illustrating some some term that hereinafter will use may help to understand the present invention.

" medical implant " refers to implant (wholly or in part) or is inserted into device or object or composition in health. Therefore, implant refers in order to recover physiological function, minimizing/alleviate the symptom relevant with disease and/or to repair/substitute the purpose of Organ and tissue damage or ill and put into any object or the composition of health.

" diverticulitis " refers to the disease such as diverticulosis and diverticulitis. When the folliculus in colon (being called diverticulum) was outwardly by weak spot, the diverticulum disease occurred. Illness with diverticulum is called diverticulosis. When described pouch capsule infects or inflammation, described illness is called diverticulitis. Diverticulitis can cause stomachache, and particularly, around the left side of lower abdomen, and bottom GI is hemorrhage. The position that common hernia goes out is the same area that nutrient artery penetrates, and causes the neck of described capsule and approaching of artery supply.

The formation of fibr tissue when " fibre modification ", " cicatrization " or " fiberization " refer to respond damage or medical treatment intervention. Comprise (1) newly formation (blood vessel generation) of blood vessel four general compositions of fibre modification (or cicatrization) process; (2) fibroblastic migration and propagation; (3) deposition of extracellular matrix (ECM); (4) reinvent (maturation of fibr tissue and group structure). Promote (also to refer to convertibly induce at this paper, stimulate, cause, increasing, accelerate etc.) fibre modification or synulotic therapeutic agent refer to " fibre modification derivant ", " cicatrization agent " interchangeably at this paper, " fibr tissue forming agent ", " inducing the reagent of adhesion ", etc. These reagent promote fibre modification by the one or more following mechanism that comprises, for example, induce or promote blood vessel to occur, stimulate phoirocyte (such as fibroblast, smooth muscle cell, VSMC) migration or propagation, inducing cell epimatrix (ECM) produces, and promotes tissue remodeling. In addition, can have at numerous therapeutic agent described herein the additional benefit (with the cell of same type, replacing impaired cell) that also promotes regeneration.

" sclerosis " refers to a kind of tissue reaction, wherein stimulant is applied topically to tissue, causes inflammatory reaction and stimulating the site cicatricial tissue to form subsequently. To induce or promote the medicament of sclerosis to be called " curing agent " or " sclerosis reagent ". The representative example of curing agent comprises ethanol, and methyl-sulfoxide, surfactant are (for example, triton (Triton) X, the sorbitan monolaurate, sorbitan sesquioleate, glyceryl monostearate and polyoxyethylene, PCE etc.), sucrose, sodium chloride, dextrose, glycerine, minocycline, tetracycline, Doxycycline, Lauromacrogol 400, Sodium Tetradecyl Sulfate, sodium morrhuate, monoethanolamine, phenol, salad is put down (sarapin) and Sotradecol.

" radiography guiding " refers to utilize and is used for guiding and confirming the Medical imaging of accurately placing, holding medicine delivery catheter, medical apparatus, implant, biomaterial, therapeutic agent, ingate or device etc. Imaging technique operates and gets involved (that is, in order to do not need open operation) for allowing in Wicresoft's mode. According to the tissue that will treat, can use any imaging technique, but comprise, for example, x-ray, angiography, MRI, CT scan, ultrasonic, PET scanning and nuclear medicine scanning.

" endoscope guiding " refers to utilize and is used for guiding and confirming the direct visual endoscopy of target tissue of accurately placing, holding medicine delivery catheter, medical apparatus, implant, biomaterial, therapeutic agent, ingate or device etc. By via hole (mouth, anus) or little otch, small cameras being inserted in health, endoscope-use is not in directly visual (that is, in order to need open operation) of allowing in Wicresoft's mode. According to the tissue that will treat, can use any endoscopic technique, but comprise, for example, the endoscope of flexible endoscope, rigidity, gastroscope, ERCP, bronchoscope, proctoscope, angioscope and Sigmoidoscope.

Term as used herein " (inter-react) reacts to each other " and " (inter-reaction) reacts to each other " refer to covalent bond, non-covalent bond or both formation. Described term thereby comprise crosslinkedly, it comprises by covalent bond and forms the intermolecular cross-linking that produces and also have optional intramolecular crosslinking. Entanglement is another example of non-covalent bond, and it can produce after reacting to each other between two or more reactive groups. Covalent bond between two reactive groups can be that directly in this case, the atom in reactive group directly is attached to the atom in another reactive group, and perhaps it can be indirectly by connecting base. Non-covalent bond comprises the association of ion (static) key, hydrogen bond or hydrophobic molecule fragment, and it can be identical or different. Except covalent bond, crosslinked matrix also can comprise non-covalent bond in so intermolecular and/or molecule.

When about polymer, term " hydrophily " and " hydrophobicity " are generally to limit according to the HLB value, and the HLB value is the hydrophilic-lipophilic balance value. High HLB value representation hydrophilic compounds, and low HLB value characterizes hydrophobic compound. The HLB value is well-known in the art, and generally in 1 to 18 scope. Preferred polyfunctional compound's core is hydrophilic, even as long as the polyfunctional compound is contained at least one hydrophilic component as a whole, crosslinkable hydrophobicity composition also can exist.

Term " effective dose " refers to reagent that required effect is provided or the amount of composition. The actual amount that is defined as effective dose will change according to the factor of the size such as the patient, general health and illness, sex and age, and can more easily by the care-giver, be determined. Term " original position " refers to the position in administration as used herein. Thereby, described reagent and composition can be sent, injected or alternate manner is administered to privileged site in patient body, such as diverticulum.

Term " aqueous medium " comprises moisture solution, suspension, dispersion, colloid etc. Described term " aqueous environments " refers to the environment that contains aqueous medium. Similarly, term " dry environment " refers to the environment that does not contain aqueous medium.

Term " activating agent ", " bioactivator ", " therapeutic agent ", " pharmacologically active agents " and " medicine " use interchangeably at this paper, refer to and are suitable for the chemical material or the compound that are administered to the patient and induce Expected Results. Described term comprises treatment effectively and prevents effective reagent. Also comprise those compounds of inducing equally Expected Results of specifically mentioning or other derivative of compounds and analog.

As mentioned above, the invention provides composition, implant and the method that is used for the treatment of the diverticulum disease. Therapeutic agent below in greater detail; Be used for sending composition and the implant of described therapeutic agent; With utilize the reagent discussed at this paper and the method for combination treatment diverticulitis.

Therapeutic agent

Identify many therapeutic agents (at this paper also referred to as " therapeutic agent " or " medicine "), can be used for inducing the closure of cicatrization and diverticulum. Described reagent can with one or more other material formulations, for example, the carrier of polymerization, described preparation is discussed below. Identify particularly many suitable therapeutic agents here, and based in vitro and in vivo (animal) model, such as those that provide in an embodiment, easily determined other therapeutic agent. Can identify and promote fibrotic therapeutic agent by body inner model such as rat carotid artery model. One or more therapeutic agents can be incorporated in the host and be used for the treatment of the diverticulum disease. The host can be mammal, and it can be that the people is (such as patient or experimenter or the inhuman mammal of needs treatment. Exemplary non-human mammal includes, but not limited to non-human primates, rodent (for example, rat, mouse, rabbit, hamster), cat, dog, horse, pig, ox, sheep, or goat. The host who needs treatment has been developed or has been in host in the risk of development diverticulum disease.

The fibre modification derivant

In one embodiment of the invention, will induce fibrotic pharmacological agents or be suitable for comprising or discharge the implant of inducing fibre modification reagent and be administered on diverticulum or wherein. Thereby, in one embodiment, provide a kind of medical implant, composition at least a that it comprises (i) fibre modification derivant (fibr tissue forming agent) and (ii) comprises the fibre modification derivant. In the time of in being placed on diverticulum, described fibr tissue forming agent can induce fibre modification to form, otherwise fibre modification will not occur, forms. In another embodiment, the method that is provided for inducing fibre modification in diverticulum and is used for the treatment of the diverticulum disease, wherein fibre modification derivant and/or implant/composition of comprising the fibre modification derivant are put into the host (for example, mammal) with diverticulum.

As discussing in more detail here, therapeutic agent comprises the fibre modification derivant, i.e. diverticulum wall stimulus, for example, talcum powder, metallic beryllium and oxide thereof, copper, silk, the silk suture of coating, uncoated silk suture, precursor (origin silk), degumed silk, Sa Ransu, silica, the silicate of crystallization, talcum, silica flour, and ethanol; Extracellular matrix components; Fibronectin, collagen, fibrin, or fibrinogen. The fibre modification derivant can be also poly-(PETP (Dacron), polylysine, poly-(ethene-altogether-vinylacetate), chitosan, N-carboxyl butyl chitosan, RGD protein, or the polymer of vinyl chloride. Therapeutic agent comprises adhesive, such as cyanoacrylate and crosslinked PEG-methylated collagen and also can comprise inflammatory cytokine (for example, TGF β, PDGF, VEGF, bFGF, TNF α, NGF, GM-CSF, IGF-a, IL-1, IL-8, IL-6 and growth hormone); CTGF (CTGF); Bone morphogenetic protein (BMP) (for example, BMP-2, BMP-3, BMP-4, BMP-5, BMP-6 or BMP-7); With bleomycin or its analog or derivative. The fibre modification derivant also comprises the propagation reagent that stimulates cellular proliferation, for example, dexamethasone, isotretinoin, 17-β-estradiol, estradiol, diethylstilbestrol, ciclosporin A, all-trans retinoic acid (ATRA), and analog and derivative.

In one embodiment, being suitable for the fibre modification of using or adhesion derivant in the diverticulum treatment is silk. Silk refers to fibrous proteins, and can obtain from many sources, is generally spider and silkworm. Typical silk contains 75% the true fiber of having an appointment, and is called fibroin, and about 35% sericin, and described sericin is the viscous protein matter that described filament is kept together. Filament is generally very very thin and reach 300-900 rice. Have several different family's sericulture species to be used for the production of business silk, still, silkworm (Bombyx mori) is the most frequently used, and most of silks are all from this source. Other suitable silkworm comprises castor silkworm (Philosamia cynthia ricini), giant silkworm (Antheraea yamamai), tussah (Antheraea pernyi) and Antheraea mylitta. Spider silk is difficult to obtain relatively more, but, the restructuring technology promise to be the means that a kind of acquisition has the spider silk of economic worth (see, for example, U.S. Patent number 6,268,169; 5,994,099; 5,989,894; With 5,728,810, it is exemplary). Other source that biotechnology allows the software engineering researchers invent silk to produce, comprise animal (for example, goat) and plant (for example, potato). Silk from any these sources may be used to the present invention.

A kind of commercially available silk-fibroin can be from Parsippany, N.J. (the Croda of standing grain major company of (Parsippany of New Jersey), Inc.) obtain, with trade name CROSILK LIQUID (silk amino acid), CROSILK 10,000 (silk of hydrolysis), CROSILK POWDER (pulverous silk) and CROSILKQUAT (cocodiammonium hydroxypropyl silk amino acid) sell. Another example of commercially available silk-fibroin is SERICIN, can be from Pan Defa pharmaceuticals (Pentapharm, LTD), and the department of Kordia, BV, Holland obtains. The further details of this silk-fibroin mixture can be at U.S. Patent number 4,906, finds in 460, and described patent authorizing Kim etc., transfer Sorenco. Be used for comprising natural (former) silk at silk of the present invention, hydrolyzed-silk and modify after silk, namely carried out chemistry, machinery or steam and processed, for example acid treatment or acetylizad (see, for example, U.S. Patent number 5,747,015).

Raw silk typically is wound in a sufficiently solid chain and is used for braiding or knitting. Can produce by this method four kinds of dissimilar silk threads: organizine (organzine), crape, weft yarn (tram) and twisting monofilament (thrown singles). Organizine is to give raw silk the preliminary silk thread that is wound around and in opposite direction, two these silk threads is intertwined and makes subsequently by a direction. Crape is similar to organizine, but the winding degree is larger. Only being wound around two or more raw silks in a direction makes weft yarn. The twisting monofilament is the single raw silk silk thread that only is wound around in one direction. The silk thread of any these types may be used to the present invention.

Being used for silk of the present invention can exist with the appropriate format that the medical implant that is applied to diverticulum connects with the described silk of any permission, and for example, described silk can exist with the form based on silk thread or powder. Described silk can be prepared with powder type by some diverse ways. For example, described silk can be ground (for example, freeze grinding (cryomil)) powdered form. Alternatively, described silk can be dissolved in suitable solvent (for example, HFIP or 9M LiBr) and follow its spraying (electron spray, spray-drying) or add in non-solvent to produce powder. And described silk can have any molecular weight, and wherein various molecular weight typically obtain by the hydrolysis of natural silk, and wherein the degree of hydrolysising condition and intensity determine the molecular weight of product. For example, described silk can have approximately average (counting all or weight average) molecular weight of 200 to 5,000. See, for example, introduction can be used for the JP-B-59-29199 (the Japan Patent publication of examining) of the condition of hydrolyzed-silk.

Discussion about silk can see in following document, it is only exemplary, Hinman, M.B. etc. " Synthetic spider silk:a modular fibre " (synthetic spider silk: model fibre) Trends in Biotechnology (biotechnology trend), 2000,18 (9) 374-379; Vollrath, F. and Knight, D.P. " Liquid crystalline spinning of spider silk " (the liquid crystal spinning of spider silk) Nature (nature), 2001,410 (6828) 541-548; And Hayashi, C.Y. etc. " Hypotheses that correlate the sequence; structure; and mechanical properties of spider silk proteins " (sequence of spider silk, the hypothesis of structure and engineering properties) Int.J.Biol. Macromolecules (international bio macromolecule magazine), 1999,24 (2-3), 265-270; With U.S. Patent number 6,427,933.

Described silk can be precursor, and part is come unstuck, or degumed silk. Described silk can also further comprise coating. Described coating can be the coating of siloxanes-Ji, the coating of cerul, or the coating of degradable polyalcohol group.

In another embodiment, described fibre modification derivant is fibroin protein, or its one or more fragments. In a certain embodiment, described fibroin protein can be the synthetic analog of making and having the known heavy complex sequences of one or more fibroin protein.

In another embodiment, described fibr tissue forming agent is sarecin. Sarecin is the component that can be used for participating in the precursor of inducing fibrosis reaction.

be suitable for application to the fibre modification of diverticulum and other representative example of adhesion derivant (fibr tissue forming agent) and comprise that stimulant (for example, talcum, talcum powder, copper, metallicity beryllium (or its oxide), fine hair (wool) are (for example, animal down, wood shavings, with synthetic fine hair), cotton, silica flour, silica, crystalline silicate), polymer (for example, polylysine, polyurethane, poly-(PETP), polytetrafluoroethylene (PTFE) (PTFE), poly-(alkyl cyanoacrylate) and poly-(ethene-altogether-vinylacetate), the polymer of vinyl chloride, peptide with high-lysine content, the growth factor and the inflammatory cytokine that relate to the synthetic and tissue remodeling of blood vessel generation, migration of fibroblast cells, fibroblast proliferation, ECM, such as EGF (EGF) family, transforminggrowthfactor-α (TGF-α), transforming growth factor β (TGF-β-1, TGF-β-2, TGF-β-3, platelet-derived growth factor (PDGF), fibroblast growth factor (acidity-aFGF, and alkalescence-bFGF), fibroblast stimulating factor-1, activator protein, VEGF (comprises VEGF-2, VEGF-3, VEGF-A, VEGF-B, VEGF-C, placenta growth factor-PIGF), angiogenin, IGF (IGF), HGF (HGF), CTGF (CTGF), marrow colony stimulating factor (CSFs), MCP, granulocyte-macrophage colony stimutaing factor (GM-CSF), granulocyte-colony stimulating factor (G-CSF), macrophage colony stimulatory factor (M-CSF), erythropoietin(EPO), interleukin (IL-1 particularly, IL-8, and IL-6), TNF-α (TNF α), nerve growth factor (NGF), interferon-' alpha ', interferon-beta, histamine, endothelin-1, Angiotensin II, growth hormone (GH), and synthetic peptide, the analog of these factors or derivative also are suitable for discharging from concrete implant as herein described.

The example of other of fibr tissue forming agent comprises CTGF (CTGF); Inflammatory microcrystal (for example, the crystal mineral matter is such as crystalline silicate); Bromocriptine, methergine, methotrexate (MTX), chitosan, N-carboxylic butyl chitosan, carbon tetrachloride, thioacetamide, fibrillatable albumen, ethanol, bleomycin, generally at one or two end, comprise the natural existence of Arg-Gly-Asp (RGD) sequence or synthetic peptide (is seen, for example U.S. Patent number 5,997,895), with organize adhesive, such as cyanoacrylate and crosslinked PEG-methylated collagen compositions, such as what the following describes. The example of other fibre modification derivant comprises bone morphogenetic protein (for example, BMP-2, BMP-3, BMP-4, BMP-5, BMP-6 (Vgr-1), BMP-7 (OP-1), BMP-8, BMP-9, BMP-10, BMP-11, BMP-12, BMP-13, BMP-14, BMP-15 and BMP-16). In these, BMP-2, BMP-3, BMP-4, BMP-5, BMP-6 and BMP-7 are particularly useful. Bone morphogenetic protein exists, for example, and U.S. Patent number 4,877,864; 5,013,649; 5,661,007; 5,688,678; 6,177,406; 6,432,919; With 6,534,268 and Wozney, J.M. etc., (1988) Science (science): 242 (4885); Be described in 1528-1534.

As mentioned above, a kind of fibre modification derivant is fine hair. The fiber that term " fine hair " refers to without any ordered arrangement tangles group, and term " fiber " refers to and has length diameter ratio (" aspect ratio ") was at least about 3: 1 and the particle on almost parallel limit.

The fine hair that can use in composition described herein and method is at medical implant and be adjacent to the fiberization of inducing enhancing between the tissue of medical implant in body. In other words, there is no described fine hair, medical implant will produce " normally " and adhere between adjacent tissue and medical implant, and under described fine hair exists, identical medical implant can produce the adhesion (for example, the apposition via the enhancing that exists for described fine hair reacts) of enhancing.

Fine hair as the fibre modification derivant can obtain or preparation from natural origin (for example, animal down and wood shavings). Alternatively, it can be artificial synthetic (for example, the fine hair of polymerization and mineral wool).

" animal down " refers to animal fiber, generally by sheep or lamb, and goat (for example, Angora goat and Kashmir goat), camel, alpaca, yamma, the fur of vicugna etc. obtains. Animal down is the dead tissue with complicated morphology and chemical constitution, and this makes it is unique among the fabric fiber. On morphology, villus fiber is Biocomposite material, and each component has different physics and chemistries and forms. Villus fiber generally is comprised of the cortical cell of three dissimilar spindle shapes, described cortical cell by the sheath of the overlapping rectangular cell that is called as epidermis institute around, it forms the skin of described fiber. About 90% cortical cell type is comprised of the intermediate filament with the matrix followed of longitudinal arrangement. Remainder comprises film and from nucleus and cytoplasmic residue.

The animal down fiber shows diameter, length and curling (that is, the measurement of curvature of fiber) of certain limit, and it allows described villus fiber entrapped air. Animal down is also hygroscopic and can changes and the large water gaging of absorption and desorption along with the relative humidity around described fiber. And, if animal down absorbs water its release heat. These character promote the special quality of insulation of animal down.

Animal down belongs to and is called the keratic kinds of protein of a-, and described a-keratin also comprises the material such as hoof (hoove), angle, first, pawl and beak. The characteristic feature of a-keratin (also referred to as " hard " keratin) is that the concentration ratio of sulphur is higher such as those " soft " keratin in skin. The animal down of cleaning contains the protein of the high cutin of 82% sulfur content of having an appointment, and approximately 17% described fiber is the protein with relative low sulfur content (＜3%). Sulphur in fine hair exists with the form of amino acid cysteine. Due to high cysteine content, animal down is highly cross-linked by disulfide bond, and it is insoluble basically that described disulfide bond makes it. Estimate, animal down contain have an appointment 170 kinds of dissimilar relative molecular masses less than 10,000 to the polypeptide that changes in greater than 50,000. The protein group that forms animal down is not evenly distributed on whole fibers, but is gathered in multiple zone. Animal down also contains the material of 1% nonprotein of having an appointment, and described material mainly is comprised of lipid and polysaccharide material, trace element and the pigment (for example, melanin) of free and structure.

Animal down is usually by shearing every year and from animal, obtaining. Thereby fibre length mainly determines by the speed of growth, and it depends on again heredity and factor environment. For example, typical Merino wool fibre is 50-125mm length and has irregular curling (curvature). The diameter scope that the performance of animal down fiber is certain, it also depends on science of heredity and environment. For example, the coarse wool fiber generally has the diameter of 25-70mm, and meticulous Merino wool fibre generally has the diameter of 10-25mm.

Another example of the fine hair of natural origin is wood shavings, and described wood shavings are special preparation, the fibers non-compression wood through being usually used in surgical dressing and packaging material. The wood shavings fiber also can obtain from pine needle.

Even fine hair is usually relevant with the fiber that is obtained by natural origin, multiple synthetic fine hair is also available. Synthetic fine hair comprises, for example, mineral wool, such as mineral wool, rock wool (stone wool) and slag wool, the fine hair of being made by polymeric material. For example, can form mineral wool from inorganic material such as glass, stone or the slag of fusing, it is spun into filamentary structure. Inorganic rock or slag are the main components (general 98%) of rock wool. Remaining 2% organic matter content is generally thermosetting resin adhesive (adhesive) and a small amount of oil. The mineral wool product contains 95% the inorganic material of having an appointment usually. Mineral wool is by husky or recirculation glass, and lime stone and soda ash are made, and described mineral wool is the same composition for glass object such as glass pane or the vial be familiar with. In addition, glass fibre can comprise a small amount of boron. Rock wool can be made by volcanic rock, is generally basalt or dolomite. Slag wool is made by blast-furnace cinder (refuse).

Can find the discussion of fine hair in following document, be only exemplary: Encyclopedia of Polymer Science and Technology (polymer science and technology encyclopedia), John Wiley ﹠ Sons, Inc. (2003); Dowling and Sparrow, TIBS 16:115-118 (1991); Powman, J. Chromatogr (chromatogram magazine) .B 787:63-76 (2003); Hearle, Intl.J.Biol.Macromol (international bio macromolecule magazine) .27:123-38 (2000); With Vuyst etc., Eur.Resp.J. (Europe is replied and learned magazine) 8:2149-73 (1995).

In certain embodiments, villus fiber has approximately, or at least about, 1,2,3,4,5,6,7,8,9,10,15,20,25,30,35,40,45,50mm or longer average length. In certain embodiments, the length of villus fiber is at about 1-5mm, 5-10mm, and 10-50mm, 50-100mm, 1-10mm, 1-50mm, or in the scope of 1-100mm. In certain embodiments, villus fiber has approximately, or at least about, the average diameter of 1,2,3,4,5,6,7,8,9,10,15,20,25,30,35,40,45,50mm. In certain embodiments, the diameter of villus fiber is at about 1-3mm, 3-5mm, and 5-10mm, 10-50mm, 1-10mm, or in the scope of 1-50mm. In certain embodiments, the average length of villus fiber is 3 with the diameter ratio: Isosorbide-5-Nitrae: 1,5: 1,6: 1,7: 1,8: 1,9: 1,10: 1 or larger.

In certain embodiments, fine hair further can be processed into other form or shape, for example, sheet, powder, line, braid, filament, fiber, film, foam etc. In certain embodiments, described fine hair further is processed into line or powder. Other embodiments at some, further be processed into described fine hair the form of spiral or coil.

Fine hair can use separately or can be used in combination with all medical implants as described herein. In certain embodiments, fine hair can be used in combination with one or more other fibre modification derivant described herein. Can fine hair be fixed to medical implant by any of many methods. The method that is fit to comprises, unlimitedly, fine hair is interweaved in implant, and fine hair is interweaved in implant structure; Via knotting or stitching, it is attached to implant around described implant structure with fine hair; Utilize adhesive that fine hair is attached to medical implant; With utilizing one or more sutures with fine hair " seam " to medical implant. In one aspect, a plurality of independent fine hair braids or line are attached to described medical implant.

In one embodiment, described fine hair only is fixed to described medical implant outside. In another embodiment, described fine hair is fixed to the distal region of medical implant. Described fine hair can be attached to the implant part of described medical implant, or it can be attached to the implant part of described medical implant, or it can all be attached to implant and the implant part of described medical implant.

The fine hair line can be positioned on implant with multiple structure, can produce the partially or completely covering to described implant outside. Described line can be attached to around described implant end. The fine hair line can be attached in the band of medical implant. Described adhering to can be vertical, level or cornerwise mode. According to the specific design of described medical implant, the line of polymerization can invest the implant component of implant component or medical implant. Alternatively, or in addition, can allow that the fine hair line extends some distances from described medical implant. For example, in certain embodiments, only an end of fine hair line can be fixed to described medical implant, therefore allows that the other end of described line extends away from described implant. Alternatively, the two ends of described line can be fixed to medical implant, yet the mid portion of described line is not fixed to described medical implant, and the end of described line is fixed with mutually abundant short distance, so that described mid portion freely extends away from described medical implant.

In another embodiment, the end of fine hair line can be attached to described medical implant, and/or along one or more points of fine hair line, can be attached to described medical implant. In another embodiment, the end of described fine hair line is not attached to described medical implant. On the contrary, the one or more points along described fine hair line are attached to described medical implant. In another embodiment, the fine hair line can be made preform structure (for example, mesh, ring bundle etc.), then it is attached to described medical implant.

Be suitable for inducing other representative instance of fibrotic fibre modification derivant to comprise the cross-linked composition that comprises amido functional group within diverticulum. For example, the polyethylene glycol of aminofunctional (for example, 4-arm four-amino PEG[10k]) PEG (for example, pentaerythrite PEG ether four-succinimido glutarate) that can be functionalized with 4-arm NHS reacts under alkaline buffer condition. In another example, the PEG of 4-arm thiol-functional (for example, pentaerythrite PEG ether four-mercaptan) can be replaced by the PEG of 4-arm amino-functional, thereby the amount of the amido functional group in final composition can change. These reagent can mix and the cross-linked hydrogel that provides original position to form when using. These reagent can be pre-mixed to produce cross-linked material. Described material can be made various ways such as rod, pipe, film, mesh, screen cloth, line, fiber, plate or spheroid. Also can grind described cross-linked material to produce granular materials. These materials can be dry (for example, air, vacuum, freeze-drying) and as dry powder material. Alternatively, can be only before application the described material of hydration. These materials can also comprise a kind of of fibre modification derivant described herein.

other representative example that is used for the treatment of the fibre modification derivant of diverticulum disease comprises the component of extracellular matrix (for example, fibronectin, fibrin, fibrinogen, collagen (for example, bovine collagen), fiber and non-fiber collagen, adhesiveness glycoprotein, proteoglycan (for example, heparin sulfate, chondroitin sulfate, dermatan sulfate), hyaluronan, be rich in the acidic secretion protein (SPARC) of cysteine, thrombospondin, special that element and cell adhesion molecule (comprise integrin, vitronectin, fibronectin, laminin, hyaluronic acid, elastin laminin, bitronectin), the protein of finding in basement membrane, and fibrillatable albumen), with the inhibitor of matrix metalloproteinase, such as TIMPs (matrix metalloproteinase organize inhibitor) and synthetic TIMPs, for example, horse cubic meter department he (marimistat), Ba Misita (batimistat), Doxycycline, tetracycline, minocycline, TROCADE, Ro-1130830, CGS27023A, and BMS-275291.

In independent embodiment, described reagent is diverticulum vascular wall stimulus; The fibr tissue forming agent is or comprises silk; The fibr tissue forming agent is or comprises silk; The fibr tissue forming agent is or comprises spider silk; The fibr tissue forming agent is or comprises the recombinant silk; The fibr tissue forming agent is or comprises raw silk; The fibr tissue forming agent is or comprises the silk of hydrolysis; The fibr tissue forming agent is or comprises acid-treated; The fibr tissue forming agent is or comprises the silk of acidylate; The fibr tissue forming agent is the form of twisted wire (strand); The form that the fibr tissue forming agent is bunch; The fibr tissue forming agent is particulate form; The fibr tissue forming agent is or comprises mineral grain; The fibr tissue forming agent is or comprises talcum; The fibr tissue forming agent is or comprises chitosan; The fibr tissue forming agent is or comprises polylysine; The fibr tissue forming agent is or comprises fibronectin; The fibr tissue forming agent is or comprises bleomycin; The fibr tissue forming agent is or comprises CTGF; The fibr tissue forming agent is the form of line, or with line, contacts. Randomly, described line is biodegradable (for example, it comprises the material that selects the group that free polyester, poly-acid anhydrides, poly-(acid anhydride ester), poly-(ester-acid amide), poly-(ester-urea), poe, polyphosphate, poly-phosphine piperazine, polybutylcyanoacrylate, collagen, chitosan, hyaluronic acid, chromic catgut, alginates, starch, cellulose and cellulose esters form); Or described line is not biodegradable (for example, it comprises the material of the group of selecting free polyester, polyurethane, siloxanes, polyethylene, polypropylene, polystyrene, polyacrylate, polymethacrylates, polyacrylic acid, polymethylacrylic acid and silk composition); Described line scribbles polymer, and described line scribbles the medicament of inducing fibrosis reaction in the patient, and described line scribbles the medicament of induced osteogenesis reaction in the patient; Described composition also comprises the reagent that promotes the bone growth. The reagent that promotes the bone growth is bone morphogenetic protein or promotes that the reagent of bone growth is osteogenic growth factor (for example, TGF, platelet-derived growth factor and fibroblast growth factor); Described composition also comprises medicament (curing agent, for example curing agent of the group of the free following composition of choosing: ethanol, methyl-sulfoxide of inducing sclerosis, sucrose, sodium chloride, dextrose, glycerine, minocycline, tetracycline, Doxycycline, Lauromacrogol 400, Sodium Tetradecyl Sulfate, sodium morrhuate, and Sotradecol, or described curing agent can be surfactant); Described composition also comprises inflammatory cytokine (for example, selecting free TGF β, PDGF, VEGF, bFGF, TNF α, NGF, GM-CSF, IGF-a, IL-1, IL-1-β, IL-8, IL-6, and the inflammatory cytokine of the group of growth hormone composition); Described composition also comprises that the reagent that stimulates cellular proliferation (for example, select free dexamethasone, isotretinoin (Accutane), 17-β-estradiol, estradiol, 1-α-25 dihydroxy vitamin d3, diethylstilbestrol, ciclosporin A, L-NAME, all-trans retinoic acid (ATRA), and the cell expansion agents of the group of analog and derivative composition); Described composition also comprises filler; Described composition also comprises sealant; Described composition also comprises polymer support; Described composition also comprises can resorbent Inorganic Non-metallic Materials; Described composition also comprises contrast preparation; Described composition also comprises line; Described composition with bunch form exist; Described composition exists with the form of gel; Described composition exists with the form of paste; Described composition exists with the form of spray; Described composition exists with aerocolloidal form; Described composition exists with the form of suspension; Described composition exists with the form of emulsion or micro emulsion; Described composition exists with the form of microsphere; Described composition exists with the form of particulate; Described composition exists with the form of solid implant.

In each embodiment of the present invention, implant or composition can comprise the fibrotic reagent of promotion and bring into play inhibiting the second composition or compound in the treatment site or on its pathologic process. The representative example of reagent that can be suppressed at the pathologic process (for example inflammation relevant with diverticulosis) in diverticulum treatment site comprises, but be not limited to, the compound of following classification: antiinflammatory (for example, dexamethasone, cortisone, fludrocortison, metacortandracin, prednisolone, 6 alpha-methylprednisolones, fluoxyprednisolone and betamethasone); Matrix metalloproteinase (MMP) inhibitor (for example, horse cubic meter department he, Ba Misita, the representative example of TIMP is included in U.S. Patent number 5,665,777; 5,985,911; 6,288,261; 5,952,320; 6,441,189; 6,235,786; 6,294,573; 6,294,539; 6,563,002; 6,071,903; 6,358,980; 5,852,213; 6,124,502; 6,160,132; 6,197,791; 6,172,057; 6,288,086; 6,342,508; 6,228,869; 5,977,408; 5,929,097; 6,498,167; 6,534,491; 6,548,524; 5,962,481; 6,197,795; 6,162,814; 6,441,023; 6,444,704; 6,462,073; 6,162,821; 6,444,639; 6,262,080; 6,486,193; 6,329,550; 6,544,980; 6,352,976; 5,968,795; 5,789,434; 5,932,763; 6,500,847; 5,925,637; 6,225,314; 5,804,581; 5,863,915; 5,859,047; 5,861,428; 5,886,043; 6,288,063; 5,939,583; 6,166,082; 5,874,473; 5,886,022; 5,932,577; 5,854,277; 5,886,024; 6,495,565; 6,642,255; 6,495,548; 6,479,502; 5,696,082; 5,700,838; 6,444,639; 6,262,080; 6,486,193; 6,329,550; 6,544,980; 6,352,976; 5,968,795; 5,789,434; 5,932,763; 6,500,847; 5,925,637; 6,225,314; 5,804,581; 5,863,915; 5,859,047; 5,861,428; 5,886,043; 6,288,063; 5,939,583; 6,166,082; 5,874,473; 5,886,022; 5,932,577; 5,854,277; 5,886,024; 6,495,565; 6,642,255; 6,495,548; 6,479,502; 5,696,082; 5,700,838; 5,861,436; 5,691,382; 5,763,621; 5,866,717; 5,902,791; 5,962,529; 6,017,889; 6,022,873; 6,022,898; 6,103,739; 6,127,427; 6,258,851; 6,310,084; 6,358,987; 5,872,152; 5,917,090; 6,124,329; 6,329,373; 6,344,457; 5,698,706; 5,872,146; 5,853,623; 6,624,144; 6,462,042; 5,981,491; 5,955,435; 6,090,840; 6,114,372; 6,566,384; 5,994,293; 6,063,786; 6,469,020; 6,118,001; 6,187,924; 6,310,088; 5,994,312; 6,180,611; 6,110,896; 6,380,253; 5,455,262; 5,470,834; 6,147,114; 6,333,324; 6,489,324; 6,362,183; 6,372,758; 6,448,250; 6,492,367; 6,380,258; 6,583,299; 5,239,078; 5,892,112; 5,773,438; 5,696,147; 6,066,662; 6,600,057; 5,990,158; 5,731,293; 6,277,876; 6,521,606; 6,168,807; 6,506,414; 6,620,813; 5,684,152; 6,451,791; 6,476,027; 6,013,649; 6,503,892; 6,420,427; 6,300,514; 6,403,644; 6,177,466; 6,569,899; 5,594,006; 6,417,229; 5,861,510; 6,156,798; 6,387,931; 6,350,907; 6,090,852; 6,458,822; 6,509,337; 6,147,061; 6,114,568; 6,118,016; 5,804,593; 5,847,153; 5,859,061; 6,194,451; 6,482,827; 6,638,952; 5,677,282; 6,365,630; 6,130,254; 6,455,569; 6,057,369; 6,576,628; 6,110,924; 6,472,396; 6,548,667; 5,618,844; 6,495,578; 6,627,411; 5,514,716; 5,256,657; 5,773,428; 6,037,472; 6,579,890; 5,932,595; 6,013,792; 6,420,415; 5,532,265; 5,639,746; 5,672,598; 5,830,915; 6,630,516; 5,324,634; 6,277,061; 6,140,099; 6,455,570; 5,595,885; 6,093,398; 6,379,667; 5,641,636; 5,698,404; 6,448,058; 6,008,220; 6,265,432; 6,169,103; 6,133,304; 6,541,521; 6,624,196; 6,307,089; 6,239,288; 5,756,545; 6,020,366; 6,117,869; 6,294,674; 6,037,361; 6,399,612; 6,495,568; 6,624,177; 5,948,780; 6,620,835; 6,284,513; 5,977,141; 6,153,612; 6,297,247; 6,559,142; 6,555,535; 6,350,885; 5,627,206; 5,665,764; 5,958,972; 6,420,408; 6,492,422; 6,340,709; 6,022,948; 6,274,703; 6,294,694; 6,531,499; 6,465,508; 6,437,177; 6,376,665; 5,268,384; 5,183,900; 5,189,178; 6,511,993; 6,617,354; 6,331,563; 5,962,466; 5,861,427; 5,830,869; With 6,087, the representative example of the TIMP in 359), cell factor inhibitors (chlorpromazine, Mycophenolic Acid, rapamycin, 1 alpha-hydroxy vitamin D₃), IMPDH (inosine monophosphate dehydrogenase) inhibitor (Mycophenolic Acid for example, Ribavirin, amino thiadiazoles (aminothiadiazole), thiophene is held up woods (thiophenfurin), and thiazole is held up woods, viral amidine (viramidine)) (representative example is included in U.S. Patent number 5,536,747, 5,807,876, 5,932,600, 6,054,472, 6,128,582, 6,344,465, 6,395,763, 6,399,773, 6,420,403, 6,479,628, 6,498,178, 6,514,979, 6,518,291, 6,541,496, 6,596,747, 6,617,323, with 6, 624, 184, Application No. 2002/0040022A1, 2002/0052513A1, 2002/0055483A1, 2002/0068346A1, 2002/0111378A1, 2002/0111495A1, 2002/0123520A1, 2002/0143176A1, 2002/0147160A1, 2002/0161038A1, 2002/0173491A1, 2002/0183315A1, 2002/0193612A1, 2003/0027845A1, 2003/0068302A1, 2003/0105073A1, 2003/0130254A1, 2003/0143197A1, 2003/0144300A1, 2003/0166201A1, 2003/0181497A1, 2003/0186974A1, 2003/0186989A1, and 2003/0195202A1, with PCT publication number WO 00/24725A1, WO 00/25780A1, WO 00/26197A1, WO 00/51615A1, WO 00/56331A1, WO 00/73288A1, WO 01/00622A1, WO 01/66706A1, WO 01/79246A2, WO 01/81340A2, WO 01/85952A2, WO 02/16382A1, WO 02/18369A2, WO 02/051814A1, WO 02/057287A2, WO 02/057425A2, WO 02/060875A1, WO 02/060896A1, WO 02/060898A1, WO 02/068058A2, WO 03/020298A1, WO 03/037349A1, WO 03/039548A1, WO 03/045901A2, WO 03/047512A2, WO 03/053958A1, WO 03/055447A2, WO 03/059269A2, WO 03/063573A2, WO 03/087071A1, WO 99/001545A1, WO 97/40028A1, WO 97/41211A1, WO 98/40381A1, with WO 99/55663A1), p 38 map kinase inhibitor (MAPK) (for example, GW-2286, CGP-52411, BIRB-798, SB220025, RO-320-1195, RWJ-67657, RWJ-68354, SCIO-469) (representative example is included in U.S. Patent number 6, 300, 347, 6,316,464, 6,316,466, 6,376,527, 6,444,696, 6,479,507, 6,509,361, 6,579,874, with 6, 630, 485, with U.S. Patent Application Publication No. 2001/0044538A1, 2002/0013354A1, 2002/0049220A1, 2002/0103245A1, 2002/0151491A1, 2002/0156114A1, 2003/0018051A1, 2003/0073832A1, 2003/0130257A1, 2003/0130273A1, 2003/0130319A1, 2003/0139388A1, 2003/0139462A1, 2003/0149031A1, 2003/0166647A1, and 2003/0181411A1, with PCT publication number WO 00/63204A2, WO 01/21591A1, WO 01/35959A1, WO 01/74811A2, WO 02/18379A2, WO 02/064594A2, WO 02/083622A2, WO 02/094842A2, WO 02/096426A1, WO 02/101015A2, WO 02/103000A2, WO 03/008413A1, WO 03/016248A2, WO 03/020715A1, WO 03/024899A2, WO 03/031431A1, WO 03/040103A1, WO 03/053940A1, WO 03/053941A2, WO 03/063799A2, WO 03/079986A2, WO 03/080024A2, WO 03/082287A1, WO 97/44467A1, WO 99/01449A1, with WO 99/58523A1), and immunomodulator (rapamycin, everolimus, ABT-578, the imuran azithromycin, the analog of rapamycin, tacrolimus and derivative thereof are (for example, EP 0184162B1 and be described in U.S. Patent number 6, 258, those in 823) and everolimus and derivative thereof (for example, U.S. Patent number 5, 665, 772). other representative example of sirolimus analog and derivative comprises ABT-578 and sees PCT publication number WO 97/10502, WO 96/41807, WO 96/35423, WO 96/03430, WO 96/00282, WO 95/16691, WO 95/15328, WO 95/07468, WO 95/04738, WO 95/04060, WO 94/25022, WO 94/21644, WO 94/18207, WO 94/10843, WO 94/09010, WO 94/04540, WO 94/02485, WO 94/02137, WO 94/02136, WO 93/25533, WO 93/18043, WO 93/13663, WO 93/11130, WO 93/10122, WO 93/04680, WO 92/14737, with WO 92/05179 with at U.S. Patent number 6, 342, 507, 5,985,890, 5,604,234, 5,597,715, 5,583,139, 5,563,172, 5,561,228, 5,561,137, 5,541,193, 5,541,189, 5,534,632, 5,527,907, 5,484,799, 5,457,194, 5,457,182, 5,362,735, 5,324,644, 5,318,895, 5,310,903, 5,310,901, 5,258,389, 5,252,732, 5,247,076, 5,225,403, 5,221,625, 5,210,030, 5,208,241, 5,200,411, 5,198,421, 5,147,877, 5,140,018, 5,116,756, 5,109,112, 5,093,338, with 5,091, those in 389.

other example that can be included in the medicine in composition of the present invention and implant comprises tyrosine kinase inhibitor, such as Imatinib (imantinib), ZK-222584, CGP-52411, CGP-53716, NVP-AAK980-NX, CP-127374, CP-564959, PD-171026, PD-173956, PD-180970, SU-0879, and SKI-606. other example that can be included in the medicine in composition of the present invention and implant comprises that the MMP inhibitor is such as aulin, PKF-241-466, PKF-242-484, CGS-27023A, SAR-943, Bai Masita (primomastat), SC-77964, PNU-171829, AG-3433, PNU-142769, SU-5402, and ground thiophene Li Botaimu (dexlipotam). other example that can be included in the medicine in composition of the present invention and implant comprises that p 38 map kinase inhibitor is such as CGH-2466 and PD-98-59. other example that can be included in the medicine in composition of the present invention and implant comprises immunodepressant such as A Jisu (argyrin) B, macrolide, ADZ-62-826, CCI-779, Tilomisole, Amcinonide, FK-778, AVE-1726, and MDL-28842. other example of cell factor inhibitors comprises TNF-484A, PD-172084, CP-293121, CP-353164, and PD-168787. other example that can be included in the medicine in composition of the present invention and implant comprises the NFKB inhibitor, such as, AVE-0547, AVE-0545, and IPL-576092. other example that can be included in the medicine in composition of the present invention and implant comprises the HMGCoA reductase inhibitor, such as, Pravastatin (pravestatin), Atorvastatin, Fluvastatin, dalvastatin, Glenvastatin, Pitavastatin, CP-83101, U-20685, the natural death of cerebral cells antagonist (for example, Tuo Luokesi amine (troloxamine), TCH-346 (N-methyl-N-propargyl-10-amino methyl-dibenzo (b, f) oxepin (oxepin)), caspase inhibitors (for example, PF-5901 (phenmethylol, α-amyl group-3-(2-quinolyl methoxyl group)-), and jnk inhibitor (for example, AS-602801).

In each embodiment of the present invention, diverticulum implant or composition in conjunction with or with the fibrotic composition of promotion, and composition or the compound that stimulates cellular proliferation that play a role is coated with. The representative example of the reagent that stimulates cellular proliferation comprises, pyruvic acid, naltrexone, leptin, D-Glucose, insulin, Amlodipine, alginates compound sugar, minoxidil, dexamethasone, isotretinoin, (Accutane), 17-β-estradiol, estradiol, 1-α-25 dihydroxyvitamin D₃, diethylstilbestrol, ciclosporin A, L-NAME (L-NG-nitroarginine methyl esters (hydrochloride)), all-trans retinoic acid (ATRA), and analog and derivative. other example of the reagent that stimulates cellular proliferation comprises: sphingosine 1-phosphate acceptor activator (for example, and FTY-720 (1,3-PD, 2-amino-2-(2-(4-octyl phenyl) ethyl)-, hydrochloride, immunostimulant such as Imupedone (ketone, [5-amino-2-(4-methyl isophthalic acid-piperidyl) phenyl] (4-chlorphenyl)-, DIAPEP227 synthetic peptide (Peptor Ltd. Israel (Peptor Ltd., Israel)), with the nerve growth factor activator, for example, NG-012 (5H, 9H, 13H, 21H, 25H,-dibenzo [k, u] [1, 5, 9, 15, 19] five oxa-ring four cosin-5, 9, 13, 21, 25-five ketone (pentone), 7, 8, 11, 12, 15, 16, 23, 24, 27, 28-decahydro-2, 4, 18, 20-tetrahydroxy-11-(methylol)-7, 15, 23, the 27-tetramethyl-, NG-121, SS-701 (2, 2 ': 6 ', 2 " three pyridines (terpyridine), 4 '-(4-aminomethyl phenyl)-tri hydrochloride, AMPAlex (piperidines), 1-(6-quinoxalinyl carbonyl)-, RGH-2716 (8-[4, 4-two (4-fluorophenyl) butyl]-3-(1, the 1-dimethyl ethyl)-4-methylene-1-oxa--3, 8-diaza-spiro [4.5] decane-2-ketone), and TDN-345 (1-oxa--3, 8-diaza spiro [4.5] decane-2-ketone, 8-[4, 4-two (4-fluorophenyl) butyl]-3-(1, the 1-dimethyl ethyl)-4-methylene-).

Styptic

Hemorrhage in order to process, comprise the bottom gastrointestinal bleeding, it is the result of hemorrhage of diverticulum, described diverticulum implant or composition can comprise fibr tissue forming agent and styptic (thrombosis or block agglutinant), and described styptic promotes grumeleuse and hemostasis when medical implant (or composition) is implanted. Styptic (haemostat) or hemostasis reagent (haemostatic agent) are any reagent that chemically or mechanically stops from the blood flow of open vascular. Styptic can directly be coated to bleeding part, and described reagent works under fluid flow blood existence actively. Therefore, styptic can pass through with the one or more steps interference in coagulation cascade chemically or biology ground resistance Hemostatic Oral Liquid flows, such as passing through the accelerated solidification process (for example, COSTASIS). The grumeleuse that then will increase is as the physical obstacle of blood flow. Alternatively, styptic can mechanically or physically block blood flow (for example, COSEAL) and thereby can be called the sealant reagent of liquid, gas or solid seepage (be used for prevent) in more direct mode. Styptic can be applied or claps (claped) surperficial so that the obstacle of blood flow to be provided to tissue.

In multiple embodiments, the diverticulum implant contains styptic or comprises the composition of styptic and/or promote fibrotic reagent or composition. In some alternative embodiment, implant is coated with the fibrotic composition of promotion on a face, and uses hemostasis composition or reagent coating on another face of described implant. The representative instance of styptic comprises fibrin; Aminocaproic acid; Tranexamic acid; Aprotinin; Minirin; Vitamin K; Tisseel  and FloSeal  (it is the preparation that contains fibrinogen) (hundred special medicine companies (Baxter Healthcare Corp.), Glan Dai Er (Glendale), California (CA)); CrossSeal  (American Red Cross (American Red Cross)); CoSeal  (preparation that contains PEG) and CoStasis  (preparation that contains collagen) (blood vessel technology Biomatera Inc. (Angiotech BioMaterials Corp.), Palo Alto (Palo Alto), California (CA)); With CryoSeal  AHS (themogenesis (Thermogenesis), Sacramento (Sacramento), California (CA)).

Anti-infective

In one embodiment, provide the composition and the medical implant that comprise fibr tissue forming agent and anti-infective, described anti-infective reduces the possibility that infects in medical implant. Infection is to be implanted in host or patient and the common complication that causes by the foreign matter such as medical treatment device and implant. Foreign substance is for microbial adhesion and settle down the place that provides desirable. In addition, according to nonrestrictive theory, due to the result of host for the defence damage of infecting in the microenvironment around foreign substance, the host will be developed the risk that infects and may be increased. These factors make medical implant responsive especially to infecting.

The composition that treatment and/or processing diverticulum infect (diverticulitis) can comprise anti-infective, antibiotic, or inhibition (weaken or reduce) is grown or other reagent of division speed or kill microorganisms (for example, bacterium and yeast). When concentrated stool, diverticulitis, while producing local infection's (or abscess formation) in described diverticulum, can occur in the coprolite of holding back in a kind of diverticulum. When serious, this can cause boring a hole and spread the formation of peritonitis. Even in the processing of the diverticulum that there is no acute infection, the diverticulum chamber can be aseptic, thereby within bacterium is not included in the cicatricial tissue of development. This will reduce in the infection of subsequently time point development or the possibility of abscess.

Anti-infective refers to the reagent that reduces infection potential. By the mensuration by the conventional enforcement of those skilled in the art, for example the external test by the represented definite bacterial growth inhibition of M.I.C. (MIC) shows, reagent is active anti-infective for microorganism. In certain embodiments, anti-infective is to have chemotherapeutics (for example, anthracycline, 5-FU, antifol, podophyllotoxin, camptothecine, hydroxycarbamide and the platinum complex of antimicrobial acivity with low dose.

Anticorrisive agent refers to effectively corrosion-resistant reagent or material, that is, needn't kill described biology by the growth that suppresses infectious organisms and infect with prevention. The representative instance of anticorrisive agent comprises chlorhexidine (chlorhexadine), triclosan and PCMX (chloroxylenol).

Antibiotic refers to the reagent that kills or suppress growth of microorganism. Antibiotic can have one or both narrow or activity wide region for Gram-positive and gram-negative biological. Can identify antibiotic agent by the external inhibition of bacterial growth, shown in M.I.C. measures as described herein. Antibiotic representative instance comprises gentamicin sulphate, amikacin sulfate, kanamycin sulfate, PB, neomycinsulphate, brizolina, metronidazole, Ciprofloxacin, Piperacillin, Cefoxitin, Cefepime, azithromycin and TMP (Trimethoprom)-Sulfamethoxazole.

Within multiple embodiments of the present invention, compositions comprises, perhaps implant load or scribble and promote fibrotic compositions, and load or (for example scribble anti-infective, antibiotic, chemotherapeutics, and/or antiseptic) or comprise the compositions of antibiotic (or antiseptic).The representative instance that reagent here is provided is such as the chemotherapeutics that can discharge and have with very little dosage effective antimicrobial acivity from compositions.Anti-infective miscellaneous can be used in combination with the present composition.The anti-infective that is fit to can easily be determined by the method that implement this area, and illustrate as the mensuration that provides among the embodiment 41.Be described in greater detail below several representative instances of anti-infective: (A) anthracycline (for example, doxorubicin and mitoxantrone); (B) the fluorine pyrimidine (for example, 5-FU); (C) antifol (for example, methotrexate); (D) podophyllotoxin (for example, etoposide); (E) camptothecine; (F) hydroxyurea; (G) platinum complex (for example, cisplatin).

Anti-infective has protecting from infection, reduces the performance that abscess forms incidence rate, treatment diverticulitis and/or promotes the sterilization of diverticulum chamber during the cicatrization process.Such anti-infective includes, but are not limited to antibiotic and anticarcinogen.In addition, implant can scribble antimicrobial agents.Implant is provided at U.S. Patent number 5,520,664, U.S. Patent number 5 with the representative instance of the coating of the implant that contains antimicrobial agents, 709,672, U.S. Patent number 6,361,526, U.S. Patent number 6,261,271, U.S. Patent number 5,902,283, U.S. Patent number 5,624,704, with U.S. Patent number 5,709, in 672.

Anti-infective-antibiotic

Antibiotic and antibiotic combination that the medical field technical staff uses comprise following exemplary antibiotic: the 4th generation penicillin such as mezlocillin and piperacillin (ureido-penicillins (ureidopenicillin)), Carbenicillin and ticarcillin (penicillin carboxy), and analog and derivant; First generation cephalosporin is such as cefazolin sodium, cefazolin sodium, cefalexin (cefalexin), cefazolin sodium (cefazolin sodium), cefaloject (cephapirin sodium), and cefalotin (Keflin), and analog and derivant; Ticarcillin; Second generation cephalosporin such as cefuroxime (new bacterium spirit (oral) and Zinocef), cefotetan (Cefotan), and cefoxitin (Cefoxitin), and analog and derivant; Third generation cephalosporin such as Naxcel (ceftiofur sodium), cefdinir (Omnicef), cefoperazone (cefoperazone), ceftazidime (ceftazidime), and ceftriaxone (Ceftriaxone), and cefotaxime (Cefotaxime), and analog and derivant; With the 4th generation cephalosporin such as cefepime (Maxipime) and analog and derivant; Monobactam such as aztreonam and analog thereof and derivant; Carbapenem is such as imipenum, Ai Tapeinan (ertapenem) and meropenem, and analog and derivant.Also comprise protein synthesis inhibitor,, comprise streptomycin, gentamycin, gentamycin sulfate, tobramycin, and amikacin, amikacin sulfate, and analog and derivant such as aminoglycoside; Protein synthesis inhibitor, such as comprising macrolide (erythromycin), long-acting macrolide (azithromycin) and lincosamide (clindamycin) and streptogramin (quinoline slave Pu Ding-dalfopristin (Syneroid)), clarithromycin, kanamycin, kanamycin sulfate, and the MSL of analog and derivant group.Other exemplary antibiotic comprises the DNA synthetic inhibitor, such as quinolinones, comprise ciprofloxacin, ofloxacin, Gatifloxacin, Moxifloxacin, levofloxacin, trovafloxacin and analog thereof and derivant, and other DNA synthetic inhibitor such as metronidazole and analog and derivant.Other antibiotic comprises folic acid metabolism inhibitor such as sulfonamides and trimethoprim, and analog and derivant.Other reagent includes but not limited to cefixime, spectinomycin, tetracycline, nitrofurantoin, doxycycline, polymyxin B, neomycin, polygynax, and analog and derivant.In certain embodiments, described anti-infective is a gentamycin sulfate, amikacin sulfate, kanamycin sulfate, polymyxin B, polygynax, cefazolin sodium, metronidazole, ciprofloxacin, piperacillin, cefoxitin, cefepime, azithromycin, or trimethoprim-sulfamethoxazole.

And, can make up and send other therapeutic agent.Such combination comprises, for example, but is not limited to amoxicillin and clavulanic acid, ampicillin and sulbactam, trimethoprim-sulfamethoxazole, ampicillin and probenecid, amoxicillin and probenecid, benzylpenicillin and probenecid, and penicillin and penicillinase inhibitor.

Antibiotic described herein and that the medical field technical staff uses can dosage forms for oral administration (according to the factor such as patient's age and/or weight and/or quality, every day, 1-2 restrained).As described herein, also can one or more antibiotic of parenteral administration or can be comprising described fibre modification combination of agents thing administration of antibiotics, or can with the implant combined administration.

Anti-infective-chemotherapeutics

Also be provided at here be attached on the implant among or from the reagent (for example, chemotherapeutics) of its release, or be implanted in compositions within the diverticulum, and it has effective antimicrobial acivity with very little dosage.Anti-infective miscellaneous can form agent with fibrous tissue and be used in combination.Be described in greater detail below several representative instances of chemotherapeutics/anti-infective: (A) anthracycline (for example, doxorubicin and mitoxantrone); (B) the fluorine pyrimidine (for example, 5-FU); (C) antifol (for example, methotrexate); (D) podophyllotoxin (for example, etoposide); (E) camptothecine; (F) hydroxyurea; (G) platinum complex (for example, cisplatin).

A. Anthracyclines

Anthracyclines has following general structure, and wherein the R group can be different organic groups:

According to U.S. Pat 5,594,158, the suitable R group is as follows: R ₁Be CH ₃Or CH ₂OH; R ₂Be gentle amine (daunosamine) or H; R ₃And R ₄Be OH, NO independently ₂, NH ₂, F, Cl, Br, I, CN, H or derive from their group a kind of; R ₅Be hydrogen, hydroxyl or methoxyl group; And R _6-8Be hydrogen.Alternatively, R ₅And R ₆Be hydrogen and R ₇And R ₈For alkyl or halogen or vice versa.

According to United States Patent (USP) 5,843,903, R ₁Can be the peptide of puting together.According to United States Patent (USP) 4,296,105, R ₅Can be the alkyl group of ether connection.According to United States Patent (USP) 4,215,062, R ₅Can be the alkyl of OH or ether connection.R ₁Can also be connected with the ring of anthracycline by the group by non-C (O), the group of described non-C (O) is such as being alkyl or the branched alkyl that contains C (O) coupling part endways, such as-CH ₂CH (CH ₂-X) C (O)-R ₁, wherein X is H or alkyl group (see, for example, United States Patent (USP) 4,215,062).R ₂Can alternatively be the group by functional group=N-NHC (O)-Y connection, wherein Y is this class group such as the phenyl ring of phenyl or replacement.Alternatively, R ₃Can have following array structure:

R wherein ₉For in the plane of a loop or outer OH or be second sugar moieties, such as R ₃R ₁₀Can for H or with form secondary amine (referring to United States Patent (USP) 5,843,903) such as aromatic group, this class group of 5 or 6 yuan of heterocycles of containing the saturated or fractional saturation of at least one ring nitrogen.Alternatively, R ₁₀Can derive from and contain-C (O) CH (NHR ₁₁) (R ₁₂) aminoacid of structure, wherein R ₁₁Be H; Or R ₁₀Can with R ₁₂Form C _3-4Unit's alkylidene.R ₁₂Can be H, alkyl, aminoalkyl, amino, hydroxyl, sulfydryl, phenyl, benzyl or methyl mercapto (referring to United States Patent (USP) 4,296,105).

Exemplary anthracycline is doxorubicin, daunorubicin, idarubicin, epirubicin, pirarubicin, zorubicin and carubicin.Suitable compound has following structure:

Other suitable anthracycline is antramycin, mitoxantrone, menogaril, nogalamycin, Aclacnomycin A, Olivomycin A, the chromomycin A with following structure ₃And plicamycin:

Other representational anthracycline comprises FCE 23762, doxorubicin derivant (J.Liq.Chromatogr (liquid chromatograph magazine) .17 (18): 3911-3923 such as Quaglia, 1994), At mycin (Zou etc., J.Pharm.Sci. (pharmaceutical science magazine) 82 (11): 1151-1154,1993), ruboxyl (Rapoport etc., J.Controlled Release (controlled release magazine) 58 (2): 153-162,1999), anthracycline disaccharide doxorubicin analog (Pratesi etc., Clin.Cancer Res. (Clinical Cancer Research) 4 (11): 2833-2839,1998), N-(trifluoroacetyl group) doxorubicin and 4 '-O-acetyl group-N-(trifluoroacetyl group) doxorubicin (Berube ﹠amp; Lepage, Synth.Commun.28 (6): 1109-1116,1998), 2-pyrrolin and doxorubicin (Proc.Nat ' l Acad.Sci.U.S.A. (NAS's journal) 95 (4): 1794-1799 such as Nagy, 1998), disaccharide doxorubicin analog (Arcamone etc., J.Nat ' l Cancer Inst (national cancer research magazine) .89 (16): 1217-1223,1997), 4-demethoxylation-7-O-[2, two deoxidation-the 4-O-(2 of 6-, 3,6-three deoxidations-3-amino-α-L-lysol-hexose pyrans glycosyl)-and α-L-lysol-hexose pyrans glycosyl] adriamycinone (adriamicinone) doxorubicin disaccharide analog (Monteagudo etc., Carbohydr.Res. (carbohydrate compound research) 300 (1): 11-16,1997), 2-pyrrolin and doxorubicin (Proc.Nat ' l Acad.Sci.U.S.A.94 (2): 652-656 such as Nagy, 1997), morpholinyl doxorubicin analog (Duran etc., CancerChemother.Pharmacol. (cancer chemotherapeutic drug) 38 (3): 210-216,1996), enamino malonyl-Beta-alanine doxorubicin derivant (Seitz etc., Tetrahedron Lett. (tetrahedron communication) 36 (9): 1413-16,1995), cephalosporin doxorubicin derivant (Vrudhula etc., J.Med.Chem. (pharmaceutical chemistry magazine) 38 (8): 1380-5,1995), hydroxyrubicin (Solary etc., Int.J.Cancer (international journal of cancer) 58 (1): 85-94,1994), methoxyl group morpholinyl doxorubicin derivant (Kuhl etc., Cancer Chemother.Pharmacol. (cancer chemotherapeutic drug) 33 (1): 10-16,1993), (6-maleimide base caproyl) hydrazone doxorubicin derivant (Bioconjugate Chem. (bioconjugates chemistry) 4 (6): 521-7 such as Willner, 1993), N-(5,5-diacetoxy penta-1-yl) doxorubicin (Cherif ﹠amp; Farquhar, J.Med.Chem.35 (17): 3208-14,1992), FCE23762 methoxyl group morpholinyl doxorubicin derivant (Ripamonti etc., Br.J.Cancer (cancer magazine) 65 (5): 703-7,1992), N-hydroxy-succinamide ester doxorubicin derivant (Demant etc., Biochim.Biophys.Acta (" biochemistry and biophysics's journal ") 1118 (1): 83-90,1991), poly deoxynucleosides doxorubicin derivant (Ruggiero etc., Biochim.Biophys.Acta (" biochemistry and biophysics's journal ") 1129 (3): 294-302,1991), morpholinyl doxorubicin derivant (EPA 434960), mitoxantrone doxorubicin analog (Krapcho etc., J.Med.Chem. (pharmaceutical chemistry magazine) 34 (8): 2373-80.1991), AD198 doxorubicin analog (Traganos etc., Cancer Res. (" cancer research ") 51 (14): 3682-9,1991), 4-demethoxylation-3 '-N-TFA base doxorubicin (Drug Des.Delivery (medicine is sent) 6 (2): 123-9 such as Horton, 1990), 4 '-epirubicin (4 '-epidoxorubicin) (Drzewoski etc., Pol.J.Pharmacol.Pharm. (" Polish pharmacology and materia medica magazine ") 40 (2): 159-65,1988; Weenen etc., Eur.J.Cancer Clin.Oncol. (" European cancer Journal of Clinical Oncology ") 20 (7): 919-26,1984), alkylation cyano group morpholinyl doxorubicin derivant (Scudder etc., J.Nat ' l Cancer Inst. (" National Cancer Institute's magazine ") 80 (16): 1294-8,1988), deoxidation dihydro iodooxorubicin (EPA 275966), Hydroxydaunomycin (Kalishevskaya etc., Vestn.Mosk.Univ.16 (Biol.1): 21-7,1988), 4 '-deoxidation doxorubicin (Leuk.Res. (" leukocyte research ") 10 (12): 1455-9 such as Schoelzel, 1986), 4-demethoxylation-4 '-o-methyl doxorubicin (Giuliani etc., Proc.Int.Congr.Chemother.16:285-70-285-77,1983), 3 '-deaminizating-3 '-hydroxyl doxorubicin (J.Antibiot. (" antibiotic magazine ") 37 (8): 853-8 such as Horton, 1984), 4-demethoxylation doxorubicin analog (Barbieri etc., Drugs Exp.Clin.Res. (" clinical drug experimentation ") 10 (2): 85-90,1984), N-L-leucyl doxorubicin derivant (Trouet etc., anthracyclines (Anthracyclines)-Proc.Int.Symp.Tumor Pharmacother.179-81,1983), 3 '-deaminizating-3 '-(4-methoxyl group-piperidino) doxorubicin derivant (U.S.4,314,054), 3 '-deaminizating-3 '-(4-morpholinyl) doxorubicin derivant (U.S.4,301,277), 4 '-deoxidation doxorubicin and 4 '-o-methyl doxorubicin (Giuliani etc., " international journal of cancer " (Int.J.Cancer) 27 (1): 5-13,1981), aglycone doxorubicin derivant (Chan ﹠amp; Watson, " pharmaceutical science magazine " (J.Pharm.Sci.) 67 (12): 1748-52,1978), SM 5887 (" Japanese pharmacy " (Pharma Japan) 1468:20,1995), MX-2 (" Japanese pharmacy " (Pharma Japan) 1420:19,1994), 4 '-deoxidation-13 (S)-dihydro-4 '-iodine doxorubicin (EP 275966), morpholinyl doxorubicin derivant (EPA 434960), 3 '-deaminizating-3 '-(4-methoxyl group-piperidino) doxorubicin derivant (U.S.4,314,054), doxorubicin-14-valerate, morpholinyl doxorubicin (U.S.5,004,606), 3 '-deaminizating-3 '-(3 " cyano group-4 "-morpholinyl doxorubicins, 3 '-deaminizating-3 '-(3 " cyano group-4 "-morpholinyl)-13-dihydro doxorubicin, (3 '-deaminizating-3 '-(3 " cyano group-4 "-morpholinyl) daunorubicin, 3 '-deaminizating-3 '-(3 " cyano group-4 "-morpholinyl)-3-dihydrodaunomycin and 3 '-deaminizating-3 '-(4 " morpholinyl-5-imino group doxorubicin and derivant (U.S.4; 585; 859); 3 '-deaminizating-3 '-(4-methoxyl group-piperidino) doxorubicin derivant (U.S.4; 314; 054) and 3-deaminizating-3-(4-morpholinyl) doxorubicin derivant (U.S.4,301,277).

B. Fluoropyrimidine analogue

In one aspect of the method, described therapeutic agent is a fluoropyrimidine analogue, such as 5-fluorouracil or its analog or derivant, comprises carmofur, doxifluridine, emitefur, ftorafur and floxuridine.Exemplary compounds has following structure:

A

	R ₁	R ₂
	R ₁	R ₂	5-fluorouracil carmofur doxifluridine floxuridine emitefur ftorafur	H C(O)NH(CH ₂) ₅CH ₃ A ₁ A ₂ CH ₂OCH ₂CH ₃ C	H H H H B H

Other suitable fluoropyrimidine analogue comprises 5-FudR (5-fluoro-BrdU) or its analog or derivant, comprises idoxuridine (5-IudR), 5-bromouracil deoxyribose (5-BudR), fluorouridine triphosphate (5-FUTP) and fluorodeoxyuridine one phosphoric acid (5-dFUMP).Exemplary compounds has following structure:

5-fluoro-2 '-BrdU: R=F

5-bromo-2 '-BrdU: R=Br

5-iodo-2 '-BrdU: R=I

Other representative example of fluoropyrimidine analogue comprises the N3-alkylation analog (Kozai etc. of 5-fluorouracil, J.Chem.Soc.Perkin Trans.1 (19): 3145-3146,1998), contain 1, (Gomez etc. " tetrahedron " (Tetrahedron) 54 (43): 13295-13312 for the 5-fluorouracil derivant of 4-oxa-loop section in heptan, 1998), 5-fluorouracil and nucleoside analog (Li, " anticancer research " (Anticancer Res.) 17 (1A): 21-27,1997), cis-and trans-5-fluoro-5,6-dihydro-6-alkoxyl uracil (Van der Wilt etc., " Britain's cancer magazine " (Br.J.Cancer) 68 (4): 702-7,1993), Pentamethylene. 5-fluorouracil analog (Hronowski ﹠amp; Szarek, " Canadian Journal of Chemistry " (Can.J.Chem.) 70 (4): 1162-9,1992), A-OT-fluorouracil (Zhang etc., " Chinese Journal of Pharmaceuticals " (Zongguo Yiyao Gongye Zazhi) 20 (11): 513-15,1989), N4-trimethoxy benzoyl-5 '-deoxidation-5-fluorine cytidine and 5 '-(Miwa etc. " chemicals bulletin " (Chem.Pharm.Bull.) 38 (4): 998-1003 for '-Deoxy-5-fluorouridine, 1990), 1-hexyl carbamoyl-5-fluorouracil (Hoshi etc., J.Pharmacobio-Dun.3 (9): 478-81,1980; Maehara etc., " chemotherapy " be (Basel) 34 (6) (Chemotherapy): 484-9,1988), B-3839 (Prajda etc., " in the body " (In Vivo) 2 (2): 151-4,1988), (Anai etc. " oncology " (Oncology) 45 (3): 144-7 for uracil-1-(2-tetrahydrofuran base)-5-fluorouracil, 1988), 1-(2 '-deoxidation-2 '-fluoro-beta-D-arabinofuranosyl adenin base)-5-fluorouracil (Suzuko etc., " molecular pharmacology " (Mol.Pharmacol.) 31 (3): 301-6,1987), doxifluridine (Matuura etc., Oyo Yakuri 29 (5): 803-31,1985), 5 '-'-Deoxy-5-fluorouridine (Bollag ﹠amp; Hartmann; " European cancer magazine " (Eur.J.Cancer) 16 (4): 427-32; 1980), 1-acetyl group-3-O-toluyl groups-5-fluorouracil (Okada; Hiroshima J.Med.Sci.28 (1): 49-66,1979), 5-fluorouracil-m-formoxyl benzene-sulphonic acid ester (JP55059173), N '-(2-furan alkyls)-5-fluorouracil (JP 53149985) and 1-(2-tetrahydrofuran base)-5-fluorouracil (JP 52089680).

Think that these chemical compounds play therapeutic agent by the antimetabolite as pyrimidine.

C. Antifol

In one aspect of the method, therapeutic agent is an antifol, such as methotrexate or derivatives thereof or analog, comprises edatrexate, trimetrexate, Raltitrexed, piritrexim, 9,10-dimethylpteroylglutamic acid, Tomudex and Pteropterin.The methotrexate analog has following general structure:

Symbol R group can be selected from organic group, and particularly United States Patent (USP) 5,166, and 149 and 5,382, those groups described in 582.For example, R ₁Can be N, R ₂Can be N or C (CH ₃), R ₃And R ₃' can be H or alkyl, for example CH ₃, R ₄Can be singly-bound or NR, wherein R is H or alkyl.R ₅, R ₆, and/or R ₈Can be H, OCH ₃Or they are chosen as halogen or hydrogen group.

R ₇Side chain for following general structure:

Wherein with regard to methotrexate, n=1, with regard to Pteropterin, n=3.Carboxyl on the side chain can esterified or salify, such as Zn ²⁺Salt.R ₉And R ₁₀Can be NH ₂Maybe can replace for alkyl.

Typical folic acid antagonist immunomodulator compounds has following structure:

	R ₀	R ₁	R ₂	R ₃	R ₄	R ₅	R ₆	R ₇	R ₈
	R ₀	R ₁	R ₂	R ₃	R ₄	R ₅	R ₆	R ₇	R ₈	Methotrexate edatrexate trimetrexate Pteropterin 9,10-dimethylpteroylglutamic acid Peritrexi m	NH ₂ NH ₂ NH ₂ OH OH NH ₂	N N CH N N N	N N C(CH ₃) N N C(CH ₃)	H H H H CH ₃ H	N(CH ₃) CH(CH ₂CH ₃) NH NH N(CH ₃) singly-bound	H H H H H OCH ₃	H H OCH ₃ H H H	A(n＝1) A(n＝1) OCH ₃ A(n＝3) A(n＝1) H	H H OCH ₃ H H OCH ₃

Think that these chemical compounds play the antimetabolite of folic acid.

D. Podophyllotoxin

In one aspect of the method, therapeutic agent is podophyllotoxin or derivatives thereof or analog.Such typical compound is etoposide or teniposide, and they have following structure:

The representational example of other of podophyllotoxin comprises Cu (II)-VP-16 (etoposide) complex, and (Tawa etc. " bioorganic pesticide thing chemistry " (Bioorg.Med.Chem.) 6 (7): 1003-1008,1998), etoposide analog (the Ji etc. that contain pyrroles's amidino, " bioorganic pesticide thing chemistry communication " (Bioorg.Med.Chem.Lett.) 7 (5): 607-612,1997), 4 beta-amino etoposide analog (Hu, University of North Carolina Dissertation, 1992), (Zhou etc. " pharmaceutical chemistry magazine " (J.Med.Chem.) 37 (2): 287-92 for the fragrant amino etoposide analog of gamma lactone ring-modification, 1994), N-glucityl etoposide analog (Allevi etc., " tetrahedron communication " (Tetrahedron Lett.) 34 (45): 7313-16,1993), etoposide A-ring analogues (Kadow etc., " bioorganic pesticide thing chemistry communication " (Bioorg.Med.Chem.Lett.) 2 (1): 17-22,1992), 4 '-dehydroxylation-4 '-methyl etoposide (Saulnier etc., " bioorganic pesticide thing chemistry communication " (Bioorg.Med.Chem.Lett.) 2 (10): 1213-18,1992), (Sinha etc. " European cancer magazine " (Eur.J.Cancer) 26 (5): 590-3 for pendular ring (pendulum ring) etoposide analog, 1990) and E-ring deoxidation etoposide analog (Saulnier etc. " pharmaceutical chemistry magazine " (J.Med.Chem.) 32 (7): 1418-20,1989).

Think that these chemical compounds play topoisomerase II inhibitor and/or dna cleavage agent.

E. Camptothecine

In one aspect of the method, therapeutic agent is camptothecine or its analog or derivant.Camptothecine has following general structure.

In this structure, X typically is O, but can be other group, for example, and the NH on the 21-lactam derivatives in the situation.R ₁Typically be H or OH, but can be other group, for example C of terminal hydroxylization _1-3Alkane.R ₂Typically be H or contain amino group, such as (CH ₃) ₂NHCH ₂, but can be other group, for example NO ₂, NH ₂, halogen (for example United States Patent (USP) 5,552,156 in disclosed) or contain the short alkane of these groups.R ₃Typically be H or short alkyl, such as C ₂H ₅R ₄Typically be H, but can be other group, for example have R ₁Methylene-dioxy.

Typical Comptothecin compounds comprises hycamtin, irinotecan (CPT-11), 9-aminocamptothecin, 21-lactams-20 (S)-camptothecine, 10,11-methylene-dioxy camptothecine, SN-38,9-nitrocamptothecin, 10-hydroxycamptothecine.Exemplary compounds has following structure:

	R ₁	R ₂	R ₃
	R ₁	R ₂	R ₃	Camptothecine: hycamtin: SN-38:	H OH OH	H (CH ₃) ₂NHCH ₂ H	H H C ₂H ₅

X: for most of analog is O, is NH for the 21-lactams

Camptothecine has 5 rings shown in this article.The ring that is labeled as E must be complete (lactone but not carboxylate form) so that maximum activity and minimum toxicity are arranged.

Think that camptothecine plays topoisomerase I inhibitor and/or dna cleavage agent.

F. The hydroxyl ureas

Therapeutic agent of the present invention can be hydroxyurea.The hydroxyl ureas has following general structure:

Suitable hydroxyl ureas for example is disclosed in United States Patent (USP) 6,080, in 874, and R wherein ₁For:

And R ₂Be alkyl and the R that contains 1-4 carbon ₃For one of H, acyl group, methyl, ethyl and composition thereof, such as methyl ether.

Other suitable hydroxyl ureas for example is disclosed in United States Patent (USP) 5,665,768, in, R wherein ₁Be cycloalkenyl, for example N-[3-[5-(4-fluorobenzene sulfenyl)-furyl]-2-cyclopentenes-1-yl] the N-hydroxyurea; R ₂For H or contain the alkyl and the R of 1-4 carbon ₃Be H; X is H or cation.

Other suitable hydroxyl ureas is disclosed in, and for example United States Patent (USP) 4,299, in 778, and R wherein ₁Be the phenyl that is replaced by one or more fluorine atoms; R ₂Be cyclopropyl; And R ₃With X be H.

Other suitable hydroxyl ureas is disclosed in, and for example United States Patent (USP) 5,066, in 658, and R wherein ₂And R ₃Form with adjacent nitrogen:

Wherein m is 1 or 2, and n is that 0-2 and Y are alkyl.

In one aspect, described hydroxyurea has following structure:

Hydroxyurea

Think that these chemical compounds work by inhibition DNA is synthetic.

G. Platinum complex

In one aspect of the method, therapeutic agent is a platinum compounds.In general, suitable platinum complex can be the complex of Pt (II) or Pt (IV), and contains following this basic structure:

Wherein X and Y are the anion leaving group, such as sulfate, phosphate, carboxylate and halogen; R ₁And R ₂For can further arbitrarily substituted alkyl, amine, aminoalkyl, and be essentially the group of inertia or bridging.With regard to Pt (II) complex, Z ₁And Z ₂All do not exist.With regard to Pt (IV), Z ₁And Z ₂Can be anionic group, such as halogen, hydroxyl, carboxylate, ester, sulfate or phosphate.For example, referring to U.S. Patent number 4,588,831 and 4,250,189.

Suitable platinum complex can contain a plurality of Pt atoms.For example, referring to U.S. Patent number 5,409,915 and 5,380,897.For example two platinum of following type and three platinum complexs:

Typical platinum compounds is cisplatin, carboplatin, oxaliplatin and the miboplatin with following structure:

Other representational platinum compounds comprises (CPA) ₂Pt[DOLYM] and (DACH) Pt[DOLYM] cisplatin (Choi etc. " drug research archives " (Arch.Pharmacal Res.) 22 (2): 151-156,1999), cis-[PtCl ₂(4,7-H-5-methyl-7-oxo) 1,2,4-[triazol [1,5-a] pyrimidine] ₂] (Navarro etc. " pharmaceutical chemistry magazine " (J.Med.Chem.) 41 (3): 332-338,1998), [Pt (cis-1,4-DACH) (trans-Cl ₂) (CBDCA)] (Shamsuddin etc. " inorganic chemistry " (Inorg.Chem.) 36 (25): 5969-5971 for the 1/2MeOH cisplatin, 1997), 4-Pvridoxic Acid ester diamidogen hydroxyl platinum (pyridoxate diammine hydroxy platinum) (Tokunaga etc. " pharmaceutical science " (Pharm.Sci.) 3 (7): 353-356,1997), Pt (II) ... Pt (II) (Pt ₂[NHCHN (C (CH ₂) (CH ₃))] ₄) (Navarro etc. " inorganic chemistry " (Inorg.Chem.) 35 (26): 7829-7835,1996), 254-S cisplatin analog (Koga etc. " neurological's research " (Neurol.Res.) 18 (3): 244-247,1996), contain cisplatin analog (the Koeckerbauer ﹠amp of o-phenylenediamine part; Bednarski, " inorganic biochemistry magazine " (J.Inorg.Biochem.) 62 (4): 281-298,1996), trans, cis-[Pt (OAc) ₂I ₂(alkene)] (Kratochwil etc. " pharmaceutical chemistry magazine " (J.Med.Chem.) 39 (13): 2499-2507,1996), contain estrogen 1, (Bednarski " inorganic biochemistry magazine " (J.Inorg.Biochem.) 62 (1): 75 for the cisplatin analog of 2-diaryl ethylenediamine part (aminoacid and the glutathion that have sulfur-bearing), 1996), cis-1,4-diamino-cyclohexane cisplatin analog (Shamsuddin etc. " inorganic biochemistry magazine " (J.Inorg.Biochem.) 61 (4): 291-301,1996), cis-[Pt (NH ₃) (4-amino TEMP-O) { d (GpG) }] and 5 ' orientation isomer (Dunham ﹠amp; Lippard " Journal of the American Chemical Society " (J.Am.Chem.Soc.) 117 (43): 10702-12,1995), contain cisplatin analog (the Koeckerbauer ﹠amp of chelating diamidogen; Bednarski, " pharmaceutical science magazine " (J.Pharm.Sci.) 84 (7): 819-23,1995), contain 1, the cisplatin analog of 2-diaryl ethylenediamine part (Otto etc. " cancer research and Journal of Clinical Oncology " (J.Cancer Res.Clin.Oncol.121 (1): 31-8,1995), (ethylenediamine) platinum (II) complex (Pasini etc., J.Chem.Soc.Dalton Trans.4:579-85,1995), (Yang etc. " international oncology's magazine " (Int.J.Oncol.) 5 (3): 597-602 for CI-973 cisplatin analog, 1994), cis-diaminedichloroplatinum (II) and analog cis-1 thereof, 1-cyclobutane dicarboxylic acid (2R)-2-methyl isophthalic acid, 4-butanediamine platinum (II) and cis-diamidogen (glycolic acid) platinum (Claycamp﹠amp; Zimbrick " inorganic biochemistry magazine " (J.Inorg.Biochem.) 26 (4): 257-67,1986; Fan etc. " cancer research " (Cancer Res.) 48 (11): 3135-9,1988; Heiger-Bemays etc., " biochemistry " (Biochemistry) 29 (36): 8461-6,1990; Kikkawa etc., " clinical experiment cancer research magazine " (J.Exp.Clin.Cancer Res.) 12 (4): 233-40,1993; Murray etc., " biochemistry " (Biochemistry) 31 (47): 11812-17,1992; Takahashi etc.; " cancer chemotherapy pharmacology " (Cancer Chemother.Pharmacol.) 33 (1): 31-5; 1993); (Yoshida etc. " biochemistry pharmacology " (Biochem.Pharmacol.) 48 (4): 793-9 for cis-amine-cyclohexylamine-dichloro platinum (II); 1994); together with-bisphosphonates cisplatin analog (FR 2683529); (meso-1; 2-two (2; 6-two chloro-4-hydroxy phenyls) dichloro platinum (II) (Bednarski etc. ethylenediamine); " pharmaceutical chemistry magazine " (J.Med.Chem.) 35 (23): 4479-85; 1992); (Hartwig etc. " Journal of the American Chemical Society " (J.Am.Chem.Soc.) 114 (21): 8292-3 to contain the cisplatin analog of tethers (tethered) dansyl base; 1992); platinum (II) polyamines class (Siegmann etc.; Inorg.Met.-ContainingPolym.Mater. (Proc.Am.Chem.Soc.Int.Symp.); 335-61; 1990); dichloro (ethylenediamine) platinum (the II) (Eastman of cis-(3H); " biochemistry yearbook " (Anal.Biochem.) 197 (2): 311-15,1991); trans-diaminedichloroplatinum (II) and cis-(Pt (NH ₃) ₂(N ₃-cytosine) (Bellon ﹠amp C1); Lippard, " biophysics and chemistry " be 35 (2-3): 179-88 (Biophys.Chem.), 1990), 3H-cis-1,2-diamino-cyclohexane dichloro platinum (II) and 3H-cis-1,2-diamino-cyclohexane-malonic acid platinum (II) (Oswald etc., " chemistry, pathology and pharmaceutical research communication " (Res.Commun.Chem.Pathol.Pharmacol.) 64 (1): 41-58,1989), diamino monocarboxylic acid platinum (EPA296321), contain trans-(D, 1)-1, platinum analogs (the Wyrick ﹠amp of 2-diamino-cyclohexane carrier ligand; Chaney, " labelled compound and with radiopharmaceutical magazine " (J.Labelled Compd.Radiopharm.) 25 (4): 349-57,1988), amino alkylamino anthraquinone-deutero-cisplatin analog (Kitov etc., " European pharmaceutical chemistry magazine " (Eur.J.Med.Chem.) 23 (4): 381-3,1988), spiroplatin, carboplatin, iproplatin and JM40 platinum analogs (Schroyen etc. " European clinical cancer oncology magazine " (Eur.J.Cancer Clin.Oncol.) 24 (8): 1309-12,1988), the cis-platinum derivative (Orbell etc. " Chinese Journal of Inorganic Chemistry " (Inorg.Chim.Acta) 152 (2): 125-34,1988) that contains the bidentate tertiary diamine, platinum (II), platinum (IV) (Liu ﹠amp; Wang, " Shandong Medical University's journal) " (Shandong Yike DaxueXuebao) 24 (1): 35-41,1986), cis-diamidogen (1, the 1-cyclobutane dicarboxylic acid-) platinum (II) (carboplatin, JM8) and (JM40) (Begg etc. of ethylenediamine-malonic acid platinum (II), " tumor radiotherapy " (Radiother.Oncol.) 9 (2): 157-65,1987), JM8 and JM9 cisplatin analog (Harstrick etc., Int.J.Androl.10 (1); 139-45,1987), (NPr4) 2 ((PtCL4). cis-(PtCl2-(NH2Me) 2)) (Brammer etc., " chemical association and chemical communication magazine " be 6:443-5 (J.Chem.Soc.Chem.Commun.), 1987), aliphatic tricarboxylic acids platinum complex (EPA 185225) and cis-dichloro (aminoacid) (tert-butylamine) platinum (II) complex (Pasini ﹠amp; Bersanetti, " Chinese Journal of Inorganic Chemistry " (Inorg.Chim.Acta) 107 (4): 259-67,1985).Think that these chemical compounds by working in conjunction with DNA, promptly play the alkylating agent of DNA.

The dosed administration of therapeutic agent

As described herein, multiple compositions and implant can be used for the treatment of diverticulum disease.Because make medical implant and compositions with multiple structure, form and size, thus definite dosage of therapeutic agent with size, the surface area of implant, the difference of the part of design and applied implant and changing.In addition, when the total amount of the medicine of determining to be administered to the host and material, can consider the number and the size of the diverticulum that exists.Yet some principle can be applied in the application of this area.With medication dose calculation is the function of the dosage on the per unit area (for example, the part of the implant of coating), can measure the total drug dose of using, and can measure the surface concentration of suitable active medicine.No matter whether the method for medicament administration in compositions or be applied to medical implant, should give to use separately under following administration guideline or the anticarcinogen/anti-infective described herein of coupling.

(a) anthracycline. the doxorubicin in the anthracycline is used as example, no matter be, mix in the polymer that constitutes the implant component as the polymer coating coating, still be with or without carrier polymer and use, the accumulated dose that is coated on the doxorubicin on the implant preferably is no more than 25mg (in the scope of 0.1 μ g-25mg).In particularly preferred embodiments, the coated drug total amount is in 1 μ g-5mg scope.Dosage on the per unit area (medication amount of the function of the surface area of the implant part that promptly is coated with and/or mixes as medicine) is at 0.01 μ g-100 μ g/mm ²The scope of surface area.In another particularly preferred embodiment, with 0.1 μ g/mm ²-10 μ g/mm ²Dosage doxorubicin is coated on the diverticulum surface.Because different implants will discharge doxorubicin with different rates, thus preferably above-mentioned administration parameter and the medicine rate of release from implant surface is used in combination, so that keep 10 on described surface ^-7-10 ^-4The doxorubicin least concentration of M.Preferably, lip-deep drug level surpasses known multiple bacterioid and the lethal doxorubicin concentration of fungus of making and (promptly surpasses 10 ^-4M), although with regard to some embodiments, lower concentration is just enough.In preferred embodiments, doxorubicin discharges so that anti-infection activity is kept several hours time limits to some months from implant surface.In particularly preferred embodiments, medicine discharges with valid density in month time limit in 1 week-6.Analog and derivant (as mentioned above) with the active doxorubicin of identity function also can be used for purpose of the present invention; The relative potency of comparing with parent compound according to analog or derivant is adjusted above-mentioned administration parameter (for example double the chemical compound of doxorubicin effect with half of above-mentioned parameter, to give effect be half chemical compound etc. of doxorubicin to double above-mentioned parameter) then.

With mitoxantrone another example as anthracycline, no matter be as the polymer coating coating, mix in the polymer that constitutes implant, or with or be coated with without carrier polymer, the accumulated dose of the mitoxantrone of application preferably is no more than 5mg (in the scope of 0.01 μ g-5mg).In particularly preferred embodiments, the medicine total amount of application is in 0.1 μ g-1mg scope.Dosage on the per unit area medication amount of the function of the surface area of medicinal application and/or the implant of mixing part (promptly as) is at 0.01 μ g-20 μ g/mm ²The scope of surface area.In particularly preferred embodiments, should be with 0.05 μ g/mm ²-3 μ g/mm ²Dosage mitoxantrone is applied in the diverticulum surface.Because different implants will discharge mitoxantrone with different rates, preferably above-mentioned administration parameter is used in combination with the rate of release of medicine from implant surface, so that keep 10 ^-5-10 ^-6The mitoxantrone least concentration of M.Preferably, the drug level on the implant surface surpasses known multiple bacterioid and the lethal mitoxantrone concentration of fungus of making and (promptly surpasses 10 ^-5M), although with regard to some embodiment, lower levels of drugs is just enough.In one embodiment, mitoxantrone discharges so that anti-infection activity is kept several hours time limits to some months from implant surface.In another embodiment, medicine discharges with valid density in month time limit in 1 week-6.Based on disclosure provided herein, analog and derivant (as mentioned above) with the active mitoxantrone of identity function can be used for method and composition of the present invention; The relative potency of comparing with parent compound according to analog or derivant (is for example adjusted above-mentioned administration parameter then, double the chemical compound of mitoxantrone effect with half of above-mentioned parameter, to give effect be half chemical compound etc. of mitoxantrone to double above-mentioned parameter).

(b) fluorine pyrimidine. the 5-fluorouracil in the fluorine pyrimidine is used as example, no matter be as polymer coating use, mix the polymer that constitutes implant, or with or without the carrier polymer application, the accumulated dose of the 5-fluorouracil of coating preferably is no more than 250mg (in the scope of 1.0 μ g-250mg).In particularly preferred embodiments, the coated drug total amount is in 10 μ g-25mg scopes.The dosage of per unit area (medication amount of the function of the surface area of the implant part that promptly is coated with and/or mixes as medicine) is at 0.1 μ g-1mg/mm ²The scope of surface area.In one embodiment, with 1.0 μ g/mm ²-50 μ g/mm ²Dosage 5-fluorouracil is coated on diverticulum or implant surface.Because different implants will discharge 5-fluorouracil with different rates, thus above-mentioned administration parameter can be used in combination with the rate of release of medicine from implant surface, so that keep 10 ^-4-10 ^-7The 5-fluorouracil least concentration of M.Preferably, lip-deep drug level surpasses known multiple bacterioid and the lethal 5-fluorouracil concentration of fungus of making and (promptly surpasses 10 ^-4M), although with regard to some embodiment, lower levels of drugs is just enough.In another embodiment, 5-fluorouracil discharges so that anti-infection activity is kept several hours time limits to some months from implant surface.In another embodiment, medicine discharges with valid density in month time limit in 1 week-6.Can use analog and derivant (as mentioned above) with the active 5-fluorouracil of identity function.The relative potency of comparing with parent compound according to analog or derivant is adjusted above-mentioned administration parameter (promptly double the chemical compound of 5-fluorouracil effect with half of above-mentioned parameter, to give effect be half chemical compound etc. of 5-fluorouracil to double above-mentioned parameter) then.

(c) podophyllotoxin. the etoposide in the podophyllotoxin is used as example, no matter be as the polymer coating coating, mix the polymer that constitutes implant, or with or be coated with without carrier polymer, the accumulated dose of the etoposide of coating preferably is no more than 25mg (in the scope of 0.1 μ g-25mg).In particularly preferred embodiments, the coated drug total amount is in 1 μ g-5mg scope.Dosage on the per unit area (medication amount of the function of the surface area of the implant part that promptly is coated with and/or mixes as medicine) is at 0.01 μ g-100 μ g/mm ²The scope of surface area.In one embodiment, with 0.1 μ g/mm ²-10 μ g/mm ²Dosage etoposide is coated on the diverticulum surface.Above-mentioned administration parameter should be used in combination with the rate of release of medicine from implant surface, so that keep 10 ^-5-10 ^-6The etoposide concentration of M.Must guarantee that surface drug concentration surpasses known multiple bacterioid and the lethal etoposide concentration of fungus of making and (promptly surpasses 10 ^-5M; Although with regard in some embodiment, lower levels of drugs is just enough).In one embodiment, etoposide discharges so that anti-infection activity is kept several hours time limits to some months from implant surface.In another embodiment, medicine discharges with valid density in month time limit in 1 week-6.Based on description provided herein, analog and derivant (as mentioned above) with the active etoposide of identity function can be used for compositions described herein and method.The relative potency of comparing with parent compound according to analog or derivant is adjusted above-mentioned administration parameter (promptly double the chemical compound of etoposide effect with half of above-mentioned parameter, to give effect be half chemical compound etc. of etoposide to double above-mentioned parameter) then.

(d) hemorrhage.Utilize CoStasis  as exemplary hemorrhage, no matter it applies, mixes in the polymer that constitutes implant, applies, still is coated to tissue as implant as polymer coating, as implant or send from implant or compositions, or be coated to CoStasis  cumulative volume on implant or the tissue surface, preferably be no more than 25mL (scope of 0.2mL to 25mL).In one embodiment, the total amount of the CoStasis  in compositions or the implant is within 0.5mL to 15mL scope.In another embodiment, the amount of the implant of per unit area or tissue (that is, as apply and/or in conjunction with its implant or the amount of the CoStasis  of the function of the surface area of the part of tissue) is at 0.01mL-5.0mL/cm ²In the scope of the surface area of coating.In another embodiment, with CoStasis  with 0.1mL/cm ²-0.5mL/cm ²The long-pending dosage of coated surfaces be coated on implant or the tissue surface.Be included at one or more pharmacological agents under the situation of described compositions, CoStasis  can discharge such pharmacologically active agents with different rates, thereby, above-mentioned dosed administration parametric optimization be used in combination from the release rate of drugs of compositions or implant so that the pharmacologically active agents of the 0.01nm-1000 μ M of Cmin is delivered to described tissue.In one embodiment, from the implant surface release reagent, so that with the time limit in the promotion of the fibre modification in diverticulum a few hours to the several months scope.In another embodiment, from the implant surface release reagent, so that bacterial growth is suppressed time limit in a few hours to the several months scope.For example, reagent can be discharged the time limit of 1 hour-30 days scopes with valid density.The relative potency of comparing with the parent pharmacologically active agents according to the analog or the derivant of pharmacologically active agents, analog or derivant for the component of CoStasis  or compositions, adjust above-mentioned CoStasis  administration parameter (for example give the chemical compound of twice effect with half of above-mentioned parameter, to give effect be chemical compound of half etc. to double above-mentioned parameter).

Utilize Tisseel  as exemplary hemorrhage, no matter it applies, mixes in the polymer that constitutes implant, applies, still is coated to tissue as implant as polymer coating, as implant or send from implant or compositions, or be coated to Tisseel  cumulative volume on implant or the tissue surface, preferably be no more than 25mL (scope of 0.2mL to 25mL).In one embodiment, the total amount of the Tisseel  in compositions or the implant is within 0.5mL to 15mL scope.In another embodiment, the amount of the implant of per unit area or tissue (that is, as apply and/or in conjunction with its implant or the amount of the Tisseel  of the function of the surface area of the part of tissue) is at 0.01mL-5.0mL/cm ²In the scope of the surface area of coating.In another embodiment, with Tisseel  with 0.1mL/cm ²-0.5mL/cm ²The long-pending dosage of coated surfaces be coated on implant or the tissue surface.Under one or more pharmacological agents are included in situation in the described compositions, Tisseel  can discharge such pharmacologically active agents with different rates, thereby, above-mentioned dosed administration parametric optimization be used in combination from the release rate of drugs of compositions or implant so that the pharmacologically active agents of the 0.01nM-1000 μ M of Cmin is delivered to described tissue.In one embodiment, from the implant surface release reagent, so that with the time limit in the promotion of the fibre modification in diverticulum a few hours to the several months scope.In another embodiment, from the implant surface release reagent, so that bacterial growth is suppressed time limit in a few hours to the several months scope.For example, reagent can be discharged the time limit of 1 hour-30 days scopes with valid density.The relative potency of comparing with the parent pharmacologically active agents according to the analog or the derivant of pharmacologically active agents, analog or derivant for the component of Tisseel  or Tisseel , adjust above-mentioned Tisseel  administration parameter (for example give the chemical compound of twice effect with half of above-mentioned parameter, to give effect be chemical compound of half etc. to double above-mentioned parameter).

Utilize FloSeal  as exemplary hemorrhage, no matter it applies, mixes in the polymer that constitutes implant, applies, still is coated to tissue as implant as polymer coating, as implant or send from implant or compositions, or be coated to FloSeal  cumulative volume on implant or the tissue surface, preferably be no more than 25mL (scope of 0.2mL to 25mL).In one embodiment, the total amount of the FloSeal  in compositions or the implant is within 0.5mL to 15mL scope.In another embodiment, the amount of the implant of per unit area or tissue (that is, as apply and/or in conjunction with its implant or the amount of the FloSeal  of the function of the surface area of the part of tissue) is at 0.01mL-5.0mL/cm ²In the scope of the surface area of coating.In another embodiment, with FloSeal  with 0.1mL/cm ²-0.5mL/cm ²The long-pending dosage of coated surfaces be coated on implant or the tissue surface.Under one or more pharmacological agents are included in situation in the described compositions, FloSeal  can discharge such pharmacologically active agents with different rates, thereby, above-mentioned dosed administration parametric optimization be used in combination from the release rate of drugs of compositions or implant so that the pharmacologically active agents of the 0.01nM-1000 μ M of Cmin is delivered to described tissue.In one embodiment, from the implant surface release reagent so that with the fibre modification in the diverticulum promote in a few hours to the several months scope during.In another embodiment, from the implant surface release reagent so that with bacterial growth suppress in a few hours to the several months scope during.For example, can with reagent with valid density discharge 1 hour-30 days scopes during.The relative potency of comparing with the parent pharmacologically active agents according to the analog or the derivant of pharmacologically active agents, for its analog or derivant, can adjust above-mentioned FloSeal  administration parameter (for example give the chemical compound of twice effect with half of above-mentioned parameter, to give effect be chemical compound of half etc. to double above-mentioned parameter).

Utilize CoSeal  as exemplary hemorrhage, no matter it applies, mixes in the polymer that constitutes implant, applies, still is coated to tissue as implant as polymer coating, as implant or send from implant or compositions, or be coated to CoSeal  cumulative volume on implant or the tissue surface, preferably be no more than 30mL (scope of 0.2mL to 30mL).In one embodiment, the total amount of the CoSeal  in compositions or the implant is within 0.5mL to 15mL scope.In another embodiment, the amount of the implant of per unit area or tissue (that is, as apply and/or in conjunction with its implant or the amount of the CoSeal  of the function of the surface area of the part of tissue) is at 0.01mL-5.0mL/cm ²In the scope of the surface area of coating.In another embodiment, with CoSeal  with 0.1mL/cm ²-0.5mL/cm ²The long-pending dosage of coated surfaces be coated on implant or the tissue surface.Under one or more pharmacological agents are included in situation in the described compositions, CoSeal  can discharge such pharmacologically active agents with different rates, thereby, above-mentioned dosed administration parametric optimization be used in combination from the release rate of drugs of compositions or implant so that the pharmacologically active agents of the 0.01nM-1000 μ M of Cmin is delivered to described tissue.In one embodiment, from the implant surface release reagent so that with the fibre modification in the diverticulum promote in a few hours to the several months scope during.In another embodiment, from the implant surface release reagent so that with bacterial growth suppress in a few hours to the several months scope during.For example, can with reagent with valid density discharge 1 hour-30 days scopes during.The relative potency of comparing with the parent pharmacologically active agents according to the analog or the derivant of pharmacologically active agents, derivant or analog for the physiologically active agent of CoSeal , adjust above-mentioned CoSeal  administration parameter (for example give the chemical compound of twice effect with half of above-mentioned parameter, to give effect be chemical compound of half etc. to double above-mentioned parameter).

According in disclosure provided herein, anthracycline (for example, doxorubicin or mitoxantrone), fluorine pyrimidine (for example, 5-fluorouracil), antifol are (for example, the combination of methotrexate and/or podophyllotoxin (for example, etoposide) can be used for strengthening the antibacterial activity of diverticulum implant.Similarly, anthracycline (for example, doxorubicin or mitoxantrone), fluorine pyrimidine (for example, 5-fluorouracil), antifol are (for example, methotrexate) and/or the combination of podophyllotoxin (for example, etoposide) can combine to strengthen effect with traditional antibiotic and/or antifungal.In another embodiment, described anti-infective can also form agent and/or hemorrhage with fibrous tissue and combines and be used for the acute diverticulitis of integrated treatment.

Be used to produce the compositions that comprises the fibre modification derivant and the method for medical implant

Medicine applies, medicine implant dipping or that contain medicine here is provided, and described implant is induced in diverticulum and is adhered to or fibre modification, or promotes with scar tissue or fibre modification tissue in situ " filling " diverticulum capsule.In multiple embodiments, induce fibre modification by local or regional release of specific pharmacological agents, described pharmacological agents is at the diverticulum internal fixation.Can utilize many methods to be used to optimize the fibre modification derivant, and in these several are described below to the sending of diverticulum.

Contain or discharge the implant of fibre modification derivant

Medical implant contains and/or is suitable for to discharge the reagent of inducing fibre modification or adhering to surrounding tissue as described herein.By following method, medical implant can be suitable for the fibre modification derivant is attached in their structure, be suitable for having the face coat of fibre modification derivant and/or be suitable for discharging the fibre modification derivant: (a) directly required fibre modification derivant or the compositions that contains the fibre modification derivant are fixed to described implant (for example, by the described medical implant of spraying with medicine and/or carrier (polymeric or non-polymeric)-pharmaceutical composition with generation film or coating on the inside of described implant or outer surface all or part of; By implant being immersed medicine and/or carrier (polymeric or non-polymeric)-drug solution to apply all or part of of described implant; Perhaps by other covalently or non-covalently (for example, mechanically adhere to, or use binding agent or heat treatment, electrostatic, ionic, hydrogen bond or hydrophobic interaction) via knotting therapeutic agent is attached to implant surface); (b) by using the material coating medical implant such as hydrogel, described hydrogel can absorb required fibre modification derivant or compositions again; (c) (for example interweave in medical implant by " line " that will comprise or scribble the fibre modification derivant, by the polymeric twisted wire of inducing fibrotic material to form (for example, silk, collagen, EVA, PLA, polyurethane, polymeric pharmaceutical composition) or comprise and/or discharge the polymer of fibre modification derivant from described line); (d) by with containing the fibre modification derivant all or part of implant of sleeve, covering or mesh covered of (that is, comprising the covering of fibre modification derivant-polymer) such as the silk, collagen, EVA, PLA, polyurethane or the polymeric compositions that contain the fibre modification derivant; (e) with required reagent or compositions (for example, constituting described implant) from polymer such as the polymeric compositions of silk, collagen, EVA, PLA, polyurethane or fibre modification derivant; (f) flood described implant in addition with required fibre modification derivant or compositions; (g) scratch on implant surface all or part of (that is, producing ridge or impression) thus produce the stimulation of described tissue and finally cause fibre modification; (h) described implant is all or part of by inducing fibrotic metal alloy (for example, copper) to form; (i) make up all or part of of described implant itself from degradable or the nondegradable polymer that discharges one or more fibre modification derivants; (j) use the multiple medicines thing release medical implant system of specialization (to be described in U.S. Patent number .6,562,065; Application No. 2003/0199970 and 2003/0167085; With in PCT publication number WO03/015664 and WO 02/32347) send the fibre modification derivant alone or in combination.

Filler. in one embodiment, implant is or comprises filler.Filler refers to separately or is used in combination with sealing partially or completely with another kind of material (for example, polymer) or fills space (for example, diverticulum) among the host or liquid, solid or the semi-solid composition in chamber.Can directly be coated to filler in the therapentic part or can be injected into directly and center in the tissue of area for treatment.Filler also refers to and experiences chemical reaction, precipitation or crystalline chemical compound and mixture in position, and described filler can partially or completely seal or fill space or the chamber in the host.Filler can be used for increasing volume, extends, or dilutes other solid.Filler can have fixed volume or can increase on volume when it contacts with body fluid among the host and begins swelling.According to the method for using, filler can be the form of injectable form (for example, solution, gel, paste, etc.) or implant.For example, described filler can be the form of three-dimensional body, such as, film, mesh, microsphere, pearl or other shape).In certain embodiments, described filler can make up to promote described reagent to be delivered among the host with polymeric compositions (for example, gel or hydrogel).

The representative instance of filler comprises inorganic material such as mineral, glass, and pottery is (for example, that grind and pottery and glass powder), clay, calcium carbonate, magnesium carbonate, Pumex, Talcum, zinc oxide, hydroxyapatite, corn starch, cellulose, timber (for example, sawdust), naturally occurring material is such as bone, leather, angle, hair, the multiple protein material, such as collagen and the material that contains collagen (for example, the injectable product of collagen base comprises by non--Niu the people, or recombinant sources obtain those), polysaccharide (for example, hyaluronic acid) and synthetic polymer is (for example, the ethylene vinyl alcohol polymer implant, acrylate, methacrylate, acrylic acid, polydimethylsiloxane, siloxanes, etc.).

Can be combined for the filler that the treatment diverticulitis is used with one or more fibre modification derivants described herein.Filler includes but not limited to, is purchased the injectable product of product such as the collagen base, comprise by non--Niu, the people, or recombinant sources obtain those; From this pharmaceuticals of Aunar (ArtesMedical, Inc.) (Santiago (San Diego), Injectable microspheres body CA); ENTERYX (from the ethylene vinyl alcohol polymer implant of Boston technology Corp (Boston Scientific Corporation)); The gel of hydroxyapatite load (COAPATITE, from biotype pharmaceuticals (BioFormMedical, Inc.) Sheng Mateao (San Mateo), CA); Micronized alloderm acellular substrate (CYMETRA, from biological cell company (LifeCell Corporation), Branchburg, NJ); The stable hyaluronic acid of non-animal (from NASHA and the DEFLUX of Q-Med); Microballon (the DURASPHERE that contains the RESEARCH OF PYROCARBON coating in the hydrogel of beta glucan, from card (the Carbon Medical Technologies of this medical technology company, Inc.) Sao Paulo (St.Paul) MN and Boston technology Corp (Boston Scientific Corporation), Nei Dike (Natick), MA); The collagen fiber of transforming (organ generation company (Organogenesis, Inc.), Canton, MA); Hylan polymer (from the HYLAGEL URO of Genzyme); From Uroplasty, Inc. (Minneapolis (Minneapolis), MACROPLASTIQUE MN) (polydimethylsiloxane in the hydrogel carrier); Microsphere (for example, the acrylic acid pearl, such as can obtain from biosphere medical company (BiosphereMedical, Inc.), Ma Er Greensboro (Marlborough), Massachusetts (MA)) those; Contain silk and the proteinic urethra filler of elastin laminin (protein polymer technology company (Proteinpolymer Technologies), Santiago (San Diego), California (CA)); The crosslinked silicon microsphere of filling with biocompatible polymer (UROVIVE, from U.S.'s medical system (AmericanMedical Systems), Ming Neitongka (Minnetonka), MN); With from Micro Therapeutics (Microtherapeutics, Inc.), holy Clement (San Clemente), California (CA) and lucky Knicks medical company (Genyx Medical, Inc.), Aliso Viejo, the URYX filler and the Embolyx of California (CA).The manufacturer of other the carrier that is suitable for using in filled compositions comprises the (CR.Bard of CR. The Budd Co., Inc.) (mountain (Murray Hill) in silent, New Jersey (NJ)), (the Collagenesis of collagen company, Inc.) (Acker pause (Acton), Massachusetts (MA)), U.S.'s medical system (American Medical Systems), Men Te (Mentor), (the Nuo Wude (Norwood) of Ou Meiwen company (UromedCorporation), Massachusetts (MA)), Boston technology Corp (BostonScientific Corporation), (the Johnson ﹠amp of Johson ﹠ Johnson; Johnson) this Kanggong department of dust (Ethicon, Inc.), Cook group company (Cook Group, Inc.) (Bloomington (Bloomington), Indiana (IN)), (W.L.Gore of Ge Er affiliated company; Associates) and SURx company (SURx, Inc). (Pleasonton, California (CA)).

