CN1341032A - Medical adhesives - Google Patents

Abstract

Approaches have been developed to apply multicomponent medical adhesives that improve binding of the medical adhesive (106) to a substrate (104) having covalently bound adhesive components. Use of the multicomponent adhesive reduces the possibility of adverse effects due to the adhesive leaving the application site. In preferred approaches, the application of the adhesive leads to increased bond strengths. The medical adhesive (106) and/or the substrate (104) can be bioresorbable.

Description

Medical adhesives

Background of invention

The present invention relates to be applicable to the binding agent of medical science/surgery/tissue adhesion, and connect the method for attachment of basal layer and natural tissues or other basal layer.

The surgery glue/adhesive provides selectable stitching thread, envelope sealing thread or analog will be near the soft degree of wound tissue.Some tissue needs careful especially suturing skill/stitching maneuver, and the organ as neural and particular importance becomes the selection that almost can not repair again after the application of surgical adhesive.Have our needed potential sealed nature and unified pressure distribution when usually, binding agent is used to repair the wound of parenchima.Particularly, because binding agent tends to the length range that distributes all standing wound of pressure, surgical adhesive provides a kind of does not have the dangerous method of pressing close to wound of tissue of tearing to the pain tissue.

Usually, whether surgical adhesive can comprise synthetic polymer according to them, and natural (biology) polymer or both all comprise and are classified.Polymer based on various synthetic urethanes has developed into surgery glue.The compositions of this surgical adhesive based on urethanes has had low relatively toxicity, strong adhesive effect and treatment time fast.Natural surgical adhesive is normally based on protein.For example, the fibrin viscose glue comprises the azelon proteinogen.Fibrinogen is usually used in the treatment of people or other mammiferous mechanicalness wound.There is potential toxic defective in synthetic binding agent.On the other hand, biology/natural binding agent contains low relatively bonding (adhesion) ability and degradation time fast usually.Tissue adhesive's migration that can produce from application points to other position in the past brings adverse influence, as causes the result of thrombosis.

The application that medical adhesives can be used to other purpose comprises, for example, and the production of medical devices and/or implantation.

Summary of the invention

First aspect, the present invention relates to a kind of compositions of substrate/adhesive ingredients, and it comprises the first biocompatibility basal layer of the composition with a kind of medical adhesives by being covalently bound to the biocompatibility basal layer.

On the other hand, the present invention relates to a kind of the first biocompatibility basal layer be fixed (securing) method in the second biocompatibility basal layer.This method comprises by contacting with second basal layer through the compositions of substrate/bonding composition and the residual components of medical adhesives, forms adhesive bond.The compositions of this substrate/bonding composition comprises the first biocompatibility basal layer with medical adhesives composition, and it is covalently bound to the first biocompatibility basal layer.

More advance on the one hand, the present invention relates to a kind of bonding system, it comprises the first biocompatibility basal layer of the protein ingredient with medical adhesives, and wherein this protein ingredient forms the coating and the second medical adhesives composition on the first biocompatibility basal layer.This coating composition is to contact to form after surpassing 1 hour between protein ingredient and the first biocompatibility basal layer.The application of the second medical adhesives composition between first basal layer and second basal layer causes forming adhesive bond after curing.

In addition, the invention still further relates to the method that the first biocompatibility basal layer is fixed in the second biocompatibility basal layer.This method comprises that the combination by the composition of bonding system forms adhesive bond.This bonding system comprises the first biocompatibility basal layer and the second medical adhesives composition of the protein ingredient with medical adhesives relevant with the first biocompatibility basal layer.The application of the second medical adhesives composition between first basal layer and second basal layer causes forming adhesive bond after curing, make second composition of medical adhesives have a part at least between first and second basal layeres like this.

On the other hand, the present invention relates to the method that a kind of preparation is used for the first biocompatibility basal layer of the bonding second biocompatibility basal layer.The composition of medical adhesives and fixing (securing) chemical compound all are applied to first basal layer of a part at least.Fixed compound helps to keep the connection between the first biocompatibility basal layer and the adhesive compound.

In addition on the one hand, the present invention relates to comprise the biocompatibility basal layer of the medical adhesives composition that is added into the base infrastructure composition.

And, the invention still further relates to a kind of method that forms the biocompatibility basal layer, it is a kind of composition mixing by the part of a kind of composition of medical adhesives and biocompatibility basal layer, to form from mixture, makes up the biocompatibility basal layer from mixture.

In addition, the present invention relates to a kind of method that forms prosthese.This method comprises fixes first basal layer and second basal layer with medical adhesives.This first basal layer contains relevant adhesive ingredients, and the binding agent remainder is between first and second basal layeres.This method further comprises in this basal layer implant patient body.

Description of drawings

Fig. 1. for using medical adhesives is connected basal layer with natural tissues perspective view.

Fig. 2. the perspective view that partly is connected for a kind of composition of multicomponent medical adhesives or multicomponent and basal layer.

Fig. 3. for being used to measure the test set figure that adhesive bond is sheared tearing strength.

Fig. 4. be the block diagram of the average shear breaking strength of five kinds of dissimilar basal layeres measuring.

The detailed description of preferred version

The improvement of the method for the application of multicomponent medical science/surgery/tissue adhesive and the improvement of medical devices are disclosed.Particularly, a kind of composition of medical adhesives is connected with the biocompatibility basal layer before the application of binding agent remainder.The basal layer that contains a kind of composition of medical adhesives is fixed in natural tissues or uses on other biocompatibility basal layer of another kind of composition of medical adhesives.Basal layer with one or more compositions of continuous medical adhesives can form part or all of medical device, medical adhesives can be used for this medical device is applied to the basal layer of support like this, and it can be the natural tissues or second biocompatible materials that will join in the medical device.Although usually binding agent can very effectively connect basal layer and natural tissues, before this basal layer is implanted to the patient or central this binding agent also be used for interconnecting between two basal layeres.This binding agent helps to reduce suture and stitches the number of ordering, for the surgical operation of operation and complexity has been saved the time.This binding agent is specially adapted to be difficult to order etc. with suture or seam the connection of the small component of fixed medical device.

Usually, needing binding agent is because in the pressure distribution of its potential sealing characteristics and homogeneous in order to the wound of repairing parenchima.The composition of initial medical adhesives and being connected of first basal layer before the tissue or second basal layer cause the increase of the branch resistance to spalling of final adhesive bond.And the composition of medical adhesives separates with adhesive bond with the part that has reduced binding agent being connected of basal layer, in the probability of patient's body-internal-circulation.Preferably implement in the embodiment at some, a kind of composition of medical adhesives is covalently bound to basal layer.In selectable embodiment, in basal layer formed, a kind of composition of this binding agent was added in the basal layer.

With reference to figure 1, whole arrangement is the structure 100 that is connected by the medical adhesives 106 between basal layer 104 and the natural tissues 102 by natural tissues 102 and basal layer 104.The part of tissue 102 and the part of basal layer 104 or basal layer 104 form sealing or adherent combination.As mentioned above, the basal layer beyond the tissue can be used in and replaces tissue 102.About Fig. 2, the composition 108 of medical adhesives preferably begins to be applied on the basal layer 104, it or by covalent bond as coating or by in the substrate that joins basal layer.

Can be used to the formation or the implantation of prosthese in adhesion organization described herein, as the surgical operation sticking patch.For example, the basal layer that comprises a bonding composition, be used to cover the fixing of wound site, it is by with the remainder of binding agent or be positioned over the tissue that basal layer will be placed, or be positioned on the first composition basal layer of binding agent of previous application, make basal layer by connecting and fixedly being attached to tissue.This sticking patch can comprise multilamellar.This multilamellar can continuous application to wound, perhaps they are partly or entirely bonding before being applied to wound.The multilamellar thing can be pieced together, and usually, the top layer of prosthese can be to have identical size with bottom or greater than bottom.This medical adhesives can be used to the multilamellar thing is fixed together, and/or sticking patch is bonded in the wound.The multilamellar thing can form from tissue, and after one's own heart package is knitted, or synthetic.