Fibre modification derivant regionality and part are delivered to diverticulum

Multiple medicine delivery technique can be used for regional and local delivering therapeutic agents.In these technology several can be suitable for realizing the fibre modification derivant of preferential elevated levels within diverticulum, comprise: (a) utilize part or regional delivery fibrous tissue to form agent and (usually, under endoscope or radioactivity guiding, drug delivery tube is advanced to the opening that arrives at diverticulum in the tissue up to them to the drug delivery tube in the diverticulum; Can discharge with high local concentrations that fibrous tissue forms agent so that the medicine of therapeutic dose is delivered to diverticulum from catheter lumen then); (b) medicine location technology such as magnetic, medicine hyperacoustic or the MRI-guiding is sent; (c) chemical modification of design inductive medicine of fibre modification or preparation, being used for increasing the reagent that enters into diverticulum (for example absorbs, modified medicaments or preparation are to comprise the antibody at component of organization damage or treatment, the component of component of organization such as macrophage described damage or treatment, neutrophil cell, smooth muscle cell, fibroblast, extracellular matrix components, fibrin, coagulation cascade); (d) chemical modification of fibrotic medicine or preparation is induced in design, is used for medicine is navigated to hemorrhage zone or disruptive vascular system, such as the liposome that drug encapsulation is arrived the site orientation; And/or (e) microgranule silk and/or silk thread (silk strand) (for example, linear, ramose and/or coiling) also can be used for targeted delivery (via endoscope or guide catheter) in diverticulum; (f) with injectable agent for stanching such as COSTASIS ((the Angiotech Pharmaceuticals of Angiotech Pharmaceuticals, Inc that comprises collagen, Inc.), Vancouver (Vancouver), BC) or by 4-arm mercaptan PEG (10K), 4-arm NHS PEG (10K), the material made from methylated collagen (following described), or by 4-arm mercaptan PEG (10K), the material that 4-arm NHS PEG (10K) and collagen or gelatin are made, independent or loading is applied to diverticulum together with fibre modification derivant and/or anti-infective; (g) preparation that comprises PEG that sprayable original position is formed is such as COSEAL (Angiotech Pharmaceuticals, Inc, Canada), FOCALSEAL (builds the company of praising (Genzyme Corporation), Cambridge (Cambridge), Massachusetts (MA)), SPRAYGEL or DURASEAL are (from converging (the ConfluentSurgical of surgery company, Inc.), Waltham (Waltham), Massachusetts (MA)) separately or load with fibre modification derivant and/or anti-infective and/or hemorrhage and be applied to diverticulum together; (h) will comprise preparation such as the FLOSEAL of fibrinogen or TISSEAL (all from Irving Baxter health care company (Baxter Healthcare Corporation); Freemont (Fremont), California (CA)), independent or loading is applied to diverticulum together with fibre modification derivant and/or anti-infective; (i) comprise hyaluronic preparation (noncrosslinking, crosslinked or chemical modification) such as PERLANE or RESTYLANE (all from Q-medicine AB company (Q-Med AB), Sweden), HYLAFORM (Yin Aimude company (Inamed Corporation); Santa Barbara (Santa Barbara), California (CA)), SYNVISC (bio-matrix company (Biomatrix, Inc.); Ridgefied, New Jersey (NJ)), SEPRAFILM or SEPRACOAT (come the self-built company (Genzyme Corporation) that praises; Cambridge (Cambridge), Massachusetts (MA)), it loads fibre modification derivant and/or anti-infective and/or hemorrhage to be applied to diverticulum; (j) be used for polymer gel such as the REPEL that surgical operation implants (life medical science company (and Life Medical Sciences, Inc.); Princeton (Princeton), New Jersey (NJ)) or FLOWGEL (Irving Baxter health care company (BaxterHealthcare Corporation), Deerfield (Deerfield), Illinois (IL)), it loads fibre modification derivant and/or anti-infective and/or hemorrhage to be applied to diverticulum; (k) (for example will comprise one or more cyanoacrylate monomers, methyl 2-cyanoacrylate, cyanacrylate, Tisuacryl, octyl 2-cyanoacrylate, alpha-cyanoacrylate methoxyl group propyl ester) surgical operation adhesive such as the DERMABOND ((Johnson of Johson ﹠ Johnson; Johnson, Inc.)), INDERMIL (U.S.'s surgery (United States Surgical); Norwalk (Norwalk), Connecticut (CT)), GLUSTITCH (black lock Therapy Products Inc. (Blacklock Medical Products, Inc.), Canada) or TISSUMEND II (veterinary products laboratory (Veterinary Products Laboratories); Phoenix (Phoenix), AZ), VETBOND (3M company (3M Company); Sao Paulo (St.Paul), Minnesota (MN)), TISSUEMEND (TEI Biological Science Co., Ltd (TEIBiosciences, Inc.); Boston (Boston), Massachusetts (MA)), HISTOACRYL or HISTOACRYL BLUE (Davis and the (Davis of Ge Ke company; Geck); St. Louis (St.Louis), Missouri (MO)) and ORABASE SOOTHE-N-SEAL LIQUIDPROTECTANT (Colgate-Palmolive Company (Colgate-Palmolive Company); New York (NewYork); New York (NY)), separately or load with fibre modification derivant and/or anti-infective and/or hemorrhage and be applied to diverticulum together; (I) loading is with the tissue filling agent of other biocompatibility of fibre modification derivant and/or anti-infective and/or hemorrhage, such as by (the BioCure of Biotherapeutics company, Inc.) (nox (Norcross), Georgia (GA)), 3M company (3M Company) and Buddhist nun's Ormond (Neomend of company, Inc.) those of (Sani Wei Er (Sunnyvale), California (CA)) making are administered to diverticulum with it; (m) gel of polysaccharide gel such as ADCON series (Greer technology company (and Gliatech, Inc.); Cleveland (Cleveland), Ohio (OH)), separately or load with fibre modification derivant and/or anti-infective and/or hemorrhage and be applied to diverticulum together; (n) film, and sponge or mesh such as INTERCEED or VICRYL mesh (this Kanggong department of dust (Ethicon, Inc.), (a Johnson ﹠amp of Johson ﹠ Johnson; Johnson Company), Somerville (Somerville), New Jersey (NJ)), and GELFOAM ((the Pharmacia ﹠amp of Pharmacia S.P.A.; Upjohn Company); Kalamazoo (Kalamazoo), Michigan (MI)), separately or load with fibre modification derivant and/or anti-infective and/or hemorrhage and be applied to diverticulum together; (o) polymeric (noncrosslinking and crosslinked) twisted wire, fabric, fiber, granule, polymeric knitting, braiding, material non-woven or electron spray is (for example, linear, ramose and/or coiling; Hydrogel and non-aqueous gel coating) also can be used for targeted delivery (via endoscope or guide catheter) in diverticulum; (p) form Polyethylene Glycol (for example, 4-arm four-amino PEG) [10k] from aminofunctional) and the functionalized PEG (for example, tetramethylolmethane gathers (ethylene glycol) ether four-succinimido glutarate) of 4-arm NHS (10K)) hydrogel.This hydrogel can also comprise collagen, methylated collagen and/or gelatin.Other hydrogel (for example can comprise crosslinked polysaccharide, carboxymethyl cellulose, glucosan, hyaluronic acid, chitosan, alginate etc.), cross-linked hydrogel (for example, polyacrylate, polyacrylic acid, polymethylacrylic acid, poly-(hydroxyethyl meth acrylate)) based on vinyl.These hydrogels can also comprise fibre modification derivant and/or anti-infective and/or hemorrhage, and it can be applied to diverticulum.

In one embodiment, can or be administered to diverticulum with mesh or film or the insertion of other materials similar.This mesh, film or materials similar can, at least in part, fill described diverticulum.Original position sealant, glue or suppository can be used for keeping at diverticulum the position of mesh or film.In other embodiments, fibre modification derivant, anti-infective and/or hemorrhage also can be used in combination with described mesh or film.One or more reagent can be applied directly to the diverticulum tissue or be applied to each mesh or film according to method described herein.

In one embodiment, described fibre modification derivant can be delivered to diverticulum via the conduit that is inserted in the diverticulum endoscope or under the radiographic X guiding as solution.The fibre modification derivant directly can be merged in the solution so that homogeneous phase solution or dispersion to be provided.In certain embodiments, described solution is aqueous solution.Described aqueous solution can also comprise buffer salt, and viscosity modifier (for example hyaluronic acid, alginate, CMC etc.).In another aspect of the present invention, described solution can comprise biocompatible solvent, such as ethanol, and DMSO, glycerol, PEG-200, PEG-300 or NMP.

The slow release of fibre modification derivant and coating agent

For many above-mentioned therapeutic agents, the fibre modification derivant can be attached in the carrier so that can treatment level be delivered locally in the diverticulum with the sufficiently long cycle, be used for healing fully and fibre modification (several weeks are to the several months) takes place.For example, can mix required fibre modification derivant, fusion, put together, thereby or modify in addition and comprise polymer composition (it can be biodegradable or not biodegradable) or non-polymer compositions so that discharge the fibre modification derivant through cycle regular hour.For above-mentioned embodiment, can be with biodegradable and not biodegradable polymer, polymeric conjugates and non-polymeric material are used for finishing fibre modification derivant, hemorrhage and/or anti-infective and are delivered locally to diverticulum.

Be suitable for the fibre modification derivant, the representational example that hemorrhage and/or anti-infective are delivered to the Biodegradable polymeric in the diverticulum comprises albumin, collagen, gelatin, hyaluronic acid, hyaluronic aliphatic series, the ester of heteroatomic and aromatics, the derivatives of hyaluronic acids that comprises mercaptan, starch, cellulose and cellulose derivative (methylcellulose for example, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, carboxymethyl cellulose, Cellacefate, cellulose acetate succinate, Hydroxypropyl Methylcellulose Phathalate), casein, glucosan, Sensor Chip CM 5, amino-glucosan, polysaccharide, fibrinogen, based on poly-(ethylene glycol) and poly-(terephthalic acids butene esters) gather (ether-ether) segmented copolymer, (for example U.S. Patent number 6 for tyrosine-derived polycarbonate-based, 120,491), poly-(hydroxy acid), poly-(D, the L-lactide), poly-(D, L-lactide-co-glycolide), poly-(Acetic acid, hydroxy-, bimol. cyclic ester), poly-(butyric ester) Ju diethyleno dioxide ketone, poly-(alkyl carbonate) and poly-(ortho esters), polyesters, poly-(hydroxypentanoic acid) Ju diethyleno dioxide ketone, poly-(ethylene terephthalate), poly-(maleic acid), poly-(hydroxymalonic acid), poly-(acrylamide), polyanhydrides, poly-(ester-acid amide), poly-(ester-imidodicarbonic diamide), poly-(ester-urea), poly-(ester-urethanes-urea), poly-(acid anhydride-ester), poly-(acid anhydride-imidodicarbonic diamide), group of polyphosphazenes, poly-(aminoacid), poly-(alkylene oxide)-poly-(ester) block copolymer (X-Y for example, X-Y-X or Y-X-Y, wherein X is a polyalkylene oxide, Y is polyester (PLGA for example, PLA, PCL Ju diethyleno dioxide ketone and copolymer thereof) and copolymer and admixture.[generally referring to Illum, L.Davids, S.S. (eds.) " polymer in the medicine controlled releasing " (" Polymer in Controlled Drug Delivery ") Wright, Bristol, 1987; Arshady-" controlled release magazine " (J.Controlled Release) 17:1-22,1991; Pitt " International Journal of Pharmaceutical Medicine " is 59:173-196 (Int.J.Phar), and 1990; Holland etc.-" controlled release magazine " (J.Controlled Release) 4:155-0180,1986].

Be suitable for sending the fibre modification derivant, that the representational example of hemorrhage and/or the anti-infective nondegradable polymer in the diverticulum comprises is poly-(ethylene-altogether-vinylacetate) (" EVA ") copolymer, silicone rubber, acrylate copolymer [for example, polyacrylic acid, polymethylacrylic acid, polymethyl methacrylate, poly-(butyl methacrylate)], [for example gather (alkyl cyanoacrylate), poly-(ethyl cyanoacrylate), poly-(butyl cyanoacrylate), poly-(hexyl cyanoacrylate) and poly-(octyl cyanoacrylate)], polyethylene, polypropylene, polyamide-based (nylon 6,6), polyurethane (comprising hydrophilic polyurethane), poly-(ester-urethane), poly-(ether-urethane), poly-(ester-urea), poly-(carbonic ester-urethane), polyethers (poly-(oxirane), poly-(propylene oxide), polyoxyalkylene ether block copolymers such as PLURONICs and PLURONICs R and poly-(butanediol) based on oxirane and propylene oxide, polymer (the polystyrene of styrene-based, poly-(styrene sulfonic acid), poly-(styrene)-block-poly-(isobutene .)-block-poly-(styrene), poly-(styrene)-poly-(isoprene) block copolymer] and polyvinyl (polyvinylpyrrolidone, poly-(vinyl alcohol), poly-(vinylacetate phthalic acid ester) and copolymer and admixture.The polymer that is developed can also for anionic (for example alginate, carrageenan, carboxymethyl cellulose, poly-(acrylamido-2-methyl propane sulfonic acid) and copolymer thereof, poly-(methacrylic acid) and copolymer thereof and poly-(acrylic acid) and copolymer and admixture) or cationic (for example chitosan, poly-L-Lysine, polyaziridine and poly-(allyl amine)) and admixture thereof (generally referring to Dunn etc., " application polymer science magazine " (J.Applied Polymer Sci.) 50:353-365,1993; Cascone etc., " material science magazine: medicinal materials " (J.Materials Sci.Materials in Medicine) 5:770-774,1994; Shiraishi etc., " bio-pharmaceutical bulletin " (Biol.Pharm.Bull.) 16 (11): 1164-1168,1993; Thacharodi and Rao, " International Journal of Pharmaceutical Medicine " (Int ' l J.Pharm.) 120:115-118,1995; Miyazaki etc., " International Journal of Pharmaceutical Medicine " (118:257-263 of Int ' lJ.Pharm.), 1995).

Be used for aforementioned therapies agent slow release is comprised poly-(ethylene-altogether-vinylacetate) to the particularly preferred polymer support of diverticulum, cellulose esters (NC Nitroncellulose), poly-(hydroxyl-metacrylate), poly-(methyl methacrylate), poly-(ethylene-altogether-acrylic acid), poly-(vinyl pyrrolidone), polyurethanes (for example, CHRONOFLEX AL and CHRONOFLEX AR are (from (the CardioTech International of Ka Diou technology Internaional, Inc, Inc.), Wo Ben, Massachusetts (MA)) and BIONATE ((the polymer Technology Group of polymer technology group limited company, Inc.), Emeryville, CA), poly-(D, L-lactic acid) oligomer and polymer, poly-(L-lactic acid) oligomer and polymer, poly-(glycolic), the copolymer of lactic acid and glycolic, poly-(caprolactone), poly-(valerolactone), polyanhydrides, poly-(acid anhydride ester), poly-(ester-acid amide), poly-(ester-urea), the copolymer of poly-(caprolactone) or poly-(lactic acid) and Polyethylene Glycol (for example MePEG), comprise and be selected from following monomeric one or more the polymer of residue: lactide, lactic acid, Acetic acid, hydroxy-, bimol. cyclic ester, glycolic, the e-caprolactone, γ-Ji Neizhi, hydroxypentanoic acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolacton, gamma-valerolactone, γ-decalactone, δ-Gui Neizhi, trimethylene carbonate, 1,4-diox-2-ketone or 1,5-cyclic heptane dioxide-2 ketone, poly-(alkylene oxide)-poly-(ester) block copolymer is (for example, X-Y, X-Y-X, Y-X-Y, R-(Y-X) _n, or R-(X-Y) _nWherein X be polyalkylene oxide (for example, poly-(ethylene glycol), the block copolymer of poly-(propylene glycol) and poly-(oxirane) and poly-(expoxy propane) (for example, from BASF AG (BASF Corporation), Mang Teaolifu (MountOlive), the polymer of the poloxamer of New Jersey (NJ) and poloxamer R series), and Y is a polyester, wherein said polyester can comprise and is selected from lactide, lactic acid, Acetic acid, hydroxy-, bimol. cyclic ester, glycolic, the e-caprolactone, γ-Ji Neizhi, hydroxypentanoic acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolacton, gamma-valerolactone, γ-decalactone, δ-Gui Neizhi, trimethylene carbonate, 1,4-diox-2-ketone or 1, monomeric one or more the residue of 5-cyclic heptane dioxide-2 ketone, silicone rubber, poly-(styrene) block-poly-(isobutene .)-block-poly-(styrene), poly-(acrylate) polymer and, the admixture of above-mentioned arbitrary substance, mixture or copolymer.Other preferred polymer comprises: collagen; Polymer based on poly-(alkylene oxide); Polysaccharide, such as the copolymer of hyaluronic acid, chitosan and fucosan and polysaccharide and degradable polymer, and above-mentioned cross-linked composition.

Other can continue local delivery fibre modification derivant, hemorrhage and/or anti-infective comprise carboxylic acid polyalcohol to the representational polymer in the diverticulum, poly-acetate esters, polyacrylamide, polycarbonate-based, polyethers, the polyethylene kind that replaces, the polyvinyl butyral resin class, polysilanes, polyureas, the polyoxide class, polystyrene type, polysulfide, polysulfones, polysulfonides, the polyvinylhalide class, pyrrolidinone compounds, isoprene rubber, thermoset polymer, crosslinkable acrylic acid and methacrylate polymer, ethylene acrylic acid co polymer, styrene acrylic copolymer, vinyl acetic acid ester polymer and copolymer, vinyl acetal polymer and copolymer, epoxy, melamine, other amino resins, phenol polymer and copolymer thereof, the water-insoluble cellulose ester polymer (comprises cellulose-acetate propionate, cellulose acetate, NC Nitroncellulose, cellulose acetate-butyrate, celluloid, Cellacefate and composition thereof), polyvinylpyrrolidone (pvp), polyethylene glycols, poly(ethylene oxide), polyvinyl alcohol, polyethers, acrylic polyol, glucosan, xanthan gum, hydroxypropyl cellulose, methylcellulose and N-vinyl pyrrolidone, the N-vinyl lactam, the N-vinyl butyrate lactam, the N-caprolactam, other has the homopolymer and the copolymer of the vinyl compound of polarity side group, the acrylate and the methacrylate that have hydrophilic esterification group, hydroxy acrylate and acrylic acid and combination thereof; The homopolymer and the copolymer of cellulose esters and ethers, ethyl cellulose, NC Nitroncellulose, hydroxyethyl-cellulose, celluloid, cellulose acetate, cellulose acetate-butyrate, cellulose-acetate propionate, polyacrylate, natural and synthetic elastomer, acetal, styrene polybutadiene, acrylic resin, polyvinylidene chloride, Merlon, vinyl compound, polrvinyl chloride and polyvinyl chloroacetate (polyvinylchloride acetate).

The representational example of the patent relevant with drug delivery polymer and preparation thereof comprises: PCT publication number WO 98/19713, WO 01/17575, WO 01/41821, WO 01/41822 and WO01/15526 (and corresponding U. S. application); With U.S. Patent number 4,500,676,4,582,865,4,629,623,4,636,524,4,713,448,4,795,741,4,913,743,5,069,899,5,099,013,5,128,326,5,143,724,5,153,174,5,246,698,5,266,563,5,399,351,5,525,348,5,800,412,5,837,226,5,942,555,5,997,517,6,007,833,6,071,447,6,090,995,6,106,473,6,110,483,6,121,027,6,156,345,6,214,901,6,368,611,6,630,155,6,528,080, RE37,950,6,46,1631,6,143,314,5,990,194,5,792,469,5,780,044,5,759,563,5,744,153,5,739,176,5,733,950,5,681,873,5,599,552,5,340,849,5,278,202,5,278,201,6,589,549,6,287,588,6,201,072,6,117,949,6,004,573,5,702,717,6,413,539 and 5,714,159,5,612,052; With U.S. Patent Application Publication No. 2003/0068377,2002/0192286,2002/0076441 and 2002/0090398.

Polymer as described herein can also be formed suitable fusion or copolymerizationization according to fibre modification derivant, hemorrhage and/or the anti-infective of delivery treatments dosage to the required difference of diverticulum.

The polymer support that is used for fibre modification derivant, hemorrhage and/or anti-infective can be made the various forms that has required release characteristics and/or have special properties.For example, the form that polymer support can be formed in contact certain trigger situation, can discharge therapeutic agent during such as pH (for example, referring to Heller etc. the drug delivery system of main regulation " chemically from " (" ChemicallySelf-Regulated Drug Delivery Systems "), in " the polymer III in the medicine " (Polymer inMedicine III), Elsevier Science Publishers B.V, Amsterdam, 1988, pp.175-188; Kang etc., " journal of applied " (J Applied PolymerSci.) 48:343-354,1993; Dong etc. " controlled release magazine " (J.Controlled Release) 19:171-178,1992; Dong and Hoffman, R " controlled release magazine " (J.Controlled Release) 15:141-152,1991; Kim etc. " controlled release magazine " (J.Controlled Release) 28:143-152,1994; Comejo-Bravo etc., " controlled release magazine " (J.Controlled Release) 33:223-229,1995; Wu and Lee " drug research " (Pharm.Res.) 10 (10): 1544-1547,1993; Serres etc. " drug research " (Pharm.Res.) 13 (2): 196-201,1996; Peppas " ultimate principle of pH-and thermal sensitivity delivery system " (" Fundamentals of pH-and Temperature-Sensitive DeliverySystems "), in (eds.) such as Gumy " beat and pass medicine " (Pulsatile Drug Delivery), Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart, 1993, pp.41-55; Doelker " cellulose derivative " (" Cellulose derivatives ") 1993, at (Biopolymer) I of Peppas and Langer (eds.) " biopolymer ", Springer-Verlag, Berlin) in.The example of representational pH-sensitive polymer comprises: poly-(acrylic acid) and derivant thereof (comprise that homopolymer for example is such as poly-(amino carboxylic acid); Poly-(acrylic acid); Poly-(methacrylic acid); The copolymer of this class homopolymer; With poly-(acrylic acid) with such as the copolymer of aforesaid acryl monomer.Other pH sensitive polymer comprises: polysaccharide, such as Cellacefate; Hydroxypropyl Methylcellulose Phathalate; HPMC-AS; Acetic acid benzenetricarboxylic acid cellulose; And chitosan.Other pH sensitive polymer comprises any mixture of pH sensitive polymer and water-soluble polymer.

Equally, can send the fibre modification derivant by the thermosensitive polymer carrier, hemorrhage, and/or anti-infective in diverticulum (for example, referring to " are attached to and are used for the new hydrogel vagina release and the thermal sensitivity Pluronic bioadhesion polyacrylic acid backbone " such as Chen (" Novel Hydrogels of aTemperature-Sensitive Pluronic Grafted to a Bioadhesive Polyacrylic acidBackbone for Vaginal Drug Delivery "), at " control release biological active material inner seminar journal " (Proceed.Intern.Symp.Contro1.Rel.Bioact.Mater.) 22:167-168, Controlled Release Society, Inc.1995; Okano " MOLECULE DESIGN that is used for the S-R hydrogel of temporary transient controlled release " (" Molecular Design of Stimuli-ResponsiveHydrogels for Temporal Controlled Drug Delivery "), at the inner seminar journal of control release biological active material " (Proceed.Intern.Symp.Control.Rel.Bioact.Mater.) 22:111-112, Controlled Release Society is among the Inc.1995; Johnston etc. " drug research " (Pharm.Res.) 9 (3): 425-433,1992; Tung " International Journal of Pharmaceutical Medicine " (107:85-90 of Int ' lJ.Pharm.), 1994; Harsh and Gehrke, " controlled release magazine " be 17:175-186 (J.ControlledRelease), and 1991; Bae etc. " drug research " (Pharm.Res.) 8 (4): 531-537,1991; Dinarvand and D ' Emanuele " controlled release magazine " be 36:221-227 (J.ControlledRelease), and 1995; Yu and Grainger " new thermal sensitivity amphiphilic gel: poly--the N-N-isopropylacrylamide-altogether-sodium acrylate-altogether-n-N-alkyl acrylamide network structure is synthesized and materialization characterizes ", (" Novel Thermo-sensitive Amphiphilic Gels:Poly-N-isopropylacrylamide-co-sodium acrylate-co-n-N-alkylacrylamideNetwork Synthesis and Physicochemical Characterization ") is in " chemistry and bioscience development ", (Dept.of Chemical ﹠amp; Biological Sci.), Oregon Graduate Institute ofScience ﹠amp; Technology, Beaverton, OR is among the pp.820-821; Zhou and Smid " physical hydrogel of association star polymer " (" Physical Hydrogels of Associative Starpolymer "), Polymer Research Institute, at " chemical developer " (Dept.of Chemistry), College of Environmental Science and Forestry, State Univ.of New York, Syracuse, NY is among the pp.822-823; Hoffman etc. " irritant reaction hydrogel mesopore size and water ' structure ' sign " (" Characterizing Pore Sizes and Water ' Structure ' inStimuli-Responsive Hydrogels. "), Center for Bioengineering, University of Washington (Univ.ofWashington), Seattle, WA, p.828; Yu and Grainger " the cancellated thermal sensitivity swelling character of crosslinked N-N-isopropylacrylamide: cation, anion and both sexes hydrogel " (" Thermo-sensitive Swelling Behavior in Crosslinked N-isopropylacrylamideNetworks:Cationic; Anionic and Ampholytic Hydrogels "), " chemistry and bioscience development " (Dept.of Chemical ﹠amp; Biological Sci.), Oregon Graduate Institute ofScience ﹠amp; Technology, Beaverton, OR, pp.829-830; Kim etc. " drug research " (Pharm.Res.) 9 (3): 283-290,1992; Bae etc. (drug research) (Pharm.Res.) 8 (5): 624-628,1991; Kono etc. " controlled release magazine " (J.Controlled Release) 30:69-75,1994; Yoshida etc. " controlled release magazine " (J.Controlled Release) 32:97-102,1994; Okano etc. " controlled release magazine " (J.Controlled Release) 36:125-133,1995; Chun and Kim " controlled release magazine " (J.Controlled Release) 38:39-47,1996; D ' Emanuele and Dinarvand " International Journal of Pharmaceutical Medicine " (Int ' l J.Pharm.) 118:237-242,1995; Katono etc. " controlled release magazine " (J.Controlled Release) 16:215-228,1991; Hoffman " the hot reversible hydrogel that contains the bioactivator kind " (" Thermally Reversible Hydrogels Containing BiologicallyActive Species ") is at (eds.) such as Migliaresi " polymer in the medicine " (Polymer inMedicine) III, Elsevier Science Publishers B.V.Amsterdam, 1988, among the pp.161-167; Hoffman " application in treatment and diagnosis of thermally reversible polymer and hydrogel " (" Applications of Thermally Reversible Polymer and Hydrogels inTherapeutics and Diagnostics "), international symposium (Third International Symposium on Recent Advances in Drug DeliverySystems) the 3rd relevant medicine-releasing system latest developments, Salt Lake City, UT, Feb.24-27,1987, pp.297-305; Gutowska etc. " controlled release magazine " (J.Controlled Release) 22:95-104,1992; Palasis and Gehrke " controlled release magazine " (J.Controlled Release) 18:1-12,1992; Paavola etc. " drug research " (Pharm.Res.12 (12): 1997-2002,1995).

The representational example of hot glue cohesion compound and gelation temperature thereof [LCST (℃)] comprising: homopolymer, such as poly-(N-methyl N-n-propyl group acrylamide), 19.8; Poly-(N-n-propyl group acrylamide), 21.5; Poly-(N-methyl-N-isopropyl propyl group acrylamide), 22.3; Poly-(N-n-propyl methyl amide), 28.0; Poly-(N-N-isopropylacrylamide), 30.9; Poly-(N, n-diethyl acrylamide), 32.0; Poly-(N-isopropyl methyl acrylamide), 44.0; Poly-(N-cyclopropyl acrylamide), 45.5; Poly-(N-ethyl-methyl acrylamide), 50.0; Poly-(N-methyl-N-ethyl acrylamide), 56.0; Poly-(N-cyclopropyl Methacrylamide), 59.0; With poly-(N-ethyl acrylamide), 72.0.In addition; copolymer between above-mentioned by preparing (wherein) monomer or by with this class homopolymer and other water-soluble polymer, such as acryl monomer (for example acrylic acid and derivant thereof; such as methacrylic acid, acrylate and derivant thereof, such as butyl methacrylate, acrylamide and N-n-butyl acrylamide) combination prepares hot glue cohesion compound.

Other representational example of hot glue cohesion compound comprises: cellulose ether derivative, and such as hydroxypropyl cellulose, 41 ℃; Methylcellulose, 55 ℃; Hydroxypropyl emthylcellulose, 66 ℃; With poly(ethylene oxide)-polyester block copolymer of ethylhydroxyethylcellulose, structure X-Y, Y-X-Y and X-Y-X, wherein X is that poly(ethylene oxide) and Y are biodegradable polyester (for example PLG-PEG-PLG); With PLURONIC such as F-127,10-15 ℃; L-122,19 ℃; L-92,26 ℃; L-81,20 ℃; And L-61,24 ℃.

Relating to the hot glue cohesion compound and the patent of preparation thereof and the representational example of patent application comprises: U.S. Patent number 6,451,346; 6,201,072; 6,117,949; 6,004,573; 5,702,717; With 5,484,610; With PCT publication number WO 99/07343; WO 99/18142; WO03/17972; WO 01/82970; WO 00/18821; WO 97/15287; WO 01/41735; WO00/00222; With WO 00/38651.

Another representative instance of gel combination is the gel that is combined to form by chitosan soln and phosphoglyceride.

Fibre modification derivant, hemorrhage and/or anti-infective can be connected in the substrate of described polymer by inaccessible (occlusion), and it can pass through covalent bonds, or is encapsulated in the microcapsule.In some preferred embodiment of the present invention, therapeutic combination is made non-capsule, provide such as line, film and the spray of microsphere (nanometer-micron size), paste, all size.

In certain embodiments, therapeutic combination can be made any size between the 50nm-500 μ m, this depends on concrete application (diverticulum can exist with size with the multiple region of anatomy as described below).These compositionss can be the form of microsphere (porous or imporosity), microgranule and/or nano-particle.Can form these compositionss by spray drying method, polishing, coacervation, W/O (water/oil) emulsion process, W/O/W emulsion process and solvent evaporated method.In certain embodiments, these compositionss can comprise microemulsion, Emulsion, liposome and micelle.Alternatively, also be easy to this based composition is used as " spray ", it can film-forming or the tissue surface coating in implant site.Can prepare this class spray by the microsphere of various grade sizes, comprise: for example 0.1 μ m-3 μ m, 10 μ m-30um and 30 μ m-100 μ m, and it is desirable to send via the delivery port of endoscope.

Therapeutic combination of the present invention can also be prepared into various pastes or gel form.For example, in one embodiment of the invention, such therapeutic combination is provided, its under a kind of temperature for liquid (for example temperature is higher than 37 ℃, such as 40 ℃, 45 ℃, 50 ℃, 55 ℃ or 60 ℃) and be solid or semisolid (for example at environment body temperature or be lower than under 37 ℃ the arbitrary temp) under the another kind of temperature.Be easy to use various technology to prepare this class " hot paste " (for example referring to PCT publication number WO 98/24427).Other paste can be used as liquid, it is gone into aqueous body environment because of the water soluble ingredient stripping of paste and encapsulated drug precipitation in vivo and solidifies in vivo.These contain fibre modification derivant, hemorrhage and/or anti-infective " paste " and " gel " and are particularly useful at ray to become mutually and endoscope is coated on the chamber of diverticulum under guiding.

Of the present invention further aspect in, provide be suitable for containing and discharge that the hydrophobic fibre degeneration is inductive, the polymer support of hemostatic and/or anti-infective chemical compound, and/or with the carrier that contains hydrophobic compound of saccharide, protein or polypeptides in combination.In certain embodiments, polymer support provides therapeutic agent (for example, the reagent of fibre modification derivant, anti-infective, antibiotic or another kind of type) from comprising carrier and combination of agents thing slow release.In some embodiment, polymer support contains or comprises zone, hole or the granule of one or more hydrophobic compounds.For example, in one embodiment of the invention, hydrophobic compound can be combined in and contain in the hydrophobicity treatment chemical compound substrate, then described substrate is combined in the polymer support.Many substrate can be used in this aspect, comprise, for example, carbohydrate and polysaccharide are such as starch, cellulose, glucosan, methylcellulose, sodium alginate, heparin, chitosan and hyaluronic acid and protein or polypeptide be such as albumin, collagen, fibrin and/or gelatin.In alternative embodiment, hydrophobic compound can be included in the hydrophobic core, and this core is included in the hydrophilic shell.

In another embodiment, being used for therapeutic agent delivery can be the material that original position forms to the polymer support of diverticulum.In one embodiment, precursor can polymerization or the monomer or the macromonomer of crosslinked unsaturated group for containing.For example, these monomers or macromonomer can be injected into the diverticulum capsule then or be injected on the diverticulum surface and use radiation source (for example visible light or UV light) or free radical system (for example potassium peroxydisulfate and ascorbic acid or ferrum and hydrogen peroxide) to carry out in-situ polymerization or crosslinked.Can be before reagent be injected into diverticulum, simultaneously or carry out polymerization or cross-linking step afterwards immediately.The representational case description of compositions that carries out radical polymerization or cross-linking reaction is at WO01/44307, WO 01/68720, WO 02/072166, WO 03/043552, WO 93/17669 and WO 00/64977; U.S. Patent number 5,900,245; 6,051,248; 6,083,524; 6,177,095; 6,201,065; 6,217,894; 6,639,014; 6,352,710; 6,410,645; 6,531,147; 5,567,435; 5,986,043; With 6,602,975; In U.S. Patent Publication No. 2002/012796,2002/0127266,2002/0151650,2003/0104032,2002/0091229 and 2003/0059906.

In another embodiment, described reagent can carry out electrophilic-necleophilic reaction and generate crosslinked substrate.End have nucleophilic group such as amine, sulfydryl, hydroxyl ,-PH ₂Or CO-NH-NH ₂Polymer can be used as nucleopilic reagent, the polymer that end has electrophilic group can be used as electrophilic reagent, described electrophilic group such as succinimido, carboxylic acid, aldehyde, epoxide, isocyanates (ester), vinyl, ethylene sulfoxide, maleimide ,-S-S-(C ₅H ₄N) or activatory ester, such as use in peptide is synthetic.For example, can under alkali condition, (pH＞about 8) make deutero-Polyethylene Glycol of 4-arm mercaptan (for example, poly-(ethylene glycol) ether four-sulfydryl of tetramethylolmethane) and the deutero-Polyethylene Glycol of 4 arm NHS-(for example poly-(ethylene glycol) ether four-succinimido glutarate of tetramethylolmethane) reaction.The representational case description of compositions that carries out this electrophilic-nucleophilic cross-linking reaction is for example: U.S. Patent number 5,752,974; 5,807,581; 5,874,500; 5,936,035; 6,051,648; 6,165,489; 6,312,725; 6,458,889; 6,495,127; 6,534,591; 6,624,245; 6,566,406; 6,610,033; 6,632,457; U.S. Patent Application Publication No. 2003/0077272A1; With title is " tissue reactive compounds and compositions and application thereof " (" Tissue Reactive Compounds andCompositions and Uses Thereof) the co-pending patent application of (U.S. serial 60/437 that December in 2002 was submitted on the 30th; U.S. serial 60/44 that on January 17th, 384 and 2003 submitted to; 924) and " from the fast gelation polymer composition, passing medicine " (" Drug Delivery from Rapid Gelling PolymerComposition ") (the U.S. serial US 60/437 that December in 2002 was submitted on the 30th; the U.S. serial US 60/440,875 of submission on January 17th, 471 and 2003).

In another embodiment, the polymer that has electrophilic or a nucleophilic end can also comprise that can increase original position forms the machinery of compositions and/or the polymer of adhesive property.This polymer can be degradable or nondegradable polymer.For example, described polymer can be collagen or collagen derivant, for example, and methylated collagen.Poly-(ethylene glycol) ether four-sulfydryl of an exemplary application tetramethylolmethane of the compositions that original position forms] (4-arm mercaptan PEG), tetramethylolmethane gathers (ethylene glycol) ether four-succinimido glutarate] (4-arm NHS PEG) and methylated collagen is as reactive reagent.When mixing with suitable reducing, said composition can produce crosslinked hydrogel.(see, for example, U.S. Patent number 5,874,500; 6,051,648; 6,166,130; 5,565,519 and 6,312,725).

In another embodiment, the material polymers of described original position formation can be a polyester.Can comprise poly-(hydroxyl ester) with the polyester in the compositions that forms in position.In another embodiment, described polyester can comprise one or more residues of monomers, and described monomer is selected from lactide, lactic acid, Acetic acid, hydroxy-, bimol. cyclic ester, glycolic, e-caprolactone, γ-caprolactone, hydroxypentanoic acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolacton, gamma-valerolactone, γ-decalactone, δ-Gui Neizhi, propylene carbonate, 1,4-diox-2-ketone or 1,5-cyclic heptane dioxide-2-ketone.The representative example of the compositions of these types is described in U.S. Patent number 5,874,500; 5,936,035; 6,312,725; 6,495,127 and PCT publication number WO 2004/028547 in.

In another embodiment, have the polymer of electrophilic end can be partially or completely by micromolecule or comprise that the oligomer of electrophilic group (for example, two succinimido glutarates) replaces.

In another embodiment, have the polymer of nucleophilic end can be partially or completely by micromolecule or comprise that the oligomer of nucleophilic group (for example, dicysteine, two lysines, three lysines etc.) replaces.

Other example that operable original position forms material comprises based on proteinic crosslinked those and (being described in, for example U.S. Patent number RE38158; 4,839,345; 5,514,379,5,583,114; 6,310,036; 6,458,147; 6,371,975; U.S. Patent Application Publication No. 2004/0063613A1,2002/0161399A1, and 2001/0018598A1, and PCT publication number WO 03/090683, WO 01/45761, among WO 99/66964 and the WO 96/03159), and those (seeing, for example PCT publication number WO 04/021983) of adding the polymer of medicated cap based on isocyanates or isothiocyanate.

First and second synthetic polymers

In one embodiment, crosslinking polymer composition (in other words, crosslinked substrate) be that first synthetic polymer by will containing two or more nucleophilic groups prepares with second synthetic polymer reaction that contains two or more electrophilic groups, wherein electrophilic group can with the nucleophilic group covalent bond.In one embodiment, right and wrong are immunogenic separately for first and second polymer.In another embodiment, described substrate is not easy to by for example matrix metalloproteinase (for example, collagenase) enzyme catalysis division, and therefore expection has the long-term persistency bigger than the compositions of collagen-Ji in vivo.

As used herein, term " polymer " " refer specifically to poly-alkyls, polyamino acid class, polyalkylene oxide class and polysaccharide.In addition, for outside or oral use, described polymer can be polyacrylic acid or carbomer.As used herein, term " synthetic polymer " refers to and is not polymer naturally occurring and that produce via chemosynthesis.Thereby, get rid of naturally occurring protein such as collagen and naturally occurring polysaccharide particularly such as hyaluronic acid.Comprise synthetic collagen and synthetic hyaluronic acid, and their derivant.The synthetic polymer that contains nucleophilic or electrophilic group is also referred to as " multifunctional activatory synthetic polymer " here.Term " multifunctional activatory " (or, " activatory " simply) refer to and have or chemical modification is to have two or more can the reaction each other with the nucleophilic that forms covalent bond or the synthetic polymer of electrophilic group (that is, nucleophilic group and electrophilic group react).The type of multifunctional activatory synthetic polymer comprises the polymer that difunctionality is activatory, four senses are activatory and star-branched.

The multifunctional activatory synthetic polymer of Shi Yonging must contain at least two in the present invention, and more preferably, at least three functional groups are so that form three-dimensional crosslinked network with the synthetic polymer that contains a plurality of nucleophilic groups (that is, " many nucleophilic polymer ").In other words, they must be that difunctionality is activatory at least, and more preferably trifunctional or four senses are activatory.If the first synthetic polymer activatory synthetic polymer that is difunctionality, then second synthetic polymer must contain three or more functional groups so that obtain three-dimensional crosslinked network.Most preferably, first and second synthetic polymers all contain at least three functional groups.

The synthetic polymer that contains a plurality of nucleophilic groups also usually is called " many nucleophilic polymer " here.For the application among the present invention, many nucleophilic polymer must contain at least two, more preferably, and at least three nucleophilic groups.If use the synthetic polymer that only contains two nucleophilic groups, then must use the synthetic polymer that contains three or more electrophilic groups so that obtain three-dimensional crosslinked network.

Preferred many nucleophilic polymer of using in the compositions and methods of the invention comprise and contain or be modified to the synthetic polymer that contains a plurality of nucleophilic groups such as primary amino radical and mercapto.Preferred many nucleophilic polymer comprise: (i) synthetic polypeptide, described polypeptide have synthesized and have contained two or more primary amino radicals or mercapto; (ii) be modified to the Polyethylene Glycol that contains two or more primary amino radicals or mercapto.Usually, mercapto is tending towards carrying out than the reaction of primary amino radical and electrophilic group with the reaction of electrophilic group slowlyer.

In one embodiment, many nucleophilics polypeptide is synthetic polypeptide, and it synthesizes and mixes amino acid residue (as lysine) that contains primary amino radical and/or the aminoacid (as cysteine) that contains sulfydryl.Especially preferably poly-(lysine), it is the polymer of the synthetic generation of amino acid lysine (145MW).Prepared and had 6 poly-(lysines) to about 4,000 primary amino radicals, molecular weight corresponding to about 870 to about 580,000.

Be used for poly-(lysine) of the present invention and preferably have about 1,000 to about 300,000 molecular weight; 5,000 to about 100,000 molecular weight more preferably from about; 8,000 to about 15,000 molecular weight most preferably from about.Poly-(lysine) of variable molecular weight can be by commercial sources from (the Peninsula Laboratories of peninsula laboratory company, Inc.) (Bel covers (Belmont), California (Calif.)) and aldrich chemicals (Aldrich Chemical) (Milwaukee (Milwaukee), winconsin (WI)) obtain.

Polyethylene Glycol can be according to for example, Poly (Ethylene Glycol) Chemistry:Biotechnical and Biomedical Applications (poly-(ethylene glycol) chemistry: biotechnology and biomedical applications), J.Milton Harris, ed.Plenum Press, the method that provides in the 22nd chapter of N.Y. (1992) contains a plurality of primary amino radicals or mercapto through chemical modification.Modified and Polyethylene Glycol that contain two or more primary amino radicals is called " polyamino PEG " in this article.Modified and Polyethylene Glycol that contain two or more mercaptos is called " many-mercapto PEG " in this article.Term used herein " Polyethylene Glycol " comprises modified or deutero-Polyethylene Glycol.

The polyamino PEG of various ways can obtain with title " Jeffamine " from sea-gull polymer (ShearwaterPolymers) (Huntsville (Huntsville), Alabama (Ala.)) with from Heng Ziman chemical company (Huntsman Chemical Company) (Utah State (Utah)) by commercial sources.Be used for polyamino PEG of the present invention and comprise Huntsman ' s Jeffamine diamidogen (" D " series) and triamine (" T " series), its each molecule contains two and three primary amino radicals respectively.

Polyamine is as ethylenediamine (H ₂N-CH ₂-CH ₂-NH ₂), tetra-methylenedimine (H ₂N-(CH ₂) ₄-NH ₂), five methylene diamine (cadaverine) (H ₂N-(CH ₂) ₅-NH ₂), hexamethylene diamine (H ₂N-(CH ₂) ₆-NH ₂), diethylenetriamine (HN-(CH ₂-CH ₂-NH ₂) ₂) and three (2-amino-ethyl) amine (N-(CH ₂-CH ₂-NH ₂) ₃) also can be as the synthetic polymer that contains a plurality of nucleophilic groups.

The synthetic polymer that contains a plurality of electrophilic groups is also referred to as " many electrophilic polymer " in this article.For being used for the present invention, multifunctional activatory synthetic polymer must contain at least two, and more preferably at least 3 electrophilic groups are so that the three-dimensional crosslinked network of formation and many nucleophilic polymer.The preferred many electrophilic polymer that are used for the present composition are to contain the polymer that can form two or more succinimidos of covalent bond with the nucleophilic group on other molecule.Succinimido with contain primary amino radical (NH ₂) material, as polyamino PEG, poly-(lysine), perhaps collagen has highly reactive.Succinimido with contain the material of mercapto (SH), have less reactive as many-mercapto PEG or the material that contains the synthetic polypeptide of a plurality of cysteine residues.

Term used herein " contains two or more succinimidos " and is intended to comprise preferably the polymer that contains two or more succinimidos that can obtain by commercial sources, and must be chemically derived to contain those polymer of two or more succinimidos.Term used herein " succinimido " is intended to comprise other variant of sulfosuccinimide base and " general " succinimido.The existence of sodium sulfite part is used to increase the dissolubility of polymer on the sulfosuccinimide base.

Hydrophilic polymer, especially multiple deutero-Polyethylene Glycol is preferred in the compositions of the present invention.Term used herein " PEG " refers to have repetitive structure (OCH ₂-CH ₂) _nPolymer.Some of PEG structures specific, four sense activated form are at United States Patent (USP) 5,874, show among Fig. 4 to 13 of 500, here with this patent in conjunction with as a reference.The example of suitable PEGS comprises PEG succinyl phosphorons amino propyl acid ester (SE-PEG), PEG succinimido butanimide (SSA-PEG) and PEG carbonic acid succinimide ester (SC-PEG).In one aspect of the invention, by with poly-(ethylene glycol) ether four-sulfydryl of tetramethylolmethane] (4-arm mercaptan PEG) and tetramethylolmethane gather (ethylene glycol) ether four-succinimido glutarate] (4-arm NHS PEG) form crosslinked substrate as the reaction reaction original position.The structure of these reactants is at United States Patent (USP) 5,874, shows in 500.Each of these materials all has core, its structure can add the deutero-residue of ethylene oxide by each hydroxyl in tetramethylolmethane, the terminal hydroxyl (derived from ethylene oxide) of deriving is then observed to contain mercapto (thereby forming 4-arm mercaptan PEG) or N-hydroxy-succinamide base (thereby formation 4-arm NHS is PEG), choose wantonly between ethylene oxide main backbone derived and reactive functional groups and have linking group, wherein this product can obtain with COSEAL from Angiotech Pharmaceuticals, Inc (Angiotech Pharmaceuticals Inc) by commercial sources.Randomly, in one or two these molecules, there is group " D ", as more going through below.

As discussed above, be used for preferred activated polyglycol derivant of the present invention and contain succinimido as reactive group.Yet, can connect different activated groups along the site of the length of PEG molecule.For example, PEG can derive the formation official can activatory PEG propionic aldehyde (A-PEG), the perhaps activatory PEG glycidyl ether of sense (E-PEG), the perhaps activatory PEG-isocyanates of sense (I-PEG), the perhaps activatory PEG-vinyl sulfone of sense (V-PEG).

Hydrophobic polymer can also be used to prepare compositions of the present invention.Be used for hydrophobic polymer of the present invention and preferably contain, perhaps can derive and contain two or more electrophilic groups, as succinimido, most preferably two, three or four electrophilic groups.Term used herein " hydrophobic polymer " refers to contain the oxygen of relative small scale or the polymer of nitrogen-atoms.

The hydrophobic polymer that has contained two or more succinimidos comprises, but be not limited to, two succinimido suberates (DSS), two (sulfosuccinimide base) suberates (BS3), dithio two (succinyl phosphorons amino propyl acid ester) (DSP), two (2-butanimide oxygen base ketonic oxygen base) ethyl sulfone (BSOCOES) and 3,3 '-dithio two (sulfosuccinimide base propionic ester) (DTSPP) and their analog and derivant.Above referenced polymer can (Rockford (Rockford), III.), respectively with catalog number (Cat.No.) 21555,21579,22585,21554 and 21577 obtain from Pierre Si (Pierce) by commercial sources.

Be used for preferred hydrophobic polymer of the present invention and have carbochain usually no longer than about 14 carbon.Polymer with the carbochain of being longer than 14 carbon in fact has very weak dissolubility in aqueous solution usually, therefore, has the very long response time when with the aqueous solution of the synthetic polymer that contains a plurality of nucleophilic groups.

Some polymer as polyprotic acid, can be derived and contains two or more functional groups, as succinimido.Be used for polyprotic acid of the present invention and include, but not limited to tricarboxylic acids based on trimethylolpropane, based on the tetrabasic carboxylic acid of two (trimethylolpropanes), 1,5-pentanedicarboxylic acid., suberic acid (suberic acid), and hexadecandioic acid (hexadecane diacid) (hexadecandioic acid (hexadecane diacid)).Many these polyprotic acid can obtain from Du Pont's chemical company (DuPont Chemical Company) (Wilmington, Delaware (DE)) by commercial sources.According to conventional methods, can with polyprotic acid by with the N-hydroxy-succinamide (NHS) of suitable mole at N, N '-dicyclohexylcarbodiimide (DCC) exists down reactive chemistry to derive to contain two or more succinimidos.

Polyhydric alcohol such as trimethylolpropane and two (trimethylolpropane) can change into carboxylic acid form with several different methods, further derive to produce trifunctional and the activatory polymer of four senses respectively by in the presence of DCC, reacting then with NHS, as describing in the U. S. application series number 08/403,358.Polyprotic acid such as 1,5-pentanedicarboxylic acid. (HOOC-(CH ₂) ₅-COOH), suberic acid (HOOC-(CH ₂) ₆-COOH), and hexadecandioic acid (hexadecane diacid) (HOOC-(CH ₂) ₁₄-COOH) derive and produce the activatory polymer of difunctionality by adding succinimido.

Polyamines such as ethylenediamine, tetra-methylenedimine, five methylene diamine (cadaverine), hexamethylene diamine, diethylenetriamine, can be chemically derived become polyprotic acid with three (2-amino-ethyl) amine, it can react to derive in the presence of DCC then and contain two or more succinimidos by the N-hydroxy-succinamide with suitable mole, as describing in the U. S. application series number 08/403,358.Many these polyamines can obtain from Du Pont's chemical company (DuPont Chemical Company) by commercial sources.

In preferred embodiments, the first synthetic polymer will contain a plurality of nucleophilic groups (following with " X " representative), and it will react with second synthetic polymer that contains a plurality of electrophilic groups (with " Y " representative), cause covalently bound polymer network, and will be as follows:

Polymer-X _m+ polymer-Y _n→ polymer-Z-polymer

M≤2 wherein, n≤2, and m+n≤5;

Wherein exemplary X group comprises-NH ₂,-SH ,-OH ,-PH ₂, CO-NH-NH ₂, or the like, polymer-X wherein _mMiddle X group can be identical or different;

Wherein exemplary Y group comprises-CO ₂-N (COCH ₂) ₂,-CO ₂H ,-CHO ,-CHOCH ₂(epoxide) ,-N=C=O ,-SO ₂-CH=CH ₂,-N (COCH) ₂(that is, between two CH bases, having 5 yuan of heterocycles) with two keys ,-S-S-(C ₅H ₄N), or the like, polymer-Y wherein _nMiddle Y group can be identical or different; And

Wherein Z is that nucleophilic group (X) and electrophilic group (Y) are united the functional group of generation.

As mentioned above, the present invention also imagines X and Y can be identical or different, and promptly synthetic polymer can have two different electrophilic groups, and perhaps two different nucleophilic groups are as glutathion.

In one embodiment, the main chain of at least a synthetic polymer comprises the alkylene oxide residue, Tathagata autoxidation ethylene, propylene oxide, and composition thereof residue.Term " main chain " refers to the pith of polymer.

For example, the synthetic polymer that contains the alkylene oxide residue can be described by formula X-polymer-X or Y-polymer-Y, and wherein X and Y as above define, term " polymer " " representative-(CH ₂CH ₂O) _n-or-(CH (CH ₃) CH ₂O) _n-or-(CH ₂-CH ₂-O) _n-(CH (CH ₃) CH ₂-O) _n-.In these situations, synthetic polymer can be dual functional.

By linking group (following with " Q " representative) coupling polymer main chain, many linking groups are known or possible usually for needed X of functional group or Y.The method of the multiple functionalized polymeric of many preparations is arranged, and certain methods is listed below:

Polymer-Q ₁-X+ polymer-Q ₂-Y → polymer-Q ₁-Z-Q ₂-polymer

Exemplary Q group comprises-O-(CH ₂) _n-;-S-(CH ₂) _n-;-NH-(CH ₂) _n-;-O ₂C-NH-(CH ₂) _n-;-O ₂C-(CH ₂) _n-;-O ₂C-(CR ¹H) _n-; With-O-R ₂-CO-NH-, it provides the synthetic polymer of part-structure respectively: polymer-O-(CH ₂) _n-(X or Y); Polymer-S-(CH ₂) _n-(X or Y); Polymer-NH-(CH ₂) _n-(X or Y); Polymer-O ₂C-NH-(CH ₂) _n-(X or Y); Polymer-O ₂C-(CH ₂) _n-(X or Y); Polymer-O ₂C-(CR ¹H) _n-(X or Y); And polymer-O-R ₂-CO-NH-(X or Y).In these structures, n=1-10, R ¹=H or alkyl (that is CH, ₃, C ₂H ₅, etc.); R ²=CH ₂, or CO-NH-CH ₂CH ₂And Q ₁And Q ₂Can be identical or different.

For example, work as Q ₂=OCH ₂CH ₂(there is not Q in this situation ₁); Y=-CO ₂-N (COCH ₂) ₂And X=-NH ₂,-SH, or-during OH, gained reaction and Z group can be as follows:

Polymer-NH ₂+ polymer-O-CH ₂-CH ₂-CO ₂-N (COCH ₂) ₂→ polymer-NH-CO-CH ₂-CH ₂-O-polymer;

Polymer-SH+ polymer-O-CH ₂-CH ₂-CO ₂-N (COCH ₂) ₂→

Polymer-S-COCH ₂CH ₂-O-polymer; With

Polymer-OH+ polymer-O-CH ₂-CH ₂-CO ₂-N (COCH ₂) ₂→

Polymer-O-COCH ₂CH ₂-O-polymer.

If exist, can between polymer and linking group, insert other group, represent with " D " below.A purpose of this D group be influence the crosslinked intravital degradation rate of polymer composition, for example, increase degradation rate, perhaps reduce degradation rate.This is useful in many cases, for example, when medicine has been incorporated into substrate, and wishes to increase or reduce depolymerization speed to influence the drug delivery profile of desirable direction.Relate to every kind of first and second synthetic polymers with D and Q group cross-linking reaction be illustrated in following demonstration.

Polymer-D-Q-X+ polymer-D-Q-Y → polymer-D-Q-Z-Q-D-polymer

Some useful biodegradable groups " D " comprise from one or more alpha-hydroxy acids, for example, and lactic acid, glycolic, and cyclisation product (for example, lactide, Acetic acid, hydroxy-, bimol. cyclic ester), 6-caprolactone and amino acids formed polymer.This polymer can be called polylactide, poly-Acetic acid, hydroxy-, bimol. cyclic ester, poly-(altogether-lactide-Acetic acid, hydroxy-, bimol. cyclic ester); Poly--6-caprolactone, polypeptide (be also referred to as polyamino acid, for example, multiple dipeptides or tripeptides) and poly-(anhydride).

At the conventional method that is used for preparing the crosslinked polymer composition that is used for the context of the invention, first synthetic polymer that will contain a plurality of nucleophilic groups mixes with second synthetic polymer that contains a plurality of electrophilic groups.Because the formation of three-dimensional crosslinked network appears in the reaction between the electrophilic group on the nucleophilic group and second synthetic polymer on first synthetic polymer.

The concentration that is used to prepare first synthetic polymer of the present composition and second synthetic polymer will depend on many factors and become, and described factor comprises type and the molecular weight and the desirable final application of used concrete synthetic polymer.Usually, when using many-amino PEG as first synthetic polymer, it preferably arrives the concentration use of about 20% scope with about 0.5% of final composition weight, and second synthetic polymer is with the about 0.5% concentration use to about 20% scope of final composition weight.For example, the final composition with 1 gram (1000 milligrams) gross weight contains and has an appointment 5 to about more than 200 milligrams-amino PEG and about 5 to about 200 milligram of second synthetic polymer.

The use of the higher concentration of first and second synthetic polymers will cause forming tightr crosslinked network, produce harder, more firm gel.Be intended for use in organizing enhanced compositions will use the concentration of the more high-end preferred concentration range for that is positioned at preferred concentration range for of first and second synthetic polymers usually.Plan prevents that as biological adhesive or be used to the compositions of adhesion from not needing for membrane and can contain than low copolymer concentration.

Will be also and the water reaction because contain the polymer of a plurality of electrophilic groups, thus usually with aseptic, dried forms is preserved and use second synthetic polymer to prevent because this type of electrophilic group is exposed to behind the aqueous medium forfeiture that the hydrolysis of generation usually causes crosslinked ability.The method of synthetic hydrophilic polymer that contains a plurality of electrophilic groups with the preparation of aseptic, dried forms is at United States Patent (USP) 5,643, provides in 464.For example, exsiccant synthetic polymer can be compression molded into thin slice or film, and it can use gamma-rays then, or preferred e-x radiation x sterilization.Gained desciccator diaphragm or sheet can be cut into desirable size or mince littler granule.Therefore compare, the polymer that contains a plurality of nucleophilic groups is not that water is reactive and can preserve in aqueous solution usually.

In certain embodiments, above-mentioned one or both electrophilics-or the polymer of nucleophilic-end can with synthetic or naturally occurring combination of polymers.Existence synthetic or naturally occurring polymer can strengthen the machinery and/or the sticking property of the compositions of original position formation.Can be included in the naturally occurring polymer of the material that original position forms and comprise naturally occurring protein from the polymer of naturally occurring polymer-derived; as collagen; collagen derivant (as methylated collagen); fibrinogen, thrombin, albumin; fibrin; with the derivant of naturally occurring polysaccharide,, comprise deacetylated and the acidifying glycosaminoglycans derivant of desulfurization as glycosaminoglycans.

On the one hand, the compositions that comprises naturally occurring protein and aforesaid first and second synthetic polymers is used to form according to crosslinked substrate of the present invention.On the one hand, the compositions that comprises collagen and aforesaid first and second synthetic polymers is used to form according to crosslinked substrate of the present invention.On the one hand, the compositions that comprises methylated collagen and aforesaid first and second synthetic polymers is used to form according to crosslinked substrate of the present invention.On the one hand, the compositions that comprises fibrinogen and aforesaid first and second synthetic polymers is used to form according to crosslinked substrate of the present invention.On the one hand, the compositions that comprises thrombin and aforesaid first and second synthetic polymers is used to form according to crosslinked substrate of the present invention.On the one hand, the compositions that comprises albumin and aforesaid first and second synthetic polymers is used to form according to crosslinked substrate of the present invention.On the one hand, the compositions that comprises fibrin and aforesaid first and second synthetic polymers is used to form according to crosslinked substrate of the present invention.On the one hand, the compositions that comprises naturally occurring polysaccharide and aforesaid first and second synthetic polymers is used to form according to crosslinked substrate of the present invention.On the one hand, the compositions that comprises glycosaminoglycans and aforesaid first and second synthetic polymers is used to form according to crosslinked substrate of the present invention.On the one hand, the compositions that comprises deacetylated glycosaminoglycans and aforesaid first and second synthetic polymers is used to form according to crosslinked substrate of the present invention.On the one hand, the compositions that comprises desulfurization acidify glycosaminoglycans and aforesaid first and second synthetic polymers is used to form according to crosslinked substrate of the present invention.

On the one hand, the compositions that comprises naturally occurring protein and aforesaid first synthetic polymer is used to form according to crosslinked substrate of the present invention.On the one hand, the compositions that comprises collagen and aforesaid first synthetic polymer is used to form according to crosslinked substrate of the present invention.On the one hand, the compositions that comprises methylated collagen and aforesaid first synthetic polymer is used to form according to crosslinked substrate of the present invention.On the one hand, the compositions that comprises fibrinogen and aforesaid first synthetic polymer is used to form according to crosslinked substrate of the present invention.On the one hand, the compositions that comprises thrombin and aforesaid first synthetic polymer is used to form according to crosslinked substrate of the present invention.On the one hand, the compositions that comprises albumin and aforesaid first synthetic polymer is used to form according to crosslinked substrate of the present invention.On the one hand, the compositions that comprises fibrin and aforesaid first synthetic polymer is used to form according to crosslinked substrate of the present invention.On the one hand, the compositions that comprises naturally occurring polysaccharide and aforesaid first synthetic polymer is used to form according to crosslinked substrate of the present invention.On the one hand, the compositions that comprises glycosaminoglycans and aforesaid first synthetic polymer is used to form according to crosslinked substrate of the present invention.On the one hand, the compositions that comprises deacetylated glycosaminoglycans and aforesaid first synthetic polymer is used to form according to crosslinked substrate of the present invention.On the one hand, the compositions that comprises desulfurization acidify glycosaminoglycans and aforesaid first synthetic polymer is used to form according to crosslinked substrate of the present invention.

On the one hand, the compositions that comprises naturally occurring protein and aforesaid second synthetic polymer is used to form according to crosslinked substrate of the present invention.On the one hand, the compositions that comprises collagen and aforesaid second synthetic polymer is used to form according to crosslinked substrate of the present invention.On the one hand, the compositions that comprises methylated collagen and aforesaid second synthetic polymer is used to form according to crosslinked substrate of the present invention.On the one hand, the compositions that comprises fibrinogen and aforesaid second synthetic polymer is used to form according to crosslinked substrate of the present invention.On the one hand, the compositions that comprises thrombin and aforesaid second synthetic polymer is used to form according to crosslinked substrate of the present invention.On the one hand, the compositions that comprises albumin and aforesaid second synthetic polymer is used to form according to crosslinked substrate of the present invention.On the one hand, the compositions that comprises fibrin and aforesaid second synthetic polymer is used to form according to crosslinked substrate of the present invention.On the one hand, the compositions that comprises naturally occurring polysaccharide and aforesaid second synthetic polymer is used to form according to crosslinked substrate of the present invention.On the one hand, the compositions that comprises glycosaminoglycans and aforesaid second synthetic polymer is used to form according to crosslinked substrate of the present invention.On the one hand, the compositions that comprises deacetylated glycosaminoglycans and aforesaid second synthetic polymer is used to form according to crosslinked substrate of the present invention.On the one hand, the compositions that comprises desulfurization acidify glycosaminoglycans and aforesaid second synthetic polymer is used to form according to crosslinked substrate of the present invention.

Contain and to cause with the existence of the protein of the functional group of functional group reactions on the how activatory synthetic polymer or polysaccharide component when mixing with synthetic polymer and/or forming crosslinked synthetic polymer-naturally occurring polymeric matrix when crosslinked.Particularly, when naturally occurring polymer (protein or polysaccharide) also contains nucleophilic group, during as primary amino radical, on second synthetic polymer electrophilic group will with the primary amino radical on these components, and first the nucleophilic group reaction on the synthetic polymer, cause these other components to become the part of polymeric matrix.For example, being rich in the protein of lysine such as collagen can be especially and the reaction of the electrophilic group on the synthetic polymer.

On the one hand, naturally occurring protein is polymer, can be collagen.Term used herein " collagen ", or " Collagen material " refers to the collagen of form of ownership, comprise treated or modify and be intended to comprise from those of the collagen of any type in any source, include, but are not limited to, collagen from tissue extraction or reorganization generation, the collagen analog, collagen derivant, modified collagen, and denatured collagen, as gelatin.

Usually, compositions of the present invention can comprise the collagen from any source; For example, collagen can be from people or other mammal source, and as cattle or pig dermis and extraction of people's Placenta Hominis and purification, perhaps can recombinate or pass through other method produces.From the collagen formulations purification in the solution of Corii Bovis seu Bubali, nonantigenic substantially is well known in the art.U.S. Patent number 5,428,022 discloses from the method for extraction of people's Placenta Hominis and collagen purification.U.S. Patent number 5,667,839 disclose transgenic animal, comprise the method that produces recombinant human collagen in the milk of transgenic milch cow.Any type, the collagen that includes, but not limited to I, II, III, IV type or its combination can be used for compositions of the present invention, although usually preferred type i collagen.Can use the collagen that contains non-end peptide (atelopeptide) or end peptide; Yet, when the collagen that uses from the xenogenesis source, during as bovine collagen, preferred non-end peptide collagen usually because with contain the collagen of holding peptide and compare it and have the immunogenicity that reduces.

Before be not preferred in the compositions of the present invention, although can use previous crosslinked collagen by the crosslinked collagen of method such as heat, radiation or chemical cross-linking agent.Noncrosslinking non-end peptide fiber collagen can be learned company (Inamed Aesthetics) (Santa Barbara (Santa Barbara) from the Yin Aimu dolantin by commercial sources, California (CA)), obtain with trade mark ZYDERM I collagen and ZYDERM II collagen collagen concentration respectively with 35mg/ml and 65mg/ml.The non-end peptide fiber collagen of glutaraldehyde cross-linking can obtain with the collagen concentration of trade mark ZYPLAST collagen with 35mg/ml from Yin Aimude company (InamedCorporation) (Santa Barbara (Santa Barbara), California (CA)) by commercial sources.

Be used for collagen of the present invention and be generally aqueous suspension, its concentration arrives about 120mg/ml for about 20mg/ml; Preferred about 30mg/ml is to about 90mg/ml.

Because its viscosity robustness, non-fiber collagen can be preferred for being intended to as in the compositions of biological adhesive.Term " non-fiber collagen " refers to point out as the optical clarity of the waterborne suspension by collagen, is essentially any modification of non-fibers form or the Collagen material of unmodified for 7 times at pH.

Can be used for compositions of the present invention for the collagen of non-fibers form.Term " non-fiber collagen " is intended to comprise the collagen-type of the non-fiber of native form as used herein, thereby and is the collagen of non-fibers form through chemical modification under neutral pH or about neutral pH.The non-fiber of native form (perhaps microfibre) collagen-type comprises IV, VI or VII form.

In neutral pH is that the collagen of the chemical modification of non-fibers form comprises succinyl group collagen and methylated collagen; they both can be according to the U.S. Patent number of authorizing 14 days Augusts in 1979 of Miyata etc. 4; the method preparation of describing in 164,559, with the complete combination of described patent as a reference.Because its inherent viscosity, methylated collagen is particularly preferred for as in the disclosed biological viscosity compositions in the U. S. application series number 08/476,825.

The collagen that is used for crosslinked polymer composition of the present invention can begin with fibers form, makes non-fibrosis by adding one or more fiber distintegrants then.The fiber distintegrant must exist with capacity makes that collagen is non-fiber shape basically under pH7, as above-mentioned.Be used for fiber distintegrant of the present invention and include, but not limited to multiple biocompatible alcohol, aminoacid (for example, arginine), inorganic salt (for example, sodium chloride and potassium chloride), and sugar (the multiple sugar that for example, comprises sucrose).

On the one hand, polymer can be collagen or collagen derivant, for example, and methylated collagen.The example that original position forms compositions uses poly-(ethylene glycol) ether four-sulfydryl of tetramethylolmethane] (4-arm mercaptan PEG), poly-(ethylene glycol) ether four-succinimido glutarate of tetramethylolmethane] (4-arm NHS PEG) and methylated collagen be as reaction reagent.Said composition can produce crosslinked hydrogel when mixing with the buffer agent that suits.(see, for example, U.S. Patent number 5,874,500; 6,051,648; 6,166,130; 5,565,519 and 6,312,725).

On the other hand, naturally occurring polymer can be a glycosaminoglycans.Glycosaminoglycans can contain anion and Cationic functional groups as hyaluronic acid in every polymeric chain, it can form intramolecularly and/or intermolecular ionomer, and is responsible for hyaluronic thixotroping (perhaps shear thinning) character.

In some aspects, glycosaminoglycans can be derived.For example, can by for example deacetylated, desulfurization acidify or both chemically derived glycosaminoglycans with comprise can with the primary amino radical of electrophilic group reaction on the synthetic polymer molecule.Can comprise following according to one or both deutero-glycosaminoglycans of said method: hyaluronic acid, chondroitin sulfate A, chondroitin sulfate B (dermatan sulfate), chondroitin sulfate C, chitin (can be derivatized to chitosan), keratan sulfate, keratosulfate and heparin.Derive by deacetylated and/or desulfurization acidify and to describe in further detail in the U.S. Patent Application Serial 08/146,843 common transfer, permission that covalentlying bind in of glycosaminoglycans and gained glycosaminoglycans derivant and synthetic hydrophilic polymer submitted on November 3rd, 1993.

Usually, collagen is added first synthetic polymer, then the collagen and first synthetic polymer are fully mixed to realize homogeneous compositions.Add second synthetic polymer then and be mixed in collagen/first synthetic polymer blends, wherein it causes forming the cross-linked network of homogeneity with primary amino radical on covalent bond first synthetic polymer or the primary amino radical on mercapto and the collagen.Multiple deacetylated and/or desulfurization acidify glycosaminoglycans derivant can be attached in the compositions with the above-mentioned similar manner of describing about collagen.In addition, the introducing such as the hydrocolloid of carboxymethyl cellulose can promote tissue to adhere to and/or swellability.

Using of crosslinked synthetic polymer compositions

Can be before first and second synthetic polymers be crosslinked, during or use compositions of the present invention afterwards with two kinds of synthetic polymers.Some purposes discussed in detail strengthens as tissue below, may need compositions crosslinked before using, and other application adheres to as tissue, needs compositions preceding the using of crosslinked reaching " balance ".Crosslinkedly reach equilibrated point and be defined as the point that compositions feels that no longer viscosity or sense of touch are clamminess in this article.

In order to use compositions before crosslinked, first synthetic polymer and second synthetic polymer can be included in the independent cylinder of two compartment syringes.In this case, two kinds of synthetic polymer reality are not mixed, and are expressed into that time patient's the tissue from the syringe needle point up to two kinds of polymer.This allows most cross-linking reactions to react in position, avoids the syringe needle blocking problem, if two kinds of synthetic polymers mix too early and send crosslinked too fast between preceding two kinds of components from syringe needle, the syringe needle blocking problem takes place so usually.Use as above-mentioned pair of compartment syringe allows the syringe needle of use than minor diameter, when in delicate tissue, when carrying out soft tissue enhancement as around eyes, is favourable than minor diameter.

Alternatively, can before being delivered to tissue site, mix first synthetic polymer and second synthetic polymer according to said method, after mixing then immediately (preferably, in about 60 seconds) be expelled to desirable tissue site.

In another embodiment of the present invention, mix first synthetic polymer and second synthetic polymer, then it is extruded and allows crosslinked in blocks or other solid form.Then linked solid is dewatered to remove all unconjugated water basically.The gained drying solid can be milled or is ground into granule; be suspended in non-aqueous fluid carrier then; comprise; but be not limited in collagen, glycogen, glycerol, dextrose, maltose, fatty acid (as Semen Maydis oil, soybean oil and Oleum sesami) triglyceride and the lecithin of hyaluronic acid, dextran sulfate, glucosan, the noncrosslinking collagen of succinyl groupization, methylated noncrosslinked.The granule suspension can be by small size needle injection to tissue site.In case in tissue, crosslinked polymer beads expands rehydration and size 5 times at least.

Hydrophilic polymer+many crosslinkable components

As mentioned above, first and/or second synthetic polymer can with hydrophilic polymer, for example collagen or methylated collagen are combined to form and can be used for compositions of the present invention.In a common embodiment, can be used for compositions of the present invention and comprise that hydrophilic polymer makes up two or more crosslinkable components.This embodiment is the chapters and sections more detailed description below.The hydrophilic polymer component:

The hydrophilic polymer component can be synthetic or naturally occurring hydrophilic polymer.Naturally occurring hydrophilic polymer can include, but are not limited to: protein, and as collagen and derivant thereof, fibronectin, albumin, globulin, fibrinogen and fibrin, especially preferred collagen; Carboxylated polysaccharide is as polymannuronic acid and Poly Gal A Galacturonan; The amination polysaccharide, glycosaminoglycans especially, as hyaluronic acid, chitin, chondroitin sulfate A, B or C, keratan sulfate, keratosulfate and heparin; With activatory polysaccharide, as glucosan and starch derivatives.Collagen (for example, methylated collagen) and glycosaminoglycans are the preferred naturally occurring hydrophilic polymeies that is used for this paper.

Usually, can use collagen in the compositions of the inventive method from any source; For example, collagen can be from people or other mammal source, and as cattle or pig dermis and extraction of people's Placenta Hominis and purification, perhaps can recombinate or pass through other method produces.From the collagen formulations purification in the solution of Corii Bovis seu Bubali, nonantigenic substantially is well known in the art.See, the U.S. Patent number 5,428,022 of Palefsky etc. for example, it discloses from people's Placenta Hominis and has extracted and the method for collagen purification.Also referring to the U.S. Patent number 5,667,839 of Berg, it discloses transgenic animal, comprises the method that produces recombinant human collagen in the milk of transgenic milch cow.Unless otherwise noted, term used herein " collagen " or " Collagen material " refer to the collagen of form of ownership, comprise the collagen of processing or modifying.

Any type, the collagen that includes, but not limited to I, II, III, IV type or its combination can be used for compositions of the present invention, although usually preferred type i collagen.Can use and contain non-end peptide or end peptide collagen; Yet, when the collagen that uses from such source, during as bovine collagen, preferred non-end peptide collagen usually because it with contain the collagen of holding peptide and compare and have littler immunogenicity.

Before be not preferred in the compositions of the present invention, although can use previous crosslinked collagen by the crosslinked collagen of method such as heat, radiation or chemical cross-linking agent.Noncrosslinking non-end peptide fiber collagen can be by commercial sources from wheat lattice medical company (McGhan Medical Corporation) (Santa Barbara (Santa Barbara), California (Calif.)) respectively with trade mark ZYDERM ^I collagen and ZYDERM ^II collagen obtains with the collagen concentration of 35mg/ml and 65mg/ml.The non-end peptide fiber collagen of glutaraldehyde cross-linking can be by commercial sources from wheat lattice medical company (McGhanMedical Corporation) with trade mark ZYPLAST ^Collagen obtains with the collagen concentration of 35mg/ml.

It is common to be used for collagen of the present invention, although be not essential, is aqueous suspension, and its concentration arrives about 120mg/ml for about 20mg/ml, and preferably about 30mg/ml is to about 90mg/ml.

Although preferred complete collagen also can use the collagen of degeneration, so-called gelatin in compositions of the present invention.Gelatin can have the benefit than the faster degraded of collagen.

Because the bigger concentration of surface area that it is bigger and reactive group, preferred non-fiber collagen usually.Term " non-fiber collagen " refers to point out as the optical clarity of the aqueous suspension by collagen, be essentially any modification of non-fibers form or the Collagen material of unmodified under pH7.

In neutral pH is that the collagen of the chemical modification of non-fibers form comprises succinyl group collagen, propylated collagen, ethylization collagen, methylated collagen or the like; they both can be according to the U.S. Patent number 4 of Miyata etc.; 164; the method preparation of describing in 559, with the complete combination of described patent as a reference.Because its inherent viscosity, preferable methyl collagen especially, open in the U.S. Patent number 5,614,587 as Rhee etc.

The collagen that is used for cross-linkable composition of the present invention can begin with fibers form, makes non-fibrosis by adding one or more fiber distintegrants then.The fiber distintegrant must exist with capacity makes that collagen is for 7 times non-fiber at pH basically, as above-mentioned.Be used for fiber distintegrant of the present invention and include, but not limited to multiple biocompatible alcohol, aminoacid, inorganic salt, and sugar, especially preferred biocompatible alcohol.Preferred biocompatible alcohol comprises glycerol and propylene glycol.The alcohol of biocompatible, as ethanol, methanol and isopropyl alcohol since they the potential adverse effect of the patient body of accepting them is not preferred among the present invention.Preferred amino acids comprises arginine.Preferred inorganic salt comprises sodium chloride and potassium chloride.Although sugar, as comprise that the multiple sugar of sucrose can be used for enforcement of the present invention, they are preferred not as the fiber distintegrant of other type, because they have the cells in vivo toxic effect.

Because fiber collagen has the reactive group of small surface area and low concentration than non-fiber collagen, so fiber collagen is more not preferred.Yet, disclosed in 587 as United States Patent (USP) 5,614, if do not need optical clarity, fiber collagen so, perhaps non-fiber collagen and fibrocollagenous mixture can be preferred in the long-standing in vivo compositions of meaning.

Can also use synthetic hydrophilic polymer among the present invention.Useful synthesis hydrophilic polymer includes, but not limited to polyalkylene oxide, and especially Polyethylene Glycol and poly-(oxirane)-poly-(propylene oxide) copolymer comprises block and random copolymer; Polyhydric alcohol, as glycerol, polyglycereol (especially highly branched polyglycereol), propylene glycol and the trimethylene glycol that replaces with one or more polyalkylene oxides, for example, single-, two-and three-polyoxyethylene glycerol, single-and two-polyoxyethylated propylene glycol, and single-and two-polyoxyethylene trimethylene glycol; The polyoxyethylene sorbitol, the polyoxyethylene glucose; Acrylate copolymer and analog thereof and copolymer, as polyacrylic acid self, polymethylacrylic acid, poly-(hydroxyethyl-methacrylate), poly-(hydroxyethylmethacry,ate), poly-(methyl alkyl sulfoxide methacrylate), poly-(methyl alkyl sulfoxide acrylate) and front any copolymer and/or with the other acrylate kind such as the copolymer of amino-ethyl acrylate and list-2-(propenyloxy group) ethyl succinate; Poly; Poly-(acrylamide), own as poly-(acrylamide), poly-(Methacrylamide), poly-(DMAA) and poly-(N-isopropyl-acrylamide); Poly-(enol) is as poly-(vinyl alcohol); Poly-(N-vinyl lactam), as poly-(vinyl pyrrolidone), poly-(N-caprolactam), and copolymer; The Ju oxazoline comprises poly-(Jia oxazolin) and poly-(ethyl oxazoline); And polyvinylamine.The polymer tabulation that must emphasize the front is not an exhaustive, as will be apparent to those skilled in the art, can use many other synthetic hydrophilic polymeies.

Crosslinkable component:

Compositions of the present invention also comprises many crosslinkable components.Every kind of crosslinkable component participates in causing the reaction of crosslinked substrate.Before finishing cross-linking reaction, crosslinkable component provides necessary adhesion properties, and it makes can carry out the inventive method.

Select crosslinkable component to make crosslinked generation can be used for biocompatible, the non-immunogenic substrate of multiple background, described background comprises that adhesion prevents, bioactivator is sent, organizes enhancing, and other application.Crosslinkable component of the present invention comprises: component A, it has m nucleophilic group, wherein m 〉=2, and B component, its have can with n electrophilic group of m nucleophilic group reaction, wherein n 〉=2 and m+n 〉=4.Can also have the third optional component: optional component C, it has at least one functional group, this functional group be parent electricity and can with the nucleophilic group reaction of component A, perhaps functional group be nucleophilic and can with the electrophilic group reaction of B component.Thereby component A, B and C go up total summation 〉=5 of the functional group's (when existing) that exists; That is, total functional group of obtaining of m+n+p necessary 〉=5; Wherein p goes up functional group's number for component C, and as noted, 〉=1.Every kind of component all is biocompatible and non-immunogenic, and at least a component comprises hydrophilic polymer.And as will be appreciated, compositions can contain other crosslinkable component D, E, F or the like, forms in the formation of crosslinked biomaterial by the covalent bond with other component thereby have one or more reactive nucleophilics or electrophilic group and participation.

M on a component A nucleophilic group can be all identical, and perhaps alternatively, A can contain two or more different nucleophilic groups.Similarly, the electrophilic group of the n on the B component can be identical, perhaps can have two or more different electrophilic groups.Functional group on the optional components C is if nucleophilic, and is can or can be not identical with nucleophilic group on the component A, and on the contrary, if electrophilic, the functional group on the optional components C is can or can be not identical with electrophilic group on the B component.

Therefore, represent described component by following structural formula

(I) R ¹(-[Q ¹] _q-X) _m(component A),

(II) R ²(-[Q ²] _r-Y) _n(B component) and

(III) R ³(-[Q ³] _s-Fn) _p(optional components C),

Wherein:

R ¹, R ²And R ³Be independently selected from by C ₂To C ₁₄Alkyl contains heteroatomic C ₂To C ₁₄Alkyl, the group that hydrophilic polymer and hydrophobic polymer are formed, condition is R ¹, R ²And R ³At least one be hydrophilic polymer, preferred synthetic hydrophilic polymer.

On behalf of component A, X go up one of m nucleophilic group, and the last a plurality of X parts of A can be identical or different;

Y represents one of n electrophilic group on the B component, and the last a plurality of Y parts of A can be identical or different;

Fn represents the functional group on the optional components C;

Q ¹, Q ²And Q ³Be linking group;

M 〉=2, n 〉=2, m+n is 〉=4, q and r are 0 or 1 independently, when having optional components C, p 〉=1, and s is 0 or 1 independently.

Reactive group:

X can be any nucleophilic group almost, as long as can react with electrophilic group Y.Similarly, Y can be any electrophilic group almost, as long as can react with X.Unique restriction is actual restriction, is that the reaction between X and the Y should quite soon and react when mixing with aqueous medium automatically, does not need heating or the deleterious or abiotic degradable catalysts of possibility or other chemical agent.Also preferred, although be not essential, react and do not need ultraviolet or other radiation.Ideally, be reflected at 60 minutes between X and the Y, finish in preferred 30 minutes.Most preferably, be reflected at about 5 to 15 minutes or shorter time in finish.

The example of suitable nucleophilic group as X includes, but not limited to-NH ₂,-NHR ⁴,-N (R ⁴) ₂,-SH ,-OH ,-COOH ,-C ₆H ₄-OH ,-PH ₂,-PHR ⁵,-P (R ⁵) ₂,-NH-NH ₂,-CO-NH-NH ₂,-C ₅H ₄N, or the like, R wherein ⁴And R ⁵Be alkyl, be generally alkyl or monocyclic aryl, preferred alkyl, most preferably low alkyl group.Organic metal part also is the operable nucleophilic group of the present invention, especially as the organic metal part of carbanion donor.Yet, not preferred organic metal nucleopilic reagent.The example of organic metal part comprises: Grignard degree of functionality-R ⁶MgHal, wherein R ⁶Be carbon atom (replacement or unsubstituted), Hal is a halogen, usually bromine, iodine or chlorine, preferably bromine; The degree of functionality that contains lithium, lithium alkylide group usually; The degree of functionality that contains sodium.

It will be appreciated by one of skill in the art that some nucleophilic group must be with the alkali activation reacting with electrophilic reagent.For example, when having electrophilic sulfydryl and hydroxyl in the compositions crosslinkable, compositions must be mixed so that remove deprotonation and provide-S with aqueous alkali ^-Or-O ^-Kind is reacting with electrophilic reagent.Participate in cross-linking reaction unless wish alkali, preferred non-nucleophilic base.In some embodiments, alkali can exist with the component of buffer.Suitable alkali and corresponding cross-linking reaction are described among the part E hereinafter.

Must carry out in the compositions crosslinkable, i.e. the selection of the electrophilic group that provides on the B component, thus may react with specific nucleophilic group.Thereby, when X partly is amino, select Y group to react with amino.Similarly, when X partly was the sulfydryl part, corresponding electrophilic group was the sulfydryl reactive group, or the like.

As an example, when X was amino (although common not necessarily primary amino radical), the electrophilic group of the last existence of Y was amino reactive group, as, be not limited to: (1) carboxylate comprises cyclic ester and " activation " ester; (2) the acid chloride group (CO-Cl); (3) anhydride ((CO)-O-(CO)-R); (4) ketone and aldehyde comprise α, beta-unsaturated aldehyde and ketone, as-CH=CH-CH=O and-CH=CH-C (CH ₃)=O; (5) halogenide; (6) isocyanates (N=C=O); (7) isothiocyanate (N=C=S); (8) epoxide; (9) activatory hydroxyl (for example, with conventional activator such as carbonyl dimidazoles or sulfonic acid chloride activation); (10) alkene comprises the alkene of puting together, as ethylene sulfonyl (SO ₂CH=CH ₂) and similar functional group, comprise acrylate (CO ₂-C=CH ₂), methacrylate (CO ₂-C (CH ₃)=CH ₂)), ethyl acrylate (CO ₂-C (CH ₂CH ₃)=CH ₂), and aziridinyl is (CH=CH-C=NH).Because hydroxy-acid group itself is difficult for and the nucleophilic amine reaction, the component of hydroxy-acid group must activate so that be that amine is reactive so contain.Can finish activation with several different methods, but be usually directed in the presence of dehydrant such as dicyclohexylcarbodiimide (DCC) or 1,3-Dicyclohexylurea (DHU), react with the suitable chemical compound that contains hydroxyl.For example, carboxylic acid N-hydroxyl-butanimide that can replace with alkoxyl or N-hydroxysulphosuccinimide react in the presence of DCC and form reactive electrophilic group respectively, N-hydroxyl-succinimide ester or N-hydroxysulphosuccinimide ester.Carboxylic acid can also be by reacting with carboxylic acid halides such as acid chloride (for example, chloroacetic chloride), so that the reactive acid anhydride group to be provided.In another example, can use-case carboxylic acid be changed into the acid chloride group as thionyl chloride or acyl chlorides that can exchange reaction.The particular agent that is used for implementing this type of priming reaction and step are well known by persons skilled in the art and describe at relevant teaching material and document.

Similarly, when X was sulfydryl, the electrophilic group of the last existence of Y was the group with the sulfydryl partial reaction.This type of reactive group comprises when reacting with sulfydryl those groups that form thioester bond, those that describe in PCT publication number WO 00/62827 as Wallace etc.As explaining in detail that therein this type of " sulfydryl reactivity " group includes, but are not limited to: blended anhydride; The ester derivant of phosphorus; The ester derivant of paranitrophenol, p-nitrophenyl thiophenol and Pentafluorophenol; The ester of the azanol that replaces comprises N-hydroxyl phthalimide ester, N-hydroxy-succinamide ester, N-hydroxysulphosuccinimide ester and N-hydroxyl glutarimide ester; The ester of I-hydroxybenzotriazole; 3-hydroxyl-3,4-dihydro-phentriazine-4-ketone; 3-hydroxyl-3,4-dihydro-chinazoline-4-ketone; The carbonylic imidazole derivant; Acid chloride; Ketenes; And isocyanates.Use these sulfydryl reactive groups, auxiliary reagent can also be used to promote key to form, for example, 1-ethyl-3-[3-dimethylaminopropyl] carbodiimide can be used to promote sulfydryl is coupled to the group that contains carboxyl.

Except forming the sulfydryl reactive group of thioester bond, can use multiple other sulfydryl reactive functional group degree that forms other type bonds.For example, the chemical compound that contains the methylene imine ester derivant can form imino group-thioester bond with sulfydryl.Alternatively, the sulfydryl reactive group can be used for forming disulfide bond with sulfydryl; This type of group has structure-S-S-Ar usually, wherein Ar replaces or the unsubstituted heteroaryl moieties of nitrogen or the non-heterocyclic aromatic base that partly replaces with electrophilic of containing, thereby Ar can be for for example, 4-pyridine radicals, o-nitrophenyl ,-nitrobenzophenone, right-nitrobenzophenone, 2,4-dinitrophenyl, 2-nitro-4 benzoic acid, 2-nitro-4-pyridine radicals or the like.In this type of situation, auxiliary reagent, that is, gentle oxidant as hydrogen peroxide, can be used to promote disulfide bond to form.

Another kind of sulfydryl reactive group and sulfydryl form thioether bond.This type of group comprises maleimide amino, haloalkyl, epoxy, imino group and '-aziridino (aziridino) and the alkene (comprise and put together alkene) of particularly maleimide amino, replacement; as ethylene sulfonyl, aziridinyl, acrylate, methacrylate; and α, β-undersaturated aldehyde and ketone.Such sulfydryl reactive group is especially preferred, because thioether bond can provide crosslinked and longer faster body internal stability.

When X be-during OH, the electrophilic functional group on all the other components must and hydroxyl reaction.Hydroxyl can be as above about the hydroxy-acid group activation, perhaps it can be in the presence of alkali directly and enough reactive electrophilic reagents, as epoxide group, aziridine group, carboxylic acid halides or anhydride reaction.

When X is organic metal nucleopilic reagent such as Grignard degree of functionality or alkyl lithio, be to contain those of carbonyl with the suitable electrophilic functional group of its reaction, for example comprise ketone and aldehyde.

Also understand some functional group and can be used as nucleopilic reagent or electrophilic reagent reaction, this depends on selected reaction gametophyte and/or reaction condition.For example, hydroxy-acid group can still usually as electrophilic reagent, allow to follow the replacement hydroxyl at the carbonyl carbon nucleophillic attack with the nucleopilic reagent that arrives as the nucleopilic reagent reaction in the presence of great alkali.

When causing the covalent bond in the cross-linked structure to comprise during specific electrophilic component in the specific nucleophilic component covalent bond compositions crosslinkable, only as an example, below everyly (, omit optional linking group Q for clear ¹And Q ²):

Table

Representative nucleophilic component (A, optional component C element FN _NU)	Representative electrophilic component (B, FN _EL)	The gained key
	Representative electrophilic component (B, FN _EL)	The gained key	R ¹-NH ₂	R ²-O-(CO)-O-N(COCH ₂) (carbonic acid succinimide ester end)	R ¹-NH-(CO)-O-R ²
R ¹-SH	R ²-O-(CO)-O-N(COCH ₂)	R ¹-S-(CO)-O-R ²	R ¹-NH ₂		R ¹-NH-(CO)-O-R ²
R ¹-SH	R ²-O-(CO)-O-N(COCH ₂)	R ¹-S-(CO)-O-R ²	R ¹-OH	R ²-O-(CO)-O-N(COCH ₂)	R ¹-O-(CO)-R ²
R ¹-NH ₂	R ²-O(CO)-CH＝CH ₂(acrylate end)	R ¹-NH-CH ₂CH ₂-(CO)-O-R ²	R ¹-OH	R ²-O-(CO)-O-N(COCH ₂)	R ¹-O-(CO)-R ²
R ¹-NH ₂	R ²-O(CO)-CH＝CH ₂(acrylate end)	R ¹-NH-CH ₂CH ₂-(CO)-O-R ²	R ¹-SH	R ²-O-(CO)-CH＝CH ₂	R ¹-S-CH ₂CH ₂-(CO)-O-R ²
R ¹-OH	R ²-O-(CO)-CH＝CH ₂	R ¹-O-CH ₂CH ₂-(CO)-O-R ₂	R ¹-SH	R ²-O-(CO)-CH＝CH ₂	R ¹-S-CH ₂CH ₂-(CO)-O-R ²

Linking group:

X of functional group on the optional components C and Y and FN can be directly connected to the chemical compound core (R on the optional components C respectively ¹, R ²Or R ³), perhaps they can connect by linking group indirectly, and long linking group is also referred to as " cahin extension agent ".At structural formula (I), (II) and (III) in, optional linking group is by Q ¹, Q ²And Q ³Q is wherein worked as in representative, and r and s equal at 1 o'clock, has linking group (Y, Fn, mn and p such as front define for R, X).

Suitable linking group is well known in the art.See, for example, International Patent Publication No. WO 97/22371.Linking group is used to avoid form relevant sterically hindered problem with intermolecular direct key sometimes.Linking group can additionally be used for some multifunctional activatory chemical compounds are linked together and obtain bigger molecule.In preferred embodiments, linking group can be used for use with the gained gel formation after change the degraded character of compositions.For example, linking group can be incorporated among component A, B or the optional components C to promote hydrolysis, hinders hydrolysis, and the enzymatic degradation site perhaps is provided.

Provide the example of the linking group in hydrolyzable site to comprise: ester bond particularly; Anhydride bond is as the anhydride bond by obtaining in conjunction with 1,3-propanedicarboxylic acid and succinic acid; Original acid ester key; The orthocarbonic acid ester bond is as the propylene carbonate key; Amido link; The phosphoric acid ester bond; The alpha-hydroxy acid key is as can be by obtaining in conjunction with lactic acid and glycolic; Based on the key of lactone, as can be by obtaining in conjunction with caprolactone, valerolactone, gamma-butyrolacton with to-Er Evil ketone; And amido link, as the amido link in dimer, oligomer or poly-(aminoacid) fragment.The example of non-degradable linking group comprises butanimide, propanoic acid and carboxylic formic acid ester bond.See, for example, PCT WO 99/07417.The example of the degradable key of enzyme comprises Leu-Gly-Pro-Ala, and it can pass through degraded by collagenase; And Gly-Pro-Lys, it can be degraded by fibrinolysin.

Linking group can also strengthen or suppress the reactivity of multiple nucleophilic and electrophilic group.For example, the electron withdraw group in of sulfydryl and two carbon can be estimated because the reduction nucleophilicity reduces the effectiveness in its coupling.Carbon-to-carbon double bond and carbonyl will also have this effect.On the contrary, the electron withdraw group adjacent with carbonyl (for example, the reactive carbonyl of glutaryl-N-hydroxy-succinamide base) can increase the reactivity of carbonyl carbon about the nucleopilic reagent that enters.Compare, thereby the neutral body bulky group can be used to reduce reactivity and reduces coupling speed near the functional group owing to sterically hindered.

As an example, gone out concrete linking group and respective components structure at the following table middle finger:

Table

Linking group	Component structure
Linking group	Component structure	-O-(CH ₂) _n-	Component A:R ¹-O-(CH ₂) _n-X B component: R ²-O-(CH ₂) _n-Y optional components C:R ³-O-(CH ₂) _n-Z

Linking group	Component structure
Linking group	Component structure	-S-(CH ₂) _n-	Component A:R ¹-S-(CH ₂) n-X B component: R ²-S-(CH ₂) _n-Y optional components C:R ³-S-(CH ₂) _n-Z
-NH-(CH ₂) _n-	Component A:R ¹-NH-(CH ₂) _n-X B component: R ²-NH-(CH ₂) _n-Y optional components C:R ³-NH-(CH ₂) _n-Z	-S-(CH ₂) _n-
-NH-(CH ₂) _n-		-O-(CO)-NH-(CH ₂) _n-	Component A:R ¹-O-(CO)-NH-(CH ₂) _n-X B component: R ²-O-(CO)-NH-(CH ₂) _n-Y optional components C:R ³-O-(CO)-NH-(CH ₂) _n-Z
-NH-(CO)-O-(CH ₂) _n-	Component A:R ¹-NH-(CO)-O-(CH ₂) _n-X B component: R ²-NH-(CO)-O-(CH ₂) _n-Y optional components C:R ³-NH-(CO)-O-(CH ₂) _n-Z	-O-(CO)-NH-(CH ₂) _n-
-NH-(CO)-O-(CH ₂) _n-		-O-(CO)-(CH ₂) _n-	Component A:R ¹-O-(CO)-(CH ₂) _n-X B component: R ²-O-(CO)-(CH ₂) _n-Y optional components C:R ³-O-(CO)-(CH ₂) _n-Z
-(CO)-O-(CH ₂) _n-	Component A:R ¹-(CO)-O-(CH ₂) _n-X B component: R ²-(CO)-O-(CH ₂) _n-Y optional components C:R ³-(CO)-O-(CH ₂) _n-Z	-O-(CO)-(CH ₂) _n-
-(CO)-O-(CH ₂) _n-		-O-(CO)-O-(CH ₂) _n-	Component A:R ¹-O-(CO)-O-(CH ₂) _n-X B component: R ²-O-(CO)-O-(CH ₂) _n-Y optional components C:R ³-O-(CO)-O-(CH ₂) _n-Z
-O-(CO)-CHR ⁷-	Component A:R ¹-O-(CO)-CHR ⁷-X B component: R ²-O-(CO)-CHR ⁷-y optional components C:R ³-O-(CO)-CHR ⁷-Z	-O-(CO)-O-(CH ₂) _n-
-O-(CO)-CHR ⁷-		-O-R ⁸-(CO)-NH-	Component A:R ¹-O-R ⁸-(CO)-NH-X B component: R ²-O-R ⁸-(CO)-NH-Y optional components C:R ³-O-R ⁸-(CO)-NH-Z

In last table, n is generally 1 to about 10, R ⁷Be generally alkyl, typically be alkyl or aryl, preferred alkyl, low alkyl group most preferably, R ⁸Be alkylene, contain heteroatomic alkylene, the alkylene of replacement, the heteroatomic alkylene that perhaps contains replacement typically is alkylidene or arlydene (once more, optional that replace and/or contain hetero atom), preferred low-grade alkylidene (for example, methylene, 1, the 2-ethylidene, positive propylidene, positive butylidene, or the like), phenylene, perhaps acyl ammonia alkylidene (for example ,-(CO)-NH-CH ₂).

Other General Principle of considering about linking group is as follows: if will use higher molecular weight component, they preferably have aforesaid biodegradable key, thereby do not produce greater than 20,000 molar fragments during absorbing in health again.In addition, in order to promote water miscibility and/or dissolubility, can wish to add enough electric charges or hydrophilic.Use known chemosynthesis can easily introduce hydrophilic group, as long as they do not cause undesirable reduction of undesirable swelling or compressive strength.Particularly, poly-alkoxyl fragment can weaken gel strength.

The component core:

" core " of every kind of crosslinkable component comprises nucleophilic or the bonded molecular structure of electrophilic group.For component A, use formula (I) R ¹-[Q ¹] _q-X) _m, for B component, use formula (II) R ²(-[Q ²] _r-Y) _n, for optional components C, use formula (III) R ³(-[Q ³] _s-Fn) _p, " core " group is R ¹, R ²And R ³Each molecule core of the reactive component of compositions crosslinkable is selected from synthetic and naturally occurring hydrophilic polymer, hydrophobic polymer and C usually ₂-C ₁₄Alkyl, 0 to 2 is selected from N, the heteroatomic C of O and S ₂-C ₁₄Alkyl, condition are crosslinkable component A, and B comprises the molecule core of synthetic hydrophilic polymer with at least one of the C that chooses wantonly.In preferred embodiments, at least one of A and B comprises the molecule core of synthetic hydrophilic polymer.

Hydrophilic crosslinkable component

On the one hand, crosslinkable component is a hydrophilic polymer.Term used herein " hydrophilic polymer " refers to synthetic polymer, and it has mean molecule quantity and effectively makes this polymer be the composition of " hydrophilic " as defined above.As above discuss, the synthetic crosslinkable hydrophilic polymer that can be used for this paper includes, but are not limited to: polyalkylene oxide, and especially Polyethylene Glycol and poly-(oxirane)-poly-(propylene oxide) copolymer comprises block and random copolymer; Polyhydric alcohol, as glycerol, polyglycereol (especially highly branched polyglycereol), propylene glycol and the propylene glycol that replaces with one or more polyalkylene oxides, for example, single-, two-and three-polyoxyethylene glycerol, single-and two-polyoxyethylated propylene glycol, and single-and two-polyoxyethylene trimethylene glycol; The polyoxyethylene sorbitol, the polyoxyethylene glucose; Acrylate copolymer and analog thereof and copolymer, as polyacrylic acid self, polymethylacrylic acid, poly-(hydroxyethyl-methacrylate), poly-(hydroxyethylmethacry,ate), poly-(methyl alkyl sulfoxide methacrylate), poly-(methyl alkyl sulfoxide acrylate) and front any copolymer and/or with the other acrylate kind such as the copolymer of amino-ethyl acrylate and list-2-(propenyloxy group) ethyl succinate; Poly; Poly-(acrylamide), own as poly-(acrylamide), poly-(Methacrylamide), poly-(DMAA) and poly-(N-isopropyl-acrylamide); Poly-(enol) is as poly-(vinyl alcohol); Poly-(N-vinyl lactam), as poly-(vinyl pyrrolidone), poly-(N-caprolactam), and copolymer; The Ju oxazoline comprises poly-(Jia oxazolin) and poly-(ethyl oxazoline); And polyvinylamine.The polymer tabulation that must emphasize the front is not limit, as will be apparent to those skilled in the art, can use many other synthetic hydrophilic polymeies.

Synthetic crosslinkable hydrophilic polymer can be homopolymer, block copolymer, random copolymer, perhaps graft copolymer.In addition, polymer can be a straight or branched, if side chain, can be highly branched, dendritic, super branched or star polymer by bottom line.This polymer can comprise biodegradable fragment and block, and it is distributed in the molecular structure of whole polymer or with single block and exists, and perhaps is present in the block copolymer.Biodegradable fragment is that degraded is so that those fragments of fracture covalent bond.Usually, biodegradable fragment is the fragment of hydrolysis and/or original position enzymatic lysis in the presence of water.Biodegradable fragment can be made up of small molecule segment, and described small molecule segment is such as ester bond, anhydride bond, original acid ester key, orthocarbonic acid ester bond, amido link, phosphonate bond or the like.Bigger biodegradable " block " will be made up of oligomerization that mixes hydrophilic polymer or polymeric segment usually.Illustrational biodegradable oligomerization and polymeric segment for example comprise, poly-(aminoacid) fragment, poly-(ortho esters) fragment, poly-(orthocarbonic ester) fragment, or the like.

Other suitable synthetic crosslinkable hydrophilic polymer comprises the polypeptide of chemosynthesis, and is especially synthetic and in conjunction with containing the aminoacid (as lysine) of primary amino radical and/or containing many nucleophilics polypeptide of the aminoacid (as, cysteine) of mercapto.Especially preferably poly-(lysine), it is the polymer of the synthetic generation of amino acid lysine (145MW).Prepared and had 6 poly-(lysines) to about 4,000 primary amino radicals, molecular weight corresponding to about 870 to about 580,000.Be used for poly-(lysine) of the present invention and preferably have about 1,000 to about 300,000 molecular weight; 5,000 to about 100,000 molecular weight more preferably from about; 8,000 to about 15,000 molecular weight most preferably from about.Poly-(lysine) of variable molecular weight can by commercial sources from peninsula laboratory company (Peninsula Laboratories, Inc). (Bellmont, California (Belmont, Calif.)) obtains.

Synthetic crosslinkable hydrophilic polymer can be homopolymer, block copolymer, random copolymer, perhaps graft copolymer.In addition, polymer can be a straight or branched, if branched, can be highly branched, dendritic, super branched or star polymer by bottom line.This polymer can comprise biodegradable fragment and block, and it is distributed in the molecular structure of whole polymer or with single block and exists, and perhaps is present in the block copolymer.Biodegradable fragment is that degraded is so that those fragments of fracture covalent bond.Typically, biodegradable fragment is the fragment of hydrolysis and/or original position enzymatic cutting in the presence of water.Biodegradable fragment can be made up of small molecule segment, and described small molecule segment is such as ester bond, anhydride bond, original acid ester key, orthocarbonic acid ester bond, amido link, phosphonate bond or the like.Bigger biodegradable " block " will be made up of the oligomerization or the polymeric segment that are attached in the hydrophilic polymer usually.Biodegradable oligomerization of the property illustrated and polymeric segment for example comprise, poly-(aminoacid) fragment, poly-(ortho esters) fragment, poly-(orthocarbonic ester) fragment, or the like.

As noted above, although can use multiple different synthetic crosslinkable hydrophilic polymer in the present composition, but preferred synthetic crosslinkable hydrophilic polymer is Polyethylene Glycol (PEG) and polyglycereol (PG), especially highly branched polyglycereol.The PEG of various ways is widely used in the modification of bioactive molecule, because PEG lacks toxicity, antigenicity and immunogenicity (promptly, be biocompatible), can be prepared so that have the dissolubility of wide region, and the conformation of common not interferases activity and/or peptide.For some application, especially preferred synthetic crosslinkable hydrophilic polymer is Polyethylene Glycol (PEG), it has about 100 to about 100, the molecular weight of 000 mole scope, although for highly branched PEG, can use more high molecular weight polymers-up to 1,000,000 or above-condition be to mix biodegradable site will have molecular weight less than about 30,000 to guarantee all catabolites.Yet for most PEG, preferred molecular weight is about 1,000 to about 20,000 moles, more preferably about 7,500 in about 20,000 mole scopes.Most preferably, Polyethylene Glycol has about 10,000 molar molecular weight.

Naturally occurring crosslinkable hydrophilic polymer includes, but are not limited to: protein, and as collagen, fibronectin, albumin, globulin, fibrinogen and fibrin, especially preferred collagen; Carboxylated polysaccharide is as polymannuronate and polygalacturonic acid; The amination polysaccharide, glycosaminoglycans especially, as hyaluronic acid, chitin, chondroitin sulfate A, B or C, keratan sulfate, keratosulfate and heparin; With activatory polysaccharide, as glucosan and starch derivatives.Collagen and glycosaminoglycans are the examples that is used for the naturally occurring hydrophilic polymer of this paper, and methylated collagen is a preferred hydrophilic.

Any hydrophilic polymer of this paper must contain, and perhaps be activated and contain functional group, that is, nucleophilic or electrophilic group, it makes can be crosslinked.The activation of PEG is discussed below; Yet, will understand, following discussion is used to illustrate purpose and can uses similar techniques to other polymer.

For PEG, at first, multiple functionalized poly (ethylene glycol) has been effective to (see Abuchowski etc., Enzymes as Drugs (as the enzyme of medicine), John Wiley﹠amp such as protein modification; Sons: New York, N.Y. (1981) pp.367-383; With Dreborg etc., " the comment summary of medicine carrier system " (Crit.Rev.Therap.Drug Carrier Syst.) (1990) 6:315), chemistry of peptides (is seen Mutter etc., The Peptides (peptide), U.S. academic press (Academic): New York, N.Y.2:285-332; With Zalipsky etc., Int.J.Peptide Protein Res (international peptide protein research magazine). (1987) 30:740) and polymeric drug synthetic (see Zalipsky etc., Eur.Polym.J (European polymer magazine). (1983) 19:1177; With Ouchi etc., " macromolecular science The Chemicals " be (1987) A24:1011 (J.Macromol.Sci.Chem.)) in the field.

The activated form of PEG comprises multifunctional activatory PEG, can obtain by commercial sources, and use the known method preparation easily.For example, see Poly (ethylene Glycol) Chemistry:Biotechnical and Biomedical Applications (poly-(ethylene glycol) chemistry: biotechnology and biological medicine are used), J.Milton Harris, ed.Plenum Press, the 22nd chapter of NY (1992); With (the Shearwater Polymers of sea-gull Polymer Company, Inc.) catalogue (Catalog), PolyethyleneGlycol Derivatives (polyethyleneglycol derivative), Huntsville (Huntsville), Alabama (Alabama) are (1997-1998).

Some of PEG are specific, the structure of the activatory form of four senses is at United States Patent (USP) 5,874, show among Fig. 1 to 10 of 500, and they are by with activatory PEG and polyamino PEG, promptly have the vague generalization product that the PEG of two or more primary amino radicals reacts.Illustrated activatory PEG has tetramethylolmethane (2,2-two (hydroxymethyl)-1, ammediol) core.As will be apparent to those skilled in the art, this type of activatory PEG is easily by with the hydroxyl of the exposure in the PEGization polyhydric alcohol (promptly, terminal hydroxyl on the PEG chain) changes into hydroxy-acid group (typically by in the presence of nitrogenous base, reacting), prepare by obtaining multifunctional activatory PEG then with N-hydroxy-succinamide, N-hydroxysulphosuccinimide or the like esterification with anhydride.