Can select, medical adhesives can be used to prosthese is connected in patient's natural supporting tissue.Usually, though all devices can be connected with one or more compositions of binding agent, the part of prosthetic device is to form from the basal layer of one or more coordinators that contain binding agent.The remainder of binding agent can be added to the prosthese that contains the first bonding composition or the surface of natural supporting tissue.After having used the residual components of binding agent, prosthese is connected with supporting tissue.For example, the prosthese of heart as heart valve or lobe ring, can be fixed on the intravital natural supporting tissue of patient (as body ring (annulus)) by medical adhesives of the present invention.

Binding agent preferably is present on the contact surface that has between porous and hydrophilic first and second basal layeres.Particularly, the contact surface of binding agent should be by fully porous, like this binding agent be introduced in the biocompatibility material or with the biocompatibility material, obtain the combination of machinery between basal layer and the binding agent.Same, the contact surface of binding agent between tissue and biocompatibility basal layer should have sufficient hydrophilic makes binding agent that moistening basal layer be arranged, and makes contact fully between basal layer, binding agent and the tissue, forms stable combination.

The medical adhesives of suitable composite parts comprises synthetic chemical compound, natural material or their combination.The composition of the synthetic chemical compound that is fit to of medical adhesives comprises, for example, and based on the polymer of urethanes.The composition of the natural material that is fit to of medical adhesives comprises, for example, and multiple protein material and relevant binding agent.In certain embodiments, one or more compositions of medical adhesives are natural materials, and as protein, and one or more compositions are synthetic chemical compounds, as cross-linking agent.

In certain embodiments, medical adhesives has biology absorbability again, is meant that binding agent behind reasonable time under the natural physiological conditions, is absorbed by the patient again.Binding agent should be consistent with the time of the process of natural healing by resorbent process.Usually, the medical adhesives of one or more compositions can be absorbed again, and binding agent is fully absorbed in a period of time by the patient like this.Therefore, by substituting the extracellular structure of binding agent, natural agglutination provides being connected between basal layer and the natural tissues gradually.In case binding agent is absorbed again, replaced by the natural engineering properties that more approaches of the natural tissues of healing by any potential change of the engineering properties of the tissue that binding agent brought.

The basal layer that contains the medical adhesives of bonding composition is finally used preceding preparation in the residual components of medical adhesives.The stability of determining to depend on the adhesive ingredients that is applied to basal layer of the suitable time of application of bonding composition on basal layer of medical adhesives.The remainder of medical adhesives was used before forming sealing or adhesive bond between basal layer and the second layer basal layer usually immediately.Like this, adhesive bond forms, and when medical adhesives solidifies when being enough to fixedly adhesive bond, this adhesive bond can keep.

A. prosthese and sticking patch

The prosthese that adheres to medical adhesives generally includes at least basal epithelial cell layer or the synthetic basal layer as the part of prosthese.This basal layer is suitable for use as the adhering to or connect of a kind of composition of medical adhesives.Usually, the design prosthese is implanted a very long time in patient's body.Prosthese comprises, for example, and the heart of reparation, the heart valve of repairing, the ring of valvoplasty, blood vessel and stent be film fixedly, blood vessel graft or pipeline, gauze, the line of stitching usefulness, lead, permanent keep somewhere through the skin device, blood vessel or cardiovascular branch road, the graft of skin is used for wound healing, surgical patch, neurologic growth holder, with the graft of bone alternative, replace prosthese as the joint.Surgical patch and other prosthese can be absorbed by complete biology again, and whole like this surgical patch is absorbed by the patient after certain hour again.The biomedical articles that is designed to stay for some time in vivo also is fit to use medical adhesives.These devices comprise, for example, and the Hickman conduit.