Hydrophobic polymer

Compositions crosslinkable of the present invention can also comprise hydrophobic polymer, although for most purposes, and the preferred hydrophilic polymer.Polylactic acid and polyglycolic acid are the examples of operable two kinds of hydrophobic polymers.For other hydrophobic polymer, contain the short chain oligomer of about 14 carbon atoms at most with only using, to avoid the relevant problem of dissolubility between the reaction period.

Lower-molecular-weight component:

Point out that as top the molecule core of one or more crosslinkable components can also be a low molecular weight compound, promptly contain and be selected from N, O, 0 to 2 heteroatomic C of S and combination thereof ₂-C ₁₄Alkyl.This molecule core can replace with nucleophilic group or with electrophilic group.

When replacing the low-molecular-weight core with primary amino radical, component for example can be, ethylenediamine (H ₂N-CH ₂CH ₂-NH ₂), butanediamine (H ₂N-(CH ₄)-NH ₂), five methylene diamine (cadaverine) (H ₂N-(CH ₅)-NH ₂), hexamethylene diamine (H ₂N-(CH ₆)-NH ₂), two (2-amino-ethyl) amine (HN-[CH ₂CH ₂-NH ₂] ₂), or three (2-amino-ethyl) amine (N-[CH ₂CH ₂-NH ₂] ₃).

Low molecular weight diol and polyhydric alcohol comprise trimethylolpropane, two (trimethylolpropane), tetramethylolmethane and diglycerol, they all need with the alkali activation so that promote their reactions as nucleopilic reagent.This type of dihydroxylic alcohols and polyhydric alcohol can also functionalised to provide two-and many-carboxylic acid, functional group, and it is above-mentioned as this paper, also can be under certain conditions as nucleopilic reagent.The polyprotic acid that is used for the present composition comprises, but be not limited to, tricarboxylic acids based on trimethylolpropane, tetrabasic carboxylic acid based on two (trimethylolpropanes), 1,5-pentanedicarboxylic acid., suberic acid (suberic acid), and hexadecandioic acid (hexadecane diacid) (hexadecandioic acid (hexadecane diacid)), all these can be by commercial sources acquisition and/or easily synthetic with known technology.

Low-molecular-weight two-comprise with many-electrophilic reagent, for example, two succinimido suberates (DSS), two (sulfosuccinimide base) suberate (BS ₃), dithio two (succinyl phosphorons amino propyl acid ester) (DSP), two (2-butanimide oxygen base ketonic oxygen base) ethyl sulfone (BSOCOES) and 3,3 '-dithio two (sulfosuccinimide base propionic ester) are (DTSPP) and their analog and derivant.Chemical compound above-mentioned can (Rockford (Rockford) III.) obtains from Pi Ersi (Pierce) by commercial sources.This two-and many-electrophilic reagent can also be from two-and polyprotic acid synthesize, for example, in the presence of DCC, react by N-hydroxy-succinamide with suitable mole.Can use multiple known technology that polyhydric alcohol such as trimethylolpropane and two (trimethylolpropane) are changed into carboxylic acid form, produce trifunctional and four functional activated polymers then by in the presence of DCC, further deriving with NHS.

Delivery system:

The suitable delivery system that is used for homogenizing dry powder composite (containing at least two kinds of crosslinkable polymer) and two kinds of buffer can comprise many compartments sprayer unit, wherein one or more compartments contain powder, the buffer that provides aqueous environments required is provided one or more compartments, thereby compositions is exposed to aqueous environments when leaving compartment.To organize many devices of sealant/hemorrhage be well known in the art and can be used for enforcement of the present invention to be suitable for sending multicomponent.Alternatively, can use the controlled extrusion system delivering compositions of any kind, perhaps it can be sent so that dry powder form is manual, and is exposed to aqueous environments in site of administration.

Homogenizing dry powder compositions and two kinds of buffer can be by placing independent syringe cylinder conveniently to form under aseptic condition each of three kinds of compositions (dried powder, acidic buffer and alkaline buffer).For example, compositions, first buffer and second buffer can be deposited separately in the many compartments injector system with a plurality of tubes, mixing head and outlet opening.Can add the first buffer dissolved composition and form homogeneous phase solution in hold the tube of compositions, it be expressed in the mixing head then.Can simultaneously second buffer be expressed in the mixing head.Then, resulting composition can be expressed on the surface by the hole.

For example, the syringe cylinder that holds dried powder and alkaline buffer can be the part of double syringe system, for example, and the dual barrel syringe of describing in the United States Patent (USP) 4,359,049 of Redl etc.In this embodiment, can add acidic buffer, thereby produce homogeneous phase solution to the syringe cylinder that also holds dried powder.In other words, acidic buffer can be added (for example, injection) in the syringe cylinder that holds dried powder, thereby produce the homogeneous phase solution of first kind and second kind component.This homogeneous phase solution can be expressed in the mixing head then, and alkaline buffer is expressed in the mixing head simultaneously.In mixing head, homogeneous phase solution and alkaline buffer are mixed together, thereby form reactant mixture.Afterwards, reactant mixture is expressed on the surface (for example, tissue) by the hole, forms film on this surface, and it can be used as confining bed or barrier layer or analog.When forming by homogeneous phase solution in the mixing mixing head and alkaline buffer, reactant mixture begins to form three dimensional matrix immediately.Therefore, be expressed into tissue from mixing head fast after reactant mixture is preferably formed, thereby form three dimensional matrix organizationally and it can adhere to this tissue.

Other system of two kinds of reaction liquids of combination is well known in the art, and comprises the U.S. Patent number 6,454,786 of Holm etc.; 6,461,325 of Delmotte etc.; 5,585,007 of Antanavich etc.; 5,116,315 and the Redl etc. of Capozzi etc. 4,631,055 in the system described.Preserve and handle:

Because crosslinkable component contains the electrophilic group with water reaction, thus one or more components of electrophilic usually with aseptic, dried forms is preserved and use to prevent that water from separating.The method for preparing the synthetic hydrophilic polymer that contains a plurality of electrophilic groups of aseptic, dried forms proposes in the U.S. Patent number 5,643,464 of the common Rhee of transferring etc.For example, dry synthetic polymer can be compression molded into thin slice or film, it can use gamma-rays then, preferred e-x radiation x sterilization.Gained desciccator diaphragm or sheet can be cut into desirable size or mince littler granule.

Therefore the component that contains multiple nucleophilic group is not that water is reactive and can kept dry or preserve in aqueous solution usually.If preserve with dry, granular solids, the various ingredients of compositions crosslinkable can fusion and preservation in single container so.All components should be up to just taking place with preceding with mixing of water, saline or other aqueous medium.

In alternative embodiment, linked can mix in a kind of single aqueous medium, and wherein they can all be not reactive, that is, and and such as in low pH buffer.Afterwards, they can be sprayed on the target tissue site with high pH buffer, and their fast reactions afterwards also form gel.

The suitable liquid medium of preserving compositions crosslinkable comprises aqueous buffer solution, and as sodium dihydrogen phosphate/sodium hydrogen phosphate, sodium carbonate/bicarbonate, glutamate, Glu or acetate, concentration is 0.5 to 300mM.Usually, be the sulfydryl reactive component that preparation replaces with dimaleoyl imino or succinimido in about 5 to 6 the dilution buffer liquid at water or pH, as PEG.The pK that is used to prepare many sulfydryls component such as sulfydryl-PEG is the quick-gelatinizing time of the compositions of about buffer of 8 to 10.5 mixture of can be used for realizing containing sulfydryl-PEG and SG-PEG.These comprise carbonate, borate and AMPSO (3-[(1,1-dimethyl-2-hydroxyethyl) amino] 2-hydroxyl-propane-sulfonic acid).By contrast, use the combination of dimaleoyl imino PEG and sulfydryl-PEG, for preferably about 5 to 9 the pH of liquid medium that is used to prepare sulfydryl PEG.

Collagen+fibrinogen and/or thrombin are (for example, Costasis)

On the other hand, polymer composition can comprise collagen, and it makes up with fibrinogen and/or thrombin.(see, for example, U.S. Patent number 5,290,552; 6,096,309; 5,997,811; 5,968,018 and 6,123,687).For example, waterborne compositions can comprise fibrinogen and FXIII, and especially consumption is enough to the blood plasma of multiviscosisty compositions, collagen, the polymeric thrombin of the fibrinogen that its consumption is enough to exist in the catalyst composition, and Ca ²⁺And randomly, its consumption is enough to hinder the degraded antifibrinolytic agent of gained viscosity grumeleuse.Compositions can be mixed with two-part compositions, it only mixes before use, and wherein fibrinogen/FXIII and collagen are formed first component, and thrombin and antifibrinolytic agent and Ca2+ form second component.

The blood plasma that provides fibrinogen to originate can be from obtaining the patient of its delivering compositions.After the standard fabrication, blood plasma can " tale quale " uses, and described standard fabrication comprises the centrifugal cellular component that goes out blood.Alternatively, the further processing to concentrate fibrinogen of blood plasma can be prepared cryoprecipitate.Can blood plasma is freezing at least about 1 hour-20 ℃ of pacts, prepare cryoprecipitate in about 4 ℃ of overnight storage frozen plasma slowly to thaw then.The centrifugal blood plasma that thaws also comprises the cryoprecipitate that remains 1/5 blood plasma and collects cryoprecipitate to provide by removing about 4/5 blood plasma.Can use other fibrinogen/FXIII prepared product, as cryoprecipitate, patient from body fibrin sealant, fibrinogen analog or other single donor or commercial fibrin sealant material.About 0.5ml provides about 1 to the 2ml binding compositions to about 1.0ml blood plasma or blood plasma-cryoprecipitate, and it enough is used for the middle ear surgical operation.Because preparation and the multiple variation for preparing the method for said preparation, other plasma proteins (for example, albumin, plasminogen, Feng's von willebrand's factor, VIII factor or the like) can exist or can not be present in fibrinogen/FXII separator.

Collagen, preferably hypoallergenic collagen is present in the compositions with the amount of the bond property of enough thickener compositions and enhancing preparation.Collagen can be non-end peptide collagen or end peptide collagen, for example, and natural collagen.Except thickener composition, collagen also comes fortifying fibre albumen by macromole lattice structure or support as the absorption of fibrin network.This has provided the greater strength and the durability of gained gelled block, and (that is, AFG) compare, this grumeleuse has the fibrinogen of relative low concentration with multiple spissated self property fibrin virgin rubber preparation.

It is " near natural " at least in its architectural feature that used form of collagen can be described as.It can further be characterized by at the pH that is higher than 5 and cause insoluble fibre; Except that non-crosslinked or as the complex combination thing, the part of bone for example, it is usually by fibrous greater than 50nm of in a small amount diameter by weight, about 1 to 25 volume % usually, and if any, very little basically change is arranged in fibriilar helical structure.In addition, collagen compositions must be able to strengthen the gelation in the surgical operation adhesion compositions.

Can use many by the obtainable collagen formulations of commercial sources.ZYDERM collagen implant (ZYDERM Collagen Implant) (ZCI) has in 90% volume content by 5 to 10nm diameter fibers, the distribution of fiber diameters that remaining 10% usefulness is formed greater than the diameter fibers of about 50nm.ZCI can be with the isotonic saline solution of phosphate-buffered, and fiber slurry and solution among the pH 7.2 obtain, and available thin gauge needle injection.As different, can use the crosslinked with collagen that obtains with ZYPLAST with ZCI.ZYPLAST is the external source of ZCI crosslinked (glutaraldehyde) form basically.The diameter that this material has a high level is greater than the fibril of about 50nm and keep insoluble in wide pH scope.Crosslinked have an endogenous crosslinked effect of finding in many tissues in the analogue body.

Thrombin as the catalyst of fibrinogen so that fibrin to be provided---a kind of insoluble polymer and be present in the compositions with the polymeric amount of the fibrinogen that exists in the enough catalysis patient blood plasma.Thrombin also activates FXIII, and a kind of plasma proteins of covalent cross-linking in the catalysis fibre albumen makes that the gained grumeleuse is insoluble.Usually, thrombin is with about 0.01 to about 1000 or the activity of bigger NIH unit (NIHu), and usually about 1 to about 500NIHu, the most common about concentration of 200 to about 500NIHu is present in the adhesive composition.Thrombin can be from multiple host animal source, easily from cattle.Thrombin can be commercially available from multiple source, comprises Parker-Davis (Parke-Davis), and it is packed in the bottle with buffer salt and stabilizing agent lyophilizing usually, and it provides about 1000NIHu to 10, the thrombin activity of 000NIHu.Usually by sterile distilled water or the reconstruct of isotonic saline solution adding powder are prepared thrombin.Alternatively, can use the coagulant in thrombin analog or reptile source.

Compositions can additionally comprise the antifibrinolytic agent of effective dose to strengthen the integrity of agglutination gelled block between the emergence period.Many antifibrinolytic agents are known and comprise aprotinin, C1-esterase inhibitor and epsilon-amino-just-caproic acid (EACA).Epsilon-amino-just-caproic acid is unique antifibrinolytic agent of FDA approval, and is effective under the concentration of the final adhesive composition of about 40mg/ml at about 5mg/ml, is more typically about 20 and arrives about 30mg/ml.EACA can obtain by the solution of commercial sources with concentration with about 250mg/ml.Easily, with commercial solution with distilled water diluting so that the solution of desired concentration to be provided.Wish that this solution is used for the freeze dried thrombin of reconstruct to obtain desirable concentration of thrombin.

Other case description that forms material based on proteinic crosslinked original position is in for example, U.S. Patent number RE38158; 4,839,345; 5,514,379,5,583,114; 6,458,147; 6,371,975; 5,290,552; 6,096,309; U.S. Patent Application Publication No. 2002/0161399; 2001/0018598 and PCT publication number WO 03/090683; WO 01/45761; WO 99/66964 and WO 96/03159).

The autoreaction chemical compound

On the one hand, discharge therapeutic agent from crosslinked substrate, described crosslinked substrate is at least partly from the autoreaction compound formation.Autoreaction chemical compound used herein comprises the core that replaces with minimum three reactive groups.Reactive group can be directly connected to the core of chemical compound, and perhaps reactive group can be connected to the core of chemical compound indirectly, and for example, reactive group connects core by one or more linking groups.

At least one the key that each that must be present in three reactive groups in the autoreaction chemical compound can experience with remaining two reactive group forms reaction.In order to illustrate, mention when these chemical compound reactions form crosslinked substrate, reactive group on chemical compound of the most common generation and the reaction of the reactive group on another chemical compound.That is, term " autoreaction " is not intended to and refers to that each autoreaction chemical compound must react with himself, but when many identical autoreaction chemical compounds combinations and when experiencing cross-linking reaction, so these chemical compounds formation substrate that will react to each other.These chemical compounds can react with other chemical compound that has with they identical chemical constitutions for " autoreaction " is meant them.

The autoreaction chemical compound comprises at least 4 components: a core and three reactive groups.In one embodiment, the autoreaction chemical compound can characterize by through type (I), and wherein R is a core, and reactive group passes through X ¹, X ²And X ³Representative, joint (L) is optional to be present between core and the functional group.

Core R is connected to the multivalence part (that is, it is at least trivalent) of at least three groups and passable, perhaps for example can contain hydrophilic polymer, hydrophobic polymer, amphipathic nature polyalcohol, C _2-14Alkyl or contain heteroatomic C _2-14Alkyl.Linking group L ¹, L ², and L ³Can be identical or different.Symbol p, q and r are 0 (when not having joint) or 1 (when having joint).Reactive group X ¹, X ²And X ³Can be identical or different.Each of these reactive groups and at least one other reactive group reaction form three dimensional matrix.Therefore, X ¹Can with X ²And/or X ³Reaction, X ²Can with X ¹And/or X ³Reaction, X ³Can with X ¹And/or X ²Reaction or the like.The trivalent core can be directly or indirectly in conjunction with three functional groups, and the tetravalence core will be directly or indirectly in conjunction with four functional groups, or the like.

Each side chain typically has a reactive group.Yet the present invention also comprises the autoreaction chemical compound, and wherein side chain contains more than one reactive group.Thereby in another embodiment of the present invention, the autoreaction chemical compound has formula (II):

[X′-(L ⁴) _a-Y′-(L ⁵) _b] _c-R′

Wherein: a and b are the integer of 0-1; C is the integer of 3-12; R ' is selected from hydrophilic polymer, hydrophobic polymer, amphipathic nature polyalcohol, C _2-14Alkyl and contain heteroatomic C _2-14Alkyl; X ' and Y ' are reactive group and can be identical or different; L ⁴And L ⁵Be linking group.Each reactive group and another reactive group formation three dimensional matrix that reacts to each other.This chemical compound is essentially non-reacted in initial environment, but when being exposed to the change of initial environment, have reactivity, form three dimensional matrix in the environment of this change thereby described change provides the many autoreaction chemical compounds of the environment of change to interact.In a preferred embodiment, R is a hydrophilic polymer.In another preferred embodiment, X ' is that nucleophilic group and Y ' are electrophilic group.

Following autoreaction chemical compound is an example of formula (II) chemical compound:

R wherein ⁴Have formula:

Thereby in formula (II), a and b are 1; C is 4; Core R ' is a hydrophilic polymer, four sense activated polyglycol, (C (CH ₂-O-) ₄X ' is the electrophilic reaction base, succinimido; Y ' is necleophilic reaction base-CH-NH ₂L ⁴For-C (O)-O-; And L ⁵For-(CH ₂-CH ₂-O-CH ₂) _x-CH ₂-O-C (O)-(CH ₂) ₂-.

Can easily synthesize autoreaction chemical compound of the present invention by technology well known in the art.Provide representative synthetic below:

The selective response base makes chemical compound essentially no reactivity in initial environment.When being exposed to the specific change of initial environment, the environment of change is provided, make this responding property of chemical compound and many autoreaction chemical compounds then can in the environment that changes, interact and form three dimensional matrix.The example that changes in the initial environment is discussed in more detail below, but comprises the adding aqueous medium, and the change of pH is exposed to ultraviolet radiation, the change of temperature, perhaps catalytic oxidation reduction initiator.

Can also select core and reactive group so that the chemical compound with one or more following features is provided: be biocompatible, right and wrong are immunogenic, do not stay any toxicity, inflammatory or immunogenic response product in site of administration.Similarly, can also select core and reactive group so that the substrate of the gained with one or more these features is provided.

In one embodiment of the invention, immediately or behind the environment that changes being exposed to immediately, the autoreaction chemical compound just interacts and forms three dimensional matrix basically.Term " basically immediately " is intended to refer to be less than 5 minutes, preferably is less than in 2 minutes, and term " immediately " is intended to refer to be less than in 1 minute, preferably is less than in 30 seconds.

In one embodiment, autoreaction chemical compound and gained substrate are not subjected to the enzymatic cutting of matrix metalloproteinase such as collagenase, and therefore are not easy degradation in vivo.In addition, the autoreaction chemical compound can easily be controlled to strengthen some character according to every kind of components selection and amount, for example, and compressive strength, swellability, viscosity, hydrophilic, optical clarity or the like.

In a preferred embodiment, R is a hydrophilic polymer.In another preferred embodiment, X is a nucleophilic group, and Y is an electrophilic group, and Z is electrophilic or nucleophilic group.Other embodiments describe in detail below.

When the compressive strength of less swollen substrate of hope or increase, the interaction of higher degree, for example, crosslinked can be useful.In those embodiments, can wish that n is the integer of 2-12.In addition, when utilizing many autoreaction chemical compounds, described chemical compound can be identical or different.

A. Reactive group

Before the use, the autoreaction chemical compound is preserved to guarantee that chemical compound keeps non-reacted basically before use in initial environment.When changing this environment, make chemical compound have reactivity and then chemical compound lot react to each other and form desirable substrate.Thereby the character by the reactive group that relates to is determined initial environment, and the environment that changes.

The reactive group number can be identical or different.Yet in one embodiment of the invention, the number of reactive group is equal approximately.As above hereinafter used, term " about " refers to 2: 1 to 1: 2 ratio of a kind of reactive group molal quantity and another differential responses base molal quantity.Common preferred 1: 1: 1 reactive group mol ratio.

Usually, when character was liquid, the autoreaction compound concentrations was about 1 to 50wt% in the environment that changes, usually about 2 to 40wt% scope.The preferred concentration of chemical compound depends on many factors in the liquid, comprises the type (being the type of molecule core and reactive group) of chemical compound, the final use of their molecular weight and gained three dimensional matrix.For example, use the chemical compound of higher concentration, or use more that the chemical compound of highly functionalization will cause forming tightr crosslinked network, produce harder, more firm gel.Therefore, be intended to be used to organize enhanced compositions will use the autoreaction chemical compound of the higher-end concentration that falls into preferred concentration range for usually.Therefore be intended to as biological adhesive or prevent adherent compositions not need and can contain the autoreaction chemical compound of low concentration for film.

1) Electrophilic and necleophilic reaction base

In one embodiment of the invention, reactive group is electrophilic and nucleophilic group, its experience nucleophilic substitution, nucleophilic addition, or both.Term " electrophilic " refers to be subject to nucleophillic attack, promptly is easy to and the reactive group of the nucleophilic group that enters reaction.The electrophilic group of this paper be positively charged or electron deficiency, typically be electron deficiency.Term " nucleophilic " refer to be rich in electronics, have as the unshared electron pair of reaction site and with the reactive group of positively charged or the reaction of electron deficiency site.For this type of reactive group, the change in the initial environment comprises the change that adds aqueous medium and/or pH.

In one embodiment of the invention, X1 (being also referred to as X herein) can be nucleophilic group, and (being also referred to as Y herein) can for electrophilic group or vice versa for X2, and X3 (being also referred to as Z herein) can be electrophilic or nucleophilic group.

X can be any nucleophilic group almost, if can with electrophilic group Y and also with Z, when Z is electrophilic (Z _EL) time, react.Similarly, Y can be any electrophilic group almost, if can with X and also with Z, when Z is nucleophilic (Z _NU) time, react.Unique restriction is actual restriction, is X and Y, X and Z _ELOr Y and Z _NUBetween reaction should be quite fast and when mixes, react automatically with aqueous medium, do not need to heat or possible deleterious or abiotic degradable catalysts or other chemical reagent.Although is not essential preferably also, reacts and do not need ultraviolet or other radiation.In one embodiment, X and Y, X and Z _ELOr Y and Z _NUBetween be reflected at 60 minutes, finish in preferred 30 minutes.Most preferably, be reflected at about 5 to 15 minutes or shorter time in finish.

Suitable to X or Fn _NUThe example of nucleophilic group include, but are not limited to :-NH ₂,-NHR ¹,-N (R ¹) ₂,-SH ,-OH ,-COOH ,-C ₆H ₄-OH ,-H ,-PH ₂,-PHR ¹,-P (R ¹) ₂,-NH-NH ₂,-CO-NH-NH ₂,-C ₅H ₄N or the like, wherein R ¹Be alkyl and each R ¹Can be identical or different.R ¹Typically be alkyl or monocyclic aryl, preferred alkyl, most preferably low alkyl group.Organic metal part also is useful nucleophilic group for purpose of the present invention, especially as those organic metal parts of carbanion donor.The example of organic metal part comprises: Grignard degree of functionality-R ²MgHal, wherein R ²Be carbon atom (replacement or unsubstituted) that Hal is a halogen, typically is bromine, iodine or chlorine, preferred bromine; The degree of functionality that contains lithium typically is the lithium alkylide group; The degree of functionality that contains sodium.

Those of ordinary skills will understand that some nucleophilic group must be with the alkali activation reacting with electrophilic group.For example, when having nucleophilic sulfydryl and hydroxyl in the autoreaction chemical compound, chemical compound must mix with aqueous base so that remove deprotonation and provide-S ^-Or-O ^-Kind is reacting with electrophilic group.Participate in reaction unless wish alkali, preferred non-nucleophilic base.In some embodiments, alkali can exist with the component of buffer.Suitable alkali and corresponding cross-linking reaction are described hereinafter.

The selection of the electrophilic group that provides on the autoreaction chemical compound must be provided, thus may with specific nucleophilic group reaction.Therefore, when the X reactive group is amino, select Y and any Z _ELGroup is to react with amino.Similarly, when the X reactive group was the sulfydryl part, corresponding electrophilic group was the sulfydryl reactive group, or the like.Usually, suitable to Y or Z _ELThe example of electrophilic group include, but not limited to-CO-Cl ,-(CO)-O-(CO)-R (wherein R is an alkyl) ,-CH=CH-CH=O and-CH=CH-C (CH ₃)=O, halogen ,-N=C=O ,-N=C=S ,-SO ₂CH=CH ₂,-O (CO)-C=CH ₂,-O (CO)-C (CH ₃)=CH ₂,-S-S-(C ₅H ₄N) ,-O (CO)-C (CH ₂CH ₃)=CH ₂,-CH=CH-C=NH ,-COOH ,-(CO) O-N (COCH ₂) ₂,-CHO ,-(CO) O-N (COCH ₂) ₂-S (O) ₂OH and-N (COCH) ₂

When X is amino (although needing not to be primary amino radical usually), Y and Z _ELThe electrophilic group of last existence is the amine reactive group.Limit as an example and not, representative amine reactive group comprises following group or its free radical: (1) carboxylate comprises cyclic ester and " activation " ester; (2) the acid chloride group (CO-Cl); (3) anhydride ((CO)-O-(CO)-R), wherein R is an alkyl; (4) ketone and aldehyde comprise α, beta-unsaturated aldehyde and ketone, as-CH=CH-CH=O and-CH=CH-C (CH ₃)=O; (5) halogen group; (6) NCO (N=C=O); (7) sulfo-isocyanide acyl group group (thioisocyanato) (N=C=S); (8) epoxide; (9) activatory hydroxyl (for example, with conventional activator such as N,N'-carbonyldiimidazole or sulfonic acid chloride activation); (10) alkene comprises the alkene of puting together, as ethylene sulfonyl (SO ₂CH=CH ₂) and similar functional group, comprise acrylate (O (CO)-C=CH ₂), methacrylate (O (CO)-C (CH ₃)=CH ₂), ethyl acrylate (O (CO)-C (CH ₂CH ₃)=CH ₂), and aziridinyl is (CH=CH-C=NH).

In one embodiment, the amine reactive group contains the electrophilic reaction carbonyl of the nucleophillic attack that is subject to primary amine or secondary amine, for example, and carboxylate above-mentioned and aldehyde, and carboxyl is (COOH).

Because hydroxy-acid group itself is difficult for and the nucleophilic amine reaction, the component of hydroxy-acid group must activate so that be that amine is reactive so contain.Can finish activation with several different methods, but be usually directed in the presence of dehydrant such as dicyclohexylcarbodiimide (DCC) or 1,3-Dicyclohexylurea (DHU), react with the suitable chemical compound that contains hydroxyl.For example, carboxylic acid N-hydroxyl-butanimide that can replace with alkoxyl or N-hydroxysulphosuccinimide react in the presence of DCC and form reactive electrophilic group respectively, N-hydroxyl-succinimide ester and N-hydroxysulphosuccinimide ester.Carboxylic acid can also be by reacting with carboxylic acid halides such as acid chloride (for example, chloroacetic chloride) and activating, so that the reactive acid anhydride group to be provided.In another example, can use-case carboxylic acid be changed into the acid chloride group as thionyl chloride or acyl chlorides that can exchange reaction.The particular agent that is used for implementing this type of priming reaction and step are that those of ordinary skills are known and describe at relevant teaching material and document.

Therefore, in one embodiment, the amine reactive group is selected from succinimido ester (O (CO)-N (COCH ₂) ₂), sulfosuccinimide base ester (O (CO)-N (COCH ₂) ₂-S (O) ₂OH), dimaleoyl imino (N (COCH) ₂), epoxy, isocyanide acyl, sulfo-isocyanide acyl, and ethylsulfonyl.

Similarly, when X is sulfydryl, Y and Z _ELThe electrophilic group of last existence is the group with the sulfydryl partial reaction.This type of reactive group comprises when reacting with sulfydryl those groups that form thioester bond, those that describe in WO 00/62827 as Wallace etc.As explaining in detail that therein the sulfydryl reactive group includes, but are not limited to: blended anhydride; The ester derivant of phosphorus; The ester derivant of paranitrophenol, p-nitrophenyl thiophenol and Pentafluorophenol; The ester of the azanol that replaces comprises N-hydroxyphthalimide ester, N-hydroxy-succinamide ester, N-hydroxysulphosuccinimide ester and N-hydroxyl glutarimide ester; The ester of I-hydroxybenzotriazole; 3-hydroxyl-3,4-dihydro-phentriazine-4-ketone; 3-hydroxyl-3,4-dihydro-chinazoline-4-ketone; The carbonylic imidazole derivant; Acid chloride; Ketenes; And isocyanates.Use these sulfydryl reactive groups, auxiliary reagent also can be used to promote key to form, for example, 1-ethyl-3-[3-dimethylaminopropyl] carbodiimide can be used to promote sulfydryl is coupled to the group that contains carboxyl.

Except forming the sulfydryl reactive group of thioester bond, can use multiple other sulfydryl reactive functional group degree that forms other type bonds.For example, the chemical compound and the sulfydryl formation imino group-thioester bond that contain the methylene imine ester derivant.Alternatively, can use the sulfydryl reactive group that forms disulfide bond with sulfydryl; This type of group has structure-S-S-Ar usually, wherein Ar replaces or the unsubstituted heteroaromatic part of nitrogen or the non-heterocyclic aromatic group that partly replaces with electrophilic of containing, thereby Ar can be for for example, 4-pyridine radicals, o-nitrophenyl ,-nitrobenzophenone, right-nitrobenzophenone, 2,4-dinitrophenyl, 2-nitro-4 benzoic acid, 2-nitro-4-pyridine radicals or the like.In this type of situation, auxiliary reagent, that is, gentle oxidant as hydrogen peroxide, can be used to promote disulfide bond to form.

Another kind of sulfydryl reactive group and sulfydryl form thioether bond.This type of group is particularly including dimaleoyl imino, haloalkyl, epoxy, imino group and '-aziridino and the alkene (comprise and put together alkene) of dimaleoyl imino, replacement; as ethylene sulfonyl, aziridinyl, acrylate, methacrylate; and α, β-undersaturated aldehyde and ketone.

When X be-during OH, the electrophilic functional group on all the other components must and hydroxyl reaction.Hydroxyl can be as above about the hydroxy-acid group activation, perhaps it can be in the presence of alkali directly and enough reactive electrophilic groups, react as epoxide group, aziridine group, carboxylic acid halides, anhydride or the like.

When X is organic metal nucleophilic group such as Grignard degree of functionality or alkyl lithio, be to contain those of carbonyl with the suitable electrophilic functional group of its reaction, for example comprise ketone and aldehyde.

Understand that also some functional group can be used as nucleophilic group or electrophilic group reaction, this depends on selected reaction gametophyte and/or reaction condition.For example, hydroxy-acid group can be in the presence of great alkali as the nucleophilic group reaction, but usually as electrophilic group, allow the nucleophillic attack on carbonyl carbon and follow the replacement hydroxyl with the nucleophilic group of introducing.

Be elucidated later herein below these and other embodiment, the covalent bond that produces after specific necleophilic reaction base and the specific electrophilic reaction base covalent bond on the autoreaction chemical compound in its mesostroma comprises, only as an example, and following table:

Table

Representative nucleophilic group (X, Z _NU)	Representative electrophilic group (Y, Z _EL)	The gained key
Representative nucleophilic group (X, Z _NU)	Representative electrophilic group (Y, Z _EL)	The gained key	-NH ₂	-O-(CO)-O-N(COCH ₂) ₂Carbonic acid succinimide ester end	-NH-(CO)-O-
-SH	-O-(CO)-O-N(COCH ₂) ₂	-S-(CO)-O-	-NH ₂	-O-(CO)-O-N(COCH ₂) ₂Carbonic acid succinimide ester end	-NH-(CO)-O-
-SH	-O-(CO)-O-N(COCH ₂) ₂	-S-(CO)-O-	-OH	-O-(CO)-O-N(COCH ₂) ₂	-O-(CO)-
-NH ₂	-O(CO)-CH＝CH ₂The acrylate end	-NH-CH ₂CH ₂-(CO)-O-	-OH	-O-(CO)-O-N(COCH ₂) ₂	-O-(CO)-
-NH ₂	-O(CO)-CH＝CH ₂The acrylate end	-NH-CH ₂CH ₂-(CO)-O-	-SH	-O-(CO)-CH＝CH ₂	-S-CH ₂CH ₂-(CO)-O-
-OH	-O-(CO)-CH＝CH ₂	-O-CH ₂CH ₂-(CO)-O-	-SH	-O-(CO)-CH＝CH ₂	-S-CH ₂CH ₂-(CO)-O-

For the autoreaction chemical compound that contains electrophilic and necleophilic reaction base, initial environment typically can be for dry and aseptic.Because electrophilic group and water reaction, so will prevent hydrolysis with aseptic, dried forms preservation.Dry synthetic polymer can be compression molded into thin slice or film, it can be sterilized with γ or e-x radiation x then.Gained desciccator diaphragm or sheet can be cut into desirable size or mince littler granule.The change of exsiccant initial environment will typically comprise the adding aqueous medium.

In one embodiment, initial environment can be an aqueous medium, as low pH buffer, promptly has the pH less than about 6.0, and wherein all right and wrong are reactive for electrophilic and nucleophilic group.The suitable liquid medium of preserving this compounds comprises aqueous buffer solution, and as sodium dihydrogen phosphate/sodium hydrogen phosphate, sodium carbonate/bicarbonate, glutamate, Glu or acetate, concentration is 0.5 to 300mM.The change of initial low pH aqueous environments will comprise typically that increasing pH arrives pH 7.0 at least, more preferably increases pH and arrives pH 9.5 at least.

In another embodiment, the change of initial dry environment comprises and the autoreaction chemical compound is dissolved in to form homogeneous phase solution in first buffer of pH in about 1.0 to 5.5 scopes and (ii) add pH to this homogeneous phase solution be about 6.0 to 11.0 second buffer.Buffer can be aqueous and can be any pharmaceutically acceptable alkalescence or acidic composition.Term " buffer " is used to refer to acidity and alkaline aqueous solution with ordinary meaning, and wherein this solution can or can not brought into play the function that buffering effect (that is the resistance that behind adding acid or the alkali pH is changed) is provided in compositions of the present invention.For example, the autoreaction chemical compound can be the form of even dried powder.This powder then with the combination of the buffer of the pH with about 1.0 to 5.5 scopes to form the homogeneous phase acidic aqueous solution, this solution is combined to form reaction solution with the buffer with about pH of 6.0 to 11.0 then.For example, the 0.375g dried powder can be used for providing homogeneous phase solution with the combination of 0.75g acidic buffer after mixing, and wherein the combination of this solution and 1.1g alkaline buffer is to provide the reactant mixture that forms three dimensional matrix basically immediately.

Acidic buffer with pH scope of about 1.0 to 5.5 comprises, be used to illustrate and do not limit: citric acid, hydrochloric acid, phosphoric acid, sulphuric acid, AMPSO (3-[(1,1-dimethyl-2-hydroxyethyl) amino] 2-hydroxyl-propane-sulfonic acid), the solution of acetic acid, lactic acid and their combination.In preferred embodiments, acidic buffer is the solution of citric acid, hydrochloric acid, phosphoric acid, sulphuric acid and their combination.No matter accurate acidulant, acidic buffer preferably has the reactive pH that hinders nucleophilic group on the core.For example, 2.1 pH enough hinders the nucleophilicity of mercapto usually.When core contains amido as nucleophilic group, typically preferred low pH.Usually, acidic buffer is an acid solution, and it is when contact during nucleophilic group, makes the non-relatively nucleophilic of those nucleophilic groups.

Representative acidic buffer is a hydrochloric acid solution, has the concentration of about 6.3mM and 2.1 to 2.3 pH.Can promptly, prepare this buffer by with concentrated hydrochloric acid and water combination by the dilute with water concentrated hydrochloric acid.Similarly, this buffer A can also be by being diluted to the 1.23g concentrated hydrochloric acid 2 liters of volumes, perhaps the 1.84g concentrated hydrochloric acid is diluted to 3 liters of volumes, perhaps the 2.45g concentrated hydrochloric acid is diluted to 4 liters of volumes, perhaps the 3.07g concentrated hydrochloric acid is diluted to 5 liters of volumes, perhaps the 3.68g concentrated hydrochloric acid is diluted to 6 liters of volumes and prepares easily.Reason for safety preferably is added to concentrated acid in the water.

Alkaline buffer with about pH of 6.0 to 11.0 is as illustrating and restrictively not comprising: glutamate, Glu, acetate, carbonate and bicarbonate are (for example, sodium carbonate, crystal carbonate and sodium bicarbonate), borate, phosphate and hydrophosphate (for example, one hypophosphite monohydrate sodium dihydrogen and sodium hydrogen phosphate), and the combination solution.In preferred embodiments, alkaline buffer is the solution of carbonate, phosphate and combination thereof.

Usually, alkaline buffer in when the homogeneous phase solution that adds chemical compound and first buffer with the aqueous solution of the effect of acidic buffer, thereby nucleophilic group obtains their nucleophilic feature (sheltering by the effect of acidic buffer) once more on the core, thereby allows the electrophilic group on nucleophilic group and the core to interact.

Representative alkaline buffer is carbonate and phosphatic aqueous solution.This buffer can be by preparing aqueous slkali and salt solution mix.Can be by with 34.7g one hypophosphite monohydrate sodium dihydrogen, 49.3g crystal carbonate and enough hydrations of 2 liters of liquor capacities are provided and prepare described saline solution.Similarly, can be by with 104.0g one hypophosphite monohydrate sodium dihydrogen, 147.94g crystal carbonate and enough hydrations of 6 liters of saline solution are provided and prepare 6 liters of solution.Can be by with 7.2g sodium hydroxide and 180.0g hydration and prepare alkaline buffer.Typically on demand aqueous slkali is added saline solution and prepare alkaline buffer, finally provide to have desirable pH, for example, the mixture of 9.65 to 9.75 pH.

Usually, the alkaline kind that exists in the alkaline buffer should be enough alkalescence with in and the acidity that provides of acidic buffer, thereby but needn't self nucleophilic like this it will react substantially with the electrophilic group on the core.Owing to this reason, the preferred alkali of " soft " relatively in this embodiment of the present invention is as carbonate and phosphate.

In order to illustrate the preparation of three dimensional matrix of the present invention, the mixture of autoreaction chemical compound and first acidic buffer (for example, acid solution, for example, dilute hydrochloric acid solution) can be merged and form homogeneous phase solution.This homogeneous phase solution and second alkaline buffer (for example, alkaline solution for example, contains the aqueous solution of phosphate and carbonate) mix, so the formation three dimensional matrix interact with each other immediately basically of the reactive group on the autoreaction chemical compound core.

2) The redox reaction base

In one embodiment of the invention, reactive group is a vinyl, and as styrene derivative, it experiences radical polymerization when causing with redox initiator.Term " oxidoreduction " refers to be subject to the activatory reactive group of oxidation-reduction.Term " vinyl " refers to be formed by redox initiator activation and reaction back the reactive group of free radical.X, Y can be identical with different vinyls with Z, for example, the methacrylic acid group.

For the autoreaction chemical compound that contains the vinyl reactive group, initial environment will typically be aqueous environments.The change of initial environment comprises the adding redox initiator.

3) The oxidative coupling reaction base

In one embodiment of the invention, reactive group experience oxidative coupling reaction.For example, X, Y and Z can be halogen group, as chlorine, have adjacent electron-withdrawing group having on the carbon of halogen (for example, " L " connect base on).Representative electron-withdrawing group comprises nitro, aryl or the like.

For this type of reactive group, the change in the initial environment comprises the change of pH.For example, at alkali, exist down as KOH, so the dehydrogenation of autoreaction chemical compound experience, the chlorine coupling reaction forms two keys between carbon atom, illustrate as following:

For the autoreaction chemical compound that contains the oxidative coupling reaction base, initial environment typically can be for dry and aseptic, perhaps non-alkaline medium.The change of initial environment typically comprises adding alkali.

4) The Photoinitiated reactions base

In one embodiment of the invention, reactive group is light-initiated group.For this type of reactive group, the change of initial environment comprises and is exposed to ultraviolet radiation.

In one embodiment of the invention, X can be azido (N ₃), Y can for alkyl as-CH (CH ₃) ₂, or vice versa.Be exposed to ultraviolet radiation then the bonding of key below providing will be provided between group :-NH-C (CH ₃) ₂-CH ₂-.In another embodiment of the present invention, X can be benzophenone ((C ₆H ₄)-C (O)-(C ₆H ₅)) base, Y can be alkyl, as-CH (CH ₃) ₂, or vice versa.Be exposed to ultraviolet radiation then the bonding of key below providing will be provided between group:

For the autoreaction chemical compound that contains light-initiated reactive group, the environment that initial environment typically will cover for ultraviolet radiation.This can preserve in ultraviolet radiation impermeability container for for example.

The change of initial environment will typically comprise and be exposed to ultraviolet radiation.

5) The temperature sensitivity reactive group

In one embodiment of the invention, reactive group is the responsive to temperature group, and it experiences thermal chemical reaction.For this type of reactive group, therefore the change in the initial environment comprises the change of temperature.Term " temperature sensitivity " refer under a kind of temperature or in the temperature range for chemically inert and in different temperatures or temperature range for reactive reactive group.

In one embodiment of the invention, X, Y and Z are identical or different vinyl.

For the autoreaction chemical compound that contains temperature sensitive reactive group, initial environment is typically in about 10 to 30 ℃ scope.

The change of initial environment will typically comprise the change temperature in about 20 to 40 ℃ scope.

B. Linking group

Reactive group can be directly connected to core, and perhaps they can connect indirectly by linking group, and long linking group is also referred to as " cahin extension agent ".In the formula in the above (I), optional linking group passes through L ¹, L ²And L ³P is wherein worked as in representative, and q and r equal at 1 o'clock, have linking group.

Suitable linking group is well known in the art.See, for example, the WO 97/22371 of Rhee etc.When can being used to avoid having, linking group forms relevant sterically hindered problem with intermolecular Direct Bonding.Linking group can additionally be used for some autoreaction chemical compounds are linked together and obtain bigger molecule.In one embodiment, linking group can be used for use with the gained gel formation after change the degraded character of compositions.For example, linking group can be used to promote hydrolysis, hinders hydrolysis, and the enzymatic degradation site perhaps is provided.

The example of linking group that the hydrolyzable site is provided is particularly including ester bond; Anhydride bond is as the anhydride bond by obtaining in conjunction with glutarate and succinate; Original acid ester key; The orthocarbonic acid ester bond is as the propylene carbonate key; Amido link; The phosphoric acid ester bond; The alpha-hydroxy acid key is as by obtaining in conjunction with lactic acid and glycolic those; Based on the key of lactone, as those by obtaining in conjunction with caprolactone, valerolactone, gamma-butyrolacton with to-Er Evil ketone; And amido link, as the amido link in dimer, oligomer or poly-(aminoacid) fragment.The example of non-degradable linking group comprises butanimide, propanoic acid and carboxylic methyl ester key.See, for example, the WO 99/07417 of Coury etc.The example of the degradable key of enzyme comprises Leu-Gly-Pro-Ala, and it can pass through degraded by collagenase; And Gly-Pro-Lys, it can be degraded by fibrinolysin.

Can also comprise that linking group is to strengthen or to suppress the reactivity of multiple reactive group.For example, sulfydryl-electron withdraw group in individual and two carbon can estimate that reduction owing to nucleophilicity reduces the effectiveness in its coupling.Carbon-to-carbon double bond and carbonyl will also have this effect.On the contrary, the electron withdraw group adjacent with carbonyl (for example, the reactive carbonyl of glutaryl-N-hydroxy-succinamide base) can increase the reactivity of carbonyl carbon about the nucleophilic group of introducing.Compare, the neutral body bulky group can be used to reduce reactivity and therefore reduce coupling speed owing to sterically hindered near the reactive group.

As an example, gone out concrete linking group and corresponding chemical formula at the following table middle finger:

Table

Linking group	Component structure
Linking group	Component structure	-O-(CH ₂) _x-	-O-(CH ₂) _x-X -O-(CH ₂) _x-Y -O-(CH ₂) _x-Z
-S-(CH ₂) _x-	-S-(CH ₂) _x-X -S-(CH ₂) _x-Y -S-(CH ₂) _x-Z	-O-(CH ₂) _x-	-O-(CH ₂) _x-X -O-(CH ₂) _x-Y -O-(CH ₂) _x-Z

Linking group	Component structure
Linking group	Component structure	-NH-(CH ₂) _x-	-NH-(CH ₂) _x-X -NH-(CH ₂) _x-Y -NH-(CH ₂) _x-Z
-O-(CO)-NH-(CH ₂) _x-	-O-(CO)-NH-(CH ₂) _x-X -O-(CO)-NH-(CH ₂) _x-Y -O-(CO)-NH-(CH ₂) _x-Z	-NH-(CH ₂) _x-	-NH-(CH ₂) _x-X -NH-(CH ₂) _x-Y -NH-(CH ₂) _x-Z
-O-(CO)-NH-(CH ₂) _x-		-NH-(CO)-O-(CH ₂) _x-	-NH-(CO)-O-(CH ₂) _x-X -NH-(CO)-O-(CH ₂) _x-Y -NH-(CO)-O-(CH ₂) _x-Z
-O-(CO)-(CH ₂) _x-	-O-(CO)-(CH ₂) _x-X -O-(CO)-(CH ₂) _x-Y -O-(CO)-(CH ₂) _x-Z	-NH-(CO)-O-(CH ₂) _x-
-O-(CO)-(CH ₂) _x-	-O-(CO)-(CH ₂) _x-X -O-(CO)-(CH ₂) _x-Y -O-(CO)-(CH ₂) _x-Z	-(CO)-O-(CH ₂) _x-	-(CO)-O-(CH ₂) _n-X -(CO)-O-(CH ₂) _n-Y -(CO)-O-(CH ₂) _n-Z
-O-(CO)-O-(CH ₂) _x-	-O-(CO)-O-(CH ₂) _x-X -O-(CO)-O-(CH ₂) _x-Y -O-(CO)-O-(CH ₂) _x-Z	-(CO)-O-(CH ₂) _x-	-(CO)-O-(CH ₂) _n-X -(CO)-O-(CH ₂) _n-Y -(CO)-O-(CH ₂) _n-Z
-O-(CO)-O-(CH ₂) _x-		-O-(CO)-CHR ²-	-O-(CO)-CHR ²-X -O-(CO)-CHR ²-Y -O-(CO)-CHR ²-Z
-O-R ³-(CO)-NH-	-O-R ³-(CO)-NH-X -O-R ³-(CO)-NH-Y -O-R ³-(CO)-NH-Z	-O-(CO)-CHR ²-	-O-(CO)-CHR ²-X -O-(CO)-CHR ²-Y -O-(CO)-CHR ²-Z

In last table, x is generally 1 to about 10, R ²Be generally alkyl, typically be alkyl or aryl, preferred alkyl, low alkyl group most preferably, R ³Be alkylene, contain heteroatomic alkylene, the alkylene of replacement, what perhaps replace contains heteroatomic alkylene), typically be alkylidene or arlydene (once more, optional that replace and/or contain hetero atom), preferred low-grade alkylidene (for example, methylene, 1, the 2-ethylidene, positive propylidene, positive butylidene, or the like), phenylene, perhaps the acylamino-alkylidene (for example ,-(CO)-NH-CH ₂).

Other General Principle of considering about linking group is as follows.If will use the autoreaction chemical compound of higher molecular weight, it preferably has aforesaid biodegradable key so, thereby does not produce greater than 20,000 molar fragments during absorbing in health again.In addition, in order to promote water miscibility and/or dissolubility, can wish to add enough electric charges or hydrophilic.Use known chemosynthesis can easily introduce hydrophilic group, as long as they do not cause undesirable reduction of undesirable swelling or compressive strength.Particularly, poly-alkoxyl fragment can weaken gel strength.

C. Core

" core " of every kind of autoreaction chemical compound comprises the bonded molecular structure of reactive group.The molecule core can be polymer, and it comprises synthetic polymer and naturally occurring polymer.In one embodiment, core is for containing the unitary polymer of repeated monomer.Polymer can be for hydrophilic, hydrophobic or amphipathic.The molecule core can also be a lower-molecular-weight component, as C _2-14Alkyl or contain heteroatomic C _2-14Alkyl.Contain heteroatomic C _2-14Alkyl can have the N of being selected from, 1 or 2 hetero atom of O and S.In preferred embodiments, the autoreaction chemical compound comprises the molecule core of synthetic hydrophilic polymer.

1) Hydrophilic polymer

As mentioned above, term used herein " hydrophilic polymer " refers to such polymer, and it has mean molecule quantity and natural make or through selecting to make the composition of " hydrophilic " on this polyalcohol integral.Preferred polymer is for highly pure or be purified to highly pure state, thus this polymer for or the treated pharmaceutical purity that becomes.Most hydrophilic polymeies can by mix can be used for aqueous solution form hydrogen bond enough numbers oxygen (nitrogen perhaps more infrequently) atom and become water dissolvable.

Synthetic hydrophilic polymer can be homopolymer, block copolymer, comprises two-block and three-block copolymer, random copolymer, perhaps graft copolymer.In addition, polymer can be a straight or branched, if branched, can be highly branched, dendritic (dendrimeric), super branched or star polymer by bottom line.This polymer can comprise biodegradable fragment and block, and it is distributed in the molecular structure of whole polymer or exists with single block, perhaps is present in the block copolymer.Biodegradable fragment is preferably degraded so that rupture covalent bond.Typically, biodegradable fragment is the fragment of hydrolysis and/or original position enzymatic lysis in the presence of water.Biodegradable fragment can be made up of small molecule segment, and described small molecule segment is such as ester bond, anhydride bond, original acid ester key, orthocarbonic acid ester bond, amido link, phosphonate bond or the like.Bigger biodegradable " block " will be made up of the oligomerization or the poly fragment that are attached in the hydrophilic polymer usually.Biodegradable illustrative oligomerization and polymeric segment for example comprise, poly-(aminoacid) fragment, poly-(ortho esters) fragment, poly-(orthocarbonic ester) fragment, or the like.Other biodegradable fragment that can form the hydrophilic polymer core comprises polyester, as polylactide, and polyethers, as polyalkylene oxide, polyamide, as protein, and polyurethane.For example, the core of autoreaction chemical compound can be the diblock copolymer of four sense activated polyglycol and polylactide.

The synthetic hydrophilic polymer that is used for this paper includes, but are not limited to: polyalkylene oxide, especially Polyethylene Glycol (PEG) and poly-(oxirane)-poly-(expoxy propane) copolymer comprises block and random copolymer; Polyhydric alcohol, as glycerol, polyglycereol (PG) and especially highly branched polyglycereol, propylene glycol; The polyhydric alcohol that the dihydroxylic alcohols of poly-(oxyalkylene)-replace and poly-(oxyalkylene) replace, as single-, two-and three-polyoxyethylene glycerol, single-and two-polyoxyethylated propylene glycol, and single-and two-polyoxyethylene trimethylene glycol; The polyoxyethylene sorbitol, the polyoxyethylene glucose; Poly-(acrylic acid) and analog and copolymer, as polyacrylic acid self, polymethylacrylic acid, poly-(hydroxyethyl-methacrylate), poly-(hydroxyethylmethacry,ate), poly-(methyl alkyl sulfoxide methacrylate), poly-(methyl alkyl sulfoxide acrylate) and front any copolymer and/or with the other acrylate kind such as the copolymer of acrylic-amino ethyl ester and list-2-(propenyloxy group) ethyl succinate; Poly; Poly-(acrylamide), own as poly-(acrylamide), poly-(MAAm), poly-(DMAA) and poly-(N-isopropyl-acrylamide), and copolymer; Poly-(enol) is as poly-(vinyl alcohol) and copolymer thereof; Poly-(N-vinyl lactam), as poly-(vinyl pyrrolidone), poly-(N-caprolactam), and copolymer; The Ju oxazoline comprises poly-(Jia oxazolin) and poly-(ethyl oxazoline); And polyvinylamine, and any copolymer of front.The polymer tabulation that must emphasize the front is not limit, as will be apparent to those skilled in the art, can use many other synthetic hydrophilic polymeies.

It will be appreciated by one of skill in the art that in fact to prepare synthetic polymer that as Polyethylene Glycol, and as commonly used in this area, term used herein " molecular weight " refers to the weight average molecular weight of many molecules of any given sample with definite molecular weight.Thereby the sample of PEG 2,000 can contain molecular weight ranges and be for example statistics mixture of 1,500 to 2,500 daltonian polymer molecule, and a molecule and another molecule are slightly different within the specific limits.The explanation of certain limit molecular weight points out that mean molecule quantity can be the arbitrary value between the specified scope, and can comprise the molecule outside these scopes.Thereby about 800 to about 20,000 molecular weight ranges shows at least about 800, up to the mean molecule quantity of about 20kDa.

Other suitable synthetic hydrophilic polymer comprises polypeptide, especially many nucleophilics polypeptide of chemosynthesis, its synthetic and aminoacid (as cysteine) that mix the aminoacid that contains primary amino radical (as, lysine) and/or contain mercapto.Especially preferably poly-(lysine), it is the polymer of the synthetic generation of amino acid lysine (145MW).Prepared and had 6 poly-(lysines) to about 4,000 primary amino radicals, molecular weight corresponding to about 870 to about 580,000.Be used for poly-(lysine) of the present invention and preferably have about 1,000 to about 300,000 molecular weight; 5,000 to about 100,000 molecular weight more preferably from about; 8,000 to about 15,000 molecular weight most preferably from about.Poly-(lysine) of variable molecular weight can by commercial sources from peninsula laboratory company (Peninsula Laboratories, Inc). (Bellmont, California) obtains.

Although can use the synthetic hydrophilic polymer of many differences in the The compounds of this invention, preferred synthesis hydrophilic polymer is PEG and PG, especially highly branched PG.The PEG of various ways is widely used in the modification of bioactive molecule, because PEG lacks toxicity, antigenicity and immunogenicity (promptly, be biocompatible), can prepare so that have the dissolubility of wide region, and the conformation of interferases activity and/or peptide not typically.For some application, especially preferred synthetic hydrophilic polymer is PEG, it has about 100 to the interior molecular weight of about 100,000 scopes, although for highly branched PEG, can use the much higher polymer of molecular weight, up to 1,000,000 or more than, condition is to add biodegradable site will have the molecular weight less than about 30,000 to guarantee all catabolites.Yet for most PEG, preferred molecular weight is about 1,000 to about 20,000, and more preferably from about 7,500 in about 20,000 scopes.Most preferably, Polyethylene Glycol has about 10,000 molecular weight.

Naturally occurring hydrophilic polymer includes, but are not limited to: protein, and as collagen, fibronectin, albumin, globulin, fibrinogen, fibrin and thrombin, especially preferred collagen; Carboxylated polysaccharide is as polymannuronate and polygalacturonic acid; The amination polysaccharide, glycosaminoglycans especially, as hyaluronic acid, chitin, chondroitin sulfate A, B or C, keratan sulfate, keratosulfate and heparin; With activatory polysaccharide, as glucosan and starch derivatives.Collagen and glycosaminoglycans are the preferred naturally occurring hydrophilic polymeies that is used for this paper.

Unless otherwise indicated, term used herein " collagen " refers to the collagen of form of ownership, comprises those collagens of processing or modifying.Thereby, can be used for chemical compound of the present invention from the collagen in any source; For example, can originate as cattle or pig dermis and extraction of people's Placenta Hominis and collagen purification from people or other mammal, perhaps can recombinate or pass through other method produces.From the collagen formulations purification in the solution of Corii Bovis seu Bubali, nonantigenic substantially is well known in the art.For example, the U.S. Patent number 5,428 of Palefsky etc., 022 discloses from the method for extraction of people's Placenta Hominis and collagen purification, and the U.S. Patent number 5,667 of Berg, 839 disclose transgenic animal, comprise the method that produces recombinant human collagen in the milk of transgenic milch cow.At the U.S. Patent number 6,413,742 of Olsen etc., 6,428,978 and the Berg etc. of Olsen etc. 6,653,450 in the not genetically modified recombinant collagen described in yeast and other cell line express.

Any type, the collagen that includes, but not limited to I, II, III, IV type or its any combination can be used for chemical compound of the present invention, although usually preferred type i collagen.Can use the collagen that contains non-end peptide or end peptide; Yet, when the collagen that uses from natural origin, during as bovine collagen, preferred non-end peptide collagen usually because it with contain the collagen of holding peptide and compare and have littler immunogenicity.

Previous not by being preferred among the present invention, although can use previous crosslinked collagen such as heat, radiation or the crosslinked collagen of chemical cross-linking agent.

It is common to be used for collagen of the present invention, although be not essential, is aqueous suspension, and its concentration arrives about 120mg/ml for about 20mg/ml, and preferably about 30mg/ml is to about 90mg/ml.Although preferred intact collagen also can use the collagen of degeneration, so-called gelatin.Gelatin can have the other benefit than the faster degraded of collagen.

Non-fiber collagen is preferred in the chemical compound of the present invention usually, although also can use fiber collagen.Term " non-fiber collagen " refers to be essentially any modification of non-fibers form or the collagen-based materials of unmodified, and promptly not combining closely with other tropocollagen molecule forms the molecule collagen of fiber.Usually, non-fibrocollagenous solution is more transparent than viscose original solution.The non-fiber of native form (perhaps microfibre) collagen-type comprises IV, VI and VII type.

In neutral pH is that the collagen of the chemical modification of non-fibers form comprises succinyl group collagen and methylated collagen, the method preparation that they both describe in can the U.S. Patent number 4,164,559 according to Miyata etc.Methylated collagen contains reactive amino, is the component that preferably contains nucleopilic reagent in the present composition.On the other hand, methylated collagen is to form the component that exists first and second components in the reaction except substrate of the present invention.Methylated collagen is described in the U.S. Patent number 5,614,587 of Rhee etc. for example.

The collagen that is used for the present composition can begin with fibers form, makes non-fibrosis by adding one or more fiber distintegrants then.The fiber distintegrant must exist with capacity makes that collagen is for 7 times non-fiber at pH basically, as above-mentioned.Be used for fiber distintegrant of the present invention and include, but not limited to multiple biocompatible alcohol, aminoacid, inorganic salt, and saccharide, especially preferred biocompatible alcohol.Preferred biocompatible alcohol comprises glycerol and propylene glycol.The alcohol of biocompatible, as ethanol, methanol and isopropyl alcohol since they the potential adverse effect of the patient body of accepting them is not preferred among the present invention.Preferred amino acids comprises arginine.Preferred inorganic salt comprises sodium chloride and potassium chloride.Although sugar, as comprise that the multiple sugar of sucrose can be used for enforcement of the present invention, they are preferred not as the fiber distintegrant of other type, because they can have the cells in vivo toxic effect.

Fiber collagen more is not preferred for chemical compound of the present invention.Yet disclosed in the U.S. Patent number 5,614,587 as Rhee etc., fiber collagen, perhaps non-fiber collagen and fibrocollagenous mixture can be preferred in the long-standing in vivo chemical compound of meaning.

2) Hydrophobic polymer

The core of autoreaction chemical compound can also comprise hydrophobic polymer, comprises the multifunctional kind of low-molecular-weight, although for most purposes, and the preferred hydrophilic polymer.Usually, this paper " hydrophobic polymer " contains the oxygen and/or the nitrogen-atoms of relative small scale.Be used for preferred hydrophobic polymer of the present invention and have carbochain usually no longer than about 14 carbon.Polymer with the carbochain of being longer than 14 carbon basically has the dissolubility of non-constant usually in aqueous solution, have the very long response time when with the aqueous solution that contains the synthetic polymer of a plurality of nucleophilic groups for example like this.Thereby the use of short chain oligomer can be avoided the relevant problem of dissolubility between the reaction period.Polylactic acid and polyglycolic acid are two kinds of especially examples of suitable hydrophobic polymer.

3) Amphipathic nature polyalcohol

Usually, amphipathic nature polyalcohol has hydrophilic segment and hydrophobic (perhaps lipophilic) part.Hydrophilic segment can be at an end of core, hydrophobic part is in end opposite, and perhaps hydrophilic and hydrophobic part can random distribution (random copolymer) or be sequence or grafting form (block copolymer) the amphipathic nature polyalcohol core with formation autoreaction chemical compound.Hydrophilic and hydrophobic part can comprise any of above-mentioned hydrophilic and hydrophobic polymer.

Alternatively, the amphipathic nature polyalcohol core can be the hydrophilic polymer modified with hydrophobic part (for example, alkylation PEG or the hydrophilic polymer of modifying with one or more aliphatic chains), perhaps the hydrophobic polymer of modifying with hydrophilic segment (for example, " PEGization " phospholipid is as Pegylation phospholipid).

4) Lower-molecular-weight component

Point out that as top the molecule core of autoreaction chemical compound can also be a low molecular weight compound, it is defined as C in this article _2-14Alkyl or contain heteroatomic C _2-14Alkyl, it contains 1 to 2 hetero atom and their combination that is selected from N, O, S.This molecule core can replace with any reactive group described herein.

Alkane is suitable C _2-14Alkyl molecule core.The representative alkane that replaces with nucleophilic primary amino radical and Y electrophilic group comprises ethylene amines (H ₂N-CH ₂CH ₂-Y), tetramethylene amine (H ₂N-(CH ₄)-Y), pentamethylene amine (H ₂N-(CH ₅)-Y) and hexa-methylene amine (H ₂N-(CH ₆)-Y).

Low molecular weight diol and polyhydric alcohol also are suitable C _2-14Alkyl and comprise trimethylolpropane, two (trimethylolpropane), tetramethylolmethane and diglycerol.Polyprotic acid also is suitable C _2-14Alkyl and comprise tricarboxylic acids based on trimethylolpropane, based on the tetrabasic carboxylic acid of two (trimethylolpropanes), 1,5-pentanedicarboxylic acid., suberic acid (suberic acid), and hexadecandioic acid (hexadecane diacid) (hexadecandioic acid (hexadecane diacid)).

Low-molecular-weight two-and many-electrophilic reagent be the heteroatomic C that contains that suits _2-14Alkyl molecule core.These comprise, for example, and two succinimido suberates (DSS), two (sulfosuccinimide base) suberate (BS ₃), dithio two (succinyl phosphorons amino propyl acid ester) (DSP), two (2-succinimido oxygen base ketonic oxygen base) ethyl sulfone (BSOCOES) and 3,3 '-dithio two (sulfosuccinimide base propionic ester) (DTSPP) and their analog and derivant.

In one embodiment of the invention, autoreaction chemical compound of the present invention comprises the low molecular weight substance core, has many acrylate parts and many mercaptos.

D. Preparation

Can easily synthesize autoreaction chemical compound hydrophilic to contain, hydrophobic or amphipathic nature polyalcohol core or low-molecular-weight core, it is with allowing to crosslinked desirable functional group, and promptly nucleophilic and electrophilic group are functionalized.For example, be discussed below the preparation of the autoreaction chemical compound of (PEG) core that has Polyethylene Glycol.Yet the discussion that understanding is following is used to illustrate and can uses similar techniques for other polymer.

About PEG, at first, (seeing Abuchowski etc., Enzymes asDrugs (as the medicine of enzyme), John Wiley ﹠amp such as protein modification; Sons: New York, N.Y. (1981) 367-383 page or leaf; With (1990) Crit.Rev.Therap.Drug Carrier Syst.6:315 such as Dreborg), chemistry of peptides is (referring to Mutter etc., The Peptides (peptide), U.S. academic press (Academic): New York, N.Y.2:285-332; With (1987) Int.J.Peptide Protein Res (international peptide protein matter research magazine) .30:740 such as Zalipsky) and polymeric drug is synthetic (referring to (1983) Eur.Polym.J. such as Zalipsky (European polymer magazine) 19:1177; With (1987) J. Macromol.Sci.Chem. (polymer science The Chemicals) A24:1011 such as Ouchi) etc. the field effectively used multiple functionalized PEG.

The functionalized form of PEG comprises multiple functionalized PEG, can obtain by commercial sources, and also can easily prepare with known method.For example, see Poly (ethylene Glycol) Chemistry:Biotechnical and Biomedical Applications (poly-(ethylene glycol) chemistry: biotechnology and biological medicine are used), J.Milton Harris, ed.Plenum Press, the 22nd chapter of NY (1992).

The multiple functionalized form of PEG is even more important and comprises PEG 1,3-propanedicarboxylic acid succinimide ester, PEG succinyl phosphorons amino propyl acid ester, succinimido butyrate, PEG acetic acid succinimide ester, PEG succinimido butanimide, PEG carbonic acid succinimide ester, PEG propionic aldehyde, PEG glycidyl ether, PEG-isocyanates and PEG-vinyl sulfone(Remzaol.Many these type of forms of PEG are at the U.S. Patent number 5,328,955 and 6,534 of Rhee etc., describe in 591.Similarly, the various ways of polyamino PEG can be by commercial sources from such as Korea S Shang Bai company (the SunBio of SouthKorea) PEG of branch company specialty retail department (PEG Shop) (www.sunbio.com), ((favour is than longevity garden mansion in Nof Corp. (Nippon Oil and Fats), 20-3 Ah is than fast 4-fourth order, the Shibuya district, Tokyo) (Yebisu Garden Place Tower, 20-3Ebisu 4-chome, Shibuya-ku, Tokyo)), how but tal fibre is treated company (Nektar Therapeutics) (San Carlos, California was Hai Ou Polymer Company in the past, the Huntsville, the Alabama) with from the source of Heng Ziman chemistry group company (Huntsman ' s Performance Chemicals Group) (Houston, Texas) with title Jeffamine ^The polyoxygenated enamine obtains.Can be used for polyamino PEG of the present invention and comprise polyetheramine diamidogen (" D " series) and triamine (" T " series), its each molecule contains two and three primary amino radicals.Similarly poly-(sulfydryl) but PEG also can from how tal fibre treatment company (Nektar Therapeutics), for example, obtain with the form of poly-(ethylene glycol) ether four sulfydryls (molecular weight 10,000) of tetramethylolmethane.The multiple functionalized form of these of PEG can be comprised the reactive group of other hope then by modification.

With the butanimide radical reaction terminal hydroxyl being changed into active ester is a kind of technology that preparation has the core of electrophilic group.Can modify this core then, comprise with nucleophilic group such as primary amine, mercaptan and hydroxyl modified.Other reagent that transforms hydroxyl comprises N,N'-carbonyldiimidazole and sulfonic acid chloride.Yet, to discuss as this paper, multiple electrophilic group can be advantageously used in and corresponding nucleophilic group reaction.The example of this type of electrophilic group comprises the acid chloride group; Anhydride, ketone, aldehyde, isocyanates, isothiocyanate, epoxide and alkene comprise conjugated alkene, as ethylsulfonyl (SO ₂CH=CH ₂) and similar functional group.

Other in-situ cross-linked material

The original position of multiple other type forms material, can unite use with anti-scarring agent according to the present invention.It can be biocompatible cross linked polymer that original position forms material, its from have can reaction in-situ and the water solublity precursor of crosslinked electrophilic and nucleophilic group form (see, for example, U.S. Patent number 6,566,406).It can be hydrogel that original position forms material, it can be combined to form by physics and chemical crosslinking process, wherein physical crosslinking natural or synthetic component mediation by one or more, described component reaches certain hour at deposition site stabilize water gel formation precursor solution and has more elastic chemical crosslinking with enough formation and (see, for example, U.S. Patent number 6,818,018).When the aqueous fluids that is exposed to from physiological environment, can form original position from the dried hydrogel precursor and form material (see, for example, U.S. Patent number 6,703,047).It can be hydrogel matrix that this original position forms material, and it is dispersed or dissolved in the controlled release that hydrophobic relatively speed modifier formation mixture provides relative low-molecular-weight treatment kind by at first treating kind; Described mixture forms the microgranule that is dispersed in the biological absorbable hydrogel, thereby discharges water-soluble therapeutic agents (see, for example, 6,632,457) in a controlled manner.It can be multicomponent hydrogel system (see, for example, U.S. Patent number 6,379,373) that original position forms material.It can be the multi-arm block copolymer that original position forms material, it comprises the prostheses molecule, as residue of polyol, with covalently bound at least three copolymer arms to the prostheses molecule, each copolymer arm comprises covalently bound inner hydrophobic polymer segments to the prostheses molecule and covalently bound to the segmental outside hydrophilic polymer fragment of this hydrophobic polymer, and wherein prostheses molecule and hydrophobic polymer fragment define the hydrophobic core district and (see, for example, 6,730,334).Original position forms material can comprise the gel formation macromonomer, and it comprises at least 4 polymer blocks, and wherein at least two blocks are hydrophobic and at least one block is hydrophilic, and comprises crosslinkable group (see, for example, 6,639,014).It can be the water-soluble macromolecule monomer that original position forms material, and it comprises at least one the hydrolyzable key that forms from carbonic ester Huo Er Evil ketone groups, at least one water-soluble polymer block, with at least one polymerisable group (see, for example, U.S. Patent number 6,177,095).Original position forms material can comprise polyalkylene block copolymers, and it forms weak physical crosslinking and has the gel of sticking with paste the sample denseness to be provided at physiological temp.(see, for example, U.S. Patent number 4,911,926).It can be heat irreversible gel (see, for example, U.S. Patent number 5,126,141) from polyoxyalkylene polymers and ionic polysaccharide preparation that original position forms material.It can be the gel formation compositions that original position forms material, it comprise chitin derivatives (see, for example, U.S. Patent number 5,093,319), chitosan grumeleuse (see, for example, U.S. Patent number 4,532,134), perhaps hyaluronic acid (see, for example, U.S. Patent number 4,141,973).Original position forms the in-situ modification that material can be alginate (see, for example, U.S. Patent number 5,266,326).Can form original position from the unsaturated water-soluble macromolecule monomer of ethylenic (ethylenically) and form material, described macromonomer can contact with tissue, cell and bioactive molecule and be cross-linked to form gel (see, for example, U.S. Patent number 5,573,934).Original position forms material and can comprise and the unsaturated cyano compound that contains the cyano group that is connected carbon atom, unites the urethane prepolymer (see, for example, U.S. Patent number 4,740,534) of use as cyano group (methyl) acrylic acid and ester thereof.It can be biodegradable hydrogel that original position forms material, and it is by from the monomeric light-initiated radical polymerization effect polymerization of water-soluble macromolecule (see, for example, U.S. Patent number 5,410,016).Original position forms material and can form from two kinds of component mixtures, described mixture comprises that proteinic first of the serum albumin in the aqueous buffer solution that comprises the pH with about 8.0-11.0 scope and the second portion that comprises bi-functional cross-linking agent water compatible or water soluble (see, for example, U.S. Patent number 5,583,114).

On the other hand, operable original position formation material comprises those materials based on protein cross.For example, original position formation material can and gather the biodegradable hydrogel that (ethylene glycol) polymer solution is formed by reorganization or natural human serum albumin, and wherein described solution crosslinking forms mechanical on-liquid covered structure when mixing, and it is as sealant.See, for example, U.S. Patent number 6,458,147 and 6,371,975.Original position forms material can be by forming based on two kinds of fibrinogen and thrombin independent mixture, described mixture when before application site or on distribute the formation biological adhesive together during mixing and form the fibrin sealant.See, for example, U.S. Patent number 6,764,467.Original position forms material can be made up of the collagen and the albumin of supersound process, described collagen and albumin when with glutaraldehyde and aminoacid or chemistry of peptides when crosslinked formation develop the cohesive material of adhesion properties.See, for example, U.S. Patent number 6,310,036.Original position forms the viscogel of the hydration that material can be made up of aqueous solution, and it is basically by have amino protein (for example, gelatin, albumin) composition, described protein and N-hydroxyl polyurethane compound crosslink at side chain.See, for example, U.S. Patent number 4,839,345.It can be the hydrogel for preparing from protein or polysaccharide main chain (for example, albumin or polymannuronate) in conjunction with cross-linking agent (for example, the multivalence derivant of Polyethylene Glycol or poly alkylene glycol) that original position forms material.See, for example, U.S. Patent number 5,514,379.Original position forms material can be made up of polymerisable collagen compositions, and said composition is applied to organize and is exposed to initiator then with polymerization collagen, thereby forms sealing on the wound opening in tissue.See, for example, U.S. Patent number 5,874,537.It can be two kinds of component mixtures that original position forms material, it by the protein in the aqueous buffer solution of the pH with about 8.0-11.0 scope (for example, serum albumin) and the difunctional polyethylene glycol oxide type of water solublity cross-linking agent form, this cross-linking agent changes into strong elasticity binding compositions with liquid, its original position seal tissue.See, for example, U.S. Patent number 5,583,114 and RE38158 and PCT publication number WO 96/03159.Original position forms material can be made up of the protein in the liquid carrier, surfactant and lipid, and it is crosslinked and be used as original position sealant or bonding agent by adding cross-linking agent.See, for example, Application No. 2004/0063613A1 and PCT publication number WO 01/45761 and WO 03/090683.Original position forms material and can be made up of two kinds of liquid components that do not contain enzyme, mix described component by component being assigned to the conduit that uses at the vascular puncture position, wherein when mixing, two kinds of liquid component chemical crosslinkings form the mechanical on-liquid substrate in airtight vascular puncture site.See, for example, Application No. 2002/0161399A1 and 2001/0018598A1.Original position forms the crosslinked albumin compositions that material can be made up of albumin preparation and carbodiimide preparation, and described preparation mixes to be used as biological adhesive or sealant under the crosslinked condition of albumin allowing.See, for example, PCT publication number WO99/66964.Original position forms material can be made up of collagen and peroxidase and hydrogen peroxide, thereby collagen is through being cross-linked to form the semi-solid gel that seals wound.See, for example, PCT publication number WO01/35882.

On the other hand, operable original position formation material comprises those materials based on the polymer of isocyanates or isothiocyanate end-blocking (capped).For example, original position forms material can be made up of isocyanate-terminated polymer, and described polymer is a fluid composition, its when contacting body fluid or organizing by in-situ polymerization be cross-linked to form the solid adhesive coating.See, for example, PCT publication number WO04/021983.It can be the moisturecuring encapsulant composition that original position forms material, and it is made up of active isocyanide acyl-end capped isocyanate prepolymer that contains the polyol component with 2,000 to 20,000 molecular weight and isocyanuric acid esterification catalyst.See, for example, U.S. Patent number 5,206,331.

In another embodiment, reagent can experience electrophilic-necleophilic reaction to produce crosslinked substrate.Contain and/or with nucleophilic group such as amine, sulfydryl, hydroxyl ,-PH ₂Or CO-NH-NH ₂End capped polymer can be used as nucleopilic reagent, and contain and/or with electrophilic group such as succinimido, carboxylic acid, aldehyde, epoxide, isocyanates, vinyl, vinyl sulfone, maleimide ,-S-S-(C ₅H ₄N) or such as the end capped polymer of employed activatory ester in peptide is synthetic can be used as electrophilic reagent.For example, 4-arm mercaptan deutero-poly-(ethylene glycol) (for example, tetramethylolmethane gathers (ethylene glycol) ether four sulfydryls) can react down at alkali condition (pH＞about 8) with the deutero-Polyethylene Glycol of 4 arm NHS-(for example, poly-(ethylene glycol) ether four-succinimido 1,3-propanedicarboxylic acid of tetramethylolmethane).The representative example of compositions that experiences such electrophilic-nucleophilic cross-linking reaction is at for example U.S. Patent number 5,752,974; 5,807,581; 5,874,500; 5,936,035; 6,051,648; 6,165,489; 6,312,725; 6,458,889; 6,495,127; 6,534,591; 6,624,245; 6,566,406; 6,610,033; 6,632,457; With description among PCT application publication number WO 04/060405 and the WO 04/060346.

In another embodiment, electrophilic-or nucleophilic-end capped polymer can also comprise the machinery that can strengthen the compositions that original position forms and/or the polymer of bond properties.This polymer can be degradable or nondegradable polymer.For example, described polymer can be collagen or collagen derivant, for example methylated collagen.The example that original position forms compositions uses poly-(ethylene glycol) ether four-sulfydryl of tetramethylolmethane) (4-arm mercaptan PEG), poly-(ethylene glycol) ether four-succinimido glutarate of tetramethylolmethane] (4-arm NHS PEG) and methylated collagen is as reaction reagent.Said composition can produce crosslinked hydrogel when mixing with the buffer agent that suits.(see, for example, U.S. Patent number 5,874,500; 6,051,648; 6,166,130; 5,565,519 and 6,312,725).

In another embodiment, can use the reagent that can form covalent bond with the tissue that it is administered to.Contain and/or can be used as described reagent with the end capped polymer of electrophilic group, described electrophilic group such as succinimido, aldehyde, epoxide, isocyanates, vinyl, vinyl sulfone(Remzaol, maleimide ,-S-S-(C ₅H ₄N) or such as being used for the synthetic activatory ester of peptide.For example, the deutero-Polyethylene Glycol of 4-arm NHS-(for example, poly-(ethylene glycol) ether four succinimido glutarates of tetramethylolmethane) can be administered to described tissue with solid form or solution form.In preferred embodiments, the deutero-Polyethylene Glycol of 4 arm NHS-is administered to described tissue under alkali condition (pH＞about 8).Other representative example of operable this combination of attributes thing is disclosed in PCT application publication number WO04/060405 and WO 04/060346, and in the Application No. 10/749,123.

In another embodiment, described original position formation material polymers can be a polyester.The polyester that can be used for original position formation compositions comprises poly-(hydroxy ester).In another embodiment, described polyester can comprise and is selected from following monomeric one or more residue: lactide, lactic acid, Acetic acid, hydroxy-, bimol. cyclic ester, glycolic, e-caprolactone, γ-Ji Neizhi, hydroxypentanoic acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolacton, gamma-valerolactone, γ-decalactone, δ-Gui Neizhi, trimethylene carbonate, 1,4-diox-2-ketone or 1,5-cyclic heptane dioxide (dioxepan)-2 ketone.The representative example of the compositions of these types is described in U.S. Patent number 5,874,500; 5,936,035; 6,312,725; 6,495,127 and PCT publication number WO 2004/028547 in.

In another embodiment, described electrophilic terminated polymer can be partially or completely by micromolecule that comprises electrophilic group (for example, two succinimido glutarates) or oligomer displacement.

In another embodiment, described nucleophilic-terminated polymer can be partially or completely by comprise a kind of nucleophilic group (for example, cystine, two lysines, three lysines, etc.) micromolecule or oligomer displacement.

Other example that operable original position forms material comprises based on those of protein cross and (for example, is described in U.S. Patent number RE38158; 4,839,345; 5,514,379,5,583,114; 6,310,036; 6,458,147; 6,371,975; U.S. Patent Application Publication No. 2004/0063613A1,2002/0161399A1, and 2001/0018598A1, and PCT publication number WO 03/090683, WO 01/45761, among WO 99/66964 and the WO 96/03159) and add the polymer of medicated cap those (referring to, PCT publication number WO 04/021983 for example) based on isocyanates or isothiocyanate.

Other example of the original position formation material of special value is arranged in the diverticulum treatment, make up individually and with above-mentioned therapeutic agent, can comprise the reagent that comprises one or more alpha-cyanoacrylate ester groups.These reagent can be used for preparation poly-(alkyl cyanoacrylate) or (for example gather (carboxyalkyl cyanoacrylate), poly-(MCA), poly-(ethyl cyanoacrylate), poly-(butyl cyanoacrylate), poly-(isobutyl cyanoacrylate), poly-(hexyl cyanoacrylate), poly-(methoxy-propyl cyanoacrylate) and poly-(octyl cyanoacrylate)) and these copolymer and mixture.The instantiation of admixture comprises cyanacrylate and acrylic acid methoxyl group propyl ester, the admixture of alpha-cyanoacrylate methoxyl group propyl ester and octyl 2-cyanoacrylate and alpha-cyanoacrylate methoxyl group butyl ester and Tisuacryl.The example of the cyanoacrylate that operable merchant sells comprises DERMABOND, INDERMIL, GLUSTITCH, VETBOND, HISTOACRYL, TISSUEMEND, TISSUMEND II, HISTOACRYL BLUE and ORABASESOOTHE-N-SEAL LIQUID PROTECTANT.

In another embodiment, cyanoacrylate compositions can also comprise the reaction rate of stablizing described reagent or changing cyanoacrylate, changes the flexibility of final cure polymer, or changes the additive of product viscosity.For example, based on the oxalate polymer of the polymer of trimethylene carbonate or poly-(ethylene glycol) or based on the copolymer of 6-caprolactone (straight chain, side chain, three, four) can mix with 2-alkoxyalkyl cyanoacrylate (for example, 2-methoxy-propyl cyanoacrylate).The example of stabilizing agent comprises sulfur dioxide (SO ₂) or polyphosphoric acid.The representative example of these compositionss is described in U.S. Patent number 5,350, in 798 and 6,299,631.

In another embodiment, described cyanoacrylate compositions can prepare by adding the medicated cap heterochain polymer with the alpha-cyanoacrylate ester group.The heterochain polymer of cyanoacrylate-Jia medicated cap preferably has at least two cyanoacrylate ester group/chains.Heterochain polymer can comprise absorbable poly-(ester), poly-(ester-carbonic ester), poly-(ether-carbonic ester) and poly-(ether-ester).At U.S. Patent number 5,653, poly-(ether-ester) described in 992 and 5,714,159 can also be used as heterochain polymer.Three poly-(6-caprolactone-be total to-trimethylene carbonate) is the example of operable poly-(ester-carbonic ester).Described heterochain polymer can be a polyethers.The example of operable polyethers comprises poly-(ethylene glycol), the block copolymer (for example, including but not limited to the polymer of the poloxamer group of poloxamer (PLURONIC) F127 or F68) of poly-(propylene glycol) and poly-(ethylene glycol) and poly-(propylene glycol).The representative example of these compositionss is described in U.S. Patent number 6,699, in 940.

In another aspect of this invention, can send bioactive fiber degeneration derivant, anti-infective and/or hemorrhage with non-polymeric chemical compound (for example, carrier).These non-polymeric carriers can comprise sucrose derivative (for example, sucrose acetate isobutyrate, sucrose oleate), and sterol is as cholesterol, stigmasterol, cupreol and estradiol; Cholesterol ester is as cholesteryl stearate; C ₁₂-C ₂₄Fatty acid is as lauric acid, myristic acid, Palmic acid, stearic acid, arachidic acid, behenic acid and lignoceric acid; C ₁₈-C ₃₆Single, two and triglyceride, as monooleate glyceride, a glyceryl linoleate, Tegin L 90, a behenic acid glyceride, a myristin, a decylenic acid glyceride (glycerylmonodicenoate), glycerol-1,3-dipalmitate, two behenic acid glyceride, two myristins, two decylenic acid glyceride, three behenic acid glyceride, three myristins, three decylenic acid glyceride, glyceryl tristearate and their mixture; Sucrose fatty acid ester is as sucrose distearate and sucrose palmitate; Sorbitan fatty acid esters is as sorbitan monostearate, sorbitan monopalmitate and sorbitan tristearate; C ₁₆-C ₁₈Aliphatic alcohol is as hexadecanol, tetradecyl alchohol, octadecanol and cetostearyl alcohol; The ester of aliphatic alcohol and fatty acid is as hexadecyl palmitate and Palmic acid octadecanol and hexadecanol ester (cetearyl palmitate); The anhydride of fatty acid is as stearic anhydride; Phospholipid comprises phosphatidylcholine (lecithin), Phosphatidylserine, PHOSPHATIDYL ETHANOLAMINE, phosphatidylinositols and dissolving derivant (lysoderivatives) thereof; Sphingol and derivant thereof; Sphingomyelins (spingomyelins) is as stearoyl, palmityl and two tridecanoyl sphingomyelins; Ceramide is as stearoyl and palmityl ceramide; Glycosphingolipids; Lanoline and lanolin alcohol, calcium phosphate, sintering and unsintered hydroxyapatite, zeolite; And combination and mixture.

The representative example that relates to the patent of non-polymer delivery system and their preparation comprises U.S. Patent number 5,736,152; 5,888,533; 6,120,789; 5,968,542; With 5,747,058.

In certain embodiments of the present invention, provide to comprise (i) the fibre modification derivant and/or the (ii) therapeutic combination of anti-infective.Described therapeutic combination can comprise one or more other therapeutic agents (as described above all), for example, and hemorrhage.Can comprise with other reagent of therapeutic combination combination, for example, antiinflammatory, matrix metallo-proteinase inhibitor, cytokine inhibitor, IMPDH inhibitor, immunomodulator, tyrosine kinase inhibitors, p38MAP inhibitors of kinases, NFK beta inhibitor, the HMGCoA reductase inhibitor, the apoptosis antagonist, Caspase inhibitor, and jnk inhibitor.

In one aspect, the invention provides comprise i) fibrous tissue forms the agent and the ii) compound compositions of polymer or original position formation cross linked polymer.Followingly be, but whole anything but preferably to be included in the fibre modification derivant in the present composition and the classification of fibre modification derivant:

1a. promote the fibrous tissue of cell regeneration to form agent.

2a. the fibrous tissue that promotes blood vessel to take place forms agent.

3a. promote the fibrous tissue of fibroblast migration to form agent.

4a. promote the fibrous tissue of fibroblast proliferation to form agent.

5a. promote the fibrous tissue of extrtacellular matrix deposition to form agent.

6a. promote the fibrous tissue of tissue remodeling to form agent.

7a. fibrous tissue forms agent, it is diverticulum wall stimulus object that described fibrous tissue forms agent.

8a. fibrous tissue forms agent, it is silk (such as the silk of the silk of silkworm silk, spider silk, recombinant silk, raw silk, hydrolysis, acid-treated silk and acidylate) that described fibrous tissue forms agent.

9a. fibrous tissue forms agent, it is Talcum that described fibrous tissue forms agent.

10a. fibrous tissue forms agent, it is chitosan that described fibrous tissue forms agent.

11a. fibrous tissue forms agent, it is polylysine that described fibrous tissue forms agent.

12a. fibrous tissue forms agent, it is fibronectin that described fibrous tissue forms agent.

13a. fibrous tissue forms agent, it is bleomycin or its analog or derivant that described fibrous tissue forms agent.

14a. fibrous tissue forms agent, it is Connective Tissue Growth Factor (CTGF) that described fibrous tissue forms agent.

15a. fibrous tissue forms agent, it is metallic beryllium or its oxide that described fibrous tissue forms agent.

16a. fibrous tissue forms agent, it is copper that described fibrous tissue forms agent.

17a. fibrous tissue forms agent, it is Sa Ransu that described fibrous tissue forms agent.

18a. fibrous tissue forms agent, it is Silicon stone that described fibrous tissue forms agent.

19a. fibrous tissue forms agent, it is crystalline silicate that described fibrous tissue forms agent.

20a. fibrous tissue forms agent, it is silica flour that described fibrous tissue forms agent.

21a. fibrous tissue forms agent, it is Pulvis Talci that described fibrous tissue forms agent.

22a. fibrous tissue forms agent, it is ethanol that described fibrous tissue forms agent.

23a. fibrous tissue forms agent, it is the component of extracellular matrix that described fibrous tissue forms agent.

24a. fibrous tissue forms agent, it is collagen that described fibrous tissue forms agent.

25a. fibrous tissue forms agent, it is fibrin that described fibrous tissue forms agent.

26a. fibrous tissue forms agent, it is fibrinogen that described fibrous tissue forms agent.

27a. fibrous tissue forms agent, it is poly-(ethylene terephthalate) that described fibrous tissue forms agent.

28a. fibrous tissue forms agent, it is poly-(ethylene-be total to-vinylacetate) that described fibrous tissue forms agent.

29a. fibrous tissue forms agent, it is N-carboxylic butyl chitosan that described fibrous tissue forms agent.

30a. fibrous tissue forms agent, it is RGD protein that described fibrous tissue forms agent.

31a. fibrous tissue forms agent, it is the polymer of vinyl chloride that described fibrous tissue forms agent.

32a. fibrous tissue forms agent, it is cyanoacrylate that described fibrous tissue forms agent.

33a. fibrous tissue forms agent, it is crosslinked poly-(ethylene glycol)-methylated collagen that described fibrous tissue forms agent.

34a. fibrous tissue forms agent, it is inflammatory cytokine that described fibrous tissue forms agent.

35a. fibrous tissue forms agent, it is TGF β that described fibrous tissue forms agent.

36a. fibrous tissue forms agent, it is PDGF that described fibrous tissue forms agent.

37a. fibrous tissue forms agent, it is VEGF that described fibrous tissue forms agent.

38a. fibrous tissue forms agent, it is TNF α that described fibrous tissue forms agent.

39a. fibrous tissue forms agent, it is NGF that described fibrous tissue forms agent.

40a. fibrous tissue forms agent, it is GM-CSF that described fibrous tissue forms agent.

41a. fibrous tissue forms agent, it is IGF-a that described fibrous tissue forms agent.

42a. fibrous tissue forms agent, it is IL-1 that described fibrous tissue forms agent.

43a. fibrous tissue forms agent, it is IL-8 that described fibrous tissue forms agent.

44a. fibrous tissue forms agent, it is IL-6 that described fibrous tissue forms agent.

45a. fibrous tissue forms agent, it is growth hormone that described fibrous tissue forms agent.

46a. fibrous tissue forms agent, it is bone morphogenetic protein that described fibrous tissue forms agent.

47a. fibrous tissue forms agent, it is cell proliferating agent that described fibrous tissue forms agent.

48a. fibrous tissue forms agent, it is dexamethasone that described fibrous tissue forms agent.

49a. fibrous tissue forms agent, it is isotretinoin that described fibrous tissue forms agent.

50a. fibrous tissue forms agent, it is 17-that described fibrous tissue forms agent.

51a. fibrous tissue forms agent, it is estradiol that described fibrous tissue forms agent.

52a. fibrous tissue forms agent, it is diethylstilbestrol (diethylstibesterol) that described fibrous tissue forms agent.

53a. fibrous tissue forms agent, it is ciclosporin A that described fibrous tissue forms agent.

54a. fibrous tissue forms agent, it is all-trans retinoic acid or its analog or derivant that described fibrous tissue forms agent.

55a. fibrous tissue forms agent, it is fine hair (comprising animal down, wood shavings, and mineral wool) that described fibrous tissue forms agent.

56a. fibrous tissue forms agent, it is cotton that described fibrous tissue forms agent.

57a. fibrous tissue forms agent, it is bFGF that described fibrous tissue forms agent.

58a. fibrous tissue forms agent, it is polyurethane that described fibrous tissue forms agent.

59a. fibrous tissue forms agent, it is politef that described fibrous tissue forms agent.

60a. fibrous tissue forms agent, it is poly-(alkyl cyanoacrylate) that described fibrous tissue forms agent.

61a. fibrous tissue forms agent, it is activator protein that described fibrous tissue forms agent.

62a. fibrous tissue forms agent, it is angiogenin that described fibrous tissue forms agent.

63a. fibrous tissue forms agent, it is insulinoid somatomedin (IGF) that described fibrous tissue forms agent.

64a. fibrous tissue forms agent, it is hepatocyte growth factor (HGF) that described fibrous tissue forms agent.

65a. fibrous tissue forms agent, it is colony-stimulating factor (CSF) that described fibrous tissue forms agent.

66a. fibrous tissue forms agent, it is erythropoietin that described fibrous tissue forms agent.

67a. fibrous tissue forms agent, it is interferon that described fibrous tissue forms agent.

68a. fibrous tissue forms agent, it is endothelin-1 that described fibrous tissue forms agent.

69a. fibrous tissue forms agent, it is Angiotensin II that described fibrous tissue forms agent.

70a. fibrous tissue forms agent, it is bromocriptine that described fibrous tissue forms agent.

71a. fibrous tissue forms agent, it is D-lysergic acid (+)-butanolamide-(2) that described fibrous tissue forms agent.

72a. fibrous tissue forms agent, it is fibrosis albumen that described fibrous tissue forms agent.

73a. fibrous tissue forms agent, it is fibrin that described fibrous tissue forms agent.

74a. fibrous tissue forms agent, it is adhesive glycoprotein that described fibrous tissue forms agent.

75a. fibrous tissue forms agent, it is Dan Baijutang that described fibrous tissue forms agent.

76a. fibrous tissue forms agent, it is hyaluronan that described fibrous tissue forms agent.

77a. fibrous tissue forms agent, it is acidity and the secreted protein (SPARC) that is rich in cysteine that described fibrous tissue forms agent.

78a. fibrous tissue forms agent, it is thrombospondin that described fibrous tissue forms agent.

79a. fibrous tissue forms agent, it is to bind element that described fibrous tissue forms agent.

80a. fibrous tissue forms agent, it is cell adhesion molecule that described fibrous tissue forms agent.

81a. fibrous tissue forms agent, it is the inhibitor of matrix metalloproteinase that described fibrous tissue forms agent.

82a. fibrous tissue forms agent, it is the tissue depressant of matrix metalloproteinase that described fibrous tissue forms agent.

83a. fibrous tissue forms agent, it is methotrexate that described fibrous tissue forms agent.

84a. fibrous tissue forms agent, it is carbon tetrachloride that described fibrous tissue forms agent.

85a. fibrous tissue forms agent, it is thioacetamide that described fibrous tissue forms agent.

1. as mentioned above, the invention provides and comprise fibrous tissue that aforesaid 86 kinds (that is, 1a to 85a) list and form each that agent or fibrous tissue form the agent classification, and each compositions of following 98 kinds (that is 1b to 97b) polymer and chemical compound:

2.1b. cross linked polymer.

3.2b. polymer with the mammalian tissues reaction.

3b. polymer, described polymer are naturally occurring polymer.

4b. polymer, described polymer is a protein.

5b. polymer, described polymer is a saccharide.

6b. biodegradable polymer.

7b. crosslinked and biodegradable polymer.

8b. not biodegradable polymer.

9b. collagen.

10b. methylated collagen.

11b. fibrinogen.

12b. thrombin.

13b. albumin.

14b. plasminogen.

15b. Feng's von willebrand's factor.

16b. Factor IX.

17b. hypoallergenic collagen.

18b. the collagen of non-end peptide.

19b. end peptide collagen.

20b. crosslinked collagen.

21b. aprotinin.

22b. gelatin.

23b. protein conjugate.

24b. gelatin conjugate.

25b. hyaluronic acid.

26b. derivatives of hyaluronic acids.

27b. synthetic polymer.

28b. by comprising the polymer that the synthetic reactant that contains the chemical compound of isocyanates forms.

29b. the synthetic chemical compound that contains isocyanates.

30b. by comprising the polymer that the synthetic reactant that contains the chemical compound of mercaptan forms.

31b. the synthetic chemical compound that contains mercaptan.

32b. by comprising the polymer that the synthetic reactant that contains the chemical compound of at least two mercaptos forms.

33b. the synthetic chemical compound that contains at least two mercaptos.

34b. by comprising the polymer that the synthetic reactant that contains the chemical compound of at least three mercaptos forms.

35b. the synthetic chemical compound that contains at least three mercaptos.

36b. by comprising the polymer that the synthetic reactant that contains the chemical compound of at least four mercaptos forms.

37b. the synthetic chemical compound that contains at least four mercaptos.

38b. by comprising the polymer that the synthetic reactant that contains amino chemical compound forms.

39b. the synthetic chemical compound that contains amino.

40b. by comprising the polymer that the synthetic reactant that contains the chemical compound of at least two amino forms.

41b. the synthetic chemical compound that contains at least two amino.

42b. by comprising the polymer that the synthetic reactant that contains the chemical compound of at least three amino forms.

43b. the synthetic chemical compound that contains at least three amino.

44b. by comprising the polymer that the synthetic reactant that contains the chemical compound of at least four amino forms.

45b. the synthetic chemical compound that contains at least four amino.

46b. by comprising the polymer that the synthetic reactant that comprises the chemical compound of carbonyl-oxygen-succinimido forms.

47b. the synthetic chemical compound that comprises carbonyl-oxygen-succinimido.

48b. by comprising the polymer that the synthetic reactant that contains the chemical compound of at least two carbonyl-oxygen-succinimido forms.

49b. the synthetic chemical compound that contains at least two carbonyl-oxygen-succinimido.

50b. by comprising the polymer that the synthetic reactant that contains the chemical compound of at least three carbonyl-oxygen-succinimido forms.

51b. the synthetic chemical compound that contains at least three carbonyl-oxygen-succinimido.

52b. by comprising the polymer that the synthetic reactant that contains the chemical compound of at least four carbonyl-oxygen-succinimido forms.

53b. the synthetic chemical compound that contains at least four carbonyl-oxygen-succinimido.

54b. by comprising the polymer that the synthetic reactant that contains the chemical compound of polyalkylene oxide forms.

55b. the synthetic chemical compound that contains polyalkylene oxide.

56b. by comprising the polymer that the synthetic reactant that contains the chemical compound of polyalkylene oxide and biodegradable polyester block forms.

57b. the synthetic chemical compound that comprises polyalkylene oxide and biodegradable polyester block.

58b. by comprising the polymer that the synthetic reactant that contains the chemical compound of polyalkylene oxide with reactive amino forms.

59b. have the synthetic chemical compound that contains polyalkylene oxide of reactive amino.

60b. by comprising the polymer that the synthetic reactant that contains the chemical compound of polyalkylene oxide with reactive mercapto forms.

61b. have the synthetic chemical compound that contains polyalkylene oxide of reactive mercapto.

62b. by comprising the polymer that the synthetic reactant that contains the chemical compound of polyalkylene oxide with reactive carbonyl-oxygen-succinimido forms.

63b. have the synthetic chemical compound that contains polyalkylene oxide of reactive carbonyl-oxygen-succinimido.

64b. by comprising the polymer that the synthetic reactant that contains the chemical compound of biodegradable polyester block forms.

65b. the synthetic chemical compound that contains the biodegradable polyester block.

66b. by the polymer that the reactant that comprises synthetic polymer forms, described synthetic polymer forms from lactic acid or lactide wholly or in part.

67b. the synthetic polymer that forms from lactic acid or lactide wholly or in part.

68b. by the polymer that the reactant that comprises synthetic polymer forms, described synthetic polymer forms from glycolic or Acetic acid, hydroxy-, bimol. cyclic ester wholly or in part.

69b. the synthetic polymer that forms from glycolic or Acetic acid, hydroxy-, bimol. cyclic ester wholly or in part.

70b. the polymer that forms by the reactant that comprises polylysine.

71b. polylysine.

72b. by comprising the polymer that the reactant of (a) protein with the chemical compound that (b) comprises the polyalkylene oxide part forms.

73b. by comprising (a) protein and (b) polymer that forms of the reactant of polylysine.

74b. by comprising (a) protein and (b) having a polymer that the reactant of the chemical compound of at least four mercaptos forms.

75b. by comprising (a) protein and (b) having a polymer that the reactant of the chemical compound of at least four amino forms.

76b. by comprising (a) protein and (b) having a polymer that the reactant of the chemical compound of at least four carbonyl-oxygen-succinimido forms.

77b. by comprising (a) protein and (b) having a polymer that the reactant of the chemical compound of the biodegradable region that is formed by the reactant that is selected from lactic acid, lactide, glycolic, Acetic acid, hydroxy-, bimol. cyclic ester and 6-caprolactone forms.

78b. by comprising the polymer that the reactant of (a) collagen with the chemical compound that (b) comprises the polyalkylene oxide part forms.

79b. by comprising (a) collagen and (b) polymer that forms of the reactant of polylysine.

80b. by comprising (a) collagen and (b) having a polymer that the reactant of the chemical compound of at least four mercaptos forms.

81b. by comprising (a) collagen and (b) having a polymer that the reactant of the chemical compound of at least four amino forms.

82b. by comprising (a) collagen and (b) having a polymer that the reactant of the chemical compound of at least four carbonyl-oxygen-succinimido forms.

83b. by comprising (a) collagen and (b) having a polymer that the reactant of the chemical compound of the biodegradable region that is formed by the reactant that is selected from lactic acid, lactide, glycolic, Acetic acid, hydroxy-, bimol. cyclic ester and 6-caprolactone forms.

84b. by comprising the polymer that the reactant of (a) methylated collagen with the chemical compound that (b) comprises the polyalkylene oxide part forms.

85b. by comprising (a) methylated collagen and (b) polymer that forms of the reactant of polylysine.

86b. by comprising (a) methylated collagen and (b) having a polymer that the reactant of the chemical compound of at least four mercaptos forms.

87b. by comprising (a) methylated collagen and (b) having a polymer that the reactant of the chemical compound of at least four amino forms.

88b. by comprising (a) methylated collagen and (b) having a polymer that the reactant of the chemical compound of at least four carbonyl-oxygen-succinimido forms.

89b. by comprising (a) methylated collagen and (b) having a polymer that the reactant of the chemical compound of the biodegradable region that is formed by the reactant that is selected from lactic acid, lactide, glycolic, Acetic acid, hydroxy-, bimol. cyclic ester and 6-caprolactone forms.

90b. by comprising the polymer that hyaluronic reactant forms.

91b. the polymer that forms by the reactant that comprises derivatives of hyaluronic acids.

92b. polymer by the reactant formation that comprises poly-(ethylene glycol) ether four-sulfydryl of the tetramethylolmethane of number-average molecular weight between 3,000 and 30,000.

93b. the tetramethylolmethane of number-average molecular weight between 3,000 and 30,000 gathers (ethylene glycol) ether four-sulfydryl.

94b. polymer by the reactant formation that comprises poly-(ethylene glycol) ether four of the tetramethylolmethane of number-average molecular weight between 3,000 and 30,000-amino.

95b. the tetramethylolmethane of number-average molecular weight between 3,000 and 30,000 gathers (ethylene glycol) ether four-amino.

96b. by comprising (a) number-average molecular weight 3,000 and 30, between 000 and comprise the synthetic compound of polyalkylene oxide zone and a plurality of nucleophilic groups and (b) number-average molecular weight 3, between 000 and 30,000 and comprise the polymer of reactant formation of the synthetic compound of polyalkylene oxide zone and a plurality of electrophilic groups.

97b. by comprising (a) number-average molecular weight 3,000 and 30, between 000 and comprise the synthetic compound of polyalkylene oxide zone and a plurality of nucleophilic groups and (b) number-average molecular weight 3, between 000 and 30,000 and comprise the mixture of the synthetic compound of polyalkylene oxide zone and a plurality of electrophilic groups.

As mentioned above, the invention provides and comprise fibrous tissue that above-mentioned 86 kinds (1a to 85a) list and form each of classification that agent or fibrous tissue form agent, each compositions with the polymer of above-mentioned 98 kinds (1b to 97b) and chemical compound: thereby, in aspect independent, the invention provides 86 and take advantage of 98=8, the compositions of 428 kinds of descriptions.

As mentioned above, can use above-mentioned polymer coating that described fibrous tissue is formed agent is coated on the part of whole implant or implant.This can pass through, for example, dipping, spraying, the electrospinning silk is smeared or is finished by vacuum moulding machine.Except that above-mentioned coating composition and method, also there are various other coating composition as known in the art and method.The representational case description of these coating compositions and method is in following document: U.S. Patent number 6,610,016; 6,358,557; 6,306,176; 6,110,483; 6,106,473; 5,997,517; 5,800,412; 5,525,348; 5,331,027; 5,001,009; 6,562,136; 6,406,754; 6,344,035; 6,254,921; 6,214,901; 6,077,698; 6,603,040; 6,278,018; 6,238,799; 6,096,726; 5,766,158; 5,599,576; 4,119,094; 4,100,309; 6,599,558; 6,369,168; 6,521,283; 6,497,916; 6251964; 6,225,431; 6,087,462; 6,083,257; 5,739,237; 5,739,236; 5,705,583; 5648442; 5645883; 5,556,710; 5,496,581; 4,689,386; 6,214,115; 6,090,901; 6,599,448; 6,054,504; 4,987,182; 4,847,324; With 4,642,267; U.S. Patent Application Publication No. 2003/0129130; 2001/0026834; 2003/0190420; 2001/0000785; 2003/0059631; 2003/0190405; 2002/0146581; 2003/020399; 2003/0129130; 2001/0026834; 2003/0190420; 2001/0000785; 2003/0059631; 2003/0190405; 2002/0146581; With 2003/020399; With PCT publication number WO 02/055121; WO 01/57048; WO 01/52915; With WO 01/01957.

In another aspect of the present invention, can use non-polymer reagent that bioactive fibrous tissue is formed agent, hemorrhage and/or anti-infective and be delivered in the diverticulum.The example of these non-polymeric reagent comprises sucrose derivative (for example, sucrose acetate isobutyrate, sucrose oleate), and sterol is as cholesterol, stigmasterol, cupreol and estradiol; Cholesterol ester is as cholesteryl stearate; C ₁₂-C ₂₄Fatty acid is as lauric acid, myristic acid, Palmic acid, stearic acid, arachidic acid, behenic acid and lignoceric acid; C ₁₈-C ₃₆Single, two and triglyceride such as monooleate glyceride, a glyceryl linoleate, Tegin L 90, a behenic acid glyceride, a myristin, a decylenic acid glyceride (glycerylmonodicenoate), glycerol-1,3-dipalmitate, two behenic acid glyceride, two myristins, two decylenic acid glyceride, three behenic acid glyceride, three myristins, three decylenic acid glyceride, glyceryl tristearate and their mixture; Sucrose fatty acid ester is as sucrose distearate and sucrose palmitate; Sorbitan fatty acid esters is as sorbitan monostearate, sorbitan monopalmitate and sorbitan tristearate; C ₁₆-C ₁₈Aliphatic alcohol is as hexadecanol, tetradecyl alchohol, octadecanol and cetostearyl alcohol; The ester of aliphatic alcohol and fatty acid is as hexadecyl palmitate and Palmic acid octadecanol and hexadecanol ester (cetearyl palmitate); The anhydride of fatty acid is as stearic anhydride; Phospholipid comprises phosphatidylcholine (lecithin), Phosphatidylserine, PHOSPHATIDYL ETHANOLAMINE, phosphatidylinositols and dissolving derivant (lysoderivatives) thereof; Sphingol and derivant thereof; Sphingomyelins (spingomyelins) is as stearoyl, palmityl and two tridecanoyl sphingomyelins; Ceramide is as stearoyl and palmityl ceramide; Glycosphingolipids; Lanoline and lanolin alcohol, calcium phosphate, sintering and unsintered hydroxyapatite, zeolite; And combination and mixture.

The representational example that relates to the patent of non-polymer delivery system and preparation thereof comprises U.S. Patent number 5,736,152,5,888,533,6,120,789; 5,968,542 and 5,747,058.

Can be used to comprise and send other carrier that fibrous tissue as herein described forms agent, hemorrhage and/or anti-infective equally comprises: hydroxypropyl cyclodextrin (Cserhati and Hollo, " International Journal of Pharmaceutical Medicine " be 108:69-75 (Int.J.Pharm.), 1994), liposome (for example, referring to Sharma etc., " cancer research " (Cancer Res.) 53:5877-5881,1993; Sharma and Straubinger, " drug research " (Pharm.Res.) 11 (60): 889-896,1994; WO 93/18751; U.S. Patent number 5,242,073), liposome/gel (WO 94/26254), nanocapsule (Bartoli etc., " microencapsulation magazine " (J.Microencapsulation) 7 (2): 191-197,1990), micelle (Alkan-Onyuksel etc., " drug research " (Pharm.Res.) 11 (2): 206-212,1994), nano-particle (Violante and Lanzafame PAACR), modified nanoparticles (U.S. Patent number 5,145,684), nano-particle (surface modification) (U.S. Patent number 5,399,363), micelle (surfactant) (U.S. Patent number 5,403,858), synthetic phosphatide cpd (U.S. Patent number 4,534,899), aerogenesis dispersion (gas bornedispersion) (U.S. Patent number 5,301,664), liquid emulsion, foam, spray, gel, lotion, cream, ointment, disperse vesicle, granule or droplet solid or liquid aersol, microemulsion (U.S. Patent number 5,330,756), polymerization housing (nanocapsule and micron capsule) (U.S. Patent number 5,439,686), Emulsion (Tarr etc. " drug research " (Pharm Res.) 4:62-165,1987), nanometer spheroid (Hagan etc., " control release biological active material international symposium journal " (Proc.Intern.Symp.Control Rel.Bioact.Mater.) 22,1995; Kwon etc., " drug research " (Pharm Res.) 12 (2): 192-195; Kwon etc., " drug research " (Pharm Res.) 10 (7): 970-974; Yokoyama etc., " controlled release magazine " be 32:269-277 (J.Contr.Rel.), and 1994; Gref etc., " science " be 263:1600-1603 (Science), and 1994; Bazile etc., " pharmaceutical science magazine " be 84:493-498 (J.Pharm.Sci.), 1994) and implant (Invest.Ophthalm.Vis.Science 34 (11): 3076-3083,1993 for U.S. Patent number 4,882,168, Jampel etc.; Walter etc., Cancer Res.54:22017-2212,1994).

In another embodiment, fibre modification derivant, hemorrhage and/or anti-infective may further include secondary carrier.This secondary carrier can (block copolymer of SDS, X-Y, X-Y-X or Y-X-Y form for example, wherein X be the form of polyester (for example PLGA, PLLA, PDLLA, PCL, poly-diethyleno dioxide ketone), zeolites or cyclodextrin for poly-(alkylene oxide) or its alkyl ether and Y for microsphere (for example PLGA, PLLA, PDLLA, PCL, gelatin, poly-diethyleno dioxide ketone, poly-(alkyl cyanoacrylate)), nanometer spheroid (for example PLGA, PLLA, PDLLA, PCL, gelatin, poly-diethyleno dioxide ketone, poly-(alkyl cyanoacrylate)), liposome, Emulsion, microemulsion, micelle.

In another embodiment, these therapeutic agents/secondary carrier compositions can a) directly be attached among the biomaterial implant or on, b) mix in the injectable solution, or c) mixes in gel or the viscosity solution, d) mix the compositions that is used for being coated with described implant, or e) after being coated with described implant with coating composition, be attached among the described implant or on.

For example, the therapeutic agent that has loaded the PLGA microsphere can be mixed in the polyurethane coating solution, then it is combined in the described implant.In another example, with polyurethane coated described implant, thereby allow that then the part drying makes the surface remain sticking.The particle form of fibre modification derivant or fibre modification derivant/secondary carrier then can be administered on viscous coating all or part of, subsequently with described implant drying.Except with one or more therapeutic agents coating implants described herein, described reagent can also with the material mixing that is used to make implant so that described reagent is mixed in the described implant.

In another example, can be coated with described implant with above-mentioned coating is any.Then, heat treatment method can be used for softening coating, subsequently, fibre modification derivant or fibre modification derivant/secondary carrier be administered on the part of whole implant or described implant (for example, outer surface).

In one embodiment, (for example produce suspension or solution thereby fibre modification derivant, hemorrhage and/or anti-infective directly can be attached in the preparation, the silk powder, bleomycin) or its (for example can be incorporated in the secondary carrier, micelle, liposome, microsphere, microgranule, the nanometer spheroid, microparticle (microparticulate), Emulsion and/or microemulsion), described secondary carrier (for example then is incorporated into filled compositions, fibrin, collagen, PEG, cyanoacrylate, or its mixture) in.In another embodiment, therapeutic agent can be incorporated into statically or covalently original position forms in one or more component of polymer of compositions.

In another embodiment, therapeutic agent can be attached in the filler in the process of the described reagent of preparation.For example, can when preparation is used as the microsphere of filler, the silk powder be added as reagent.

In another aspect of the present invention, promoting the applied implant of fiberization in the body further to be delayed the release of fibre modification derivant and/or active chemical compound or compositions is coated with.The representative example of these reagent comprises the biologically inert material such as gelatin, PLGA/MePEG film, PLA, polyurethane, silicone rubber, surfactant, lipid or Polyethylene Glycol, and bioactive substance such as heparin (for example, induce condense).

For example, in one embodiment of the invention, the activating agent on the described implant is pushed up by physical barriers and is coated with (top-coated).These barriers can comprise the material of Nondegradable or biodegradable material such as gelatin, the PLGA/MePEG film, and PLA, Polyethylene Glycol, etc.In one embodiment, the speed that spreads in barrier coatings of therapeutic agent is slower than the speed that therapeutic agent spreads in coat layer.In the situation of PLGA/MePEG, in case described PLGA/MePEG contacts with body fluid, MePEG can stripping from PLGA, stay from PLGA to (for example comprising the fibre modification derivant, silk or ciclosporin A) the passage of lower floor, described fibre modification derivant then is diffused in the blood vessel wall and causes its biologic activity.

In another embodiment of the invention, for example, use polymer (for example, PLG, PLA, or polyurethane) particle form of activating agent (for example silk or ciclosporin A) can be applied on the described implant.Dissolving slowly or degraded (for example, MePEG-PLGA or PLG) and second polymer that do not comprise activating agent can be coated on the ground floor.In case upper strata dissolving or degraded, it exposes the coating of infra, and this makes activating agent be exposed to the treatment site or discharges from coating.

In another aspect of the present invention, the skin of the applied implant of fibre modification in the inductor, hemostasis and/or infection reaction is further handled skin with cross-linked coating.This can finish by applied implant being carried out Cement Composite Treated by Plasma (plasma treatment) method.The crosslinked degree and the character of finishing can be set by changing RF power, and about isoionic location, the duration of processing and the gas composition that is introduced into plasma chamber change.

Can also be by being coated with the surperficial of described implant with inert molecule or being coated with implant surface by form of passivation with the therapeutic agent that was activated afterwards; use the protection to bioactivity surface, described inert molecule is approaching by sterically hindered prevention and avtive spot.For example, be coated with described implant with enzyme, it causes the release of fibre modification derivant or activates described fibre modification derivant.

In another strategy, can be coated with described implant with the form of passivation of fibre modification derivant, hemorrhage and/or anti-infective, in case implant is used, it then is activated.Be used or be applied in the area for treatment at the fibre modification derivant in described implant (as described below) (by, for example injection, spraying, washing, drug delivery tube or air bag) after, can successfully carry out this activation in the diverticulum by other material is expelled to.For example, can be coated with described implant with the form of passivation of fibre modification derivant.In case use described implant, with activating substance injection be administered among the treatment site or on, in described treatment site, used the fibre modification derivant of form of passivation.

For example, bioactive fiber degeneration derivant, hemorrhage and/or anti-infective can be applied on the implant with usual way.Then, can cover the outer surface that (for example, coating) comprises active therapeutic agent with Polyethylene Glycol.Can be by forming the coating combination that key carries out PEG and comprises therapeutic agent between the reactive group on two-layer.For example, use condensation reaction can form ester bond.Before using described implant, esterase is expelled to the treatment site of implant exterior circumferential.Described esterase can the key of cracking between ester and therapeutic agent, makes reagent cause the inhibition (anti-infective) of fibre modification (fibre modification derivant), hemostasis (hemorrhage) and/or bacterial growth thus.

In certain embodiments of the invention, therapeutic combination can also comprise other composition, such as surfactant (for example, pool Sha Luomu, such as F-127, L-122, L-101, L-92, L-81, and L-61), anti-inflammatory agent, antiseptic, and/or antioxidant.

In certain embodiments of the present invention, therapeutic agent or carrier can also comprise radiopaque, produce (echogenic) material of echo and nuclear magnetic resonance (MRI) responsive materials (being the MRI contrast agent) and make it possible under ultrasonic, fluoroscopy and/or MRI implant be developed.For example, the treatment implant can by produce echo radiopaque compositions manufacturing or with the said composition coating (for example with produce echo or radio-opaque material such as powdery tantalum, tungsten, brium carbonate, bismuth oxide, barium sulfate, U.S. bent neat imines (metrazimide), iopamidol, iohexol, iopromide, iobitridol, iomeprol, iopentol, ioversol, ioxilan, iodixanol, iotrolan, the acetrizoic acid derivant, amidotrizoic acid derivant, iotalamic acid derivant, iodine former times, he drew acid (ioxithalamic acid) derivant, the metrizoic acid derivant, iodamide, lypophylic agents, the microsphere or the bubble at sound wave interface are made or had by adding to adipiodone and ioglycamic acid).The coating of use generation echo can obtain the development by the implant of ultra sonic imaging.The coating that produces echo for example is described in, and U.S. Patent number 6,106 is in 473 and 6,610,016.In order under MRI, to develop, contrast agent (for example chelating gadolinium (III) or iron oxides chemical compound) can be attached among the implant or on, as for example as the component in the coating or in the voidage of implant (for example in inner chamber, storage, or in being used to form the structural material of implant).In some embodiments, the diverticulum implant can comprise radiopaque or MRI visable indicia (for example, band), and it can be used at method for implantation described implant being carried out orientation and guidance.

Perhaps or in addition, use fluorescence, or by other spectrophotography, medical implant can develop under visible light.Can be comprised that the developing agent that satisfies this purpose comprises dyestuff, pigment and other coloring agent that can improve development in endoscope between the operating period.On the one hand, described medical implant may further include coloring agent with in vivo and/or exsomatize (ex vivo) increase the development of implant.Usually, implant may be difficult to develop after insertion, particularly at the edge of implant.Thereby colorant combination can be reduced or removes the incidence rate or the seriousness of this problem to the diverticulum implant.Described coloring agent provides unique color, increases contrast, or provides unique fluorescent characteristic to described implant.On the one hand, provide the solid implant that comprises coloring agent, thereby easily develop (under visible light or use fluorescent technique) and easily it is distinguished from its implantation site.In yet another aspect, coloring agent can be included in liquid or the semi-solid combination.For example, can carry out the one-component in two component mixtures painted, thereby when exsomatizing or making up in vivo, described mixture is by fully painted.

Described coloring agent is passable, for example is that interior source compound (for example, aminoacid or vitamin) or nutrient or food material can be hydrophobicity or hydrophilic compounds also.Preferably, on employed concentration, described coloring agent has low-down toxicity or does not have toxicity.Further preferably coloring agent normally safety and enter in the body by absorption usually, such as beta-carotene.The representative example of painted nutrient (under visible light) comprises fatsoluble vitamin such as vitamin A (yellow); Water soluble vitamins such as vitamin B12 (pink-red) and folic acid (yellow-orange); Carotenoid such as beta-carotene (yellow-purple) and lycopene (redness).Other example of coloring agent comprises natural product (berry and fruit) extract such as anthrocyanin (purple) and Stigma Croci extract (dark red).Described coloring agent can be fluorescence or phosphorescent compounds such as Ipotensil (vitamin e derivative) or L-tryptophan.Can also use any derivant, analog and isomer of above-mentioned coloring compound.The method that coloring agent is mixed in implant or the therapeutic combination can depend on that the character of coloring agent changes with its desired position.For example, can select the hydrophobicity coloring agent to be used for hydrophobic base.Described coloring agent can be mixed carrier matrix, in micelle.In addition, thus the pH that can control environment further controls described color and intensity.

On the one hand, compositions of the present invention comprises that one or more are also referred to as the coloring agent of dyestuff, and it will be to give described compositions, and example gel exists with observable painted effective dose.The example of coloring agent comprises that the dyestuff that is suitable for food is such as being known as F.D.﹠amp; C. those of dyestuff and natural colorant be such as Pericarpium Vitis viniferae extract, beet red powder, beta-carotene, roucou (annato), fuchsin, Rhizoma Curcumae Longae, Fructus Capsici powder etc.Can also use any derivant, analog and isomer of above-mentioned coloring compound.The method that coloring agent is mixed in implant or the therapeutic combination can depend on that the character of coloring agent changes with its desired position.For example, can select the hydrophobicity coloring agent to be used for hydrophobic base.Described coloring agent can be mixed carrier matrix, in micelle.In addition, thus the pH that can control environment further controls described color and intensity.

In one aspect, compositions of the present invention comprises one or more antiseptic or antibacterial, its effective dose with the bacterial growth in and/or the composite inhibiting anticorrosion to compositions exists, for example, bismuth tribromophenate, methyl hydroxybenzoate, bacitracin, nipagin A, nipasol, erythromycin, chlorocresol, benzalkonium chloride etc.The other example of antiseptic comprises p-methoxybenzoic acid ester (paraoxybenzoic acid esters), chlorobutanol, benzylalcohol, phenethanol, dehydroactic acid, sorbic acid etc.In one aspect, compositions of the present invention comprises that one or more kill antibacterial (being also referred to as antibacterial) reagent.

On the one hand, compositions of the present invention comprises the antioxidant that one or more exist with effective dose.The example of antioxidant comprises sulphite, alpha-tocopherol and ascorbic acid.

In related fields of the present invention, implant and compositions are provided, after using described implant or applying said compositions, it discharges the reagent of inducing fibre modification, hemostatic and/or anti-infection activity in vivo.In some aspects, with therapeutic agent or comprise that the compositions of therapeutic agent is local or regionally be delivered to the treatment site from compositions.

Of the present invention aspect some in, therapeutic combination preferably biocompatibility and in a few hours, discharge one or more fibrous tissue in the period of a couple of days or several months and form agent, hemorrhage and/or anti-infectives.

Thereby implant of the present invention can have certain configuration discharges fibre modification derivant, hemorrhage and/or anti-infective in one or more stages, and described one or more stages have similar or different performance (for example, discharging) pattern.Described therapeutic agent is on the amount that can be sustainable (sustainable), intermittently or continue; In one or more stages; And/or delivery rate; Be effective in any or various ingredients that increases or promote fibre modification (or cicatrization), hemostasis or infection control.

Therefore, can to rate of release design with by discharging at certain hour that fibre modification is induced (cicatrization) thus thereby agent, hemorrhage and/or anti-infective are promoted at least a composition of fibre modification, hemostasis and/or infection control or increase and influence fibre modification (or cicatrization), stop blooding (grumeleuse) and/or infection.And therefore predetermined rate of release can reduce reagents loaded and/or concentration and provide minimum medicine to remove effectively also increases pharmaceutically-active efficient.In one embodiment, rate of release can provide the therapeutic agent of sustainable level to the treatment site.In another embodiment, rate of release is sustained.Described speed can reduce and/or increase in time, and it can randomly comprise non-release substantially period.Described rate of release can comprise multiple speed.In one embodiment, multiple rate of release can comprise and being selected from by constant substantially, reduces, and increases and does not discharge speed in the group of composition substantially.

On described diverticulum, among or near the total amount of fibre modification derivant, hemorrhage and/or the anti-infective that exists can from about 0.01 μ g (microgram) in about 2500mg (milligram) scope.Usually, the amount of described fibre modification derivant, hemorrhage and/or anti-infective can from 0.01 μ g in about 10 μ g scopes; Or from 10 μ g in the scope of about 1mg; Or in the scope from 1mg to about 10mg; Or in the scope from 10mg to about 100mg; Or in the scope from 100mg to about 500mg; Or from 500mg in about 2500mg scope.

On described diverticulum, among or near the dose,surface of fibre modification derivant, hemorrhage and/or anti-infective can be at every mm of surface area ²Be less than 0.01 μ g in about 250 μ g scopes.Usually, the amount of therapeutic agent can be less than 0.01 μ g/mm ²Scope in; Or from 0.01 μ g to about 10 μ g/mm ²Scope in; Or from 10 μ g to about 25 μ g/mm ²Scope in; Or from 25 μ g to about 250 μ g/mm ²Scope in.

On described diverticulum, among or near fibre modification derivant, hemorrhage and/or anti-infective can from described compositions and/or implant, discharge over a period to come, can begin to measure described period from the implantation time, and it is in being less than 1 day to about 180 days scope.Usually, described release time can also be from being less than 1 day to about 7 days approximately; From 7 days to about 14 days; From 14 days to about 28 days; From 28 days to about 56 days; From 56 days to about 90 days; From 90 days to about 180 days.

On the one hand, provide " rapid release " or " breaking " (burst) therapeutic combination, it discharges in 7 to 10 days period and surpasses 10%, 20%, or fibre modification derivant, hemorrhage and/or the anti-infective of 25% (w/v).In certain embodiments, these " rapid release " compositionss should be able to discharge required fibrous tissue formation agent, hemorrhage and/or the anti-infective of treatment level (it can be used).In other embodiments, provide the therapeutic combination of " slowly discharging ", it discharges fibre modification derivant, hemorrhage and/or the anti-infective that is less than 1% (w/v) in 7 to 10 days period.In other embodiments, therapeutic combination is provided, it is being less than the therapeutic agent of 1% (w/v) or is not discharging therapeutic combination at all surpassing to discharge in 10 days period, but keeps the whole duration of described compositions very long period such as in vivo diverticulum agglutination.

The amount of the therapeutic agent that discharges from described compositions and/or implant can be determined based on the extracorporeal releasing characteristic of described reagent from compositions as the function of time.By placing the phosphate buffer (pH 7.4) of suitable buffer such as 0.1M to determine in-vitro release rate in 37 ℃ at fibre modification derivant (cicatrization), hemorrhage and/or anti-infective in compositions or the implant.Then, the sample of buffer solution regularly removed by HPLC or by the gravimetric analysis mode analyzes, thereby and described buffer be replaced and avoid any saturation effect.

Based on in-vitro release rate, every day, the amount of release of fibre modification derivant, hemorrhage and/or anti-infective can be from about 0.0001 μ g (microgram) to about 2500mg (milligram).Usually, the amount of the therapeutic agent that can discharge at a day can be in the scope of 0.0001-0.01 μ g; 0.01 the about 10 μ g of μ g-; Or from 10 μ g to about 1mg; Or from 1mg to about 10mg, or from 10mg to about 100mg; Or from 100mg to about 500mg; Or from 500mg to about 2500mg.In one embodiment, prepare fibre modification derivant, hemorrhage and/or anti-infective so that the diverticulum tissue obtains in stable still constant substantially mode, thereby described reagent is remained unchanged in tissue substantially.In another embodiment, the preparation therapeutic agent, so that responsive diverticulum tissue obtains in the mode that continues and/or be controlled, this has caused the efficient and/or the effect that increase.In addition, rate of release can all change in any or two processes in initial sum release stage subsequently.Can also exist the other stage to carry out the release of same substance and/or different material.

In one embodiment, the rate of release of fibre modification derivant, hemorrhage and/or anti-infective can be categorized as the combination of zero level, one-level or zero level and one-level.

In addition, therapeutic combination of the present invention preferably has the stable pot-life that is at least the several months, and can be produced under aseptic condition and keep.By the described compositions of preparation under gnotobasis, and/or can use the obtainable method in this area that they are carried out final sterilization, described compositions can be aseptic.Many medicines are made into aseptic and this standard is by USP XXII＜1211〉defined.Term " USP " refer to American Pharmacopeia (see www.usp.org, Rockville, MD).By multiple that in industry, accepted and list in USP XXII＜1211〉in method can realize sterilization, comprise gaseous sterilization, ionizing radiation, perhaps when suitable, filtration.Can be by also being in USPXXII＜1211〉in the operation handled of the defined asceptic of being called keep aseptic.The acceptable gas that is used for gaseous sterilization comprises oxirane.The acceptable ray type that is used for the ionizing radiation method for example comprises the gamma-rays from cobalt 60 source and electron ray.Gamma-ray typical doses is 2.5MRad.By radiation of final use gamma-rays or electron sterilization method, also can take place aseptic.Utilize the appropriate bore size, for example 0.22 μ m and suitable material, for example the filter of politef (for example, polytetrafluoroethylene (TEFLON)) is realized filtering.The combination of these methods can also be used to prepare the compositions of sterile form.

On the other hand, reagent of the present invention, compositions and implant are included in the container, and this allows them to be used as the purpose of expectation.Important container characteristics is to allow to add the composition medium, such as water or for example brinish spatial content of other aqueous medium, acceptable light transmission, thereby prevent that luminous energy from damaging compositions in the described container (referring to USP XXII＜661 〉), the acceptable restriction (referring to USPXXII) of extractable in the container material is for humidity (referring to USPXXII＜671 〉) or the acceptable barrier ability of oxygen.For oxygen infiltration, can be by in container, including a kind of noble gas of malleation, such as highly purified nitrogen, or noble gas, control as argon.

The typical material that is used to produce the container that is used for medicine comprises that USPI is to III type and NP type glass (referring to USP XXII＜661 〉), polyethylene, polytetrafluoroethylene, siloxanes and grey fourth glue.For parenteral, preferred USPI is to the glass and the polyethylene of III type.

In certain embodiments, the fibre modification derivant of Miao Shuing, hemorrhage, anti-infective or derivatives thereof and analog in this article can be used to produce the variant of above-mentioned composition.In addition, therapeutic agent can be with polymer support as herein described or is not used in the compositions with polymer support.

Can be incorporated among the described implant or on or other reagent of from described implant, discharging comprise that extracellular matrix components such as fibrous structure albumen (for example, fibrillar collagen, non-fiber collagen and elastin laminin), viscous glycoprotein (for example, laminin and fibronectin), Dan Baijutang (for example, heparin sulfate, chondroitin sulfate, dermatan sulfate), hyaluronan (for example hyaluronic acid), be rich in the acidic secretion protein (SPARC) of cysteine, thrombospondin, bind the inhibitor of plain and matrix metalloproteinase, (for example TIMPs and synthetic property TIMPs, such as, horse cubic meter department he, Ba Misita, doxycycline, tetracycline, minocycline, TROCADE, Ro-1130830, CGS 27023A, BMS-275291) and polylysine.The somatomedin and the inflammatory cytokine that relate to the synthetic and tissue remodeling of blood vessel generation, fibroblast migration, fibroblast proliferation, ECM, such as epidermal growth factor (EGF) family, transforminggrowthfactor-(TGF-α), transforming growth factor-beta (TGF-β-1, TGF-β-2, TGF-β-3, platelet-derived somatomedin (PDGF), fibroblast growth factor (acidity-aFGF; And alkalescence-bFGF), bone morphogenetic protein, activator protein, VEGF (VEGF, VEGF-B, VEGF-C, placental growth factor-PIGF), angiogenin, insulin like growth factor (IGF), hepatocyte growth factor (HGF), Connective Tissue Growth Factor (CTGF), bone marrow colony stimulating factor (CSFs), granulocyte-macrophage colony stimutaing factor (GM-CSF), granulocyte-colony stimulating factor (G-CSF), M-CSF (M-CSF), erythropoietin, interleukin (IL-1 particularly, IL-8, IL-6), tumor necrosis factor-alpha (TNF9), nerve growth factor (NGF), interferon-' alpha ', interferon-beta and growth hormone (GH) also are adapted to be incorporated into and discharge from specificity diverticulum implant.Can be applied on the diverticulum implant or comprise binding agent such as cyanoacrylate or by 4-arm mercaptan PEG (10K) by other reagent of its release, the material that 4-arm NHS PEG (10K) and methylated collagen make.

The device of treatment or prevention diverticulum disease

In certain embodiments, provide medical implant, described medical implant comprises (i) fibre modification derivant and (ii) comprises compositions at least a of fibre modification derivant.In another embodiment, with the inductive pharmacological agents of fibre modification, be suitable for comprising or the implant that discharges reagent, anti-infective and/or the hemorrhage of inducing fibre modification (by one or more mechanism described herein) is administered on the diverticulum or within.In the time of in being placed on diverticulum, exist fibrous tissue to form agent and form, otherwise fibre modification formation can not taking place to induce fibre modification.Implant/the compositions that to induce fibrotic, pharmacological agents and/or comprise fibre modification derivant (and/or anti-infective and/or hemorrhage) is incorporated among the host (people or inhuman mammal) with diverticulum according to method described herein, so that described reagent causes fibrotic formation in diverticulum, is not having generation in addition of described fibre modification under the situation of described reagent.

That also be provided for obtaining diverticulum chamber path here and be used to use the device of inducing the fibre modification treatment.The chamber of body passageway can enter via endoscope's (for example, colonoscope, gastroscope, ERCP, bronchoscope, cystoscope etc.) or under the guiding of radiography (x-ray, fluoroscopy, ultrasonic, CT scan, MRI scanning, PET scanning or other imaging pattern).When development enters into the diverticulum opening in chamber of described path, can use multiple special conduit to be used to send above-mentioned therapeutic agent and compositions described herein.These devices all have makes fibre modification derivant, hemorrhage and/or the anti-infective positioning delivery chamber in the diverticulum chamber, and this can be in direct vision (splanchnoscopy) or radiography guiding realization down.

Conduit

Many catheter in blood vessel (conduit that contains one or more chambeies, it is suitable for transmitting aqueous, microparticle, fluid or gel preparation to blood flow, blood vessel wall, speckle or aneurysmal sack) can be used for directly, the fixed point medicine (for example sends, the micro-syringe conduit, be placed in the target tissue or the conduit of next-door neighbour's target tissue), localized drug delivery (promptly, be placed on the endarterial conduit of supply target organ or tissue), or system's medicine is sent (that is, being placed on intra-arterial and intravenous catheter in the peripheral circulation system).For example, being suitable for the conduit that uses and balloon catheter can be from end aperture, by one or more side ports, by the microporosity external structure or by direct injection expectation tissue or vessel position fibrous tissue is formed agent and be delivered to desirable tissue or vessel position.

Can utilize multiple conduit to be used for regionality or localized drug delivery.Be used in the blood vessel of delivering drugs air bag and non-balloon catheter for example in U.S. Patent number 5,180,366; 5,171,217; 5,049,132; 5,021,044; 6,592,568; 5,304,121; 5,295,962; 5,286,254; 5,254,089; 5,112,305; PCT publication number WO 93/08866, WO 92/11890 and WO 92/11895; With JACC 23:1234-1244 (1994) such as Riessen, Kandarpa K.J.Vasc.Interv.Radio (blood vessel intervention radiation magazine) .11 (suppl.): 419-423 (2000), and Yang, X. (2003) Imaging of VascularGene Therapy (blood vessel gene therapy imaging) 228 (1): describe among the 36-49.

In addition, a lot of physics as described herein is got involved the application such as heat energy (heat or cold therapy), cautery, electricity, RF energy, laser, radioactivity, ultrasonic, airbag inflation, physics abrasion etc., the added advantage on surface, chamber that will have the damage diverticulum may maybe may be can't help the cooperativing medicine-feeding of fibre modification derivant and the healing/synulotic cascade of further amplifying to cause.Though in fact any delivery catheter of suitable length, flexibility and chamber size can be used to therapeutic agent delivery around the diverticulum neutralization, array apparatus is the nonrestrictive conduit example that can be used for the treatment of diverticulum disease down.

Drug delivery tube

Can use multiple drug delivery tube maybe can make it be suitable for using, be used for delivery of agents or comprise described combination of agents thing to the host.The side opening of conduit by endoscope's (or under radiography guiding) advanced up to entering the diverticulum chamber.Fibre modification derivant or implant can be administered in the diverticulum chamber via conduit then.The example of drug delivery tube comprises diffusion conduit, infusion catheter and direct injection conduit.Drug delivery tube can be to activate medicine and/or promote medicine to be delivered to the drug delivery system of the energy startup in the tissue (for example, the diverticulum surface), such as the delivery system of electroporation, ultrasonic, laser or other energy base.

The representative example of drug delivery tube comprises balloon catheter, as from (the Nei Dike (Natick) of Boston technology Corp (Boston Scientific Corporation), Massachusetts (MA)) CHANNEL and TRANSPORT balloon catheter, with from senior cardiovascular system (the Advanced Cardiovascular Systems of company, Inc.) Stack of (Santa Clara (Santa Clara), California (CA)) perfusion coronary artery expansion (Stack Perfusion Coronary Dilitation) conduit.Other example of drug delivery tube comprises infusion catheter, as available from heart company (CordisCorporation) (Miami lake (Miami Lakes), Florida (FL)) CRESCENDO coronary infusion conduit, available from (the Microtherapeutics of Micro Therapeutics, Inc.) (holy Clement (SanClemente), California (CA)) Cragg-McNamara band valve infusion catheter, DISPATCH conduit available from Boston technology Corp (Boston Scientific Corporation), come bootstrap company (Guidant Corporation) (Houston (Houston), Texas (TX)) GALILEOCentering conduit, with infusion cover conduit, as from local medical company (LocalMed, Inc.) the INFUSASLEEVE conduit of (Sani Wei Er (Sunnyvale), California (CA)).Infusion cover conduit is at for example U.S. Patent number 5,318,531; 5,336,178; 5,279,565; 5,364,356; 5,772,629; 5,810,767; With 5,941, describe in 868.The conduit of sending with machinery or electricity enhancing medicine comprises for example pressure-driven conduit (needle injection catheter that for example has syringe ports, as can be available from (the InterVentional Technologies of interventional technique company, Inc.) (Santiago, INFILTRATOR conduit California (CA))) (referring to, for example, U.S. Patent number 5,354,279) and ultrasonic auxiliary (phonophoresis) and ionotherapy conduit (referring to, for example, Singh, J. etc. (1989) " drug design is sent " (Drug Des.Deliv.): 4:1-12 and U.S. Patent number 5,362,309; 5,318,014; 5,315,998; 5,304,120; 5,282,785; With 5,267,985).

RF (radio frequency) ablation catheter.

In the treatment diverticulum disease, can use the conduit of multiple delivery of energy maybe can make it be suitable for using.Radio-frequency (RF) ablation is that the altofrequency energy is delivered to step in the tissue.Can use any that two types RF melts: temperature controlled or fluid-cooled melts.The energy of careful controlled quentity controlled variable is delivered to the diverticulum surface, so that skin breakage (but being not enough to cause perforation of diverticulum) or damage are enough to cause (or stimulation) healing reaction.A kind of like this device can use separately to induce fibre modification, perhaps can be administered in the diverticulum chamber with fibre modification derivant or implant to be used in combination.Exemplary RF ablation catheter comprises by Medtronic (Medtronic), Minneapolis (Minneapolis), Minnesota (MN) (for example, RF CONTACTR (Dual-Curve series (Series); RFENHANCR (SC) series; RF CONDUCTR (MC) Series; RF MARINR (MC) series; With 5F RF MARINR (SC) series) and Boston technology Corp (Boston ScientificCorp.), Nei Dike (Natick), Massachusetts (MA) (for example, BLAZER II XP; BLAZERII HTD; POLARIS T temperature ablation catheter; CHILLI cools off ablation catheter; CHILLI RPM cools off ablation catheter; STEEROCATH-T temperature ablation catheter; And EPT-1000XP) conduit of Zhi Zaoing.

The heat energy conduit.

Can use the multiple conduit of sending heat energy (heat, microwave, cold therapy) or can make its be suitable for using (referring to, for example UROLOGIX transurethral thermotherapy method (UROLOGIX TransurethralThermal Therapy) (T3), (the Urologix of You Luoji Ces Co.,Ltd, Inc.), Minneapolis (Minneapolis), Minnesota (MN); Neya etc., " circulation " be 91:2445-53 (1995) (Circulation)), be used for the treatment of diverticulum disease as described herein.The heat energy of careful controlled quentity controlled variable is delivered to the diverticulum surface, so that skin breakage (but being not enough to cause perforation of diverticulum) or damage are enough to cause (or stimulation) healing reaction.The heat energy conduit can use separately to induce fibre modification, perhaps can be administered in the diverticulum chamber with fibre modification derivant or implant to be used in combination.The example of heat energy conduit comprises SPINECATH dish inner catheter (SPINECATH Intradiscal Catheter) and AUTHERM reduced pressure conduit (AUTHERM Decompression Catheter) (Xerox's brightness (Smith ﹠amp; Nephew, Inc) .), An Dufo (Andover), Massachusetts (MA)) and comprise the cryoablation device (apply extremely low temperature to the tissue those) such as the CRYOCOR ((CryoCor of CryoCor company, Inc.), Santiago (San Diego), California (CA)); CLOSURE (VNUS Med Tech Inc. (VNUSMedical Technologies, Inc.), San Jose (San Jose), California (CA)); With FREEZOR and CRYOTHERAPY (CryoCath technology company (CryoCathTechnologies, Inc.), Ke Kelan, Quebec (Quebec)).

Laser aid.

Can use the multiple conduit of sending laser energy maybe can make it be suitable for using, be used for the treatment of diverticulum disease.The luminous energy of careful controlled quentity controlled variable is delivered to the diverticulum surface, so that skin breakage, but be not enough to cause perforation of diverticulum, or damage, be enough to cause (stimulate or promote) healing reaction (referring to, for example, Capon etc., Am.J.Clin.Dermatol (the clinical skin magazine of the U.S.) .4:1-12 (2003); Reddy, J.Clin.Laser Med.Surg (clinical laser medicine surgical operation magazine) .22:141-50 (2004); Vladimirov etc., Biochemistry (Moscow) (biochemistry (Moscow)) 69:81-90 (2004); Schindl, etc., J.Investig.Med. (research medical journal) 48:312-26 (2000)).This device can use separately to induce fibre modification, perhaps can be administered in the diverticulum chamber with fibre modification derivant or implant to be used in combination.The example of sending the conduit of laser energy comprises the CLIRPATH ((Spectranetics of Spectranetics company, Corp.), Colorado Quan Cheng (Colorado Springs), the state of Colorado (CO)) and Trimedyne the laser catheter ((Trimedyne of Trimedyne company, Inc.), Irving (Irvine), California (CA); Referring to, for example, U.S. Patent number 5,496,309); Argon or Nd:YAG laser (referring to, for example,, Hunter, " the North America surgical clinical) (Surg.Clin.North Am.) 69 (6): 1147-66 (1989).

Radioactivity and brachytherapy device.

Can use multiple conduit and implant of sending radiant energy maybe can make it be suitable for using, be used for the treatment of diverticulum disease.The radioactivity energy of careful controlled quentity controlled variable is delivered to the diverticulum surface, so that skin breakage (but being not enough to cause perforation of diverticulum) or damage are enough to cause (or stimulating or promotion) healing reaction.This intervention can be used separately inducing fibre modification, or is used in combination with fibre modification derivant or implant using in the diverticulum chamber.Low dose of radioactivity stimulation healing and fiberization (referring to, for example, Vladimirov etc., as above; Hill etc., " the biomedical international magazine of radiation oncology " (Int.J.Radial Oncol.Biol.Phys.) 49:353-65 (2001); Rodemann etc., " radioactive indicator oncology " be 35:83-90 (1995) (Radiother.Oncol.); O ' Sullivan etc., " tumour radiotherapy collection of thesis " (Semin.Radiat Oncol.) 13:274-89 (2003); Schindl etc., as above); Conlon etc., " clinical periodontology magazine " be 23:492-96 (1996) (J.Clin.Periodontol.), produces the permanent and degradable local width of cloth and penetrates the source, particularly can be used for the enforcement of this embodiment.

Several radionuclides any that is used for brachytherapy in the blood vessel can be applied to diverticulum (referring to, for example, Nath etc., " cardiovascular radiation medicine and pharmacology " (Cardiovasc.Radiat Med.) 5:88-96 (2004); Von Neumann-Cosel, " medical science medicine bioengineering " is 48:1855-62 (2003) (Phys.Med.Biol.); Lehmann etc., " applying clinical medicine medical journal " be 4:58-63 (2003) (J.Appl.Clin.Med.Phys.); Yue etc., " cardiovascular radiation medicine and pharmacology " are 5:142-50 (2004) (Cardiovasc.RadiatMed.)).Being used for radioactivity is delivered to the system of tissue and conduit is availablely (to see for those skilled in the art, for example, Guglielmi detachable coil (Qureshi etc., neurosurgery focus (Neurosurg.Focus) 10: " preview of neurosurgery magazine " (Preview of J.Neurosurg.) 94:880-85 (2001)); The lead source, the air bag source (referring to, for example, Lehmann etc., as above); Balloon catheter as described herein).Can be used for the delivery treatments compositions sells product to the merchant of diverticulum and comprises that β ray conduit is such as the BETA-CATH System from Novoste company (Novoste Corporation) (Atlanta (Atlanta), the Georgia State (GA)); Come the interior radiation therapy (GALILEO Intravascular RadiotherapySystem) of GALILEO blood vessel of bootstrap company (Guidant Corporation) (indiana Pohle this (Indianapolis), Indiana (IN)); With the gamma-rays conduit such as from (the Johnson ﹠amp of Johson ﹠ Johnson; JohnsonCorporation) the CHECKMATE System of (new Boulogne Zwick (New Brunswick), New Jersey (NJ)).Can use or other radioactivity and the brachytherapy device that are suitable for using comprise from Varian medical system (Varian MedicalSystems) (Charlottesville (Charlottesville) according to method as described herein, Virginia (VA)) GammaMedplus, it is used in from northern beach medical treatment accelerator (North Shore MedicalAccelerator), PC, Smith town (Smithtown), New York (NY)) in the MAMMOSITERTS device and the brachytherapy kind of implanting usefulness such as I-PLANT High Activity125 iodine Seeds (implant scientific company (Implant Sciences Corporation), Wakefield (Wakefield), Massachusetts (MA)).

Balloon catheter.Multiple balloon catheter can be used for the treatment of diverticulum disease.Be delivered in the diverticulum chamber balloon catheter and careful expansion, so that diverticulum skin breakage (but being not enough to cause perforation of diverticulum), or damage, be enough to cause (or stimulation) healing reaction.This intervention can be used separately inducing fibre modification, or is used in combination with fibre modification derivant or implant using in the diverticulum chamber.The representative example of drug delivery tube comprises balloon catheter, as from (the Nei Dike of Boston technology Corp (BostonScientific Corporation), MA) CHANNEL and TRANSPORT balloon catheter, with from senior cardiovascular system (the Advanced Cardiovascular Systems of company, Inc.) Stack of (Santa Clara, California (CA)) perfusion coronary artery expansion (StackPerfusion Coronary Dilitation) conduit.

Operable balloon catheter system comprises following gas-bag system: wherein air bag can expand at desired locations, and wherein required fibre modification derivant can be sent by the hole that is arranged in airbag wall.Operable other balloon catheter comprises the system with a plurality of holes between two air bags.This system can be directed to desired locations, so that expandable air bag component is positioned at any end of the specific site of being treated.Air bag can expand with the zone of isolating for treatment then.The compositions that will contain fibrous formation agent is then injected isolated zone by a plurality of holes between two air bags.The medicine of these types is sent the representative example of air bag at U.S. Patent number 5,087, describes in 244,6,623,452,5,397,307,4,636,195 and 4,994,033.

Ultrasonic waveguide.Can use the multiple conduit of sending ultrasonic energy to be used for the treatment of diverticulum disease.The acoustic energy of careful controlled quentity controlled variable is delivered to the diverticulum surface, so that skin breakage (but being not enough to cause perforation of diverticulum) or damage are enough to cause (or stimulation) healing reaction.This intervention can be used separately inducing fibre modification, or is used in combination with fibre modification derivant or implant using in the diverticulum chamber.The example of operable ultrasonic waveguide and system includes but not limited to those of following description: Martin etc., IEEE sonics and newspaper supplementary issue (the Transactions on Sonics andUltrasonics Supp.) 27:277 (1980) of ultrasound wave association; Gage application technology (Gage Applied Technologies), Lachin (Lachine), Quebec (Quebec) (for example, COMPUSCOPE (CS) 8500); U.S. Patent number 4,602,633; U.S. Patent number 4,692,139; Atar etc., the ultrasonic cardiography (Echocardiography)-" the ultrasonic combined technical journal of cardiovascular " (J.Cardiovasc.Ultrasound Allied Tech.) 18:233-37 (2001); Horiuchi etc., " endourology magazine " be 19:130-32 (2005) (J.Endourology); Dick etc., " research radiology " be 33:85-90 (19985) (InvestigativeRadiology); (also referring to, for example, auspicious plucked instrument consulting group (RasorConsulting Group), Los Gatos, California (CA.)).Also referring to, for example, U.S. Patent number 6,723,064; 6,689,086; 6,623,444; 6,592,520; 6,296,619; With 6,527,759.The representative instance of ultrasonic waveguide comprises IVUS conduit, diagnostic catheter and delivery catheter, and commercially available ultrasonic waveguide is such as from the ACUNAV conduit of Siemens (Siemens), from the ViewMate conduit of EPMedSystems and from the EAGLE EYE GOLD conduit of volcano treatment (VolcanoTherapeutics).

The diverticulum Surface Physical is denuded/is degraded.The multiple conduit on abrade tissue surface can be used for the treatment of diverticulum disease during their contacts.The diverticulum surface is a mechanical damage, so that with described surface abrasion (but being not enough to cause perforation of diverticulum) or damage, be enough to cause (or stimulating or promotion) healing reaction.This intervention can be used alone inducing fibre modification, or is used in combination with fibre modification derivant or implant using in the diverticulum chamber.A kind of like this example of device is rotating blade (rotoblade), and it is a high speed rotating unit.The atherosclerotic plaque excision is the step of removing speckle to the tremulous pulse of cardiac muscle from supply blood.The device that is used for the atherosclerotic plaque excision comprises laser catheter or revolving scraper (" grinding stone " device on the catheter tip), its can be used for or be suitable for being used for the treatment of diverticulum disease (also referring to, for example, the prune dissection catheterectomy conduit of tissue).

The representative instance of the device on abrasion diverticulum surface comprises those that are used for atherosclerotic plaque excision step.Atherosclerotic plaque excision device typically has little machine driving instrument, and described instrument will be organized (fatty deposits is such as speckle typically) or scrape, cuts, and perhaps is broken into granule and removes obstruction from the inside of blood vessel (for example tremulous pulse).After scraping off from arterial wall, this speckle is stored in the most advanced and sophisticated of conduit safely and removes from health.Being used for the atherosclerotic plaque excision device of vascular applications can ortho states use or adapts to for the present invention's purposes or improve.

In another embodiment, described atherosclerotic plaque excision device can be that rotate or directed atherosclerotic plaque excision device.Rotating the atherosclerotic plaque excision is minimally-invasive treatment, is used to grind IC plaque sometimes.During rotating the atherosclerotic plaque excision, the high speed rotating unit (being called " rotating blade " or " turnery device (rotablator) ") that is connected to catheter tip is used to grind off the material of therapentic part.In some embodiments, atherosclerotic plaque excision conduit can comprise the collecting chamber of rotary knife cutter and fragment.

Atherosclerotic plaque excision device merchant several rotations and orientation sells.For example, the atherosclerotic plaque excision device of rotation comprises that the ROTOBLATOR from Boston technology Corp (Boston ScientificCorporation) (Nei Dike MA) rotates atherosclerotic plaque excision system and directed atherosclerotic plaque excision device such as FLEXI-CUT that comes bootstrap company (Guidant Corporation) and FX miniRAIL Cutting Gas bag apparatus.

In one aspect, atherosclerotic plaque excision device can be an atherosclerotic plaque excision conduit.Atherosclerotic plaque excision conduit can be, for example, the directed atherosclerotic plaque excision of 9-F Simpson conduit (referring to, for example, Zeller etc., " intravascular therapy " (Endovasc.Ther.) 11 (6): 676-85 (2004) or Schechter etc., " vascular interventional radiology magazine " (J.Vasc.Interv.Radiol.) (1993) 4 (6): 819-24.

The atherosclerotic plaque excision conduit that uses in the enforcement of described method here and the representative instance of device be can use or be suitable for and unrestriction ground, those that in following U.S. Patent number, describe: 5,087,265 comprised; 5,423,846; 6,001,112; 5,865,844; 5,156,610; 5,356,418; 6,482,216; 5,312,427; 6,428,, 551; 5,030,201; 6,503,261 and 6,596,005.

Can be used for or be suitable for being used to denuding and/or the exemplary device on corrosion diverticulum surface comprises that the merchant sells product such as from Fox person of outstanding talent (the FoxHollow Technologies of technology company, Inc.) (Redwood city (Redwood City), California (CA)) SILVERHAWK speckle device for excising, laser catheter is such as from Spectranetics (Colorado Quan Cheng, the CLIRPATH line of the excimer laser conduit state of Colorado (CO)) and from ev3 company (ev3 Inc.), Johnson ﹠ Johnson/(the Johnson ﹠amp of heart company; Johnson/Cordis Corporation), Paasche prestige medical skill (Pathway MedicalTechnologies), Bao Si medical company (Possis Medical Inc.), Lu Mengde (Lumend) (Redwood city, California (CA)), intracavitary therapy (Intraluminal Therapeutics) (Carlsbad (Carlsbad), California (CA)), fluorine Ka Diya (Flowcardia) (Sani Wei Er (Sunnyvale), California (CA)), Corazon technology (Corazon Technologies) (door Lip river Parker (Menlo Park), California (CA)), and the atherosclerotic plaque excision device of Mai Denike (Medtronic) company (Medtronic Inc.) (Minneapolis (Minneapolis), the Minnesota State (MN)).

Another method that is used to denude the diverticulum surface is via " endoscope's dissecting knife ".Endoscope apparatus and method are described in for example international application published WO 96/25107A1, WO 04/064623A2, WO 01/06943A1, WO 03/096871A2 and U.S. Patent number 6,482,219; 6,277,135; 6,165,184; With 4,539, in 976.

The other case description of device that can be used to denude the diverticulum tissue surface is in international application published WO 01/89370A2 and WO 01/166018A1.

In another embodiment, the laying apparatus of intracavity can be used for physically denuding or corrosion diverticulum surface.For example, the laying apparatus of intracavity can be used for via conduit with liquid form but at the hardened polymer injection of body temperature diverticulum, with sealing diverticulum chamber.For example, described polymer can be a gel, such as hydrogel, or is suitable for fibrous tissue is formed the polymer that agent is delivered to the another kind of type of diverticulum.Described multiple intracavity paving compositions and step (referring to, for example, Slepian M.J. " cardiology meeting summary " is 1996Mar (Semin.Interv.Cardiol.); 1 (1): 103-16; Slepian MJ. " clinical cardiology " is 1994Nov (Cardiol.Clin.); 12 (4): 715-37; International application published WO 90/01969A1, WO 04/087065A2, WO 91/12846A1; With U.S. Patent number 5,749,922; 5,328,471; With 5,749,915.Though described the pattern of above-mentioned conduit for the enforcement of other form of therapy, delivery treatments to diverticulum is the embodiment that this paper is intended to be used to obtaining to lead to also to revise these devices.In many cases, these independent interventions can be enough, perhaps can be used in combination with fibre modification derivant, hemorrhage and/or anti-infective.

In other embodiments, for bonded each said apparatus of each mentioned reagent, for each combination, open independently, described reagent can be present in the compositions with polymer.In one embodiment, described polymer is biodegradable.In another embodiment, described polymer is not biodegradable.Can be with the further feature and the character of the included polymer of each combination of said apparatus and reagent, statement in more detail here.

Except the implant that is used for the treatment of diverticulum disease with induce the fibre modification compositions, also provide method.For example, for each of above-mentioned implant, and each possible combination for implant and fibre modification derivant, method is provided, wherein specific implant is incorporated into animal (in people (patient or experimenter) or the inhuman mammal, described inhuman mammal includes, but are not limited to, rabbit, rat, mice, hamster, Canis familiaris L., inhuman primates, cat, goat, pig, sheep, goat, horse, cattle), be advanced into the position of diverticulum, get involved (as mentioned above with specific physics, the chamber Surface Physical of diverticulum is broken), and/or being applied in of fibre modification derivant or compositions induce fibre modification in the diverticulum, otherwise described fibre modification will can not take place.Each implant of determining at this paper can be " a specific implant ".

In certain embodiments, can by with fiber (line) thus medical implant is modified on the surface that is attached to described implant.Described fiber can be polymeric and/or can be by the material that fibrous tissue is formed, such as silk formation or by its coating.For example, described line can form from the silk suture material.The existence of described line can cause the substrate reaction for the cell of described implant outside and/or extracellular increase.Described line can be attached to described implant by any one or the combination of using subsequently method, described method comprises the use adhesive, thermal weld, roll extrusion, parcel, braiding, knotting etc.Described line can be coated with material, and described material delays line material and the time that on every side tissue contacts with blood, allow thus described implant settled and not since polymer line have a caused problem relevant with thrombosis.The example that can be used to prepare the material of coating comprises gelatin, polyester (for example, PLGA, PLA, MePEG-PLGA, PLGA-PEG-PLGA, and admixture), lipid, fatty acid, sugar ester, the nucleic acid ester, polyanhydride, poe and PVA, described coating can be degraded or dissolve after implantation.Described coating can also comprise fibrous tissue and form agent and/or bioactivator, they can, the probability (for example, heparin, hydrophobic quaternary amine heparin complex etc.) of thrombosis incident in the middle of for example reducing.Except polymer line, can be coated with all or part of of described implant with the polymer support that comprises the fibre modification derivant.

Described fiber (line) can also comprise by applying coating or the compositions that magnetic field is affected.For example, implant can be aggregated thing line coating, and described polymer line is formed agent (for example, silk suture) coating by fibrous tissue, comprises it or forms from it.Thereby magnetic field can be applied on the applied implant relative to each other to come thereby polymer fiber is positioned and arrange the surface area that increases the fiber that contacts with the Biomedia of stimulation fiberization with the surface of described implant.Use several different methods, can will have active component of magnetic force and polymer fiber to link together.For example, by magnetic force active substance such as magnetic iron ore was added to before the extruding polymer fiber magnetic force active substance is impregnated in the process of preparation fiber.Use, for example, adhesive or polymer coating can be applied to the magnetic force active component on the part of whole fiber or fiber.Described polymer fiber (or its part) can be heated or make its plasticising with solvent, then rolls in the magnetic force active component, thereby makes the magnetic force material give prominence to or be encapsulated into the surface of fiber at described fiber surface.

Described line (having or do not have the magnetic force component) can be attached to described implant with various configurations, and described configuration can cause the covering partially or completely to described implant outside.Described polymer line can be attached to the end of implant or the mid portion of implant, and described connection can be vertical, level or diagonal manner.

The whole body of fibre modification derivant, regionality and local delivery

Can obtain whole body, regionality and local delivery that multiple medicine delivery technique carries out therapeutic agent.The some of them technology can be near medical implant, be suitable for obtaining the fibre modification derivant of preferential elevated levels, described technology comprises: (a) use drug delivery tube that fibrous tissue is formed the agent part, (typically, drug delivery tube advances in the tissue up to reaching required anatomical location by circulating or directly be inserted under endoscope or lonizing radiation guidance to described implant tissue on every side for regionality or systemic delivery; Then, thus the reagent that fibrous tissue forms can discharge medicine with therapeutic dose with high local concentrations from tube chamber be delivered to tissue around the described implant); (b) the medicine location technology is such as magnetic, and the medicine that ultrasound wave or MRI instruct is sent; (c) thus the chemical modification of design fibre modification induced drug or preparation to the absorption of impaired tissue (for example increases described reagent, thereby modifying described medicine or preparation comprises directly at the impaired or component of organization for the treatment of such as macrophage, neutrophil cell, smooth muscle cell, fibroblast, extracellular matrix components, the antibody of neovascularity tissue); (d) thus the chemical modification of design fibre modification induced drug or preparation makes medicine is positioned hemorrhage zone or ruined vascular system, such as with drug encapsulation in the liposome that navigates to the site; And/or (e) the described fibre modification derivant of direct injection, for example under endoscopic observation.

Infiltration in the tissue of fibre modification derivant around the implant

Alternatively, can be before implantation process, among or the tissue cavity that with the fibre modification derivant described implant settled afterwards handle.This can finish in some modes, described mode comprises that (a) forms agent with fibrous tissue and locally apply to that (what be particularly useful in this embodiment is the application of polymer support, and described carrier forms agent with fibrous tissue and discharges in the time range of a few hours to several weeks in the dissection gap that can settle described implant; Fluid, dark suspension suspension, Emulsion, microemulsion, microsphere, paste, gel, microparticle, spray, aerosol, solid implant and can be delivered to the zone that described implant can be inserted into discharging other preparation that fibrous tissue forms agent delivery catheter or other applicator by specialization); (b) microparticle silk and/or silk chain silk thread (for example, straight line, side chain, and/or curl) are being useful in the targeted delivery of implantation site also; (c) with the sprayable preparation that comprises collagen such as COSTASIS ((the Angiotech Pharmaceuticals of Angiotech Pharmaceuticals, Inc, Inc.), Vancouver (Vancouver), BC) or by 4-arm mercaptan PEG (10K), 4-arm NHS PEG (10K), the material made from methylated collagen (described here), or by 4-arm mercaptan PEG (10K), the material that 4-arm NHS PEG (10K) and collagen or gel are made, independent or loading is applied to implantation site (or described implant surface) together with the fibre modification derivant; (d) preparation that comprises PEG such as COSEAL ((the Angiotech Pharmaceuticals of Angiotech Pharmaceuticals, Inc that sprayable original position is formed, Inc.), Canada), FOCALSEAL (builds the company of praising (Genzyme Corporation), Cambridge (Cambridge), Massachusetts (MA)), SPRAYGEL or DURASEAL are (from converging (the Confluent Surgical of surgery company, Inc.), Waltham (Waltham), Massachusetts (MA)), independent or loading is applied to implantation site (or described implant surface) together with the fibre modification derivant; (e) will comprise preparation such as the FLOSEAL of fibrinogen or TISSEAL (all from Irving Baxter health care company (Baxter HealthcareCorporation); Freemont (Fremont), California (CA)), independent or loading is applied to implantation site (or described implant surface) together with the fibre modification derivant; (f) comprise hyaluronic preparation (noncrosslinking, crosslinked or chemical modification) such as PERLANE or RESTYLANE (all from Q-Med AB, Sweden), HYLAFORM (Yin Aimude company (Inamed Corporation); The Santa Barbara, California (CA)), SYNVISC (bio-matrix company (Biomatrix, Inc.); Ridgefied, New Jersey (NJ)), SEPRAFILM or SEPRACOAT (come the self-built company (Genzyme Corporation) that praises; Cambridge (Cambridge), Massachusetts (MA)), it loads to be applied to the caused fibre modification of fibre modification derivant of implantation site (or implant surface); (g) be used for polymer gel such as the REPEL that surgical operation implants (life medical science company (and LifeMedical Sciences, Inc.); Princeton (Princeton), New Jersey (NJ)) or FLOWGEL (Irving Baxter health care company (Baxter Healthcare Corporation), Deerfield, Illinois (IL)), it loads to be applied to the fibre modification derivant of implantation site (or implant surface); (h) be used for prosthese and tissue maintenance orthopedics's " cement " in place, it loads to be applied to the fibre modification derivant of implantation site (or described implant surface), such as the OSTEOBOND ((Zimmer of Qi Mo company, Inc.), Warsaw, IN), LVC ((the Wright Medical Technology of Lai Te Healtech S.A., Inc.), Arlington (Arlington), Tennessee State (TN)), SIMPLEX P (Stryker company (Stryker Corporation), Kalamazoo, the state of Michigan (MI)), PALACOS ((the Smith ﹠amp of brightness PLC company of Xerox; Nephew PLC Corporation), Britain), and ENDURANCE ((the Johnson ﹠amp of Johson ﹠ Johnson; Johnson, Inc.), new Boulogne Zwick, New Jersey (NJ)); (i) (for example will comprise one or more cyanoacrylate monomers, methyl 2-cyanoacrylate, cyanacrylate, Tisuacryl, octyl 2-cyanoacrylate, alpha-cyanoacrylate methoxyl group propyl ester) surgical operation adhesive such as the DERMABOND ((Johnson of Johson ﹠ Johnson; Johnson, Inc.)), INDERMIL (U.S.'s surgery (United States Surgical); Norwalk (Norwalk), the Connecticut State (CT)), GLUSTITCH (black lock Therapy Products Inc. (Blacklock MedicalProducts, Inc.), Canada) or TISSUMEND II (veterinary products laboratory (VeterinaryProducts Laboratories); Phoenix (Phoenix), Arizona State (AZ)), VETBOND (3M company (3M Company); Sao Paulo (St.Paul), the Minnesota State (MN)), TISSUEMEND (TEI Biological Science Co., Ltd (TEI Biosciences, Inc.); Boston (Boston), Massachusetts (MA)), HISTOACRYL or HISTOACRYL BLUE (Davis and the (Davis of Ge Ke company; Geck); St. Louis (St.Louis), Missouri (MO)) and ORABASESOOTHE-N-SEAL LIQUID PROTECTANT (Colgate-Palmolive Company (Colgate-Palmolive Company); New York (New York); New York (NY)), independent or loading is applied to implantation site (or described implant surface) together with the fibre modification derivant; (j) (or synthetic property bone material is such as calcium sulfate to comprise the implant of hydroxyapatite, VITOSS and CORTOSS are (from the (Orthovita of this Vita company difficult to understand, Inc.), Malvern, Pennsylvania (PA)), it loads to be applied to the fibre modification derivant of implantation site (or described implant surface); (k) loading is with the tissue filling agent of other biocompatibility of fibre modification derivant, such as by (the BioCure of Biotherapeutics company, Inc.) (Norcross, the Georgia State (GA)), 3M company (3M Company) and Buddhist nun's Ormond (Neomend of company, Inc.) those of (Sani Wei Er (Sunnyvale), California (CA)) making, it loads to be applied to the fibre modification derivant of implantation site (or described implant surface); (1) gel of polysaccharide gel such as ADCON series (Greer technology company (and Gliatech, Inc.); Cleveland (Cleveland), Ohio (OH)); (m) film, and sponge or mesh such as INTERCEED or VICRYL mesh (this Kanggong department of dust (Ethicon, Inc.), (the Johnson ﹠amp of Johson ﹠ Johnson; JohnsonCompany), Somerville (Somerville), New Jersey (NJ)), and GELFOAM ((the Pharmacia ﹠amp of Pharmacia S.P.A.; Upjohn Company); Kalamazoo, Michigan (MI)), it loads to be applied to the fibre modification derivant of implantation site (or described implant surface); (n) form Polyethylene Glycol (for example, 4-arm four-amino PEG) [10k] from aminofunctional) and the functionalized PEG (for example, tetramethylolmethane gathers (ethylene glycol) ether four-succinimido glutarate) of 4-arm NHS (10K)) hydrogel.This hydrogel can also comprise collagen, methylated collagen and/or gelatin.This hydrogel (for example can also comprise above-mentioned fibre modification derivant, silk powder or silk thread), (o) increase bone and integrate (osteointegration) and/or osteogenetic compositions, (for example comprise the material formed by β-tricalcium phosphate, VITOSS by the E-Interpore-Cross world (E-Interpore-Cross International) making, PROOSTEON 500R), hydroxyapatite or Ca ₁₀(PO ₄) ₆OH (for example, by Ceramed Denta, company limited Lakewood company (Ceramed Denta, Inc.Lakewood, CO) OSTEOGRAF of Zhi Zaoing), calcium carbonate or CaCO ₃, (for example, by Lai Te Healtech S.A. (Wright Medical Technology, Inc.) OSTEOSET of Zhi Zuoing and ALLOMATRIX), calcium phosphate is (for example by the (Merck of Merck ﹠ Co., Inc. for calcium sulfate; Co.Inc.), WhitehouseStation, New Jersey (NJ), the CALCIBON of manufacturing is by Synthes-Strates, the NORIAN SRS that Switzerland (Switzerland) makes), and synthetic bone filler (for example, the bone filler of CORTOSS and processing is for example by (the Geistlich Biomaterials of Geistlich Biomatera Inc., Inc.), the BIOOSS of Switzerland (Switzerland) manufacturing).The representative example of these materials is described in U.S. Patent number 3,929,971,4,861,733; 6,527,810; 4,772,468; 4,882,149; 5,167,961; 6,576,015; 4,839,215; 5,614,206; 5,807,567; 6,030,636; 6,652,887; 6,206,957; 6,485,754; 4,347,234; 4,291,013; 5,129,905; 5,336,264; 5,569,442; 5,571,493; 5,683,667; 5,709,742; 5,820,632; 5,658,332; 5,681,872; 5,914,356; 5,939,039; 6,325,987; 6,383,519; 6,458,162; 6,736,799; 6,521,246; With 6,709,744.

In one embodiment, described fibre modification derivant can be used as solution and sends.Described fibre modification derivant directly can be mixed in the solution so that homogeneous phase solution or dispersion to be provided.In certain embodiments, described solution is aqueous solution.Described aqueous solution can also comprise buffer salt, and viscosity modifier (for example, hyaluronic acid, alginate, CMC etc.).In another aspect of the present invention, described solution can comprise biocompatible solvent, such as ethanol, and DMSO, glycerol, PEG-200, PEG-300 or NMP.

In certain embodiments, the method for inducing fibre modification to be used for the treatment of diverticulum disease in diverticulum comprises the flushing (lavation, cleaning) of diverticulum and surrounding tissue.Introducing before fibrous tissue forms agent, compositions or implant, can with described diverticulum flushing with clean or remove undesirable be retained in particulate matter in the diverticulum that will seal or close, cell, tissue, fecal matter (for the Gl diverticulum), microorganism, etc.Thisly be used for washing, clean and the method for rinsing tissue or organ is to be conventional enforcement by the medical field technical staff preparing for the position of medical procedure.Any one or the complete soln that are used to wash diverticulum can contain one or more anti-infectives, such as the described herein of antibiotic, antiseptic or other and the anti-infective that used by those skilled in the art.Play prevention or treatment infection and/or make the minimized effect of microorganisms spreading with anti-infective cleaning or flushing diverticulum.One or more solution can be used with one or more rinsing steps, for example, described step can comprise washing to remove undesired material, the described position of sterilizing, with use the solution rinsing, to form compositions, compositions or the implant of agent identical with sending fibrous tissue for compositions wherein.

In certain embodiments, hemorrhage or the compositions that comprises hemorrhage (for example, COSTASIS) or sealant, also can be included in the rinse solution.Can be with polymer or carrier polymer and hemorrhage combination.Can also comprise the hemorrhage of polymer or carrier polymer or comprise the compositions of hemorrhage, can be applied to the tissue around diverticulum or the diverticulum, with in diverticulum position control over bleeding and induce cicatrization.

Also describe in more detail as this paper institute, the method for inducing fibre modification and/or treatment to have the host of diverticulum disease in diverticulum can also comprise diagnosis algorithm.In order to determine or to confirm the existence of diverticulum in the host, by the intravital position of method check body such as splanchnoscopy or radiography analysis.Splanchnoscopy allows that the chemical development of target tissue is to confirm the accurate placement that has and guide implant or compositions of diverticulum.By via hole (mouth, anus) or little otch small cameras being inserted in the health, endoscope-use is in allowing with the chemical development of (that is, not needing open surgical operation) of Wicresoft's mode.Can use any endoscopic technique, but specific endoscope may be well suited for intravital particular organization of body or position.The example of endoscope comprises flexible endoscope, inflexible endoscope, gastroscope, ERCP, bronchoscope, rectoscope, angioscope and colonoscope.

Alternatively, diagnosis can comprise the radiography analysis.Use imaging technique to allow mode (that is, not needing open surgical operation) operation and to get involved with Wicresoft.Several imaging techniques are available for these application in the method described herein.Can determine technique of choice on the ground, top of organizing that will treat.The representative instance of imaging technique comprises X-ray, angiography, MRI, CT scan, ultrasound wave, PET scanning and nuclear medicine scanning.

The method of treatment or prevention diverticulum disease

Also be provided for treating the method for diverticulum disease at this paper.Therefore, for each above-mentioned implant with for each above-mentioned implant, compositions or contain the combination of the implant of fibre modification derivant, provide method thus specific implant to be incorporated in the mammal, and be advanced to the diverticulum position.Specific physics intervention (diverticulum chamber Surface Physical is broken as described herein) and/or fibre modification derivant or compositions are applied in the described diverticulum can induce fibre modification, otherwise described fibre modification will can not take place.

Be provided for also here treating that experience is operating, endoscope or minimally-invasive treatment patient's method, wherein medical implant placed a part as described method.Such as here description, be to be understood that, " induce fibre modification " and refer to the quantity of implant scar tissue on every side statistically evident increase (or increasing significantly clinically), the combination that perhaps implant is attached in the surrounding tissue improves, and does not mean the fault of any complication of permanent prevention or implant.

Can carry out the diagnosis of diverticulum disease with the barium enema, described barium enema can be described to radiography the degree and the seriousness of diverticulum.Typical radioactivity finding is to have the folliculus that keeps contrast and spastic colon.Often influence whole colon, but the most frequent influence left side and sigmoid colon.Yet most of hemorrhage diverticulums occur in the right side of health.Splanchnoscopy can be got rid of the infringement of association, and inflexible sigmoidoscopy advances without rectosigmoid joint usually.Colonoscopy is convenient to distinguish diverticulum disease, angiodysplasia or cancer.It also is convenient to chemical development and enlivens the bleeding part, finally finds the described bleeding part that enlivens with this technology in up to 85% patient.The colonoscopy intervention is convenient to the electrocoagulation at chemical development bleeding part and described position or is washed with epinephrine.It also is convenient to identify the disease of other association.

Here the compositions that provides and implant can be delivered to diverticulum position (for example, via the conduit that inserts through the side opening that is placed on the colonoscope in the diverticulum) and infect, induce hemostasis, and/or permanently diverticulum be scabbed close with treatment.Can directly be delivered to described compositions in the diverticulum or diverticulum around tissue in (for example, by injection or via conduit).In one embodiment, fibrous tissue formation agent and/or anti-infective can or be loaded in the hemostatic composition with the hemorrhage combination and close to stop hemorrhage or diverticulum is scabbed.The representative instance of hemorrhage and hemostatic composition is as described herein and for example comprises polymer (carrier polymer), CT3 is (from blood vessel technology Biomatera Inc. (AngiotechBioMaterials Corp.) Palo Alto (Palo Alto), the compositions that comprises electrophilic and nucleophilic PEG derivant and methylated collagen of California (CA)) and the surgical sealants sold of merchant, such as the sprayable preparation that contains collagen, it comprises COSTASIS (blood vessel technology Biomatera Inc. (Angiotech BioMaterials Corp.)); The sprayable preparation that contains PEG such as COSEAL or ADHIBIT (blood vessel technology Biomatera Inc. (Angiotech BioMaterialsCorp.)); With the preparation that contains fibrinogen such as FLOSEAL or TISSEAL (both is from Irving Baxter health care company (Baxter Healthcare Corporation), Freemont (Fremont), California (CA)); The GELFOAM ((Pharmacia﹠amp of Pharmacia S.P.A.; Upjohn Company); Kalamazoo, Michigan (MI)); And AVITINE (CR Bard company limited (CR Bard, Inc.), Piano, Texas (TX)).

In one embodiment, described compositions can be the form of slow releasing preparation (for example, injectable compositions, spray and gel).Also be provided for treating the applicator that comprises the present composition and the test kit of diverticulitis.In another embodiment, fibre modification derivant and/or infectious agent can be joined cyanoacrylate adhesive, then it is delivered to diverticulum (all utilize colonoscopy as described herein) via conduit.

In certain embodiments, induce fibrotic (synulotic) reagent, hemorrhage and/or infectious agent (and one or more the compositions that comprises these reagent) can be included in the sealant spray of polymer, its freezing film or coating are to promote fibre modification and to seal diverticulum.Comprise that the spray of organizing mucoadhesive polymers can be from aforesaid microsphere preparation, the described mucoadhesive polymers of organizing contains fibre modification derivant, hemorrhage and/or infectious agent.

Many operable polymer and carrier system non-polymer are here described.These compositionss can also comprise one or more fibre modification derivants to promote the formation of granulation tissue.These compositionss can also comprise one or more hemorrhages with promote to solidify and/or one or more anti-infectives to protect from infection.For original position forms compositions, one or more fibre modification derivants, hemorrhage and/or infectious agent directly can be attached in the preparation to produce suspension or solution (for example, silk powder, bleomycin), or described reagent can be incorporated into secondary carrier (for example, micelle, liposome, microsphere, microgranule, nanometer spheroid, microparticle, Emulsion and/or microemulsion) in, described secondary carrier then is incorporated in the compositions of original position formation.In another embodiment, described fibre modification derivant, hemorrhage and/or infectious agent can be statically or covalently are attached in one or more component of polymer of original position formation compositions.

In another embodiment, can with fibre modification derivant, hemorrhage and/or infectious agent directly in conjunction with or (for example be attached in gel or the hot gel by secondary carrier, hyaluronic acid, poloxamer F127, polyester-PEG-polyester [PLGA-PEG-PLGA].Can before or after the using of sealant, these gels be administered to the treatment site.

In another embodiment, fibre modification derivant, hemorrhage and/or infectious agent can be attached in the biodegradable or soluble film or mesh that is applied to therapentic part subsequently.Then, the composition spray that original position can be formed seals diverticulum and thus to the film or the mesh of therapentic part to film.

In another embodiment, can be before the biodegradable or soluble film that will comprise fibre modification derivant, hemorrhage and/or infectious agent or mesh be applied to area for treatment, the sealant of original position is administered to diverticulum.The exemplary material that is used to prepare these films or mesh is hyaluronic acid (crosslinked or noncrosslinking), cellulose derivative (for example, hydroxypropyl cellulose) and crosslinked poly-(ethylene glycol).

In another embodiment, fibre modification derivant, hemorrhage and/or infectious agent can be the injectable forms that can be injected directly in diverticulum (therapentic part) or the therapentic part tissue on every side.Thereby fibre modification derivant, hemorrhage and/or infectious agent can directly be attached in the preparation and (for example to produce suspension or solution, the silk powder, or bleomycin) or its can be incorporated into secondary carrier (for example, micelle, liposome, microsphere, microgranule, nanometer spheroid, microparticle, Emulsion and/or microemulsion) in, described secondary carrier then is incorporated in the compositions of original position formation.In another embodiment, described fibre modification derivant, hemorrhage and/or infectious agent can be statically or covalently are incorporated into one or more component of polymer of the compositions that original position forms.These injectable compositionss also can comprise polymer to strengthen the viscosity of solution.Operable polymer comprises hyaluronic acid, CMC, poloxamer F127, and X-Y, X-Y-X, or the gel of Y-X-Y form (ordinary gel and hot gel), wherein X is that degradable polyester and Y are polyalkylene oxides, preferably Polyethylene Glycol or its monomethyl ether.In another embodiment, injectable preparation also can comprise biocompatible solvent.These can comprise ethanol, DMSO, NMP, poly-(ethylene glycol)-200, and/or poly-(ethylene glycol)-300.

In another embodiment, described fibre modification derivant can be the form of fiber, fabric, coil, line, single thread fiber or multifilament fiber, and it is introduced directly into therapentic part via conduit or endoscope's delivery apparatus.For example, the silk fabric directly can be sent into diverticulum.

In another embodiment, described fibre modification derivant can apply or be attached on polymer fiber, fabric, coil, line, single thread fiber or the multifilament fiber or wherein, it is introduced directly into therapentic part via conduit or endoscope's delivery apparatus.For example, silk fiber can be attached in the terylene woven thing, then it directly be sent into diverticulum.

Such as here description, any potentially adhesion described herein or fibre modification derivant can use separately, or are combined and used in the enforcement of this embodiment.The exemplary fibrous tissue of using in being used for the treatment of the compositions of diverticulosis forms agent and comprises Talcum, silk, chitosan, polylysine, fibronectin (fibroncectin), bleomycin and CTFG, and above-mentioned analog and derivant.Equally such as here description, can use any fibre modification derivant with each of known in the art and numerous anti-infectives described herein, and can use any fibre modification derivant with each of known in the art and numerous hemorrhages described in detail here.Any hemorrhage also can use together with any anti-infective.

Describe multiple compositions and implant and be used for the treatment of diverticulitis.Because make implant (for example, compositions and device), so the exact dose of using will change with implant size, surface area and design with multiple structure, form and size.Yet, some principle can be applied in the application of this area.Drug dose may be calculated the function of the dosage of per unit area (part of applied implant), can measure the total drug dose of using and can determine the suitable surface concentration of active medicine.No matter application process or medicine is attached in implant or the compositions is used separately or is formed agent with the exemplary fibrous tissue that anti-infective or hemorrhage use and can use under following dosed administration criterion.

Talcum is used as exemplary fibers degeneration derivant, no matter it is to use as polymer coating, be attached in the polymer of forming implant, or with or use without polymer support, preferably be no more than 100mg (scope of 1 μ g-100mg) from implant or compositions is sent or be applied to implant surface steatitic accumulated dose.In one embodiment, the steatitic total amount that discharges from compositions or implant is in the scope of 10 μ g-50mg.The dosage of the implant of per unit area (that is, be applied as medicine and/or the steatitic dosage of the function of the surface area of the part of bonded implant) should be at 0.05 μ g-10 μ g/mm ²In the applied surface area.In another embodiment, with 0.05 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area (amount) is administered to implant surface with Talcum.(polymer with non-polymer) drug delivery vehicle and specific implant discharge Talcum with different rates because specific, so above administration parameter can be used in combination with the release rate of drugs from described compositions or implant, so that the Talcum of the 0.01nM-1000 μ M of Cmin is delivered to described tissue.In another embodiment, thus Talcum discharges from the surface of implant and promotes fibre modification the diverticulum in the period of a few hours to several months in the scope.For example, Talcum can discharge the period that reaches 1 hour-30 days scopes with valid density.Can also be used for here compositions and method with having active steatitic analog of identity function and derivant (as previously described); Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the Talcum effect with half of above-mentioned parameter, use half in chemical compound of Talcum effect etc.) with the twice of above-mentioned parameter.

Silk is used as exemplary fibers degeneration derivant, no matter it is to use as polymer coating, be attached in the polymer of forming implant, or with or use without polymer support, preferably be no more than 100mg (scope of 1 μ g-100mg) from implant or compositions accumulated dose that send or that be applied to the silk on the implant surface.In one embodiment, the total amount of the silk that discharges from compositions or implant should be in the scope of 10 μ g-50mg.The dosage of the implant of per unit area (that is, be applied as medicine and/or the dosage of the silk of the function of the surface area of the part of bonded implant) should be at 0.05 μ g-10 μ g/mm ²In the applied surface area.In another embodiment, with 0.05 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to implant surface with silk.(polymer with non-polymer) drug delivery vehicle and specific implant discharge silk with different rates because specific, so above administration parameter can be used in combination with the release rate of drugs from described compositions or implant, so that the silk of the 0.01nM 1000 μ M of Cmin is delivered to described tissue.In one embodiment, thus silk discharges from the surface of implant and promotes fibre modification the diverticulum in the period of a few hours to several months in the scope.For example, silk can discharge the period that reaches 1 hour-30 days scopes with valid density.Can be used for here compositions and method with having the analog of the active silk of identity function and derivant (as previously described); Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles an effect with half of above-mentioned parameter, use half in chemical compound of silk effect etc.) with the twice of above-mentioned parameter.

Chitosan is used as exemplary fibers degeneration derivant, no matter it is to use as polymer coating, be attached in the polymer of forming implant, or with or use without polymer support, preferably be no more than 100mg (scope of 1 μ g-100mg) from implant or compositions accumulated dose that send or that be applied to the chitosan on the implant surface.In one embodiment, the total amount of the chitosan that discharges from compositions or implant is in the scope of 10 μ g-50mg.The dosage of the implant of per unit area (that is, be applied as medicine and/or the dosage of the chitosan of the function of the surface area of the part of bonded implant) should be at 0.05 μ g-10 μ g/mm so ²In the applied surface area.In another embodiment, with 0.05 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to implant surface with chitosan.(polymer with non-polymer) drug delivery vehicle and specific implant discharge chitosan with different rates because specific, so above administration parameter can be used in combination with the release rate of drugs from described compositions or implant, so that the chitosan of the 0.01nM-1000 μ M of Cmin is delivered to described tissue.In one embodiment, thus chitosan discharges from the surface of implant and promotes fibre modification the diverticulum in the period of a few hours to several months in the scope.For example, chitosan can discharge the period that reaches 1 hour-30 days scopes with valid density.Can be used for here compositions and method with having the analog of the active chitosan of identity function and derivant (as previously described); Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the chitosan effect with half of above-mentioned parameter, use half in chemical compound of chitosan effect etc.) with the twice of above-mentioned parameter.

Polylysine is used as exemplary fibers degeneration derivant, no matter it is to use as polymer coating, be attached in the polymer of forming implant, or with or use without polymer support, preferably be no more than 100mg (scope of 1 μ g-100mg) from implant or compositions accumulated dose that send or that be applied to the polylysine on the implant surface.In one embodiment, the total amount of the polylysine that discharges from compositions or implant is in the scope of 10 μ g-50mg.The dosage of the implant of per unit area (that is, be applied as medicine and/or the dosage of the polylysine of the function of the surface area of the part of bonded implant) is at 0.05 μ g-10 μ g/mm so ²In the applied surface area.In another embodiment, with 0.05 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to implant surface with polylysine.(polymer with non-polymer) drug delivery vehicle and specific implant discharge polylysine with different rates because specific, so above administration parameter can be used in combination with the release rate of drugs from described compositions or implant, so that the polylysine of the 0.01nM-1000 μ M of Cmin is delivered to described tissue.In one embodiment, thus polylysine discharges from the surface of implant and promotes fibre modification the diverticulum in the period of a few hours to several months in the scope.For example, polylysine can discharge the period that reaches 1 hour-30 days scopes with valid density.Can be used for here compositions and method with having the analog of the active polylysine of identity function and derivant (as previously described); Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the polylysine effect with half of above-mentioned parameter, use half in chemical compound of polylysine effect etc.) with the twice of above-mentioned parameter.

Fibronectin is used as exemplary fibers degeneration derivant, no matter it is to use as polymer coating, be attached in the polymer of forming implant, or with or use without polymer support, preferably be no more than 100mg (scope of 1 μ g-100mg) from implant or compositions accumulated dose that send or that be applied to the fibronectin on the implant surface.In one embodiment, the total amount of the fibronectin that discharges from compositions or implant is in the scope of 10 μ g-50mg.The dosage of the implant of per unit area (that is, be applied as medicine and/or the dosage of the fibronectin of the function of the surface area of the part of bonded implant) is at 0.05 μ g-10 μ g/mm so ²In the applied surface area.In another embodiment, with 0.05 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to implant surface with fibronectin.(polymer with non-polymer) drug delivery vehicle and specific implant discharge fibronectin with different rates because specific, so above administration parameter can be used in combination with the release rate of drugs from described compositions or implant, so that the fibronectin of the 0.01nM 1000 μ M of Cmin is delivered to described tissue.In one embodiment, thus fibronectin discharges from the surface of implant and promotes fibre modification the diverticulum in the period of a few hours to several months in the scope.For example, fibronectin can discharge the period that reaches 1 hour-30 days scopes with valid density.Can be used for here compositions and method with having the analog of the active fibronectin of identity function and derivant (as previously described); Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the fibronectin effect with half of above-mentioned parameter, use half in chemical compound of fibronectin effect etc.) with the twice of above-mentioned parameter.

Bleomycin is used as exemplary fibers degeneration derivant, no matter it is to use as polymer coating, be attached in the polymer of forming implant, or with or use without polymer support, preferably be no more than 100mg (scope of 0.01 μ g-100mg) from implant or compositions accumulated dose that send or that be applied to the bleomycin on the implant surface.In one embodiment, the total amount of the bleomycin that discharges from compositions or implant is in the scope of 0.10 μ g-50mg.The dosage of the implant of per unit area (that is, be applied as medicine and/or the dosage of the bleomycin of the function of the surface area of the part of bonded implant) is at 0.005 μ g-10 μ g/mm so ²In the applied surface area.In another embodiment, preferably with 0.005 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to implant surface with bleomycin.(polymer with non-polymer) drug delivery vehicle and specific implant discharge bleomycin with different rates because specific, so above administration parameter can be used in combination with the release rate of drugs from described compositions or implant, so that the bleomycin of the 0.001nM 1000 μ M of Cmin is delivered to described tissue.In one embodiment, thus bleomycin discharges from the surface of implant and promotes fibre modification the diverticulum in the period of a few hours to several months in the scope.For example, bleomycin can discharge the period that reaches 1 hour-30 days scopes with valid density.Can be used for here compositions and method with having the analog of the active bleomycin of identity function and derivant (as previously described); Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the bleomycin effect with half of above-mentioned parameter, use half in chemical compound of bleomycin effect etc.) with the twice of above-mentioned parameter.

CTFG is used as exemplary fibers degeneration derivant, no matter it is to use as polymer coating, be attached in the polymer of forming implant, or with or use without polymer support, preferably be no more than 100mg (scope of 0.01 μ g-100mg) from implant or compositions accumulated dose that send or that be applied to the CTFG on the implant surface.In one embodiment, the total amount of the CTFG that discharges from compositions or implant is in the scope of 0.10 μ g-50mg.The dosage of the implant of per unit area (that is, be applied as medicine and/or the dosage of the CTFG of the function of the surface area of the part of bonded implant) is at 0.005 μ g-10 μ g/mm so ²In the applied surface area.In another embodiment, with 0.005 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to implant surface with CTFG.(polymer with non-polymer) drug delivery vehicle and specific implant discharge CTFG with different rates because specific, so above administration parameter can be used in combination with the release rate of drugs from described compositions or implant, so that the CTFG of the 0.001nM 1000 μ M of Cmin is delivered to described tissue.In one embodiment, thus CTFG discharges from the surface of implant and promotes fibre modification the diverticulum in the period of a few hours to several months in the scope.For example, CTFG can discharge the period that reaches 1 hour-30 days scopes with valid density.Can be used for here compositions and method with having the analog of the active CTFG of identity function and derivant (as previously described); Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the CTFG effect with half of above-mentioned parameter, use half in chemical compound of CTFG effect etc.) with the twice of above-mentioned parameter.

For enforcement of the present invention, particularly suitable reagent is the reagent as the tissue stimulation thing, and described tissue stimulation thing is such as silk, Silicon stone, bleomycin, neomycin, Pulvis Talci, metallic beryllium, and copper.(for example can be incorporated into implant, device) among or on or other reagent of discharging from described implant comprise extracellular matrix components such as fibrous structure protein (for example, fiber collagen, non-fiber collagen and elastin laminin), adhesiveness glycoprotein (for example laminin and fibronectin), Dan Baijutang (for example, heparin sulfate, chondroitin sulfate, dermatan sulfate), hyaluronan (for example hyaluronic acid) is rich in the acidic secretion protein (SPARC) of cysteine, thrombospondin, bind plain, the inhibitor of matrix metalloproteinase (for example, TIMPs and synthetic property TIMPs, such as horse cubic meter department he, Ba Misita, doxycycline, tetracycline, minocycline, TROCADE, Ro-1130830, CGS27023A, and BMS-275291) and polylysine.The somatomedin and the inflammatory cytokine that relate to the synthetic and tissue remodeling of blood vessel generation, fibroblast migration, fibroblast proliferation, ECM are such as epidermal growth factor (EGF) family, transforminggrowthfactor-(TGF-α), transforming growth factor-beta (TGF-β-1, TGF-β-2, TGF-β-3), platelet-derived somatomedin (PDGF), fibroblast growth factor (acidity-aFGF; And alkalescence-bFGF), bone morphogenetic protein, activator protein, VEGF (VEGF, VEGF-B, VEGF-C, placental growth factor-PIGF), angiogenin, insulin like growth factor (IGF), hepatocyte growth factor (HGF), Connective Tissue Growth Factor (CTGF), bone marrow colony stimulating factor (CSFs), granulocyte-macrophage colony stimutaing factor (GM-CSF), granulocyte-colony stimulating factor (G-CSF), M-CSF (M-CSF), erythropoietin, interleukin (IL-1 particularly, IL-8, IL-6), tumor necrosis factor-alpha (TNF α), nerve growth factor (NGF), interferon-' alpha ', interferon-beta, and growth hormone (GH) also is suitable for discharging from concrete implant described herein.Can be applied on the implant or comprise adhesive such as cyanoacrylate or CT3 by other reagent of its release.

In related fields of the present invention, implant, implantable tissue filling agent are provided, and other compositions, wherein said implant discharges induces fibrotic reagent in vivo." release of reagent " refers to any statistically evident existence of described reagent or its subfraction, and it separates and/or keep active in (or within) on the surface of described implant from implant.In another aspect of this invention, provide method to be used to prepare implant, it comprises the step of coating (for example, spraying is immersed, and wraps up, or passes through its drug administration) implant.In addition, thus can make up described implant and make implant itself be included in the implant or induce fibrotic material on every side.Depend on the site and the character of required treatment, the implant of broad variety can be used in the method and composition as described herein.

In each embodiment of the present invention, described implant is also applied with compositions or chemical compound, and described compositions or chemical compound prolong a period of time after implant with the active performance of fibre modification derivant.The representative example of these reagent comprises heparin, PLGA/MePEG, PLA, and Polyethylene Glycol.In other embodiments, fibre modification induces implant before using, be activated in the process or afterwards (for example, the reagent first-selection of the non-activity on the implant be activated into induce or acceleration bodies in the reagent of fiberization).

Can utilize above-mentioned fibre modification derivant, each of or derivatives thereof and analog is to produce the variation of above-mentioned composition.Described reagent also can be having or not having the composition forms of polymer support to use, and any or multiple can use to contain the composition forms that fibrous tissue forms agent, anti-infective and/or hemorrhage of carrier as described herein.

The method of treatment diverticulum disease

Also treatment experience is operating, endoscope or minimally-invasive treatment patient's method by the invention provides, and wherein therapeutic agent or implant is sent into diverticulum.Diverticulum disease is the mucosa of wherein hollow organ such as gastrointestinal (GI) road, urinary tract or respiratory tract and the disease that tela submucosa exists hernia to go out, and its muscular wall by body passage produces and turns up.Though diverticulum can occur in any piped organ, diverticulum disease and GI road, bottom (large intestine or colon) have great clinical relatedness, and it can cause life-threatening inflammation and infection (diverticulitis) or hemorrhage (bottom GI is hemorrhage) there.Below several concrete clinical diseases will be described in more detail, for example, comprise that diverticulosis and diverticulitis, diverticulosis of colon, acute diverticulitis, GI are hemorrhage, the diverticulum disease of hemorrhage of diverticulum, appendicitis, pharyngoesophageal diverticulum (esophagus), Meckel diverticulum inflammation (small intestinal is unusual), diverticulum of small intestine, gastric diverticulum and urinary system diverticulum, can utilize reagent as described herein, preparation and implant treatment for described diverticulum.

For instance, the host such as the patient in the treatment hemorrhage of diverticulum and thus the treatment or the prevention diverticulum disease method can comprise following.That the patient who shows diverticulum disease symptom (for example, stomachache and bottom GI are hemorrhage) can experience physics or radiographic inspection (for example, X-ray, ultrasound wave, or CT scan) or two kinds of inspections are with the degree of definite diverticulum disease.In case patient diagnosis has diverticulum disease, then can utilize method and composition treatment patient as described herein immediately, in diverticulum, induce fibre modification with stop hemorrhage or, alternatively, after acute attack is calmed down (for example, any time up to about 6 weeks), to prevent new hemorrhage recurrence.In order to treat or prevent hemorrhage of diverticulum, the patient can use intravenous calmness (for example, midazolam and demerol or fentanyl), is placed on patient's left side then.For example, when diagnosing and treat colonic diverticula, side-looking (end viewing) colonoscope is advanced and visually checks whole intestinal by colon, identification diverticulum disease and hemorrhage position.In case determine bleeding part and relevant diverticulum, the nozzle delivery catheter introduced by the biopsy inlet of colonoscope.Multiple delivery catheter is described in this and is used for medical field.

Implant or compositions can be delivered to diverticulum to induce fibre modification and to stop hemorrhage.For example, nozzle duct comprises the syringe part of the assembly that is configured to hold the multicomponent therapy.Multicomponent therapy (seeing the description of the test kit here) is included in original position and (for example forms hemostatic composition, from (the Orthovita of this Vita limited company difficult to understand, Inc.) (Malvem, PA) VITAGEL, from blood vessel technology medicine (the Angiotech Pharmaceuticals of limited company, Inc.) (Vancouver (Vancouver), BC)) COSTASIS and mixing portion.Described syringe partly is configured to only make up and mixed the component of described compositions before sending diverticulum.Can be used to the mixing of this step and the embodiment of distributor is described among the common pending application PCT/US2004/037450.One or more components of described compositions also can comprise vasoconstriction reagent (for example epinephrine).Inlet by colonoscope is delivered to therapentic part and operation with nozzle duct and syringe tip is positioned at the place, hole of diverticulum inside or diverticulum.Propulsion nozzle conduit plunger makes injector activity, and described compositions is delivered to diverticulum.The chamber or the hole of the crosslinked sealing diverticulum of described compositions subsequently produce hemorrhage control.

In another embodiment, be used for having the method for patient's treatment diverticulum disease of diverticulum disease, can carry out following exemplary method in diagnosis.Use intravenous calmness (for example, midazolam and demerol or fentanyl) to the patient and be placed on their left lateral position then.For example, when the treatment diverticular disease of colon, the side-looking colonoscope is advanced and visually check whole intestinal by colon, and locate the diverticulum opening in the enteric cavity.In case determine described opening, the inlet of indurative pin by colonoscope advanced.With described pin invest be equipped with rinse solution () syringe for example, saline, described rinse solution (for example can comprise antiseptic, chlorhexidine), antibiotic agent (for example, gentamycin sulfate or doxycycline), and/or any other anti-infective (as described herein), such as (for example, the 5-fluorouracil of the chemotherapeutics with antimicrobial acivity, doxorubicin, mitoxantrone, methotrexate, or etoposide), to remove intestinal flora, to comprise anaerobe and the aerobic bacteria that is present in the diverticulum.Described pin is advanced into the opening of infected diverticulum by the biopsy inlet.Described diverticulum is gently washed with rinse solution.In case described diverticulum has been removed fragment (cell, fecal matter), then the pin in the biopsy inlet has been replaced with the nozzle delivery catheter.The nozzle delivery catheter is used for the compositions that the multicomponent original position forms is delivered to described diverticulum, as described herein.The chamber of the crosslink part of described compositions subsequently or complete closed diverticulum or hole, therefore reduce hemorrhage, infect or the probability of inflammation.

Diverticulosis of colon

The diverticulosis of large intestine is acquired disease, and is general especially in the Western countries.The incidence rate of diverticulosis along with the age increase-influence 30% surpass 60 years old the people and 50% surpass 80 years old people.Because the incidence rate of diverticulosis continues to increase,, developed considerably less new therapy for it so it is significant health problem.

Colonic diverticula is the mucosa bag that stretches out by the colon musculature.Typically, mucosa is deviate from by damaged in the muscle, and straight vessels (with the tremulous pulse of blood supply to mucosa) penetrates the colon musculature there.Usually can carry out the diagnosis of diverticulum disease with CT scan or by the barium enema, it can describe to radiography the degree and the seriousness of diverticulum.Typical radioactivity finding is to have the folliculus that keeps contrast and spastic colon.Usually influence whole colons, but most of diverticulum occurs in (95%) in the sigmoid colon, and right side diverticulum (caecum and ascending colon) is not too common (situation of 6-7%).The patient that great majority have diverticulosis keeps asymptomatic, but the patient of 10-20% will be developed complication such as infecting (diverticulitis), fistula (the unusual connection between 2 organs-through being everlasting between colon and the bladder), intestinal obstruction or hemorrhage.If Symptomatic, the treatment of current diverticulum disease relates to the infection fragment that open surgery is excised described colon; Method as described herein provides the therapy of Wicresoft, it can be carried out as operating alternative.

Acute diverticulitis

In acute diverticulitis, do not wish to be subject to theory, the small fragment of stool (gastrolith) can be trapped in diverticulum, and it causes the attenuation of diverticulum wall and produces part (with comprising) micropunch along with infection and in the site of perforation inflammation.In some cases, if the perforation of leaving takes place, the abscess that then described infection can develop into diverticulum week forms, cellulitis, abdominal part or pelvic abscess form and/or general peritonitis.With the patient with wide spectrum oral or the treatment of intravenous antibiotic characteristic, but the local attribute of described disease is for himself fully providing using that therapeutic agent as described herein gets involved, together with or alternatively independent antibiotic therapy.

Colonoscopy (or be CT scan sometimes, ultrasound wave, or other imaging technique) is used for the infected diverticulum of identification.The side opening (or under radiography guiding) of conduit (several embodiment are as described herein) by endoscope advanced up to entering the diverticulum chamber.According to the conduit that uses, can heal and fibre modification with promotion by the surface, chamber of denuding or apply energy (RF, heat, laser, ultrasound wave etc. the as described herein) diverticulum that breaks.Under the situation of serious inflammation of diverticulum and fragility, preferably do not use these conduits, because they will increase the danger of perforation; In this case, therapeutic agent can be used via list or multi-cavity drug delivery tube.Infiltrate diverticulum infects and/or impel fibre modification and diverticulum with treatment permanent filling/closure with anti-infective and/or fibre modification derivant then.As mentioned above, also advantageously with the form delivering therapeutic agents of slow releasing preparation (or send in the diverticulum chamber implant) to treat described infection up hill and dale and to promote the healing fully of diverticulum.Discharge described therapeutic agent and reach 7 days at least, and preferably reached 30-60 days and above preparation is effective especially for this embodiment.Under hemorrhage or danger of bleeding are obvious situation, hemorrhage can be added that also anti-infective or fibre modification derivant use together.

In one embodiment, can fibre modification derivant, anti-infective and/or hemorrhage be delivered to diverticulum by the endoscopic procedures of abdominal part.In this embodiment, as the part of standard abdominal part endoscope step, endoscope is inserted in the abdominal part (typically via umbilicus).With diverticulum location, and pierce through the outer wall of diverticulum, so that it enters described chamber via the injection device that the side mouth of endoscope is sent.Then therapeutic agent or compositions are gone into the diverticulum chamber via tube injection.Because disruptive danger, this method can be kept by the situation that colonoscopy can not be carried out.

Hemorrhage of diverticulum

Hemorrhage of diverticulum occurs among the patient with diverticulosis of 5-15%, and in many (up to 1/3rd), amount of bleeding is enough to cause cardiovascular unstability greatly.The definite reason of hemorrhage of diverticulum is unknown, but diverticulum is considered to important for the tight anatomy association of straight vessels.According to non-limiting theory, the position that hernia goes out can be identical with the position that nutrient artery penetrates, and the local inflammation of diverticulitis causes the erosion of arterial wall.The approaching of this diverticulum bag cervical region and tremulous pulse supply may be the reason of observed massive hemorrhage in having the patient of diverticulosis.The mean age of patient during hemorrhage of diverticulum is 65 years old.As a result, mortality rate and sickness rate height (10% to 20%), part is other disease such as heart, pulmonary owing to the patient has, the common disease of the disease of kidney.

Diagnose the degree and the seriousness of the diverticulum that it can describe to exist to radiography by the barium enema.Right colon is modal hemorrhage source and is 48% to 90% patient's reason.The critical vessel visualization is suitable for having the patient who enlivens hemorrhage (0.5ml-1.0ml/min).Evaluation is from the inspection of Mesenteric artery (because right colonorrhagia is modal), and then checks inferior mesenteric artery and coeliac artery.Angiography not only has high expectancy, and it also can detect hemorrhage other reason such as the angiodysplasia of GI, tumor or diffusivity mucosal bleeding.Angiography can also be used to introduce remedially vasospasm material or thromboembolism optionally.The danger relevant with the vasospasm material is included in removes described therapy 50% patient's hemorrhage again rate later on, the coronary perfusion of reduction, hypertension and cardiac arrhythmia; Hemorrhage it is relevant with colon infarction but thromboembolism can stop sometimes.The nuclear scanning of using technetium is used for detecting hemorrhage slowly source (be hemorrhage speed less than 0.1ml/min time) in diagnosis.

Usually hemorrhage of diverticulum is a large amount of, painless and from restrictive.If necessary, the patient is carried out supportive treatment with capacity recovery, disorders of hemostasis correction and transfusion.The patient often needs many times blood transfusion, and the general each bleeding episodes of patient will receive the lamination cell (packed cells) of 7.6 units.Fortunately, only by utilizing supportive measurement, hemorrhage of diverticulum spontaneously stops under 70 to 95% situation.Usually, if the patient need be less than the blood of 4 units within first 24 hours, stopped bleeding in 99% patient then.No matter positive recovery, it is unstable that about 15% patient also will continue, and will need surgical operation hemorrhage to attempt to stop, but this is relevant with very high mortality rate (14% to 38%).Unfortunately, the periodic bleeding episodes that need enter hospital for the second time also is common and occurs among 25% the patient who has above-mentioned hemorrhage of diverticulum.After second time bleeding episodes, the danger of recurrence further increases to hemorrhage for the third time probability and increases to and surpass 50%.Thereby, there is significant demand for the therapy that can promptly be used for control over bleeding, and needs the minimizing patient to suffer the treatment of hemorrhage risk subsequently.

The inspection of endoscope can determine that the infringement of association is such as pernicious and Angiodysplastic existence.Chemical development active hemorrhage position is convenient in colonoscopy, finally finds described bleeding part with this technology in up to 85% patient.Colonoscope is got involved and is convenient to the chemical development bleeding part, and the electric coagulation of bleeding part washes described zone and the disease of differentiating other association with epinephrine.For the purposes of method as described herein, colonoscopy (or CT scan, ultrasound wave, or other imaging technique) sometimes is used to discern the diverticulum as hemorrhage source.The side opening (or under radiography guiding) of special conduit (being described in above-mentioned part) by endoscope advanced enter the diverticulum chamber of hemorrhage origin up to it.According to the conduit that uses, can also cause healing and fibre modification to promote thrombosis by the surface, chamber of denuding or apply energy (RF, heat, laser, ultrasound wave etc. the as described herein) diverticulum that breaks.Under the situation of serious inflammation of diverticulum and fragility, preferably do not use these conduits, because they will increase the danger of perforation; In these cases, therapeutic agent can be used via list or multi-cavity drug delivery tube.Infiltrate separately then with hemorrhage or with the combination of fibre modification derivant diverticulum with permanent filling/closure of impelling fibre modification and diverticulum and/or with the anti-infective combination to treat or prevention infection.As mentioned above, the form delivering therapeutic agents with slow releasing preparation (or send in the diverticulum chamber implant) is hemorrhage to treat up hill and dale also advantageously, promotes the healing fully of diverticulum, and/or reduces the incidence rate that infects.Discharge described therapeutic agent and reach 7 days at least, and preferably reached 30-60 days and longer preparation is effective especially for this embodiment.Ideal implant is not only induced hemostasis in acute bleeding control, and can induce permanent healing and fibre modification, thereby reduces subsequently (recurrent) danger of bleeding and incidence rate.

The treatment of typhlitic Wicresoft

Though be not real diverticulum, vermiform appendix is similar in many aspects, and be suitable for utilizing compositions of the present invention, implant and method treatment.Vermiform appendix is the cecum capsule that breaks away from caecum, and it does not cause clinical problem usually.Yet, being similar to diverticulum, the cervical region of vermiform appendix can be blocked by gastrolith, causes the attenuation of vermiform appendix wall and produces local (with comprising) micropunch, has in site of perforation and infects and inflammation (acute appendicitis).Sometimes, if (vermiform appendix of perforation) takes place in the perforation of leaving, described infection can develop into abscess and form and/or general peritonitis.Acute appendicitis has or not perforation, is to need surgical operation to remove the medical first aid of vermiform appendix.

With carrying out typhlitic minimally-invasive treatment for the described same procedure of diverticulitis with above.Briefly, colonoscopy (or CT scan, ultrasound wave, or other imaging technique) sometimes is used for locating the vermiform appendix of caecum.The side opening (or under radiography guiding) of special conduit (being described in above-mentioned part) by endoscope advanced enter the vermiform appendix chamber up to it.According to the conduit that uses, can heal and fibre modification with promotion by the surface, chamber of denuding or apply energy (aforesaid RF, heat, laser, the ultrasound wave etc.) vermiform appendix that breaks.Under the situation of vermiform appendix attenuation or fragility, preferably do not use these conduits, because they will increase the danger of perforation; In these cases, therapeutic agent can be used via list or multi-cavity drug delivery tube.Then vermiform appendix is poured into to promote fibre modification and permanent filling/closed vermiform appendix with fibre modification derivant or compositions.Under the situation of acute appendicitis, also should send the part of anti-infective (have or do not have hemorrhage) as treatment.As mentioned above, also can advantageously therapeutic agent delivery be gone into the vermiform appendix chamber to promote healing completely with the form of slow releasing preparation (or implant).Discharge described therapeutic agent and reach 7 days at least, and preferably reached 30 to 60 days and above preparation is effective especially for this embodiment.

Though be described as traditionally occurring in the large intestine, should be noted that diverticulum can occur in any piped organ, such as the other parts of gastrointestinal tract, respiratory tract and urinary tract.Describe for colonic diverticula as above, can use the fibre modification derivant of Wicresoft, local delivery, anti-infective, and/or hemorrhage and one or more these diverticulum diseases of combination treatment of comprising these reagent.The example of non-diverticular disease of colon includes but not limited to following.

In one embodiment, can fibre modification derivant, anti-infective and/or hemorrhage be delivered to diverticulum or vermiform appendix by the endoscopic procedures of abdominal part.In this embodiment, as the part of standard abdominal part endoscope step, endoscope is inserted in the abdominal part (typically via umbilicus).With vermiform appendix or diverticulum location, and pierce through the outer wall of vermiform appendix or diverticulum, so that it enters described chamber via the injection device that the side mouth of endoscope is sent.Then therapeutic agent or compositions are gone into diverticulum chamber or vermiform appendix via tube injection.Because disruptive danger, this method can be kept by the situation that colonoscopy can not be carried out.In the abdominal part and the treatment of pelvis abscess

In another embodiment, provide compositions and method to be used to enter and treat in the abdominal part and abscess pelvis.Utilize CT or ultrasonic leading, pin can be used for conduit is inserted described abscess.Described pin can comprise that the echo coating is to strengthen visibility.Can discharge the content of abscess by the syringe that is attached to described pin.Can be with comprising that anti-infective such as antibiotic solution washes described abscess to treat any infection relevant with abscess.After conduit being inserted abscess, the compositions that comprises fibrous tissue formation agent as described herein can be sent into abscess with sealing and filling and airtight (seal off) described abscess.In one embodiment, described compositions be the polymer that forms of original position (for example, COSTASIS).In another embodiment, described compositions is binding agent (for example, CT3 or cyanoacrylate, it is as described herein).Anti-infective (for example, antibiotic or chemotherapeutics) can be included in fibrous tissue and form in the compositions to prevent the infection and recurrence of therapentic part.

Esophagus (pharyngoesophagus) diverticulum

Pharyngoesophageal diverticulum is by give prominence to the diverticulum capsule that produces by damaged pharynx (pharangeal) mucosa in the flesh layer (by outstanding (herneation) that is split by musculi thyreopharyngeus (thyropharangeus muscle) and the bonded Killian of intrinsic laryngeal muscle (cricopharangeus muscle)).Pharyngoesophageal diverticulum can enlarge; The compression esophagus, and cause dysphagia (swallowing and the difficulty of taking food), the anti-stream of the not digest food after diet, suction and cough.

Though frequent expectant treatment, in some patient, described symptom is enough serious, so that must correct described diverticulum by surgical operation.Typically, this realizes by open surgical method under general anesthesia the patient.Determine down described capsule at sternocleidomastoid (stemomastoid muscle), the cervical region of crosscut capsule is removed whole capsules, and damaged in swallowing with suture is closed.

Alternatively, splanchnoscopy can be utilized and intracavity enters pharyngoesophageal diverticulum.According to method as described herein, comprise that the Injectable composition of filler or filler and fibrous tissue formation agent can be injected directly into pharyngoesophageal diverticulum.Though patient (host) is under general anesthesia or calmness, bivalve esophagus speculum inserted a page or leaf sheet is positioned in the capsule so that preceding page or leaf sheet is positioned in the esophageal lumen then.Endoscope can be advanced in the diverticulum chamber, described capsule is developed and cleaning down to remove any content.In case diverticulum develops up hill and dale and is ready to, then can be with fibre modification derivant, anti-infective and/or hemorrhage, or its compositions, (and/or polymer and/or filler) infiltrates the diverticulum chamber via the side mouth of endoscope.As mentioned above, the injectable materials that is fit to that will contain the fibre modification derivant is injected into diverticulum and (makes up separately or with polymer support, it can be the form of example gel agent, paste or spray), (for example to strengthen cicatrization and permanent closure pharyngoesophageal diverticulum, do not wish to be subject to theory, by inducing the generation of filling and sealing the fibrous tissue of diverticulum capsule), therefore weaken or alleviate patient's dysphagia.Described those are identical for diverticulitis to be used for the therapeutic agent, polymer and the preparation that are fit to that this method implements and front.

The Meckel diverticulum inflammation

Meckel diverticulum (persistency of embryonic structure-omphalomescenteric conduit) is modal small intestinal congenital anomaly.It occurs among 2% the crowd, and finds apart from the ileocecum lobe 60cm in the terminal ileum.When inflammation and infection, Meckel diverticulum is simulated appendicitis clinically and is often appeared among the young child (2 years old).In some patients, if described symptom is enough serious so that must the surgical excision diverticulum-particularly it causes that GI is hemorrhage.Typically, this realizes by open abdominal surgery method under general anesthetic, wherein determines diverticulum, and the cervical region of the described capsule of crosscut excises whole capsules, and damaged with in the suture sealing ileum.

Alternatively, splanchnoscopy can be utilized and intracavity enters Meckel diverticulum.According to method and composition as described herein, the Injectable composition that comprises fibrous tissue formation agent, hemorrhage and/or anti-infective can be injected directly into Meckel diverticulum.Though the patient is under general anesthesia or calmness, endoscope can be advanced in the diverticulum chamber, make described capsule develop then cleaning down to remove any content.In case described diverticulum is developed up hill and dale and be ready to, then can fibre modification is inductive, anti-infective and/or hemostatic compositions (and/or polymer and/or filler) infiltrate via the side mouth of endoscope or introduce in the diverticulum chamber.As mentioned above, the injectable materials that is fit to that will contain fibre modification derivant, anti-infective and/or hemorrhage is injected into diverticulum and (makes up separately or with filler or polymer support, it can be the form of example gel agent, paste or spray), (for example to strengthen cicatrization and permanent closure Meckel diverticulum, by inducing the generation of filling and sealing the fibrous tissue of diverticulum capsule), therefore alleviate patient's symptom.Described those are identical for diverticulitis to be used for the therapeutic agent, polymer and the preparation that are fit to that this method implements and front.

Diverticulum of small intestine

It is asymptomatic that diverticulosis of small intestine is considered to rare relatively (1% crowd) and Most patients.Yet diverticulum of small intestine can produce life-threatening complication when symptom is arranged.Duodenal diverticulum is modal, single-shot normally, and trend towards occurring in duodenal second portion.It is multiple that jejuno-ileal diverticula trends towards and great majority are found near jejunum.When diverticulum becomes obstruction and inflammation, similar pancreatitis of symptom or cholecystitis, and can bore a hole sometimes.Operative treatment is dangerous and generally do not show and must do this treatment, and reason is the high rate of pancreas gallbladder complication (bile duct injury, pancreatitis, etc.).