B, basal layer

The basal layer of suitable biocompatibility is from the combination of natural material, synthetic material or above-mentioned material and form.Natural, promptly be used for biomaterial of the present invention and comprise relevant complete living tissue, isolated cell tissue, regenerative cell's tissue.These are for example organized can be from following acquisition: natural cardiac valve, natural valvular part such as large artery trunks source, wall and lobule, pericardial tissue, as the pericardium prosthese, tissue connects, by graft, tendon, ligament, the skin prosthese, blood vessel, cartilage, cerebral dura mater, skin, skeleton, fascia, tela submucosa, umbilical cord tissue etc.

The source of natural tissues is selected from animal varieties, mammal normally, and as the mankind, cattle, pig is hunted sea dog, horse, dog and kangaroo.These natural tissues generally include collagen material.Natural tissues is that the typical case is but must is not soft tissue.The tissue that organization material is specially adapted to valvular prosthese forms.This tissue can become tissue alive, isolated cells tissue or regenerative cell's tissue.The immediate description of isolated cell technology for example, at United States Patent (USP) 5,855, relates in 620, and open in the International Application No. WO 96/32905 of PCT and WO96/03093, at this both is incorporated herein by reference.

Tissue can be fixed by crosslinked.Fixed form has by mechanical fixed, for example, and the degraded of the enzyme by suppressing this tissue.Glutaraldehyde or formaldehyde are the materials that typically is used for fixing, but other fixture also can use, as other dual functional aldehyde, and epoxide and genipin (genipin) and aforesaid derivant.Tissue can be used for crosslinked or noncrosslinking form, relies on type, purposes or other the factor of tissue.Usually, if use heteroplasm to transplant, this is organized as crosslinked and/or removes (decellularized) of cellization.

Relevant synthetic material comprises, for example, and polymer and pottery.Pottery includes but not limited to, hydroxyapatite, vitriol and RESEARCH OF PYROCARBON.If desired, before being used as basal layer, pottery can be used polymer, protein or the coating of other chemical compound.Suitable synthetic material comprises that hydrogel and other can not resist the synthetic material of serious dehydration.Base layer material can be from the biopolymer preparation of synthetic polymer and purification.

Suitable synthetic polymer includes but not limited to, polyamide (as nylon), polyester, polystyrene, polyacrylate, polyvinyl is (as polyethylene, politef, polypropylene and polrvinyl chloride), Merlon, polyurethane, polydimethylsiloxane, cellulose ethanoate, poly methyl methacrylate, ethylene vinyl acetate, polysulfones, NC Nitroncellulose and similar copolymer.The material of these synthetic polymers can be woven or be knitted into net, to form substrate or basal layer.Perhaps, the material of synthetic polymer can be cast or be fashioned into suitable form.

Biopolymer can by fermentation and similarly method external by natural generation or preparation.The purifying biological polymer can be made the local basal layer that forms by technology as braiding, woollen yarn knitting, casting, plastic film, extruding, celluar localization (alignment) and magnetic force location (alignment).About the localized description reference of magnetic force, for example, R.T. Tranquilloet al., Biomaterials 17:349-357 (1996).Suitable biopolymer includes but not limited to, collagen, elastin, silkworm silk, Keratin, animal glue, polyamines acid, cat internal organs stitching thread, polysaccharide (as cellulose and starch) and their copolymer.

The special basal layer that is used for being connected with adhesive ingredients can form the complete whole medical device or the part of medical device.Same, different basal layeres can combined formation medical device.For example, fixed, xenogeneic tissue heart valve can combine with serving textile and form valvular prosthese.This fixing organization and/or sutures can combine with the composition of one or more binding agents.Adhesive ingredients can a plurality of parts with combine with basal layer before or after medical devices combines.Select the composition of binding agent and the distinct methods that combines of basal layer, can influence the structural order of medical devices.

C. medical adhesives

The binding agent that is suitable for medical science/tissue/surgery preferably has compound composition.Usually, binding agent contains two compositions, although suitable bonding can have plural composition.Except adhesive ingredients, medical adhesives can also comprise multiple following with the additive that is described in detail.As mentioned above, medical adhesives can comprise synthetic compound, natural tissues/material or their combination.

Medical adhesives is normally nontoxic.The application of binding agent as described herein is the circulation that approaches to be designed to reduce or eliminate one or more compositions of binding agent and/or binding agent.And, by reducing or eliminating the circulation of binding agent or adhesive ingredients, exist the danger of the potential migration of binding agent to reduce or eliminate accordingly.

About composite adhesives, preferred adhesive for example comprises the polymer based on urethanes, the mixture of copolymer and above-mentioned substance.Polyurethane is the ester-acid amide derivant of carboxylic acid.Urethane ester oligomer/prepolymer is to form by terminal-reactive functional group.This prepolymer is particularly suitable for forming crosslinked mixed polymer, and they show the scope of polyurethane and the required character of other composition.For the formation of binding agent, in certain embodiments, the prepolymer of urethanes can be used as a kind of composition of binding agent and the another kind of or multiple composition that one or more cross-linking agent become binding agent.

Isocyanates (NCO)-the end-blocking urethane prepolymer is the composition that is particularly suitable for as binding agent.Polyurethane comprises the prepolymer (oligomer of urethanes) of polyurethane, and it can form by the reaction of dichloro formic acid and diamidogen or vulcabond and polyol.The polymerization that relates to the urethanes of vulcabond and polyol can be used as preparation has the isocyanate functional group at its end urethane prepolymer.The urethane prepolymer that is fit to can form by the reaction of poly-vulcabond and polyhydric alcohol.

Suitable polyisocyanate comprises, for example, comprises the fragrant adoption vulcabond that has 6-20 carbon atom except that-NCO group,, as right-, adjacent-, with-phenylene vulcabond (PDI), 2,4-and 2,6-toluylene group diisocyanate (TDI), diphenyl-methane-2,4 ' and 4,4 '-vulcabond, diphenyl-methane-2,4 ' and 4,4 '-vulcabond (MDI), naphthalene-1, the 5-vulcabond, tritan. 4,4 '; 4 "-triisocyanate, the polymethylene polyphenylene paracyanogen acid esters (PAPI) that phosgenation by aniline-formaldehyde products obtains, adjacent-and-isocyanide-benzene sulfonyl-isocyanates, or the like; The aliphatic polymeric isocyanate that comprises 2-18 carbon atom, as ethylidene diisocyanate, tetramethylene diisocyanate, hexamethylene diisocyanate, 12 alkylidene vulcabond, 1,6,11-undecyl vulcabond, 2,2,4-trimethyl cyclohexane vulcabond, lysinediisocyanate, 2,6-two isocyanato-methylhexanoic acid esters, two (2-isocyanato--ethyl) fumarate, two (2-isocyanato--ethyl) carbonic ester, 2-isocyanates-ethyl-2,6-two isocyanato-alkyl caproates etc.; The alicyclic ring polyisocyanate that comprises 4-15 carbon atom, as isophorone diisocyanate, the double-hexyl methane vulcabond, inferior cyclohexane diisocyanate, the inferior cyclohexyl vulcabond of methyl, the inferior cyclohexyl-1 of two (2-isocyanato--ethyl) 4-, 2-dicarboxylic ester etc.; The araliphatic polyisocyanate that comprises 8-15 carbon atom, as eylylene diisocyanate, diethylbenzene group diisocyanate etc.; Modified polyisocyanate with these polyisocyanate, comprise urethanes, carbodiimides, allophanates, carbamide, two reducing urination, urethdione, urethimine, isocyanates and/or oxaolidong group, as urethane-modified TDI, the MDI of carbodiimides modification, urethane-modified MDI etc.; The mixture of above-mentioned substance.