Alternatively, can utilize splanchnoscopy (ERCP) intracavity to enter diverticulum of small intestine.According to method and composition as described herein, the Injectable composition that comprises fibrous tissue formation agent, hemorrhage and/or anti-infective can be injected directly into diverticulum of small intestine.When the patient is in general anesthesia or calm following time, endoscope can be advanced in the diverticulum chamber, make described capsule develop then cleaning down to remove any content.In case described diverticulum develops up hill and dale and is ready to, can be fibrotic, anti-infective and/or hemostatic compositions infiltrate in the diverticulum chamber via the side mouth of endoscope with inducing.As mentioned above, the injectable materials that is fit to that will contain fibre modification derivant, anti-infective and/or hemorrhage be injected into diverticulum (separately or with filler and/or polymer or polymer support combination, it can be the form of example gel agent, paste or spray), (for example to strengthen cicatrization and permanent closure diverticulum of small intestine, by inducing the generation of filling and sealing the fibrous tissue of diverticulum capsule), therefore alleviate patient's symptom.Described those are identical for diverticulitis to be used for the therapeutic agent, polymer and the preparation that are fit to that this method implements and front.

Gastric diverticulum

Gastric diverticulum is rare and great majority are asymptomatic.Yet, gastric diverticulum can when symptom is arranged, produce complication such as hemorrhage, block and perforation.

Alternatively, can utilize the gastroscope intracavity to enter gastric diverticulum.According to method and composition as described herein, the Injectable composition that comprises fibrous tissue formation agent, hemorrhage and/or anti-infective can be injected directly into gastric diverticulum.When the patient is in general anesthesia or calm following time, gastroscope can be advanced in the diverticulum chamber, make described capsule develop then cleaning down to remove any content.In case described diverticulum is video picture and being ready to up hill and dale, can be fibrotic, anti-infective and/or hemostatic compositions infiltrate in the diverticulum chamber via the side mouth of endoscope with inducing.As mentioned above, the injectable materials that is fit to that will contain fibre modification derivant, anti-infective and/or hemorrhage be injected into diverticulum (separately or with filler and/or polymer or polymer support combination, it can be the form of example gel agent, paste or spray), (for example to strengthen cicatrization and permanent closure gastric diverticulum, by inducing the generation of filling and sealing the fibrous tissue of diverticulum capsule), therefore alleviate patient's symptom.Described those are identical for diverticulitis to be used for the therapeutic agent, polymer and the preparation that are fit to that this method implements and front.

The urinary system diverticulum

The urinary system diverticulum is that common (especially in bladder, sometimes in ureter) and great majority are asymptomatic.Yet, the urinary system diverticulum can when symptom is arranged, produce complication such as hemorrhage, block and perforation.

Alternatively, can utilize the cystoscopy intracavity to enter the urinary system diverticulum.According to method and composition as described herein, the Injectable composition that comprises fibrous tissue formation agent, hemorrhage and/or anti-infective can be injected directly into the urinary system diverticulum.When the patient is in general anesthesia or calm following time, cystoscope can be advanced in the diverticulum chamber, make described capsule develop then cleaning down to remove any content.In case described diverticulum develops up hill and dale and is ready to, can be fibrotic, anti-infective and/or hemostatic compositions infiltrate in the diverticulum chamber via the side mouth of endoscope with inducing.As mentioned above, the injectable materials that is fit to that will contain fibre modification derivant, anti-infective and/or hemorrhage be injected into diverticulum (separately or with filler and/or polymer or polymer support combination, it can be the form of example gel agent, paste or spray), (for example to strengthen cicatrization and permanent closure urinary system diverticulum, by inducing the generation of filling and sealing the fibrous tissue of diverticulum capsule), therefore alleviate patient's symptom.Described those are identical for diverticulitis to be used for the therapeutic agent, polymer and the preparation that are fit to that this method implements and front.

Optional diverticulum treatment

As mentioned above, the disease that the diverticulosis right and wrong are usually seen, it can easily be diagnosed such as barium enema or colonoscopy with the routine diagnosis property testing.Equally, great majority have Symptomatic diverticulitis or from diverticulum disease and the hemorrhage patient of GI often at first with non-surgery operation, the therapy for treating that is of no curative effect, for example, the systemic antibiotics that is used for the treatment of diverticulitis, use transfusion, and the hemorrhage supportive care of GI with fluidic.Patient with definite Symptomatic diverticulum disease is in the danger with the increase of infectious-related complication equally.For example, 25% the patient with above-mentioned hemorrhage of diverticulum will have for the second time hemorrhage, be to surpass 50% and have hemorrhage for the third time probability.Therefore, many patients have definite diverticulum disease and are in from their danger of the significant complication of disease progression.At present, the unique preventative therapy that can offer these patients is the infected colon parts of optional excision.This is not only the method for extremely invading, and many patients who benefits from their diverticulum of surgical resection often are not the surgical operation candidates, and reason is the age, as the result's that loses blood weakness or other concurrent medical disease.Therefore, to contain the colon fragment of diverticulum be to the inapplicable therapy of many patients to surgical resection.Thereby, there is significant demand for Wicresoft, medicable therapy, described therapy can be as the prophylactic treatment among the diverticulosis patient to reduce the danger (such as hemorrhage repeatedly) with infectious-related complication.

Method as described herein, compositions, reagent and implant are suitable for preventative processing diverticulosis.Can be in the calm art of light (promptly the patient, not needing general anesthesia) following time carries out method as described herein, and described method is Wicresoft's (for example, colonoscopy or radiographic X guiding), makes described method be suitable for not being the patient of surgical operation candidate.Equally, in the diverticulum wall, induce the implant (or biomaterial) of adhesion or fibrotic therapeutic agent or medicine dipping to promote diverticulum original position " filling ", thereby, remove the diverticulum chamber and reduced the danger that will develop (infection or hemorrhage) with infectious-related complication.According to clinical setting, the adding of anti-infective and/or hemorrhage can further increase the effect of described method.The permanent closure of diverticulum and cicatrization can be effective in cure in many patients (that is, wherein can infect by eliminating, inflammation or and/or hemorrhage diverticulum capsule) and can have effect so that provide alternative approach for open surgical resection (with its complication).

With with the diverticulum treatment of choosing wantonly for diverticulitis and hemorrhage described same procedure.In brief, colonoscopy (or be CT scan sometimes, ultrasound wave, or other imaging technique) is used to identify described diverticulum.The side opening (or under radiography guiding) by endoscope of conduit as described herein advanced enter the diverticulum chamber up to it.According to employed conduit, can heal and fibre modification with promotion by the surface, chamber of denuding or apply energy (aforesaid RF, heat, laser, ultrasound wave etc.) the described diverticulum that breaks.Under the situation of diverticulum attenuation or bad development, preferably do not use these conduits, because they will increase the danger of perforation.In these cases, therapeutic agent can be used via list or multi-cavity drug delivery tube.Then with the compositions perfusion of diverticulum with fibre modification derivant or promotion fibre modification and permanent filling/closed diverticulum.Sometimes anti-infective and/or hemorrhage can be sent as the part of treatment.As mentioned above, also can advantageously therapeutic agent delivery be gone into the diverticulum chamber to promote healing completely with the form of slow releasing preparation (or implant).Discharge described therapeutic agent and reach 7 days at least, and preferably reached 30 to 60 days and above preparation is effective especially for this embodiment.

The test kit of delivery of agents and compositions

In one embodiment, reagent as described herein (forming agent such as fibrous tissue) and compositions are packaged in the test kit, use it for anti-fibrous tissue formation agent is introduced or is delivered in the diverticulum.Described test kit can comprise buffer solution, and the instructions of writing or illustrate in addition.A kind of test kit that typically in medical applications, uses, described test kit comprises: (a) homogenizing dry powder composite, described homogenizing dry powder composite comprises: (i) have first component of the core that replaces with m nucleophilic group, wherein m 〉=2; Second composition that (ii) has the core that replaces with n electrophilic group, wherein n 〉=2 and m+n＞4; But the reactive reactivity that is endowed when being exposed to aqueous environments of wherein said nucleophilic and electrophilic group right and wrong in dry environment, so that described component reacts to each other in aqueous environments to form three dimensional matrix; (b) first buffer solution of pH in about 1.0 to 5.5 scopes; (c) second buffer solution of pH in about 6.0 to 11.0 scopes; Wherein each component is independent pack and mixing immediately before using.Before using, preferably each component is remained in the independent aseptic packaging.

In another embodiment, described test kit can also comprise the delivery system of will allow that described compositions is sent as spray.Described spray can produce and pass through nozzle by the described component of artificial mixing and transmit them.Spray produces and can also realize by utilizing flowing of gas (for example, air, nitrogen, carbon dioxide).

In one embodiment, described test kit comprises the delivery system that is used for compositions as described herein.The delivery apparatus that can be included in the test kit comprises multicomponent injection device and/or pressurized delivery device as described herein.

In another embodiment of described test kit, in described test kit, comprise the multicomponent injection device.Such as here description, described multicomponent sprayer unit can be many compartments injector system, described many compartments injector system has a plurality of tubes, mixing head and outlet opening, wherein described dry powder composite, first buffer and second buffer is contained in many compartments injector system individually.

In another embodiment of test kit, described test kit comprises pressurized delivery device.As mentioned above, pressurized delivery device of the present invention comprises a plurality of fluid components imports that are suitable for separately with the connection of different fluid components sources; At least one is suitable for the carrier fluid import that is connected with pressurization carrier current body source; Be positioned at bubbler surface and at least one carrier fluid import in a plurality of fluid components imports downstream; With the outlet of extending through the bubbler surface, wherein said bubbler surface is suitable for receiving fluid components thereon and having such shape, it is effectively with the guiding of the fluid components of each reception and remain in the different flow path of outlet, to use pressurization carrier fluid from least one carrier fluid import to mix by the there and to distribute.

The test kit of expecting under the present invention is not limited to device as described herein and can comprises that medicine sends known any delivery apparatus that other is fit in the field.

In certain embodiments, will be included in the test kit, be used for a kind of like this bioactive agent delivery is delivered to the host, particularly among host's diverticulum such as the therapeutic agent that fibrous tissue forms agent.Fibrous tissue can be formed agent and mix with described component, perhaps described fibrous tissue can be formed agent and pack separately to form homogeneous mixture.Test kit can use in the treatment of diverticulum disease as described herein.In one embodiment, the mixture of described therapeutic agent and described component is a homogeneous mixture.No matter pack, before using, each component and fibrous tissue form agent should be in aseptic packaging together or individually.

Use described test kit here in can described method, described method compositions need be applied to injured tissues or organ with seal stomach intestinal, esophageal tissue or pancreatic tissue to stop or minimizing the seepage of Excreta (GI road) or organising content thing.Described test kit can also be used to seal urinary tract (for example, bladder or urethra) to stop or minimizing leakage of urine.Can 1) surface by applying them to a kind of tissue then can be with second tissue facing to the extruding fast of first tissue, or 2) applying said compositions uses described compositions by making described tissue tight be close to then.In addition, described compositions can be used for filling the space in the soft and hard tissue that is produced by disease or surgical operation.

Therefore, one embodiment of the invention are methods of sealing patient tissue, and described method comprises the following steps: that (a) provides compositions as described herein; (b) aqueous environments is given nucleophilic and the electrophilic group reactivity reacts to each other with realization by described compositions is exposed to; Wherein said exposure comprises: (i) with described composition dissolves at first buffer solution of pH in about 1.0 to 5.5 scopes to form homogeneous phase solution and (ii) second buffer solution of pH in about 6.0 to 11.0 scopes to be added into described homogeneous phase solution to form mixture; (c) the described mixture of placement contacts with tissue and makes three dimensional matrix form and seal described tissue.In another embodiment, can be together with the medical treatment device applying said compositions of implanting, so that it prevents from described device or from the gas of device-organizational interface, the seepage of liquid or solid.

Thereby, in certain embodiments, described compositions and fibrous tissue are formed the performance of agent combination with further enhancing sealant or binding agent.In one embodiment, (that is, cicatrization) reagent that fibrous tissue forms can be included in the sealing spray of polymer, and its freezing film or coating are to promote fibre modification and sealing gas leakage.Here exemplary fibrous tissue described in detail forms agent and comprises Talcum, silk, fine hair, chitosan, polylysine, fibronectin, bleomycin and Connective Tissue Growth Factor (CTGF), and above-mentioned analog and derivant.

Pharmaceutical carrier

Pharmaceutical composition can be sterilized water or non-aqueous solution agent, suspension or Emulsion, and it comprises physiologically acceptable excipient (excipient or carrier medicinal or that be fit to) (that is, not disturbing the active non-toxicant of effective ingredient) in addition.Such compositions can be the form of solid, liquid or gas (aerosol).Pharmaceutical composition can also contain other component biologic activity or non-activity.Such component (for example includes, but not limited to buffer agent, neutral buffered saline or phosphate buffered saline (PBS)), saccharide (for example, glucose, mannose, sucrose or glucosan), mannitol, protein, polypeptide or aminoacid are such as glycine, antioxidant, chelating agen such as EDTA or glutathion, stabilizing agent, dyestuff, flavoring agent and suspending agent and/or antiseptic.

For any suitable carrier or excipient known to those of ordinary skills can adopt in the described here pharmaceutical composition.The carrier of therapeutic use is well-known, and is described in for example Remingtons Pharmaceutical Sciences (Remington's Pharmaceutical Science), among the MackPublishing Co. (A.R.Gennaro ed.1985).Usually, select the type of carrier based on method of application.Can the compounding pharmaceutical compositions be used for using of any suitable mode.

Composition of liquid medicine can comprise, for example, following one or more: sterile diluent is such as water for injection, saline solution, preferred normal saline, Lin Ge (Ringer) solution, isotonic sodium chloride can serve as the nonvolatile oil of solvent or suspension media, Polyethylene Glycol, glycerol, propylene glycol or other solvent; Antibacterial; Antioxidant; Chelating agen; Be used for buffer and reagent such as sodium chloride or dextrose that tensity is adjusted.

Can be with the mode drug administration compositions of the disease that is suitable for treating (or prevention), the technical staff determines as medical field.Such as here description, suitable dosage of using and the persistent period that is fit to and frequency will be determined by following these factors, as patient's disease, the type and the seriousness of patient disease, the particular form of effective ingredient and the method for using.Usually, suitable dosage and treatment plan treat and/or prevent benefit (for example, the clinical effectiveness of improvement are alleviated fully or partly such as more frequent to be enough to provide, or long no disease and/or total survival rate, or the minimizing of serious symptom) amount provides described compositions.For preventive use, select to be enough to prevent, postpone the outbreak of diverticulum disease, or weaken the dosage of diverticulum disease seriousness.Optimal dose can utilize experimental model and/or clinical trial to determine usually.Optimal dose can depend on body quality, weight, or patient's blood volume.

Delivery system

Many-compartment device

The suitable delivery system that is used for homogenizing dry powder composite and two kinds of buffer can comprise multi-compartment device, wherein one or more compartments contain powder, the buffer that provides aqueous environments required is provided one or more compartments, thereby compositions is exposed to aqueous environments when leaving compartment.To organize many devices of sealant/hemorrhage be well known in the art and can be used for enforcement of the present invention to be suitable for sending multicomponent.Alternatively, can use the controlled extrusion system delivering compositions of any kind, perhaps it can be sent so that dry powder form is manual, and is exposed to aqueous environments in site of administration.

Homogenizing dry powder composite and two kinds of buffer can be by placing independent syringe cylinder conveniently to form under aseptic condition each of three kinds of compositions (dried powder, acidic buffer and alkaline buffer).For example, compositions, first kind of buffer and second kind of buffer can be deposited separately in the many compartments injector system with a plurality of tubes, mixing head and outlet opening.Can add first kind of buffer dissolved composition and form homogeneous phase solution in hold the tube of compositions, it be expressed in the mixing head then.Can simultaneously second kind of buffer be expressed in the mixing head.At last, resulting composition can then be expressed on the surface by the hole.

For example, the syringe cylinder that holds dried powder and alkaline buffer can be the double syringe system, for example, and the part of the dual barrel syringe of describing in the United States Patent (USP) 4,359,049 of Redl etc.In this embodiment, can add acidic buffer, thereby produce homogeneous phase solution to the syringe cylinder that also holds dried powder.In other words, acidic buffer can be added (for example, injection) in the syringe cylinder that holds dried powder, thereby produce the homogeneous phase solution of first kind and second kind component.This homogeneous phase solution can be expressed in the mixing head then, and alkaline buffer is expressed in the mixing head simultaneously.In mixing head, homogeneous phase solution and alkaline buffer are mixed together, thereby form reactant mixture.Afterwards, reactant mixture is expressed on the surface (for example, tissue) by the hole, forms film on this surface, and it can be used as sealant or barrier etc.When forming by homogeneous phase solution in the mixing mixing head and alkaline buffer, reactant mixture begins to form three dimensional matrix immediately.Therefore, be expressed into tissue from mixing head very fast after reactant mixture is preferably formed, thereby form three dimensional matrix organizationally and it can adhere to this tissue.

Other system of two kinds of reaction liquids of combination is well known in the art, and comprises the U.S. Patent number 6,454,786 of Holm etc.; 6,461,325 of Delmotte etc.; 5,585,007 of Antanavich etc.; 5,116,315 of Capozzi etc.; The system of describing in the U.S. Patent Application Publication No. 2004/0068266 of 4,631,055 and the Delmotte of Redl etc.

Pressurized delivery device

Be used to distribute other delivery system of multi-component combination of the present invention can comprise pressurized delivery device, the example is described in the U.S. Patent Application Serial of submitting on October 1st, 2004 of owning together 10/957 common co-pending, 493, and exercise question is in " Mixing and dispensing FluidComponents of a multicomponent Composition " (mixing and distribute the fluid components of multi-component combination).A kind of like this pressurized delivery device can comprise the bubbler surface with the outlet of extending by the there, and it is positioned at the downstream of a plurality of imports.Though at least one import is suitable for being connected with pressurization carrier current body source, each of a plurality of imports is suitable for connecting with different fluid components sources.Utilize this device, dry powder solution and first kind of buffer are pre-mixed the homogeneous phase solution of describing as pro-to form, and subsequently this solution are connected with the first fluid component.Second fluid components will be connected with second buffer solution that pro-is described.In case the bubbler surface receives the fluid components from import, then the fluid components of each reception advances facing to outlet and is used for by pressurization from the carrier fluid of carrier fluid import so that by its mixing and distribution, described carrier fluid typically gas such as air.Bubbler surface and import can provide the component of mixing nozzle.

Usually, have the gas of two kinds strengthen reactive component one that nozzle is used to distribute multi-component combination relate to internal mix those and relate to those of external mix.When the bubbler surface is a nozzle part, described nozzle can be thought inside mix nozzle.Unlike other internal mix technology, the inside mix nozzle of pressurized delivery device of the present invention provides several independent features that also jointly work to remove deoppilation.For example, the bubbler surface typically has such shape, and it is effective to fluid components guiding that will be separately receives and remains in the lip-deep different flow path of bubbler of outlet, to mix therein and by its distribution.Because the minimum time of staying of mixture in nozzle, before the pressurized carrier fluid of mixture forced to leave described nozzle, reactive component had little time to solidify and stopped nozzles.In addition, described outlet can with may reside in nozzle in any or all of carrier fluid import align, discharge mixture with enhance fluid component blended mode direct pressurized carrier fluid and in the spurting mode.Because influence the performance of described device, so the bubbler surface can be permanent fixed or fix with respect to import with respect to the orientation on the bubbler surface of import; Yet when the bubbler surface separated with import, described nozzle can be dismantled to promote cleaning and/or replacement part.For example, the bubbler surface can be interchangeable and/or disposable.Even so, when pressurized delivery device of the present invention has with the discerptible bubbler of import surface, can constituent apparatus allowing of the unique structure assembling of described part with the import of bubbler surface in alignment, thereby optimize the performance of described device.

Usually, can adopt any of many carrier fluids with pressurized delivery device of the present invention.For example, described carrier fluid can be gasiform and/or liquid in nature.Yet typically, described carrier fluid is chemically inert with respect to fluid components.The noble gas unrestriction ground that is fit to comprises air, carbon dioxide, nitrogen, argon, helium, the fluoridized alkane of gaseous state and ether, gasiform chlorofluorocarbon etc.The inert fluid unrestriction ground that is fit to comprises polysiloxanes, fluoridized polyethers etc.Compressed air provides economical and practical carrier fluid to use for pressurized delivery device.The equipment related with compressed air is well-known in the art and can comprises compressed gas cylinder or cylinder and compressor.In some cases, one or more check-valves can be provided, for example, one-way cock is to prevent to increase owing to the pressure relevant with the use of pressurized delivery device the backflow of the fluid components that produces.Such check-valves can be positioned at the upstream on bubbler surface, for example, and at the intracavity that is connected with import.When snout cavity in short-term, for example, about 2 to about 5 centimetre lengths, such check-valves is useful especially, because the potentiality that reflux are tending towards being inversely proportional to the length in chamber; Yet check-valves also can adopt with long chamber.

The part of described device contact multi-component combination and its fluid components is preferably inert and repel for the material that is contacted.Thereby the part of described device contacting with fluid in operation is selected according to being suitable for particular fluid.For example, described device or its assembly can be by manufacturings such as plastics such as Merlon, polyurethane, polyester, acrylic compounds resin, abs polymer, polysulfones.Also can use adhesion inhibition coating such as polysiloxanes, fluoridized polymer etc.Thereby, the inert typically and optional repulsion fluid components in described bubbler surface.Similarly, can the contacting with fluid component or the surface, chamber of carrier fluid typically also be the corresponding fluid of inert and optional repulsion.

Pressurized delivery device of the present invention is useful especially for distributing multi-component combination.Though can use some gaseous component, pressurized delivery device is useful especially for liquid.Thereby at least a fluid components is normally liquid.Usually, each fluid components comprises liquid.For example, pressurized delivery device is useful for distributing the compositions such as fluid mixture, and wherein the mixing of multiple fluid causes viscosity to increase, and is enough to weaken mix flow.Such compositions can be by relative to each other being that chemically reactive fluid components forms.In some cases, can provide cross-linking agent.

Then, in force, the bubbler surface has the outlet by its extension, thereby the bubbler surface is the downstream in the import of multiple fluid component and at least one carrier fluid import.From the different fluid components of each fluid components import guiding facing to the bubbler surface.In some cases, guide fluid components with substantially the same flow velocity facing to the bubbler surface.Alternatively, guide fluid components facing to described bubbler surface with different flow velocitys.Typically, the flow velocity of carrier fluid is higher than the flow velocity of fluid components.The bubbler surface keeps and guides the fluid components of each reception in facing to the different flow path of outlet.Pressurization carrier fluid from least one carrier fluid import also passes through described outlets direct, distributes described compositions thereby mix the fluid components and the described outlet of process that are present in outlet.

The present invention, aspect multiple in, the embodiment of following itemize is provided.

1. treat the method for diverticulum disease, described method comprise will the treatment effective dose fibrous tissue form agent or comprise compositions that fibrous tissue forms agent and be incorporated in the diverticulum among the host, wherein said fibrous tissue forms agent inducing fibrosis reaction in described diverticulum, therefore treats the diverticulum disease among the host.

2. the 1st method, wherein said diverticulum disease is a diverticulosis.

3. the 1st method, wherein said diverticulum disease is a diverticulitis.

4. the 1st method, wherein said diverticulum disease is a diverticulosis of colon.

5. the 1st method, wherein said diverticulum disease is a hemorrhage of diverticulum.

6. the 1st method, wherein said diverticulum disease is pharyngoesophagus (esophagus) diverticulum.

7. the 1st method, wherein said diverticulum disease is a Meckel diverticulum.

8. the 1st method, wherein said diverticulum disease is a diverticulosis of small intestine.

9. the 1st method, wherein said diverticulum disease is the gastric diverticulum disease.

10. the 1st method, wherein said diverticulum disease is the urinary tract diverticulosis.

11. the 1st method, wherein said fibrous tissue forms agent and promotes regeneration.

12. the 1st method, wherein said fibrous tissue form agent and promote fibre modification and promote regeneration.

13. forming agent, the 1st method, wherein said fibrous tissue promote blood vessel to take place.

14. the 1st method, wherein said fibrous tissue form agent and promote the fibroblast migration.

15. the 1st method, wherein said fibrous tissue forms agent and promotes fibroblast proliferation.

16. the 1st method, wherein said fibrous tissue forms the deposition that agent promotes extracellular matrix (ECM).

17. the 1st method, wherein said fibrous tissue forms agent and promotes tissue remodeling.

18. the 1st method, it is diverticulum wall stimulus object that wherein said fibrous tissue forms agent.

Be or comprise silk 19. the 1st method, wherein said fibrous tissue form agent.

Be or comprise silkworm silk 20. the 1st method, wherein said fibrous tissue form agent.

Be or comprise spider silk 21. the 1st method, wherein said fibrous tissue form agent.

Be or comprise the recombinant silk 22. the 1st method, wherein said fibrous tissue form agent.

Be or comprise raw silk 23. the 1st method, wherein said fibrous tissue form agent.

24. the 1st method, wherein said fibrous tissue forms the silk that agent is or comprises hydrolysis.

25. the 1st method, wherein said fibrous tissue formation agent is or comprises acid-treated.

26. the 1st method, wherein said fibrous tissue forms the silk that agent is or comprises acidylate.

27. the 1st method, it is the form of twisted wire that wherein said fibrous tissue forms agent.

28. the 1st method, wherein said fibrous tissue form the form that agent is bunch.

Be or comprise mineral grain 29. the 1st method, wherein said fibrous tissue form agent.

Be or comprise chitosan 30. the 1st method, wherein said fibrous tissue form agent.

Be or comprise polylysine 31. the 1st method, wherein said fibrous tissue form agent.

Be or comprise fibronectin 32. the 1st method, wherein said fibrous tissue form agent.

Be or comprise bleomycin 33. the 1st method, wherein said fibrous tissue form agent.

Be or comprise CTGF 34. the 1st method, wherein said fibrous tissue form agent.

Be or comprise fine hair 35. the 1st method, wherein said fibrous tissue form agent.

Be or comprise animal down 36. the 1st method, wherein said fibrous tissue form agent.

Be or comprise wood shavings 37. the 1st method, wherein said fibrous tissue form agent.

Be or comprise synthetic fine hair 38. the 1st method, wherein said fibrous tissue form agent.

39. the 1st method, it is the form of line that wherein said fibrous tissue forms agent, perhaps contacts with line.

40. the 39th method, wherein said line is biodegradable.

41. the 40th method, wherein said biodegradable line comprise the material that is selected from the group of being made up of polyester, poly-anhydride, poly-(anhydride ester), poly-(ester-acid amide), poly-(ester-urea), poe, poly phosphate, poly-phosphazine, polybutylcyanoacrylate, collagen, chitosan, hyaluronic acid, chromic catgut, alginate, starch, cellulose and cellulose esters.

42. the 39th method, wherein said line are not biodegradable.

43. the 42nd method, wherein said not biodegradable line comprise the material that is selected from the group of being made up of polyester, polyurethane, siloxanes, polyethylene, polypropylene, polystyrene, polyacrylate, polymethacrylates and silk.

44. the 39th method, wherein said line scribbles polymer.

45. the 39th method, wherein said line scribble the medicament of inducing fibrosis reaction in the host.

46. the 1st method, it is the form of microgranule that wherein said fibrous tissue forms agent.

47. the 46th method, wherein said microgranule are biodegradable microgranules.

48. the 47th method, wherein said Biodegradable microparticle comprise the material that is selected from the group of being made up of polyester, poly-anhydride, poly-(anhydride ester), poly-(ester-acid amide), poly-(ester-urea), poe, poly phosphate, poly-phosphazine, polybutylcyanoacrylate, collagen, chitosan, hyaluronic acid, chromic catgut, alginate, starch, cellulose and cellulose esters.

49. the 46th method, wherein said microgranule are not biodegradable microgranules.

50. the 49th method, wherein said not biodegradable microgranule comprise the material that is selected from the group of being made up of polyester, polyurethane, siloxanes, polyethylene, polypropylene, polystyrene, polyacrylate, polymethacrylates and silk.

51. the 46th method, wherein said microgranule are the particulate form that is selected from the member of the group of being made up of silk, Talcum, starch, glass, silicate, Silicon stone, calcium phosphate, calcium sulfate, calcium carbonate, hydroxyapatite, synthetic mineral, polymethyl methacrylate, silver nitrate, pottery and other inorganic particle.

52. the 46th method, wherein said microgranule scribbles polymer.

53. the 46th method, wherein said microgranule scribble the medicament of inducing fibrosis reaction in the host.

54. the 46th method, wherein said microgranule scribble the member who is selected from the group of being made up of silk, Talcum, starch, glass, silicate, Silicon stone, calcium phosphate, calcium sulfate, calcium carbonate, hydroxyapatite, synthetic mineral, polymethyl methacrylate, silver nitrate, pottery and other inorganic particle.

55. the 1st method, wherein said compositions comprises somatomedin.

56. the 55th method, wherein said somatomedin is selected from transforming growth factor, platelet derived growth factor and fibroblast growth factor.

57. the 1st method, wherein said compositions also comprises polymer.

58. the 1st method, wherein said compositions also comprises polymer, and described polymer is perhaps to comprise copolymer.

59. the 1st method, wherein said compositions also comprises polymer, and described polymer is perhaps to comprise block copolymer.

60. the 1st method, wherein said compositions also comprises polymer, and described polymer is perhaps to comprise random copolymer.

61. the 1st method, wherein said compositions also comprises polymer, and described polymer is perhaps to comprise biodegradable polymer.

62. the 1st method, wherein said compositions also comprises polymer, and described polymer is perhaps to comprise not biodegradable polymer.

63. the 1st method, wherein said compositions also comprises polymer, and described polymer is perhaps to comprise hydrophilic polymer.

64. the 1st method, wherein said compositions also comprises polymer, and described polymer is perhaps to comprise hydrophobic polymer.

65. the 1st method, wherein said compositions also comprises polymer, and described polymer is perhaps to comprise the polymer of possess hydrophilic property domain.

66. the 1st method, wherein said compositions also comprises polymer, and described polymer is, perhaps comprises, and has the polymer in hydrophobic structure territory.

67. the 1st method, wherein said compositions also comprises polymer, and described polymer is perhaps to comprise non-conductive polymer.

68. the 1st method, wherein said compositions also comprises polymer, and described polymer is perhaps to comprise elastomer.

69. the 1st method, wherein said compositions also comprises polymer, and described polymer is perhaps to comprise hydrogel.

70. the 1st method, wherein said compositions also comprises polymer, and described polymer is perhaps to comprise siloxane polymer.

71. the 1st method, wherein said compositions also comprises polymer, and described polymer is perhaps to comprise hydrocarbon polymer.

72. the 1st method, wherein said compositions also comprises polymer, and described polymer is perhaps to comprise the styrene derived polymers.

73. the 1st method, wherein said compositions also comprises polymer, and described polymer is perhaps to comprise butadiene-derived polymers.

74. the 1st method, wherein said compositions also comprises polymer, and described polymer is perhaps to comprise macromonomer.

75. the 1st method, wherein said compositions also comprises polymer, and described polymer is perhaps to comprise poly-(ethylene glycol).

76. the 1st method, wherein said compositions also comprises polymer, and described polymer is perhaps to comprise the collagen or derivatives thereof.

77. the 1st method, wherein said compositions also comprises polymer, and described polymer is perhaps to comprise methylated collagen.

78. the 1st method, wherein said compositions also comprises polymer composition, and wherein said polymer composition comprises collagen or derivatives thereof and fibrinogen.

79. the 1st method, wherein said compositions also comprises polymer composition, and wherein said polymer composition comprises collagen or derivatives thereof and thrombin.

80. the 1st method, wherein said compositions also comprises polymer composition, and wherein said polymer composition comprises (a) collagen or derivatives thereof; (b) fibrinogen; (c) thrombin.

81. the 1st method, wherein said compositions also comprises polymer composition, and wherein said polymer composition comprises methylated collagen and poly-(ethylene glycol) or derivatives thereof.

82. the 1st method, wherein said compositions also comprises hemorrhage, and described hemorrhage comprises collagen polymer.

83. the 1st method, wherein said compositions also comprises hemorrhage, and described hemorrhage comprises collagen polymer, and wherein said hemorrhage is CT3.

84. the 1st method, wherein said compositions also comprises hemorrhage, and described hemorrhage comprises collagen polymer, and wherein said hemorrhage is COSTASIS.

85. the 1st method, wherein said compositions also comprises hemorrhage, and described hemorrhage comprises poly-(ethylene glycol).

86. the 1st method, wherein said compositions also comprises hemorrhage, and wherein said hemorrhage is COSEAL, TISSEAL or FLOSEAL.

87. the 1st method, wherein said compositions also comprises hemorrhage, and described hemorrhage comprises fibrin.

88. the 1st method, wherein said compositions also comprises polymer, and described polymer is perhaps to comprise amorphous polymer.

89. the 1st method, wherein said compositions also comprises polymer, and described polymer is perhaps to comprise cyanoacrylate.

90. the 89th method, wherein said cyanoacrylate are selected from methyl 2-cyanoacrylate, cyanacrylate, Tisuacryl, octyl 2-cyanoacrylate and alpha-cyanoacrylate methoxyl group propyl ester.

91. the 1st method, wherein said compositions comprises polymer, and described polymer is, or comprises, poly-(alkyl cyanoacrylate).

92. the 91st method, wherein said poly-(alkyl cyanoacrylate) are selected from poly-(MCA), poly-(ethyl cyanoacrylate), poly-(butyl cyanoacrylate), poly-(isobutyl cyanoacrylate), poly-(hexyl cyanoacrylate) and poly-(octyl cyanoacrylate).

93. the 1st method, wherein said compositions comprises polymer, and described polymer is perhaps to comprise poly-(carboxyalkyl cyanoacrylate).

94. the 93rd method, wherein said poly-(carboxyalkyl cyanoacrylate) is poly-(methoxy-propyl cyanoacrylate).

95. the 57th method, wherein said polymer is crosslinked.

96. the 57th method, wherein said polymer and mammalian tissues reaction.

97. the 57th method, wherein said polymer are naturally occurring polymer.

98. the 57th method, wherein said polymer is a protein.

99. the 57th method, wherein said polymer is a saccharide.

100. the 57th method, wherein said polymer are crosslinked with biodegradable.

101. the 1st method, wherein said compositions comprises fibrinogen.

102. the 1st method, wherein said compositions comprises thrombin.

103. the 1st method, wherein said compositions comprises calcium salt.

104. the 1st method, wherein said compositions comprise anti-fibrinolytic (antifibronolytic) agent.

105. the 1st method, wherein said compositions comprises the fibrinogen analog.

106. the 1st method, wherein said compositions comprises albumin.

107. the 1st method, wherein said compositions comprises plasminogen.

108. the 1st method, wherein said compositions comprises Feng's von willebrand's factor.

109. the 1st method, wherein said compositions comprises Factor IX.

110. the 1st method, wherein said compositions comprises hypoallergenic collagen.

111. the 1st method, wherein said compositions comprise non-end peptide collagen.

112. the 1st method, wherein said compositions comprises crosslinked collagen.

113. the 1st method, wherein said compositions comprises aprotinin.

114. the 1st method, wherein said compositions comprise epsilon-amino-just-caproic acid.

115. the 1st method, wherein said compositions comprises gelatin.

116. the 1st method, wherein said compositions comprises protein conjugate.

117. the 1st method, wherein said compositions comprises the gelatin conjugate.

118. the 1st method, wherein said compositions comprises hyaluronic acid.

119. the 1st method, wherein said compositions comprises derivatives of hyaluronic acids.

120. the 1st method, wherein said compositions comprises synthetic polymer.

121. the 57th method, wherein said polymer forms by comprising the synthetic reactant that contains the chemical compound of isocyanates.

122. the 1st method, wherein said compositions comprise the synthetic chemical compound that contains isocyanates.

123. the 57th method, wherein said polymer forms by comprising the synthetic reactant that contains the chemical compound of mercaptan.

124. the 1st method, wherein said compositions comprise the synthetic chemical compound that contains mercaptan.

125. the 57th method, wherein said polymer forms by comprising the synthetic reactant that contains the chemical compound of two mercaptos at least.

126. the 1st method, wherein said compositions comprise the synthetic chemical compound that contains at least two mercaptos.

127. the 57th method, wherein said polymer forms by comprising the synthetic reactant that contains the chemical compound of three mercaptos at least.

128. the 1st method, wherein said compositions comprise the synthetic chemical compound that contains at least three mercaptos.

129. the 57th method, wherein said polymer forms by comprising the synthetic reactant that contains the chemical compound of four mercaptos at least.

130. the 1st method, wherein said compositions comprise the synthetic chemical compound that contains at least four mercaptos.

131. the 57th method, wherein said polymer forms by comprising the synthetic reactant that contains amino chemical compound.

132. the 1st method, wherein said compositions comprise the synthetic amino chemical compound that contains.

133. the 57th method, wherein said polymer forms by comprising the synthetic reactant that contains the chemical compound of two amino at least.

134. the 1st method, wherein said compositions comprise the synthetic chemical compound that contains at least two amino.

135. the 57th method, wherein said polymer forms by comprising the synthetic reactant that contains the chemical compound of three amino at least.

136. the 1st method, wherein said compositions comprise the synthetic chemical compound that contains at least three amino.

137. the 57th method, wherein said polymer forms by comprising the synthetic reactant that contains the chemical compound of four amino at least.

138. the 1st method, wherein said compositions comprise the synthetic chemical compound that contains at least four amino.

139. the 57th method, wherein said polymer forms by comprising the synthetic reactant that contains the chemical compound of carbonyl-oxygen-succinimido.

140. the 1st method, wherein said compositions comprise the synthetic chemical compound that contains carbonyl-oxygen-succinimido.

141. the 57th method, wherein said polymer forms by comprising the synthetic reactant that comprises the chemical compound of two carbonyl-oxygen-succinimido at least.

142. the 1st method, wherein said compositions comprise the synthetic chemical compound that contains at least two carbonyl-oxygen-succinimido.

143. the 57th method, wherein said polymer forms by comprising the synthetic reactant that contains the chemical compound of three carbonyl-oxygen-succinimido at least.

144. the 1st method, wherein said compositions comprise the synthetic chemical compound that contains at least three carbonyl-oxygen-succinimido.

145. the 57th method, wherein said polymer forms by comprising the synthetic reactant that contains the chemical compound of four carbonyl-oxygen-succinimido at least.

146. the 1st method, wherein said compositions comprise the synthetic chemical compound that contains at least four carbonyl-oxygen-succinimido.

147. the 57th method, wherein said polymer forms by comprising the synthetic reactant that contains the chemical compound of polyalkylene oxide.

148. the 1st method, wherein said compositions comprise the synthetic chemical compound that contains polyalkylene oxide.

149. the 57th method, wherein said polymer forms by comprising the synthetic reactant that contains the chemical compound of polyalkylene oxide and biodegradable polyester block.

150. the 1st method, wherein said compositions comprise the synthetic chemical compound that contains polyalkylene oxide and biodegradable polyester block.

151. the 57th method, wherein said polymer forms by comprising synthetic reactant with chemical compound that contains polyalkylene oxide of reactive amino.

152. the 1st method, wherein said compositions comprise the synthetic chemical compound that contains polyalkylene oxide with reactive amino.

153. the 57th method, wherein said polymer forms by comprising synthetic reactant with chemical compound that contains polyalkylene oxide of reactive mercapto.

154. the 1st method, wherein said compositions comprise the synthetic chemical compound that contains polyalkylene oxide with reactive mercapto.

155. the 57th method, wherein said polymer forms by comprising synthetic reactant with chemical compound that contains polyalkylene oxide of reactive carbonyl-oxygen-succinimido.

156. the 1st method, wherein said compositions comprise the synthetic chemical compound that contains polyalkylene oxide with reactive carbonyl-oxygen-succinimido.

157. the 57th method, wherein said polymer forms by comprising the synthetic reactant that contains the chemical compound of biodegradable polyester block.

158. the 1st method, wherein said compositions comprise the synthetic chemical compound that contains the biodegradable polyester block.

159. the 57th method, wherein said polymer is formed by the reactant that comprises the synthetic polymer that is formed by lactic acid or lactide wholly or in part.

160. the 1st method, wherein said compositions comprise the synthetic polymer that is formed by lactic acid or lactide wholly or in part.

161. the 57th method, wherein said polymer is formed by the reactant that comprises the synthetic polymer that is formed by glycolic or Acetic acid, hydroxy-, bimol. cyclic ester wholly or in part.

162. the 1st method, wherein said compositions comprise the synthetic polymer that is formed by glycolic or Acetic acid, hydroxy-, bimol. cyclic ester wholly or in part.

163. the 57th method, wherein said polymer is formed by the reactant that comprises polylysine.

164. the 1st method, wherein said compositions comprises polylysine.

165. the 57th method, wherein said polymer forms by comprising the reactant of (a) protein with the chemical compound that (b) comprises the polyalkylene oxide part.

166. the 1st method, wherein said compositions comprise (a) protein and (b) comprise the chemical compound of polyalkylene oxide part.

167. the 57th method, wherein said polymer by comprise (a) protein and (b) reactant of polylysine form.

168. the 1st method, wherein said compositions comprise (a) protein and (b) polylysine.

169. the 57th method, wherein said polymer forms with the reactant that (b) has the chemical compound of four mercaptos by comprising (a) protein at least.

170. the 1st method, wherein said compositions comprise (a) protein and (b) have the chemical compound of at least four mercaptos.

171. the 57th method, wherein said polymer forms with the reactant that (b) has the chemical compound of four amino by comprising (a) protein at least.

172. the 1st method, wherein said compositions comprise (a) protein and (b) have the chemical compound of at least four amino.

173. the 57th method, wherein said polymer forms with the reactant that (b) has the chemical compound of four carbonyl-oxygen-butanimide group by comprising (a) protein at least.

174. the 1st method, wherein said compositions comprise (a) protein and (b) have the chemical compound of at least four carbonyl-oxygen-butanimide group.

175. the 57th method, wherein said polymer forms with the reactant that (b) has the chemical compound of the biodegradable region that is formed by the reactant that is selected from lactic acid, lactide, glycolic, Acetic acid, hydroxy-, bimol. cyclic ester and 6-caprolactone by comprising (a) protein.

176. the chemical compound that the 1st method, wherein said compositions comprise (a) protein and (b) have the biodegradable region that is formed by the reactant that is selected from lactic acid, lactide, glycolic, Acetic acid, hydroxy-, bimol. cyclic ester and 6-caprolactone.

177. the 57th method, wherein said polymer forms by comprising the reactant of (a) collagen with the chemical compound that (b) comprises the polyalkylene oxide part.

178. the 1st method, wherein said compositions comprise (a) collagen and (b) comprise the chemical compound of polyalkylene oxide part.

179. the 57th method, wherein said polymer by comprise (a) collagen and (b) reactant of polylysine form.

180. the 1st method, wherein said compositions comprise (a) collagen and (b) polylysine.

181. the 57th method, wherein said polymer forms with the reactant that (b) has the chemical compound of four mercaptos by comprising (a) collagen at least.

182. the 1st method, wherein said compositions comprise (a) collagen and (b) have the chemical compound of at least four mercaptos.

183. the 57th method, wherein said polymer forms with the reactant that (b) has the chemical compound of four amino by comprising (a) collagen at least.

184. the 1st method, wherein said compositions comprise (a) collagen and (b) have the chemical compound of at least four amino.

185. the 57th method, wherein said polymer forms with the reactant that (b) has the chemical compound of four carbonyl-oxygen-butanimide group by comprising (a) collagen at least.

186. the 1st method, wherein said compositions comprise (a) collagen and (b) have the chemical compound of at least four carbonyl-oxygen-butanimide group.

187. the 57th method, wherein said polymer forms with the reactant that (b) has the chemical compound of the biodegradable region that is formed by the reactant that is selected from lactic acid, lactide, glycolic, Acetic acid, hydroxy-, bimol. cyclic ester and 6-caprolactone by comprising (a) collagen.

188. the chemical compound that the 1st method, wherein said compositions comprise (a) collagen and (b) have the biodegradable region that is formed by the reactant that is selected from lactic acid, lactide, glycolic, Acetic acid, hydroxy-, bimol. cyclic ester and 6-caprolactone.

189. the 57th method, wherein said polymer forms by comprising the reactant of (a) methylated collagen with the chemical compound that (b) comprises the polyalkylene oxide part.

190. the 1st method, wherein said compositions comprise (a) methylated collagen and (b) comprise the chemical compound of polyalkylene oxide part.

191. the 57th method, wherein said polymer by comprise (a) methylated collagen and (b) reactant of polylysine form.

192. the 1st method, wherein said compositions comprise (a) methylated collagen and (b) polylysine.

193. the 57th method, wherein said polymer forms with the reactant that (b) has the chemical compound of four mercaptos by comprising (a) methylated collagen at least.

194. the 1st method, wherein said compositions comprise (a) methylated collagen and (b) have the chemical compound of at least four mercaptos.

195. the 57th method, wherein said polymer forms with the reactant that (b) has the chemical compound of four amino by comprising (a) methylated collagen at least.

196. the 1st method, wherein said compositions comprise (a) methylated collagen and (b) have the chemical compound of at least four amino.

197. the 57th method, wherein said polymer forms with the reactant that (b) has the chemical compound of four carbonyl-oxygen-butanimide group by comprising (a) methylated collagen at least.

198. the 1st method, wherein said compositions comprise (a) methylated collagen and (b) have the chemical compound of at least four carbonyl-oxygen-butanimide group.

199. the 57th method, wherein said polymer forms with the reactant that (b) has the chemical compound of the biodegradable region that is formed by the reactant that is selected from lactic acid, lactide, glycolic, Acetic acid, hydroxy-, bimol. cyclic ester and 6-caprolactone by comprising (a) methylated collagen.

200. the chemical compound that the 1st method, wherein said compositions comprise (a) methylated collagen and (b) have the biodegradable region that is formed by the reactant that is selected from lactic acid, lactide, glycolic, Acetic acid, hydroxy-, bimol. cyclic ester and 6-caprolactone.

201. the 57th method, wherein said polymer forms by comprising hyaluronic reactant.

202. the 1st method, wherein said compositions comprises hyaluronic acid.

203. the 57th method, wherein said polymer is formed by the reactant that comprises derivatives of hyaluronic acids.

204. the 1st method, wherein said compositions comprises derivatives of hyaluronic acids.

205. the 57th method, wherein said polymer is formed by the reactant that comprises poly-(ethylene glycol) ether four-sulfydryl of the tetramethylolmethane of number-average molecular weight between 3,000 and 30,000.

206. the 1st method, wherein said compositions comprise poly-(ethylene glycol) ether four-sulfydryl of the tetramethylolmethane of number-average molecular weight between 3,000 and 30,000.

207. the 57th method, wherein said polymer is formed by the reactant that comprises poly-(ethylene glycol) ether four of the tetramethylolmethane of number-average molecular weight between 3,000 and 30,000-amino.

208. the 1st method, wherein said compositions comprise poly-(ethylene glycol) ether four-amino of the tetramethylolmethane of number-average molecular weight between 3,000 and 30,000.

209. the 57th method, wherein said polymer is by comprising (a) synthetic number-average molecular weight 3,000 and 30, between 000 and comprise the chemical compound of polyalkylene oxide zone and a plurality of nucleophilic groups and (b) synthetic number-average molecular weight 3, between 000 and 30,000 and comprise the reactant formation of the chemical compound of polyalkylene oxide zone and a plurality of electrophilic groups.

210. the 1st method, wherein said compositions comprises (a) synthetic number-average molecular weight 3,000 and 30, between 000 and comprise the chemical compound of polyalkylene oxide zone and a plurality of nucleophilic groups, (b) synthetic number-average molecular weight is 3, between 000 and 30,000 and comprise the chemical compound of polyalkylene oxide zone and a plurality of electrophilic groups.

211. the 1st method, wherein said compositions comprises coloring agent.

212. the 1st method, wherein said compositions is aseptic.

213. the 1st method, wherein said compositions also comprises second forms of pharmacologically active agents.

214. the 1st method, wherein said compositions also comprises antiinflammatory.

215. the 1st method, wherein said compositions also comprises infection inhibitor.

216. the 1st method, wherein said compositions also comprises anthracycline.

217. the 1st method, wherein said compositions also comprises doxorubicin.

218. the 1st method, wherein said compositions also comprises mitoxantrone.

219. the 1st method, wherein said compositions also comprises the fluorine pyrimidine.

220. the 1st method, wherein said compositions also comprise 5-fluorouracil (5-FU).

221. the 1st method, wherein said compositions also comprises antifol.

222. the 1st method, wherein said compositions also comprises methotrexate.

223. the 1st method, wherein said compositions also comprises podophyllotoxin.

224. the 1st method, wherein said compositions also comprises etoposide.

225. the 1st method, wherein said compositions also comprises camptothecine.

226. the 1st method, wherein said compositions also comprises hydroxyurea.

227. the 1st method, wherein said compositions also comprises platinum complex.

228. the 1st method, wherein said compositions also comprises cisplatin.

229. the 1st method, wherein said compositions also comprises anti-infective.

230. the 1st method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is an antibiotic.

231. the 1st method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a doxycycline.

232. the 1st method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a metronidazole.

233. the 1st method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a trimethoprim-sulfamethoxazole.

234. the 1st method, wherein said compositions also comprises anti-infective, wherein said anti-infective be the 4th generation penicillin.

235. the 1st method, wherein said compositions also comprises anti-infective, wherein said anti-infective be selected from urea groups penicillin and penicillin carboxy the 4th generation penicillin, or its analog or derivant.

236. the 1st method, wherein said compositions also comprises anti-infective, wherein said anti-infective be selected from mezlocillin, piperacillin, Carbenicillin and ticarcillin the 4th generation penicillin.

237. the 1st method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a first generation cephalosporin.

238. the 1st method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is the first generation cephalosporin that is selected from cefazolin sodium, cefalexin, cefazolin sodium, cefaloject and cefalotin.

239. the 1st method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a penicillin carboxy.

240. according to the 601st method, wherein said penicillin carboxy is a ticarcillin.

241. the 1st method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a second generation cephalosporin.

242. the 1st method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is the second generation cephalosporin that is selected from cefuroxime, cefotetan and cefoxitin.

243. the 1st method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a third generation cephalosporin.

244. the 1st method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is the third generation cephalosporin that is selected from ceftiofur sodium, cefdinir, cefoperazone, ceftazidime, ceftriaxone and cefotaxime.

245. the 1st method, wherein said compositions also comprises anti-infective, wherein said anti-infective be the 4th generation cephalosporin.

246. the 245th method, wherein said the 4th generation cephalosporin be cefepime.

247. the 1st method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a monobactam.

248. the 247th method, wherein said monobactam is an aztreonam.

249. the 1st method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a carbapenem.

250. the 1st method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is the carbapenem that is selected from imipenum, Ai Tapeinan and meropenem.

251. the 1st method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is an aminoglycoside.

252. the 1st method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is the aminoglycoside that is selected from streptomycin, gentamycin, tobramycin and amikacin.

253. the 1st method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is the MSL group membership who is selected from macrolide, long-acting macrolide, lincosamide and streptogramin.

254. the 1st method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is the MSL group membership who is selected from erythromycin, azithromycin, clindamycin, quinoline slave Pu Ding-dalfopristin (Syneroid), clarithromycin and kanamycin sulfate.

255. the 1st method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a quinolinones.

256. the 1st method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is the quinolinones that is selected from ciprofloxacin, ofloxacin, Gatifloxacin, Moxifloxacin, levofloxacin and trovafloxacin.

257. the 1st method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is the DNA synthetic inhibitor.

258. the 257th method, wherein said DNA synthetic inhibitor is a metronidazole.

259. the 1st method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a sulfonamide.

260. the 259th method, wherein said sulfonamide is a trimethoprim.

261. the 1st method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is selected from cefixime, spectinomycin, tetracycline, nitrofurantoin, polymyxin B and polygynax.

262. the 1st method, wherein said compositions also comprises developing agent.

263. the 1st method, wherein said compositions also comprises developing agent, and described developing agent is radio-opaque material, and wherein said radio-opaque material comprises metal, halogenated compound or contains the chemical compound of barium.

264. the 1st method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises barium, tantalum or technetium.

265. the 1st method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises MRI response material or echo material.

266. the 1st method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises gadolinium chelate compound.

267. the 1st method, wherein said compositions also comprises a kind of developing agent, and described developing agent is, or comprises ferrum, magnesium, manganese, copper or chromium.

268. the 1st method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises iron oxide compound.

269. the 1st method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises dyestuff, pigment or coloring agent.

270. forming agent, the 1st method, wherein said fibrous tissue in the administration cycle to about 90 days scopes constantly, discharge from the compositions that comprises fibrous tissue and form agent with valid density by diffusion.

271. forming agent corrosion by described compositions in the administration cycle to about 90 days scopes constantly, the 1st method, wherein said fibrous tissue discharge from the compositions that comprises fibrous tissue and form agent with valid density.

272. the 1st method, wherein said compositions also comprises inflammatory cytokine.

273. the 1st method, wherein said compositions also comprises the reagent that stimulates cellular proliferation.

274. the 1st method, wherein said compositions also comprises the reagent that stimulates cellular proliferation, and wherein said propagation reagent is selected from the group of being made up of dexamethasone, isotretinoin, 17-, estradiol, diethylstilbestrol (diethylstibesterol), ciclosporin A, complete-trans retinoic acid (ATRA) and analog thereof or derivant.

275. the 1st method, wherein said compositions also comprises polymeric carrier.

276. the 1st method, wherein said compositions are the forms of gel, paste or spray.

277. the 1st method, wherein said compositions are the forms of mesh or film.

278. the 1st method is wherein sent described fibrous tissue from device and is formed agent, and described device is delivered to described fibrous tissue formation agent in the described diverticulum.

279. the 1st method is wherein sent described fibrous tissue from implant and formed agent, wherein said implant is or comprises microsphere.

280. the 1st method is wherein sent described fibrous tissue from implant and formed agent, wherein said implant is or comprises mesh.

281. the 1st method is wherein sent described fibrous tissue from implant and formed agent, wherein said implant is or comprises film.

282. the 1st method is wherein sent described fibrous tissue from device and formed agent, wherein said device is a conduit.

283. the 1st method is wherein sent described fibrous tissue from device and formed agent, wherein said device is a drug delivery tube.

284. the 1st method is wherein sent described fibrous tissue from device and formed agent, wherein said device is the radio-frequency (RF) ablation conduit.

285. the 1st method is wherein sent described fibrous tissue from device and formed agent, wherein said device is the temperature ablation catheter.

286. the 1st method is wherein sent described fibrous tissue from device and formed agent, wherein said device is the heat energy conduit.

287. the 1st method is wherein sent described fibrous tissue from device and formed agent, wherein said device is the cryoablation conduit.

288. the 1st method is wherein sent described fibrous tissue from device and formed agent, wherein said device is a laser catheter.

289. the 1st method is wherein sent described fibrous tissue from device and formed agent, wherein said device is the radioactivity delivery catheter.

290. the 1st method is wherein sent described fibrous tissue from device and formed agent, wherein said device is a balloon catheter.

291. the 1st method is wherein sent described fibrous tissue from device and formed agent, wherein said device is the ultrasonic energy delivery catheter.

292. the 1st method is wherein sent described fibrous tissue from device and formed agent, wherein said device is a rotation atherosclerotic plaque excision device.

293. the 1st method is wherein sent described fibrous tissue from device and formed agent, wherein said device is that rotation atherosclerotic plaque excision device is a rotating blade.

294. the 1st method is wherein sent described fibrous tissue from device and formed agent, wherein said device is the tissue abrasion device.

295. the 1st method is wherein sent described fibrous tissue from device and formed agent, wherein said device is a rotation atherosclerotic plaque excision device.

296. the 1st method is wherein sent described fibrous tissue from device and formed agent, wherein said device is a rotation atherosclerotic plaque excision conduit.

297. the 1st method is wherein sent described fibrous tissue from device and formed agent, wherein said device is endoscope's dissecting knife.

298. the 1st method is wherein introduced described fibrous tissue formation agent by sending from device, wherein said device also comprises coating, and described coating comprises described fibrous tissue formation agent.

299. the 1st method is wherein introduced described fibrous tissue formation agent by sending from device, wherein said device also comprises coating, and described coating is configured on the surface of described device.

300. the 1st method is wherein introduced described fibrous tissue formation agent by sending from device, wherein said device also comprises coating, and wherein said coating directly contacts described device.

301. the 1st method is wherein introduced described fibrous tissue formation agent by sending from device, wherein said device also comprises coating, and the described device of wherein said coating mediate contact.

302. the 1st method is wherein introduced described fibrous tissue formation agent by sending from device, wherein said device also comprises coating, and wherein said coating layer portion covers described device.

303. the 1st method is wherein introduced described fibrous tissue formation agent by sending from device, wherein said device also comprises coating, and wherein said coating covers described device fully.

304. the 1st method is wherein introduced described fibrous tissue formation agent by sending from device, wherein said fibrous tissue forms hole or the hole that agent is positioned at described device.

305. the 1st method is wherein introduced described fibrous tissue formation agent by sending from device, wherein said fibrous tissue forms passage, chamber or the divet that agent is positioned at described device.

306. the 1st method is wherein introduced described fibrous tissue formation agent by sending from device, wherein said device also comprises the echo material.

307. the 1st method is wherein introduced described fibrous tissue and formed agent by sending from device, wherein said device also comprises the echo material, and the wherein said echo material form that is coating.

308. the 1st method is wherein introduced described fibrous tissue formation agent by sending from device, wherein said device is aseptic.

309. the 1st method is wherein introduced described reagent by sending from device, wherein said fibrous tissue forms near the tissue of agent described device use is discharged into later described device.

310. the 1st method is wherein introduced described fibrous tissue formation agent by sending from device, wherein said fibrous tissue forms near the tissue of agent described device use is discharged into later described device, and wherein said tissue is a connective tissue.

311. the 1st method is wherein introduced described fibrous tissue formation agent by sending from device, wherein said fibrous tissue forms near the tissue of agent described device use is discharged into later described device, and wherein said tissue is a muscular tissue.

312. the 1st method is wherein introduced described fibrous tissue formation agent by sending from device, wherein said fibrous tissue forms near the tissue of agent described device use is discharged into later described device, and wherein said tissue is a nervous tissue.

313. the 1st method is wherein introduced described fibrous tissue formation agent by sending from device, wherein said fibrous tissue forms near the tissue of agent described device use is discharged into later described device, and wherein said tissue is an epithelial tissue.

314. the 1st method is wherein introduced described fibrous tissue and formed agent by sending from device, wherein said fibrous tissue forms agent and discharges from described device with valid density in described device uses cycle in about 1 year scope.

315. the 1st method is wherein introduced described fibrous tissue and formed agent by sending from device, wherein said fibrous tissue forms agent and discharges from described device with valid density in the cycle in about 1 month to 6 months scopes.

316. the 1st method wherein introduce described fibrous tissue formation agent by sending from device, and wherein said fibrous tissue discharged from described device with valid density in the formation cycle of agent in about 1-90 days scope.

317. the 1st method wherein introduce described fibrous tissue formation agent by sending from device, and wherein said fibrous tissue formation agent discharges from described device with valid density with constant rate of speed.

318. the 1st method wherein introduce described fibrous tissue formation agent by sending from device, and wherein said fibrous tissue formation agent discharges from described device with valid density with the speed that increases progressively.

319. the 1st method wherein introduce described fibrous tissue formation agent by sending from device, and wherein said reagent discharges from described device with valid density with the speed of successively decreasing.

320. it is that about 0.01 μ g is to about 10 μ g that the 1st method, wherein said fibrous tissue form agent.

321. it is that about 10 μ g are to about 10mg that the 1st method, wherein said fibrous tissue form agent.

322. it is that about 10mg is to about 250mg that the 1st method, wherein said fibrous tissue form agent.

323. it is that about 250mg is to about 1000mg that the 1st method, wherein said fibrous tissue form agent.

324. it is that about 1000mg is to about 2500mg that the 1st method, wherein said fibrous tissue form agent.

325. the 1st method wherein introduce described fibrous tissue formation agent by sending from implant, and the surface of wherein said implant comprises less than 0.01 μ g fibrous tissue formation agent/mm ²The implant surface that described reagent place uses.

326. the 1st method is wherein introduced described fibrous tissue formation agent by sending from implant, and the surface of wherein said implant comprises about 0.01 μ g to about 1 μ g fibrous tissue formation agent/mm ²The applied implant surface of described reagent.

327. the 1st method is wherein introduced described fibrous tissue formation agent by sending from implant, and the surface of wherein said implant comprises about 1 μ g to about 10 μ g fibrous tissue formation agent/mm ²The applied implant surface of described reagent.

328. the 1st method is wherein introduced described fibrous tissue formation agent by sending from implant, and the surface of wherein said implant comprises about 10 μ g to about 250 μ g fibrous tissue formation agent/mm ²The applied implant surface of described reagent.

329. the 1st method is wherein introduced described fibrous tissue formation agent by sending from implant, and the surface of wherein said implant comprises about 250 μ g to about 1000 μ g fibrous tissue formation agent/mm ²Described fibrous tissue forms the applied implant surface of agent.

330. the 1st method is wherein introduced described fibrous tissue formation agent by sending from implant, and the surface of wherein said implant comprises about 1000 μ g to about 2500 μ g fibrous tissue formation agent/mm ²The applied implant surface of described reagent.

331. the 1st method is wherein introduced described fibrous tissue formation agent by sending from implant, wherein said implant also comprises coating, and wherein said coating is a uniform coating.

332. the 1st method is wherein introduced described fibrous tissue formation agent by sending from implant, wherein said implant also comprises coating, and wherein said coating is inhomogeneous coating.

333. the 1st method is wherein introduced described fibrous tissue formation agent by sending from implant, wherein said implant also comprises coating, and wherein said coating is discontinuous coating.

334. the 1st method is wherein introduced described fibrous tissue formation agent by sending from implant, wherein said implant also comprises coating, and wherein said coating is to form the coating of pattern.

335. the 1st method is wherein introduced described fibrous tissue formation agent by sending from implant, wherein said implant also comprises coating, and wherein said coating has 100 μ m or littler thickness.

336. the 1st method is wherein introduced described fibrous tissue formation agent by sending from implant, wherein said implant also comprises coating, and wherein said coating has 10 μ m or littler thickness.

337. the 1st method is wherein introduced described fibrous tissue formation agent by sending from implant, wherein said implant also comprises coating, and wherein said coating adheres to the surface of described implant when described implant is used.

338. the 1st method is wherein introduced described fibrous tissue formation agent by sending from implant, wherein said implant also comprises coating, and wherein said coating is at room temperature stablized the cycle at least 1 year.

339. the 1st method, wherein introduce described fibrous tissue formation agent by sending from implant, wherein said implant also comprises coating, and wherein said fibrous tissue forms agent and is present in the described coating to the amount in about 1 weight % scope with about 0.0001 weight %.

340. the 1st method, wherein introduce described fibrous tissue formation agent by sending from implant, wherein said implant also comprises coating, and wherein said fibrous tissue forms agent and is present in the described coating to the amount in about 10 weight % scopes with about 1 weight %.

341. the 1st method, wherein introduce described fibrous tissue formation agent by sending from implant, wherein said implant also comprises coating, and wherein said fibrous tissue forms agent and is present in the described coating to the amount in about 25 weight % scopes with about 10 weight %.

342. the 1st method, wherein introduce described fibrous tissue formation agent by sending from implant, wherein said implant also comprises coating, and wherein said fibrous tissue forms agent and is present in the described coating to the amount in about 70 weight % scopes with about 25 weight %.

343. the 1st method is wherein introduced described fibrous tissue formation agent by sending from implant, wherein said implant also comprises coating, and wherein said coating comprises polymer.

344. the 1st method is wherein introduced described fibrous tissue formation agent by sending from implant, wherein said implant comprises first coating with first compositions and second coating with second compositions.

345. the 1st method, wherein introduce described fibrous tissue formation agent by sending from implant, wherein said implant comprises first coating with first compositions and second coating with second compositions, and wherein first compositions is different with second compositions.

346. the 1st method wherein forms described fibrous tissue agent or comprises described fibrous tissue and forms the compositions injection of agent or be sprayed to described diverticulum.

347. the 1st method wherein forms described fibrous tissue agent or comprises described fibrous tissue and forms the compositions injection of agent or be sprayed to tissue or center in the tissue of described diverticulum.

348. the 1st method, wherein said compositions also comprises filler.

349. the 1st method, wherein said compositions is a sealant.

350. the 1st method, wherein said compositions is a hemorrhage.

351. the 1st method, wherein said compositions also comprises filler, and wherein said filler comprises microsphere.

352. the 1st method, wherein said compositions also comprises filler, and wherein said filler comprises the gel of hydroxyapatite load.

353. the 1st method, wherein said compositions also comprises filler, and wherein said filler comprises micronized alloderm acellular substrate.

354. the 1st method, wherein said compositions also comprises filler, and wherein said filler comprises hyaluronic acid.

355. the 1st method, wherein said compositions also comprises filler, and wherein said filler comprises the microballon in the hydrogel.

356. the 1st method, wherein said compositions also comprises filler, and wherein said filler comprises extra large blue polymer.

357. the 1st method, wherein said compositions also comprises filler, and wherein said filler comprises silicon microsphere and biocompatible polymer.

358. the 1st method, described method also comprises the existence that manifests diverticulum.

359. the 358th method, the existence that wherein manifests diverticulum comprises splanchnoscopy.

360. the 358th method, the existence that wherein manifests diverticulum comprises the radiography imaging.

361. the 1st method, described method are washed described diverticulum with rinse solution before also being included in and introducing described fibrous tissue formation agent.

362. the 361st method, wherein said rinse solution comprise (a) anti-infective or (b) antiseptic or (c) anti-infective and antiseptic.

363. be used for inducing fibrotic method at its host's diverticulum of needs, described method comprises the diverticulum that compositions is incorporated into described host, described compositions comprises fibrous tissue and forms agent, and wherein said reagent is induced fibre modification in described diverticulum.

364. the 363rd method is wherein induced fibre modification prevention or treatment diverticulum disease in diverticulum.

365. the 364th method, wherein said diverticulum disease is a diverticulitis.

366. the 364th method, wherein said diverticulum disease is a diverticulosis.

367. the 364th method, wherein said diverticulum disease is a hemorrhage of diverticulum.

368. the 364th method, wherein said diverticulum disease are pharyngoesophagus (esophagus) diverticulums.

369. the 364th method, wherein said diverticulum disease is a Meckel diverticulum.

370. the 364th method, wherein said diverticulum disease is a diverticulosis of small intestine.

371. the 364th method, wherein said diverticulum disease are gastric diverticulum disease or urinary tract diverticulosis.

372. the 364th method, wherein said diverticulum disease is a diverticulosis of colon.

373. the 363rd method, wherein said fibrous tissue forms agent and promotes regeneration.

374. the 363rd method, wherein said fibrous tissue form agent and promote fibre modification and promote regeneration.

375. forming agent, the 363rd method, wherein said fibrous tissue promote blood vessel to take place.

376. the 363rd method, wherein said fibrous tissue form agent and promote the fibroblast migration.

377. the 363rd method, wherein said fibrous tissue forms agent and promotes fibroblast proliferation.

378. the 363rd method, wherein said fibrous tissue forms the deposition that agent promotes extracellular matrix (ECM).

379. the 363rd method, wherein said fibrous tissue forms agent and promotes tissue remodeling.

380. the 363rd method, it is diverticulum wall stimulus object that wherein said fibrous tissue forms agent.

Be or comprise silk 381. the 363rd method, wherein said fibrous tissue form agent.

Be or comprise silkworm silk 382. the 363rd method, wherein said fibrous tissue form agent.

Be or comprise spider silk 383. the 363rd method, wherein said fibrous tissue form agent.

Be or comprise the recombinant silk 384. the 363rd method, wherein said fibrous tissue form agent.

Be or comprise raw silk 385. the 363rd method, wherein said fibrous tissue form agent.

386. the 363rd method, wherein said fibrous tissue forms the silk that agent is or comprises hydrolysis.

387. the 363rd method, wherein said fibrous tissue formation agent is or comprises acid-treated.

388. the 363rd method, wherein said fibrous tissue forms the silk that agent is or comprises acidylate.

389. the 363rd method, it is the form of twisted wire that wherein said fibrous tissue forms agent.

390. the 363rd method, wherein said fibrous tissue form the form that agent is bunch.

Be or comprise mineral grain 391. the 363rd method, wherein said fibrous tissue form agent.

Be or comprise chitosan 392. the 363rd method, wherein said fibrous tissue form agent.

Be or comprise polylysine 393. the 363rd method, wherein said fibrous tissue form agent.

Be or comprise fibronectin 394. the 363rd method, wherein said fibrous tissue form agent.

Be or comprise bleomycin 395. the 363rd method, wherein said fibrous tissue form agent.

Be or comprise CTGF 396. the 363rd method, wherein said fibrous tissue form agent.

Be or comprise fine hair 397. the 363rd method, wherein said fibrous tissue form agent.

Be or comprise animal down 398. the 363rd method, wherein said fibrous tissue form agent.

Be or comprise wood shavings 399. the 363rd method, wherein said fibrous tissue form agent.

Be or comprise synthetic fine hair 400. the 363rd method, wherein said fibrous tissue form agent.

401. the 363rd method, it is the form of line that wherein said fibrous tissue forms agent, or contacts with line.

402. the 401st method, wherein said line is biodegradable.

403. the 402nd method, wherein said biodegradable line comprise the material that is selected from the group of being made up of polyester, poly-anhydride, poly-(anhydride ester), poly-(ester-acid amide), poly-(ester-urea), poe, poly phosphate, poly-phosphazine, polybutylcyanoacrylate, collagen, chitosan, hyaluronic acid, chromic catgut, alginate, starch, cellulose and cellulose esters.

404. the 401st method, wherein said line are not biodegradable.

405. the 404th method, wherein said not biodegradable line comprise the material that is selected from the group of being made up of polyester, polyurethane, siloxanes, polyethylene, polypropylene, polystyrene, polyacrylate, polymethacrylates and silk.

406. the 401st method,, wherein said line scribbles polymer.

407. the 401st method, wherein said line scribble the medicament of inducing fibrosis reaction in the host.

408. the 363rd method, it is the form of microgranule that wherein said fibrous tissue forms agent.

409. the 408th method, wherein said microgranule are biodegradable microgranules.

410. the 409th method, wherein said biodegradable microgranule comprise the material that is selected from the group of being made up of polyester, poly-anhydride, poly-(anhydride ester), poly-(ester-acid amide), poly-(ester-urea), poe, poly phosphate, poly-phosphazine, polybutylcyanoacrylate, collagen, chitosan, hyaluronic acid, chromic catgut, alginate, starch, cellulose and cellulose esters.

411. the 408th method, wherein said microgranule are not biodegradable microgranules.

412. the 411st method, wherein said not biodegradable microgranule comprise the material that is selected from the group of being made up of polyester, polyurethane, siloxanes, polyethylene, polypropylene, polystyrene, polyacrylate, polymethacrylates and silk.

413. the 408th method, wherein said microgranule are the particulate form that is selected from the member of the group of being made up of silk, Talcum, starch, glass, silicate, Silicon stone, calcium phosphate, calcium sulfate, calcium carbonate, hydroxyapatite, synthetic mineral, polymethyl methacrylate, silver nitrate, pottery and other inorganic particle.

414. the 408th method, wherein said microgranule scribbles polymer.

415. the 408th method, wherein said microgranule scribble the medicament of inducing fibrosis reaction in the host.

416. the 408th method, wherein said microgranule scribble the member who is selected from the group of being made up of silk, Talcum, starch, glass, silicate, Silicon stone, calcium phosphate, calcium sulfate, calcium carbonate, hydroxyapatite, synthetic mineral, polymethyl methacrylate, silver nitrate, pottery and other inorganic particle.

417. the 363rd method, wherein said compositions comprises somatomedin.

418. the 417th method, wherein said somatomedin is selected from transforming growth factor, platelet derived growth factor and fibroblast growth factor.

419. the 363rd method, wherein said compositions also comprises polymer.

420. the 363rd method, wherein said compositions also comprises polymer, and described polymer is perhaps to comprise copolymer.

421. the 363rd method, wherein said compositions also comprises polymer, and described polymer is perhaps to comprise block copolymer.

422. the 363rd method, wherein said compositions also comprises polymer, and described polymer is perhaps to comprise random copolymer.

423. the 363rd method, wherein said compositions also comprises polymer, and described polymer is perhaps to comprise biodegradable polymer.

424. the 363rd method, wherein said compositions also comprises polymer, and described polymer is perhaps to comprise not biodegradable polymer.

425. the 363rd method, wherein said compositions also comprises polymer, and described polymer is perhaps to comprise hydrophilic polymer.

426. the 363rd method, wherein said compositions also comprises polymer, and described polymer is perhaps to comprise hydrophobic polymer.

427. the 363rd method, wherein said compositions also comprises polymer, and described polymer is perhaps to comprise the polymer of possess hydrophilic property domain.

428. the 363rd method, wherein said compositions also comprises polymer, and described polymer is, perhaps comprises, and has the polymer in hydrophobic structure territory.

429. the 363rd method, wherein said compositions also comprises polymer, and described polymer is perhaps to comprise non-conductive polymer.

430. the 363rd method, wherein said compositions also comprises polymer, and described polymer is perhaps to comprise elastomer.

431. the 363rd method, wherein said compositions also comprises polymer, and described polymer is perhaps to comprise hydrogel.

432. the 363rd method, wherein said compositions also comprises polymer, and described polymer is perhaps to comprise siloxane polymer.

433. the 363rd method, wherein said compositions also comprises polymer, and described polymer is perhaps to comprise hydrocarbon polymer.

434. the 363rd method, wherein said compositions also comprises polymer, and described polymer is perhaps to comprise the styrene derived polymers.

435. the 363rd method, wherein said compositions also comprises polymer, and described polymer is perhaps to comprise the butadiene derived polymer.

436. the 363rd method, wherein said compositions also comprises polymer, and described polymer is perhaps to comprise macromonomer.

437. the 363rd method, wherein said compositions also comprises polymer, and described polymer is perhaps to comprise poly-(ethylene glycol).

438. the 363rd method, wherein said compositions also comprises polymer, and described polymer is perhaps to comprise the collagen or derivatives thereof.

439. the 363rd method, wherein said compositions also comprises polymer, and described polymer is perhaps to comprise methylated collagen.

440. the 363rd method, wherein said compositions also comprises polymer composition, and wherein said polymer composition comprises collagen or derivatives thereof and fibrinogen.

441. the 363rd method, wherein said compositions also comprises polymer composition, and wherein said polymer composition comprises collagen or derivatives thereof and thrombin.

442. the 363rd method, wherein said compositions also comprises polymer composition, and wherein said polymer composition comprises (a) collagen or derivatives thereof; (b) fibrinogen; (c) thrombin.

443. the 363rd method, wherein said compositions also comprises polymer composition, and wherein said polymer composition comprises methylated collagen and poly-(ethylene glycol) or derivatives thereof.

444. the 363rd method, wherein said compositions also comprises hemorrhage, and described hemorrhage comprises collagen polymer.

445. the 363rd method, wherein said compositions also comprises hemorrhage, and described hemorrhage comprises collagen polymer, and wherein said hemorrhage is CT3.

446. the 363rd method, wherein said compositions also comprises hemorrhage, and described hemorrhage comprises collagen polymer, and wherein said hemorrhage is COSTASIS.

447. the 363rd method, wherein said compositions also comprises hemorrhage, and described hemorrhage comprises poly-(ethylene glycol).

448. the 363rd method, wherein said compositions also comprises hemorrhage, and wherein said hemorrhage is COSEAL, TISSEAL or FLOSEAL.

449. the 363rd method, wherein said compositions also comprises hemorrhage, and described hemorrhage comprises fibrin.

450. the 363rd method, wherein said compositions also comprises polymer, and described polymer is perhaps to comprise amorphous polymer.

451. the 363rd method, wherein said compositions also comprises polymer, and described polymer is perhaps to comprise cyanoacrylate.

452. the 451st method, wherein said cyanoacrylate are selected from methyl 2-cyanoacrylate, cyanacrylate, Tisuacryl, octyl 2-cyanoacrylate and alpha-cyanoacrylate methoxyl group propyl ester.

453. the 363rd method, wherein said compositions comprises polymer, and described polymer is, or comprises, poly-(alkyl cyanoacrylate).

454. the 453rd method, wherein said poly-(alkyl cyanoacrylate) are selected from poly-(MCA), poly-(ethyl cyanoacrylate), poly-(butyl cyanoacrylate), poly-(isobutyl cyanoacrylate), poly-(hexyl cyanoacrylate) and poly-(octyl cyanoacrylate).

455. the 363rd method, wherein said compositions comprises polymer, and described polymer is perhaps to comprise poly-(carboxyalkyl cyanoacrylate).

456. the 455th method, wherein said poly-(carboxyalkyl cyanoacrylate) is poly-(methoxy-propyl cyanoacrylate).

457. the 419th method, wherein said polymer is crosslinked.

458. the 419th method, wherein said polymer and mammalian tissues reaction.

459. the 419th method, wherein said polymer are naturally occurring polymer.

460. the 419th method, wherein said polymer is a protein.

461. the 419th method, wherein said polymer is a saccharide.

462. the 419th method, wherein said polymer are crosslinked with biodegradable.

463. the 363rd method, wherein said compositions comprises fibrinogen.

464. the 363rd method, wherein said compositions comprises thrombin.

465. the 363rd method, wherein said compositions comprises calcium salt.

466. the 363rd method, wherein said compositions comprises antifibrinolytic agent.

467. the 363rd method, wherein said compositions comprises the fibrinogen analog.

468. the 363rd method, wherein said compositions comprises albumin.

469. the 363rd method, wherein said compositions comprises plasminogen.

470. the 363rd method, wherein said compositions comprise Feng's von willebrand's factor (vonWillebrands factor).

471. the 363rd method, wherein said compositions comprises Feng's von willebrand's factor.

472. the 363rd method, wherein said compositions comprises hypoallergenic collagen.

473. the 363rd method, wherein said compositions comprise non-end peptide collagen.

474. the 363rd method, wherein said compositions comprises crosslinked collagen.

475. the 363rd method, wherein said compositions comprises aprotinin.

476. the 363rd method, wherein said compositions comprise epsilon-amino-just-caproic acid.

477. the 363rd method, wherein said compositions comprises gelatin.

478. the 363rd method, wherein said compositions comprises protein conjugate.

479. the 363rd method, wherein said compositions comprises the gelatin conjugate.

480. the 363rd method, wherein said compositions comprises hyaluronic acid.

481. the 363rd method, wherein said compositions comprises derivatives of hyaluronic acids.

482. the 363rd method, wherein said compositions comprises synthetic polymer.

483. the 419th method, wherein said polymer forms by comprising the synthetic reactant that contains the chemical compound of isocyanates.

484. the 363rd method, wherein said compositions comprise the synthetic chemical compound that contains isocyanates.

485. the 419th method, wherein said polymer forms by comprising the synthetic reactant that contains the chemical compound of mercaptan.

486. the 363rd method, wherein said compositions comprise the synthetic chemical compound that contains mercaptan.

487. the 419th method, wherein said polymer forms by comprising the synthetic reactant that contains the chemical compound of two mercaptos at least.

488. the 363rd method, wherein said compositions comprise the synthetic chemical compound that contains at least two mercaptos.

489. the 419th method, wherein said polymer forms by comprising the synthetic reactant that contains the chemical compound of three mercaptos at least.

490. the 363rd method, wherein said compositions comprise the synthetic chemical compound that contains at least three mercaptos.

491. the 419th method, wherein said polymer forms by comprising the synthetic reactant that contains the chemical compound of four mercaptos at least.

492. the 363rd method, wherein said compositions comprise the synthetic chemical compound that contains at least four mercaptos.

493. the 419th method, wherein said polymer forms by comprising the synthetic reactant that contains amino chemical compound.

494. the 363rd method, wherein said compositions comprise the synthetic amino chemical compound that contains.

495. the 419th method, wherein said polymer forms by comprising the synthetic reactant that contains the chemical compound of two amino at least.

496. the 363rd method, wherein said compositions comprise the synthetic chemical compound that contains at least two amino.

497. the 419th method, wherein said polymer forms by comprising the synthetic reactant that contains the chemical compound of three amino at least.

498. the 363rd method, wherein said compositions comprise the synthetic chemical compound that contains at least three amino.

499. the 419th method, wherein said polymer forms by comprising the synthetic reactant that contains the chemical compound of four amino at least.

500. the 363rd method, wherein said compositions comprise the synthetic chemical compound that contains at least four amino.

501. the 419th method, wherein said polymer forms by comprising the synthetic reactant that contains the chemical compound of carbonyl-oxygen-succinimido.

502. the 363rd method, wherein said compositions comprise the synthetic chemical compound that contains carbonyl-oxygen-succinimido.

503. the 419th method, wherein said polymer forms by comprising the synthetic reactant that comprises the chemical compound of two carbonyl-oxygen-succinimido at least.

504. the 363rd method, wherein said compositions comprise the synthetic chemical compound that comprises at least two carbonyl-oxygen-succinimido.

505. the 419th method, wherein said polymer forms by comprising the synthetic reactant that comprises the chemical compound of three carbonyl-oxygen-succinimido at least.

506. the 363rd method, wherein said compositions comprise the synthetic chemical compound that comprises at least three carbonyl-oxygen-succinimido.

507. the 419th method, wherein said polymer forms by comprising the synthetic reactant that comprises the chemical compound of four carbonyl-oxygen-succinimido at least.

508. the 363rd method, wherein said compositions comprise the synthetic chemical compound that comprises at least four carbonyl-oxygen-succinimido.

509. the 419th method, wherein said polymer forms by comprising the synthetic reactant that contains the chemical compound of polyalkylene oxide.

510. the 363rd method, wherein said compositions comprise the synthetic chemical compound that contains polyalkylene oxide.

511. the 419th method, wherein said polymer forms by comprising the synthetic reactant that contains the chemical compound of polyalkylene oxide and biodegradable polyester block.

512. the 363rd method, wherein said compositions comprise the synthetic chemical compound that contains polyalkylene oxide and biodegradable polyester block.

513. the 419th method, wherein said polymer forms by comprising synthetic reactant with chemical compound that contains polyalkylene oxide of reactive amino.

514. the 363rd method, wherein said compositions comprise the synthetic chemical compound that contains polyalkylene oxide with reactive amino.

515. the 419th method, wherein said polymer forms by comprising synthetic reactant with chemical compound that contains polyalkylene oxide of reactive mercapto.

516. the 363rd method, wherein said compositions comprise the synthetic chemical compound that contains polyalkylene oxide with reactive mercapto.

517. the 419th method, wherein said polymer forms by comprising synthetic reactant with chemical compound that contains polyalkylene oxide of reactive carbonyl-oxygen-succinimido.

518. the 363rd method, wherein said compositions comprise the synthetic chemical compound that contains polyalkylene oxide with reactive carbonyl-oxygen-succinimido.

519. the 419th method, wherein said polymer forms by comprising the synthetic reactant that contains the chemical compound of biodegradable polyester block.

520. the 363rd method, wherein said compositions comprise the synthetic chemical compound that contains the biodegradable polyester block.

521. the 419th method, wherein said polymer is formed by the reactant that comprises the synthetic polymer that is formed by lactic acid or lactide wholly or in part.

522. the 363rd method, wherein said compositions comprise the synthetic polymer that is formed by lactic acid or lactide wholly or in part.

523. the 419th method, wherein said polymer is formed by the reactant that comprises the synthetic polymer that is formed by glycolic or Acetic acid, hydroxy-, bimol. cyclic ester wholly or in part.

524. the 363rd method, wherein said compositions comprise the synthetic polymer that is formed by glycolic or Acetic acid, hydroxy-, bimol. cyclic ester wholly or in part.

525. the 419th method, wherein said polymer is formed by the reactant that comprises polylysine.

526. the 363rd method, wherein said compositions comprises polylysine.

527. the 419th method, wherein said polymer forms by comprising the reactant of (a) protein with the chemical compound that (b) comprises the polyalkylene oxide part.

528. the 363rd method, wherein said compositions comprise (a) protein and (b) comprise the chemical compound of polyalkylene oxide part.

529. the 419th method, wherein said polymer by comprise (a) protein and (b) reactant of polylysine form.

530. the 363rd method, wherein said compositions comprise (a) protein and (b) polylysine.

531. the 419th method, wherein said polymer forms with the reactant that (b) has the chemical compound of four mercaptos by comprising (a) protein at least.

532. the 363rd method, wherein said compositions comprise (a) protein and (b) have the chemical compound of at least four mercaptos.

533. the 419th method, wherein said polymer forms with the reactant that (b) has the chemical compound of four amino by comprising (a) protein at least.

534. the 363rd method, wherein said compositions comprise (a) protein and (b) have the chemical compound of at least four amino.

535. the 419th method, wherein said polymer forms with the reactant that (b) has the chemical compound of four carbonyl-oxygen-butanimide group by comprising (a) protein at least.

536. the 363rd method, wherein said compositions comprise (a) protein and (b) have the chemical compound of at least four carbonyl-oxygen-butanimide group.

537. the 419th method, wherein said polymer forms with the reactant that (b) has the chemical compound of the biodegradable region that is formed by the reactant that is selected from lactic acid, lactide, glycolic, Acetic acid, hydroxy-, bimol. cyclic ester and 6-caprolactone by comprising (a) protein.

538. the chemical compound that the 363rd method, wherein said compositions comprise (a) protein and (b) have the biodegradable region that is formed by the reactant that is selected from lactic acid, lactide, glycolic, Acetic acid, hydroxy-, bimol. cyclic ester and 6-caprolactone.

539. the 419th method, wherein said polymer forms by comprising the reactant of (a) collagen with the chemical compound that (b) comprises the polyalkylene oxide part.

540. the 363rd method, wherein said compositions comprise (a) collagen and (b) comprise the chemical compound of polyalkylene oxide part.

541. the 419th method, wherein said polymer by comprise (a) collagen and (b) reactant of polylysine form.

542. the 363rd method, wherein said compositions comprise (a) collagen and (b) polylysine.

543. the 419th method, wherein said polymer forms with the reactant that (b) has the chemical compound of four mercaptos by comprising (a) collagen at least.

544. the 363rd method, wherein said compositions comprise (a) collagen and (b) have the chemical compound of at least four mercaptos.

545. the 419th method, wherein said polymer forms with the reactant that (b) has the chemical compound of four amino by comprising (a) collagen at least.

546. the 363rd method, wherein said compositions comprise (a) collagen and (b) have the chemical compound of at least four amino.

547. the 419th method, wherein said polymer forms with the reactant that (b) has the chemical compound of four carbonyl-oxygen-butanimide group by comprising (a) collagen at least.

548. the 363rd method, wherein said compositions comprise (a) collagen and (b) have the chemical compound of at least four carbonyl-oxygen-butanimide group.

549. the 419th method, wherein said polymer forms with the reactant that (b) has the chemical compound of the biodegradable region that is formed by the reactant that is selected from lactic acid, lactide, glycolic, Acetic acid, hydroxy-, bimol. cyclic ester and 6-caprolactone by comprising (a) collagen.

550. the chemical compound that the 363rd method, wherein said compositions comprise (a) collagen and (b) have the biodegradable region that is formed by the reactant that is selected from lactic acid, lactide, glycolic, Acetic acid, hydroxy-, bimol. cyclic ester and 6-caprolactone.

551. the 419th method, wherein said polymer forms by comprising the reactant of (a) methylated collagen with the chemical compound that (b) comprises the polyalkylene oxide part.

552. the 363rd method, wherein said compositions comprise (a) methylated collagen and (b) comprise the chemical compound of polyalkylene oxide part.

553. the 419th method, wherein said polymer by comprise (a) methylated collagen and (b) reactant of polylysine form.

554. the 363rd method, wherein said compositions comprise (a) methylated collagen and (b) polylysine.

555. the 419th method, wherein said polymer forms with the reactant that (b) has the chemical compound of four mercaptos by comprising (a) methylated collagen at least.

556. the 363rd method, wherein said compositions comprise (a) methylated collagen and (b) have the chemical compound of at least four mercaptos.

557. the 419th method, wherein said polymer forms with the reactant that (b) has the chemical compound of four amino by comprising (a) methylated collagen at least.

558. the 363rd method, wherein said compositions comprise (a) methylated collagen and (b) have the chemical compound of at least four amino.

559. the 419th method, wherein said polymer forms with the reactant that (b) has the chemical compound of four carbonyl-oxygen-butanimide group by comprising (a) methylated collagen at least.

560. the 363rd method, wherein said compositions comprise (a) methylated collagen and (b) have the chemical compound of at least four carbonyl-oxygen-butanimide group.

561. the 419th method, wherein said polymer forms with the reactant that (b) has the chemical compound of the biodegradable region that is formed by the reactant that is selected from lactic acid, lactide, glycolic, Acetic acid, hydroxy-, bimol. cyclic ester and 6-caprolactone by comprising (a) methylated collagen.

562. the chemical compound that the 363rd method, wherein said compositions comprise (a) methylated collagen and (b) have the biodegradable region that is formed by the reactant that is selected from lactic acid, lactide, glycolic, Acetic acid, hydroxy-, bimol. cyclic ester and 6-caprolactone.

563. the 419th method, wherein said polymer forms by comprising hyaluronic reactant.

564. the 363rd method, wherein said compositions comprises hyaluronic acid.

565. the 419th method, wherein said polymer is formed by the reactant that comprises derivatives of hyaluronic acids.

566. the 363rd method, wherein said compositions comprises derivatives of hyaluronic acids.

567. the 419th method, wherein said polymer is formed by the reactant that comprises poly-(ethylene glycol) ether four-sulfydryl of the tetramethylolmethane of number-average molecular weight between 3,000 and 30,000.

568. the 363rd method, wherein said compositions comprise poly-(ethylene glycol) ether four-sulfydryl of the tetramethylolmethane of number-average molecular weight between 3,000 and 30,000.

569. the 419th method, wherein said polymer is formed by the reactant that comprises poly-(ethylene glycol) ether four of the tetramethylolmethane of number-average molecular weight between 3,000 and 30,000-amino.

570. the 363rd method, wherein said compositions comprise poly-(ethylene glycol) ether four-amino of the tetramethylolmethane of number-average molecular weight between 3,000 and 30,000.

571. the 419th method, wherein said polymer is by comprising (a) synthetic number-average molecular weight 3,000 and 30, between 000 and comprise the chemical compound of polyalkylene oxide zone and a plurality of nucleophilic groups and (b) synthetic number-average molecular weight 3, between 000 and 30,000 and comprise the reactant formation of the chemical compound of polyalkylene oxide zone and a plurality of electrophilic groups.

572. the 363rd method, wherein said compositions comprises (a) synthetic number-average molecular weight 3,000 and 30, between 000 and comprise the chemical compound of polyalkylene oxide zone and a plurality of nucleophilic groups, (b) synthetic number-average molecular weight is 3, between 000 and 30,000 and comprise the chemical compound of polyalkylene oxide zone and a plurality of electrophilic groups.

573. the 363rd method, wherein said compositions comprises coloring agent.

574. the 363rd method, wherein said compositions is aseptic.

575. the 363rd method, wherein said compositions also comprises second forms of pharmacologically active agents.

576. the 363rd method, wherein said compositions also comprises anti-inflammatory agent.

577. the 363rd method, wherein said compositions also comprises infection inhibitor.

578. the 363rd method, wherein said compositions also comprises anthracycline.

579. the 363rd method, wherein said compositions also comprises doxorubicin.

580. the 363rd method, wherein said compositions also comprises mitoxantrone.

581. the 363rd method, wherein said compositions also comprises the fluorine pyrimidine.

582. the 363rd method, wherein said compositions also comprise 5-fluorouracil (5-FU).

583. the 363rd method, wherein said compositions also comprises antifol.

584. the 363rd method, wherein said compositions also comprises methotrexate.

585. the 363rd method, wherein said compositions also comprises podophyllotoxin.

586. the 363rd method, wherein said compositions also comprises etoposide.

587. the 363rd method, wherein said compositions also comprises camptothecine.

588. the 363rd method, wherein said compositions also comprises hydroxyurea.

589. the 363rd method, wherein said compositions also comprises platinum complex.

590. the 363rd method, wherein said compositions also comprises cisplatin.

591. the 363rd method, wherein said compositions also comprises anti-infective.

592. the 363rd method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is an antibiotic.

593. the 363rd method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a doxycycline.

594. the 363rd method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a metronidazole.

595. the 363rd method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a trimethoprim-sulfamethoxazole.

596. the 363rd method, wherein said compositions also comprises anti-infective, wherein said anti-infective be the 4th generation penicillin.

597. the 363rd method, wherein said compositions also comprises anti-infective, wherein said anti-infective be selected from urea groups penicillin and penicillin carboxy the 4th generation penicillin, or its analog or derivant.

598. the 363rd method, wherein said compositions also comprises anti-infective, wherein said anti-infective be selected from mezlocillin, piperacillin, Carbenicillin and ticarcillin the 4th generation penicillin.

599. the 363rd method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a first generation cephalosporin.

600. the 363rd method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is the first generation cephalosporin that is selected from cefazolin sodium, cefalexin, cefazolin sodium, cefaloject and cefalotin.

601. the 363rd method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a penicillin carboxy.

602. according to the 239th method, wherein said penicillin carboxy is a ticarcillin.

603. the 363rd method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a second generation cephalosporin.

604. the 363rd method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is the second generation cephalosporin that is selected from cefuroxime, cefotetan and cefoxitin.

605. the 363rd method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a third generation cephalosporin.

606. the 363rd method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is the third generation cephalosporin that is selected from ceftiofur sodium, cefdinir, cefoperazone, ceftazidime, ceftriaxone and cefotaxime.

607. the 363rd method, wherein said compositions also comprises anti-infective, wherein said anti-infective be the 4th generation cephalosporin.

608. the 602nd method, wherein said the 4th generation cephalosporin be cefepime.

609. the 363rd method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a monobactam.

610. the 609th method, wherein said monobactam is an aztreonam.

611. the 363rd method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a carbapenem.

612. the 363rd method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is the carbapenem that is selected from imipenum, Ai Tapeinan and meropenem.

613. the 363rd method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is an aminoglycoside.

614. the 363rd method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is the aminoglycoside that is selected from streptomycin, gentamycin, tobramycin and amikacin.

615. the 363rd method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is the MSL group membership who is selected from macrolide, long-acting macrolide, lincosamide and streptogramin.

616. the 363rd method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is the MSL group membership who is selected from erythromycin, azithromycin, clindamycin, quinoline slave Pu Ding-dalfopristin, clarithromycin and kanamycin sulfate.

617. the 363rd method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a quinolinones.

618. the 363rd method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is the quinolinones that is selected from ciprofloxacin, ofloxacin, Gatifloxacin, Moxifloxacin, levofloxacin and trovafloxacin.

619. the 363rd method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is the DNA synthetic inhibitor.

620. the 619th method, wherein said DNA synthetic inhibitor is a metronidazole.

621. the 363rd method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a sulfonamide.

622. the 621st method, wherein said sulfonamide is a trimethoprim.

623. the 363rd method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is selected from cefixime, spectinomycin, tetracycline, nitrofurantoin, polymyxin B and polygynax.

624. the 363rd method, wherein said compositions also comprises developing agent.

625. the 363rd method, wherein said compositions also comprises developing agent, and described developing agent is radio-opaque material, and wherein said radio-opaque material comprises metal, halogenated compound or contains the chemical compound of barium.

626. the 363rd method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises barium, tantalum or technetium.

627. the 363rd method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises MRI response material or echo material.

628. the 363rd method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises gadolinium chelate compound.

629. the 363rd method, wherein said compositions also comprises a kind of developing agent, and described developing agent is, or comprises ferrum, magnesium, manganese, copper or chromium.

630. the 363rd method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises iron oxide compound.

631. the 363rd method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises dyestuff, pigment or coloring agent.

632. forming agent, the 363rd method, wherein said fibrous tissue in the administration cycle to about 90 days scopes constantly, discharge from the compositions that comprises fibrous tissue and form agent with valid density by diffusion.

633. forming agent corrosion by described compositions in the administration cycle to about 90 days scopes constantly, the 363rd method, wherein said fibrous tissue discharge from the compositions that comprises described fibrous tissue and form agent with valid density.

634. the 363rd method, wherein said compositions also comprises inflammatory cytokine.

635. the 363rd method, wherein said compositions also comprises the reagent that stimulates cellular proliferation.

636. the 363rd method, wherein said compositions also comprises the reagent that stimulates cellular proliferation, and wherein said propagation reagent is selected from the group of being made up of dexamethasone, isotretinoin, 17-, estradiol, diethylstilbestrol, ciclosporin A, complete-trans retinoic acid (ATRA) and analog thereof and derivant.

637. the 363rd method, wherein said compositions also comprises polymeric carrier.

638. the 363rd method, wherein said compositions are the forms of gel, paste or spray.

639. the 363rd method, wherein said compositions are the forms of mesh or film.

640. the 363rd method is wherein sent described fibrous tissue from device and is formed agent, and described device is delivered to described fibrous tissue formation agent in the described diverticulum.

641. the 363rd method is wherein sent described fibrous tissue from implant and formed agent, wherein said implant is or comprises microsphere.

642. the 363rd method is wherein sent described fibrous tissue from implant and formed agent, wherein said implant is or comprises mesh.

643. the 363rd method is wherein sent described fibrous tissue from implant and formed agent, wherein said implant is or comprises film.

644. the 363rd method is wherein sent described fibrous tissue from device and formed agent, wherein said device is a conduit.

645. the 363rd method is wherein sent described fibrous tissue from device and formed agent, wherein said device is a drug delivery tube.

646. the 363rd method is wherein sent described fibrous tissue from device and formed agent, wherein said device is the radio-frequency (RF) ablation conduit.

647. the 363rd method is wherein sent described fibrous tissue from device and formed agent, wherein said device is the temperature ablation catheter.

648. the 363rd method is wherein sent described fibrous tissue from device and formed agent, wherein said device is the heat energy conduit.

649. the 363rd method is wherein sent described fibrous tissue from device and formed agent, wherein said device is the cryoablation conduit.

650. the 363rd method is wherein sent described fibrous tissue from device and formed agent, wherein said device is a laser catheter.

651. the 363rd method is wherein sent described fibrous tissue from device and formed agent, wherein said device is the radioactivity delivery catheter.

652. the 363rd method is wherein sent described fibrous tissue from device and formed agent, wherein said device is a balloon catheter.

653. the 363rd method is wherein sent described fibrous tissue from device and formed agent, wherein said device is the ultrasonic energy delivery catheter.

654. the 363rd method is wherein sent described fibrous tissue from device and formed agent, wherein said device is a rotation atherosclerotic plaque excision device.

655. the 363rd method is wherein sent described fibrous tissue from device and formed agent, wherein said device is that rotation atherosclerotic plaque excision device is a rotating blade.

656. the 363rd method is wherein sent described fibrous tissue from device and formed agent, wherein said device is the tissue abrasion device.

657. the 363rd method is wherein sent described fibrous tissue from device and formed agent, wherein said device is an atherosclerotic plaque excision conduit.

658. the 363rd method is wherein sent described fibrous tissue from device and formed agent, wherein said device is an atherosclerotic plaque excision conduit.

659. the 363rd method is wherein sent described fibrous tissue from device and formed agent, wherein said device is endoscope's dissecting knife.

660. the 363rd method is wherein introduced described fibrous tissue formation agent by sending from device, wherein said device also comprises coating, and described coating comprises described fibrous tissue formation agent.

661. the 363rd method is wherein introduced described fibrous tissue formation agent by sending from device, wherein said device also comprises coating, and described coating is configured on the surface of described device.

662. the 363rd method is wherein introduced described fibrous tissue formation agent by sending from device, wherein said device also comprises coating, and wherein said coating directly contacts described device.

663. the 363rd method is wherein introduced described fibrous tissue formation agent by sending from device, wherein said device also comprises coating, and the described device of wherein said coating mediate contact.

664. the 363rd method is wherein introduced described fibrous tissue formation agent by sending from device, wherein said device also comprises coating, and wherein said coating layer portion covers described device.

665. the 363rd method is wherein introduced described fibrous tissue formation agent by sending from device, wherein said device also comprises coating, and wherein said coating covers described device fully.

666. the 363rd method is wherein introduced described fibrous tissue formation agent by sending from device, wherein said fibrous tissue forms hole or the hole that agent is positioned at described device.

667. the 363rd method is wherein introduced described fibrous tissue formation agent by sending from device, wherein said fibrous tissue forms passage, chamber or the divet that agent is positioned at described device.

668. the 363rd method is wherein introduced described fibrous tissue formation agent by sending from device, wherein said device also comprises the echo material.

669. the 363rd method is wherein introduced described fibrous tissue and formed agent by sending from device, wherein said device also comprises the echo material, and the wherein said echo material form that is coating.

670. the 363rd method is wherein introduced described reagent by sending from device, wherein said device is aseptic.

671. the 363rd method is wherein introduced described reagent by sending from device, wherein said fibrous tissue forms near the tissue of agent described device use is discharged into later described device.

672. the 363rd method is wherein introduced described reagent by sending from device, wherein said fibrous tissue forms near the tissue of agent described device use is discharged into later described device, and wherein said tissue is a connective tissue.

673. the 363rd method is wherein introduced described reagent by sending from device, wherein said fibrous tissue forms near the tissue of agent described device use is discharged into later described device, and wherein said tissue is a muscular tissue.

674. the 363rd method is wherein introduced described reagent by sending from device, wherein said fibrous tissue forms near the tissue of agent described device use is discharged into later described device, and wherein said tissue is a nervous tissue.

675. the 363rd method is wherein introduced described reagent by sending from device, wherein said fibrous tissue forms near the tissue of agent described device use is discharged into later described device, and wherein said tissue is an epithelial tissue.

676. the 363rd method is wherein introduced described reagent by sending from device, wherein said fibrous tissue forms agent and discharges from described device with valid density in about 1 year cycle in described device use.

677. the 363rd method is wherein introduced described reagent by sending from device, wherein said fibrous tissue forms agent and discharges from described device with valid density in the cycle in about 1 month to 6 months scopes.

678. the 363rd method is wherein introduced described reagent by sending from device, and wherein said fibrous tissue discharged from described device with valid density in the formation cycle of agent in about 1-90 days scope.

679. the 363rd method is wherein introduced described reagent by sending from device, and wherein said fibrous tissue formation agent discharges from described device with valid density with constant rate of speed.

680. the 363rd method wherein introduce described fibrous tissue formation agent by sending from device, and wherein said fibrous tissue formation agent discharges from described device with valid density with the speed that increases progressively.

681. the 363rd method wherein introduce described fibrous tissue formation agent by sending from device, and wherein said reagent discharges from described device with valid density with the speed of successively decreasing.

682. the 363rd method, wherein said compositions comprise about 0.01 μ g to about 10 μ g fibrous tissue formation agent.

683. the 363rd method, wherein said compositions comprise about 10 μ g to about 10mg fibrous tissue formation agent.

684. the 363rd method, wherein said compositions comprise about 10mg to about 250mg fibrous tissue formation agent.

685. the 363rd method, wherein said compositions comprise about 250mg to about 1000mg fibrous tissue formation agent.

686. the 363rd method, wherein said compositions comprise about 1000mg to about 2500mg fibrous tissue formation agent.

687. the 363rd method wherein introduce described fibrous tissue formation agent by sending from implant, and the surface of wherein said implant comprises less than 0.01 μ g fibrous tissue formation agent/mm ²The applied implant surface of described reagent.

688. the 363rd method is wherein introduced described fibrous tissue formation agent by sending from implant, and the surface of wherein said implant comprises about 0.01 μ g to about 1 μ g fibrous tissue formation agent/mm ²The applied implant surface of described reagent.

689. the 363rd method is wherein introduced described fibrous tissue formation agent by sending from implant, and the surface of wherein said implant comprises about 1 μ g to about 10 μ g fibrous tissue formation agent/mm ²The applied implant surface of described reagent.

690. the 363rd method is wherein introduced described fibrous tissue formation agent by sending from implant, and the surface of wherein said implant comprises about 10 μ g to about 250 μ g fibrous tissue formation agent/mm ²The applied implant surface of described reagent.

691. the 363rd method is wherein introduced described reagent by sending from implant, and the surface of wherein said implant comprises about 250 μ g to about 1000 μ g fibrous tissue formation agent/mm ²Described fibrous tissue forms the applied implant surface of agent.

692. the 363rd method is wherein introduced described reagent by sending from implant, and the surface of wherein said implant comprises about 1000 μ g to about 2500 μ g fibrous tissue formation agent/mm ²The applied implant surface of described reagent.

693. the 363rd method is wherein introduced described reagent by sending from implant, wherein said implant also comprises coating, and wherein said coating is a uniform coating.

694. the 363rd method is wherein introduced described reagent by sending from implant, wherein said implant also comprises coating, and wherein said coating is inhomogeneous coating.

695. the 363rd method is wherein introduced described reagent by sending from implant, wherein said implant also comprises coating, and wherein said coating is discontinuous coating.

696. the 363rd method is wherein introduced described reagent by sending from implant, wherein said implant also comprises coating, and wherein said coating is to form the coating of pattern.

697. the 363rd method is wherein introduced described reagent by sending from implant, wherein said implant also comprises coating, and wherein said coating has 100 μ m or littler thickness.

698. the 363rd method is wherein introduced described reagent by sending from implant, wherein said implant also comprises coating, and wherein said coating has 10 μ m or littler thickness.

699. the 363rd method is wherein introduced described reagent by sending from implant, wherein said implant also comprises coating, and wherein said coating adheres to the surface of described implant when described implant is used.

700. the 363rd method is wherein introduced described reagent by sending from implant, wherein said implant also comprises coating, and wherein said coating is at room temperature stablized the cycle at least 1 year.

701. the 363rd method is wherein introduced described reagent by sending from implant, wherein said implant also comprises coating, and wherein said fibrous tissue forms agent and is present in the described coating to the amount in about 1 weight % scope with about 0.0001 weight %.

702. the 363rd method is wherein introduced described reagent by sending from implant, wherein said implant also comprises coating, and wherein said reagent is present in the described coating with the amount of about 1 weight % to about 10 weight % scopes.

703. the 363rd method is wherein introduced described reagent by sending from implant, wherein said implant also comprises coating, and wherein said reagent is present in the described coating with the amount of about 10 weight % to about 25 weight % scopes.

704. the 363rd method is wherein introduced described reagent by sending from implant, wherein said implant also comprises coating, and wherein said fibrous tissue forms agent and is present in the described coating to the amount in about 70 weight % scopes with about 25 weight %.

705. the 363rd method is wherein introduced described reagent by sending from implant, wherein said implant also comprises coating, and wherein said coating comprises polymer.

706. the 363rd method is wherein introduced described reagent by sending from implant, wherein said implant comprises first coating with first compositions and second coating with second compositions.

707. the 363rd method is wherein introduced described reagent by sending from implant, wherein said implant comprises first coating with first compositions and second coating with second compositions, and wherein first compositions is different with second compositions.