As surgery glue, this is organized preferred polyisocyanate and comprises aromatic poly-isocyanate (preferred vulcabond), more preferably PDI, TDI (comprises 2,4-and 2,6-isomer, and the mixture of isomer and TDI), MDI (comprise 4,4 '-and 2,4 '-isomer, and isomer and MDI or PAPI mixture), with the modified polyisocyanate that contains urethanes, carbodiimides, allophanate, carbamide, biuret and/or isocyanate groups, from PDI, among TDI and/or the MDI deutero-those.

Because hypotoxicity ,-PDI (being PPDI hereinafter) is particularly preferred.Embodiment preferred comprises that PPDI and one or more other smaller doses (are no more than 50% of approximate weight ratio usually in addition, preferably be no more than the approximate weight ratio 30%) the combination of polyisocyanate, as aromatic poly-isocyanate, TDI particularly, MDI, the MDI of modification and their mixture.Preferably, other polyisocyanate is in reaction in the early stage of prepolymer reaction, so that PPDI to be provided end capped prepolymer.

The polyhydric alcohol that is suitable for forming prepolymer comprises the Hydrophilicrto polyether polyhydric alcohol, the mixture of other polyhydric alcohol and above-mentioned substance.Typical suitable Hydrophilicrto polyether polyhydric alcohol comprises oxireme (claiming EO hereinafter) or EO and other basic anhydride (claiming AO hereinafter) and the adduct that contains one or more compound formation of at least two active hydrogen atoms, as polyhydroxy-alcohol, polyhydroxy phenol, amine, polycarboxylic acid, phosphorous acid etc.Suitable polyhydroxy-alcohol comprises dihydroxy alcohol, as 7 glycol, propylene glycol, 1,3 and 1, the 4-butanediol, 1,6-hexanediol, neopentyl glycol, diethylene glycol, two (methylol) cyclohexane extraction, two (ethoxy) benzene, hydrogenated bisphenol A, A Hydrogenated Bisphenol A F, polybutylene alcohol, polyester-diol and silanol stopped polysiloxanes; Trihydroxylic alcohol, as glycerol, trimethyl alcohol propane, trimethyl alcohol ethane, 1,2,3-butantriol, 1,2,6-hexanetriol and polyester triol; With contain 4-8 or more polyhydric polyhydroxy-alcohol, as tetramethylolmethane, diglycerol, d methylglycoside, sorbitol, xylitol, mannitol, glucose, fructose, sucrose etc.The typical polyhydroxy phenols that is fit to comprises monocycle or polycyclic phenol, as hydroquinone, and catechol, Syringaresinol, 1,2,3-benzenetriol and bis-phenol such as Bisphenol F, bisphenol S etc., and phenol formaldehyde condensation product.

The amine that is suitable for forming PEPA comprises ammonia; Alkanolamine, as single-, two-and three-ethanolamine, isopropanolamine etc.; The monoamine of aliphatic, aromatic, aromatic yl aliphat and alicyclic ring is as C ₁-C ₂₀Alkylamine (methyl, ethyl, isopropyl, butyl, octyl group and lauryl amine etc.), aniline, toluidines, naphthols amine, benzene methanamine, cyclohexylamine etc., aliphatic, aromatic series, aromatic yl aliphat and alicyclic ring polyamines are as C ₂-C ₆Alkyl diamine (ethylene diamine), diethylenetriamines, toluenediamine, phenylenediamine, xylylene amine, methylene dianiline, diphenyl ether diamidogen, isophorone diamine, cyclohexylidene diamidogen, dicyclohexyl methyl hydride diamidogen etc.; With heterocyclic polyamines, as piperazine, N-amino-ethyl-piperazine and other heterocyclic polyamines disclose in publication number is the Japan Patent of No.21044/1980.

Make up the suitable AO that is used for the production polyether polyol with EO and comprise, for example, expoxy propane (being PO hereinafter), 1,2-, 2,3-, 1,3-and 1,4-epoxy butane, styrene oxide, chloropropylene oxide etc., and aforesaid compositions.The AO that preferably comprises PO.