708. the 363rd method is wherein with described reagent or comprise the injection of described combination of agents thing or be sprayed in the described diverticulum.

709. the 363rd method is wherein with described reagent or comprise the injection of described combination of agents thing or be sprayed to tissue or center in the tissue of described diverticulum.

710. the 363rd method, wherein said compositions also comprises filler.

711. the 363rd method, wherein said compositions is a sealant.

712. the 363rd method, wherein said compositions is a hemorrhage.

713. the 363rd method, wherein said compositions also comprises filler, and wherein said filler comprises microsphere.

714. the 363rd method, wherein said compositions also comprises filler, and wherein said filler comprises the gel of hydroxyapatite load.

715. the 363rd method, wherein said compositions also comprises filler, and wherein said filler comprises micronized alloderm acellular substrate.

716. the 363rd method, wherein said compositions also comprises filler, and wherein said filler comprises hyaluronic acid.

717. the 363rd method, wherein said compositions also comprises filler, and wherein said filler comprises the microballon in the hydrogel.

718. the 363rd method, wherein said compositions also comprises filler, and wherein said filler comprises extra large blue polymer.

719. the 363rd method, wherein said compositions also comprises filler, and wherein said filler comprises silicon microsphere and biocompatible polymer.

720. the 363rd method, described method also comprises the existence that manifests diverticulum.

721. the 720th method, the existence that wherein manifests diverticulum comprises splanchnoscopy.

722. the 720th method, the existence that wherein manifests diverticulum comprises the radiography imaging.

723. the 363rd method, described method are washed described diverticulum with rinse solution before also being included in and introducing described fibrous tissue formation agent.

724. the 723rd method, wherein said rinse solution comprise (a) anti-infective or (b) antiseptic or (c) anti-infective and antiseptic.

725. comprising (a) fibrous tissue, a compositions, described compositions form agent and (b) polymer or in-situ polymerization and form the chemical compound of cross linked polymer.

726. the 725th compositions, wherein said fibrous tissue forms agent and promotes regeneration.

727. the 725th compositions, wherein said fibrous tissue form agent and promote fibre modification and promote regeneration.

728. forming agent, the 725th compositions, wherein said fibrous tissue promote blood vessel to take place.

729. the 725th compositions, wherein said fibrous tissue form agent and promote the fibroblast migration.

730. the 725th compositions, wherein said fibrous tissue forms agent and promotes fibroblast proliferation.

731. the 725th compositions, wherein said fibrous tissue forms the deposition that agent promotes extracellular matrix (ECM).

732. the 725th compositions, wherein said fibrous tissue forms agent and promotes tissue remodeling.

733. the 725th compositions, it is diverticulum wall stimulus object that wherein said fibrous tissue forms agent.

Be or comprise silk 734. the 725th compositions, wherein said fibrous tissue form agent.

Be or comprise silkworm silk 735. the 725th compositions, wherein said fibrous tissue form agent.

Be or comprise spider silk 736. the 725th compositions, wherein said fibrous tissue form agent.

Be or comprise the recombinant silk 737. the 725th compositions, wherein said fibrous tissue form agent.

Be or comprise raw silk 738. the 725th compositions, wherein said fibrous tissue form agent.

739. the 725th compositions, wherein said fibrous tissue forms the silk that agent is or comprises hydrolysis.

740. the 725th compositions, wherein said fibrous tissue formation agent is or comprises acid-treated.

741. the 725th compositions, wherein said fibrous tissue forms the silk that agent is or comprises acidylate.

742. the 725th compositions, it is the form of twisted wire that wherein said fibrous tissue forms agent.

743. the 725th compositions, wherein said fibrous tissue form the form that agent is bunch.

Be or comprise mineral grain 744. the 725th compositions, wherein said fibrous tissue form agent.

Be or comprise chitosan 745. the 725th compositions, wherein said fibrous tissue form agent.

Be or comprise polylysine 746. the 725th compositions, wherein said fibrous tissue form agent.

Be or comprise fibronectin 747. the 725th compositions, wherein said fibrous tissue form agent.

Be or comprise bleomycin 748. the 725th compositions, wherein said fibrous tissue form agent.

Be or comprise CTGF 749. the 725th compositions, wherein said fibrous tissue form agent.

Be or comprise fine hair 750. the 725th compositions, wherein said fibrous tissue form agent.

Be or comprise animal down 751. the 725th compositions, wherein said fibrous tissue form agent.

Be or comprise wood shavings 752. the 725th compositions, wherein said fibrous tissue form agent.

Be or comprise synthetic fine hair 753. the 725th compositions, wherein said fibrous tissue form agent.

754. the 725th compositions, it is the form of line that wherein said fibrous tissue forms agent, or contacts with line.

755. the 754th compositions, wherein said line is biodegradable.

756. the 755th compositions, wherein said biodegradable line comprise the material that is selected from the group of being made up of polyester, poly-anhydride, poly-(anhydride ester), poly-(ester-acid amide), poly-(ester-urea), poe, poly phosphate, poly-phosphazine, polybutylcyanoacrylate, collagen, chitosan, hyaluronic acid, chromic catgut, alginate, starch, cellulose and cellulose esters.

757. the 754th compositions, wherein said line are not biodegradable.

758. the 757th compositions, wherein said not biodegradable line comprise the material that is selected from the group of being made up of polyester, polyurethane, siloxanes, polyethylene, polypropylene, polystyrene, polyacrylate, polymethacrylates and silk.

759. the 754th compositions, wherein said line scribbles polymer.

760. the 754th compositions, wherein said line scribble the medicament of inducing fibrosis reaction in described host.

761. the 725th compositions, it is the form of microgranule that wherein said fibrous tissue forms agent.

762. the 761st compositions, wherein said microgranule are biodegradable microgranules.

763. the 762nd compositions, wherein said Biodegradable microparticle comprise the material that is selected from the group of being made up of polyester, poly-anhydride, poly-(anhydride ester), poly-(ester-acid amide), poly-(ester-urea), poe, poly phosphate, poly-phosphazine, polybutylcyanoacrylate, collagen, chitosan, hyaluronic acid, chromic catgut, alginate, starch, cellulose and cellulose esters.

764. the 761st compositions, wherein said microgranule are biodegradable microgranules.

765. the 764th compositions, wherein said not biodegradable microgranule comprise the material that is selected from the group of being made up of polyester, polyurethane, siloxanes, polyethylene, polypropylene, polystyrene, polyacrylate, polymethacrylates and silk.

766. the 761st compositions, wherein said microgranule are the particulate form that is selected from the member of the group of being made up of silk, Talcum, starch, glass, silicate, Silicon stone, calcium phosphate, calcium sulfate, calcium carbonate, hydroxyapatite, synthetic mineral, polymethyl methacrylate, silver nitrate, pottery and other inorganic particle.

767. the 761st compositions, wherein said microgranule scribbles polymer.

768. the 761st compositions, wherein said microgranule scribble the medicament of inducing fibrosis reaction in described host.

769. the 761st compositions, wherein said microgranule scribble the member who is selected from the group of being made up of silk, Talcum, starch, glass, silicate, Silicon stone, calcium phosphate, calcium sulfate, calcium carbonate, hydroxyapatite, synthetic mineral, polymethyl methacrylate, silver nitrate, pottery and other inorganic particle.

770. the 725th compositions, wherein said compositions comprises somatomedin.

771. the 770th compositions, wherein said somatomedin is selected from transforming growth factor, platelet derived growth factor and fibroblast growth factor.

772. the compositions of any one of 725-771 item, wherein said polymer are, or comprise copolymer.

773. the compositions of any one of 725-771 item, wherein said polymer are, or comprise block copolymer.

774. the compositions of any one of 725-771 item, wherein said polymer are, or comprise random copolymer.

775. the compositions of any one of 725-771 item, wherein said polymer are, or comprise biodegradable polymer.

776. the compositions of any one of 725-771 item, wherein said polymer are, or comprise not biodegradable polymer.

777. the compositions of any one of 725-771 item, wherein said polymer are, or comprise hydrophilic polymer.

778. the compositions of any one of 725-771 item, wherein said polymer are, or comprise hydrophobic polymer.

779. the compositions of any one of 725-771 item, wherein said polymer are, or comprise the polymer of possess hydrophilic property domain.

780. the compositions of any one of 725-771 item, wherein said polymer be, or comprise, and has the polymer in hydrophobic structure territory.

781. the compositions of any one of 725-771 item, wherein said polymer are, or comprise non-conductive polymer.

782. the compositions of any one of 725-771 item, wherein said polymer are, or comprise elastomer.

783. the compositions of any one of 725-771 item, wherein said polymer are, or comprise hydrogel.

784. the compositions of any one of 725-771 item, wherein said polymer are, or comprise siloxane polymer.

785. the compositions of any one of 725-771 item, wherein said polymer are, or comprise hydrocarbon polymer.

786. the compositions of any one of 725-771 item, wherein said polymer are, or comprise the styrene derived polymer.

787. the compositions of any one of 725-771 item, wherein said polymer are, or comprise the butadiene derived polymer.

788. the compositions of any one of 725-771 item, wherein said polymer are, or comprise macromonomer.

789. the compositions of any one of 725-771 item, wherein said polymer are, or comprise poly-(ethylene glycol).

790. the compositions of any one of 725-771 item, wherein said polymer are, or comprise the collagen or derivatives thereof.

791. the compositions of any one of 725-771 item, wherein said polymer are, or comprise methylated collagen.

792. the compositions of any one of 725-771 item, wherein said compositions also comprises polymer composition, and wherein said polymer composition comprises collagen or derivatives thereof and fibrinogen.

793. the compositions of any one of 725-771 item, wherein said compositions also comprises polymer composition, and wherein said polymer composition comprises collagen or derivatives thereof and thrombin.

794. the compositions of any one of 725-771 item, wherein said compositions also comprises polymer composition, and wherein said polymer composition comprises (a) collagen or derivatives thereof; (b) fibrinogen; (c) thrombin.

795. the compositions of any one of 725-771 item, wherein said polymer also comprises polymer composition, and wherein said polymer composition comprises methylated collagen and poly-(ethylene glycol).

796. the compositions of any one of 725-771 item, wherein said compositions also comprises hemorrhage, and described hemorrhage comprises collagen polymer.

797. the compositions of any one of 725-771 item, wherein said compositions also comprises hemorrhage, and described hemorrhage comprises collagen polymer, and wherein said hemorrhage is CT3.

798. the compositions of any one of 725-771 item, wherein said compositions also comprises hemorrhage, and described hemorrhage comprises collagen polymer, and wherein said hemorrhage is COSTASIS.

799. the compositions of any one of 725-771 item, wherein said compositions also comprises hemorrhage, and described hemorrhage comprises poly-(ethylene glycol).

800. the compositions of any one of 725-771 item, wherein said compositions also comprises hemorrhage, and wherein said hemorrhage is COSEAL, TISSEALL or FLOSEAL.

801. the compositions of any one of 725-771 item, wherein said compositions also comprises hemorrhage, and described hemorrhage comprises fibrin.

802. the compositions of any one of 725-771 item, wherein said polymer are, or comprise amorphous polymer.

803. the compositions of any one of 725-771 item, wherein said polymer are, or comprise cyanoacrylate.

804. the 803rd method, wherein said cyanoacrylate are selected from methyl 2-cyanoacrylate, cyanacrylate, Tisuacryl, octyl 2-cyanoacrylate and alpha-cyanoacrylate methoxyl group propyl ester.

805. the compositions of any one of 725-771 item, wherein said polymer are, or comprise poly-(alkyl cyanoacrylate).

806. the 805th method, wherein said poly-(alkyl cyanoacrylate) are selected from poly-(MCA), poly-(ethyl cyanoacrylate), poly-(butyl cyanoacrylate), poly-(isobutyl cyanoacrylate), poly-(hexyl cyanoacrylate) and poly-(octyl cyanoacrylate).

807. the compositions of any one of 725-771 item, wherein said polymer are, or comprise poly-(carboxyalkyl cyanoacrylate).

808. the 807th method, wherein said poly-(carboxyalkyl cyanoacrylate) is poly-(methoxy-propyl cyanoacrylate).

809. the compositions of any one of 725-771 item, wherein said polymer is crosslinked.

810. the compositions of any one of 725-771 item, wherein said polymer and mammalian tissues reaction.

811. the compositions of any one of 725-771 item, wherein said polymer are naturally occurring polymer.

812. the compositions of any one of 725-771 item, wherein said polymer is a protein.

813. the compositions of any one of 725-771 item, wherein said polymer is a saccharide.

814. the compositions of any one of 725-771 item, wherein said polymer are crosslinked with biodegradable.

815. the compositions of any one of 725-771 item, wherein said compositions comprises fibrinogen.

816. the compositions of any one of 725-771 item, wherein said compositions comprises thrombin.

817. the compositions of any one of 725-771 item, wherein said compositions comprises calcium salt.

818. the compositions of any one of 725-771 item, wherein said compositions comprises antifibrinolytic agent.

819. the compositions of any one of 725-771 item, wherein said compositions comprises the fibrinogen analog.

820. the compositions of any one of 725-771 item, wherein said compositions comprises albumin.

821. the compositions of any one of 725-771 item, wherein said compositions comprises plasminogen.

822. the compositions of any one of 725-771 item, wherein said compositions comprises Feng's von willebrand's factor.

823. the compositions of any one of 725-771 item, wherein said compositions comprises Factor IX.

824. the compositions of any one of 725-771 item, wherein said compositions comprises hypoallergenic collagen.

825. the compositions of any one of 725-771 item, wherein said compositions comprise end peptide collagen.

826. the compositions of any one of 725-771 item, wherein said compositions comprises crosslinked collagen.

827. the compositions of any one of 725-771 item, wherein said compositions comprises aprotinin.

828. the compositions of any one of 725-771 item, wherein said compositions comprise epsilon-amino-just-caproic acid.

829. the compositions of any one of 725-771 item, wherein said compositions comprises gelatin.

830. the compositions of any one of 725-771 item, wherein said compositions comprises protein conjugate.

831. the compositions of any one of 725-771 item, wherein said compositions comprises the gelatin conjugate.

832. the compositions of any one of 725-771 item, wherein said compositions comprises hyaluronic acid.

833. the compositions of any one of 725-771 item, wherein said compositions comprises derivatives of hyaluronic acids.

834. the compositions of any one of 725-771 item, wherein said compositions comprises synthetic polymer.

835. the compositions of any one of 725-771 item, wherein said polymer forms by comprising the synthetic reactant that contains the chemical compound of isocyanates.

836. the compositions of any one of 725-771 item, wherein said compositions comprise the synthetic chemical compound that contains isocyanates.

837. the compositions of any one of 725-771 item, wherein said polymer forms by comprising the synthetic reactant that contains the chemical compound of mercaptan.

838. the compositions of any one of 725-771 item, wherein said compositions comprise the synthetic chemical compound that contains mercaptan.

839. the compositions of any one of 725-771 item, wherein said polymer forms by comprising the synthetic reactant that contains the chemical compound of two mercaptos at least.

840. the compositions of any one of 725-771 item, wherein said compositions comprise the synthetic chemical compound that contains at least two mercaptos.

841. the compositions of any one of 725-771 item, wherein said polymer forms by comprising the synthetic reactant that contains the chemical compound of three mercaptos at least.

842. the compositions of any one of 725-771 item, wherein said compositions comprise the synthetic chemical compound that contains at least three mercaptos.

843. the compositions of any one of 725-771 item, wherein said polymer forms by comprising the synthetic reactant that contains the chemical compound of four mercaptos at least.

844. the compositions of any one of 725-771 item, wherein said compositions comprise the synthetic chemical compound that contains at least four mercaptos.

845. the compositions of any one of 725-771 item, wherein said polymer forms by comprising the synthetic reactant that contains amino chemical compound.

846. the compositions of any one of 725-771 item, wherein said compositions comprise the synthetic amino chemical compound that contains.

847. the compositions of any one of 725-771 item, wherein said polymer forms by comprising the synthetic reactant that contains the chemical compound of two amino at least.

848. the compositions of any one of 725-771 item, wherein said compositions comprise the synthetic chemical compound that contains at least two amino.

849. the compositions of any one of 725-771 item, wherein said polymer forms by comprising the synthetic reactant that contains the chemical compound of three amino at least.

850. the compositions of any one of 725-771 item, wherein said compositions comprise the synthetic chemical compound that contains at least three amino.

851. the compositions of any one of 725-771 item, wherein said polymer forms by comprising the synthetic reactant that contains the chemical compound of four amino at least.

852. the compositions of any one of 725-771 item, wherein said compositions comprise the synthetic chemical compound that contains at least four amino.

853. the compositions of any one of 725-771 item, wherein said polymer forms by comprising the synthetic reactant that contains the chemical compound of carbonyl-oxygen-succinimido.

854. the compositions of any one of 725-771 item, wherein said compositions comprise the synthetic chemical compound that contains carbonyl-oxygen-succinimido.

855. the compositions of any one of 725-771 item, wherein said polymer forms by comprising the synthetic reactant that contains the chemical compound of two carbonyl-oxygen-succinimido at least.

856. the compositions of any one of 725-771 item, wherein said compositions comprise the synthetic chemical compound that contains at least two carbonyl-oxygen-succinimido.

857. the compositions of any one of 725-771 item, wherein said polymer forms by comprising the synthetic reactant that contains the chemical compound of three carbonyl-oxygen-succinimido at least.

858. the compositions of any one of 725-771 item, wherein said compositions comprise the synthetic chemical compound that contains at least three carbonyl-oxygen-succinimido.

859. the compositions of any one of 725-771 item, wherein said polymer forms by comprising the synthetic reactant that contains the chemical compound of four carbonyl-oxygen-succinimido at least.

860. the compositions of any one of 725-771 item, wherein said compositions comprise the synthetic chemical compound that contains at least four carbonyl-oxygen-succinimido.

861. the compositions of any one of 725-771 item, wherein said polymer forms by comprising the synthetic reactant that contains the chemical compound of polyalkylene oxide.

862. the compositions of any one of 725-771 item, wherein said compositions comprise the synthetic chemical compound that contains polyalkylene oxide.

863. the compositions of any one of 725-771 item, wherein said compositions also comprises polymer, and wherein said polymer forms by comprising the synthetic reactant that contains the chemical compound of polyalkylene oxide and biodegradable polyester block.

864. the compositions of any one of 725-771 item, wherein said compositions comprise the synthetic chemical compound that contains polyalkylene oxide and biodegradable polyester block.

865. the compositions of any one of 725-771 item, wherein said polymer forms by comprising synthetic reactant with chemical compound that contains polyalkylene oxide of reactive amino.

866. the compositions of any one of 725-771 item, wherein said compositions comprise the synthetic chemical compound that contains polyalkylene oxide with reactive amino.

867. the compositions of any one of 725-771 item, wherein said polymer forms by comprising synthetic reactant with chemical compound that contains polyalkylene oxide of reactive mercapto.

868. the compositions of any one of 725-771 item, wherein said compositions comprise the synthetic chemical compound that contains polyalkylene oxide with reactive mercapto.

869. the compositions of any one of 725-771 item, wherein said polymer forms by comprising synthetic reactant with chemical compound that contains polyalkylene oxide of reactive carbonyl-oxygen-succinimido.

870. the compositions of any one of 725-771 item, wherein said compositions comprise the synthetic chemical compound that contains polyalkylene oxide with reactive carbonyl-oxygen-succinimido.

871. the compositions of any one of 725-771 item, wherein said polymer forms by comprising the synthetic reactant that contains the chemical compound of biodegradable polyester block.

872. the compositions of any one of 725-771 item, wherein said compositions comprise the synthetic chemical compound that contains the biodegradable polyester block.

873. the compositions of any one of 725-771 item, wherein said polymer is formed by the reactant that comprises the synthetic polymer that is formed by lactic acid or lactide wholly or in part.

874. the compositions of any one of 725-771 item, wherein said compositions comprises the polymer that is formed by lactic acid or lactide wholly or in part.

875. the compositions of any one of 725-771 item, wherein said polymer is formed by the reactant that comprises the synthetic polymer that is formed by glycolic or Acetic acid, hydroxy-, bimol. cyclic ester wholly or in part.

876. the compositions of any one of 725-771 item, wherein said compositions comprises the polymer that is formed by glycolic or Acetic acid, hydroxy-, bimol. cyclic ester wholly or in part.

877. the compositions of any one of 725-771 item, wherein said polymer is formed by the reactant that comprises polylysine.

878. the compositions of any one of 725-771 item, wherein said compositions comprises polylysine.

879. the compositions of any one of 725-771 item, wherein said polymer forms by comprising the reactant of (a) protein with the chemical compound that (b) comprises the polyalkylene oxide part.

880. the compositions of any one of 725-771 item, wherein said compositions comprise (a) protein and (b) comprise the chemical compound of polyalkylene oxide part.

881. the compositions of any one of 725-771 item, wherein said polymer by comprise (a) protein and (b) reactant of polylysine form.

882. the compositions of any one of 725-771 item, wherein said compositions comprise (a) protein and (b) polylysine.

883. the compositions of any one of 725-771 item, wherein said compositions also comprises polymer, and wherein said polymer forms with the reactant that (b) has the chemical compound of four mercaptos by comprising (a) protein at least.

884. the compositions of any one of 725-771 item, wherein said compositions comprise (a) protein and (b) have the chemical compound of at least four mercaptos.

885. the compositions of any one of 725-771 item, wherein said polymer forms with the reactant that (b) has the chemical compound of four amino by comprising (a) protein at least.

886. the compositions of any one of 725-771 item, wherein said compositions comprise (a) protein and (b) have the chemical compound of at least four amino.

887. the compositions of any one of 725-771 item, wherein said polymer forms with the reactant that (b) has the chemical compound of four carbonyl-oxygen-butanimide group by comprising (a) protein at least.

888. the compositions of any one of 725-771 item, wherein said compositions comprise (a) protein and (b) have the chemical compound of at least four carbonyl-oxygen-succinimido.

889. the compositions of any one of 725-771 item, wherein said polymer forms with the reactant that (b) has the chemical compound of the biodegradable region that is formed by the reactant that is selected from lactic acid, lactide, glycolic, Acetic acid, hydroxy-, bimol. cyclic ester and 6-caprolactone by comprising (a) protein.

890. the chemical compound that the compositions of any one of 725-771 item, wherein said compositions comprise (a) protein and (b) have the biodegradable region that is formed by the reactant that is selected from lactic acid, lactide, glycolic, Acetic acid, hydroxy-, bimol. cyclic ester and 6-caprolactone.

891. the compositions of any one of 725-771 item, wherein said polymer forms by comprising the reactant of (a) collagen with the chemical compound that (b) comprises the polyalkylene oxide part.

892. the compositions of any one of 725-771 item, wherein said compositions comprise (a) collagen and (b) comprise the chemical compound of polyalkylene oxide part.

893. the compositions of any one of 725-771 item, wherein said polymer by comprise (a) collagen and (b) reactant of polylysine form.

894. the compositions of any one of 725-771 item, wherein said compositions comprise (a) collagen and (b) polylysine.

895. the compositions of any one of 725-771 item, wherein said polymer forms with the reactant that (b) has the chemical compound of four mercaptos by comprising (a) collagen at least.

896. the compositions of any one of 725-771 item, wherein said compositions comprise (a) collagen and (b) have the chemical compound of at least four mercaptos.

897. the compositions of any one of 725-771 item, wherein said polymer forms with the reactant that (b) has the chemical compound of four amino by comprising (a) collagen at least.

898. the compositions of any one of 725-771 item, wherein said compositions comprise (a) collagen and (b) have the chemical compound of at least four amino.

899. the compositions of any one of 725-771 item, wherein said polymer forms with the reactant that (b) has the chemical compound of four carbonyl-oxygen-butanimide group by comprising (a) collagen at least.

900. the compositions of any one of 725-771 item, wherein said compositions comprise (a) collagen and (b) have the chemical compound of at least four carbonyl-oxygen-succinimido.

901. the compositions of any one of 725-771 item, wherein said polymer forms with the reactant that (b) has the chemical compound of the biodegradable region that is formed by the reactant that is selected from lactic acid, lactide, glycolic, Acetic acid, hydroxy-, bimol. cyclic ester and 6-caprolactone by comprising (a) collagen.

902. the chemical compound that the compositions of any one of 725-771 item, wherein said compositions comprise (a) collagen and (b) have the biodegradable region that is formed by the reactant that is selected from lactic acid, lactide, glycolic, Acetic acid, hydroxy-, bimol. cyclic ester and 6-caprolactone.

903. the compositions of any one of 725-771 item, wherein said polymer forms by comprising the reactant of (a) methylated collagen with the chemical compound that (b) comprises the polyalkylene oxide part.

904. the compositions of any one of 725-771 item, wherein said compositions comprise (a) methylated collagen and (b) comprise the chemical compound of polyalkylene oxide part.

905. the compositions of any one of 725-771 item, wherein said compositions also comprises polymer, and wherein said polymer by comprise (a) methylated collagen and (b) reactant of polylysine form.

906. the compositions of any one of 725-771 item, wherein said compositions comprise (a) methylated collagen and (b) polylysine.

907. the compositions of any one of 725-771 item, wherein said polymer forms with the reactant that (b) has the chemical compound of four mercaptos by comprising (a) methylated collagen at least.

908. the compositions of any one of 725-771 item, wherein said compositions comprise (a) methylated collagen and (b) have the chemical compound of at least four mercaptos.

909. the compositions of any one of 725-771 item, wherein said compositions also comprises polymer, and wherein said polymer forms with the reactant that (b) has the chemical compound of four amino by comprising (a) methylated collagen at least.

910. the compositions of any one of 725-771 item, wherein said compositions comprise (a) methylated collagen and (b) have the chemical compound of at least four amino.

911. the compositions of any one of 725-771 item, wherein said polymer forms with the reactant that (b) has the chemical compound of four carbonyl-oxygen-butanimide group by comprising (a) methylated collagen at least.

912. the compositions of any one of 725-771 item, wherein said compositions comprise (a) methylated collagen and (b) have the chemical compound of at least four carbonyl-oxygen-succinimido.

913. the compositions of any one of 725-771 item, wherein said polymer forms with the reactant that (b) has the chemical compound of the biodegradable region that is formed by the reactant that is selected from lactic acid, lactide, glycolic, Acetic acid, hydroxy-, bimol. cyclic ester and 6-caprolactone by comprising (a) methylated collagen.

914. the chemical compound that the compositions of any one of 725-771 item, wherein said compositions comprise (a) methylated collagen and (b) have the biodegradable region that is formed by the reactant that is selected from lactic acid, lactide, glycolic, Acetic acid, hydroxy-, bimol. cyclic ester and 6-caprolactone.

915. the compositions of any one of 725-771 item, wherein said polymer forms by comprising hyaluronic reactant.

916. the compositions of any one of 725-771 item, wherein said compositions comprises hyaluronic acid.

917. the compositions of any one of 725-771 item, wherein said compositions also comprises polymer, and wherein said polymer is formed by the reactant that comprises derivatives of hyaluronic acids.

918. the compositions of any one of 725-771 item, wherein said compositions comprises derivatives of hyaluronic acids.

919. the compositions of any one of 725-771 item, wherein said polymer is formed by the reactant that comprises poly-(ethylene glycol) ether four-sulfydryl of the tetramethylolmethane of number-average molecular weight between 3,000 and 30,000.

920. the compositions of any one of 725-771 item, wherein said compositions comprise poly-(ethylene glycol) ether four-sulfydryl of the tetramethylolmethane of number-average molecular weight between 3,000 and 30,000.

921. the compositions of any one of 725-771 item, wherein said polymer is formed by the reactant that comprises poly-(ethylene glycol) ether four of the tetramethylolmethane of number-average molecular weight between 3,000 and 30,000-amino.

922. the compositions of any one of 725-771 item, wherein said compositions comprise poly-(ethylene glycol) ether four-amino of the tetramethylolmethane of number-average molecular weight between 3,000 and 30,000.

923. the compositions of any one of 725-771 item, wherein said polymer is by comprising (a) synthetic number-average molecular weight 3,000 and 30, between 000 and comprise the chemical compound of polyalkylene oxide zone and a plurality of nucleophilic groups and (b) synthetic number-average molecular weight 3, between 000 and 30,000 and comprise the reactant formation of the chemical compound of polyalkylene oxide zone and a plurality of electrophilic groups.

924. the compositions of any one of 725-771 item, wherein said compositions comprises (a) synthetic number-average molecular weight 3,000 and 30, between 000 and comprise the chemical compound of polyalkylene oxide zone and a plurality of nucleophilic groups, (b) synthetic number-average molecular weight is 3, between 000 and 30,000 and comprise the chemical compound of polyalkylene oxide zone and a plurality of electrophilic groups.

925. the compositions of any one of 725-771 item, wherein said compositions comprises coloring agent.

926. the compositions of any one of 725-771 item, wherein said compositions is aseptic.

927. the compositions of any one of 725-771 item, wherein said compositions also comprises second forms of pharmacologically active agents.

928. the compositions of any one of 725-771 item, wherein said compositions also comprises antiinflammatory.

929. the compositions of any one of 725-771 item, wherein said compositions also comprises infection inhibitor.

930. the compositions of any one of 725-771 item, wherein said compositions also comprises anthracycline.

931. the compositions of any one of 725-771 item, wherein said compositions also comprises doxorubicin.

932. the compositions of any one of 725-771 item, wherein said compositions also comprises mitoxantrone.

933. the compositions of any one of 725-771 item, wherein said compositions also comprises the fluorine pyrimidine.

934. the compositions of any one of 725-771 item, wherein said compositions also comprise 5-fluorouracil (5-FU).

935. the compositions of any one of 725-771 item, wherein said compositions also comprises antifol.

936. the compositions of any one of 725-771 item, wherein said compositions also comprises methotrexate.

937. the compositions of any one of 725-771 item, wherein said compositions also comprises podophyllotoxin.

938. the compositions of any one of 725-771 item, wherein said compositions also comprises etoposide.

939. the compositions of any one of 725-771 item, wherein said compositions also comprises camptothecine.

940. the compositions of any one of 725-771 item, wherein said compositions also comprises hydroxyurea.

941. the compositions of any one of 725-771 item, wherein said compositions also comprises platinum complex.

942. the compositions of any one of 725-771 item, wherein said compositions also comprises cisplatin.

943. the compositions of any one of 725-771 item, wherein said compositions also comprises anti-infective.

944. the compositions of any one of 725-771 item, wherein said compositions also comprises anti-infective, and wherein said anti-infective is an antibiotic.

945. the compositions of any one of 725-771 item, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a doxycycline.

946. the compositions of any one of 725-771 item, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a metronidazole.

947. the compositions of any one of 725-771 item, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a trimethoprim-sulfamethoxazole.

948. the compositions of any one of 725-771 item, wherein said compositions also comprises anti-infective, wherein said anti-infective be the 4th generation penicillin.

949. the compositions of any one of 725-771 item, wherein said compositions also comprises anti-infective, wherein said anti-infective be selected from urea groups penicillin and penicillin carboxy the 4th generation penicillin, or its analog or derivant.

950. the compositions of any one of 725-771 item, wherein said compositions also comprises anti-infective, wherein said anti-infective be selected from mezlocillin, piperacillin, Carbenicillin and ticarcillin the 4th generation penicillin.

951. the compositions of any one of 725-771 item, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a first generation cephalosporin.

952. the compositions of any one of 725-771 item, wherein said compositions also comprises anti-infective, and wherein said anti-infective is the first generation cephalosporin that is selected from cefazolin sodium, cefalexin, cefazolin sodium, cefaloject and cefalotin.

953. the compositions of any one of 725-771 item, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a penicillin carboxy.

954. the 943rd compositions, wherein said penicillin carboxy is a ticarcillin.

955. the compositions of any one of 725-771 item, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a second generation cephalosporin.

956. the compositions of any one of 725-771 item, wherein said compositions also comprises anti-infective, and wherein said anti-infective is the second generation cephalosporin that is selected from cefuroxime, cefotetan and cefoxitin.

957. the compositions of any one of 725-771 item, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a third generation cephalosporin.

958. the compositions of any one of 725-771 item, wherein said compositions also comprises anti-infective, and wherein said anti-infective is the third generation cephalosporin that is selected from ceftiofur sodium, cefdinir, cefoperazone, ceftazidime, ceftriaxone and cefotaxime.

959. the compositions of any one of 725-771 item, wherein said compositions also comprises anti-infective, wherein said anti-infective be the 4th generation cephalosporin.

960. the 959th compositions, wherein said the 4th generation cephalosporin be cefepime.

961. the compositions of any one of 725-771 item, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a monobactam.

962. the 961st compositions, wherein said monobactam is an aztreonam.

963. the compositions of any one of 725-771 item, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a carbapenem.

964. the compositions of any one of 725-771 item, wherein said compositions also comprises anti-infective, and wherein said anti-infective is the carbapenem that is selected from imipenum, Ai Tapeinan and meropenem.

965. the compositions of any one of 725-771 item, wherein said compositions also comprises anti-infective, and wherein said anti-infective is an aminoglycoside.

966. the compositions of any one of 725-771 item, wherein said compositions also comprises anti-infective, and wherein said anti-infective is the aminoglycoside that is selected from streptomycin, gentamycin, tobramycin and amikacin.

967. the compositions of any one of 725-771 item, wherein said compositions also comprises anti-infective, and wherein said anti-infective is the MSL group membership who is selected from macrolide, long-acting macrolide, lincosamide and streptogramin.

968. the compositions of any one of 725-771 item, wherein said compositions also comprises anti-infective, and wherein said anti-infective is the MSL group membership who is selected from erythromycin, azithromycin, clindamycin, quinoline slave Pu Ding-dalfopristin, clarithromycin and kanamycin sulfate.

969. the compositions of any one of 725-771 item, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a quinolinones.

970. the compositions of any one of 725-771 item, wherein said compositions also comprises anti-infective, and wherein said anti-infective is the quinolinones that is selected from ciprofloxacin, ofloxacin, Gatifloxacin, Moxifloxacin, levofloxacin and trovafloxacin.

971. the compositions of any one of 725-771 item, wherein said compositions also comprises anti-infective, and wherein said anti-infective is the DNA synthetic inhibitor.

972. the 971st compositions, wherein said DNA synthetic inhibitor is a metronidazole.

973. the compositions of any one of 725-771 item, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a sulfonamide.

974. the 973rd compositions, wherein said sulfonamide is a trimethoprim.

975. the compositions of any one of 725-771 item, wherein said compositions also comprises anti-infective, and wherein said anti-infective is selected from cefixime, spectinomycin, tetracycline, nitrofurantoin, polymyxin B and polygynax.

976. the compositions of any one of 725-771 item, wherein said compositions also comprises developing agent.

977. the compositions of any one of 725-771 item, wherein said compositions also comprises developing agent, and described developing agent is radio-opaque material, and wherein said radio-opaque material comprises metal, halogenated compound or contains the chemical compound of barium.

978. the compositions of any one of 725-771 item, wherein said compositions also comprises developing agent, and described developing agent is, or comprises barium, tantalum or technetium.

979. the compositions of any one of 725-771 item, wherein said compositions also comprises developing agent, and described developing agent is, or comprises MRI response material or echo material.

980. the compositions of any one of 725-771 item, wherein said compositions also comprises developing agent, and described developing agent is, or comprises gadolinium chelate compound.

981. the compositions of any one of 725-771 item, wherein said compositions also comprises a kind of developing agent, and described developing agent is, or comprises ferrum, magnesium, manganese, copper or chromium.

982. the compositions of any one of 725-771 item, wherein said compositions also comprises developing agent, and described developing agent is, or comprises iron oxide compound.

983. the compositions of any one of 725-771 item, wherein said compositions also comprises developing agent, and described developing agent is, or comprises dyestuff, pigment or coloring agent.

984. forming agent, the compositions of any one of 725-771 item, wherein said fibrous tissue in the administration cycle to about 90 days scopes constantly, discharge from the compositions that comprises fibrous tissue and form agent with valid density by diffusion.

985. forming agent corrosion by compositions in the administration cycle to about 90 days scopes constantly, the compositions of any one of 725-771 item, wherein said fibrous tissue discharge from the compositions that comprises fibrous tissue and form agent with valid density.

986. the compositions of any one of 725-771 item, wherein said compositions also comprises inflammatory cytokine.

987. the compositions of any one of 725-771 item, wherein said compositions also comprises the reagent that stimulates cellular proliferation.

988. the compositions of any one of 725-771 item, wherein said compositions also comprises the reagent that stimulates cellular proliferation, and wherein said propagation reagent is selected from the group of being made up of dexamethasone, isotretinoin, 17-, estradiol, diethyl diethylstilbestrol, ciclosporin A, complete-trans retinoic acid (ATRA) and analog thereof and derivant.

989. the compositions of any one of 725-771 item, wherein said compositions also comprises polymeric carrier.

990. the compositions of any one of 725-771 item, wherein said compositions are the forms of gel, paste or spray.

991. the compositions of any one of 725-771 item, wherein said compositions are the forms of mesh or film.

992. the compositions of any one of 725-771 item is wherein with described reagent or comprise the injection of described combination of agents thing or be sprayed in the described diverticulum.

993. the compositions of any one of 725-771 item is wherein with described reagent or comprise the injection of described combination of agents thing or be sprayed to tissue or center in the tissue of described diverticulum.

994. the compositions of any one of 725-771 item, wherein said compositions also comprises filler.

995. the compositions of 725-771 item, wherein said compositions is a sealant.

996. the 725th compositions, wherein said compositions is a hemorrhage.

997. the compositions of any one of the 725th, wherein said compositions also comprises filler, and wherein said filler comprises microsphere.

998. the compositions of any one of 725-771 item, wherein said compositions also comprises filler, and wherein said filler comprises the gel of hydroxyapatite load.

999. the compositions of any one of 725-771 item, wherein said compositions also comprises filler, and wherein said filler comprises micronized alloderm acellular substrate.

1000. the compositions of any one of 725-771 item, wherein said compositions also comprises filler, and wherein said filler comprises hyaluronic acid.

1001. the compositions of any one of 725-771 item, wherein said compositions also comprises filler, and wherein said filler comprises the microballon in the hydrogel.

1002. the compositions of any one of 725-771 item, wherein said compositions also comprises filler, and wherein said filler comprises extra large blue polymer.

1003. the compositions of any one of 725-771 item, wherein said compositions also comprises filler, and wherein said filler comprises silicon microsphere and biocompatible polymer.

1004. comprise the compositions that fibrous tissue forms agent and filler.

1005. the 1004th compositions, wherein said fibrous tissue forms agent and promotes regeneration.

1006. the 1004th compositions, wherein said fibrous tissue form agent and promote fibre modification and promote regeneration.

1007. forming agent, the 1004th compositions, wherein said fibrous tissue promote blood vessel to take place.

1008. the 1004th compositions, wherein said fibrous tissue form agent and promote the fibroblast migration.

1009. the 1004th compositions, wherein said fibrous tissue forms agent and promotes fibroblast proliferation.

1010. the 1004th compositions, wherein said fibrous tissue forms the deposition that agent promotes extracellular matrix (ECM).

1011. the 1004th compositions, wherein said fibrous tissue forms agent and promotes tissue remodeling.

1012. the 1004th compositions, it is diverticulum wall stimulus object that wherein said fibrous tissue forms agent.

Be or comprise silk 1013. the 1004th compositions, wherein said fibrous tissue form agent.

Be or comprise silkworm silk 1014. the 1004th compositions, wherein said fibrous tissue form agent.

Be or comprise spider silk 1015. the 1004th compositions, wherein said fibrous tissue form agent.

Be or comprise the recombinant silk 1016. the 1004th compositions, wherein said fibrous tissue form agent.

Be or comprise raw silk 1017. the 1004th compositions, wherein said fibrous tissue form agent.

1018. the 1004th compositions, wherein said fibrous tissue forms the silk that agent is or comprises hydrolysis.

1019. the 1004th compositions, wherein said fibrous tissue formation agent is or comprises acid-treated.

1020. the 1004th compositions, wherein said fibrous tissue forms the silk that agent is or comprises acidylate.

1021. the 1004th compositions, it is the form of twisted wire that wherein said fibrous tissue forms agent.

1022. the 1004th compositions, wherein said fibrous tissue form the form that agent is bunch.

Be or comprise mineral grain 1023. the 1004th compositions, wherein said fibrous tissue form agent.

Be or comprise chitosan 1024. the 1004th compositions, wherein said fibrous tissue form agent.

Be or comprise polylysine 1025. the 1004th compositions, wherein said fibrous tissue form agent.

Be or comprise fibronectin 1026. the 1004th compositions, wherein said fibrous tissue form agent.

Be or comprise bleomycin 1027. the 1004th compositions, wherein said fibrous tissue form agent.

Be or comprise CTGF 1028. the 1004th compositions, wherein said fibrous tissue form agent.

Be or comprise fine hair 1029. the 1004th compositions, wherein said fibrous tissue form agent.

Be or comprise animal down 1030. the 1004th compositions, wherein said fibrous tissue form agent.

Be or comprise wood shavings 1031. the 1004th compositions, wherein said fibrous tissue form agent.

Be or comprise synthetic fine hair 1032. the 1004th compositions, wherein said fibrous tissue form agent.

1033. the 1004th compositions, it is the form of line that wherein said fibrous tissue forms agent, or contacts with line.

1034. the 1033rd compositions, wherein said line is biodegradable.

1035. the 1034th compositions, wherein said biodegradable line comprise the material that is selected from the group of being made up of polyester, poly-anhydride, poly-(anhydride ester), poly-(ester-acid amide), poly-(ester-urea), poe, poly phosphate, poly-phosphazine, polybutylcyanoacrylate, collagen, chitosan, hyaluronic acid, chromic catgut, alginate, starch, cellulose and cellulose esters.

1036. the 1033rd compositions, wherein said line are not biodegradable.

1037. the 1036th compositions, wherein said not biodegradable line comprise the material that is selected from the group of being made up of polyester, polyurethane, siloxanes, polyethylene, polypropylene, polystyrene, polyacrylate, polymethacrylates and silk.

1038. the 1033rd compositions, wherein said line scribbles polymer.

1039. the 1033rd compositions, wherein said line scribble the medicament of inducing fibrosis reaction in described host.

1040. the 1004th compositions, it is the form of microgranule that wherein said fibrous tissue forms agent.

1041. the 1040th compositions, wherein said microgranule are biodegradable microgranules.

1042. the 1041st compositions, wherein said Biodegradable microparticle comprise the material that is selected from the group of being made up of polyester, poly-anhydride, poly-(anhydride ester), poly-(ester-acid amide), poly-(ester-urea), poe, poly phosphate, poly-phosphazine, polybutylcyanoacrylate, collagen, chitosan, hyaluronic acid, chromic catgut, alginate, starch, cellulose and cellulose esters.

1043. the 1040th compositions, wherein said microgranule are not biodegradable microgranules.

1044. the 1043rd compositions, wherein said not biodegradable microgranule comprise the material that is selected from the group of being made up of polyester, polyurethane, siloxanes, polyethylene, polypropylene, polystyrene, polyacrylate, polymethacrylates and silk.

1045. the 1040th compositions, wherein said microgranule are the particulate form that is selected from the member of the group of being made up of silk, Talcum, starch, glass, silicate, Silicon stone, calcium phosphate, calcium sulfate, calcium carbonate, hydroxyapatite, synthetic mineral, polymethyl methacrylate, silver nitrate, pottery and other inorganic particle.

1046. the 1040th compositions, wherein said microgranule scribbles polymer.

1047. the 1040th compositions, wherein said microgranule scribble the medicament of inducing fibrosis reaction in described host.

1048. the 1040th compositions, wherein said microgranule scribble the member who is selected from the group of being made up of silk, Talcum, starch, glass, silicate, Silicon stone, calcium phosphate, calcium sulfate, calcium carbonate, hydroxyapatite, synthetic mineral, polymethyl methacrylate, silver nitrate, pottery and other inorganic particle.

1049. the 1004th compositions, wherein said compositions comprises somatomedin.

1050. the 1049th compositions, wherein said somatomedin is selected from transforming growth factor, platelet derived growth factor and fibroblast growth factor.

1051. the compositions of any one of 1004-1050 item, wherein said compositions also comprises polymer.

1052. the compositions of any one of 1004-1050 item, wherein said compositions also comprises polymer, and wherein said polymer is, or comprises copolymer.

1053. the compositions of any one of 1004-1050 item, wherein said compositions also comprises polymer, and wherein said polymer is, or comprises block copolymer.

1054. the compositions of any one of 1004-1050 item, wherein said compositions also comprises polymer, and wherein said polymer is, or comprises random copolymer.

1055. the compositions of any one of 1004-1050 item, wherein said compositions also comprises polymer, and wherein said polymer is, or comprises biodegradable polymer.

1056. the compositions of any one of 1004-1050 item, wherein said compositions also comprises polymer, and wherein said polymer is, or comprises not biodegradable polymer.

1057. the compositions of any one of 1004-1050 item, wherein said compositions also comprises polymer, and wherein said polymer is, or comprises hydrophilic polymer.

1058. the compositions of any one of 1004-1050 item, wherein said compositions also comprises polymer, and wherein said polymer is, or comprises hydrophobic polymer.

1059. the compositions of any one of 1004-1050 item, wherein said compositions also comprises polymer, and wherein said polymer is, or comprises the polymer of possess hydrophilic property domain.

1060. the compositions of any one of 1004-1050 item, wherein said compositions also comprises polymer, and wherein said polymer is, or comprises, and has the polymer in hydrophobic structure territory.

1061. the compositions of any one of 1004-1050 item, wherein said compositions also comprises polymer, and wherein said polymer is, or comprises non-conductive polymer.

1062. the compositions of any one of 1004-1050 item, wherein said compositions also comprises polymer, and wherein said polymer is, or comprises elastomer.

1063. the compositions of any one of 1004-1050 item, wherein said compositions also comprises polymer, and wherein said polymer is, or comprises hydrogel.

1064. the compositions of any one of 1004-1050 item, wherein said compositions also comprises polymer, and wherein said polymer is, or comprises siloxane polymer.

1065. the compositions of any one of 1004-1050 item, wherein said compositions also comprises polymer, and wherein said polymer is, or comprises hydrocarbon polymer.

1066. the compositions of any one of 1004-1050 item, wherein said compositions also comprises polymer, and wherein said polymer is, or comprises the styrene derived polymers.

1067. the compositions of any one of 1004-1050 item, wherein said compositions also comprises polymer, and wherein said polymer is, or comprises the butadiene derived polymer.

1068. the compositions of any one of 1004-1050 item, wherein said compositions also comprises polymer, and wherein said polymer is, or comprises macromonomer.

1069. the compositions of any one of 1004-1050 item, wherein said compositions also comprises polymer, and wherein said polymer is, or comprises, poly-(ethylene glycol).

1070. the compositions of any one of 1004-1050 item, wherein said compositions also comprises polymer, and wherein said polymer is, or comprises the collagen or derivatives thereof.

1071. the compositions of any one of 1004-1050 item, wherein said compositions also comprises polymer, and wherein said polymer is, or comprises methylated collagen.

1072. the compositions of any one of 1004-1050 item, wherein said compositions also comprises polymer, and wherein said compositions also comprises polymer composition, and wherein said polymer composition comprises collagen or derivatives thereof and fibrinogen.

1073. the compositions of any one of 1004-1050 item, wherein said compositions also comprises polymer, and wherein said compositions also comprises polymer composition, and wherein said polymer composition comprises collagen or derivatives thereof and thrombin.

1074. the compositions of any one of 1004-1050 item, wherein said compositions also comprises polymer, and wherein said compositions also comprises polymer composition, and wherein said polymer composition comprises (a) collagen or derivatives thereof; (b) fibrinogen; (c) thrombin.

1075. the compositions of any one of 1004-1050 item, wherein said compositions also comprises polymer, and wherein said compositions also comprises polymer composition, and wherein said polymer composition comprises methylated collagen and poly-(ethylene glycol).

1076. the compositions of any one of 1004-1050 item, wherein said compositions also comprises the hemorrhage that contains collagen polymer.

1077. the compositions of any one of 1004-1050 item, wherein said compositions also comprises the hemorrhage that contains poly-(ethylene glycol).

1078. the compositions of any one of 1004-1050 item, wherein said compositions also comprises the hemorrhage that contains collagen polymer, and wherein said hemorrhage is CT3.

1079. the compositions of any one of 1004-1050 item, wherein said compositions also comprises the hemorrhage that contains collagen polymer, and wherein said hemorrhage is COSTASIS.

1080. the compositions of any one of 1004-1050 item, wherein said compositions also comprises hemorrhage, and wherein said hemorrhage is COSEAL, TISSEALL or FLOSEAL.

1081. also comprising, the compositions of any one of 1004-1050 item, wherein said compositions contain fibrinous hemorrhage.

1082. the compositions of any one of 1004-1050 item, wherein said compositions also comprises polymer, and wherein said polymer is, or comprises amorphous polymer.

1083. the compositions of any one of 1004-1050 item, wherein said compositions also comprises polymer, and wherein said polymer is, or comprises cyanoacrylate.

1084. the 1083rd method, wherein said cyanoacrylate are selected from methyl 2-cyanoacrylate, cyanacrylate, Tisuacryl, octyl 2-cyanoacrylate and alpha-cyanoacrylate methoxyl group propyl ester.

1085. the compositions of any one of 1004-1050 item, wherein said compositions also comprises polymer, and wherein said polymer is, or comprises, poly-(alkyl cyanoacrylate).

1086. the 1085th method, wherein said poly-(alkyl cyanoacrylate) are selected from poly-(MCA), poly-(ethyl cyanoacrylate), poly-(butyl cyanoacrylate), poly-(isobutyl cyanoacrylate), poly-(hexyl cyanoacrylate) and poly-(octyl cyanoacrylate).

1087. the compositions of any one of 1004-1050 item, wherein said polymer are, or comprise poly-(carboxyalkyl cyanoacrylate).

1088. the 1087th method, wherein said poly-(carboxyalkyl cyanoacrylate) is poly-(methoxy-propyl cyanoacrylate).

1089. the compositions of any one of 1004-1050 item, wherein said compositions also comprises polymer, and wherein said polymer is crosslinked.

1090. the compositions of any one of 1004-1050 item, wherein said compositions also comprises polymer, and wherein said polymer and mammalian tissues reaction.

1091. the compositions of any one of 1004-1050 item, wherein said compositions also comprises polymer, and wherein said polymer is naturally occurring polymer.

1092. the compositions of any one of 1004-1050 item, wherein said compositions also comprises polymer, and wherein said polymer is a protein.

1093. the compositions of any one of 1004-1050 item, wherein said compositions also comprises polymer, and wherein said polymer is a saccharide.

1094. the compositions of any one of 1004-1050 item, wherein said compositions also comprises polymer, and wherein said polymer is crosslinked with biodegradable.

1095. the compositions of any one of 1004-1050 item, wherein said compositions comprises fibrinogen.

1096. the compositions of any one of 1004-1050 item, wherein said compositions comprises thrombin.

1097. the compositions of any one of 1004-1050 item, wherein said compositions comprises calcium salt.

1098. the compositions of any one of 1004-1050 item, wherein said compositions comprises antifibrinolytic agent.

1099. the compositions of any one of 1004-1050 item, wherein said compositions comprises the fibrinogen analog.

1100. the compositions of any one of 1004-1050 item, wherein said compositions comprises albumin.

1101. the compositions of any one of 1004-1050 item, wherein said compositions comprises plasminogen.

1102. the compositions of any one of 1004-1050 item, wherein said compositions comprises Feng's von willebrand's factor.

1103. the compositions of any one of 1004-1050 item, wherein said compositions comprises Factor IX.

1104. the compositions of any one of 1004-1050 item, wherein said compositions comprises hypoallergenic collagen.

1105. the compositions of any one of 1004-1050 item, wherein said compositions comprise end peptide collagen.

1106. the compositions of any one of 1004-1050 item, wherein said compositions comprises crosslinked collagen.

1107. the compositions of any one of 1004-1050 item, wherein said compositions comprises aprotinin.

1108. the compositions of any one of 1004-1050 item, wherein said compositions comprise epsilon-amino-just-caproic acid.

1109. the compositions of any one of 1004-1050 item, wherein said compositions comprises gelatin.

1110. the compositions of any one of 1004-1050 item, wherein said compositions comprises protein conjugate.

1111. the compositions of any one of 1004-1050 item, wherein said compositions comprises the gelatin conjugate.

1112. the compositions of any one of 1004-1050 item, wherein said compositions comprises hyaluronic acid.

1113. the compositions of any one of 1004-1050 item, wherein said compositions comprises derivatives of hyaluronic acids.

1114. the compositions of any one of 1004-1050 item, wherein said compositions comprises synthetic polymer.

1115. the compositions of any one of 1004-1050 item, wherein said polymer forms by comprising the synthetic reactant that contains the chemical compound of isocyanates.

1116. the compositions of any one of 1004-1050 item, wherein said compositions comprise the synthetic chemical compound that contains isocyanates.

1117. the compositions of any one of 1004-1050 item, wherein said compositions also comprises polymer, and wherein said polymer forms by comprising the synthetic reactant that contains the chemical compound of mercaptan.

1118. the compositions of any one of 1004-1050 item, wherein said compositions comprise the synthetic chemical compound that contains mercaptan.

1119. the compositions of any one of 1004-1050 item, wherein said compositions also comprises polymer, and wherein said polymer forms by comprising the synthetic reactant that contains the chemical compound of two mercaptos at least.

1120. the compositions of any one of 1004-1050 item, wherein said compositions comprise the synthetic chemical compound that contains at least two mercaptos.

1121. the compositions of any one of 1004-1050 item, wherein said compositions also comprises polymer, and wherein said polymer forms by comprising the synthetic reactant that contains the chemical compound of three mercaptos at least.

1122. the compositions of any one of 1004-1050 item, wherein said compositions comprise the synthetic chemical compound that contains at least three mercaptos.

1123. the compositions of any one of 1004-1050 item, wherein said compositions also comprises polymer, and wherein said polymer forms by comprising the synthetic reactant that contains the chemical compound of four mercaptos at least.

1124. the compositions of any one of 1004-1050 item, wherein said compositions comprise the synthetic chemical compound that contains at least four mercaptos.

1125. the compositions of any one of 1004-1050 item, wherein said compositions also comprises polymer, and wherein said polymer forms by comprising the synthetic reactant that contains amino chemical compound.

1126. the compositions of any one of 1004-1050 item, wherein said compositions comprise the synthetic amino chemical compound that contains.

1127. the compositions of any one of 1004-1050 item, wherein said compositions also comprises polymer, and wherein said polymer forms by comprising the synthetic reactant that contains the chemical compound of two amino at least.

1128. the compositions of any one of 1004-1050 item, wherein said compositions comprise the synthetic chemical compound that contains at least two amino.

1129. the compositions of any one of 1004-1050 item, wherein said compositions also comprises polymer, and wherein said polymer forms by comprising the synthetic reactant that contains the chemical compound of three amino at least.

1130. the compositions of any one of 1004-1050 item, wherein said compositions comprise the synthetic chemical compound that contains at least three amino.

1131. the compositions of any one of 1004-1050 item, wherein said compositions also comprises polymer, and wherein said polymer forms by comprising the synthetic reactant that contains the chemical compound of four amino at least.

1132. the compositions of any one of 1004-1050 item, wherein said compositions comprise the synthetic chemical compound that contains at least four amino.

1133. the compositions of any one of 1004-1050 item, wherein said compositions also comprises polymer, and wherein said polymer forms by comprising the synthetic reactant that contains the chemical compound of carbonyl-oxygen-succinimido.

1134. the compositions of any one of 1004-1050 item, wherein said compositions comprise the synthetic chemical compound that contains carbonyl-oxygen-succinimido.

1135. the compositions of any one of 1004-1050 item, wherein said compositions also comprises polymer, and wherein said polymer forms by comprising the synthetic reactant that contains the chemical compound of two carbonyl-oxygen-succinimido at least.

1136. the compositions of any one of 1004-1050 item, wherein said compositions comprise the synthetic chemical compound that contains at least two carbonyl-oxygen-succinimido.

1137. the compositions of any one of 1004-1050 item, wherein said compositions also comprises polymer, and wherein said polymer forms by comprising the synthetic reactant that contains the chemical compound of three carbonyl-oxygen-succinimido at least.

1138. the compositions of any one of 1004-1050 item, wherein said compositions comprise the synthetic chemical compound that contains at least three carbonyl-oxygen-succinimido.

1139. the compositions of any one of 1004-1050 item, wherein said compositions also comprises polymer, and wherein said polymer forms by comprising the synthetic reactant that contains the chemical compound of four carbonyl-oxygen-succinimido at least.

1140. the compositions of any one of 1004-1050 item, wherein said compositions comprise the synthetic chemical compound that contains at least four carbonyl-oxygen-succinimido.

1141. the compositions of any one of 1004-1050 item, wherein said compositions also comprises polymer, and wherein said polymer forms by comprising the synthetic reactant that contains the chemical compound of polyalkylene oxide.

1142. the compositions of any one of 1004-1050 item, wherein said compositions comprise the synthetic chemical compound that contains polyalkylene oxide.

1143. the compositions of any one of 1004-1050 item, wherein said compositions also comprises polymer, and wherein said compositions comprises polymer, and wherein said polymer forms by comprising the synthetic reactant that contains the chemical compound of polyalkylene oxide and biodegradable polyester block.

1144. the compositions of any one of 1004-1050 item, wherein said compositions comprise the synthetic chemical compound that contains polyalkylene oxide and biodegradable polyester block.

1145. the compositions of any one of 1004-1050 item, wherein said compositions also comprises polymer, and wherein said polymer forms by comprising synthetic reactant with chemical compound that contains polyalkylene oxide of reactive amino.

1146. the compositions of any one of 1004-1050 item, wherein said compositions comprise the synthetic chemical compound that contains polyalkylene oxide with reactive amino.

1147. the compositions of any one of 1004-1050 item, wherein said compositions also comprises polymer, and wherein said polymer forms by comprising synthetic reactant with chemical compound that contains polyalkylene oxide of reactive mercapto.

1148. the compositions of any one of 1004-1050 item, wherein said compositions comprise the synthetic chemical compound that contains polyalkylene oxide with reactive mercapto.

1149. the compositions of any one of 1004-1050 item, wherein said compositions also comprises polymer, and wherein said polymer forms by comprising synthetic reactant with chemical compound that contains polyalkylene oxide of reactive carbonyl-oxygen-succinimido.

1150. the compositions of any one of 1004-1050 item, wherein said compositions comprise the synthetic chemical compound that contains polyalkylene oxide with reactive carbonyl-oxygen-succinimido.

1151. the compositions of any one of 1004-1050 item, wherein said compositions also comprises polymer, and wherein said polymer forms by comprising the synthetic reactant that contains the chemical compound of biodegradable polyester block.

1152. the compositions of any one of 1004-1050 item, wherein said compositions comprise the synthetic chemical compound that contains the biodegradable polyester block.

1153. the compositions of any one of 1004-1050 item, wherein said compositions also comprises polymer, and wherein said polymer is formed by the reactant that comprises the synthetic polymer that is formed by lactic acid or lactide wholly or in part.

1154. the compositions of any one of 1004-1050 item, wherein said compositions comprises the synthetic polymer that is formed by lactic acid or lactide wholly or in part.

1155. the compositions of any one of 1004-1050 item, wherein said compositions also comprises polymer, and wherein said polymer is formed by the reactant that comprises the synthetic polymer that is formed by glycolic or Acetic acid, hydroxy-, bimol. cyclic ester wholly or in part.

1156. the compositions of any one of 1004-1050 item, wherein said compositions comprises the synthetic polymer that is formed by glycolic or Acetic acid, hydroxy-, bimol. cyclic ester wholly or in part.

1157. the compositions of any one of 1004-1050 item, wherein said compositions also comprises polymer, and wherein said polymer is formed by the reactant that comprises polylysine.

1158. the compositions of any one of 1004-1050 item, wherein said compositions comprises polylysine.

1159. the compositions of any one of 1004-1050 item, wherein said compositions also comprises polymer, and wherein said polymer forms by comprising the reactant of (a) protein with the chemical compound that (b) comprises the polyalkylene oxide part.

1160. the compositions of any one of 1004-1050 item, wherein said compositions comprise (a) protein and (b) comprise the chemical compound of polyalkylene oxide part.

1161. the compositions of any one of 1004-1050 item, wherein said compositions also comprises polymer, and wherein said polymer by comprise (a) protein and (b) reactant of polylysine form.

1162. the compositions of any one of 1004-1050 item, wherein said compositions comprise (a) protein and (b) polylysine.

1163. the compositions of any one of 1004-1050 item, wherein said compositions also comprises polymer, and wherein said polymer forms with the reactant that (b) has the chemical compound of four mercaptos by comprising (a) protein at least.

1164. the compositions of any one of 1004-1050 item, wherein said compositions comprise (a) protein and (b) have the chemical compound of at least four mercaptos.

1165. the compositions of any one of 1004-1050 item, wherein said compositions also comprises polymer, and wherein said polymer forms with the reactant that (b) has the chemical compound of four amino by comprising (a) protein at least.

1166. the compositions of any one of 1004-1050 item, wherein said compositions comprise (a) protein and (b) have the chemical compound of at least four amino.

1167. the compositions of any one of 1004-1050 item, wherein said compositions also comprises polymer, and wherein said polymer forms with the reactant that (b) has the chemical compound of four carbonyl-oxygen-succinimido by comprising (a) protein at least.

1168. the compositions of any one of 1004-1050 item, wherein said compositions comprise (a) protein and (b) have the chemical compound of at least four carbonyl-oxygen-succinimido.

1169. the compositions of any one of 1004-1050 item, wherein said compositions also comprises polymer, and wherein said polymer forms with the reactant that (b) has the chemical compound of the biodegradable region that is formed by the reactant that is selected from lactic acid, lactide, glycolic, Acetic acid, hydroxy-, bimol. cyclic ester and 6-caprolactone by comprising (a) protein.

1170. the chemical compound that the compositions of any one of 1004-1050 item, wherein said compositions comprise (a) protein and (b) have the biodegradable region that is formed by the reactant that is selected from lactic acid, lactide, glycolic, Acetic acid, hydroxy-, bimol. cyclic ester and 6-caprolactone.

1171. the compositions of any one of 1004-1050 item, wherein said compositions also comprises polymer, and wherein said polymer forms by comprising the reactant of (a) collagen with the chemical compound that (b) comprises the polyalkylene oxide part.

1172. the compositions of any one of 1004-1050 item, wherein said compositions comprise (a) collagen and (b) comprise the chemical compound of polyalkylene oxide part.

1173. the compositions of any one of 1004-1050 item, wherein said polymer by comprise (a) collagen and (b) reactant of polylysine form.

1174. the compositions of any one of 1004-1050 item, wherein said compositions comprise (a) collagen and (b) polylysine.

1175. the compositions of any one of 1004-1050 item, wherein said polymer forms with the reactant that (b) has the chemical compound of four mercaptos by comprising (a) collagen at least.

1176. the compositions of any one of 1004-1050 item, wherein said compositions comprise (a) collagen and (b) have the chemical compound of at least four mercaptos.

1177. the compositions of any one of 1004-1050 item, wherein said compositions also comprises polymer, and wherein said polymer forms with the reactant that (b) has the chemical compound of four amino by comprising (a) collagen at least.

1178. the compositions of any one of 1004-1050 item, wherein said compositions comprise (a) collagen and (b) have the chemical compound of at least four amino.

1179. the compositions of any one of 1004-1050 item, wherein said compositions also comprises polymer, and wherein said polymer forms with the reactant that (b) has the chemical compound of four carbonyl-oxygen-butanimide group by comprising (a) collagen at least.

1180. the compositions of any one of 1004-1050 item, wherein said compositions comprise (a) collagen and (b) have the chemical compound of at least four carbonyl-oxygen-succinimido.

1181. the compositions of any one of 1004-1050 item, wherein said compositions also comprises polymer, and wherein said polymer forms with the reactant that (b) has the chemical compound of the biodegradable region that is formed by the reactant that is selected from lactic acid, lactide, glycolic, Acetic acid, hydroxy-, bimol. cyclic ester and 6-caprolactone by comprising (a) collagen.

1182. the chemical compound that the compositions of any one of 1004-1050 item, wherein said compositions comprise (a) collagen and (b) have the biodegradable region that is formed by the reactant that is selected from lactic acid, lactide, glycolic, Acetic acid, hydroxy-, bimol. cyclic ester and 6-caprolactone.

1183. the compositions of any one of 1004-1050 item, wherein said compositions also comprises polymer, and wherein said polymer forms by comprising the reactant of (a) methylated collagen with the chemical compound that (b) comprises the polyalkylene oxide part.

1184. the compositions of any one of 1004-1050 item, wherein said compositions comprise (a) methylated collagen and (b) comprise the chemical compound of polyalkylene oxide part.

1185. the compositions of any one of 1004-1050 item, wherein said compositions also comprises polymer, and wherein said polymer by comprise (a) methylated collagen and (b) reactant of polylysine form.

1186. the compositions of any one of 1004-1050 item, wherein said compositions comprise (a) methylated collagen and (b) polylysine.

1187. the compositions of any one of 1004-1050 item, wherein said compositions also comprises polymer, and wherein said polymer forms with the reactant that (b) has the chemical compound of four mercaptos by comprising (a) methylated collagen at least.

1188. the compositions of any one of 1004-1050 item, wherein said compositions comprise (a) methylated collagen and (b) have the chemical compound of at least four mercaptos.

1189. the compositions of any one of 1004-1050 item, wherein said compositions also comprises polymer, and wherein said polymer forms with the reactant that (b) has the chemical compound of four amino by comprising (a) methylated collagen at least.

1190. the compositions of any one of 1004-1050 item, wherein said compositions comprise (a) methylated collagen and (b) have the chemical compound of at least four amino.

1191. the compositions of any one of 1004-1050 item, wherein said compositions also comprises polymer, and wherein said polymer forms with the reactant that (b) has the chemical compound of four carbonyl-oxygen-butanimide group by comprising (a) methylated collagen at least.

1192. the compositions of any one of 1004-1050 item, wherein said compositions comprise (a) methylated collagen and (b) have the chemical compound of at least four carbonyl-oxygen-succinimido.

1193. the compositions of any one of 1004-1050 item, wherein said compositions also comprises polymer, and wherein said polymer forms with the reactant that (b) has the chemical compound of the biodegradable region that is formed by the reactant that is selected from lactic acid, lactide, glycolic, Acetic acid, hydroxy-, bimol. cyclic ester and 6-caprolactone by comprising (a) methylated collagen.

1194. the chemical compound that the compositions of any one of 1004-1050 item, wherein said compositions comprise (a) methylated collagen and (b) have the biodegradable region that is formed by the reactant that is selected from lactic acid, lactide, glycolic, Acetic acid, hydroxy-, bimol. cyclic ester and 6-caprolactone.

1195. the compositions of any one of 1004-1050 item, wherein said compositions also comprises polymer, and wherein said polymer forms by comprising hyaluronic reactant.

1196. the compositions of any one of 1004-1050 item, wherein said compositions comprises hyaluronic acid.

1197. the compositions of any one of 1004-1050 item, wherein said compositions also comprises polymer, and wherein said polymer is formed by the reactant that comprises derivatives of hyaluronic acids.

1198. the compositions of any one of 1004-1050 item, wherein said compositions comprises derivatives of hyaluronic acids.

1199. the compositions of any one of 1004-1050 item, wherein said compositions also comprises polymer, and wherein said polymer is formed by the reactant that comprises poly-(ethylene glycol) ether four-sulfydryl of the tetramethylolmethane of number-average molecular weight between 3,000 and 30,000.

1200. the compositions of any one of 1004-1050 item, wherein said compositions comprise poly-(ethylene glycol) ether four-sulfydryl of the tetramethylolmethane of number-average molecular weight between 3,000 and 30,000.

1201. the compositions of any one of 1004-1050 item, wherein said compositions also comprises polymer, and wherein said polymer is formed by the reactant that comprises poly-(ethylene glycol) ether four of the tetramethylolmethane of number-average molecular weight between 3,000 and 30,000-amino.

1202. the compositions of any one of 1004-1050 item, wherein said compositions comprise poly-(ethylene glycol) ether four-amino of the tetramethylolmethane of number-average molecular weight between 3,000 and 30,000.

1203. the compositions of any one of 1004-1050 item, wherein said compositions also comprises polymer, and wherein said polymer is by comprising (a) synthetic number-average molecular weight 3,000 and 30, between 000 and comprise the chemical compound of polyalkylene oxide zone and a plurality of nucleophilic groups and (b) synthetic number-average molecular weight 3, between 000 and 30,000 and comprise the reactant formation of the chemical compound of polyalkylene oxide zone and a plurality of electrophilic groups.

1204. the compositions of any one of 1004-1050 item, wherein said compositions comprises (a) synthetic number-average molecular weight 3,000 and 30, between 000 and comprise the chemical compound of polyalkylene oxide zone and a plurality of nucleophilic groups, (b) synthetic number-average molecular weight is 3, between 000 and 30,000 and comprise the chemical compound of polyalkylene oxide zone and a plurality of electrophilic groups.

1205. the compositions of any one of 1004-1050 item, wherein said compositions comprises coloring agent.

1206. the compositions of any one of 1004-1050 item, wherein said compositions is aseptic.

1207. the compositions of any one of 1004-1050 item, wherein said compositions also comprises second forms of pharmacologically active agents.

1208. the compositions of any one of 1004-1050 item, wherein said compositions also comprises antiinflammatory.

1209. the compositions of any one of 1004-1050 item, wherein said compositions also comprises infection inhibitor.

1210. the compositions of any one of 1004-1050 item, wherein said compositions also comprises anthracycline.

1211. the compositions of any one of 1004-1050 item, wherein said compositions also comprises doxorubicin.

1212. the compositions of any one of 1004-1050 item, wherein said compositions also comprises mitoxantrone.

1213. the compositions of any one of 1004-1050 item, wherein said compositions also comprises the fluorine pyrimidine.

1214. the compositions of any one of 1004-1050 item, wherein said compositions also comprise 5-fluorouracil (5-FU).

1215. the compositions of any one of 1004-1050 item, wherein said compositions also comprises antifol.

1216. the compositions of any one of 1004-1050 item, wherein said compositions also comprises methotrexate.

1217. the compositions of any one of 1004-1050 item, wherein said compositions also comprises podophyllotoxin.

1218. the compositions of any one of 1004-1050 item, wherein said compositions also comprises etoposide.

1219. the compositions of any one of 1004-1050 item, wherein said compositions also comprises camptothecine.

1220. the compositions of any one of 1004-1050 item, wherein said compositions also comprises hydroxyurea.

1221. the compositions of any one of 1004-1050 item, wherein said compositions also comprises platinum complex.

1222. the compositions of any one of 1004-1050 item, wherein said compositions also comprises cisplatin.

1223. the compositions of any one of 1004-1050 item, wherein said compositions also comprises anti-infective.

1224. the compositions of any one of 1004-1050 item, wherein said compositions also comprises anti-infective, and wherein said anti-infective is an antibiotic.

1225. the compositions of any one of 1004-1050 item, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a doxycycline.

1226. the compositions of any one of 1004-1050 item, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a metronidazole.

1227. the compositions of any one of 1004-1050 item, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a trimethoprim-sulfamethoxazole.

1228. the compositions of any one of 1004-1050 item, wherein said compositions also comprises anti-infective, wherein said anti-infective be the 4th generation penicillin.

1229. the compositions of any one of 1004-1050 item, wherein said compositions also comprises anti-infective, wherein said anti-infective be selected from urea groups penicillin and penicillin carboxy the 4th generation penicillin, or its analog or derivant.

1230. the compositions of any one of 1004-1050 item, wherein said compositions also comprises anti-infective, wherein said anti-infective be selected from mezlocillin, piperacillin, Carbenicillin and ticarcillin the 4th generation penicillin.

1231. the compositions of any one of 1004-1050 item, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a first generation cephalosporin.

1232. the compositions of any one of 1004-1050 item, wherein said compositions also comprises anti-infective, and wherein said anti-infective is the first generation cephalosporin that is selected from cefazolin sodium, cefalexin, cefazolin sodium, cefaloject and cefalotin.

1233. the compositions of any one of 1004-1050 item, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a penicillin carboxy.

1234. the 1233rd compositions, wherein said penicillin carboxy is a ticarcillin.

1235. the compositions of any one of 1004-1050 item, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a second generation cephalosporin.

1236. the compositions of any one of 1004-1050 item, wherein said compositions also comprises anti-infective, and wherein said anti-infective is the second generation cephalosporin that is selected from cefuroxime, cefotetan and cefoxitin.

1237. the compositions of any one of 1004-1050 item, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a third generation cephalosporin.

1238. the compositions of any one of 1004-1050 item, wherein said compositions also comprises anti-infective, and wherein said anti-infective is the third generation cephalosporin that is selected from ceftiofur sodium, cefdinir, cefoperazone, ceftazidime, ceftriaxone and cefotaxime.

1239. the compositions of any one of 1004-1050 item, wherein said compositions also comprises anti-infective, wherein said anti-infective be the 4th generation cephalosporin.

1240. the 1239th compositions, wherein said the 4th generation cephalosporin be cefepime.

1241. the compositions of any one of 1004-1050 item, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a monobactam.

1242. the 1241st compositions, wherein said monobactam is an aztreonam.

1243. the compositions of any one of 1004-1050 item, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a carbapenem.

1244. the compositions of any one of 1004-1050 item, wherein said compositions also comprises anti-infective, and wherein said anti-infective is the carbapenem that is selected from imipenum, Ai Tapeinan and meropenem.

1245. the compositions of any one of 1004-1050 item, wherein said compositions also comprises anti-infective, and wherein said anti-infective is an aminoglycoside.

1246. the compositions of any one of 1004-1050 item, wherein said compositions also comprises anti-infective, and wherein said anti-infective is the aminoglycoside that is selected from streptomycin, gentamycin, tobramycin and amikacin.

1247. the compositions of any one of 1004-1050 item, wherein said compositions also comprises anti-infective, and wherein said anti-infective is the MSL group membership who is selected from macrolide, long-acting macrolide, lincosamide and streptogramin.

1248. the compositions of any one of 1004-1050 item, wherein said compositions also comprises anti-infective, and wherein said anti-infective is the MSL group membership who is selected from erythromycin, azithromycin, clindamycin, quinoline slave Pu Ding-dalfopristin, clarithromycin and kanamycin sulfate.

1249. the compositions of any one of 1004-1050 item, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a quinolinones.

1250. the compositions of any one of 1004-1050 item, wherein said compositions also comprises anti-infective, and wherein said anti-infective is the quinolinones that is selected from ciprofloxacin, ofloxacin, Gatifloxacin, Moxifloxacin, levofloxacin and trovafloxacin.

1251. the compositions of any one of 1004-1050 item, wherein said compositions also comprises anti-infective, and wherein said anti-infective is the DNA synthetic inhibitor.

1252. the 1251st compositions, wherein said DNA synthetic inhibitor is a metronidazole.

1253. the compositions of any one of 1004-1050 item, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a sulfonamide.

1254. the 1253rd compositions, wherein said sulfonamide is a trimethoprim.

1255. the compositions of any one of 1004-1050 item, wherein said compositions also comprises anti-infective, and wherein said anti-infective is selected from cefixime, spectinomycin, tetracycline, nitrofurantoin, polymyxin B and polygynax.

1256. the compositions of any one of 1004-1050 item, wherein said compositions also comprises developing agent.

1257. the compositions of any one of 1004-1050 item, wherein said compositions also comprises developing agent, and described developing agent is radio-opaque material, and wherein said radio-opaque material comprises metal, halogenated compound or contains the chemical compound of barium.

1258. the compositions of any one of 1004-1050 item, wherein said compositions also comprises developing agent, and described developing agent is, or comprises barium, tantalum or technetium.

1259. the compositions of any one of 1004-1050 item, wherein said compositions also comprises developing agent, and described developing agent is, or comprises MRI response material or echo material.

1260. the compositions of any one of 1004-1050 item, wherein said compositions also comprises developing agent, and described developing agent is, or comprises gadolinium chelate compound.

1261. the compositions of any one of 1004-1050 item, wherein said compositions also comprises a kind of developing agent, and described developing agent is, or comprises ferrum, magnesium, manganese, copper or chromium.

1262. the compositions of any one of 1004-1050 item, wherein said compositions also comprises developing agent, and described developing agent is, or comprises iron oxide compound.

1263. the compositions of any one of 1004-1050 item, wherein said compositions also comprises developing agent, and described developing agent is, or comprises dyestuff, pigment or coloring agent.

1264. forming agent, the compositions of any one of 1004-1050 item, wherein said fibrous tissue in the administration cycle to about 90 days scopes constantly, discharge from the compositions that comprises fibrous tissue and form agent with valid density by diffusion.

1265. forming agent corrosion by described compositions in the administration cycle to about 90 days scopes constantly, the compositions of any one of 1004-1050 item, wherein said fibrous tissue discharge from the compositions that comprises fibrous tissue and form agent with valid density.

1266. the compositions of any one of 1004-1050 item, wherein said compositions also comprises inflammatory cytokine.

1267. the compositions of any one of 1004-1050 item, wherein said compositions also comprises the reagent that stimulates cellular proliferation.

1268. the compositions of any one of 1004-1050 item, wherein said compositions also comprises the reagent that stimulates cellular proliferation, and wherein said propagation reagent is selected from by dexamethasone, isotretinoin, 17-, estradiol, diethyl diethylstilbestrol, ciclosporin A, complete--the group that trans retinoic acid (ATRA) and analog thereof and derivant are formed.

1269. the compositions of any one of 1004-1050 item, wherein said compositions also comprises polymeric carrier.

1270. the compositions of any one of 1004-1050 item, wherein said compositions are the forms of gel, paste or spray.

1271. the compositions of any one of 1004-1050 item, wherein said compositions are the forms of mesh or film.

1272. the compositions of any one of 1004-1050 item is wherein with described reagent or comprise the injection of described combination of agents thing or be sprayed in the described diverticulum.

1273. the compositions of any one of 1004-1050 item is wherein with described reagent or comprise the injection of described combination of agents thing or be sprayed to tissue or center in the tissue of described diverticulum.

1274. the 1004th compositions, wherein said filler is a sealant.

1275. the 1004th compositions, wherein said filler is a hemorrhage.

1276. the compositions of any one of 1004-1050 item, wherein said filler comprises microsphere.

1277. the compositions of any one of 1004-1050 item, wherein said filler comprises the gel of hydroxyapatite load.

1278. the compositions of any one of 1004-1050 item, wherein said filler comprise micronized alloderm acellular substrate.

1279. the compositions of any one of 1004-1050 item, wherein said filler comprises hyaluronic acid.

1280. the compositions of any one of 1004-1050 item, wherein said filler comprises the microballon in the hydrogel.

1281. the compositions of any one of 1004-1050 item, wherein said filler comprise extra large blue polymer.

1282. the compositions of any one of 1004-1050 item, wherein said filler comprise silicon microsphere and biocompatible polymer.

1283. the method for treatment diverticulum disease, described method comprises compositions is incorporated in the diverticulum among the host, described compositions comprises (a) fibrous tissue and forms agent and (b) polymer or in-situ polymerization and form the chemical compound of cross linked polymer, wherein said compositions is the inducing fibrosis reaction in diverticulum, treats the diverticulum disease among the host thus.

1284. the 1283rd method, wherein said diverticulum disease is a diverticulosis.

1285. the 1283rd method, wherein said diverticulum disease is a diverticulitis.

1286. the 1283rd method, wherein said diverticulum disease is a diverticulosis of colon.

1287. the 1283rd method, wherein said diverticulum disease is a hemorrhage of diverticulum.

1288. the 1283rd method, wherein said diverticulum disease are pharyngoesophagus (esophagus) diverticulums.

1289. the 1283rd method, wherein said diverticulum disease is a Meckel diverticulum.

1290. the 1283rd method, wherein said diverticulum disease is a diverticulosis of small intestine.

1291. the 1283rd method, wherein said diverticulum disease are the gastric diverticulum diseases.

1292. the 1283rd method, wherein said diverticulum disease are the urinary tract diverticulosiss.

1293. the 1283rd method, wherein said fibrous tissue forms agent and promotes regeneration.

1294. the 1283rd method, wherein said fibrous tissue form agent and promote fibre modification and promote regeneration.

1295. forming agent, the 1283rd method, wherein said fibrous tissue promote blood vessel to take place.

1296. the 1283rd method, wherein said fibrous tissue form agent and promote the fibroblast migration.

1297. the 1283rd method, wherein said fibrous tissue forms agent and promotes fibroblast proliferation.

1298. the 1283rd method, wherein said fibrous tissue forms the deposition that agent promotes extracellular matrix (ECM).

1299. the 1283rd method, wherein said fibrous tissue forms agent and promotes tissue remodeling.

1300. the 1283rd method, it is diverticulum wall stimulus object that wherein said fibrous tissue forms agent.

Be or comprise silk 1301. the 1283rd method, wherein said fibrous tissue form agent.

Be or comprise silkworm silk 1302. the 1283rd method, wherein said fibrous tissue form agent.

Be or comprise spider silk 1303. the 1283rd method, wherein said fibrous tissue form agent.

Be or comprise the recombinant silk 1304. the 1283rd method, wherein said fibrous tissue form agent.

Be or comprise raw silk 1305. the 1283rd method, wherein said fibrous tissue form agent.

1306. the 1283rd method, wherein said fibrous tissue forms the silk that agent is or comprises hydrolysis.

1307. the 1283rd method, wherein said fibrous tissue formation agent is or comprises acid-treated.

1308. the 1283rd method, wherein said fibrous tissue forms the silk that agent is or comprises acidylate.

1309. the 1283rd method, it is the form of twisted wire that wherein said fibrous tissue forms agent.

1310. the 1283rd method, wherein said fibrous tissue form the form that agent is bunch.

Be or comprise mineral grain 1311. the 1283rd method, wherein said fibrous tissue form agent.

Be or comprise chitosan 1312. the 1283rd method, wherein said fibrous tissue form agent.

Be or comprise polylysine 1313. the 1283rd method, wherein said fibrous tissue form agent.

Be or comprise fibronectin 1314. the 1283rd method, wherein said fibrous tissue form agent.

Be or comprise bleomycin 1315. the 1283rd method, wherein said fibrous tissue form agent.

Be or comprise CTGF 1316. the 1283rd method, wherein said fibrous tissue form agent.

Be or comprise fine hair 1317. the 1283rd method, wherein said fibrous tissue form agent.

Be or comprise animal down 1318. the 1283rd method, wherein said fibrous tissue form agent.

Be or comprise wood shavings 1319. the 1283rd method, wherein said fibrous tissue form agent.

Be or comprise synthetic fine hair 1320. the 1283rd method, wherein said fibrous tissue form agent.

1321. the 1283rd method, it is the form of line that wherein said fibrous tissue forms agent, or contacts with line.

1322. the 1321st method, wherein said line is biodegradable.

1323. the 1322nd method, wherein said biodegradable line comprise the material that is selected from the group of being made up of polyester, poly-anhydride, poly-(anhydride ester), poly-(ester-acid amide), poly-(ester-urea), poe, poly phosphate, poly-phosphazine, polybutylcyanoacrylate, collagen, chitosan, hyaluronic acid, chromic catgut, alginate, starch, cellulose and cellulose esters.

1324. the 1321st method, wherein said line are not biodegradable.

1325. the 1324th method, wherein said not biodegradable line comprise the material that is selected from the group of being made up of polyester, polyurethane, siloxanes, polyethylene, polypropylene, polystyrene, polyacrylate, polymethacrylates and silk.

1326. the 1321st method, wherein said line scribbles polymer.

1327. the 1321st method, wherein said line scribble the medicament of inducing fibrosis reaction in the host.

1328. the 1283rd method, it is the form of microgranule that wherein said fibrous tissue forms agent.

1329. the 1328th method, wherein said microgranule are biodegradable microgranules.

1330. the 1329th method, wherein said Biodegradable microparticle comprise the material that is selected from the group of being made up of polyester, poly-anhydride, poly-(anhydride ester), poly-(ester-acid amide), poly-(ester-urea), poe, poly phosphate, poly-phosphazine, polybutylcyanoacrylate, collagen, chitosan, hyaluronic acid, chromic catgut, alginate, starch, cellulose and cellulose esters.

1331. the 1328th method, wherein said microgranule are not biodegradable microgranules.

1332. the 1331st method, wherein said not biodegradable microgranule comprise the material that is selected from the group of being made up of polyester, polyurethane, siloxanes, polyethylene, polypropylene, polystyrene, polyacrylate, polymethacrylates and silk.

1333. the 1328th method, wherein said microgranule are the particulate form that is selected from the member of the group of being made up of silk, Talcum, starch, glass, silicate, silicon dioxide, calcium phosphate, calcium sulfate, calcium carbonate, hydroxyapatite, synthetic mineral, polymethyl methacrylate, silver nitrate, pottery and other inorganic particle.

1334. the 1328th method, wherein said microgranule scribbles polymer.

1335. the 1328th method, wherein said microgranule scribble the medicament of inducing fibrosis reaction in the host.

1336. the 1328th method, wherein said microgranule scribble the member who is selected from the group of being made up of silk, Talcum, starch, glass, silicate, Silicon stone, calcium phosphate, calcium sulfate, calcium carbonate, hydroxyapatite, synthetic mineral, polymethyl methacrylate, silver nitrate, pottery and other inorganic particle.

1337. the 1283rd method, wherein said compositions comprises somatomedin.

1338. the 1337th method, wherein said somatomedin is selected from transforming growth factor, platelet derived growth factor and fibroblast growth factor.

1339. the 1283rd method, wherein said polymer are, or comprise copolymer.

1340. the 1283rd method, wherein said polymer are, or comprise block copolymer.

1341. the 1283rd method, wherein said polymer are, or comprise random copolymer.

1342. the 1283rd method, wherein said polymer are, or comprise biodegradable polymer.

1343. the 1283rd method, wherein said polymer are, or comprise not biodegradable polymer.

1344. the 1283rd method, wherein said polymer are, or comprise hydrophilic polymer.

1345. the 1283rd method, wherein said polymer are, or comprise hydrophobic polymer.

1346. the 1283rd method, wherein said polymer are, or comprise the polymer of possess hydrophilic property domain.

1347. the 1283rd method, wherein said polymer be, or comprise, and has the polymer in hydrophobic structure territory.

1348. the 1283rd method, wherein said polymer are, or comprise non-conductive polymer.

1349. the 1283rd method, wherein said polymer are, or comprise elastomer.

1350. the 1283rd method, wherein said polymer are, or comprise hydrogel.

1351. the 1283rd method, wherein said polymer are, or comprise siloxane polymer.

1352. the 1283rd method, wherein said polymer are, or comprise hydrocarbon polymer.

1353. the 1283rd method, wherein said polymer are, or comprise the styrene derived polymer.

1354. the 1283rd method, wherein said polymer are, or comprise the butadiene derived polymer.

1355. the 1283rd method, wherein said polymer are, or comprise macromonomer.

1356. the 1283rd method, wherein said polymer are, or comprise poly-(ethylene glycol).

1357. the 1283rd method, wherein said polymer are, or comprise the collagen or derivatives thereof.

1358. the 1283rd method, wherein said polymer are, or comprise methylated collagen.

1359. the 1283rd method, wherein said polymer composition comprises collagen or derivatives thereof and fibrinogen.

1360. the 1283rd method, wherein said polymer composition comprises collagen or derivatives thereof and thrombin.

1361. the 1283rd method, wherein said polymer composition comprise (a) collagen or derivatives thereof; (b) fibrinogen; (c) thrombin.

1362. the 1283rd method, wherein said polymer composition comprise methylated collagen and poly-(ethylene glycol) or derivatives thereof.

1363. the 1283rd method, wherein said compositions also comprises hemorrhage, and described hemorrhage comprises collagen polymer.

1364. the 1283rd method, wherein said compositions also comprises hemorrhage, and described hemorrhage comprises collagen polymer, and wherein said hemorrhage is CT3.

1365. the 1283rd method, wherein said compositions also comprises hemorrhage, and described hemorrhage comprises collagen polymer, and wherein said hemorrhage is COSTASIS.

1366. the 1283rd method, wherein said compositions also comprises hemorrhage, and described hemorrhage comprises poly-(ethylene glycol).

1367. the 1283rd method, wherein said compositions also comprises hemorrhage, and wherein said hemorrhage is COSEAL, TISSEAL or FLOSEAL.

1368. the 1283rd method, wherein said compositions also comprises hemorrhage, and described hemorrhage comprises fibrin.

1369. the 1283rd method, wherein said polymer are, or comprise amorphous polymer.

1370. the 1283rd method, wherein said polymer are, or comprise cyanoacrylate.

1371. the 1370th method, wherein said cyanoacrylate are selected from methyl 2-cyanoacrylate, cyanacrylate, Tisuacryl, octyl 2-cyanoacrylate and alpha-cyanoacrylate methoxyl group propyl ester.

1372. the 1283rd method, wherein said polymer are, or comprise poly-(alkyl cyanoacrylate).

1373. the 1372nd method, wherein said poly-(alkyl cyanoacrylate) are selected from poly-(methyl 2-cyanoacrylate), poly-(cyanacrylate), poly-(Tisuacryl), poly-(isobutylcyanoacrylate), poly-(the own ester of alpha-cyanoacrylate) and poly-(octyl 2-cyanoacrylate).

1374. the 1283rd method, wherein said polymer are, or comprise poly-(carboxyalkyl cyanoacrylate).

1375. the 1374th method, wherein said poly-(carboxyalkyl cyanoacrylate) is poly-(methoxy-propyl cyanoacrylate).

1376. the 1283rd method, wherein said polymer is crosslinked.

1377. the 1283rd method, wherein said polymer and mammalian tissues reaction.

1378. the 1283rd method, wherein said polymer are naturally occurring polymer.

1379. the 1283rd method, wherein said polymer is a protein.

1380. the 1283rd method, wherein said polymer is a saccharide.

1381. the 1283rd method, wherein said polymer are crosslinked with biodegradable.

1382. the 1283rd method, wherein said compositions comprises fibrinogen.

1383. the 1283rd method, wherein said compositions comprises thrombin.

1384. the 1283rd method, wherein said compositions comprises calcium salt.

1385. the 1283rd method, wherein said compositions comprises antifibrinolytic agent.

1386. the 1283rd method, wherein said compositions comprises the fibrinogen analog.

1387. the 1283rd method, wherein said compositions comprises albumin.

1388. the 1283rd method, wherein said compositions comprises plasminogen.

1389. the 1283rd method, wherein said compositions comprises Feng's von willebrand's factor.

1390. the 1283rd method, wherein said compositions comprises Factor IX.

1391. the 1283rd method, wherein said compositions comprises hypoallergenic collagen.

1392. the 1283rd method, wherein said compositions comprise non-end peptide collagen.

1393. the 1283rd method, wherein said compositions comprises crosslinked collagen.

1394. the 1283rd method, wherein said compositions comprises aprotinin.

1395. the 1283rd method, wherein said compositions comprise epsilon-amino-just-caproic acid.

1396. the 1283rd method, wherein said compositions comprises gelatin.

1397. the 1283rd method, wherein said compositions comprises protein conjugate.

1398. the 1283rd method, wherein said compositions comprises the gelatin conjugate.

1399. the 1283rd method, wherein said compositions comprises hyaluronic acid.

1400. the 1283rd method, wherein said compositions comprises derivatives of hyaluronic acids.

1401. the 1283rd method, wherein said compositions comprises synthetic polymer.

1402. the 1283rd method, wherein said polymer forms by comprising the synthetic reactant that contains the chemical compound of isocyanates.

1403. the 1283rd method, wherein said compositions comprise the synthetic chemical compound that contains isocyanates.

1404. the 1283rd method, wherein said polymer forms by comprising the synthetic reactant that contains the chemical compound of mercaptan.

1405. the 1283rd method, wherein said compositions comprise the synthetic chemical compound that contains mercaptan.

1406. the 1283rd method, wherein said polymer forms by comprising the synthetic reactant that contains the chemical compound of two mercaptos at least.

1407. the 1283rd method, wherein said compositions comprise the synthetic chemical compound that contains at least two mercaptos.

1408. the 1283rd method, wherein said polymer forms by comprising the synthetic reactant that contains the chemical compound of three mercaptos at least.

1409. the 1283rd method, wherein said compositions comprise the synthetic chemical compound that contains at least three mercaptos.

1410. the 1283rd method, wherein said polymer forms by comprising the synthetic reactant that contains the chemical compound of four mercaptos at least.

1411. the 1283rd method, wherein said compositions comprise the synthetic chemical compound that contains at least four mercaptos.

1412. the 1283rd method, wherein said polymer forms by comprising the synthetic reactant that contains amino chemical compound.

1413. the 1283rd method, wherein said compositions comprise the synthetic amino chemical compound that contains.

1414. the 1283rd method, wherein said polymer forms by comprising the synthetic reactant that contains the chemical compound of two amino at least.

1415. the 1283rd method, wherein said compositions comprise the synthetic chemical compound that contains at least two amino.

1416. the 1283rd method, wherein said polymer forms by comprising the synthetic reactant that contains the chemical compound of three amino at least.

1417. the 1283rd method, wherein said compositions comprise the synthetic chemical compound that contains at least three amino.

1418. the 1283rd method, wherein said polymer forms by comprising the synthetic reactant that contains the chemical compound of four amino at least.

1419. the 1283rd method, wherein said compositions comprise the synthetic chemical compound that contains at least four amino.

1420. the 1283rd method, wherein said polymer forms by comprising the synthetic reactant that contains the chemical compound of carbonyl-oxygen-succinimido.

1421. the 1283rd method, wherein said compositions comprise the synthetic chemical compound that contains carbonyl-oxygen-succinimido.

1422. the 1283rd method, wherein said polymer forms by comprising the synthetic reactant that comprises the chemical compound of two carbonyl-oxygen-succinimido at least.

1423. the 1283rd method, wherein said compositions comprise the synthetic chemical compound that comprises at least two carbonyl-oxygen-succinimido.

1424. the 1283rd method, wherein said polymer forms by comprising the synthetic reactant that comprises the chemical compound of three carbonyl-oxygen-succinimido at least.

1425. the 1283rd method, wherein said compositions comprise the synthetic chemical compound that comprises at least three carbonyl-oxygen-succinimido.

1426. the 1283rd method, wherein said polymer forms by comprising the synthetic reactant that comprises the chemical compound of four carbonyl-oxygen-succinimido at least.

1427. the 1283rd method, wherein said compositions comprise the synthetic chemical compound that comprises at least four carbonyl-oxygen-succinimido.

1428. the 1283rd method, wherein said polymer forms by comprising the synthetic reactant that contains the chemical compound of polyalkylene oxide.

1429. the 1283rd method, wherein said compositions comprise the synthetic chemical compound that contains polyalkylene oxide.

1430. the 1283rd method, wherein said polymer forms by comprising the synthetic reactant that contains the chemical compound of polyalkylene oxide and biodegradable polyester block.

1431. the 1283rd method, wherein said compositions comprise the synthetic chemical compound that contains polyalkylene oxide and biodegradable polyester block.

1432. the 1283rd method, wherein said polymer forms by comprising synthetic reactant with chemical compound that contains polyalkylene oxide of reactive amino.

1433. the 1283rd method, wherein said compositions comprise the synthetic chemical compound that contains polyalkylene oxide with reactive amino.

1434. the 1283rd method, wherein said polymer forms by comprising synthetic reactant with chemical compound that contains polyalkylene oxide of reactive mercapto.

1435. the 1283rd method, wherein said compositions comprise the synthetic chemical compound that contains polyalkylene oxide with reactive mercapto.

1436. the 1283rd method, wherein said polymer forms by comprising synthetic reactant with chemical compound that contains polyalkylene oxide of reactive carbonyl-oxygen-succinimido.

1437. the 1283rd method, wherein said compositions comprise the synthetic chemical compound that contains polyalkylene oxide with reactive carbonyl-oxygen-succinimido.

1438. the 1283rd method, wherein said polymer forms by comprising the synthetic reactant that contains the chemical compound of biodegradable polyester block.

1439. the 1283rd method, wherein said compositions comprise the synthetic chemical compound that contains the biodegradable polyester block.

1440. the 1283rd method, wherein said polymer is formed by the reactant that comprises the synthetic polymer that is formed by lactic acid or lactide wholly or in part.

1441. the 1283rd method, wherein said compositions comprise the synthetic polymer that is formed by lactic acid or lactide wholly or in part.

1442. the 1283rd method, wherein said polymer is formed by the reactant that comprises the synthetic polymer that is formed by glycolic or Acetic acid, hydroxy-, bimol. cyclic ester wholly or in part.

1443. the 1283rd method, wherein said compositions comprise the synthetic polymer that is formed by glycolic or Acetic acid, hydroxy-, bimol. cyclic ester wholly or in part.

1444. the 1283rd method, wherein said polymer is formed by the reactant that comprises polylysine.

1445. the 1283rd method, wherein said compositions comprises polylysine.

1446. the 1283rd method, wherein said polymer forms by comprising the reactant of (a) protein with the chemical compound that (b) comprises the polyalkylene oxide part.

1447. the 1283rd method, wherein said compositions comprise (a) protein and (b) comprise the chemical compound of polyalkylene oxide part.

1448. the 1283rd method, wherein said polymer by comprise (a) protein and (b) reactant of polylysine form.

1449. the 1283rd method, wherein said compositions comprise (a) protein and (b) polylysine.

1450. the 1283rd method, wherein said polymer forms with the reactant that (b) has the chemical compound of four mercaptos by comprising (a) protein at least.

1451. the 1283rd method, wherein said compositions comprise (a) protein and (b) have the chemical compound of at least four mercaptos.

1452. the 1283rd method, wherein said polymer forms with the reactant that (b) has the chemical compound of four amino by comprising (a) protein at least.

1453. the 1283rd method, wherein said compositions comprise (a) protein and (b) have the chemical compound of at least four amino.

1454. the 1283rd method, wherein said polymer forms with the reactant that (b) has the chemical compound of four carbonyl-oxygen-butanimide group by comprising (a) protein at least.

1455. the 1283rd method, wherein said compositions comprise (a) protein and (b) have the chemical compound of at least four carbonyl-oxygen-butanimide group.

1456. the 1283rd method, wherein said polymer forms with the reactant that (b) has the chemical compound of the biodegradable region that is formed by the reactant that is selected from lactic acid, lactide, glycolic, Acetic acid, hydroxy-, bimol. cyclic ester and 6-caprolactone by comprising (a) protein.

1457. the chemical compound that the 1283rd method, wherein said compositions comprise (a) protein and (b) have the biodegradable region that is formed by the reactant that is selected from lactic acid, lactide, glycolic, Acetic acid, hydroxy-, bimol. cyclic ester and 6-caprolactone.

1458. the 1283rd method, wherein said polymer forms by comprising the reactant of (a) collagen with the chemical compound that (b) comprises the polyalkylene oxide part.

1459. the 1283rd method, wherein said compositions comprise (a) collagen and (b) comprise the chemical compound of polyalkylene oxide part.

1460. the 1283rd method, wherein said polymer by comprise (a) collagen and (b) reactant of polylysine form.

1461. the 1283rd method, wherein said compositions comprise (a) collagen and (b) polylysine.

1462. the 1283rd method, wherein said polymer forms with the reactant that (b) has the chemical compound of four mercaptos by comprising (a) collagen at least.

1463. the 1283rd method, wherein said compositions comprise (a) collagen and (b) have the chemical compound of at least four mercaptos.

1464. the 1283rd method, wherein said polymer forms with the reactant that (b) has the chemical compound of four amino by comprising (a) collagen at least.

1465. the 1283rd method, wherein said compositions comprise (a) collagen and (b) have the chemical compound of at least four amino.

1466. the 1283rd method, wherein said polymer forms with the reactant that (b) has the chemical compound of four carbonyl-oxygen-butanimide group by comprising (a) collagen at least.

1467. the 1283rd method, wherein said compositions comprise (a) collagen and (b) have the chemical compound of at least four carbonyl-oxygen-butanimide group.

1468. the 1283rd method, wherein said polymer forms with the reactant that (b) has the chemical compound of the biodegradable region that is formed by the reactant that is selected from lactic acid, lactide, glycolic, Acetic acid, hydroxy-, bimol. cyclic ester and 6-caprolactone by comprising (a) collagen.

1469. the chemical compound that the 1283rd method, wherein said compositions comprise (a) collagen and (b) have the biodegradable region that is formed by the reactant that is selected from lactic acid, lactide, glycolic, Acetic acid, hydroxy-, bimol. cyclic ester and 6-caprolactone.

1470. the 1283rd method, wherein said polymer forms by comprising the reactant of (a) methylated collagen with the chemical compound that (b) comprises the polyalkylene oxide part.

1471. the 1283rd method, wherein said compositions comprise (a) methylated collagen and (b) comprise the chemical compound of polyalkylene oxide part.

1472. the 1283rd method, wherein said polymer by comprise (a) methylated collagen and (b) reactant of polylysine form.

1473. the 1283rd method, wherein said compositions comprise (a) methylated collagen and (b) polylysine.

1474. the 1283rd method, wherein said polymer forms with the reactant that (b) has the chemical compound of four mercaptos by comprising (a) methylated collagen at least.

1475. the 1283rd method, wherein said compositions comprise (a) methylated collagen and (b) have the chemical compound of at least four mercaptos.

1476. the 1283rd method, wherein said polymer forms with the reactant that (b) has the chemical compound of four amino by comprising (a) methylated collagen at least.

1477. the 1283rd method, wherein said compositions comprise (a) methylated collagen and (b) have the chemical compound of at least four amino.

1478. the 1283rd method, wherein said polymer forms with the reactant that (b) has the chemical compound of four carbonyl-oxygen-butanimide group by comprising (a) methylated collagen at least.

1479. the 1283rd method, wherein said compositions comprise (a) methylated collagen and (b) have the chemical compound of at least four carbonyl-oxygen-butanimide group.

1480. the 1283rd method, wherein said polymer forms with the reactant that (b) has the chemical compound of the biodegradable region that is formed by the reactant that is selected from lactic acid, lactide, hydroxyacetic acid, Acetic acid, hydroxy-, bimol. cyclic ester and 6-caprolactone by comprising (a) methylated collagen.

1481. the chemical compound that the 1283rd method, wherein said compositions comprise (a) methylated collagen and (b) have the biodegradable region that is formed by the reactant that is selected from lactic acid, lactide, glycolic, Acetic acid, hydroxy-, bimol. cyclic ester and 6-caprolactone.

1482. the 1283rd method, wherein said polymer forms by comprising hyaluronic reactant.

1483. the 1283rd method, wherein said compositions comprises hyaluronic acid.

1484. the 1283rd method, wherein said polymer is formed by the reactant that comprises derivatives of hyaluronic acids.

1485. the 1283rd method, wherein said compositions comprises derivatives of hyaluronic acids.

1486. the 1283rd method, wherein said polymer is formed by the reactant that comprises poly-(ethylene glycol) ether four-sulfydryl of the tetramethylolmethane of number-average molecular weight between 3,000 and 30,000.

1487. the 1283rd method, wherein said compositions comprise poly-(ethylene glycol) ether four-sulfydryl of the tetramethylolmethane of number-average molecular weight between 3,000 and 30,000.

1488. the 1283rd method, wherein said polymer is formed by the reactant that comprises poly-(ethylene glycol) ether four of the tetramethylolmethane of number-average molecular weight between 3,000 and 30,000-amino.

1489. the 1283rd method, wherein said compositions comprise poly-(ethylene glycol) ether four-amino of the tetramethylolmethane of number-average molecular weight between 3,000 and 30,000.

1490. the 1283rd method, wherein said polymer is by comprising (a) synthetic number-average molecular weight 3,000 and 30, between 000 and comprise the chemical compound of polyalkylene oxide zone and a plurality of nucleophilic groups and (b) synthetic number-average molecular weight 3, between 000 and 30,000 and comprise the reactant formation of the chemical compound of polyalkylene oxide zone and a plurality of electrophilic groups.

1491. the 1283rd method, wherein said compositions comprises (a) synthetic number-average molecular weight 3,000 and 30, between 000 and comprise the chemical compound of polyalkylene oxide zone and a plurality of nucleophilic groups, (b) synthetic number-average molecular weight is 3, between 000 and 30,000 and comprise the chemical compound of polyalkylene oxide zone and a plurality of electrophilic groups.

1492. the 1283rd method, wherein said compositions comprises coloring agent.

1493. the 1283rd method, wherein said compositions is aseptic.

1494. the 1283rd method, wherein said compositions also comprises second forms of pharmacologically active agents.

1495. the 1283rd method, wherein said compositions also comprises antiinflammatory.

1496. the 1283rd method, wherein said compositions also comprises infection inhibitor.

1497. the 1283rd method, wherein said compositions also comprises anthracycline.

1498. the 1283rd method, wherein said compositions also comprises doxorubicin.

1499. the 1283rd method, wherein said compositions also comprises mitoxantrone.

1500. the 1283rd method, wherein said compositions also comprises the fluorine pyrimidine.

1501. the 1283rd method, wherein said compositions also comprise 5-fluorouracil (5-FU).

1502. the 1283rd method, wherein said compositions also comprises antifol.

1503. the 1283rd method, wherein said compositions also comprises methotrexate.

1504. the 1283rd method, wherein said compositions also comprises podophyllotoxin.

1505. the 1283rd method, wherein said compositions also comprises etoposide.

1506. the 1283rd method, wherein said compositions also comprises camptothecine.

1507. the 1283rd method, wherein said compositions also comprises hydroxyurea.

1508. the 1283rd method, wherein said compositions also comprises platinum complex.

1509. the 1283rd method, wherein said compositions also comprises cisplatin.

1510. the 1283rd method, wherein said compositions also comprises anti-infective.

1511. the 1283rd method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is an antibiotic.

1512. the 1283rd method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a doxycycline.

1513. the 1283rd method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a metronidazole.

1514. the 1283rd method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a trimethoprim-sulfamethoxazole.

1515. the 1283rd method, wherein said compositions also comprises anti-infective, wherein said anti-infective be the 4th generation penicillin.

1516. the 1283rd method, wherein said compositions also comprises anti-infective, wherein said anti-infective be selected from urea groups penicillin and penicillin carboxy the 4th generation penicillin, or its analog or derivant.

1517. the 1283rd method, wherein said compositions also comprises anti-infective, wherein said anti-infective be selected from mezlocillin, piperacillin, Carbenicillin and ticarcillin the 4th generation penicillin.

1518. the 1283rd method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a first generation cephalosporin.

1519. the 1283rd method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is the first generation cephalosporin that is selected from cefazolin sodium, cefalexin, cefazolin sodium, cefaloject and cefalotin.

1520. the 1283rd method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a penicillin carboxy.

1521. according to the 1520th method, wherein said penicillin carboxy is a ticarcillin.

1522. the 1283rd method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a second generation cephalosporin.

1523. the 1283rd method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is the second generation cephalosporin that is selected from cefuroxime, cefotetan and cefoxitin.

1524. the 1283rd method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a third generation cephalosporin.

1525. the 1283rd method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is the third generation cephalosporin that is selected from ceftiofur sodium, cefdinir, cefoperazone, ceftazidime, ceftriaxone and cefotaxime.

1526. the 1283rd method, wherein said compositions also comprises anti-infective, wherein said anti-infective be the 4th generation cephalosporin.

1527. the 1526th method, wherein said the 4th generation cephalosporin be cefepime.

1528. the 1283rd method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a monobactam.

1529. the 1528th method, wherein said monobactam is an aztreonam.

1530. the 1283rd method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a carbapenem.

1531. the 1283rd method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is the carbapenem that is selected from imipenum, Ai Tapeinan and meropenem.

1532. the 1283rd method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is an aminoglycoside.

1533. the 1283rd method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is the aminoglycoside that is selected from streptomycin, gentamycin, tobramycin and amikacin.

1534. the 1283rd method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is the MSL group membership who is selected from macrolide, long-acting macrolide, lincosamide and streptogramin.

1535. the 1283rd method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is the MSL group membership who is selected from erythromycin, azithromycin, clindamycin, quinoline slave Pu Ding-dalfopristin, clarithromycin and kanamycin sulfate.

1536. the 1283rd method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a quinolinones.

1537. the 1283rd method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is the quinolinones that is selected from ciprofloxacin, ofloxacin, Gatifloxacin, Moxifloxacin, levofloxacin and trovafloxacin.

1538. the 1283rd method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is the DNA synthetic inhibitor.

1539. the 1538th method, wherein said DNA synthetic inhibitor is a metronidazole.

1540. the 1283rd method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a sulfonamide.

1541. the 1540th method, wherein said sulfonamide is a trimethoprim.

1542. the 1283rd method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is selected from cefixime, spectinomycin, tetracycline, nitrofurantoin, polymyxin B and polygynax.

1543. the 1283rd method, wherein said compositions also comprises developing agent.

1544. the 1283rd method, wherein said compositions also comprises developing agent, and described developing agent is radio-opaque material, and wherein said radio-opaque material comprises metal, halogenated compound or contains the chemical compound of barium.

1545. the 1283rd method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises barium, tantalum or technetium.

1546. the 1283rd method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises MRI response material or echo material.

1547. the 1283rd method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises gadolinium chelate compound.

1548. the 1283rd method, wherein said compositions also comprises a kind of developing agent, and described developing agent is, or comprises ferrum, magnesium, manganese, copper or chromium.

1549. the 1283rd method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises iron oxide compound.

1550. the 1283rd method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises dyestuff, pigment or coloring agent.

1551. forming agent, the 1283rd method, wherein said fibrous tissue in the administration cycle to about 90 days scopes constantly, discharge from the compositions that comprises fibrous tissue and form agent with valid density by diffusion.

1552. forming agent corrosion by described compositions in the administration cycle to about 90 days scopes constantly, the 1283rd method, wherein said fibrous tissue discharge from the compositions that comprises fibrous tissue and form agent with valid density.

1553. the 1283rd method, wherein said compositions also comprises inflammatory cytokine.

1554. the 1283rd method, wherein said compositions also comprises the reagent that stimulates cellular proliferation.

1555. the 1283rd method, wherein said compositions also comprises the reagent that stimulates cellular proliferation, and wherein said propagation reagent is selected from the group of being made up of dexamethasone, isotretinoin, 17-, estradiol, diethylstibesterol, ciclosporin A, complete-trans retinoic acid (ATRA) and analog thereof and derivant.

1556. the 1283rd method, wherein said compositions also comprises polymeric carrier.

1557. the 1283rd method, wherein said compositions are the forms of gel, paste or spray.

1558. the 1283rd method, wherein said compositions are the forms of mesh or film.

1559. the 1283rd method is wherein sent described fibrous tissue from device and is formed agent, and described device is delivered to described fibrous tissue formation agent in the described diverticulum.

1560. the 1283rd method is wherein sent described fibrous tissue from implant and formed agent, wherein said implant is or comprises microsphere.

1561. the 1283rd method is wherein sent described fibrous tissue from implant and formed agent, wherein said implant is or comprises mesh.

1562. the 1283rd method is wherein sent described fibrous tissue from implant and formed agent, wherein said implant is or comprises film.

1563. the 1283rd method is wherein sent described fibrous tissue from device and formed agent, wherein said device is a conduit.

1564. the 1283rd method is wherein sent described fibrous tissue from device and formed agent, wherein said device is a drug delivery tube.

1565. the 1283rd method is wherein sent described fibrous tissue from device and formed agent, wherein said device is the radio-frequency (RF) ablation conduit.

1566. the 1283rd method is wherein sent described fibrous tissue from device and formed agent, wherein said device is the temperature ablation catheter.

1567. the 1283rd method is wherein sent described fibrous tissue from device and formed agent, wherein said device is the heat energy conduit.

1568. the 1283rd method is wherein sent described fibrous tissue from device and formed agent, wherein said device is the cryoablation conduit.

1569. the 1283rd method is wherein sent described fibrous tissue from device and formed agent, wherein said device is a laser catheter.

1570. the 1283rd method is wherein sent described fibrous tissue from device and formed agent, wherein said device is the radioactivity delivery catheter.

1571. the 1283rd method is wherein sent described fibrous tissue from device and formed agent, wherein said device is a balloon catheter.

1572. the 1283rd method is wherein sent described fibrous tissue from device and formed agent, wherein said device is the ultrasonic energy delivery catheter.

1573. the 1283rd method is wherein sent described fibrous tissue from device and formed agent, wherein said device is a rotation atherosclerotic plaque excision conduit.

1574. the 1283rd method is wherein sent described fibrous tissue from device and formed agent, wherein said device is that rotation atherosclerotic plaque excision device is a rotating blade.

1575. the 1283rd method is wherein sent described fibrous tissue from device and formed agent, wherein said device is the tissue abrasion device.

1576. the 1283rd method is wherein sent described fibrous tissue from device and formed agent, wherein said device is an atherosclerotic plaque excision device.

1577. the 1283rd method is wherein sent described fibrous tissue from device and formed agent, wherein said device is an atherosclerotic plaque excision conduit.

1578. the 1283rd method is wherein sent described fibrous tissue from device and formed agent, wherein said device is endoscope's dissecting knife.

1579. the 1283rd method is wherein introduced described fibrous tissue formation agent by sending from device, wherein said device also comprises coating, and described coating comprises described fibrous tissue formation agent.

1580. the 1283rd method is wherein introduced described fibrous tissue formation agent by sending from device, wherein said device also comprises coating, and described coating is configured on the surface of described device.

1581. the 1283rd method is wherein introduced described fibrous tissue formation agent by sending from device, wherein said device also comprises coating, and wherein said coating directly contacts described device.

1582. the 1283rd method is wherein introduced described fibrous tissue formation agent by sending from device, wherein said device also comprises coating, and the described device of wherein said coating mediate contact.

1583. the 1283rd method is wherein introduced described fibrous tissue formation agent by sending from device, wherein said device also comprises coating, and wherein said coating layer portion covers described device.

1584. the 1283rd method is wherein introduced described fibrous tissue formation agent by sending from device, wherein said device also comprises coating, and wherein said coating covers described device fully.

1585. the 1283rd method is wherein introduced described fibrous tissue formation agent by sending from device, wherein said fibrous tissue forms hole or the hole that agent is positioned at described device.

1586. the 1283rd method is wherein introduced described fibrous tissue formation agent by sending from device, wherein said fibrous tissue forms passage, chamber or the divet that agent is positioned at described device.

1587. the 1283rd method is wherein introduced described fibrous tissue formation agent by sending from device, wherein said device also comprises the echo material.

1588. the 1283rd method is wherein introduced described fibrous tissue and formed agent by sending from device, wherein said device also comprises the echo material, and the wherein said echo material form that is coating.

1589. the 1283rd method is wherein introduced described fibrous tissue formation agent by sending from device, wherein said device is aseptic.

1590. the 1283rd method is wherein introduced described reagent by sending from device, wherein said fibrous tissue forms near the tissue of agent described device use is discharged into later described device.

1591. the 1283rd method is wherein introduced described fibrous tissue formation agent by sending from device, wherein said fibrous tissue forms near the tissue of agent described device use is discharged into later described device, and wherein said tissue is a connective tissue.

1592. the 1283rd method is wherein introduced described fibrous tissue formation agent by sending from device, wherein said fibrous tissue forms near the tissue of agent described device use is discharged into later described device, and wherein said tissue is a muscular tissue.

1593. the 1283rd method is wherein introduced described fibrous tissue formation agent by sending from device, wherein said fibrous tissue forms near the tissue of agent described device use is discharged into later described device, and wherein said tissue is a nervous tissue.

1594. the 1283rd method is wherein introduced described fibrous tissue formation agent by sending from device, wherein said fibrous tissue forms near the tissue of agent described device use is discharged into later described device, and wherein said tissue is an epithelial tissue.

1595. the 1283rd method is wherein introduced described fibrous tissue formation agent by sending from device, wherein said fibrous tissue forms agent and discharges from described device with valid density in about 1 year cycle in described device use.

1596. the 1283rd method is wherein introduced described fibrous tissue and formed agent by sending from device, wherein said fibrous tissue forms agent and discharges from described device with valid density in the cycle in about 1 month to 6 months scopes.

1597. the 1283rd method wherein introduce described fibrous tissue formation agent by sending from device, and wherein said fibrous tissue discharged from described device with valid density in the formation cycle of agent in about 1-90 days scope.

1598. the 1283rd method wherein introduce described fibrous tissue formation agent by sending from device, and wherein said fibrous tissue formation agent discharges from described device with valid density with constant rate of speed.

1599. the 1283rd method wherein introduce described fibrous tissue formation agent by sending from device, and wherein said fibrous tissue formation agent discharges from described device with valid density with the speed that increases progressively.

1600. the 1283rd method wherein introduce described fibrous tissue formation agent by sending from device, and wherein said reagent discharges from described device with valid density with the speed of successively decreasing.

1601. the 1283rd method, wherein said compositions comprise the fibrous tissue formation agent of about 0.01 μ g to about 10 μ g.

1602. the 1283rd method, wherein said compositions comprise the fibrous tissue formation agent of about 10 μ g to about 10mg.

1603. the 1283rd method, wherein said compositions comprise the fibrous tissue formation agent of about 10mg to about 250mg.

1604. the 1283rd method, wherein said compositions comprise the fibrous tissue formation agent of about 250mg to about 1000mg.

1605. the 1283rd method, wherein said compositions comprise the fibrous tissue formation agent of about 1000mg to about 2500mg.

1606. the 1283rd method wherein introduce described fibrous tissue formation agent by sending from implant, and the fibrous tissue that the surface of wherein said implant comprises less than 0.01 μ g forms agent/mm ²The applied implant surface of described reagent.

1607. the 1283rd method is wherein introduced described fibrous tissue formation agent by sending from implant, and the surface of wherein said implant comprises about 0.01 μ g to about 1 μ g fibrous tissue formation agent/mm ²The applied implant surface of described reagent.

1608. the 1283rd method is wherein introduced described fibrous tissue formation agent by sending from implant, and the surface of wherein said implant comprises the fibrous tissue formation agent/mm of about 1 μ g to about 10 μ g ²The applied implant surface of described reagent.

1609. the 1283rd method is wherein introduced described fibrous tissue formation agent by sending from implant, and the surface of wherein said implant comprises about 10 μ g to about 250 μ g fibrous tissue formation agent/mm ²The applied implant surface of described reagent.

1610. the 1283rd method is wherein introduced described fibrous tissue formation agent by sending from implant, and the surface of wherein said implant comprises the fibrous tissue formation agent/mm of about 250 μ g to about 1000 μ g ²Described fibrous tissue forms the applied implant surface of agent.

1611. the 1283rd method is wherein introduced described fibrous tissue formation agent by sending from implant, and the surface of wherein said implant comprises about 1000 μ g to about 2500 μ g fibrous tissue formation agent/mm ²The applied implant surface of described reagent.

1612. the 1283rd method is wherein introduced described fibrous tissue formation agent by sending from implant, wherein said implant also comprises coating, and wherein said coating is a uniform coating.

1613. the 1283rd method is wherein introduced described fibrous tissue formation agent by sending from implant, wherein said implant also comprises coating, and wherein said coating is inhomogeneous coating.

1614. the 1283rd method is wherein introduced described fibrous tissue formation agent by sending from implant, wherein said implant also comprises coating, and wherein said coating is discontinuous coating.

1615. the 1283rd method is wherein introduced described fibrous tissue formation agent by sending from implant, wherein said implant also comprises coating, and wherein said coating is to form the coating of pattern.

1616. the 1283rd method is wherein introduced described fibrous tissue formation agent by sending from implant, wherein said implant also comprises coating, and wherein said coating has 100 μ m or littler thickness.

1617. the 1283rd method is wherein introduced described fibrous tissue formation agent by sending from implant, wherein said implant also comprises coating, and wherein said coating has 10 μ m or littler thickness.

1618. the 1283rd method is wherein introduced described fibrous tissue formation agent by sending from implant, wherein said implant also comprises coating, and wherein said coating adheres to the surface of described implant when described implant is used.

1619. the 1283rd method is wherein introduced described fibrous tissue formation agent by sending from implant, wherein said implant also comprises coating, and wherein said coating is at room temperature stablized the cycle at least 1 year.

1620. the 1283rd method, wherein introduce described fibrous tissue formation agent by sending from implant, wherein said implant also comprises coating, and wherein said fibrous tissue forms agent and is present in the described coating to the amount in about 1 weight % scope with about 0.0001 weight %.

1621. the 1283rd method, wherein introduce described fibrous tissue formation agent by sending from implant, wherein said implant also comprises coating, and wherein said fibrous tissue forms agent and is present in the described coating to the amount in about 10 weight % scopes with about 1 weight %.

1622. the 1283rd method, wherein introduce described fibrous tissue formation agent by sending from implant, wherein said implant also comprises coating, and wherein said fibrous tissue forms agent and is present in the described coating to the amount in about 25 weight % scopes with about 10 weight %.

1623. the 1283rd method, wherein introduce described fibrous tissue formation agent by sending from implant, wherein said implant also comprises coating, and wherein said fibrous tissue forms agent and is present in the described coating to the amount in about 70 weight % scopes with about 25 weight %.

1624. the 1283rd method is wherein introduced described fibrous tissue formation agent by sending from implant, wherein said implant also comprises coating, and wherein said coating comprises polymer.

1625. the 1283rd method is wherein introduced described fibrous tissue formation agent by sending from implant, wherein said implant comprises first coating with first compositions and second coating with second compositions.

1626. the 1283rd method, wherein send described fibrous tissue and form agent from implant, wherein said implant comprises first coating with first compositions and second coating with second compositions, and wherein first compositions is different with second compositions.

1627. the 1283rd method wherein forms described fibrous tissue agent or comprises described fibrous tissue and forms the compositions injection of agent or be sprayed to described diverticulum.

1628. the 1283rd method wherein forms described fibrous tissue agent or comprises described fibrous tissue and forms the compositions injection of agent or be sprayed to tissue or center in the tissue of described diverticulum.

1629. the 1283rd method, wherein said compositions also comprises filler.

1630. the 1283rd method, wherein said compositions is a sealant.

1631. the 1283rd method, wherein said compositions is a hemorrhage.

1632. the 1283rd method, wherein said compositions also comprises filler, and wherein said filler comprises microsphere.

1633. the 1283rd method, wherein said compositions also comprises filler, and wherein said filler comprises the gel of hydroxyapatite load.

1634. the 1283rd method, wherein said compositions also comprises filler, and wherein said filler comprises micronized alloderm acellular substrate.

1635. the 1283rd method, wherein said compositions also comprises filler, and wherein said filler comprises hyaluronic acid.

1636. the 1283rd method, wherein said compositions also comprises filler, and wherein said filler comprises the microballon in the hydrogel.

1637. the 1283rd method, wherein said compositions also comprises filler, and wherein said filler comprises extra large blue polymer.

1638. the 1283rd method, wherein said compositions also comprises filler, and wherein said filler comprises silicon microsphere and biocompatible polymer.

1639. the 1283rd method, described method also comprises the existence that manifests diverticulum.

1640. the 1639th method, the existence that wherein manifests diverticulum comprises splanchnoscopy.

1641. the 1639th method, the existence that wherein manifests diverticulum comprises the radiography imaging.

1642. the 1283rd method, described method are washed described diverticulum with rinse solution before also being included in and introducing described fibrous tissue formation agent.

1643. the 1642nd method, wherein said rinse solution comprise (a) anti-infective or (b) antiseptic or (c) anti-infective and antiseptic.

1644. in host's diverticulum, induce fibrotic method, described method comprises compositions is inserted among the described host, described compositions comprises (a) fibrous tissue formation agent and (b) polymer or in-situ polymerization are to form the chemical compound of cross linked polymer, and wherein said compositions is induced fibre modification in described host.

1645. the 1644th method is wherein induced fibre modification prevention or treatment diverticulum disease in diverticulum.

1646. the 1644th method, wherein said diverticulum disease is a diverticulitis.

1647. the 1644th method, wherein said diverticulum disease is a diverticulosis.

1648. the 1644th method, wherein said diverticulum disease is a hemorrhage of diverticulum.

1649. the 1644th method, wherein said diverticulum disease are pharyngoesophagus (esophagus) diverticulums.

1650. the 1644th method, wherein said diverticulum disease is a Meckel diverticulum.

1651. the 1644th method, wherein said diverticulum disease is a diverticulosis of small intestine.

1652. the 1644th method, wherein said diverticulum disease are gastric diverticulum disease or urinary tract diverticulosis.

1653. the 1644th method, wherein said diverticulum disease is a diverticulosis of colon.

1654. the 1644th method, wherein said fibrous tissue forms agent and promotes regeneration.

1655. the 1644th method, wherein said fibrous tissue form agent and promote fibre modification and promote regeneration.

1656. forming agent, the 1644th method, wherein said fibrous tissue promote blood vessel to take place.

1657. the 1644th method, wherein said fibrous tissue form agent and promote the fibroblast migration.

1658. the 1644th method, wherein said fibrous tissue forms agent and promotes fibroblast proliferation.

1659. the 1644th compositions, wherein said fibrous tissue forms the deposition that agent promotes extracellular matrix (ECM).

1660. the 1644th method, wherein said fibrous tissue forms agent and promotes tissue remodeling.

1661. the 1644th method, it is diverticulum wall stimulus object that wherein said fibrous tissue forms agent.

Be or comprise silk 1662. the 1644th method, wherein said fibrous tissue form agent.

Be or comprise silkworm silk 1663. the 1644th method, wherein said fibrous tissue form agent.

Be or comprise spider silk 1664. the 1644th method, wherein said fibrous tissue form agent.

Be or comprise the recombinant silk 1665. the 1644th method, wherein said fibrous tissue form agent.

Be or comprise raw silk 1666. the 1644th method, wherein said fibrous tissue form agent.

1667. the 1644th method, wherein said fibrous tissue forms the silk that agent is or comprises hydrolysis.

1668. the 1644th method, wherein said fibrous tissue formation agent is or comprises acid-treated.

1669. the 1644th method, wherein said fibrous tissue forms the silk that agent is or comprises acidylate.

1670. the 1644th method, it is the form of twisted wire that wherein said fibrous tissue forms agent.

1671. the 1644th method, wherein said fibrous tissue form the form that agent is bunch.

Be or comprise mineral grain 1672. the 1644th method, wherein said fibrous tissue form agent.

Be or comprise chitosan 1673. the 1644th method, wherein said fibrous tissue form agent.

Be or comprise polylysine 1674. the 1644th method, wherein said fibrous tissue form agent.

Be or comprise fibronectin 1675. the 1644th method, wherein said fibrous tissue form agent.

Be or comprise bleomycin 1676. the 1644th method, wherein said fibrous tissue form agent.

Be or comprise CTGF 1677. the 1644th method, wherein said fibrous tissue form agent.

Be or comprise fine hair 1678. the 1644th method, wherein said fibrous tissue form agent.

Be or comprise animal down 1679. the 1644th method, wherein said fibrous tissue form agent.

Be or comprise wood shavings 1680. the 1644th method, wherein said fibrous tissue form agent.

Be or comprise synthetic fine hair 1681. the 1644th method, wherein said fibrous tissue form agent.

1682. the 1644th method, it is the form of line that wherein said fibrous tissue forms agent, or contacts with line.

1683. the 1682nd method, wherein said line is biodegradable.

1684. the 1683rd method, wherein said biodegradable line comprise the material that is selected from the group of being made up of polyester, poly-anhydride, poly-(anhydride ester), poly-(ester-acid amide), poly-(ester-urea), poe, poly phosphate, poly-phosphazine, polybutylcyanoacrylate, collagen, chitosan, hyaluronic acid, chromic catgut, alginate, starch, cellulose and cellulose esters.

1685. the 1682nd method, wherein said line are not biodegradable.

1686. the 1685th method, wherein said not biodegradable line comprise the material that is selected from the group of being made up of polyester, polyurethane, siloxanes, polyethylene, polypropylene, polystyrene, polyacrylate, polymethacrylates and silk.

1687. the 1682nd method, wherein said line scribbles polymer.

1688. the 1682nd method, wherein said line scribble the medicament of inducing fibrosis reaction in the host.

1689. the 1644th method, it is the form of microgranule that wherein said fibrous tissue forms agent.

1690. the 1689th method, wherein said microgranule are biodegradable microgranules.

1691. the 1690th method, wherein said Biodegradable microparticle comprise the material that is selected from the group of being made up of polyester, poly-anhydride, poly-(anhydride ester), poly-(ester-acid amide), poly-(ester-urea), poe, poly phosphate, poly-phosphazine, polybutylcyanoacrylate, collagen, chitosan, hyaluronic acid, chromic catgut, alginate, starch, cellulose and cellulose esters.

1692. the 1689th method, wherein said microgranule are not biodegradable microgranules.

1693. the 1692nd method, wherein said not biodegradable microgranule comprise the material that is selected from the group of being made up of polyester, polyurethane, siloxanes, polyethylene, polypropylene, polystyrene, polyacrylate, polymethacrylates and silk.

1694. the 1689th method, wherein said microgranule are the particulate form that is selected from the member of the group of being made up of silk, Talcum, starch, glass, silicate, silicon dioxide, calcium phosphate, calcium sulfate, calcium carbonate, hydroxyapatite, synthetic mineral, polymethyl methacrylate, silver nitrate, pottery and other inorganic particle.

1695. the 1689th method, wherein said microgranule scribbles polymer.

1696. the 1689th method, wherein said microgranule scribble the medicament of inducing fibrosis reaction in the host.

1697. the 1689th method, wherein said microgranule scribble the member who is selected from the group of being made up of silk, Talcum, starch, glass, silicate, Silicon stone, calcium phosphate, calcium sulfate, calcium carbonate, hydroxyapatite, synthetic mineral, polymethyl methacrylate, silver nitrate, pottery and other inorganic particle.

1698. the 1644th method, wherein said compositions comprises somatomedin.

1699. the 1698th method, wherein said somatomedin is selected from transforming growth factor, platelet derived growth factor and fibroblast growth factor.

1700. the 1644th method, wherein said polymer are, or comprise copolymer.

1701. the 1644th method, wherein said polymer are, or comprise block copolymer.

1702. the 1644th method, wherein said polymer are, or comprise random copolymer.

1703. the 1644th method, wherein said polymer are, or comprise biodegradable polymer.

1704. the 1644th method, wherein said polymer are, or comprise not biodegradable polymer.

1705. the 1644th method, wherein said polymer are, or comprise hydrophilic polymer.

1706. the 1644th method, wherein said polymer are, or comprise hydrophobic polymer.

1707. the 1644th method, wherein said polymer are, or comprise the polymer of possess hydrophilic property domain.

1708. the 1644th method, wherein said polymer be, or comprise, and has the polymer in hydrophobic structure territory.

1709. the 1644th method, wherein said polymer are, or comprise non-conductive polymer.

1710. the 1644th method, wherein said polymer are, or comprise elastomer.

1711. the 1644th method, wherein said polymer are, or comprise hydrogel.

1712. the 1644th method, wherein said polymer are, or comprise siloxane polymer.

1713. the 1644th method, wherein said polymer are, or comprise hydrocarbon polymer.

1714. the 1644th method, wherein said polymer are, or comprise the styrene derived polymer.

1715. the 1644th method, wherein said polymer are, or comprise the butadiene derived polymer.

1716. the 1644th method, wherein said polymer are, or comprise macromonomer.

1717. the 1644th method, wherein said polymer are, or comprise poly-(ethylene glycol).

1718. the 1644th method, wherein said polymer are, or comprise the collagen or derivatives thereof.

1719. the 1644th method, wherein said polymer are, or comprise methylated collagen.

1720. the 1644th method, wherein said polymer composition comprises collagen or derivatives thereof and fibrinogen.

1721. the 1644th method, wherein said polymer composition comprises collagen or derivatives thereof and thrombin.

1722. the 1644th method, wherein said polymer composition comprise (a) collagen or derivatives thereof; (b) fibrinogen; (c) thrombin.

1723. the 1644th method, wherein said polymer composition comprise methylated collagen and poly-(ethylene glycol) or derivatives thereof.

1724. the 1644th method, wherein said compositions also comprises hemorrhage, and described hemorrhage comprises collagen polymer.

1725. the 1644th method, wherein said compositions also comprises hemorrhage, and described hemorrhage comprises collagen polymer, and wherein said hemorrhage is CT3.

1726. the 1644th method, wherein said compositions also comprises hemorrhage, and described hemorrhage comprises collagen polymer, and wherein said hemorrhage is COSTASIS.

1727. the 1644th method, wherein said compositions also comprises hemorrhage, and described hemorrhage comprises poly-(ethylene glycol).

1728. the 1644th method, wherein said compositions also comprises hemorrhage, and wherein said hemorrhage is COSEAL, TISSEAL or FLOSEAL.

1729. the 1644th method, wherein said compositions also comprises hemorrhage, and described hemorrhage comprises fibrin.

1730. the 1644th method, wherein said polymer are, or comprise amorphous polymer.

1731. the 1644th method, wherein said polymer are, or comprise cyanoacrylate.

1732. the 1731st method, wherein said cyanoacrylate are selected from methyl 2-cyanoacrylate, cyanacrylate, Tisuacryl, octyl 2-cyanoacrylate and alpha-cyanoacrylate methoxyl group propyl ester.

1733. the 1644th method, wherein said polymer are, or comprise poly-(alkyl cyanoacrylate).

1734. the 1733rd method, wherein said poly-(alkyl cyanoacrylate) are selected from poly-(MCA), poly-(ethyl cyanoacrylate), poly-(butyl cyanoacrylate), poly-(isobutyl cyanoacrylate), poly-(hexyl cyanoacrylate) and poly-(octyl cyanoacrylate).

1735. the 1644th method, wherein said polymer are, or comprise poly-(carboxyalkyl cyanoacrylate).

1736. the 1735th method, wherein said poly-(carboxyalkyl cyanoacrylate) is poly-(methoxy-propyl cyanoacrylate).

1737. the 1644th method, wherein said polymer is crosslinked.

1738. the 1644th method, wherein said polymer and mammalian tissues reaction.

1739. the 1644th method, wherein said polymer are naturally occurring polymer.

1740. the 1644th method, wherein said polymer is a protein.

1741. the 1644th method, wherein said polymer is a saccharide.

1742. the 1644th method, wherein said polymer are crosslinked with biodegradable.

1743. the 1644th method, wherein said compositions comprises fibrinogen.

1744. the 1644th method, wherein said compositions comprises thrombin.

1745. the 1644th method, wherein said compositions comprises calcium salt.

1746. the 1644th method, wherein said compositions comprises antifibrinolytic agent.

1747. the 1644th method, wherein said compositions comprises the fibrinogen analog.

1748. the 1644th method, wherein said compositions comprises albumin.

1749. the 1644th method, wherein said compositions comprises plasminogen.

1750. the 1644th method, wherein said compositions comprises Feng's von willebrand's factor.

1751. the 1644th method, wherein said compositions comprises Factor IX.

1752. the 1644th method, wherein said compositions comprises hypoallergenic collagen.

1753. the 1644th method, wherein said compositions comprise non-end peptide collagen.

1754. the 1644th method, wherein said compositions comprises crosslinked collagen.

1755. the 1644th method, wherein said compositions comprises aprotinin.

1756. the 1644th method, wherein said compositions comprise epsilon-amino-just-caproic acid.

1757. the 1644th method, wherein said compositions comprises gelatin.

1758. the 1644th method, wherein said compositions comprises protein conjugate.

1759. the 1644th method, wherein said compositions comprises the gelatin conjugate.

1760. the 1644th method, wherein said compositions comprises hyaluronic acid.

1761. the 1644th method, wherein said compositions comprises derivatives of hyaluronic acids.

1762. the 1644th method, wherein said compositions comprises synthetic polymer.

1763. the 1644th method, wherein said polymer forms by comprising the synthetic reactant that contains the chemical compound of isocyanates.

1764. the 1644th method, wherein said compositions comprise the synthetic chemical compound that contains isocyanates.

1765. the 1644th method, wherein said polymer forms by comprising the synthetic reactant that contains the chemical compound of mercaptan.

1766. the 1644th method, wherein said compositions comprise the synthetic chemical compound that contains mercaptan.

1767. the 1644th method, wherein said polymer forms by comprising the synthetic reactant that contains the chemical compound of two mercaptos at least.

1768. the 1644th method, wherein said compositions comprise the synthetic chemical compound that contains at least two mercaptos.

1769. the 1644th method, wherein said polymer forms by comprising the synthetic reactant that contains the chemical compound of three mercaptos at least.

1770. the 1644th method, wherein said compositions comprise the synthetic chemical compound that contains at least three mercaptos.

1771. the 1644th method, wherein said polymer forms by comprising the synthetic reactant that contains the chemical compound of four mercaptos at least.

1772. the 1644th method, wherein said compositions comprise the synthetic chemical compound that contains at least four mercaptos.

1773. the 1644th method, wherein said polymer forms by comprising the synthetic reactant that contains amino chemical compound.

1774. the 1644th method, wherein said compositions comprise the synthetic amino chemical compound that contains.

1775. the 1644th method, wherein said polymer forms by comprising the synthetic reactant that contains the chemical compound of two amino at least.

1776. the 1644th method, wherein said compositions comprise the synthetic chemical compound that contains at least two amino.

1777. the 1644th method, wherein said polymer forms by comprising the synthetic reactant that contains the chemical compound of three amino at least.

1778. the 1644th method, wherein said compositions comprise the synthetic chemical compound that contains at least three amino.

1779. the 1644th method, wherein said polymer is formed by the reactant that comprises synthetic compound, and described synthetic compound contains at least four amino.

1780. the 1644th method, wherein said compositions comprise the synthetic chemical compound that contains at least four amino.

1781. the 1644th method, wherein said polymer forms by comprising the synthetic reactant that contains the chemical compound of carbonyl-oxygen-succinimido.

1782. the 1644th method, wherein said compositions comprise the synthetic chemical compound that contains carbonyl-oxygen-succinimido.

1783. the 1644th method, wherein said polymer forms by comprising the synthetic reactant that comprises the chemical compound of two carbonyl-oxygen-succinimido at least.

1784. the 1644th method, wherein said compositions comprise the synthetic chemical compound that comprises at least two carbonyl-oxygen-succinimido.

1785. the 1644th method, wherein said polymer forms by comprising the synthetic reactant that comprises the chemical compound of three carbonyl-oxygen-succinimido at least.

1786. the 1644th method, wherein said compositions comprise the synthetic chemical compound that comprises at least three carbonyl-oxygen-succinimido.

1787. the 1644th method, wherein said polymer forms by comprising the synthetic reactant that comprises the chemical compound of four carbonyl-oxygen-succinimido at least.

1788. the 1644th method, wherein said compositions comprise the synthetic chemical compound that comprises at least four carbonyl-oxygen-succinimido.

1789. the 1644th method, wherein said polymer forms by comprising the synthetic reactant that contains the chemical compound of polyalkylene oxide.

1790. the 1644th method, wherein said compositions comprise the synthetic chemical compound that contains polyalkylene oxide.

1791. the 1644th method, wherein said polymer forms by comprising the synthetic reactant that contains the chemical compound of polyalkylene oxide and biodegradable polyester block.

1792. the 1644th method, wherein said compositions comprise the synthetic chemical compound that contains polyalkylene oxide and biodegradable polyester block.

1793. the 1644th method, wherein said polymer forms by comprising synthetic reactant with chemical compound that contains polyalkylene oxide of reactive amino.

1794. the 1644th method, wherein said compositions comprise the synthetic chemical compound that contains polyalkylene oxide with reactive amino.

1795. the 1644th method, wherein said polymer forms by comprising synthetic reactant with chemical compound that contains polyalkylene oxide of reactive mercapto.

1796. the 1644th method, wherein said compositions comprise the synthetic chemical compound that contains polyalkylene oxide with reactive mercapto.

1797. the 1644th method, wherein said polymer forms by comprising synthetic reactant with chemical compound that contains polyalkylene oxide of reactive carbonyl-oxygen-succinimido.

1798. the 1644th method, wherein said compositions comprise the synthetic chemical compound that contains polyalkylene oxide with reactive carbonyl-oxygen-succinimido.

1799. the 1644th method, wherein said polymer forms by comprising the synthetic reactant that contains the chemical compound of biodegradable polyester block.

1800. the 1644th method, wherein said compositions comprise the synthetic chemical compound that contains the biodegradable polyester block.

1801. the 1644th method, wherein said polymer is formed by the reactant that comprises the synthetic polymer that is formed by lactic acid or lactide wholly or in part.

1802. the 1644th method, wherein said compositions comprise the synthetic polymer that is formed by lactic acid or lactide wholly or in part.

1803. the 1644th method, wherein said polymer is formed by the reactant that comprises the synthetic polymer that is formed by glycolic or Acetic acid, hydroxy-, bimol. cyclic ester wholly or in part.

1804. the 1644th method, wherein said compositions comprise the synthetic polymer that is formed by glycolic or Acetic acid, hydroxy-, bimol. cyclic ester wholly or in part.

1805. the 1644th method, wherein said polymer is formed by the reactant that comprises polylysine.

1806. the 1644th method, wherein said compositions comprises polylysine.

1807. the 1644th method, wherein said polymer forms by comprising the reactant of (a) protein with the chemical compound that (b) comprises the polyalkylene oxide part.

1808. the 1644th method, wherein said compositions comprise (a) protein and (b) comprise the chemical compound of polyalkylene oxide part.

1809. the 1644th method, wherein said polymer by comprise (a) protein and (b) reactant of polylysine form.

1810. the 1644th method, wherein said compositions comprise (a) protein and (b) polylysine.

1811. the 1644th method, wherein said polymer forms with the reactant that (b) has the chemical compound of four mercaptos by comprising (a) protein at least.

1812. the 1644th method, wherein said compositions comprise (a) protein and (b) have the chemical compound of at least four mercaptos.

1813. the 1644th method, wherein said polymer forms with the reactant that (b) has the chemical compound of four amino by comprising (a) protein at least.

1814. the 1644th method, wherein said compositions comprise (a) protein and (b) have the chemical compound of at least four amino.

1815. the 1644th method, wherein said polymer forms with the reactant that (b) has the chemical compound of four carbonyl-oxygen-butanimide group by comprising (a) protein at least.

1816. the 1644th method, wherein said compositions comprise (a) protein and (b) have the chemical compound of at least four carbonyl-oxygen-butanimide group.

1817. the 1644th method, wherein said polymer forms with the reactant that (b) has the chemical compound of the biodegradable region that is formed by the reactant that is selected from lactic acid, lactide, glycolic, Acetic acid, hydroxy-, bimol. cyclic ester and 6-caprolactone by comprising (a) protein.

1818. the chemical compound that the 1644th method, wherein said compositions comprise (a) protein and (b) have the biodegradable region that is formed by the reactant that is selected from lactic acid, lactide, glycolic, Acetic acid, hydroxy-, bimol. cyclic ester and 6-caprolactone.

1819. the 1644th method, wherein said polymer forms by comprising the reactant of (a) collagen with the chemical compound that (b) comprises the polyalkylene oxide part.

1820. the 1644th method, wherein said compositions comprise (a) collagen and (b) comprise the chemical compound of polyalkylene oxide part.

1821. the 1644th method, wherein said polymer by comprise (a) collagen and (b) reactant of polylysine form.

1822. the 1644th method, wherein said compositions comprise (a) collagen and (b) polylysine.

1823. the 1644th method, wherein said polymer forms with the reactant that (b) has the chemical compound of four mercaptos by comprising (a) collagen at least.

1824. the 1644th method, wherein said compositions comprise (a) collagen and (b) have the chemical compound of at least four mercaptos.

1825. the 1644th method, wherein said polymer forms with the reactant that (b) has the chemical compound of four amino by comprising (a) collagen at least.

1826. the 1644th method, wherein said compositions comprise (a) collagen and (b) have the chemical compound of at least four amino.

1827. the 1644th method, wherein said polymer forms with the reactant that (b) has the chemical compound of four carbonyl-oxygen-butanimide group by comprising (a) collagen at least.

1828. the 1644th method, wherein said compositions comprise (a) collagen and (b) have the chemical compound of at least four carbonyl-oxygen-butanimide group.

1829. the 1644th method, wherein said polymer forms with the reactant that (b) has the chemical compound of the biodegradable region that is formed by the reactant that is selected from lactic acid, lactide, glycolic, Acetic acid, hydroxy-, bimol. cyclic ester and 6-caprolactone by comprising (a) collagen.

1830. the chemical compound that the 1644th method, wherein said compositions comprise (a) collagen and (b) have the biodegradable region that is formed by the reactant that is selected from lactic acid, lactide, glycolic, Acetic acid, hydroxy-, bimol. cyclic ester and 6-caprolactone.

1831. the 1644th method, wherein said polymer forms by comprising the reactant of (a) methylated collagen with the chemical compound that (b) comprises the polyalkylene oxide part.

1832. the 1644th method, wherein said compositions comprise (a) methylated collagen and (b) comprise the chemical compound of polyalkylene oxide part.

1833. the 1644th method, wherein said polymer by comprise (a) methylated collagen and (b) reactant of polylysine form.

1834. the 1644th method, wherein said compositions comprise (a) methylated collagen and (b) polylysine.

1835. the 1644th method, wherein said polymer forms with the reactant that (b) has the chemical compound of four mercaptos by comprising (a) methylated collagen at least.

1836. the 1644th method, wherein said compositions comprise (a) methylated collagen and (b) have the chemical compound of at least four mercaptos.

1837. the 1644th method, wherein said polymer forms with the reactant that (b) has the chemical compound of four amino by comprising (a) methylated collagen at least.

1838. the 1644th method, wherein said compositions comprise (a) methylated collagen and (b) have the chemical compound of at least four amino.

1839. the 1644th method, wherein said polymer forms with the reactant that (b) has the chemical compound of four carbonyl-oxygen-butanimide group by comprising (a) methylated collagen at least.

1840. the 1644th method, wherein said compositions comprise (a) methylated collagen and (b) have the chemical compound of at least four carbonyl-oxygen-butanimide group.

1841. the 1644th method, wherein said polymer forms with the reactant that (b) has the chemical compound of the biodegradable region that is formed by the reactant that is selected from lactic acid, lactide, glycolic, Acetic acid, hydroxy-, bimol. cyclic ester and 6-caprolactone by comprising (a) methylated collagen.

1842. the chemical compound that the 1644th method, wherein said compositions comprise (a) methylated collagen and (b) have the biodegradable region that is formed by the reactant that is selected from lactic acid, lactide, glycolic, Acetic acid, hydroxy-, bimol. cyclic ester and 6-caprolactone.

1843. the 1644th method, wherein said polymer forms by comprising hyaluronic reactant.

1844. the 1644th method, wherein said compositions comprises hyaluronic acid.

1845. the 1644th method, wherein said polymer is formed by the reactant that comprises derivatives of hyaluronic acids.

1846. the 1644th method, wherein said compositions comprises derivatives of hyaluronic acids.

1847. the 1644th method, wherein said polymer is formed by the reactant that comprises poly-(ethylene glycol) ether four-sulfydryl of the tetramethylolmethane of number-average molecular weight between 3,000 and 30,000.

1848. the 1644th method, wherein said compositions comprise poly-(ethylene glycol) ether four-sulfydryl of the tetramethylolmethane of number-average molecular weight between 3,000 and 30,000.

1849. the 1644th method, wherein said polymer is formed by the reactant that comprises poly-(ethylene glycol) ether four of the tetramethylolmethane of number-average molecular weight between 3,000 and 30,000-amino.

1850. the 1644th method, wherein said compositions comprise poly-(ethylene glycol) ether four-amino of the tetramethylolmethane of number-average molecular weight between 3,000 and 30,000.

1851. the 1644th method, wherein said polymer is by comprising (a) synthetic number-average molecular weight 3,000 and 30, between 000 and comprise the chemical compound of polyalkylene oxide zone and a plurality of nucleophilic groups and (b) synthetic number-average molecular weight 3, between 000 and 30,000 and comprise the reactant formation of the chemical compound of polyalkylene oxide zone and a plurality of electrophilic groups.

1852. the 1644th method, wherein said compositions comprises (a) synthetic number-average molecular weight 3,000 and 30, between 000 and comprise the chemical compound of polyalkylene oxide zone and a plurality of nucleophilic groups, (b) synthetic number-average molecular weight is 3, between 000 and 30,000 and comprise the chemical compound of polyalkylene oxide zone and a plurality of electrophilic groups.

1853. the 1644th method, wherein said compositions comprises coloring agent.

1854. the 1644th method, wherein said compositions is aseptic.

1855. the 1644th method, wherein said compositions also comprises second forms of pharmacologically active agents.

1856. the 1644th method, wherein said compositions also comprises antiinflammatory.

1857. the 1644th method, wherein said compositions also comprises infection inhibitor.

1858. the 1644th method, wherein said compositions also comprises anthracycline.

1859. the 1644th method, wherein said compositions also comprises doxorubicin.

1860. the 1644th method, wherein said compositions also comprises mitoxantrone.

1861. the 1644th method, wherein said compositions also comprises the fluorine pyrimidine.

1862. the 1644th method, wherein said compositions also comprise 5-fluorouracil (5-FU).

1863. the 1644th method, wherein said compositions also comprises antifol.

1864. the 1644th method, wherein said compositions also comprises methotrexate.

1865. the 1644th method, wherein said compositions also comprises podophyllotoxin.

1866. the 1644th method, wherein said compositions also comprises etoposide.

1867. the 1644th method, wherein said compositions also comprises camptothecine.

1868. the 1644th method, wherein said compositions also comprises hydroxyurea.

1869. the 1644th method, wherein said compositions also comprises platinum complex.

1870. the 1644th method, wherein said compositions also comprises cisplatin.

1871. the 1644th method, wherein said compositions also comprises anti-infective.

1872. the 1644th method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is an antibiotic.

1873. the 1644th method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a doxycycline.

1874. the 1644th method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a metronidazole.

1875. the 1644th method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a trimethoprim-sulfamethoxazole.

1876. the 1644th method, wherein said compositions also comprises anti-infective, wherein said anti-infective be the 4th generation penicillin.

1877. the 1644th method, wherein said compositions also comprises anti-infective, wherein said anti-infective be selected from urea groups penicillin and penicillin carboxy the 4th generation penicillin, or its analog or derivant.

1878. the 1644th method, wherein said compositions also comprises anti-infective, wherein said anti-infective be selected from mezlocillin, piperacillin, Carbenicillin and ticarcillin the 4th generation penicillin.

1879. the 1644th method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a first generation cephalosporin.

1880. the 1644th method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is the first generation cephalosporin that is selected from cefazolin sodium, cefalexin, cefazolin sodium, cefaloject and cefalotin.

1881. the 1644th method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a penicillin carboxy.

1882. according to the 1881st method, wherein said penicillin carboxy is a ticarcillin.

1883. the 1644th method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a second generation cephalosporin.

1884. the 1644th method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is the second generation cephalosporin that is selected from cefuroxime, cefotetan and cefoxitin.

1885. the 1644th method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a third generation cephalosporin.

1886. the 1644th method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is the third generation cephalosporin that is selected from ceftiofur sodium, cefdinir, cefoperazone, ceftazidime, ceftriaxone and cefotaxime.

1887. the 1644th method, wherein said compositions also comprises anti-infective, wherein said anti-infective be the 4th generation cephalosporin.

1888. the 1887th method, wherein said the 4th generation cephalosporin be cefepime.

1889. the 1644th method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a monobactam.

1890. the 1889th method, wherein said monobactam is an aztreonam.

1891. the 1644th method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a carbapenem.

1892. the 1644th method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is the carbapenem that is selected from imipenum, Ai Tapeinan and meropenem.

1893. the 1644th method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is an aminoglycoside.

1894. the 1644th method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is the aminoglycoside that is selected from streptomycin, gentamycin, tobramycin and amikacin.

1895. the 1644th method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is the MSL group membership who is selected from macrolide, long-acting macrolide, lincosamide and streptogramin.

1896. the 1644th method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is the MSL group membership who is selected from erythromycin, azithromycin, clindamycin, quinoline slave Pu Ding-dalfopristin, clarithromycin and kanamycin sulfate.

1897. the 1644th method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a quinolinones.

1898. the 1644th method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is the quinolinones that is selected from ciprofloxacin, ofloxacin, Gatifloxacin, Moxifloxacin, levofloxacin and trovafloxacin.

1899. the 1644th method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is the DNA synthetic inhibitor.

1900. the 1899th method, wherein said DNA synthetic inhibitor is a metronidazole.

1901. the 1644th method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a sulfonamide.

1902. the 1901st method, wherein said sulfonamide is a trimethoprim.

1903. the 1644th method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is selected from cefixime, spectinomycin, tetracycline, nitrofurantoin, polymyxin B and polygynax.

1904. the 1644th method, wherein said compositions also comprises developing agent.

1905. the 1644th method, wherein said compositions also comprises developing agent, and described developing agent is radio-opaque material, and wherein said radio-opaque material comprises metal, halogenated compound or contains the chemical compound of barium.

1906. the 1644th method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises barium, tantalum or technetium.

1907. the 1644th method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises MRI response material or echo material.

1908. the 1644th method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises gadolinium chelate compound.

1909. the 1644th method, wherein said compositions also comprises a kind of developing agent, and described developing agent is, or comprises ferrum, magnesium, manganese, copper or chromium.

1910. the 1644th method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises iron oxide compound.

1911. the 1644th method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises dyestuff, pigment or coloring agent.

1912. forming agent, the 1644th method, wherein said fibrous tissue in the administration cycle to about 90 days scopes constantly, discharge from the compositions that comprises fibrous tissue and form agent with valid density by diffusion.

1913. forming agent corrosion by described compositions in the administration cycle to about 90 days scopes constantly, the 1644th method, wherein said fibrous tissue discharge from the compositions that comprises fibrous tissue and form agent with valid density.

1914. the 1644th method, wherein said compositions also comprises inflammatory cytokine.

1915. the 1644th method, wherein said compositions also comprises the reagent that stimulates cellular proliferation.

1916. the 1644th method, wherein said compositions also comprises the reagent that stimulates cellular proliferation, and wherein said propagation reagent is selected from the group of being made up of dexamethasone, isotretinoin, 17-, estradiol, diethyl diethylstilbestrol, ciclosporin A, complete-trans retinoic acid (ATRA) and analog thereof and derivant.

1917. the 1644th method, wherein said compositions also comprises polymeric carrier.

1918. the 1644th method, wherein said compositions are the forms of gel, paste or spray.

1919. the 1644th method, wherein said compositions are the forms of mesh or film.

1920. the 1644th method is wherein sent described fibrous tissue from device and is formed agent, and described device is delivered to described fibrous tissue formation agent in the described diverticulum.

1921. the 1644th method is wherein sent described fibrous tissue from implant and formed agent, wherein said implant is or comprises microsphere.

1922. the 1644th method is wherein sent described fibrous tissue from implant and formed agent, wherein said implant is or comprises mesh.

1923. the 1644th method is wherein sent described fibrous tissue from implant and formed agent, wherein said implant is or comprises film.

1924. the 1644th method is wherein sent described fibrous tissue from device and formed agent, wherein said device is a conduit.

1925. the 1644th method is wherein sent described fibrous tissue from device and formed agent, wherein said device is a drug delivery tube.

1926. the 1644th method is wherein sent described fibrous tissue from device and formed agent, wherein said device is the radio-frequency (RF) ablation conduit.

1927. the 1644th method is wherein sent described fibrous tissue from device and formed agent, wherein said device is the temperature ablation catheter.

1928. the 1644th method is wherein sent described fibrous tissue from device and formed agent, wherein said device is the heat energy conduit.

1929. the 1644th method is wherein sent described fibrous tissue from device and formed agent, wherein said device is the cryoablation conduit.

1930. the 1644th method is wherein sent described fibrous tissue from device and formed agent, wherein said device is a laser catheter.

1931. the 1644th method is wherein sent described fibrous tissue from device and formed agent, wherein said device is the radioactivity delivery catheter.

1932. the 1644th method is wherein sent described fibrous tissue from device and formed agent, wherein said device is a balloon catheter.

1933. the 1644th method is wherein sent described fibrous tissue from device and formed agent, wherein said device is the ultrasonic energy delivery catheter.

1934. the 1644th method is wherein sent described fibrous tissue from device and formed agent, wherein said device is a rotation atherosclerotic plaque excision conduit.

1935. the 1644th method is wherein sent described fibrous tissue from device and formed agent, wherein said device is that rotation atherosclerotic plaque excision device is a rotating blade.

1936. the 1644th method is wherein sent described fibrous tissue from device and formed agent, wherein said device is the tissue abrasion device.

1937. the 1644th method is wherein sent described fibrous tissue from device and formed agent, wherein said device is an atherosclerotic plaque excision device.

1938. the 1644th method is wherein sent described fibrous tissue from device and formed agent, wherein said device is an atherosclerotic plaque excision conduit.

1939. the 1644th method is wherein sent described fibrous tissue from device and formed agent, wherein said device is endoscope's dissecting knife.

1940. the 1644th method is wherein introduced described fibrous tissue formation agent by sending from device, wherein said device also comprises coating, and described coating comprises described fibrous tissue formation agent.

1941. the 1644th method is wherein introduced described fibrous tissue formation agent by sending from device, wherein said device also comprises coating, and described coating is configured on the surface of described device.

1942. the 1644th method is wherein introduced described fibrous tissue formation agent by sending from device, wherein said device also comprises coating, and wherein said coating directly contacts described device.

1943. the 1644th method is wherein introduced described fibrous tissue formation agent by sending from device, wherein said device also comprises coating, and the described device of wherein said coating mediate contact.

1944. the 1644th method is wherein introduced described fibrous tissue formation agent by sending from device, wherein said device also comprises coating, and wherein said coating layer portion covers described device.

1945. the 1644th method is wherein introduced described fibrous tissue formation agent by sending from device, wherein said device also comprises coating, and wherein said coating covers described device fully.

1946. the 1644th method is wherein introduced described fibrous tissue formation agent by sending from device, wherein said fibrous tissue forms hole or the hole that agent is positioned at described device.

1947. the 1644th method is wherein introduced described fibrous tissue formation agent by sending from device, wherein said fibrous tissue forms passage, chamber or the divet that agent is positioned at described device.

1948. the 1644th method is wherein introduced described fibrous tissue formation agent by sending from device, wherein said device also comprises the echo material.

1949. the 1644th method is wherein introduced described fibrous tissue and formed agent by sending from device, wherein said device also comprises the echo material, and the wherein said echo material form that is coating.

1950. the 1644th method is wherein introduced described fibrous tissue formation agent by sending from device, wherein said device is aseptic.

1951. the 1644th method is wherein introduced described reagent by sending from device, wherein said fibrous tissue forms near the tissue of agent described device use is discharged into later described device.

1952. the 1644th method is wherein introduced described fibrous tissue formation agent by sending from device, wherein said fibrous tissue forms near the tissue of agent described device use is discharged into later described device, and wherein said tissue is a connective tissue.

1953. the 1644th method is wherein introduced described fibrous tissue formation agent by sending from device, wherein said fibrous tissue forms near the tissue of agent described device use is discharged into later described device, and wherein said tissue is a muscular tissue.

1954. the 1644th method is wherein introduced described fibrous tissue formation agent by sending from device, wherein said fibrous tissue forms near the tissue of agent described device use is discharged into later described device and wherein said tissue is a nervous tissue.

1955. the 1644th method is wherein introduced described fibrous tissue formation agent by sending from device, wherein said fibrous tissue forms near the tissue of agent described device use is discharged into later described device, and wherein said tissue is an epithelial tissue.

1956. the 1644th method is wherein introduced described fibrous tissue formation agent by sending from device, wherein said fibrous tissue forms agent and discharges from described device with valid density in about 1 year cycle in described device use.

1957. the 1644th method is wherein introduced described fibrous tissue and formed agent by sending from device, wherein said fibrous tissue forms agent and discharges from described device with valid density in the cycle in about 1 month to 6 months scopes.

1958. the 1644th method wherein introduce described fibrous tissue formation agent by sending from device, and wherein said fibrous tissue discharged from described device with valid density in the formation cycle of agent in about 1-90 days scope.

1959. the 1644th method wherein introduce described fibrous tissue formation agent by sending from device, and wherein said fibrous tissue formation agent discharges from described device with valid density with constant rate of speed.

1960. the 1644th method wherein introduce described fibrous tissue formation agent by sending from device, and wherein said fibrous tissue formation agent discharges from described device with valid density with the speed that increases progressively.

1961. the 1644th method wherein introduce described fibrous tissue formation agent by sending from device, and wherein said reagent discharges from described device with valid density with the speed of successively decreasing.

1962. the 1644th method, wherein said compositions comprise the fibrous tissue formation agent of about 0.01 μ g to about 10 μ g.

1963. the 1644th method, wherein said compositions comprise the fibrous tissue formation agent of about 10 μ g to about 10mg.

1964. the 1644th method, wherein said compositions comprise the fibrous tissue formation agent of about 10mg to about 250mg.

1965. the 1644th method, wherein said compositions comprise the fibrous tissue formation agent of about 250mg to about 1000mg.

1966. the 1644th method, wherein said compositions comprise the fibrous tissue formation agent of about 1000mg to about 2500mg.

1967. the 1644th method wherein introduce described fibrous tissue formation agent by sending from implant, and the fibrous tissue that the surface of wherein said implant comprises less than 0.01 μ g forms agent/mm ²The applied implant surface of described reagent.

1968. the 1644th method is wherein introduced described fibrous tissue formation agent by sending from implant, and the surface of wherein said implant comprises about 0.01 μ g to about 1 μ g fibrous tissue formation agent/mm ²The applied implant surface of described reagent.

1969. the 1644th method is wherein introduced described fibrous tissue formation agent by sending from implant, and the surface of wherein said implant comprises about 1 μ g to about 10 μ g fibrous tissue formation agent/mm ²The applied implant surface of described reagent.

1970. the 1644th method is wherein introduced described fibrous tissue formation agent by sending from implant, and the surface of wherein said implant comprises about 10 μ g to about 250 μ g fibrous tissue formation agent/mm ²The applied implant surface of described reagent.

1971. the 1644th method is wherein introduced described fibrous tissue formation agent by sending from implant, and the surface of wherein said implant comprises about 250 μ g to about 1000 μ g fibrous tissue formation agent/mm ²Described fibrous tissue forms the applied implant surface of agent.

1972. the 1644th method is wherein introduced described fibrous tissue formation agent by sending from implant, and the surface of wherein said implant comprises about 1000 μ g to about 2500 μ g fibrous tissue formation agent/mm ²The applied implant surface of described reagent.

1973. the 1644th method is wherein introduced described fibrous tissue formation agent by sending from implant, wherein said implant also comprises coating, and wherein said coating is a uniform coating.

1974. the 1644th method is wherein introduced described fibrous tissue formation agent by sending from implant, wherein said implant also comprises coating, and wherein said coating is inhomogeneous coating.

1975. the 1644th method is wherein introduced described fibrous tissue formation agent by sending from implant, wherein said implant also comprises coating, and wherein said coating is discontinuous coating.

1976. the 1644th method is wherein introduced described fibrous tissue formation agent by sending from implant, wherein said implant also comprises coating, and wherein said coating is to form the coating of pattern.

1977. the 1644th method is wherein introduced described fibrous tissue formation agent by sending from implant, wherein said implant also comprises coating, and wherein said coating has 100 μ m or littler thickness.

1978. the 1644th method is wherein introduced described fibrous tissue formation agent by sending from implant, wherein said implant also comprises coating, and wherein said coating has 10 μ m or littler thickness.

1979. the 1644th method is wherein introduced described fibrous tissue formation agent by sending from implant, wherein said implant also comprises coating, and wherein said coating adheres to the surface of described implant when described implant is used.

1980. the 1644th method is wherein introduced described fibrous tissue formation agent by sending from implant, wherein said implant also comprises coating, and wherein said coating is at room temperature stablized the cycle at least 1 year.

1981. the 1644th method, wherein introduce described fibrous tissue formation agent by sending from implant, wherein said implant also comprises coating, and wherein said fibrous tissue forms agent and is present in the described coating to the amount in about 1 weight % scope with about 0.0001 weight %.

1982. the 1644th method, wherein introduce described fibrous tissue formation agent by sending from implant, wherein said implant also comprises coating, and wherein said fibrous tissue forms agent and is present in the described coating to the amount in about 10 weight % scopes with about 1 weight %.

1983. the 1644th method, wherein introduce described fibrous tissue formation agent by sending from implant, wherein said implant also comprises coating, and wherein said fibrous tissue forms agent and is present in the described coating to the amount in about 25 weight % scopes with about 10 weight %.

1984. the 1644th method, wherein introduce described fibrous tissue formation agent by sending from implant, wherein said implant also comprises coating, and wherein said fibrous tissue forms agent and is present in the described coating to the amount in about 70 weight % scopes with about 25 weight %.

1985. the 1644th method is wherein introduced described fibrous tissue formation agent by sending from implant, wherein said implant also comprises coating, and wherein said coating comprises polymer.

1986. the 1644th method is wherein introduced described fibrous tissue formation agent by sending from implant, wherein said implant comprises first coating with first compositions and second coating with second compositions.

1987. the 1644th method, wherein introduce described fibrous tissue formation agent by sending from implant, wherein said implant comprises first coating with first compositions and second coating with second compositions, and wherein first compositions is different with second compositions.

1988. the 1644th method wherein forms described fibrous tissue agent or comprises described fibrous tissue and forms the compositions injection of agent or be sprayed to described diverticulum.

1989. the 1644th method wherein forms described fibrous tissue agent or comprises described fibrous tissue and forms the compositions injection of agent or be sprayed to tissue or center in the tissue of described diverticulum.

1990. the 1644th method, wherein said compositions also comprises filler.

1991. the 1664th method, wherein said compositions is a sealant.

1992. the 1664th method, wherein said compositions is a hemorrhage.

1993. the 1644th method, wherein said compositions also comprises filler, and wherein said filler comprises microsphere.

1994. the 1644th method, wherein said compositions also comprises filler, and wherein said filler comprises the gel of hydroxyapatite load.

1995. the 1644th method, wherein said compositions also comprises filler, and wherein said filler comprises micronized alloderm acellular substrate.

1996. the 1644th method, wherein said compositions also comprises filler, and wherein said filler comprises hyaluronic acid.

1997. the 1644th method, wherein said compositions also comprises filler, and wherein said filler comprises the microballon in the hydrogel.

1998. the 1644th method, wherein said compositions also comprises filler, and wherein said filler comprises extra large blue polymer.

1999. the 1644th method, wherein said compositions also comprises filler, and wherein said filler comprises silicon microsphere and biocompatible polymer.

2000. the 1644th method, described method also comprises the existence that manifests diverticulum.

2001. the 2000th method, the existence that wherein manifests diverticulum comprises splanchnoscopy.

2002. the 2000th method, the existence that wherein manifests diverticulum comprises the radiography imaging.

2003. the 1644th method, described method are washed described diverticulum with rinse solution before also being included in and introducing described fibrous tissue formation agent.

2004. the 2003rd method, wherein said rinse solution comprise (a) anti-infective or (b) antiseptic or (c) anti-infective and antiseptic.

2005. the 1st method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a gentamycin sulfate.

2006. the 1st method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is an amikacin sulfate.

2007. the 1st method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a kanamycin sulfate.

2008. the 1st method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a polymyxin B.

2009. the 1st method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a polygynax.

2010. the 1st method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a cefazolin sodium.

2011. the 1st method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is ciprofloxacin (ciprofloxain).

2012. the 1st method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a piperacillin.

2013. the 1st method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a cefoxitin.

2014. the 1st method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a cefepime.

2015. the 1st method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is an azithromycin.

2016. the 363rd method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a gentamycin sulfate.

2017. the 363rd method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is an amikacin sulfate.

2018. the 363rd method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a kanamycin sulfate.

2019. the 363rd method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a polymyxin B.

2020. the 363rd method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a polygynax.

2021. the 363rd method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a cefazolin sodium.

2022. the 363rd method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a ciprofloxacin.

2023. the 363rd method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a piperacillin.

2024. the 363rd method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a cefoxitin.

2025. the 363rd method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a cefepime.

2026. the 363rd method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is an azithromycin.

2027. the compositions of any one of 725-771 item, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a gentamycin sulfate.

2028. the compositions of any one of 725-771 item, wherein said compositions also comprises anti-infective, and wherein said anti-infective is an amikacin sulfate.

2029. the compositions of any one of 725-771 item, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a kanamycin sulfate.

2030. the compositions of any one of 725-771 item, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a polymyxin B.

2031. the compositions of any one of 725-771 item, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a polygynax.

2032. the compositions of any one of 725-771 item, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a cefazolin sodium.

2033. the compositions of any one of 725-771 item, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a ciprofloxacin.

2034. the compositions of any one of 725-771 item, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a piperacillin.

2035. the compositions of any one of 725-771 item, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a cefoxitin.

2036. the compositions of any one of 725-771 item, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a cefepime.

2037. the compositions of any one of 725-771 item, wherein said compositions also comprises anti-infective, and wherein said anti-infective is an azithromycin.

2038. the compositions of any one of 1004-1050 item, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a gentamycin sulfate.

2039. the compositions of any one of 1004-1050 item, wherein said compositions also comprises anti-infective, and wherein said anti-infective is an amikacin sulfate.

2040. the compositions of any one of 1004-1050 item, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a kanamycin sulfate.

2041. the compositions of any one of 1004-1050 item, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a polymyxin B.

2042. the compositions of any one of 1004-1050 item, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a polygynax.

2043. the compositions of any one of 1004-1050 item, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a cefazolin sodium.

2044. the compositions of any one of 1004-1050 item, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a ciprofloxacin.

2045. the compositions of any one of 1004-1050 item, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a piperacillin.

2046. the compositions of any one of 1004-1050 item, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a cefoxitin.

2047. the compositions of any one of 1004-1050 item, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a cefepime.

2048. the compositions of any one of 1004-1050 item, wherein said compositions also comprises anti-infective, and wherein said anti-infective is an azithromycin.

2049. the 1283rd method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a gentamycin sulfate.

2050. the 1283rd method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is an amikacin sulfate.

2051. the 1283rd method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a kanamycin sulfate.

2052. the 1283rd method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a polymyxin B.

2053. the 1283rd method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a polygynax.

2054. the 1283rd method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a cefazolin sodium.

2055. the 1283rd method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a ciprofloxacin.

2056. the 1283rd method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a piperacillin.

2057. the 1283rd method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a cefoxitin.

2058. the 1283rd method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a cefepime.

2059. the 1283rd method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is an azithromycin.

2060. the 1644th method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a gentamycin sulfate.

2061. the 1644th method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is an amikacin sulfate.

2062. the 1644th method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a kanamycin sulfate.

2063. the 1644th method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a polymyxin B.

2064. the 1644th method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a polygynax.

2065. the 1644th method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a cefazolin sodium.

2066. the 1644th method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a ciprofloxacin.

2067. the 1644th method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a piperacillin.

2068. the 1644th method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a cefoxitin.

2069. the 1644th method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is a cefepime.

2070. the 1644th method, wherein said compositions also comprises anti-infective, and wherein said anti-infective is an azithromycin.

2071. make the method for implant, described method comprises that combination (a) fibrous tissue forms agent; (b) polymer, or comprise the compositions of polymer; (c) anti-infective, wherein said fibrous tissue form agent inducing fibrosis reaction in diverticulum.

2072. the 2071st method, wherein said fibrous tissue forms agent and promotes regeneration.

2073. the 2071st method, wherein said fibrous tissue form agent and promote fibre modification and promote regeneration.

2074. forming agent, the 2071st method, wherein said fibrous tissue promote blood vessel to take place.

2075. the 2071st method, wherein said fibrous tissue form agent and promote the fibroblast migration.

2076. the 2071st method, wherein said fibrous tissue forms agent and promotes fibroblast proliferation.

2077. the 2071st method, wherein said fibrous tissue forms the deposition that agent promotes extracellular matrix (ECM).

2078. the 2071st method, wherein said fibrous tissue forms agent and promotes tissue remodeling.

2079. the 2071st method, it is diverticulum wall stimulus object that wherein said fibrous tissue forms agent.

Be or comprise silk 2080. the 2071st method, wherein said fibrous tissue form agent.

Be or comprise silkworm silk 2081. the 2071st method, wherein said fibrous tissue form agent.

Be or comprise spider silk 2082. the 2071st method, wherein said fibrous tissue form agent.

Be or comprise the recombinant silk 2083. the 2071st method, wherein said fibrous tissue form agent.

Be or comprise raw silk 2084. the 2071st method, wherein said fibrous tissue form agent.

2085. the 2071st method, wherein said fibrous tissue forms the silk that agent is or comprises hydrolysis.

2086. the 2071st method, wherein said fibrous tissue formation agent is or comprises acid-treated.

2087. the 2071st method, wherein said fibrous tissue forms the silk that agent is or comprises acidylate.

2088. the 2071st method, it is the form of twisted wire that wherein said fibrous tissue forms agent.

2089. the 2071st method, wherein said fibrous tissue form the form that agent is bunch.

Be or comprise mineral grain 2090. the 2071st method, wherein said fibrous tissue form agent.

Be or comprise chitosan 2091. the 2071st method, wherein said fibrous tissue form agent.

Be or comprise polylysine 2092. the 2071st method, wherein said fibrous tissue form agent.

Be or comprise fibronectin 2093. the 2071st method, wherein said fibrous tissue form agent.

Be or comprise bleomycin 2094. the 2071st method, wherein said fibrous tissue form agent.

Be or comprise CTGF 2095. the 2071st method, wherein said fibrous tissue form agent.

Be or comprise fine hair 2096. the 2071st method, wherein said fibrous tissue form agent.

Be or comprise animal down 2097. the 2071st method, wherein said fibrous tissue form agent.

Be or comprise wood shavings 2098. the 2071st method, wherein said fibrous tissue form agent.

Be or comprise synthetic fine hair 2099. the 2071st method, wherein said fibrous tissue form agent.

2100. the 2071st method, it is the form of line that wherein said fibrous tissue forms agent, or contacts with line.

2101. the 2100th method, wherein said line is biodegradable.

2102. the 2101st method, wherein said biodegradable line comprise the material that is selected from the group of being made up of polyester, poly-anhydride, poly-(anhydride ester), poly-(ester-acid amide), poly-(ester-urea), poe, poly phosphate, poly-phosphazine, polybutylcyanoacrylate, collagen, chitosan, hyaluronic acid, chromic catgut, alginate, starch, cellulose and cellulose esters.

2103. the 2100th method, wherein said line are not biodegradable.

2104. the 2103rd method, wherein said not biodegradable line comprise the material that is selected from the group of being made up of polyester, polyurethane, siloxanes, polyethylene, polypropylene, polystyrene, polyacrylate, polymethacrylates and silk.

2105. the 2100th method, wherein said line scribbles polymer.

2106. the 2100th method, wherein said line scribble the medicament of inducing fibrosis reaction in the host.

2107. the 2071st method, it is the form of microgranule that wherein said fibrous tissue forms agent.

2108. the 2107th method, wherein said microgranule are biodegradable microgranules.

2109. the 2108th method, wherein said Biodegradable microparticle comprise the material that is selected from the group of being made up of polyester, poly-anhydride, poly-(anhydride ester), poly-(ester-acid amide), poly-(ester-urea), poe, poly phosphate, poly-phosphazine, polybutylcyanoacrylate, collagen, chitosan, hyaluronic acid, chromic catgut, alginate, starch, cellulose and cellulose esters.

2110. the 2107th method, wherein said microgranule are not biodegradable microgranules.

2111. the 2110th method, wherein said not biodegradable microgranule comprise the material that is selected from the group of being made up of polyester, polyurethane, siloxanes, polyethylene, polypropylene, polystyrene, polyacrylate, polymethacrylates and silk.

2112. the 2107th method, wherein said microgranule are the particulate form that is selected from the member of the group of being made up of silk, Talcum, starch, glass, silicate, Silicon stone, calcium phosphate, calcium sulfate, calcium carbonate, hydroxyapatite, synthetic mineral, polymethyl methacrylate, silver nitrate, pottery and other inorganic particle.

2113. the 2107th method, wherein said microgranule scribbles polymer.

2114. the 2107th method, wherein said microgranule scribble the medicament of inducing fibrosis reaction in the host.

2115. the 2107th method, wherein said microgranule scribble the member who is selected from the group of being made up of silk, Talcum, starch, glass, silicate, Silicon stone, calcium phosphate, calcium sulfate, calcium carbonate, hydroxyapatite, synthetic mineral, polymethyl methacrylate, silver nitrate, pottery and other inorganic particle.

2116. the 2107th method, wherein said implant also comprises somatomedin.

2117. the 2116th method, wherein said somatomedin is selected from transforming growth factor, platelet derived growth factor and fibroblast growth factor.

2118. the 2071st method, wherein said polymer are, or comprise copolymer.

2119. the 2071st method, wherein said polymer are, or comprise block copolymer.

2120. the 2071st method, wherein said polymer are, or comprise random copolymer.

2121. the 2071st method, wherein said polymer are, or comprise biodegradable polymer.

2122. the 2071st method, wherein said polymer are, or comprise not biodegradable polymer.

2123. the 2071st method, wherein said polymer are, or comprise hydrophilic polymer.

2124. the 2071st method, wherein said polymer are, or comprise hydrophobic polymer.

2125. the 2071st method, wherein said polymer are, or comprise the polymer of possess hydrophilic property domain.

2126. the 2071st method, wherein said polymer be, or comprise, and has the polymer in hydrophobic structure territory.

2127. the 2071st method, wherein said polymer are, or comprise non-conductive polymer.

2128. the 2071st method, wherein said polymer are, or comprise elastomer.

2129. the 2071st method, wherein said polymer are, or comprise hydrogel.

2130. the 2071st method, wherein said polymer are, or comprise siloxane polymer.

2131. the 2071st method, wherein said polymer are, or comprise hydrocarbon polymer.

2132. the 2071st method, wherein said polymer are, or comprise the styrene derived polymer.

2133. the 2071st method, wherein said polymer are, or comprise the butadiene derived polymer.

2134. the 2071st method, wherein said polymer are, or comprise macromonomer.

2135. the 2071st method, wherein said polymer are, or comprise poly-(ethylene glycol).

2136. the 2071st method, wherein said polymer are, or comprise the collagen or derivatives thereof.

2137. the 2071st method, wherein said polymer are, or comprise methylated collagen.

2138. the 2071st method, wherein said polymer composition comprises collagen or derivatives thereof and fibrinogen.

2139. the 2071st method, wherein said polymer composition comprises collagen or derivatives thereof and thrombin.

2140. the 2071st method, wherein said polymer composition comprise (a) collagen or derivatives thereof; (b) fibrinogen; (c) thrombin.

2141. the 2071st method, wherein said polymer composition comprise methylated collagen and poly-(ethylene glycol) or derivatives thereof.

2142. the 2071st method, wherein said implant also comprises hemorrhage, and described hemorrhage comprises collagen polymer.

2143. the 2071st method, wherein said implant also comprises hemorrhage, and described hemorrhage comprises collagen polymer, and wherein said hemorrhage is CT3.

2144. the 2071st method, wherein said implant also comprises hemorrhage, and described hemorrhage comprises collagen polymer, and wherein said hemorrhage is COSTASIS.

2145. the 2071st method, wherein said implant also comprises hemorrhage, and described hemorrhage comprises poly-(ethylene glycol).

2146. the 2071st method, wherein said implant also comprises hemorrhage, and wherein said hemorrhage is COSEAL, TISSEAL or FLOSEAL.

2147. the 2071st method, wherein said implant also comprises hemorrhage, and described hemorrhage comprises fibrin.

2148. the 2071st method, wherein said polymer are, or comprise amorphous polymer.

2149. the 2071st method, wherein said polymer are, or comprise cyanoacrylate.

2150. the 2149th method, wherein said cyanoacrylate is selected from methyl 2-cyanoacrylate, cyanacrylate, Tisuacryl, octyl 2-cyanoacrylate and alpha-cyanoacrylate methoxyl group propyl ester.

2151. the 2071st method, wherein said polymer are, or comprise poly-(alkyl cyanoacrylate).

2152. the 2151st method, wherein said poly-(alkyl cyanoacrylate) are selected from poly-(MCA), poly-(ethyl cyanoacrylate), poly-(butyl cyanoacrylate), poly-(isobutyl cyanoacrylate), poly-(hexyl cyanoacrylate) and poly-(octyl cyanoacrylate).

2153. the 2071st method, wherein said polymer are, or comprise poly-(carboxyalkyl cyanoacrylate).

2154. the 2153rd method, wherein said poly-(carboxyalkyl cyanoacrylate) is poly-(methoxy-propyl cyanoacrylate).

2155. the 2071st method, wherein said polymer is crosslinked.

2156. the 2071st method, wherein said polymer and mammalian tissues reaction.

2157. the 2071st method, wherein said polymer are naturally occurring polymer.

2158. the 2071st method, wherein said polymer is a protein.

2159. the 2071st method, wherein said polymer is a saccharide.

2160. the 2071st method, wherein said polymer are crosslinked with biodegradable.

2161. the 2071st method, wherein said implant comprises fibrinogen.

2162. the 2071st method, wherein said implant comprises thrombin.

2163. the 2071st method, wherein said implant comprises calcium salt.

2164. the 2071st method, wherein said implant comprises antifibrinolytic agent.

2165. the 2071st method, wherein said implant comprises the fibrinogen analog.

2166. the 2071st method, wherein said implant comprises albumin.

2167. the 2071st method, wherein said implant comprises plasminogen.

2168. the 2071st method, wherein said implant comprises Feng's von willebrand's factor.

2169. the 2071st method, wherein said implant comprises Factor IX.

2170. the 2071st method, wherein said implant comprises hypoallergenic collagen.

2171. the 2071st method, wherein said implant comprise non-end peptide collagen.

2172. the 2071st method, wherein said implant comprises crosslinked collagen.

2173. the 2071st method, wherein said implant comprises aprotinin.

2174. the 2071st method, wherein said implant comprise epsilon-amino-just-caproic acid.

2175. the 2071st method, wherein said implant comprises gelatin.

2176. the 2071st method, wherein said implant comprises protein conjugate.

2177. the 2071st method, wherein said implant comprises the gelatin conjugate.

2178. the 2071st method, wherein said implant comprises hyaluronic acid.

2179. the 2071st method, wherein said implant comprises derivatives of hyaluronic acids.

2180. the 2071st method, wherein said implant comprises synthetic polymer.

2181. the 2071st method, wherein said polymer forms by comprising the synthetic reactant that contains the chemical compound of isocyanates.

2182. the 2071st method, wherein said implant comprise the synthetic chemical compound that contains isocyanates.

2183. the 2071st method, wherein said polymer forms by comprising the synthetic reactant that contains the chemical compound of mercaptan.

2184. the 2071st method, wherein said implant comprise the synthetic chemical compound that contains mercaptan.

2185. the 2071st method, wherein said polymer forms by comprising the synthetic reactant that contains the chemical compound of two mercaptos at least.

2186. the 2071st method, wherein said implant comprise the synthetic chemical compound that contains at least two mercaptos.

2187. the 2071st method, wherein said polymer forms by comprising the synthetic reactant that contains the chemical compound of three mercaptos at least.

2188. the 2071st method, wherein said implant comprise the synthetic chemical compound that contains at least three mercaptos.

2189. the 2071st method, wherein said polymer forms by comprising the synthetic reactant that contains the chemical compound of four mercaptos at least.

2190. the 2071st method, wherein said implant comprise the synthetic chemical compound that contains at least four mercaptos.

2191. the 2071st method, wherein said polymer forms by comprising the synthetic reactant that contains amino chemical compound.

2192. the 2071st method, wherein said implant comprise the synthetic amino chemical compound that contains.

2193. the 2071st method, wherein said polymer forms by comprising the synthetic reactant that contains the chemical compound of two amino at least.

2194. the 2071st method, wherein said implant comprise the synthetic chemical compound that contains at least two amino.

2195. the 2071st method, wherein said polymer forms by comprising the synthetic reactant that contains the chemical compound of three amino at least.

2196. the 2071st method, wherein said implant comprise the synthetic chemical compound that contains at least three amino.

2197. the 2071st method, wherein said polymer forms by comprising the synthetic reactant that contains the chemical compound of four amino at least.

2198. the 2071st method, wherein said implant comprise the synthetic chemical compound that contains at least four amino.

2199. the 2071st method, wherein said polymer forms by comprising the synthetic reactant that contains the chemical compound of carbonyl-oxygen-succinimido.

2200. the 2071st method, wherein said implant comprise the synthetic chemical compound that contains carbonyl-oxygen-succinimido.

2201. the 2071st method, wherein said polymer forms by comprising the synthetic reactant that comprises the chemical compound of two carbonyl-oxygen-succinimido at least.

2202. the 2071st method, wherein said implant comprise the synthetic chemical compound that comprises at least two carbonyl-oxygen-succinimido.

2203. the 2071st method, wherein said polymer forms by comprising the synthetic reactant that comprises the chemical compound of three carbonyl-oxygen-succinimido at least.

2204. the 2071st method, wherein said implant comprise the synthetic chemical compound that comprises at least three carbonyl-oxygen-succinimido.

2205. the 2071st method, wherein said polymer forms by comprising the synthetic reactant that comprises the chemical compound of four carbonyl-oxygen-succinimido at least.

2206. the 2071st method, wherein said implant comprise the synthetic chemical compound that comprises at least four carbonyl-oxygen-succinimido.

2207. the 2071st method, wherein said polymer forms by comprising the synthetic reactant that contains the chemical compound of polyalkylene oxide.

2208. the 2071st method, wherein said implant comprise the synthetic chemical compound that contains polyalkylene oxide.

2209. the 2071st method, wherein said polymer forms by comprising the synthetic reactant that contains the chemical compound of polyalkylene oxide and biodegradable polyester block.

2210. the 2071st method, wherein said implant comprise the synthetic chemical compound that contains polyalkylene oxide and biodegradable polyester block.

2211. the 2071st method, wherein said polymer forms by comprising synthetic reactant with chemical compound that contains polyalkylene oxide of reactive amino.

2212. the 2071st method, wherein said implant comprise the synthetic chemical compound that contains polyalkylene oxide with reactive amino.

2213. the 2071st method, wherein said polymer forms by comprising synthetic reactant with chemical compound that contains polyalkylene oxide of reactive mercapto.

2214. the 2071st method, wherein said implant comprise the synthetic chemical compound that contains polyalkylene oxide with reactive mercapto.

2215. the 2071st method, wherein said polymer forms by comprising synthetic reactant with chemical compound that contains polyalkylene oxide of reactive carbonyl-oxygen-succinimido.

2216. the 2071st method, wherein said implant comprise the synthetic chemical compound that contains polyalkylene oxide with reactive carbonyl-oxygen-succinimido.

2217. the 2071st method, wherein said polymer forms by comprising the synthetic reactant that contains the chemical compound of biodegradable polyester block.

2218. the 2071st method, wherein said implant comprise the synthetic chemical compound that contains the biodegradable polyester block.

2219. the 2071st method, wherein said polymer is formed by the reactant that comprises the synthetic polymer that is formed by lactic acid or lactide wholly or in part.

2220. the 2071st method, wherein said implant comprise the synthetic polymer that is formed by lactic acid or lactide wholly or in part.

2221. the 2071st method, wherein said polymer is formed by the reactant that comprises the synthetic polymer that is formed by glycolic or Acetic acid, hydroxy-, bimol. cyclic ester wholly or in part.

2222. the 2071st method, wherein said implant comprise the synthetic polymer that is formed by glycolic or Acetic acid, hydroxy-, bimol. cyclic ester wholly or in part.

2223. the 2071st method, wherein said polymer is formed by the reactant that comprises polylysine.

2224. the 2071st method, wherein said implant comprises polylysine.

2225. the 2071st method, wherein said polymer forms by comprising the reactant of (a) protein with the chemical compound that (b) comprises the polyalkylene oxide part.

2226. the 2071st method, wherein said implant comprise (a) protein and (b) comprise the chemical compound of polyalkylene oxide part.

2227. the 2071st method, wherein said polymer by comprise (a) protein and (b) reactant of polylysine form.

2228. the 2071st method, wherein said implant comprise (a) protein and (b) polylysine.

2229. the 2071st method, wherein said polymer forms with the reactant that (b) has the chemical compound of four mercaptos by comprising (a) protein at least.

2230. the 2071st method, wherein said implant comprise (a) protein and (b) have the chemical compound of at least four mercaptos.

2231. the 2071st method, wherein said polymer forms with the reactant that (b) has the chemical compound of four amino by comprising (a) protein at least.

2232. the 2071st method, wherein said implant comprise (a) protein and (b) have the chemical compound of at least four amino.

2233. the 2071st method, wherein said polymer forms with the reactant that (b) has the chemical compound of four carbonyl-oxygen-butanimide group by comprising (a) protein at least.

2234. the 2071st method, wherein said implant comprise (a) protein and (b) have the chemical compound of at least four carbonyl-oxygen-butanimide group.

2235. the 2071st method, wherein said polymer forms with the reactant that (b) has the chemical compound of the biodegradable region that is formed by the reactant that is selected from lactic acid, lactide, glycolic, Acetic acid, hydroxy-, bimol. cyclic ester and 6-caprolactone by comprising (a) protein.

2236. the chemical compound that the 2071st method, wherein said implant comprise (a) protein and (b) have the biodegradable region that is formed by the reactant that is selected from lactic acid, lactide, glycolic, Acetic acid, hydroxy-, bimol. cyclic ester and 6-caprolactone.

2237. the 2071st method, wherein said polymer forms by comprising the reactant of (a) collagen with the chemical compound that (b) comprises the polyalkylene oxide part.

2238. the 2071st method, wherein said implant comprise (a) collagen and (b) comprise the chemical compound of polyalkylene oxide part.

2239. the 2071st method, wherein said polymer by comprise (a) collagen and (b) reactant of polylysine form.

2240. the 2071st method, wherein said implant comprise (a) collagen and (b) polylysine.

2241. the 2071st method, wherein said polymer forms with the reactant that (b) has the chemical compound of four mercaptos by comprising (a) collagen at least.

2242. the 2071st method, wherein said implant comprise (a) collagen and (b) have the chemical compound of at least four mercaptos.

2243. the 2071st method, wherein said polymer forms with the reactant that (b) has the chemical compound of four amino by comprising (a) collagen at least.

2244. the 2071st method, wherein said implant comprise (a) collagen and (b) have the chemical compound of at least four amino.

2245. the 2071st method, wherein said polymer forms with the reactant that (b) has the chemical compound of four carbonyl-oxygen-butanimide group by comprising (a) collagen at least.

2246. the 2071st method, wherein said implant comprise (a) collagen and (b) have the chemical compound of at least four carbonyl-oxygen-butanimide group.

2247. the 2071st method, wherein said polymer forms with the reactant that (b) has the chemical compound of the biodegradable region that is formed by the reactant that is selected from lactic acid, lactide, glycolic, Acetic acid, hydroxy-, bimol. cyclic ester and 6-caprolactone by comprising (a) collagen.

2248. the chemical compound that the 2071st method, wherein said implant comprise (a) collagen and (b) have the biodegradable region that is formed by the reactant that is selected from lactic acid, lactide, glycolic, Acetic acid, hydroxy-, bimol. cyclic ester and 6-caprolactone.

2249. the 2071st method, wherein said polymer forms by comprising the reactant of (a) methylated collagen with the chemical compound that (b) comprises the polyalkylene oxide part.

2250. the 2071st method, wherein said implant comprise (a) methylated collagen and (b) comprise the chemical compound of polyalkylene oxide part.

2251. the 2071st method, wherein said polymer by comprise (a) methylated collagen and (b) reactant of polylysine form.

2252. the 2071st method, wherein said implant comprise (a) methylated collagen and (b) polylysine.

2253. the 2071st method, wherein said polymer forms with the reactant that (b) has the chemical compound of four mercaptos by comprising (a) methylated collagen at least.

2254. the 2071st method, wherein said implant comprise (a) methylated collagen and (b) have the chemical compound of at least four mercaptos.

2255. the 2071st method, wherein said polymer forms with the reactant that (b) has the chemical compound of four amino by comprising (a) methylated collagen at least.

2256. the 2071st method, wherein said implant comprise (a) methylated collagen and (b) have the chemical compound of at least four amino.

2257. the 2071st method, wherein said polymer forms with the reactant that (b) has the chemical compound of four carbonyl-oxygen-butanimide group by comprising (a) methylated collagen at least.

2258. the 2071st method, wherein said implant comprise (a) methylated collagen and (b) have the chemical compound of at least four carbonyl-oxygen-butanimide group.

2259. the 2071st method, wherein said polymer forms with the reactant that (b) has the chemical compound of the biodegradable region that is formed by the reactant that is selected from lactic acid, lactide, hydroxyacetic acid, Acetic acid, hydroxy-, bimol. cyclic ester and 6-caprolactone by comprising (a) methylated collagen.

2260. the chemical compound that the 2071st method, wherein said implant comprise (a) methylated collagen and (b) have the biodegradable region that is formed by the reactant that is selected from lactic acid, lactide, glycolic, Acetic acid, hydroxy-, bimol. cyclic ester and 6-caprolactone.

2261. the 2071st method, wherein said polymer forms by comprising hyaluronic reactant.

2262. the 2071st method, wherein said implant comprises hyaluronic acid.

2263. the 2071st method, wherein said polymer is formed by the reactant that comprises derivatives of hyaluronic acids.

2264. the 2071st method, wherein said implant comprises derivatives of hyaluronic acids.

2265. the 2071st method, wherein said polymer is formed by the reactant that comprises poly-(ethylene glycol) ether four-sulfydryl of the tetramethylolmethane of number-average molecular weight between 3,000 and 30,000.

2266. the 2071st method, wherein said implant comprise poly-(ethylene glycol) ether four-sulfydryl of the tetramethylolmethane of number-average molecular weight between 3,000 and 30,000.

2267. the 2071st method, wherein said polymer is formed by the reactant that comprises poly-(ethylene glycol) ether four of the tetramethylolmethane of number-average molecular weight between 3,000 and 30,000-amino.

2268. the 2071st method, wherein said implant comprise poly-(ethylene glycol) ether four-amino of the tetramethylolmethane of number-average molecular weight between 3,000 and 30,000.

2269. the 2071st method, wherein said polymer is by comprising (a) synthetic number-average molecular weight 3,000 and 30, between 000 and comprise the chemical compound of polyalkylene oxide zone and a plurality of nucleophilic groups and (b) synthetic number-average molecular weight 3, between 000 and 30,000 and comprise the reactant formation of the chemical compound of polyalkylene oxide zone and a plurality of electrophilic groups.

2270. the 2071st method, wherein said implant comprises (a) synthetic number-average molecular weight 3,000 and 30, between 000 and comprise the chemical compound of polyalkylene oxide zone and a plurality of nucleophilic groups, (b) synthetic number-average molecular weight is 3, between 000 and 30,000 and comprise the chemical compound of polyalkylene oxide zone and a plurality of electrophilic groups.

2271. the 2071st method, wherein said implant comprises coloring agent.

2272. the 2071st method, wherein said implant is aseptic.

2273. the 2071st method, wherein said implant also comprises other forms of pharmacologically active agents.

2274. the 2071st method, wherein said implant also comprises anti-inflammatory agent.

2275. the 2071st method, wherein said anti-infective comprises anthracycline.

2276. the 2071st method, wherein said anti-infective comprises doxorubicin.

2277. the 2071st method, wherein said anti-infective comprises mitoxantrone.

2278. the 2071st method, wherein said anti-infective comprises the fluorine pyrimidine.

2279. the 2071st method, wherein said anti-infective comprise 5-fluorouracil (5-FU).

2280. the 2071st method, wherein said anti-infective comprises antifol.

2281. the 2071st method, wherein said anti-infective comprises methotrexate.

2282. the 2071st method, wherein said anti-infective comprises podophyllotoxin.

2283. the 2071st method, wherein said anti-infective comprises etoposide.

2284. the 2071st method, wherein said anti-infective comprises camptothecine.

2285. the 2071st method, wherein said anti-infective comprises hydroxyurea.

2286. the 2071st method, wherein said anti-infective comprises platinum complex.

2287. the 2071st method, wherein said anti-infective comprises cisplatin.

2288. the 2071st method, wherein said anti-infective comprises antibiotic.

2289. the 2071st method, wherein said anti-infective comprises doxycycline.

2290. the 2071st method, wherein said anti-infective is a metronidazole.

2291. the 2071st method, wherein said anti-infective is a trimethoprim-sulfamethoxazole.

2292. the 2071st method, wherein said anti-infective be the 4th generation penicillin.

2293. the 2071st method, wherein said anti-infective be selected from urea groups penicillin and penicillin carboxy the 4th generation penicillin, or its analog or derivant.

2294. the 2071st method, wherein said anti-infective be selected from mezlocillin, piperacillin, Carbenicillin and ticarcillin the 4th generation penicillin.

2295. the 2071st method, wherein said anti-infective is a first generation cephalosporin.

2296. the 2071st method, wherein said anti-infective are the first generation cephalosporins that is selected from cefazolin sodium, cefalexin, cefazolin sodium, cefaloject and cefalotin.

2297. the 2071st method, wherein said anti-infective is a penicillin carboxy.

2298. according to the 2297th method, wherein said penicillin carboxy is a ticarcillin.

2299. the 2071st method, wherein said anti-infective is a second generation cephalosporin.

2300. the 2071st method, wherein said anti-infective are the second generation cephalosporins that is selected from cefuroxime, cefotetan and cefoxitin.

2301. the 2071st method, wherein said anti-infective is a third generation cephalosporin.

2302. the 2071st method, wherein said anti-infective are the third generation cephalosporins that is selected from ceftiofur sodium, cefdinir, cefoperazone, ceftazidime, ceftriaxone and cefotaxime.

2303. the 2071st method, wherein said anti-infective be the 4th generation cephalosporin.

2304. the 2303rd method, wherein said the 4th generation cephalosporin be cefepime.

2305. the 2071st method, wherein said anti-infective is a monobactam.

2306. the 2305th method, wherein said monobactam is an aztreonam.

2307. the 2071st method, wherein said anti-infective is a carbapenem.

2308. the 2071st method, wherein said anti-infective are the carbapenems that is selected from imipenum, Ai Tapeinan and meropenem.

2309. the 2071st method, wherein said anti-infective is an aminoglycoside.

2310. the 2071st method, wherein said anti-infective are the aminoglycosides that is selected from streptomycin, gentamycin, tobramycin and amikacin.

2311. the 2071st method, wherein said anti-infective are the MSL group memberships who is selected from macrolide, long-acting macrolide, lincosamide and streptogramin.

2312. the 2071st method, wherein said anti-infective are the MSL group memberships who is selected from erythromycin, azithromycin, clindamycin, quinoline slave Pu Ding-dalfopristin, clarithromycin and kanamycin sulfate.

2313. the 2071st method, wherein said anti-infective is a quinolinones.

2314. the 2071st method, wherein said anti-infective are to be selected from ciprofloxacin, ofloxacin, Gatifloxacin, Moxifloxacin, the quinolinones of levofloxacin and trovafloxacin.

2315. the 2071st method, wherein said anti-infective are the DNA synthetic inhibitors.

2316. the 2315th method, wherein said DNA synthetic inhibitor is a metronidazole.

2317. the 2071st method, wherein said anti-infective is a sulfonamide.

2318. the 2317th method, wherein said sulfonamide is a trimethoprim.

2319. the 2071st method, described anti-infective is selected from cefixime, spectinomycin, tetracycline, nitrofurantoin, polymyxin B, and polygynax.

2320. the 2071st method, wherein said anti-infective is a gentamycin sulfate.

2321. the 2071st method, wherein said anti-infective is an amikacin sulfate.

2322. the 2071st method, wherein said anti-infective is a kanamycin sulfate.

2323. the 2071st method, wherein said anti-infective is a polymyxin B.

2324. the 2071st method, wherein said anti-infective is a polygynax.

2325. the 2071st method, wherein said anti-infective is a cefazolin sodium.

2326. the 2071st method, wherein said anti-infective is a ciprofloxacin.

2327. the 2071st method, wherein said anti-infective is a piperacillin.

2328. the 2071st method, wherein said anti-infective is a cefoxitin.

2329. the 2071st method, wherein said anti-infective is a cefepime.

2330. the 2071st method, wherein said anti-infective is an azithromycin.

2331. the 2071st method, wherein said implant also comprises developing agent.

2332. the 2071st method, wherein said implant also comprises developing agent, and described developing agent is radio-opaque material, and wherein said radio-opaque material comprises metal, halogenated compound or contains the chemical compound of barium.

2333. the 2071st method, wherein said implant also comprises developing agent, and described developing agent is, or comprises barium, tantalum or technetium.

2334. the 2071st method, wherein said implant also comprises developing agent, and described developing agent is, or comprises MRI response material or echo material.

2335. the 2071st method, wherein said implant also comprises developing agent, and described developing agent is, or comprises gadolinium chelate compound.

2336. the 2071st method, wherein said implant also comprises a kind of developing agent, and described developing agent is, or comprises ferrum, magnesium, manganese, copper or chromium.

2337. the 2071st method, wherein said implant also comprises developing agent, and described developing agent is, or comprises iron oxide compound.

2338. the 2071st method, wherein said implant also comprises developing agent, and described developing agent is, or comprises dyestuff, pigment or coloring agent.

2339. the 2071st method, wherein said implant also comprises inflammatory cytokine.

2340. the 2071st method, wherein said implant also comprises the reagent that stimulates cellular proliferation.

2341. the 2071st method, wherein said implant also comprises the reagent that stimulates cellular proliferation, and wherein said propagation reagent is selected from the group of being made up of dexamethasone, isotretinoin, 17-, estradiol, diethyl diethylstilbestrol, ciclosporin A, complete-trans retinoic acid (ATRA) and analog thereof and derivant.

2342. the 2071st method, wherein said implant also comprises polymeric carrier.

2343. the 2071st method, wherein said implant are the forms of gel, paste or spray.

2344. the 2071st method, wherein said implant are the forms of mesh or film.

2345. the 2071st method wherein injects described implant or be sprayed in the described diverticulum.

2346. the 2071st method is wherein with the injection of described implant or be sprayed to tissue or center in the tissue of described diverticulum.

2347. the 2071st method, wherein said implant also comprises filler.

2348. the 2071st method, wherein said filler is a sealant.

2349. the 2071st method, wherein said filler is a hemorrhage.

2350. the 2071st method, wherein said implant also comprises filler, and wherein said filler comprises microsphere.

2351. the 2071st method, wherein said implant also comprises filler, and wherein said filler comprises the gel of hydroxyapatite load.

2352. the 2071st method, wherein said implant also comprises filler, and wherein said filler comprises micronized alloderm acellular substrate.

2353. the 2071st method, wherein said implant also comprises filler, and wherein said filler comprises hyaluronic acid.

2354. the 2071st method, wherein said implant also comprises filler, and wherein said filler comprises the microballon in the hydrogel.

2355. the 2071st method, wherein said implant also comprises filler, and wherein said filler comprises extra large blue polymer.

2356. the 2071st method, wherein said implant also comprises filler, and wherein said filler comprises silicon microsphere and biocompatible polymer.

2357. the test kit that uses in the treatment diverticulum disease, described test kit comprises: (a) comprise first component that following dry powder composite (i) has the core that replaces with m nucleophilic group, wherein m 〉=2; Second component that (ii) has the core that replaces with n electrophilic group, wherein n 〉=2 and m+n＞4; Be endowed reactivity when being exposed to water environment but wherein said nucleophilic and electrophilic group right and wrong in dry environment are reactive, so that described component reacts to each other in water environment and forms three-dimensional compositions; (b) first buffer solution of pH in about 1.0 to 5.5 scopes; (c) second buffer solution of pH in about 6.0 to 11.0 scopes; (d) comprise the 3rd component that fibrous tissue forms agent, wherein each component is independent pack and mixing immediately before using.

2358. the 2357th test kit, wherein before using, each component is in independent aseptic packaging.

2359. the 2357th test kit, described test kit also comprises delivery apparatus.

2360. the 2359th test kit, wherein said delivery apparatus are the multicompartment devices.

2361. the 2360th test kit wherein is configured to described device to send described compositions with spray form.

2362. the 2360th test kit wherein is configured to described device to send described compositions with the form of gel or paste.

2363. the 2361st test kit, wherein said multicompartment sprayer unit are the many compartments injector systems with a plurality of tubes, mixing head and outlet opening.

2364. the 2357th test kit, described test kit also comprises delivery catheter.

2365. the 2357th test kit, described test kit also comprises delivery catheter, wherein described conduits configurations is become to send the diverticulum of described compositions to the host.

2366. the 2363rd test kit, wherein said dry powder composite, first buffer solution, second buffer solution and described fibrous tissue form agent and are encapsulated in separately in described many compartments injector system.

2367. the 2359th test kit, wherein said delivery apparatus is a pressurized delivery device.

2368. the 2367th test kit, wherein said pressurized delivery device comprises: (a) a plurality of fluid components imports, and each is suitable for being communicated with the different fluid component source; (b) at least one carrier fluid import is suitable for being communicated with pressurization carrier current body source; (c) be positioned at the bubbler surface in a plurality of fluid components imports and at least one carrier fluid import downstream; (d) outlet of extending by the bubbler surface, wherein said bubbler surface is suitable for receiving fluid components thereon and having such shape, it is effectively with the guiding of the fluid components of each reception and remain in the different flow path of outlet, to use pressurization carrier fluid from least one carrier fluid import to mix by the there and to distribute.

2369. the 2368th test kit, wherein said pressurization carrier fluid is a forced air.

2370. the 2368th test kit, wherein said fluid components are first buffer solution and second buffer solution.

2371. the 2357th test kit wherein forms described fibrous tissue agent and described dry powder composite packing.

2372. the 2371st test kit, described test kit also comprise the pharmaceutical carrier of packing with described fibrous tissue formation agent and described dry powder composite.

2373. the 2357th test kit wherein forms agent with described fibrous tissue and is packaged as solution with first buffer.

2374. the 2357th test kit wherein forms agent with described fibrous tissue and is packaged as solution with second buffer.

2375. the 2357th test kit, described test kit also comprises the pharmaceutical carrier as the 4th component.

2376. the 2375th test kit wherein forms agent with described fibrous tissue and packs with medicinal carrier.

2377. the 2357th test kit, wherein said fibrous tissue forms agent and promotes regeneration.

2378. the 2357th test kit, wherein said fibrous tissue form agent and promote fibre modification and promote regeneration.

2379. forming agent, the 2357th test kit, wherein said fibrous tissue promote blood vessel to take place.

2380. the 2357th test kit, wherein said fibrous tissue form agent and promote the fibroblast migration.

2381. the 2357th test kit, wherein said fibrous tissue forms agent and promotes fibroblast proliferation.

2382. the 2357th test kit, wherein said fibrous tissue forms the deposition that agent promotes extracellular matrix (ECM).

2383. the 2357th test kit, wherein said fibrous tissue forms agent and promotes tissue remodeling.

2384. the 2357th test kit, it is diverticulum wall stimulus object that wherein said fibrous tissue forms agent.

Be or comprise silk 2385. the 2357th test kit, wherein said fibrous tissue form agent.

Be or comprise silkworm silk 2386. the 2357th test kit, wherein said fibrous tissue form agent.

Be or comprise spider silk 2387. the 2357th test kit, wherein said fibrous tissue form agent.

Be or comprise the recombinant silk 2388. the 2357th test kit, wherein said fibrous tissue form agent.

Be or comprise raw silk 2389. the 2357th test kit, wherein said fibrous tissue form agent.

2390. the 2357th test kit, wherein said fibrous tissue forms the silk that agent is or comprises hydrolysis.

2391. the 2357th test kit, wherein said fibrous tissue formation agent is or comprises acid-treated.

2392. the 2357th test kit, wherein said fibrous tissue forms the silk that agent is or comprises acidylate.

2393. the 2357th test kit, it is the form of twisted wire that wherein said fibrous tissue forms agent.

2394. the 2357th test kit, wherein said fibrous tissue form the form that agent is bunch.

Be or comprise mineral grain 2395. the 2357th test kit, wherein said fibrous tissue form agent.

Be or comprise chitosan 2396. the 2357th test kit, wherein said fibrous tissue form agent.

Be or comprise polylysine 2397. the 2357th test kit, wherein said fibrous tissue form agent.

Be or comprise fibronectin 2398. the 2357th test kit, wherein said fibrous tissue form agent.

Be or comprise bleomycin 2399. the 2357th test kit, wherein said fibrous tissue form agent.

Be or comprise CTGF 2400. the 2357th test kit, wherein said fibrous tissue form agent.

Be or comprise fine hair 2401. the 2357th test kit, wherein said fibrous tissue form agent.

Be or comprise animal down 2402. the 2357th test kit, wherein said fibrous tissue form agent.

Be or comprise wood shavings 2403. the 2357th test kit, wherein said fibrous tissue form agent.

Be or comprise synthetic fine hair 2404. the 2357th test kit, wherein said fibrous tissue form agent.

2405. the 2357th test kit, it is the form of line that wherein said fibrous tissue forms agent, or contacts with line.

2406. the 2405th test kit, wherein said line is biodegradable.

2407. the 2406th test kit, wherein said biodegradable line comprise the material that is selected from the group of being made up of polyester, poly-anhydride, poly-(anhydride ester), poly-(ester-acid amide), poly-(ester-urea), poe, poly phosphate, poly-phosphazine, polybutylcyanoacrylate, collagen, chitosan, hyaluronic acid, chromic catgut, alginate, starch, cellulose and cellulose esters.

2408. the 2405th test kit, wherein said line are not biodegradable.

2409. the 2408th test kit, wherein said not biodegradable line comprise the material that is selected from the group of being made up of polyester, polyurethane, siloxanes, polyethylene, polypropylene, polystyrene, polyacrylate, polymethacrylates and silk.

2410. the 2405th test kit, wherein said line scribbles polymer.

2411. the 2405th test kit, wherein said line scribble the medicament of inducing fibrosis reaction in the host.

2412. the 2357th test kit, it is the form of microgranule that wherein said fibrous tissue forms agent.

2413. the 2412nd test kit, wherein said microgranule are biodegradable microgranules.

2414. the 2413rd test kit, wherein said Biodegradable microparticle comprise the material that is selected from the group of being made up of polyester, poly-anhydride, poly-(anhydride ester), poly-(ester-acid amide), poly-(ester-urea), poe, poly phosphate, poly-phosphazine, polybutylcyanoacrylate, collagen, chitosan, hyaluronic acid, chromic catgut, alginate, starch, cellulose and cellulose esters.

2415. the 2412nd test kit, wherein said microgranule are not biodegradable microgranules.

2416. the 2415th test kit, wherein said not biodegradable microgranule comprise the material that is selected from the group of being made up of polyester, polyurethane, siloxanes, polyethylene, polypropylene, polystyrene, polyacrylate, polymethacrylates and silk.

2417. the 2412nd test kit, wherein said microgranule are the particulate form that is selected from the member of the group of being made up of silk, Talcum, starch, glass, silicate, silicon dioxide, calcium phosphate, calcium sulfate, calcium carbonate, hydroxyapatite, synthetic mineral, polymethyl methacrylate, silver nitrate, pottery and other inorganic particle.

2418. the 2412nd test kit, wherein said microgranule scribbles polymer.

2419. the 2412nd test kit, wherein said microgranule scribble the medicament of inducing fibrosis reaction in the host.

2420. the 2412nd test kit, wherein said microgranule scribble the member who is selected from the group of being made up of silk, Talcum, starch, glass, silicate, Silicon stone, calcium phosphate, calcium sulfate, calcium carbonate, hydroxyapatite, synthetic mineral, polymethyl methacrylate, silver nitrate, pottery and other inorganic particle.

2421. the 2357th test kit, wherein said the 3rd component also comprises somatomedin.

2422. the 2421st test kit, wherein said somatomedin is selected from transforming growth factor, platelet derived growth factor and fibroblast growth factor.

2423. the method for treatment diverticulum disease, described method comprise will the treatment effective dose fibrous tissue form agent or comprise compositions that fibrous tissue forms agent and be incorporated in the diverticulum among the host, it is silk that wherein said fibrous tissue forms agent, and wherein said fibrous tissue forms agent inducing fibrosis reaction in described diverticulum, therefore treats the diverticulum disease among the host.

2424. the method for treatment diverticulum disease, described method comprise will the treatment effective dose fibrous tissue form agent or comprise compositions that fibrous tissue forms agent and be incorporated in the diverticulum among the host, it is fine hair that wherein said fibrous tissue forms agent, and wherein said fibrous tissue forms agent inducing fibrosis reaction in described diverticulum, therefore treats the diverticulum disease among the host.

2425. the method for treatment diverticulum disease, described method comprise that the fibrous tissue with (a) treatment effective dose forms agent or comprises the compositions that fibrous tissue forms agent, it is silk that wherein said fibrous tissue forms agent; (b) polymer or in-situ polymerization and form the chemical compound of cross linked polymer, wherein said polymer is CT3, is incorporated in the diverticulum among the host, wherein said fibrous tissue forms agent inducing fibrosis reaction in diverticulum, therefore treats the diverticulum disease among the host.

2426. the method for treatment diverticulum disease, described method comprise that the fibrous tissue with (a) treatment effective dose forms agent or comprises the compositions that fibrous tissue forms agent, it is silk that wherein said fibrous tissue forms agent; (b) polymer or in-situ polymerization and form the chemical compound of cross linked polymer, wherein said polymer is COSTASIS, be incorporated in the diverticulum among the host, wherein said fibrous tissue forms agent inducing fibrosis reaction in diverticulum, therefore treats the diverticulum disease among the host.

2427. the method for treatment diverticulum disease, described method comprise that the fibrous tissue with (a) treatment effective dose forms agent or comprises the compositions that fibrous tissue forms agent, it is silk that wherein said fibrous tissue forms agent; (b) polymer or in-situ polymerization and form the chemical compound of cross linked polymer, wherein said polymer is a cyanoacrylate, be incorporated in the diverticulum among the host, wherein said fibrous tissue forms agent inducing fibrosis reaction in diverticulum, therefore treats the diverticulum disease among the host.

2428. the method for treatment diverticulum disease, described method comprise that the fibrous tissue with (a) treatment effective dose forms agent or comprises the compositions that fibrous tissue forms agent, it is the floss hair that wherein said fibrous tissue forms agent; (b) polymer or in-situ polymerization and form the chemical compound of cross linked polymer, wherein said polymer is CT3, is incorporated in the diverticulum among the host, wherein said fibrous tissue forms agent and cause fiberization in diverticulum, therefore treats the diverticulum disease among the host.

2429. the method for treatment diverticulum disease, described method comprise that the fibrous tissue with (a) treatment effective dose forms agent or comprises the compositions that fibrous tissue forms agent, it is the floss hair that wherein said fibrous tissue forms agent; (b) polymer or in-situ polymerization and form the chemical compound of cross linked polymer, wherein said polymer is COSTASIS, be incorporated in the diverticulum among the host, wherein said fibrous tissue forms agent inducing fibrosis reaction in diverticulum, therefore treats the diverticulum disease among the host.

2430. the method for treatment diverticulum disease, described method comprise that the fibrous tissue with (a) treatment effective dose forms agent or comprises the compositions that fibrous tissue forms agent, it is the floss hair that wherein said fibrous tissue forms agent; (b) polymer or in-situ polymerization and form the chemical compound of cross linked polymer, wherein said polymer is a cyanoacrylate, be incorporated in the diverticulum among the host, wherein said fibrous tissue forms agent inducing fibrosis reaction in diverticulum, therefore treats the diverticulum disease among the host.

2431. the method for any one of 2423-2430 item, described method also comprise anti-infective is incorporated among the described host.

2432. the 2431st method, wherein said anti-infective is a 5-fluorouracil.

2433. the 2431st method, wherein said anti-infective comprises antibiotic.

2434. the 2433rd method, wherein said antibiotic is a gentamycin sulfate.

2435. the 2433rd method, wherein said antibiotic is an amikacin sulfate.

2436. the 2433rd method, wherein said antibiotic is a kanamycin sulfate.

2437. the 2433rd method, wherein said antibiotic is a polymyxin B.

2438. the 2433rd method, wherein said antibiotic is a polygynax.

2439. the 2433rd method, wherein said antibiotic is a cefazolin sodium.

2440. the 2433rd method, wherein said antibiotic is a metronidazole.

2441. the 2433rd method, wherein said antibiotic is a ciprofloxacin.

2442. the 2433rd method, wherein said antibiotic is a piperacillin.

2443. the 2433rd method, wherein said antibiotic is a cefoxitin.

2444. the 2433rd method, wherein said antibiotic is a cefepime.

2445. the 2433rd method, wherein said antibiotic is an azithromycin.

2446. the 2433rd method, wherein said antibiotic is a trimethoprim-sulfamethoxazole.

2447. the method for any one of 2423-2430 item, wherein said diverticulum disease is a diverticulosis.

2448. the method for any one of 2423-2430 item, wherein said diverticulum disease is a diverticulitis.

2449. be used for inducing fibrotic method at its host's diverticulum of needs, described method comprises the diverticulum that compositions is incorporated into described host, described compositions comprises fibrous tissue and forms agent, it is silk that wherein said fibrous tissue forms agent, and wherein said reagent is induced fibre modification in described diverticulum.

2450. be used for inducing fibrotic method at its host's diverticulum of needs, described method comprises the diverticulum that compositions is incorporated into described host, described compositions comprises fibrous tissue and forms agent, it is fine hair that wherein said fibrous tissue forms agent, and wherein said reagent is induced fibre modification in described diverticulum.

2451. be used for inducing fibrotic method at its host's diverticulum of needs, described method comprises that the fibrous tissue with (a) treatment effective dose forms agent or comprises the compositions that fibrous tissue forms agent, it is silk that wherein said fibrous tissue forms agent; (b) polymer or in-situ polymerization and form the chemical compound of cross linked polymer, wherein said polymer is CT3, is incorporated in the diverticulum among the host; Wherein said fibrous tissue forms agent and cause fiberization in diverticulum, therefore treats the diverticulum disease among the host.

2452. be used for inducing fibrotic method at its host's diverticulum of needs, described method comprises that the fibrous tissue with (a) treatment effective dose forms agent or comprises the compositions that fibrous tissue forms agent, it is silk that wherein said fibrous tissue forms agent; (b) polymer or in-situ polymerization and form the chemical compound of cross linked polymer, wherein said polymer is COSTASIS, is incorporated in the diverticulum among the host; Wherein said fibrous tissue forms agent inducing fibrosis reaction in diverticulum, therefore treats the diverticulum disease among the host.

2453. be used for inducing fibrotic method at its host's diverticulum of needs, described method comprises that the fibrous tissue with (a) treatment effective dose forms agent or comprises the compositions that fibrous tissue forms agent, it is silk that wherein said fibrous tissue forms agent; (b) polymer or in-situ polymerization and form the chemical compound of cross linked polymer, wherein said polymer is a cyanoacrylate, be incorporated in the diverticulum among the host, wherein said fibrous tissue forms agent inducing fibrosis reaction in diverticulum, therefore treats the diverticulum disease among the host.

2454. induce fibrotic method in its host's diverticulum of needs, described method comprises that the fibrous tissue with (a) treatment effective dose forms agent or comprises the compositions that fibrous tissue forms agent, it is the floss hair that wherein said fibrous tissue forms agent; (b) polymer or in-situ polymerization and form the chemical compound of cross linked polymer, wherein said polymer is CT3, is incorporated in the diverticulum among the host; Wherein said fibrous tissue forms agent inducing fibrosis reaction in diverticulum, therefore treats the diverticulum disease among the host.

2455. be used for inducing fibrotic method at its host's diverticulum of needs, described method comprises that the fibrous tissue with (a) treatment effective dose forms agent or comprises the compositions that fibrous tissue forms agent, it is the floss hair that wherein said fibrous tissue forms agent; (b) polymer or in-situ polymerization and form the chemical compound of cross linked polymer, wherein said polymer is COSTASIS, is incorporated in the diverticulum among the host; Wherein said fibrous tissue forms agent and cause fiberization in diverticulum, therefore treats the diverticulum disease among the host.

2456. be used for inducing fibrotic method at its host's diverticulum of needs, described method comprises that the fibrous tissue with (a) treatment effective dose forms agent or comprises the compositions that fibrous tissue forms agent, it is the floss hair that wherein said fibrous tissue forms agent; (b) polymer or in-situ polymerization and form the chemical compound of cross linked polymer, wherein said polymer is a cyanoacrylate, be incorporated in the diverticulum among the host, wherein said fibrous tissue forms agent inducing fibrosis reaction in diverticulum, therefore treats the diverticulum disease among the host.

2457. the method for any one of 2449-2456 item, described method also comprise anti-infective is incorporated among the described host.

2458. the 2457th method, wherein said anti-infective is a 5-fluorouracil.

2459. the 2457th method, wherein said anti-infective is an antibiotic.

2460. the 2459th method, wherein said antibiotic is a gentamycin sulfate.

2461. the 2459th method, wherein said antibiotic is an amikacin sulfate.

2462. the 2459th method, wherein said antibiotic is a kanamycin sulfate.

2463. the 2459th method, wherein said antibiotic is a polymyxin B.

2464. the 2459th method, wherein said antibiotic is a polygynax.

2465. the 2459th method, wherein said antibiotic is a cefazolin sodium.

2466. the 2459th method, wherein said antibiotic is a metronidazole.

2467. the 2459th method, wherein said antibiotic is a ciprofloxacin.

2468. the 2459th method, wherein said antibiotic is a piperacillin.

2469. the 2459th method, wherein said antibiotic is a cefoxitin.

2470. the 2459th method, wherein said antibiotic is a cefepime.

2471. the 2459th method, wherein said antibiotic is an azithromycin.

2472. the 2459th method, wherein said antibiotic is a trimethoprim-sulfamethoxazole.

2473. the method for any one of 2449-2456 item is wherein induced fibre modification treatment or prevention (presents) diverticulum disease within described diverticulum.

2474. the 2473rd method, wherein said diverticulum disease is a diverticulosis.

2475. the 2473rd method, wherein said diverticulum disease is a diverticulitis.

2476. comprise the compositions of silk and CT3.

2477. comprise the compositions of silk and COSTASIS.

2478. comprise the compositions of silk and cyanoacrylate.

2479. comprise the compositions of fine hair and CT3.

2480. comprise the compositions of fine hair and COSTASIS.

2481. comprise the compositions of fine hair and cyanoacrylate.

2482. the compositions of any one of 2476-2481 item, described compositions also comprises anti-infective.

2483. the 2482nd compositions, wherein said anti-infective is a 5-fluorouracil.

2484. the 2482nd compositions, wherein said anti-infective is an antibiotic.

2485. the 2484th compositions, wherein said antibiotic is a gentamycin sulfate.

2486. the 2484th compositions, wherein said antibiotic is an amikacin sulfate.

2487. the 2484th compositions, wherein said antibiotic is a kanamycin sulfate.

2488. the 2484th compositions, wherein said antibiotic is a polymyxin B.

2489. the 2484th compositions, wherein said antibiotic is a polygynax.

2490. the 2484th compositions, wherein said antibiotic is a cefazolin sodium.

2491. the 2484th compositions, wherein said antibiotic is a metronidazole.

2492. the 2484th compositions, wherein said antibiotic is a ciprofloxacin.

2493. the 2484th compositions, wherein said antibiotic is a piperacillin.

2494. the 2484th compositions, wherein said antibiotic is a cefoxitin.

2495. the 2484th compositions, wherein said antibiotic is a cefepime.

2496. the 2484th compositions, wherein said antibiotic is an azithromycin.

2497. the 2484th compositions, wherein said antibiotic is a trimethoprim-sulfamethoxazole.

2498. comprise the implant of silk and CT3.

2499. comprise the implant of silk and COSTASIS.

2500. comprise the implant of silk and cyanoacrylate.

2501. comprise the implant of fine hair and CT3.

2502. comprise the implant of fine hair and COSTASIS.

2503. comprise the implant of fine hair and cyanoacrylate.

2504. the implant of any one of 2498-2503 item, described implant also comprises anti-infective.

2505. the 2504th implant, wherein said anti-infective is a 5-fluorouracil.

2506. the 2504th implant, wherein said anti-infective is an antibiotic.

2507. the 2506th implant, wherein said antibiotic is a gentamycin sulfate.

2508. the 2506th implant, wherein said antibiotic is an amikacin sulfate.

2509. the 2506th implant, wherein said antibiotic is a kanamycin sulfate.

2510. the 2506th implant, wherein said antibiotic is a polymyxin B.

2511. the 2506th implant, wherein said antibiotic is a polygynax.

2512. the 2506th implant, wherein said antibiotic is a cefazolin sodium.

2513. the 2506th implant, wherein said antibiotic is a metronidazole.

2514. the 2506th implant, wherein said antibiotic is a ciprofloxacin.

2515. the 2506th implant, wherein said antibiotic is a piperacillin.

2516. the 2506th implant, wherein said antibiotic is a cefoxitin.

2517. the 2506th implant, wherein said antibiotic is a cefepime.

2518. the 2506th implant, wherein said antibiotic is an azithromycin.

2519. the 2506th implant, wherein said antibiotic is a trimethoprim-sulfamethoxazole.

2520. comprise the compositions that fibrous tissue forms agent, use in the method for the treatment diverticulum disease, wherein described compositions is introduced diverticulum, and wherein said fibrous tissue forms agent inducing fibrosis reaction in described diverticulum.

2521. be used for inducing the fibrotic compositions that fibrous tissue forms agent that comprises, wherein described compositions prepared to be incorporated in the described diverticulum at diverticulum.

2522. the 2520th compositions, wherein said diverticulum disease are diverticulosis or diverticulitis.

2523. the 2520th or the 2521st 's compositions, wherein said fibrous tissue form agent have be selected from promote regeneration, promote blood vessel fibroblast proliferation takes place, promotes, promote extracellular matrix deposition, promote tissue remodeling and promote at least a biological activity of arterial blood tube wall stimulus object.

2524. the 2520th or the 2521st 's compositions, wherein said fibrous tissue form agent and comprise silk or fine hair.

2525. the 2520th or the 2521st 's compositions, wherein said fibrous tissue form agent and comprise mineral grain, chitosan, polylysine, fibronectin, bleomycin or CTGF.

2526. the 2520th or the 2521st 's compositions, wherein said fibrous tissue form the form that agent is (a) bunch; (b) form of line or contact with line; Or (c) form of microgranule.

2527. the 2520th or the 2521st 's compositions, described compositions also comprises polymer, or in-situ polymerization is to form the chemical compound of cross linked polymer.

2528. according to the 2527th compositions, wherein said polymer is selected from copolymer, block copolymer, random copolymer, biodegradable copolymer, not biodegradable polymer, hydrophilic polymer, hydrophobic polymer, the polymer with hydrophilic-structure territory, the polymer with hydrophobic domains, non-conductive polymer and elastomer.

2529. according to the 2527th compositions, wherein said polymer is selected from hydrogel, siloxane polymer, hydrocarbon polymer, styrene derived polymers, butadiene derived polymer, macromonomer, poly-(ethylene glycol).

2530. the 2520th or the 2521st 's compositions, described compositions also comprises polymer composition, and wherein said polymer composition comprises (a) collagen or derivatives thereof; (b) fibrinogen; (c) thrombin is at least a.

2531. the 2527th compositions, wherein said polymer are selected from (a) cyanoacrylate; (b) COSTASIS; (c) CT3.

2532. according to the 2531st compositions, wherein said cyanoacrylate is selected from methyl 2-cyanoacrylate, cyanacrylate, Tisuacryl, octyl 2-cyanoacrylate and alpha-cyanoacrylate methoxyl group propyl ester.

2533. according to the 2531st compositions, wherein said cyanoacrylate is poly-(the alkyl cyanoacrylate) that is selected from poly-(MCA), poly-(ethyl cyanoacrylate), poly-(butyl cyanoacrylate), poly-(isobutyl cyanoacrylate), poly-(hexyl cyanoacrylate) and gathers (octyl cyanoacrylate).

2534. according to the 2531st compositions, wherein said cyanoacrylate is poly-(carboxyalkyl cyanoacrylate).

2535. according to the 2535th compositions, wherein said poly-(carboxyalkyl cyanoacrylate) is poly-(methoxy-propyl cyanoacrylate).

2536. the 2520th or the 2521st 's compositions, wherein said compositions also comprises hemorrhage.

2537. the 2536th compositions, wherein said hemorrhage are selected from collagen polymer, poly-(ethylene glycol), COSEAL, TISSEAL, FLOSEAL and fibrin.

2538. the 2520th or the 2521st 's compositions, described compositions also comprises anti-infective.

2539. the 2538th compositions, wherein said anti-infective is selected from anthracycline, doxorubicin, mitoxantrone), fluorine pyrimidine, 5-fluorouracil, antifol, methotrexate, podophyllotoxin, etoposide, camptothecine, hydroxyurea, platinum complex and cisplatin.

2540. the 2538th compositions, wherein said anti-infective is an antibiotic.

2541. the 2540th compositions, wherein said antibiotic is selected from gentamycin sulfate, amikacin sulfate, kanamycin sulfate, polymyxin B, polygynax, Cefazolin sodium, metronidazole, ciprofloxacin, piperacillin, cefoxitin, cefepime, azithromycin and trimethoprim-sulfamethoxazole.

2542. according to the 2520th or the 2521st 's compositions, described compositions also comprises developing agent.

2543. according to the 2542nd compositions, wherein said developing agent is radiopaque material, echo material or MRI response material.

2544. according to the 2520th or the 2521st 's compositions, wherein said compositions is the form of spray, gel, paste, film or mesh.

Be used for the treatment of purposes in the medicine of diverticulum disease 2545. comprise compositions that fibrous tissue forms agent in preparation, wherein said medicine will be introduced in the diverticulum, and wherein said medicine is induced fibre modification in described diverticulum.

Be used for inducing purposes in the fibrotic medicine at diverticulum in preparation 2546. comprise compositions that fibrous tissue forms agent, wherein said medicine will be introduced in the described diverticulum.

2547., wherein in diverticulum, induce fibre modification treatment or prevention diverticulum disease according to the 2545th or the 2546th 's any one purposes.

2548. according to the 2547th purposes, wherein said diverticulum disease is diverticulitis or diverticulosis.

2549. according to the 2545th or the 2546th 's purposes, wherein said fibrous tissue form agent have be selected from promote regeneration, promote blood vessel fibroblast proliferation takes place, promotes, promote extracellular matrix deposition, promote tissue remodeling and promote at least a biological activity of arterial blood tube wall stimulus object.

2550. according to the 2545th or the 2546th 's purposes, wherein said fibrous tissue forms agent and comprises silk or fine hair.

2551. according to the 2545th or the 2546th 's purposes, wherein said fibrous tissue forms agent and comprises mineral grain, chitosan, polylysine, fibronectin, bleomycin or CTGF.

2552. according to the 2545th or the 2546th 's purposes, wherein said fibrous tissue forms the form that agent is (a) bunch; (b) form of line or contact with line; Or (c) form of microgranule.

2553. according to the 2545th or the 2546th 's purposes, wherein said compositions also comprises polymer, or in-situ polymerization is to form the chemical compound of cross linked polymer.

2554. according to the 2553rd purposes, wherein said polymer is selected from the polymer of copolymer, block copolymer, random copolymer, biodegradable copolymer, not biodegradable polymer, hydrophilic polymer, hydrophobic polymer, possess hydrophilic property domain, the polymer with hydrophobic structure territory, non-conductive polymer and elastomer.

2555. according to the 2553rd purposes, wherein said polymer is selected from hydrogel, siloxane polymer, hydrocarbon polymer, styrene derived polymer, butadiene derived polymer, macromonomer, poly-(ethylene glycol).

2556. according to the 2545th or the 2546th 's purposes, wherein said compositions also comprises polymer composition, wherein said polymer composition comprises (a) collagen or derivatives thereof; (b) fibrinogen; (c) thrombin is at least a.

2557. according to the 2553rd purposes, wherein said polymer is selected from (a) cyanoacrylate; (b) COSTASIS; (c) CT3.

2558. according to the 2557th purposes, wherein said cyanoacrylate is selected from methyl 2-cyanoacrylate, cyanacrylate, Tisuacryl, octyl 2-cyanoacrylate and alpha-cyanoacrylate methoxyl group propyl ester.

2559. according to the 2557th purposes, wherein said cyanoacrylate is poly-(the alkyl cyanoacrylate) that is selected from poly-(MCA), poly-(ethyl cyanoacrylate), poly-(butyl cyanoacrylate), poly-(isobutyl cyanoacrylate), poly-(hexyl cyanoacrylate) and gathers (octyl cyanoacrylate).

2560. according to the 2557th purposes, wherein said cyanoacrylate is poly-(carboxyalkyl cyanoacrylate).

2561. according to the 2560th purposes, wherein said poly-(carboxyalkyl cyanoacrylate) is poly-(methoxy-propyl cyanoacrylate).

2562. according to the 2545th or the 2546th 's purposes, wherein said compositions also comprises hemorrhage.

2563. the 2562nd purposes, wherein said hemorrhage are selected from collagen polymer, poly-(ethylene glycol), COSEAL, TISSEAL, FLOSEAL and fibrin.

2564. according to the 2545th or the 2546th 's purposes, wherein said compositions also comprises anti-infective.

2565. according to the 2564th purposes, wherein said anti-infective is selected from anthracycline, doxorubicin, mitoxantrone, fluorine pyrimidine, 5-fluorouracil, antifol, methotrexate, podophyllotoxin, etoposide, camptothecine, hydroxyurea, platinum complex and cisplatin.

2566. according to the 2564th purposes, wherein said anti-infective is an antibiotic.

2567. according to the 2567th purposes, wherein said antibiotic is selected from gentamycin sulfate, amikacin sulfate, kanamycin sulfate, polymyxin B, polygynax, Cefazolin sodium, metronidazole, ciprofloxacin, piperacillin, cefoxitin, cefepime, azithromycin and trimethoprim-sulfamethoxazole.

2568. according to the 2545th or the 2546th 's application, wherein said compositions also comprises developing agent.

2569. according to the 2568th purposes, wherein said developing agent is radiopaque material, echo material or MRI response material.

2570. according to the 2545th or the 2546th 's purposes, wherein said compositions is the form of spray, gel, paste, film or mesh.

2571. comprising (a) fibrous tissue, a compositions, described compositions form agent and (b) polymer or in-situ polymerization and form the chemical compound of cross linked polymer.

2572. according to the 2571st compositions, wherein said fibrous tissue forms agent and has the deposition that is selected from promotion regeneration, the generation of promotion blood vessel, promotes fibroblast proliferation, promotion extracellular matrix, at least one biological activity that promotes tissue remodeling and promotion arterial blood tube wall stimulus object.

2573. according to the 2571st compositions, wherein said fibrous tissue forms agent and comprises silk or fine hair.

2574. according to the 2571st compositions, wherein said fibrous tissue forms agent and comprises mineral grain, chitosan, polylysine, fibronectin, bleomycin or CTGF.

2575. according to the 2571st compositions, wherein said fibrous tissue forms the form that agent is (a) bunch; (b) form of line or contact with line; Or (c) form of microgranule.

2576. according to the 2571st compositions, wherein said polymer is selected from the polymer of copolymer, block copolymer, random copolymer, biodegradable copolymer, not biodegradable polymer, hydrophilic polymer, hydrophobic polymer, possess hydrophilic property domain, the polymer with hydrophobic structure territory, non-conductive polymer and elastomer.

2577. according to the 2571st compositions, wherein said polymer is selected from hydrogel, siloxane polymer, hydrocarbon polymer, styrene derived polymer, butadiene derived polymer, macromonomer, poly-(ethylene glycol).

2578. according to the 2571st compositions, wherein said polymer composition comprises (a) collagen or derivatives thereof; (b) fibrinogen; (c) thrombin is at least a.

2579. according to the 2578th compositions, wherein said collagen is methylated collagen.

2580. according to the 2571st compositions, wherein said polymer is selected from (a) cyanoacrylate; (b) COSTASIS; (c) CT3.

2581. according to the 2580th compositions, wherein said cyanoacrylate is selected from methyl 2-cyanoacrylate, cyanacrylate, Tisuacryl, octyl 2-cyanoacrylate and alpha-cyanoacrylate methoxyl group propyl ester.

2582. according to the 2580th compositions, wherein said cyanoacrylate is poly-(the alkyl cyanoacrylate) that is selected from poly-(MCA), poly-(ethyl cyanoacrylate), poly-(butyl cyanoacrylate), poly-(isobutyl cyanoacrylate), poly-(hexyl cyanoacrylate) and gathers (octyl cyanoacrylate).

2583. according to the 2580th compositions, wherein said cyanoacrylate is poly-(carboxyalkyl cyanoacrylate).

2584. according to the 2583rd compositions, wherein said poly-(carboxyalkyl cyanoacrylate) is poly-(methoxy-propyl cyanoacrylate).

2585. according to the 2571st compositions, wherein said compositions also comprises hemorrhage.

2586. according to the 2585th compositions, wherein said hemorrhage is selected from collagen polymer, poly-(ethylene glycol), COSEAL, TISSEAL, FLOSEAL and fibrin.

2587. according to the 2571st compositions, wherein said compositions also comprises anti-infective.

2588. according to the 2587th compositions, wherein said anti-infective is selected from anthracycline, doxorubicin, mitoxantrone, fluorine pyrimidine, 5-fluorouracil, antifol, methotrexate, podophyllotoxin, etoposide, camptothecine, hydroxyurea, platinum complex and cisplatin.

2589. according to the 2587th compositions, wherein said anti-infective is an antibiotic.

2590. according to the 2589th compositions, wherein said antibiotic is selected from gentamycin sulfate, amikacin sulfate, kanamycin sulfate, polymyxin B, polygynax, cefazolin sodium, metronidazole, ciprofloxacin, piperacillin, cefoxitin, cefepime, azithromycin and trimethoprim-sulfamethoxazole.

2591. according to the 2571st compositions, described compositions also comprises filler.

2592. according to the 2591st compositions, wherein said filler comprises microballon, extra large blue polymer, silicon microsphere and the biocompatible polymer in the gel of microsphere, hydroxyapatite load, micronized alloderm acellular substrate, hyaluronic acid, the hydrogel.

2593. according to the 2571st compositions, described compositions also comprises developing agent.

2594. according to the 2593rd compositions, wherein said developing agent is radiopaque material, echo material or MRI response material.

2595. according to the 2571st compositions, wherein said compositions is the form of spray, gel, paste, film or mesh.

2596. the test kit that uses in the treatment diverticulum disease, described test kit comprises: (a) comprise following dry powder composite: (i) have first component of the core that replaces with m nucleophilic group, wherein m 〉=2; Second component that (ii) has the core that replaces with n electrophilic group, wherein n 〉=2 and m+n＞4; Be endowed reactivity when being exposed to water environment but wherein said nucleophilic and electrophilic group right and wrong in dry environment are reactive, so that described component reacts to each other in water environment and forms three-dimensional compositions; (b) first buffer solution of pH in about 1.0 to 5.5 scopes; (c) second buffer solution of pH in about 6.0 to 11.0 scopes; (d) comprise the 3rd component that fibrous tissue forms agent, wherein each component is independent pack and mixing immediately before using.

2597. the 2596th test kit, described test kit also comprises delivery apparatus.

2598. the 2597th test kit wherein is configured to described device to send described compositions with the form of spray, gel or paste.

2599. the 2596th test kit, wherein said fibrous tissue form agent and are, perhaps comprise silk or fine hair.

2600. the 2596th test kit, wherein said the 3rd component be included in (a) and (b) or (c) in.

By the mode of illustration, but not provide the following example by the mode of restriction.

Embodiment

Embodiment 1

Be coated with medical implant with fibronectin

Apparatus for coating is made up of the suspension type agitator (flying generation that Scientific World company (FisherScientific)) of horizontal location.Stainless steel is invested on the chuck of agitator.Utilize an alpha-cyanoacrylate ester gum that one end of medical implant (for example, mesh or film) is invested described steel pole.Then agitator is rotated at 30rpm, so that all medical implant rotates with this speed along trunnion axis.Fibronectin (Ka Ou Biochemics Inc. (Calbiochem), Santiago, the Canada) solution of 1% (w/w) in the preparation sterilized water.Then described implant was immersed in described solution 2 minutes.Remove implant and air drying from described solution.In case dry, remove described implant by the cotton swab dissolving alpha-cyanoacrylate ester gum that utilizes the acetone dipping.

Embodiment 2

Be coated with medical implant with poly-L-Lysine

Poly-L-Lysine (SIGMA company (Sigma Aldrich), St. Louis, MO) solution of 1% (w/w) in the preparation sterilized water.Utilize the step coating medical implant of describing among the embodiment 1 (mesh or film).

Embodiment 3

With the chitosan-coated medical implant of N-carboxylic butyl

N-carboxylic butyl chitosan (carbomer company (Carbomer), Wei Sitebailu (Westborough), the MA) solution of 1% (w/w) in the preparation sterilized water.Utilize the step coating medical implant of describing among the embodiment 1 (mesh or film).

Embodiment 4

With the coating of the bromocriptine in poly-(ethylene-vinyl acetas) medical implant

The EVA (ethylene is to the ratio 60/40 of vinylacetate) (polymerization scientific company (Polysciences) U.S.) that in dichloromethane, prepares 4.5% (w/w).(SIGMA company (SigmaAldrich)) dissolves/is suspended in this solution with 5mg/ml with bromocriptine methanesulfonate.Utilize the method coating medical implant of describing among the embodiment 1 (mesh or film).

Embodiment 5

The preparation of inflammatory microcrystal (a hydration monosodium urate and two hydration calcium pyrophosphates)

Hydration monosodium urate (MSUM) microcrystal of growing.The solution of uric acid and sodium hydroxide is placed in ambient temperature overnight with pH 8.9 in 55 ℃.With cold (4 ℃) distilled water rinsing crystal several times and circulating air oven (fly generation you, among the Yi Siaotemupu (Fisher, Isotemp)) in 60 ℃ of dryings 12 hours.

Be prepared as follows three oblique brilliant two hydration calcium pyrophosphate (CPPD) crystal.The 250ml beaker that will contain the 103ml distilled water is heated to 60 ℃ in water-bath, and constantly stirs with the stirring rod of polytetrafluoroethylene coating.Slow down and stir and the concentrated hydrochloric acid of adding 0.71ml and the glacial acetic acid of 0.32ml, add the 0.6g calcium acetate subsequently.The 150ml beaker that will contain the 20ml distilled water is heated to 60 ℃ in water-bath, and adds the 0.6g calcium acetate.In the 250ml beaker, improve stir speed (S.S.), and add 2g acid calcium pyrophosphate rapidly.Work as CaH ₂P ₂O ₇When almost all dissolving, reduce stir speed (S.S.) and continue 5 minutes.In 15 seconds time, be accompanied by vigorous stirring the content in the small beaker is poured in the large beaker subsequently.In preparation subsequently batch, three oblique brilliant CPPD crystal of trace are added in the large beakers as the crystal seed material.Stop to stir, form white gels.Make it in the water-bath of freezing but, keep static.The pH of supernatant is always less than 3.0.Along with in 24 hours, forming CPPD crystal, described gel disintegrate (collapse).Described crystal is washed in distilled water 3 times, wash in ethanol, wash in acetone subsequently, the sector-style of going forward side by side is done.

Embodiment 6

Be coated with medical implant from EVA/DCM solution with inflammatory microcrystal (a hydration monosodium urate or two hydration calcium pyrophosphates)

The EVA solution (ratio of ethylene and vinylacetate is 60/40) (polymerization scientific company (Polysciences)) that in dichloromethane, prepares 4.5% (w/w).In pestle and mortar, inflammatory microcrystal (MSUM or CPPD) is milled to the granular size of 10-50 micron and is suspended in the described solution with 5mg/ml.Utilize the step coating medical implant of describing among the embodiment 1 (mesh or film).

Embodiment 7

With inflammatory microcrystal (a hydration monosodium urate or two hydration calcium pyrophosphates) coating medical implant

Preparation is with 80 in dichloromethane: 20w/w (PLGA: that MePEG) ratio exists is poly-(lactide common-Acetic acid, hydroxy-, bimol. cyclic ester) (85: 15) (IV 0.61) (birmingham polymer company (Birmingham Polymers), Birmingham, AL) with methoxy poly (ethylene glycol) 350 (MePEG 350) (Union Carbide Corporation (UnionCarbide), Danbury (Danbury), CT) solution of fusion.The inflammatory microcrystal is suspended in the described solution with 5mg/ml.Utilize the method coating medical implant of describing among the embodiment 1 (mesh or film).

Embodiment 8

With the hypertensin 2 coating medical implant that is packaged in the Polyethylene Glycol (PEG)

The Polyethylene Glycol (PEG 1475) (Union Carbide Corporation (Union Carbide)) of 1.8 grams is placed flat 20ml glass scintillation bottle and is warmed to 50 ℃ to melt PEG in water-bath.The glycerol (flying generation that Scientific World company (Fisher Scientific)) that adds 200mg.The hypertensin 2 (SIGMA company (Sigma Aldrich)) of 2mg is weighed in the bottle and in 50 ℃ of fusion/be dissolved among the PEG of thawing.By using clamp that described bottle is tilted in the water-bath with 10 degree.Each end of medical implant is immersed in the preparation of fusing.Remove subsequently and cool off described medical implant and stand-by in 4 ℃ of preservations.

Embodiment 9

With the transforming growth factor-beta in the crosslinked hyaluronic acid (TGF-β) coating medical implant

Dissolve 1% hyaluronic acid (HA) (sodium salt, SIGMA company (the SigmaAldrich)) solution for preparing in the water that comprises 30% glycerol (for the w/w of HA) (flying generation that Scientific World company (Fisher Scientific)) and 8mM 1-ethyl-3-(3 dimethylaminopropyl) carbodiimide (EDAC) by spending the night.(CA (Calbiochem, San Diego, CA)) is dissolved in this solution with 0.01mg/ml for Ka Ou Biochemics Inc., Santiago with TGF-β.Utilize the step coating medical implant of describing among the embodiment 1 (mesh or film).

Embodiment 10

With the fibroblast growth factor in the crosslinked chitosan (FGF) coating medical implant

Comprise 30% glycerol (for the w/w of chitosan) (flying generation that Scientific World company (Fisher Scientific)) and 0.5% glutaraldehyde (SIGMA company by the dissolving preparation of spending the night, the St. Louis, MO (Sigma, St.Louis, MO)) 1% chitosan (the medical rank in the acetic acid,diluted (pH 5), carbomer company (Carbomer), Wei Sitebailu (Westborough), MA) solution.(CA (Calbiochem, San Diego, CA)) is dissolved in this solution with 0.01mg/ml for Ka Ou Biochemics Inc., Santiago with FGF.Utilize the step coating medical implant of describing among the embodiment 1 (mesh or film).

Embodiment 11

Estimate the rat model of the fibre modification derivant in the rat

Rat caecum sidewall model is used to estimate preparation fibrosis inducibility in vivo.Sprague Dawley rat is used halothane anesthesia.Utilize aseptic prevention, abdominal part is opened via midline incision.Caecum is exposed and from the abdominal cavity, propose.Be positioned at caecum on the sidewall areas by two sutures then and adhere to.With the fibre modification derivant, for example, silk screen eye (mesh can be made by knitting silk maybe can place the fibre modification derivant described mesh outside) or silk gel preparation are coated in when using gel on caecum both sides and the peritoneum sidewall, perhaps locate between two tissues when using mesh.Place two other suture and described caecum is invested sidewall, 4 sutures, and abdominal incision altogether are with double-deck closed.After 7 days, with respect to the degree and the seriousness of tissue reaction, obduction is estimated animal, and it quantitatively and is qualitatively estimated.The exemplary materials that can test in this model comprises silk and Talcum.

Embodiment 12

Screening technique for the assessment of the reaction around the medical implant

Big rabbit is placed generalized anesthetic state.Utilize aseptic preventive measure, expose infrarenal abdominal aorta and thereon face and below clamp.Implement vertical arterial wall arteriotomy and in aorta, insert 2 mm dias, thereby the PTFE medical implant fragment of 1 centimeter length is also sewed up the nearside of medical implant and distal face and is made whole aortic flows by medical implant, in the mode of people's open surgery ventral aorta reparation described implant is included in the ventral aorta (not to be present in this model except there being aneurysm).Pass through the surgical operation mode subsequently with described aorta cut closure and with the abdominal wound closure, animal is restored.

Select animals received standard P TFE medical implant or such medical implant at random, the middle part 1cm of described implant is coated with on every side without anything or with reagent separately, adhesion between the independent induction of vascular wall reaction of described reagent or medical implant and the blood vessel wall, or be contained in the polymer of slow release, as polycaprolactone or polylactic acid.

Putting to death animal between 1 week and 6 weeks after the operation, Removing All aorta and adhesive reaction is detected in the zone relevant with described medical implant roughly.Attention from the tremulous pulse part that does not comprise medical implant, comprise the part of no coating medical implant and comprise the morphology of part blood vessel wall of medical implant or any difference on the histology with coating.

Embodiment 13

Screening technique for the assessment of the reaction around the graft

Describe all models of a kind of Sanguis Leporis seu oryctolagi pipe and identified the vascular tissue's stimulus object that can be used as diverticulum wall stimulus object.Big rabbit is placed generalized anesthetic state.Utilize aseptic preventive measure, expose infrarenal abdominal aorta and thereon face and below clamp.Implement vertical arterial wall arteriotomy and in aorta, insert 2 mm dias, thereby the PTFE graft fragment of 1 centimeter length is also sewed up the nearside of described graft and distal face and is made whole aortic flows by graft, in the mode of people's open surgical ventral aorta reparation described graft is included in the ventral aorta (not to be present in this model except there being aneurysm).Pass through the surgical operation mode subsequently with described aorta cut closure and with the abdominal wound closure, animal is restored.

Select animals received standard P TFE graft or such graft at random, the middle part 1cm of described graft is coated with on every side without anything coating or with the adherent reagent between independent induction of vascular wall reaction or stent graft and the blood vessel wall separately, or be contained in the polymer of slow release, as pla-pcl or polylactic acid.

Putting to death animal between 1 week and 6 weeks after the operation, Removing All aorta and adhesive reaction is detected in the zone relevant with described graft roughly.Attention from the tremulous pulse part that does not comprise graft, comprise the part of no coating graft and comprise the morphology of blood vessel wall of part of graft or any difference on the histology with coating.

Embodiment 14

Animal abdominal aortic aneurysm model

Described a kind of animal model identify cause fibrotic biologic activity or pungent, described material be placed on polymeric material such as on the stent graft time as diverticulum wall stimulus object.Pig or sheep are placed generalized anesthetic state.Utilize aseptic preventive measure, expose ventral aorta.Use heparin and carrying out aortal intersection clamp under the renal artery He on the bifurcation to animal.With vascular ring or the temporary transient control of folder collateral line, behind complete operation with its removal.Causing vertical arteriotomy aspect the aortal tremulous pulse, will be sewn into from the oval rectus sheath sticking patch of same animals in the aortotomy otch to generate aneurysm.Remove the aorta clamp and the closed abdominal cavity of lumbar arteries and collateral line.After 30 days, described animal is anaesthetized and opens once more stomach wall again.On iliac artery, implement venostomy, and, the normal infrarenal abdominal aorta of stent graft above the aneurysm that operation generates extended to the normal infrarenal abdominal aorta below the aneurysm that operation generates and pass the infrarenal abdominal aorta aneurysm and place by this.Described device discharges in a usual manner.

Animal is randomized into 5 groups, each winding is subjected to uncoated stent graft, comprise the stent graft of independent release polymer, or contain the stent graft of biologic activity or pungent, its as previously mentioned screening inspection determine.After arteriotomy and abdominal wound closure, allow animal restore.Insert the back during 6 weeks and 3 months at the stent graft, put to death animal and Remove All aorta.Infrarenal abdominal aorta is checked the evidence of histologic reaction and graft periphery leakage.

Embodiment 15

The Screening test method of the effect of assessment ciclosporin A on cell proliferation

Described a kind of external test method determine a kind of material whether irritation cell (for example, fibroblast) propagation (see, for example, In Vitro Toxicol (toxicity in vivo). (1990) 3:219; Biotech.Histochem. (biotechnology histochemistry) (1993) 68:29; Anal.Biochem. (biochemistry annual) (1993) 213:426).The primary human smooth muscle cell is cultivated according to the standard cell lines cultural method.When described cell converges with 70-90%, described cell is carried out trypsinization, and in 96 orifice plates, in culture medium, carry out renewed vaccination and allow its attaching of spending the night with 600 cells/well.Preparation concentration 10 in DMSO ^-2The ciclosporin A of M also then dilutes 10 times to provide a mother liquid concentration scope (10 ^-8M-10 ^-2M).In culture medium with each drug dilution degree dilution 1/1000 and join in the cell to provide the cumulative volume in 200 μ L/ holes.Every kind of drug level is all tested in triplicate hole.The plate that will comprise smooth muscle cell and ciclosporin A was in 37 ℃ of incubations 72 hours.

Go culture medium to stop measuring by light absorption.With CYQUANT 400X GR dye indicator (molecular probe company (Molecular Probes); Eugene (Eugene), 1/400 dilution OR) is added in the 1X cell lysis buffer solution, and the mixture of 200 μ L is added in the hole of described plate.In room temperature with plate lucifuge incubation 3-5 minute.In～480nm excitation wavelength and～the 520nm emission maximum reads fluorescence in fluorescence micro plate reader.The activation that meansigma methods by utilizing triplicate hole and average relative fluorescence unit and DMSO contrast recently determined is mutually bred.The data show of measuring from the typical case is in Fig. 1.

Utilize smooth muscle cell or human fibroblasts to repeat described mensuration for following proliferative therapeutic agent; Data are illustrated among the figure that mentions: dexamethasone (Fig. 2), all-trans retinoic acid (Fig. 3), isotretinoin (Fig. 4), 17-(Fig. 5) and 1 α, 25-dihydroxy-vitamin D ₃(Fig. 6).

Embodiment 16

Assessment PDGF is to the Screening test method of the effect of smooth muscle cell migration

Described a kind of external test method and determined whether irritation cell (for example, fibroblast) moves a kind of material.Before the test primary human smooth muscular cells was carried out serum starvation 16 hours in the smooth muscle cell minimal medium that contains insulin and human alkaline fibroblast growth factor (bFGF).In order to move mensuration, pair cell carries out trypsinization so that remove cell from bottle, is diluted to 2-2.5 * 10 with the washing of migration culture medium and in the migration culture medium ⁵The concentration of cell/ml.The migration culture medium is made up of the no phenol red Dulbecco Eagle improved culture medium (DMEM) that contains 0.35% human serum albumin.The smooth muscle cell of 100 μ L volumes (about 20,000-25,000 cell) is joined the top of Boyden chamber (Boyden chamber) composite set (assembly) (opening Micon A.S. (Chemicon) QCM CHEMOTAXIS 96-hole migration plate).Cumulative volume with the concentration 150 μ L of 10ng/ml adds chemotaxis reagent, the somatomedin of regenerated human blood-platelet derivative (rhPDGF-BB) to base apertures.Preparation concentration 10 in DMSO ^-210 times of the paclitaxel of M and serial dilutions are to provide a mother liquid concentration scope (10 ^-8M-10 ^-2M).Add the paclitaxel DMSO mother solution of previous preparation and in cell, add paclitaxel with 1/1000 dilution by direct cell in upper chambers.With plate incubation 4 hours so that carry out cell migration.

When finished period in 4 hour, the smooth muscle cell that discards the cell in the upper chambers and will be attached to the filter downside in cell desorption solution (Cell Detachment Solution) (opening Micon A.S. (Chemicon)) in 37 ℃ of desorptions 30 minutes.With the cracking and in room temperature incubation 15 minutes in the lysis buffer that contains DNA associativity CYQUANTGR dyestuff of isolated cell.In～480nm excitation wavelength and～the 520nm emission maximum reads fluorescence in fluorescence micro plate reader.Removing background fluorescence (the contrast chamber of no chemical inhibitor) back on average from the relative fluorescence unit in triplicate hole and by the smooth muscle cell standard curve acquisition cell migration average number that is diluted to 98 cells/well continuously from 25,000 cells/well.The cell migration average is recently determined 50% inhibition concentration (IC mutually with positive control (reacting on the smooth muscle cell chemotaxis of rhPDGF-BB) by will have paclitaxel the time ₅₀).The result that the typical case measures is illustrated among Fig. 7.(document: Biotechniques (biotechnology) 29:81 (2000) also sees reference; J.Immunol Methods (immunization method magazine) 254:85 (2001).

Embodiment 17

The all PU films of blood vessel of assessment silk coating in the body are with the evaluation cicatrization

Described a kind of rat carotid artery model and determined whether a kind of material stimulates fibre modification.To weigh the Wistar rat anesthesia of 300g-400g with halothane.Skin on the shaving neck region is also sterilized described skin.On trachea, carry out vertical incision and expose left neck artery.Always be rolled in around (common) carotid artery distal portions covering the polyurethane film of silk thread or PU film that quilt is not wrapped in contrast.Closure of wound also restores animal.After 28 days, put to death rat with carbon dioxide and carry out pressure injection with 10% buffering formaldehyde in 100mmHg then.Collect two carotid artery and carry out histology's processing.Can downcut successive transverse section every 2mm at the left neck artery of handling with on untreated right carotid respective horizontal.Use H﹠amp; E and Movat ' s stain dye with the tissue growth around the assessment carotid artery to section.Quantize by the area of area of computer aided morphometric analysis all granulation tissuies of blood vessel.Wrapped apparently higher than contrast by the granulation tissue area in organizing at the silk bag by the area in the group.(see figure 8).

Embodiment 18

The all PU films of blood vessel of the different silk suture material coatings of assessment in the body are with the evaluation cicatrization

Described a kind of rat carotid artery model and determined whether a kind of material stimulates fibre modification.To weigh the Wistar rat anesthesia of 300g-400g with halothane.Skin on the shaving neck region is also sterilized described skin.On trachea, make vertical incision and expose left neck artery.Will be from three different manufacturers (3-0Silk-Black Braided (Davis and the (Davis of Ge Ke company; Geck)), 3-0SOFSILK (U.S.'s surgery/(U.S.Surgical/Davis of Tai Ke company; Geck)) and 3-0Silk-Black Braided (LIGAPAK) (polyurethane film of the coating silk suture of one of this Kanggong department (Ethicon, Inc.)) of dust is rolled in around the general neck artery distal portions.(described polyurethane film can also applied other reagent to induce fibre modification).Closure of wound also restores animal.

After 28 days, put to death rat with carbon dioxide and carry out pressure injection with 10% buffering formaldehyde in 100mmHg then.Collect two carotid artery and carry out histology's processing.Downcut successive transverse section at the left neck artery of handling with on untreated right carotid respective horizontal every 2mm.Use H﹠amp; E and Movat ' s stain dye with the tissue growth around the assessment carotid artery to section.Quantize by the area of area of computer aided morphometric analysis all granulation tissuies of blood vessel.As shown in Figure 9, the thickness of granulation tissue is identical in three groups, shows that the hamartoplasia around the silk suture does not rely on production method.

Embodiment 19

Assessment blood vessel week silk powder is with the evaluation cicatrization in the body

Described a kind of rat carotid artery model and determined whether a kind of material stimulates fibre modification.To weigh the Wistar rat anesthesia of 300g-400g with halothane.Skin on the shaving neck region is also sterilized described skin.On trachea, make vertical incision and expose left neck artery.The silk powder is spread on the tremulous pulse of exposure, described tremulous pulse wraps up with the PU film subsequently.In on the same group animal not, use the silk powder (pollution-free protein) of natural silk powder or purification.The carotid artery of only wrapping up in the PU film is used as matched group.Closure of wound also restores animal.After 28 days, put to death rat with carbon dioxide and carry out pressure injection with 10% buffering formaldehyde in 100mmHg then.Collect two carotid artery and carry out histology's processing.Downcut successive transverse section at the left neck artery of handling with on untreated right carotid respective horizontal every 2mm.Use H﹠amp; E and Movat ' s stain dye with the tissue growth around the assessment carotid artery to section.Quantize by the area of area of computer aided morphometric analysis all granulation tissuies of tunicle inner membrance, tunicle middle level and blood vessel.

In the experiment of carrying out on one group of six rat, natural silk has caused serious cellular inflammation, and under 2/6 situation, it mainly is made up of neutrophil cell and lymphocytic infiltration in the fibrin network of no any extracellular matrix or blood vessel.In addition, treated tremulous pulse is by the elastic sheet of Hypocellular medium, fragmentation and thick neointimal hyperplasia grievous injury.Neointimal hyperplasia comprises many inflammatory cells and is occlusive under 2/6 situation.This serious immunoreation is inspired by the antigenic protein of fibroin by bag in this preparation.At the other end, regenerated silk powder has only inspired slight foreign body reaction around treated tremulous pulse.This tissue reaction feature is inflammatory cell, giant cell in the extracellular matrix and the existence of supporting blood vessel.Treated tremulous pulse is intact.These results show that removing coating protein from natural silk stops immunne response and promote the benign tissue growth.Carrying out the degraded of regenerated silk powder in some tissue slices, the display organization reaction may the ripe and healing along with the time.The cartographic represenation of area of granulation tissue is in Figure 10.

Embodiment 20

Assessment blood vessel week Pulvis Talci is with the evaluation cicatrization in the body

Described a kind of rat carotid artery model and determined whether a kind of material stimulates fibre modification.To weigh the Wistar rat anesthesia of 300g-400g with halothane.Skin on the shaving neck region is also sterilized described skin.On trachea, make vertical incision and expose left neck artery.Pulvis Talci is spread on the tremulous pulse of exposure, described tremulous pulse wraps up with the PU film subsequently.The carotid artery of only wrapping up in the PU film is used as matched group.Closure of wound also restores animal.1 or after 3 months, put to death rat with carbon dioxide and cushion formaldehyde with 10% then and carry out pressure injection in 100mmHg.Collect two carotid artery and carry out histology's processing.Downcut successive transverse section at the left neck artery of handling with on untreated right carotid respective horizontal every 2mm.Use H﹠amp; E and Movat ' s stain dye with the tissue growth around the assessment carotid artery to section.Quantize by the thickness of area of computer aided morphometric analysis all granulation tissuies of tunicle inner membrance, tunicle middle level and blood vessel.

The histopathology result is presented at 1 month and 3 months local responses identical to Pulvis Talci with morphometric analysis.Big tissue reaction has caught Pulvis Talci on circumvascular practical site.The feature of this tissue is a macrophage a large amount of in fine and close extracellular matrix, is accompanied by minority neutrophil cell, lymphocyte and blood vessel.The blood vessel of handling shows excellently and is not subject to processing influence.Generally speaking, this result shows that Pulvis Talci induced slight long-term fiberization, and it is subclinical and does not damage any adjacent tissue (seeing Figure 11) in nature.

Embodiment 21

The preparation of silk powder

Several silk fabrics (this Kanggong department (Ethicon) of dust, 4-0,638) are cut into the length of about 0.4cm.These sections are placed the 100ml round-bottomed flask that comprises 50ml 2M NaOH.Utilize magnetic stirring apparatus sample to be stirred 24 hours in room temperature.Utilize among the dense HCl and sample.Utilize subsequently based on cellulosic Dialysis tubing (WMCO approx 3000; Spectrum company (Spectrum)) composition that will neutralize is dialysed with respect to deionized water.With sample dialysis 48 hours, be accompanied by 5 times and change water.The sample of will dialysing is subsequently poured in the 100ml round-bottomed flask.Sample is carried out freezing and lyophilizing to produce fluffy powdered substance.

Embodiment 22

Utilize freeze grinding (CRYOMILL) from silk fabric preparation silk powder

Several pieces fabrics (Ai Sikang (Ethicon), 4-0,638) are cut into the length of about 0.4cm.Then these were ground 20 minutes in freeze grinding (Freezermill).Then with the stainless steel sift of described powder by 53 μ m.With the silk powder collection and be stored in the vial.

Embodiment 23

With Powdered silk/PLGA coating coating medical implant

Medical implant (for example, the tall suture fabric (vicryl braid) of common vetch) invests on the stainless steel (assisting down of bulldog clamp), and described stainless steel invests flying on your (fisher) suspension type agitator of generation of perpendicular positioning.Agitator is set at 30rpm rotates.2%PLGA (9K, 50: 50, birmingham polymer company (Birmingham the Polymers)) solution (ethyl acetate) that utilizes the air-brush sprayer unit will comprise Powdered silk is sprayed onto on the implant in the rotation.The concentration of Powdered silk in the PLGA solution is changed to 50% from 0.1%.After spray operation, allow air-dry 30 minutes of described implant, still be rotated simultaneously.Subsequently described implant is removed and under vacuum further dry 24 hours from the aspirator head.

Embodiment 24

With pulverous silk/polyurethane coating coating implant

Medical implant (for example, the tall suture fabric of common vetch) is shifted onto on the plastics aspirator head of 1ml.The open end of described aspirator head is invested on the stainless steel, and described stainless steel invests flying on your (Fisher) suspension type agitator of generation of horizontal location.Agitator is set at 30rpm rotates.2%CHRONOFLEXAL 85A ((CT Biomatera Inc.) CT Biomaterials) solution (THF) that utilizes the TLC sprayer unit will comprise Powdered silk (utilizing the freeze grinding preparation) is sprayed onto on the implant in the rotation.The concentration of Powdered silk in the polyurethane solutions is changed to 50% from 0.1%.After spray operation, allow air-dry 30 minutes of described implant, still be rotated simultaneously.Subsequently described implant is removed and under vacuum further dry 24 hours from the aspirator head.

Embodiment 25

With the applied implant of degradable coating top coating

To invest again on the suspension type agitator and from the applied implant of embodiment 24 and be rotated in 30rpm.With the TLC sprayer unit with 10%20: 80MePEG (750)-PLA block copolymer solution (acetone) is sprayed onto on the implant in the rotation.After spray operation, allow air-dry 30 minutes of described implant, still be rotated simultaneously.Can repeat to spray coating process up to the coating layer thickness or the homogeneity that need to obtain.Subsequently described implant is removed and under vacuum further dry 24 hours from the aspirator head.

Embodiment 26

With the applied implant of degradable coating top coating that contains heparin

To invest again on the suspension type agitator and from the applied implant of embodiment 24 and be rotated in 30rpm.To comprise with the TLC sprayer unit various amounts heparin benzalkonium chloride complex (polymerization scientific company (PolySciences)) 10%20: 80MePEG (750)-PLA block copolymer solution (acetone) is sprayed onto on the implant in the rotation.After spray operation, allow air-dry 30 minutes of described implant, still be rotated simultaneously.Can repeat to spray coating process up to the coating layer thickness or the homogeneity that need to obtain.Subsequently described implant is removed and under vacuum further dry 24 hours from the aspirator head.

Embodiment 27

Apply applied implant with heparin coating

To invest again on the suspension type agitator and from the applied implant of embodiment 24 and be rotated in 30rpm.The solution that will comprise the heparin benzalkonium chloride complex (polymerization scientific company (PolySciences)) among the IPA of various amounts with the TLC sprayer unit is sprayed onto on the implant in the rotation.After spray operation, allow air-dry 30 minutes of described implant, still be rotated simultaneously.Can repeat to spray coating process up to the coating layer thickness or the homogeneity that need to obtain.Subsequently described implant is removed and under vacuum further dry 24 hours from the aspirator head.

Embodiment 28

With pulverous silk/ciclosporin A/polyurethane coating coating implant

Medical implant (for example, the tall suture fabric of common vetch) is shifted onto on the plastics aspirator head of 1ml.The open end of described aspirator head is invested on the stainless steel, and described stainless steel invests flying on your (Fisher) suspension type agitator of generation of horizontal location.Agitator is set at 30rpm rotates.The 2%CHRONOFLEX AL 85A solution (THF) that utilizes the TLC sprayer unit will comprise Powdered silk and ciclosporin A is sprayed onto on the implant in the rotation.The concentration of Powdered silk in the polyurethane solutions is changed to 50% (with respect to the w/w of described polymer) and the concentration of ciclosporin A is changed to 10% (with respect to the w/w of described polymer) from 0.1% from 0.1%.After spray operation, allow air-dry 30 minutes of described implant, still be rotated simultaneously.Subsequently described implant is removed and under vacuum further dry 24 hours from the aspirator head.

Embodiment 29

Film with the silk fiber dipping

20%CHRONOFLEX AL 85A solution (THF) is cast on the release liner of silicone coating.Allow solvent seasoning.(LIGAPAK) (this Kanggong department (Ethicon, Inc.)) sheet of dust places on the surface of polyurethane film with the silk-black knit (Silk-Black Braided) of 3-0.Drop with THF adds on the surface of polyurethane film subsequently.Utilize the glass scintillation bottle as roller, the silk chain is embedded into the surface of polyurethane film.

Embodiment 30

Original position forms the gel (containing collagen and PEG) that contains silk

Prepare methylated collagen by following method: utilize pepsin dissolving cattle dermal collagen and as U.S. Patent number 4,233, carry out purification like that described in 360.Go into the 0.2M sodium radio-phosphate,P-32 solution by neutralization, pH 7.2, and the dissolved collagen of this purification is precipitated.Separate described precipitate by centrifugal final concentration to 70mg/ml.With dry two days of described material, pulverize subsequently.Adding contains the absolute methanol (40ml) of HCl (to 0.1N) and stirred four days.From acidic methanol, separate collagen, vacuum drying and by radiation sterilization.End-product is soluble in water in pH 3-4.

In order to send as gel, methylated collagen with 10mg, four-sense sulfydryl-PEG of 100mg (tetramethylolmethane gathers (ethylene glycol) ether four-sulfydryl) (10,000MW), with 100mg four-sense succinimido PEG (tetramethylolmethane gathers (ethylene glycol) ether four-succinimido glutarate) (10,000MW), in the water-soluble final volume of pH 3-4 (first kind of component) to 1ml.Second kind of component is the phosphate/carbonate buffer solution that contains a powder of 1ml.Described phosphate/carbonate buffer solution prepares by the 300mM sodium dihydrogen phosphate is mixed with the 300mM sodium carbonate.If desired, regulate pH with NaOH or HCl and reach pH 9.6.Final molar concentration is about 117mM phosphate and 183mM carbonate.The silk powder (1mg-100mg) (utilizing the freeze grinding preparation) of various amounts is added in phosphate/carbonate buffer solution.Utilize manual double syringe delivery system or air to assist double syringe delivery system (FibriJet, Verdix Corporations (Micromedics)) that various components are placed syringe and mix and be sprayed on the required test site.

Embodiment 31

With polymer/biological reagent coating silk fabric-direct impregnation

It is long that silk fabric (Ai Sikang (Ethicon), 4-0,638) is cut into about 10cm.Described silk fabric is immersed poly-(lactide-co-glycolide) (PLGA) in the chloroformic solution of (9K, 50: 50, birmingham polymer company (Birmingham Polymers)) and ciclosporin A.The concentration of PLGA is changed to 20% (w/v) and the concentration of ciclosporin A the solution is changed to saturated solution from 0.1% from 0.1%.Described silk fabric was immersed in the PLGA/ ciclosporin A solution 5 minutes.Removing the described silk fabric sector-style of going forward side by side subsequently does.The silk fabric that will be loaded with ciclosporin A then under vacuum is further dry.Be embedded in the described polyurethane film thereby be positioned on the polyurethane film by the fabric that will be coated with subsequently and in hot pressing, push the about fabric that will be coated with in 10 seconds of described film/fabric subsequently, described silk fabric is attached on the polyurethane film.

Embodiment 32

Original position forms the gel (containing PEG) that comprises silk

In order to send as gel, with four-sense succinimido PEG (tetramethylolmethane gathers (ethylene glycol) ether four-succinimido glutarate) of 200mg (10,000MW) in the water-soluble final volume of pH 2.5 (regulating) (first kind of component) to 1ml with HCl.Second kind of component be 1ml comprise the amino PEG (tetramethylolmethane gathers (ethylene glycol) ether four-amino) of 200mg four-sense (10, phosphate/carbonate buffer solution 000MW).Described phosphate/carbonate buffer solution prepares by the 300mM sodium dihydrogen phosphate is mixed with the 300mM sodium carbonate.If desired, regulate pH with NaOH or HCl and reach pH 9.6.Final molar concentration is about 117mM phosphate and 183mM carbonate.The silk powder (1mg-200mg) of various amounts is added in the acidic buffer.Utilize manual double syringe delivery system or air to assist double syringe delivery system (FibriJet, Verdix Corporations (Micromedics)) that various components are placed syringe and be sprayed on the required test site.

Embodiment 33

The coating that comprises ciclosporin A

Preparation contains the 5%CHRONOFLEX AL 85A solution (chloroform) of 0.1%-10% ciclosporin A.With one section PROLENE suture ((Johnson ﹠amp of Johson ﹠ Johnson; JohnsonCorporation), new Boulogne Zwick (New Brunswick), New Jersey (NJ)) immerse and from described coating solution, take out subsequently.The sample that will be coated with in fume hood carries out air-dry.By repeating the sample that described immersion-coating process prepares different coating thickness.The sample that will be coated with under vacuum carried out drying 24 hours subsequently.

Embodiment 34

Collagen synthesizes algoscopy

Described a kind of external test method and determined whether a kind of material promotes the deposition of extracellular matrix (ECM).Normal human dermis fibroblast is carried out trypsinization, in 12 orifice plates, be re-seeded into subsequently and contain in the phosphatic culture medium of ascorbic acid-2-with 150,000 cells/well.With described cell in 37 ℃ and 5%CO ₂Cultivate 2-3 week, changed culture medium, thereby make them form the 3-D substrate of cell and collagen every three days.After 14-21 days cultivation, replace described culture medium and allow cell tranquillization 24 hours with the culture medium of serum-free.

With medicine with 10 ^-2M is diluted among the DMSO, dilutes 10 times subsequently to provide 10 ^-2M-10 ^-8The mother liquid concentration scope of M.In the new system serum-free medium, join in the hole subsequently with 1000 times of drug dilutions and with the cumulative volume in 3ml/ hole.Subsequently in 37 ℃ with plate incubation 72 hours.After 72 hours culture medium is removed and puts into microcentrifugal tube from the hole, freezing in-20 ℃ until being used for mensuration.

Utilize procollagen 1 type C-peptide (Procollagen Type 1C-Peptide) (PIP) the EIA test kit (Taka is drawn biotech firm, Shiga Prefecture, Japan (Takara Bio Inc.Shiga, Japan)) measure synthetic collagen quantity, wherein the collagen quantity of being produced carries out stoichiometry by the amount of the propetide sheared by collagen and represents when it is secreted.To resist the PIP monoclonal antibody to be fixed on the elisa plate, add sample, will be conjugated to second kind of PIP monoclonal antibody on the horseradish peroxidase subsequently and join in the hole and carry out incubation.Behind the incubation, washing hole adds substrate solution, measures absorbance and compare with the standard curve of PIP (ng/ml) in the plate reader in 450nm.

Embodiment 35

Chicken chorio-allantois (" CAM ") algoscopy

This embodiment has described a kind of external test method and has determined whether a kind of material promotes blood vessel to take place.The tame Embryo Gallus domesticus that to be fertilized before no shell (shell-less) is cultivated was hatched 3 days.In this process, by removing the shell that is positioned at air gap periphery and with the content emptying of ovum.Cut inner shell membrane subsequently and with the perforation of the end opposite of shell so that allow the content of ovum skid off gently from flush end (blunted end).The emptying of ovum content is gone in the aseptic glass alms bowl of round bottom and with the culture dish lid to cover.Subsequently in 90% relative humidity and 3%CO ₂These are inserted in the incubator and incubation 3 days.(perhaps, the ovum content can be retained in the shell, opening is coated with Parafilm).

Fibrous tissue can be formed agent with 0.25,0.5, the cellulosic concentration of 0.5% aqueous dimethylformamide of 1,5,10,30 μ g/10 μ l aliquots is mixed.Concentration changes according to described reagent.Dissolubility according to described reagent is suitably mixed reagent with other compatible material.This solution of ten mul aliquots samples is carried out drying 1 hour on Parafilm, form the disk of diameter 2mm.The dry disk that will contain reagent on the 6th day in incubation places on the growing edge of each CAM carefully subsequently.The date of placing disk, the blood vessel generation quantity of stimulus compared with the control the time changed according to described reagent.Contrast is to place on the CAMs by the methylcellulose disk that will not have reagent in the phase same time to obtain.Exposing after 2 days (incubation the 8th day) checks vascular system by means of stereoscopic microscope.With Liposyn II, a kind of White-opalescent solution is injected among the CAM to improve the visibility of described vascular details.Undyed live body embryo's vascular system is carried out imaging with the Zeiss stereoscopic microscope, and (state of Indiana (Dage-MTI Inc.Michigan City, IN)) joins for Da Ge-MTI company, city, Michigan for described Zeiss stereoscopic microscope and video camera.Show these video signals with the 160x enlargement ratio subsequently and utilize image analysis system (Vidas, control wound company (Kontron); Etching, Germany) catch.Subsequently in chart recorder (3000 types; Ma Cuisi instrument company (Matrix Instruments), Oran Zhi Bao (Orangeburg) makes the image egative film on NY).

Film with the no shell embryo of 2% glutaraldehyde submergence, 8 ages in days in the 0.1M sodium cacodylate buffer liquid; The other fixative of injection under CAM.In position after 10 minutes, take out CAM and inserted in the fresh fixative 2 hours in room temperature.Washing tissue subsequently spends the night in containing the dimethyl arsenic acid buffer liquid of 6% sucrose.After the target area is in 1% Osmic acid., fix 1.5 hours in 4 ℃.To be organized in subsequently in the ethanol of gradient series and dewater, and exchange solvent with expoxy propane, and be embedded in the Spurr resin.Cut out slice with diamond knife, place on the copper grid, dyeing, and in the Joel1200EX ultramicroscope, check.Similarly, cut out the section of 0.5mm and be used for light microscopy with C.I. 49410. dyeing.

Growing the 11st day is used to corrode the mold technology with Embryo Gallus domesticus.(California (Ted Pella, Inc.Redding, CA)) is injected in the CAM vascular system for Te Depaila company, Lay fourth with the Mercox resin to utilize No. 30 hypodermic needles.Molding material is made up of the Mercox CL-2B polymer of 2.5 grams and the catalyst (55% benzoyl peroxide) of 0.05 gram, and it has 5 minutes polymerization time.After the injection, allow described plastics keep original position to spend the night in baking oven in 65 ℃ subsequently in one hour in room temperature.Subsequently CAM is placed 50% sodium hydrate aqueous solution to digest whole organic components.With described plastic mo(u)lding thorough washing in distilled water, air-dry, with the coating of gold/palladium, and with Philip 501B (Philips 501B) sem observation.

The 6th day of incubation, with embryo's centrally-located in the network of the radial expansion of blood vessel; CAM develops near described embryo.Vascular in these growths is near the surface and can see easily that this makes this system become the ideal model that the research blood vessel takes place.The undyed CAM capillary bed of live body can carry out non-invasive imaging with stereoscopic microscope.

Transverse section by CAM shows the outside ectoderm of being made up of two cellular layers, the mesoderm that contains blood capillary of broad and inner single endoderm cell's layer, and described blood capillary is positioned at ectoderm, under the adventitial cell.Under the ultramicroscope level, show the typical structure details of CAM blood capillary.Typically, the position of these blood vessels and ectodermic inner cell layer tight association.

With 0.25,0.5,1,5,10, or the concentration of 30 μ g is exposed to a kind of reagent after 48 hours, under condition of living body each CAM checked the effect that takes place for blood vessel with assessment with the stereoscopic microscope that has been equipped with video/computer interface.Amplification in 160x uses this imaging device, and this allows direct observation hemocyte in blood capillary; Can evaluate blood flow thus easily with the record object zone.The variation of blood vessel generating capacity is defined as the area (diameter measurement 2-6mm) of the CAM of capillary network with increase and vascular blood flow.In whole experiment, on 4 gradients, (table 1) evaluated in the zone.This raising degree of representing blood vessel to take place of measuring is measured maximum the raising in the vascular gradient and is expressed as 3.The score value of reagent is compared with the score value of contrast.

Table 1

The vascular gradient

0-does not have vascular and distributes

Some microvascular motions of 1-

2 ^*--the about 2mm of diameter enriches the vascular zone

3 ^*--what extend beyond described disk enriches vascular zone (diameter 6mm)

^*-expression positive vessels reacts

Embodiment 36

Silk suture with the coating of magnetic force active particle

The end of one section silk 5-0 suture is immersed in the THF solution of CHRONOFLEX AL 85A polyurethane solutions (approximately 10%w/v).Take out described silk, and the end that will be coated with immersion comprises in the bottle of magnetic force active particles.It is terminal to take out the silk that was coated with, and by described end is rolled between two finger tips described microgranule further is embedded in the polyurethane coating.By air-dry removal solvent.

Embodiment 37

Silk suture with the active pearl coating of magnetic force

The end of one section silk 5-0 suture is immersed in the THF solution of CHRONOFLEX AL 85A polyurethane solutions (approximately 10%w/v), described solution comprises the magnetic beads of about 5%w/w (pearl is for polymer).Take out described silk, and the end that will be coated with immersion comprises in the bottle of magnetic force active particles.It is terminal to take out the silk that was coated with, and by described end is rolled between two finger tips described microgranule further is embedded in the polyurethane coating.By air-dry removal solvent.

Embodiment 38

The blood vessel week PU film that assessment is coated with silk chain that come unstuck or untreated in the body

To weigh the Wistar rat anesthesia of 300g-400g with halothane.Skin on the shaving neck region is also sterilized described skin.Above trachea, make a vertical incision and expose left neck artery.To or contrast uncoated PU film coated with the polyurethane film of degumed silk chain (degummed silk strands), untreated silk chain is rolled in around the general neck artery distal portions.Closure of wound also restores animal.

After 28 days, put to death rat with carbon dioxide and carry out pressure injection with 10% buffering formaldehyde in 100mmHg then.Collect two carotid artery and carry out histology's processing.To downcut successive transverse section every 2mm at the left neck artery of handling with on untreated right carotid respective horizontal.Use H﹠amp; E and Movat ' s stain dye with the tissue growth around the assessment carotid artery to section.Quantize by the thickness of area of computer aided morphometric analysis all granulation tissuies of blood vessel.

Two types silk all significantly improves circumvascular granulation tissue growth on same degree.Silk chain in two groups all is broken into granule (the about 30 μ m of diameter), is dispersed in around the blood vessel and by giant cell, macrophage, Dan Baijutang substrate and blood vessel and surrounds.These features are typical foreign body reactions.Variable more in the degumed silk group by the zone ratio that foreign body reaction covered in untreated silk group.See Figure 12,13 and 14.

Embodiment 39

Utilize freeze grinding from degumed silk preparation silk powder

The fiber of degumed silk is cut into the long fragment of about 1-2cm.Use freeze grinding (freeze grinding machine (Spex Certiprep Freezer)/Mill-6850 type) that described material is clayed into power subsequently.The powder that a part was ground sieved the metallic sieve of a series of different sizes to obtain the silk powder of different magnitude range subsequently.

Embodiment 40

Be loaded with the electrospinning silk (ELECTROSPINNING) of the material of silk

By 2g PLGA being dissolved into PLGA (50: 50, Mw ≈ 54, the 000) solution of 10mL DCM preparation 20%.The silk powder (25-53 μ m) thereby be added to of various amounts is made the silk percentage ratio of polymer in every kind of solution be from 2% to 50%.Subsequently every kind of solution is packed in the 10ml syringe of being furnished with No. 18 syringe needles.Subsequently syringe is packed into and use the 20kV positive high voltage (by Jim Glassman high pressure company (Glassman High Voltage, Inc.)) in the syringe pump and to syringe needle.The target drum that grinds is the rotary drum with about 12cm diameter.Syringe pump is set at 25 μ L per minutes aspirates and described drum is rotated with about 250rpm.Distance from needle point to described bulging outer side surface is about 14cm.Thereby in spinning process with described rotary drum from one move by side to opposite side make described in the spinning material drum in fact covered fully.After finishing spinning process, on the complete length of spinning material, cause an otch with razor.Described material is removed and vacuum drying oven further dry 24 hours from drum.

Embodiment 41

Determine MIC (minimal inhibitory concentration) by microtitre broth bouillon dilution method

A. the MIC of various gram female parts and male part antibacterial measures

Basically as Amsterdam, D.1996, " Susceptibility testing of antimicrobialsin liquid media; " (carrying out antimicrobial sensitivity tests in the liquid medium within) 52-111 page or leaf. at Loman, V. edit .Antibiotics in Laboratory Medicine (antibiotic in the laboratory medicine), the 4th edition .Williams and Wilkins, Baltimore, the described MIC that carries out like that of MD. measures.In brief, in MIC (minimal inhibitory concentration) measures, multiple chemical compound is tested resisting pseudomonas aeruginosa (P.aeruginosa), Klebsiella pneumonia (K.pneumoniae), escherichia coli (E.coli), the antibacterial activity of the separator of staphylococcus epidermidis (S.epidermidus) and staphylococcus aureus (S.aureus), it is to utilize 96 hole polystyrene microtitration plates (Falcon 1177) and Mueller Hinton broth bouillon to carry out in 24 hours in 37 ℃ of incubations under aerobic conditions that described MIC measures.(MHB is used in test to great majority, except the C721 (streptococcus pyogenes (S.pyogenes)) of use Todd Hewitt broth bouillon, and the hemophilus influenza (Haemophilus influenzae) of using haemophilus (Haemophilus) test medium (HTM)).Test in triplicate.The result provides in following table 2.

Table 2

Therapeutic agent resists the minimal inhibitory concentration of various Gram-negatives and positive bacteria

Bacterial isolates	Pseudomonas aeruginosa	Klebsiella pneumonia	Escherichia coli	Staphylococcus aureus	Staphylococcus epidermidis	Streptococcus pyogenes
Bacterial isolates	Pseudomonas aeruginosa	Klebsiella pneumonia	Escherichia coli	Staphylococcus aureus	Staphylococcus epidermidis	Streptococcus pyogenes		PAE/K799	ATCC13883	UB1005	ATCC25 923
	H187	C238	C498	C622	C621	C721		PAE/K799	ATCC13883	UB1005	ATCC25 923
	H187	C238	C498	C622	C621	C721		wt	wt	wt	wt	wt	wt
Medicine	Gram-	Gram-	Gram-	Gram+	Gram+	Gram+		wt	wt	wt	wt	wt	wt
Medicine	Gram-	Gram-	Gram-	Gram+	Gram+	Gram+	Doxorubicin
	10 ^-5	10 ^-6	10 ^-4	10 ^-5	10 ^-6	10 ^-7	Doxorubicin
	10 ^-5	10 ^-6	10 ^-4	10 ^-5	10 ^-6	10 ^-7	Mitoxantrone	10 ^-5	10 ^-6	10 ^-5	10 ^-5	10 ^-5	10 ^-6
5-fluorouracil	10 ^-5	10 ^-6	10 ^-6	10 ^-7	10 ^-7	10 ^-4	Mitoxantrone	10 ^-5	10 ^-6	10 ^-5	10 ^-5	10 ^-5	10 ^-6
5-fluorouracil	10 ^-5	10 ^-6	10 ^-6	10 ^-7	10 ^-7	10 ^-4	Methotrexate	N	10 ^-6	N	10 ^-5	N	10 ^-6
Etoposide	N	10 ^-5	N	10 ^-5	10 ^-6	10 ^-5	Methotrexate	N	10 ^-6	N	10 ^-5	N	10 ^-6
Etoposide	N	10 ^-5	N	10 ^-5	10 ^-6	10 ^-5	Camptothecine	N	N	N	N	10 ^-4	N
Hydroxyurea	10 ^-4	N	N	N	N		Camptothecine	N	N	N	N	10 ^-4	N	10 ^-4
Hydroxyurea	10 ^-4	N	N	N	N		Cisplatin	10 ^-4	N	N	N	N	N	10 ^-4
Tubercidin	N	N	N	N	N	N	Cisplatin	10 ^-4	N	N	N	N	N
Tubercidin	N	N	N	N	N	N	The 2-purinethol	N	N	N	N	N	N
Ismipur	N	N	N	N	N	N	The 2-purinethol	N	N	N	N	N	N
Ismipur	N	N	N	N	N	N	Cytosine arabinoside	N	N	N	N	N	N

MIC represents with molar concentration

The Wt=wild type

The N=non-activity

B. the MIC of antibiotic resistance antibacterial

In aforesaid MIC measures to the following compounds of various concentration, mitoxantrone, cisplatin, tubercidin, methotrexate, 5-fluorouracil, etoposide, 2-purinethol, doxorubicin, Ismipur, camptothecine, the antibacterial activity of hydroxyurea and cytosine arabinoside test antagonism methicillin resistance staphylococcus aureus clinical isolates and vancomycin tolerance property sheet coccus (pediococcus) clinical isolates.Growth inhibited (MIC value＜1.0 * 10 that show these resistant bacteria bacterial strains ^-3) chemical compound comprise: mitoxantrone (two bacterial strains all are); Methotrexate (vancomycin tolerance property sheet coccus); 5-fluorouracil (two bacterial strains all are); Etoposide (two bacterial strains all are); With 2-purinethol (vancomycin tolerance property sheet coccus).

The other reagent that can test in this mensuration includes but not limited to, the 4th generation penicillin such as mezlocillin and piperacillin (urea groups penicillin (ureidopenicillin)), with Carbenicillin and ticarcillin (penicillin carboxy), and analog and derivant; First generation cephalosporin is such as cefazolin sodium, cefalexin (cefalexin), cefazolin sodium (cefazolin sodium), cefaloject (cephapirin sodium) and cefalotin (cefalotin) and analog and derivant; Ticarcillin, second generation cephalosporin such as cefuroxime (Zinocef), cefotetan (Cefotan), and cefoxitin (Cefoxitin) and analog and derivant; Third generation cephalosporin such as ceftiofur sodium (ceftiofur sodium), cefdinir (Omnicef), cefoperazone (cefoperazone), ceftazidime (ceftazidime), ceftriaxone (Ceftriaxone), cefotaxime (Cefotaxime) and analog and derivant; The 4th generation cephalosporin such as cefepime (Maxipime) and analog and derivant; Monobactam such as aztreonam and analog thereof and derivant; Carbapenem is such as imipenum, Ai Tapeinan and meropenem and analog thereof and derivant; Protein synthesis inhibitor is such as comprising streptomycin, gentamycin, the aminoglycoside of tobramycin and amikacin and analog thereof and derivant; Protein synthesis inhibitor is such as comprising macrolide (erythromycin), long-acting macrolide (azithromycin) and lincosamide (clindamycin) and streptogramin (Syneroid), clarithromycin, the MSL group of kanamycin sulfate, and analog and derivant; The DNA synthetic inhibitor is such as comprising ciprofloxacin, ofloxacin, Gatifloxacin, Moxifloxacin, levofloxacin, the quinolinones of trovafloxacin and analog thereof and derivant; DNA synthetic inhibitor such as metronidazole and analog thereof and derivant; The folic acid metabolism inhibitor that comprises sulfonamides and trimethoprim and analog thereof and derivant.Other reagent includes but not limited to cefixime, spectinomycin, tetracycline, nitrofurantoin, doxycycline, polymyxin B, neomycin, polygynax, and analog and derivant.

Embodiment 42

Estimate the rabbit model of fibre modification derivant

The fibrosis ability that the rabbit uterus angle model is used for estimating in vivo preparation.The female rabbit of ripe New Zealand white (NZW) is placed under the general anesthesia.Utilize aseptic preventive measure, with abdominal part at center line with two layer opens to expose the uterus.Two cornua uteris are lifted out the abdominal cavity and go up the evaluation size at the french scale (FrenchScale) of conduit.#8 and the angle between the #14 on french scale (2.5-4.5mm diameter) are considered suitable for this model.Make independent angle relative with peritoneal wall then also with two sutures stitchings that are placed on 2mm on the abrasion edges of regions.The cicatrix induction preparation is used to described angle and abdominal part is enclosed in three layers.After 14 days, cicatrization degree and the seriousness of animal is estimated in autopsy, quantitatively and qualitatively keeps the score.The exemplary chemical compound that can test in this model comprises, for example, and silk and Talcum.

Embodiment 43

With silk/tall suture fabric of PLGA coating common vetch

With 5g PLGA (50: 50, IV=0.15, the solution of birmingham polymer company (BirminghamPolymers, Inc.)) is dissolved in the 100mL dichloromethane.The Powdered silk of 1g (25-53 μ m, utilize freeze grinding when sieving as mentioned above and prepare) is mixed in the described solution.Utilize the tall suture fabric of step coating common vetch (VICRYL 2-0, the Ai Sikang (Ethicon) that describe among the embodiment 1; (the Johnson ﹠amp of Johson ﹠ Johnson; Johnson Corp.)).

Embodiment 44

With silk/ciclosporin A/tall suture fabric of PLGA coating common vetch

With 5g PLGA (50: 50, IV=0.15, the solution of birmingham polymer company (BirminghamPolymers, Inc.)) is dissolved in the 100mL chloroform.The Powdered silk of 1g (25-53 μ m, utilize freeze grinding when sieving as mentioned above and prepare) is mixed in the described solution.The 0.5mg ciclosporin A is joined in the described solution.Utilize the tall suture fabric of describing among the embodiment 1 (VICRYL 2-0, Ai Sikang (Ethicon)) of step coating common vetch.Other example that can similarly be applied to the fibrous tissue formation agent on the tall suture fabric of common vetch comprises Talcum, Silicon stone, starch, fibronectin, poly-(cyanacrylate), polylysine, bleomycin, and CTGF.

Embodiment 45

Silk is attached in the surgical operation mesh

(plain film (Flat Sheets), Cat#01126803 " x6 " (7.5cm * 15cm), Davao company (DAVOL)) is flat to be overlying on the glass flake with Ahmedabad hernia (Bard Hernia) mesh.Subsequently by pin is passed mesh to the opposite side of mesh and several silk sutures (PERMA-HAND silk suture (Silk Suture)-Taper Point, Cat:7730G, Ai Sikang (Ethicon)) are sewn on the mesh from a side of mesh.For every suture silk is passed described mesh at least 4 times.Cut off unnecessary suture material then.

Embodiment 46

Silk is attached in the filler

The Powdered silk of 50mg (25-53 μ m, utilize freeze grinding during screening and prepare) is joined in the bovine collagen solution (35mg/mL) [CONTIGEN, (CR The Budd Co.) CR Bard Inc. be Leishan (Murray Hill) not, NJ] of 2.5mL glutaraldehyde cross-linking.Vibrate described solution to produce final suspension.Other example that can be applied to the fibrous tissue formation agent on the implant similarly comprises: Talcum, Silicon stone, fibronectin, starch, poly-(cyanacrylate), polylysine, bleomycin, and CTGF.

Embodiment 47

Silk is attached in the surgical operation film implant

By the 1g polymer dissolution is prepared in 10ml DCM 10% 70: 30PLLA: PDLLA polymer (RESOMER LR 708, Boehringer Ingelheim company (Boehringer Ingelheim), KG, Germany) solution.The Powdered silk of 1g (25-53 μ m, utilize freeze grinding and screening and prepare) is added in the described solution.With solution stirring 1 hour.The casting cutter that utilizes 40mil is with in the film of solution-cast on release liner.Described film (50 ℃, 3 hours) in forcing air-oven is carried out drying and in vacuum drying oven dry 24 hours subsequently.

Embodiment 48

Drip (dripped-on) ciclosporin A sample of system

Polyurethane (PU) (CHRONOFLEX AL 85A) is dissolved in the oxolane (THF) solution (20ml) to form 20%.By the PU solution-cast is prepared PU film (utilizing the open cutter (opening knife) of 40MIL) on release liner.Described film is dry and carry out drying subsequently in vacuum drying oven in (50 ℃) in forcing air-oven.Final film thickness is about 100-120 μ m.Ciclosporin A is dissolved in (500 μ g/mL) forms the ciclosporin A alcoholic solution in the ethanol.The ciclosporin A solution of 50 μ l aliquots is dripped to 8 * 8mm ²On the PU film of (precuting).In fume hood ethanol evaporation and in vacuum drying oven further dry described PU sample.

Embodiment 49

The ciclosporin A sample of sealing

20% polyurethane (the CHRONOFLEX AL 85A) solution of preparation among the THF (2g PU in 10mL THF, 20mL glass scintillation bottle).100 μ g/ml ciclosporin As/chloroformic solution of 230 μ l is added in the PU solution.Utilize magnetic stirring apparatus with described solution stirring 2 hours.The casting cutter that utilizes 40mil is with in the film of PU/ ciclosporin A solution-cast on release liner.Film (50 ℃) in forcing air-oven is dry and carry out drying subsequently in vacuum drying oven.Final film thickness is about 100-120 μ m.

Embodiment 50

For releasing research and total content analysis from the ciclosporin A of polyurethane film

Utilize following parameters the release from the ciclosporin A of polyurethane film to be analyzed by HPLC.

Mobile phase	35: 65: 5: 0.1 (water/acetonitrile, tert-butyl methyl ether, phosphoric acid)
Mobile phase		Wavelength	210nm
Post	ACE C18150×4.6mm 5μm	Wavelength	210nm

Flow velocity	1.2ml/min
Flow velocity	1.2ml/min	The dilution of sample agent	1: 1 (acetonitrile/water)

Be prepared as follows reference material: the ciclosporin of about 25mg is weighed in the 25mL volumetric flask.Add diluent (1: 1 acetonitrile/water) dissolving ciclosporin and add diluent to obtain correct volume.Make the following diluent that is shown in the following table to obtain 0.2,0.5,2,5, the reference material of 10 and 20 μ g/mL.

Mother liquid concentration (μ g/ml)	Diluent volume (ml)	Final volume (ml)	Ultimate density (μ g/ml)
Mother liquid concentration (μ g/ml)	Diluent volume (ml)	Final volume (ml)	Ultimate density (μ g/ml)	1000	8	10	800
1000	5	10	500	1000	8	10	800
1000	5	10	500	1000	3	10	300
1000	2	10	200	1000	3	10	300
1000	2	10	200	1000	1	10	100
100	1	10	10	1000	1	10	100
100	1	10	10	500	1	10	50
50	1	10	0.5	500	1	10	50
50	1	10	0.5	800	1	10	80
80	1	10	0.8	800	1	10	80
80	1	10	0.8	200	1	10	20
20	1	10	2	200	1	10	20

Releasing research:

The following releasing research that carries out.The PU film is cut into the sheet of 1cm * 1cm,, and accurately is weighed in the 15cm test tube if be not this size originally.The release medium of 14ml is distributed in each test tube that comprises sample.Close the lid, and place on the rotator up to next time point in 37 ℃.Described time point is 5 hours, 1 day, 2 days, 3 days, 4 days, 5 days and subsequently after first week every other day up to detecting less than medicine or up to determining in addition.On each time point, with sample transfer in new test tube and add the release medium of 14ml.Sample is put back to 37 ℃ of baking ovens up to next time point.At different time points release medium solution is injected directly on the HPLC post and analyzes.

Total content is analyzed:

The PU film is cut into the sheet of 1cm * 1cm,, and accurately is weighed in the 15cm test tube if be not this size originally.Chloroform (0.5mL) joined in every test tube and dissolve described sample fully.In case described sample dissolution, the just acetonitrile of adding 6.0ml in each sample.Sample closed the lid and acutely shake with precipitation polyurethane.With sample centrifugal 10 minutes in 2500rpm.The supernatant of 5.0ml is transferred in the clean test tube and under nitrogen carries out drying in 35 ℃.With the reconstruct and being injected among the HPLC in the acetonitrile of 1.0ml of dried sample.For the results are shown among Figure 15 of the releasing research of the polyurethane film that has loaded 1.25% and 0.125% ciclosporin.

Embodiment 51

Four functional poly-(ethylene glycol) succinimido glutarates, (PEG-SG4), with the non-gelling preparation of silk powder

To be equipped with the 1ml syringe (syringe 1) of luer-locking running-on (luer lock) hybrid junctioin to fill PEG-SG4 (100mg) (Shang Bai company, Ao Ruida, California (Sunbio, Inc.Orinda, CA)) and the Powdered silk of 50mg (embodiment 22).The syringe (syringe 2) that 1ml is added medicated cap is filled with the 6.3mM HCl solution (pH 2.1) of 0.25ml.The syringe (syringe 3) that 1ml is added medicated cap is filled with 0.12M sodium dihydrogen phosphate and 0.2M sodium carbonate (pH 9.7) buffer of 0.25ml.By shifting content repeatedly to another syringe, the solids content of syringe 1 and the acid solution of syringe 2 are mixed by hybrid junctioin from a syringe.After mixing fully, whole mixture is shifted onto in one of described syringe.The syringe that will contain described mixture then invests the import of applicator (MICROMEDICS air-assisted spray-applicator (model SA-6105)).The syringe 3 that contains pH 9.7 solution is attached in another import of described applicator.Manufacturer is illustrated as applicator, and described preparation is coated to tissue surface.

Embodiment 52

Gelling preparation (being pre-mixed) with the silk powder

The 1ml syringe (syringe 1) that is equipped with luer-locking running-on hybrid junctioin is used PEG-SG4 (50mg) and PEG-SH4 (four functional poly-(ethylene glycol) mercaptan), and (50mg) (the Powdered silk of mixture of Shang Bai company (Sunbio, Inc.)) (being called " being pre-mixed ") and 50mg (embodiment 22) is filled.The syringe (syringe 2) that 1ml is added medicated cap is filled with the 6.3mM HCl solution (pH2.1) of 0.25ml.The syringe (syringe 3) that 1ml is added medicated cap is filled with 0.12M sodium dihydrogen phosphate and 0.2M sodium carbonate (pH 9.7) buffer of 0.25ml.Utilize among the embodiment 51 step of describing that described component is mixed and be coated to tissue surface.

Embodiment 53

Four functional poly-(ethylene glycol) amine, (PEG-N4) gelling preparations

With the 1ml syringe (syringe 1) that is equipped with luer locking running-on hybrid junctioin with PEG-SG4 (50mg) and PEG-SH4 (four functional poly-(ethylene glycol) mercaptan) (10,25, or 40mg) and Powdered (embodiment 22) filling of 50mg.The syringe (syringe 2) that 1ml is added medicated cap is filled with the 6.3mM HCl solution (pH 2.1) of 0.25ml.The syringe (syringe 3) that 1ml is added medicated cap is filled with 0.12M sodium dihydrogen phosphate and 0.2M sodium carbonate (pH 9.7) buffer of 0.25ml.1ml syringe (syringe 4) the PEG-N4 ((Sunbio of Shang Bai company of luer-locking running-on hybrid junctioin is equipped with, Inc.)) (40,25, or 10mg) mixture (amount to 50mg) of filling to make PEG-SH4 (in syringe 1) and PEG-N4 (in syringe 4).By shifting described content to another syringe, by the content of described hybrid junctioin mixing syringe 1 and syringe 2 from a syringe.After mixing fully, whole preparations are pushed one of described syringe, then it is invested an import of applicator (the auxiliary spraying-applicator of MICROMEDICS air (model SA-6105)).Syringe 4 usefulness hybrid junctioins are invested the syringe 3 that contains pH 9.7 solution.After the content of syringe 3 and 4 mixes fully, described mixture is pushed one of described syringe, then it is invested second import of described applicator.Manufacturer is illustrated as applicator, and described preparation is coated to tissue surface.

Embodiment 54

The method of treatment hemorrhage of diverticulum

The patient who shows diverticulum disease symptom (for example, stomachache and bottom GI are hemorrhage) carry out physics with the degree of radiographic X inspection (for example, X-ray, ultrasonic or CT scan) with definite diverticulum disease.Suffer from diverticulum disease in case described patient makes a definite diagnosis, then patients acuity can be handled with stop hemorrhage or, (for example, any time up to about 6 weeks) handles the patient after acute events is calmed down, to prevent new hemorrhage recurrence.In order to treat or prevent hemorrhage of diverticulum, use intravenous calmness (for example, midazolam and demerol or fentanyl) to the patient, be placed on their left side then.Advance the side-looking colonoscope and visually check whole intestinal by colon then, identification diverticulum disease and hemorrhage site.In case determine hemorrhage site and relevant diverticulum, the nozzle delivery catheter introduced by the biopsy inlet of colonoscope.Described nozzle duct comprises that being configured to contain the multicomponent original position (for example forms hemostatic composition, from (the Orthovita of this Vita limited company difficult to understand, Inc.) (Malvern, PA) (be called as COSTASIS in the past, from blood vessel technology medicine (the Angiotech Pharmaceuticals of limited company, Inc.) (Vancouver, BC))) component syringe part and be configured to before being delivered to diverticulum combination and mix the mixing portion of the component of described compositions.The mixing that can utilize in this step and the case description of distributor exist, altogether-pending application, name is called " Device and Method formixing and dispensing Fluid Components of a Multicomponent Composition (being used to mix and distribute the apparatus and method of the fluid components of multi-component combination) ", submits on November 8th, 2004 (PCT/US2004/037450).One or more components of described compositions can comprise vasoconstriction reagent (for example epinephrine).The inlet of nozzle duct by colonoscope is delivered to therapentic part, and operation and will be positioned syringe tip in described diverticulum or in the diverticulum hole.Promote the nozzle duct piston, activate described syringe, and described compositions is delivered to diverticulum.The chamber or the hole of the crosslinked sealing diverticulum of described compositions subsequently cause hemorrhage control.

Embodiment 55

The method of treatment diverticulum disease

In case described patient makes a definite diagnosis and suffers from diverticulum disease (via physics and radiographic X inspection, described in embodiment 54), then can the acute treatment patient with hemostasis (if existence), after acute hemorrhage outbreak has been calmed down (for example, any time up to about 6 weeks) patient is handled, preventing new hemorrhage recurrence, or prophylactically prevent hemorrhage outbreak.In order to treat or prevent diverticulum disease, use intravenous calmness (for example, midazolam and demerol or fentanyl) to the patient, be placed on their left side then.Then the side-looking colonoscope is visually checked the diverticulum opening in whole intestinal and the location enteric cavity by the colon propelling.In case determine opening, the inlet of indurative pin by colonoscope advanced.With described pin invest be equipped with rinse solution () syringe for example, saline, described rinse solution (for example can comprise antiseptic, chlorhexidine), antibiotic agent (for example, gentamycin sulfate or doxycycline), and/or anti-infective, such as (for example, the 5-FU of the chemotherapeutics with antimicrobial acivity, 5-fluorouracil, doxorubicin, mitoxantrone, methotrexate, or etoposide), to remove intestinal flora, be present in anaerobe and aerobe in the diverticulum.Described pin is advanced to the opening of infected diverticulum by the biopsy inlet.Diverticulum is washed gently with rinse solution.In case described diverticulum has been removed fragment, then with the pin in the nozzle delivery catheter replacement biopsy inlet.Described nozzle delivery catheter is used for that the multicomponent original position is formed compositions is delivered to diverticulum, described in embodiment 54.The crosslink part ground of described compositions subsequently or fully seal the chamber or the hole of diverticulum, therefore reduce hemorrhage, infect or the probability of inflammation.

By preceding described, although be appreciated that illustrative purposes this paper has described specific embodiments of the present invention for example, can not deviate under the spirit and scope of the present invention prerequisite, still can carry out various improvement.Therefore, except the appended claims qualification, the present invention is not limited.

Claims

1. comprise the compositions that fibrous tissue forms agent, use in the method for the treatment diverticulum disease, wherein described compositions is introduced diverticulum, and wherein said fibrous tissue forms agent inducing fibrosis reaction in described diverticulum.

2. be used for inducing the fibrotic compositions that fibrous tissue forms agent that comprises, wherein described compositions prepared to be introduced in the described diverticulum at diverticulum.

3. the compositions of claim 1, wherein said diverticulum disease is diverticulosis or diverticulitis.

4. any one compositions of claim 1 or claim 2, wherein said fibrous tissue form agent have be selected from promote regeneration, promote blood vessel fibroblast proliferation takes place, promotes, promote extracellular matrix deposition, promote tissue remodeling and promote at least one biological activity of arterial blood tube wall stimulus object.

5. any one compositions of claim 1 or claim 2, wherein said fibrous tissue forms agent and comprises silk or fine hair.

6. any one compositions of claim 1 or claim 2, wherein said fibrous tissue forms agent and comprises mineral grain, chitosan, polylysine, fibronectin, bleomycin or CTGF.

7. any one compositions of claim 1 or claim 2, wherein said fibrous tissue form the form that agent is (a) bunch; (b) form of line or contact with line; Or (c) form of microgranule.

8. any one compositions of claim 1 or claim 2, described compositions also comprises polymer, or in-situ polymerization and form the chemical compound of cross linked polymer.

9. compositions according to Claim 8, wherein said polymer is selected from the polymer of copolymer, block copolymer, random copolymer, biodegradable copolymer, not biodegradable polymer, hydrophilic polymer, hydrophobic polymer, possess hydrophilic property domain, the polymer with hydrophobic structure territory, non-conductive polymer and elastomer.

10. compositions according to Claim 8, wherein said polymer are selected from hydrogel, siloxane polymer, hydrocarbon polymer, styrene derived polymer, butadiene derived polymer, macromonomer and poly-(ethylene glycol).

11. any one compositions of claim 1 or claim 2, described compositions also comprises polymer composition, and wherein said polymer composition comprises (a) collagen or derivatives thereof; (b) fibrinogen; (c) thrombin is at least a.

12. the compositions of claim 8, wherein said polymer are selected from (a) cyanoacrylate; (b) COSTASIS; (c) CT3.

13. according to the compositions of claim 12, wherein said cyanoacrylate is selected from methyl 2-cyanoacrylate, cyanacrylate, Tisuacryl, octyl 2-cyanoacrylate and alpha-cyanoacrylate methoxyl group propyl ester.

14. according to the compositions of claim 12, wherein said cyanoacrylate is poly-(the alkyl cyanoacrylate) that is selected from poly-(MCA), poly-(ethyl cyanoacrylate), poly-(butyl cyanoacrylate), poly-(isobutyl cyanoacrylate), poly-(hexyl cyanoacrylate) and gathers (octyl cyanoacrylate).

15. according to the compositions of claim 12, wherein said cyanoacrylate is poly-(carboxyalkyl cyanoacrylate).

16. according to the compositions of claim 15, wherein said poly-(carboxyalkyl cyanoacrylate) is poly-(methoxy-propyl cyanoacrylate).

17. any one compositions of claim 1 or claim 2, wherein said compositions also comprises hemorrhage.

18. the compositions of claim 17, wherein said hemorrhage are selected from collagen polymer, poly-(ethylene glycol), COSEAL, TISSEAL, FLOSEAL and fibrin.

19. any one compositions of claim 1 or claim 2, described compositions also comprises anti-infective.

20. the compositions of claim 19, wherein said anti-infective are selected from anthracycline, doxorubicin, mitoxantrone fluorine pyrimidine, 5-fluorouracil, antifol, methotrexate, podophyllotoxin, etoposide, camptothecine, hydroxyurea, platinum complex and cisplatin.

21. the compositions of claim 19, wherein said anti-infective is an antibiotic.

22. the compositions of claim 21, wherein said antibiotic is selected from gentamycin sulfate, amikacin sulfate, kanamycin sulfate, polymyxin B, polygynax, cefazolin sodium, metronidazole, ciprofloxacin, piperacillin, cefoxitin, cefepime, azithromycin and trimethoprim-sulfamethoxazole.

23. according to the compositions of claim 1 or claim 2, described compositions also comprises developing agent.

24. according to the compositions of claim 23, wherein said developing agent is radiopaque material, echo material or MRI response material.

25. according to any one compositions of claim 1 or claim 2, wherein said compositions is the form of spray, gel, paste, film or mesh.

Be used for the treatment of purposes in the medicine of diverticulum disease 26. comprise compositions that fibrous tissue forms agent in preparation, wherein said medicine will be introduced in the diverticulum, and wherein said medicine is induced fibre modification in described diverticulum.

Be used for inducing at diverticulum the purposes of fibrotic medicine 27. comprise compositions that fibrous tissue forms agent in preparation, wherein said medicine will be introduced in the described diverticulum.

28., wherein in diverticulum, induce fibre modification treatment or prevention diverticulum disease according to any one purposes of claim 26 or claim 27.

29. according to the purposes of claim 28, wherein said diverticulum disease is diverticulitis or diverticulosis.

30. any one purposes of claim 26 or claim 27, wherein said fibrous tissue form agent have be selected from promote regeneration, promote blood vessel fibroblast proliferation takes place, promotes, promote extracellular matrix deposition, promote tissue remodeling and promote at least one biological activity of arterial blood tube wall stimulus object.

31. according to any one purposes of claim 26 or claim 27, wherein said fibrous tissue forms agent and comprises silk or fine hair.

32. according to any one purposes of claim 26 or claim 27, wherein said fibrous tissue forms agent and comprises mineral grain, chitosan, polylysine, fibronectin, bleomycin or CTGF.

33. according to any one purposes of claim 26 or claim 27, wherein said fibrous tissue forms the form that agent is (a) bunch; (b) form of line or contact with line; Or (c) form of microgranule.

34. according to any one purposes of claim 26 or claim 27, wherein said compositions also comprises polymer, or in-situ polymerization is to form the chemical compound of cross linked polymer.

35. according to the purposes of claim 34, wherein said polymer is selected from the polymer of copolymer, block copolymer, random copolymer, biodegradable copolymer, not biodegradable polymer, hydrophilic polymer, hydrophobic polymer, possess hydrophilic property domain, the polymer with hydrophobic structure territory, non-conductive polymer and elastomer.

36. according to the purposes of claim 34, wherein said polymer is selected from hydrogel, siloxane polymer, hydrocarbon polymer, styrene derived polymer, butadiene derived polymer, macromonomer and gathers (ethylene glycol).

37. any one purposes of claim 26 or claim 27, wherein said compositions also comprises polymer composition, and wherein said polymer composition comprises (a) collagen or derivatives thereof; (b) fibrinogen; (c) thrombin is at least a.

38. according to the purposes of claim 34, wherein said polymer is selected from (a) cyanoacrylate; (b) COSTASIS; (c) CT3.

39. according to the purposes of claim 38, wherein said cyanoacrylate is selected from methyl 2-cyanoacrylate, cyanacrylate, Tisuacryl, octyl 2-cyanoacrylate and alpha-cyanoacrylate methoxyl group propyl ester.

40. according to the purposes of claim 38, wherein said cyanoacrylate is poly-(the alkyl cyanoacrylate) that is selected from poly-(MCA), poly-(ethyl cyanoacrylate), poly-(butyl cyanoacrylate), poly-(isobutyl cyanoacrylate), poly-(hexyl cyanoacrylate) and gathers (octyl cyanoacrylate).

41. according to the purposes of claim 38, wherein said cyanoacrylate is poly-(carboxyalkyl cyanoacrylate).

42. according to the purposes of claim 41, wherein said poly-(carboxyalkyl cyanoacrylate) is poly-(methoxy-propyl cyanoacrylate).

43. according to any one purposes of claim 26 or claim 27, wherein said compositions also comprises hemorrhage.

44. the purposes of claim 43, wherein said hemorrhage are selected from collagen polymer, poly-(ethylene glycol), COSEAL, TISSEAL, FLOSEAL and fibrin.

45. according to any one purposes of claim 26 or claim 27, wherein said compositions also comprises anti-infective.

46. the purposes of claim 45, wherein said anti-infective are selected from anthracycline, doxorubicin, mitoxantrone fluorine pyrimidine, 5-fluorouracil, antifol, methotrexate, podophyllotoxin, etoposide, camptothecine, hydroxyurea, platinum complex and cisplatin.

47. according to the purposes of claim 45, wherein said anti-infective is an antibiotic.

48. according to the purposes of claim 47, wherein said antibiotic is selected from gentamycin sulfate, amikacin sulfate, kanamycin sulfate, polymyxin B, polygynax, cefazolin sodium, metronidazole, ciprofloxacin, piperacillin, cefoxitin, cefepime, azithromycin and trimethoprim-sulfamethoxazole.

49. according to any one purposes of claim 26 or claim 27, wherein said compositions also comprises developing agent.

50. according to the purposes of claim 49, wherein said developing agent is radiopaque material, echo material or MRJ response material.

51. according to any one purposes of claim 26 or claim 27, wherein said compositions is the form of spray, gel, paste, film or mesh.

52. comprising (a) fibrous tissue, a compositions, described compositions form agent and (b) polymer or in-situ polymerization and form the chemical compound of cross linked polymer.

53. according to the compositions of claim 52, wherein said fibrous tissue forms agent and has the deposition that is selected from promotion regeneration, the generation of promotion blood vessel, promotes fibroblast proliferation, promotion extracellular matrix, at least one biological activity that promotes tissue remodeling and promotion arterial blood tube wall stimulus object.

54. according to the compositions of claim 52, wherein said fibrous tissue forms agent and comprises silk or fine hair.

55. according to the compositions of claim 52, wherein said fibrous tissue forms agent and comprises mineral grain, chitosan, polylysine, fibronectin, bleomycin or CTGF.

56. according to the compositions of claim 52, wherein said fibrous tissue forms the form that agent is (a) bunch; (b) form of line or contact with line; Or (c) form of microgranule.

57. according to the compositions of claim 52, wherein said polymer is selected from the polymer of copolymer, block copolymer, random copolymer, biodegradable copolymer, not biodegradable polymer, hydrophilic polymer, hydrophobic polymer, possess hydrophilic property domain, the polymer with hydrophobic structure territory, non-conductive polymer and elastomer.

58. according to the compositions of claim 52, wherein said polymer is selected from hydrogel, siloxane polymer, hydrocarbon polymer, styrene derived polymer, butadiene derived polymer, macromonomer and gathers (ethylene glycol).

59. according to the compositions of claim 52, wherein said polymer composition comprises (a) collagen or derivatives thereof; (b) fibrinogen; (c) thrombin is at least a.

60. according to the compositions of claim 59, wherein said collagen is methylated collagen.

61. according to the compositions of claim 52, wherein said polymer is selected from (a) cyanoacrylate; (b) COSTASIS; (c) CT3.

62. according to the compositions of claim 61, wherein said cyanoacrylate is selected from methyl 2-cyanoacrylate, cyanacrylate, Tisuacryl, octyl 2-cyanoacrylate and alpha-cyanoacrylate methoxyl group propyl ester.

63. according to the compositions of claim 61, wherein said cyanoacrylate is poly-(the alkyl cyanoacrylate) that is selected from poly-(MCA), poly-(ethyl cyanoacrylate), poly-(butyl cyanoacrylate), poly-(isobutyl cyanoacrylate), poly-(hexyl cyanoacrylate) and gathers (octyl cyanoacrylate).

64. according to the compositions of claim 61, wherein said cyanoacrylate is poly-(carboxyalkyl cyanoacrylate).

65. according to the compositions of claim 64, wherein said poly-(carboxyalkyl cyanoacrylate) is poly-(methoxy-propyl cyanoacrylate).

66. according to the compositions of claim 52, wherein said compositions also comprises hemorrhage.

67. according to the compositions of claim 66, wherein said hemorrhage is selected from collagen polymer, poly-(ethylene glycol), COSEAL, TISSEAL, FLOSEAL and fibrin.

68. according to the compositions of claim 52, wherein said compositions also comprises anti-infective.

69. according to the compositions of claim 68, wherein said anti-infective is selected from anthracycline, doxorubicin, mitoxantrone fluorine pyrimidine, 5-fluorouracil, antifol, methotrexate, podophyllotoxin, etoposide, camptothecine, hydroxyurea, platinum complex and cisplatin.

70. according to the compositions of claim 68, wherein said anti-infective is an antibiotic.

71. according to the compositions of claim 70, wherein said antibiotic is selected from gentamycin sulfate, amikacin sulfate, kanamycin sulfate, polymyxin B, polygynax, cefazolin sodium, metronidazole, ciprofloxacin, piperacillin, cefoxitin, cefepime, azithromycin and trimethoprim-sulfamethoxazole.

72. according to the compositions of claim 52, described compositions also comprises filler.

73. according to the compositions of claim 72, wherein said filler comprises microballon, extra large blue polymer, silicon microsphere and the biocompatible polymer in the gel of microsphere, hydroxyapatite load, micronized alloderm acellular substrate, hyaluronic acid, the hydrogel.

74. according to the compositions of claim 52, described compositions also comprises developing agent.

75. according to the compositions of claim 74, wherein said developing agent is radiopaque material, echo material or MRI response material.

76. according to the compositions of claim 52, wherein said compositions is the form of spray, gel, paste, film or mesh.

77. the test kit that uses in the treatment diverticulum disease, described test kit comprises: (a) comprise following dry powder composite: (i) have first component of the core that replaces with m nucleophilic group, wherein m 〉=2; Second component that (ii) has the core that replaces with n electrophilic group, wherein n 〉=2 and m+n＞4; Be endowed reactivity when being exposed to water environment but wherein said nucleophilic and electrophilic group right and wrong in dry environment are reactive, so that described component reacts to each other in water environment and forms three-dimensional compositions; (b) first buffer solution of pH in about 1.0 to 5.5 scopes; (c) second buffer solution of pH in about 6.0 to 11.0 scopes; (d) comprise the 3rd component that fibrous tissue forms agent, wherein each component is independent pack and mixing immediately before using.

78. the test kit of claim 77, described test kit also comprises delivery apparatus.

79. the test kit of claim 78 wherein is configured described device with the form of spray, gel or paste and sends described compositions.

80. the test kit of claim 77, wherein said fibrous tissue form agent and are, perhaps comprise silk or fine hair.

81. the test kit of claim 77, wherein said the 3rd component be included in (a) and (b) or (c) in.