Formation for the prepolymer of urethanes, EO, or the adding the chemical compound that contains active hydrogen atom to and can be undertaken of the compositions of EO and AO by the mode of routine, contain or do not contain catalyst, as base catalyst, amine catalyst and acidic catalyst, under atmospheric pressure or high pressure, single step or multistep reaction.The interpolation of EO and AO can be by adding arbitrarily, and in bulk (block) adds or above-mentioned hybrid mode forms, and adds as use in bulk instead after adding arbitrarily.Adding arbitrarily is optimal way.

The Hydrophilicrto polyether polyhydric alcohol has equivalent (molecular weight of each hydroxyl) approximately from 100 to 5,000 usually, and preferable range is 200 to 3000, and wherein oxyethylene group accounts for 30% usually at least, and preferred range is to account for 50% to 90% of weight ratio.The equivalent of PEPA is higher than 5,000 and causes viscosity too big, when the equivalent of PEPA causes the elasticity of binding agent insufficient less than 100 the time.The oxygen ethylene composition of PEPA lacks hydrophilic less to accounting for 30% of weight ratio, and is low with curing efficiency a little less than the binding ability of moisture tissue.The shared ratio of the primary hydroxyl of preferred polyether polyol preferably accounts for 30% at least, more preferably accounts for 50%, preferably accounts for 70%.

Other polyhydric alcohol optional combines with hydrophilic polyether polyol, comprises low-molecular-weight polyhydric alcohol and/or hydrophobic polyhydric alcohol.The example of these polyhydric alcohol is above-mentioned polyhydroxy-alcohols as reactant formation Hydrophilicrto polyether polyhydric alcohol, and these polyhydroxy alcohols or other contain the AO adduct (as the PO adduct) of the chemical compound of active hydrogen atom, and PEPA.Suitable PEPA comprises that for example, the condensation product of binary or trihydroxylic alcohol is as ethylene glycol, propylene glycol, 1,3-and 1,4-butanediol, 1,6-hexanediol, neopentyl alcohol, diethylene glycol, glycerol, trimethyl propane alcohol etc., and/or PEPA are as above-mentioned those, dicarboxylic acids as aliphatic or aromatic dicarboxylic acids, for example comprises 1,3-propanedicarboxylic acid, adipic acid, decanedioic acid, fumaric acid, maleic acid, phthalic acid and terephthalic acids, or the one-tenth ester derivant of dicarboxylic acids, ester as acid anhydride and low alkyl comprises, for example, maleic anhydride benzene diformazan acid anhydride, the lactone polymerizate of dimethyl terephthalate (DMT) etc. and open loop, comprise, for example, 6-caprolactone.

The average equivalent that is used for preparing the end capped urethane prepolymer preferred polyhydric alcohols of NCO-is about 100 to 5,000, more preferably 200 to 3,000 and contain 2-8 hydroxyl, and preferred hydroxyl value is 2-4.

Preferably according to about 1.5 to 5.0 the mixed of NCO/OH, preferable range is approximately 1.7 to 3.0 for polyisocyanate and polyhydric alcohol.The preferred NCO-component content of final prepolymer accounts for about 1% to 10% and more preferably about weight ratio of 2% to 8% of weight ratio.Low NCO content causes weak cohesive force and high NCO content causes the key easy fracture.

The reaction of polyisocyanate and polyhydric alcohol forms urethane prepolymer.These prepolymers are oligomer of intermediate molecular weight.The size of oligomer is controlled by the relative quantity of NCO and OH functional group.Because NCO functional group is by excessive adding, when all OH functional group complete reaction post-polymerizations stop.The further polyreaction of NCO group of not participating in reaction forms final binding agent.

Binding agent that can resorbent urethanes based on biology can make by the prepolymer of suitable hydrophilic amino Ethyl formate.The prepolymer of urethanes is by organic polyisocyanate and have the PEPA formation that the following formula molecule is derived from dicarboxylic acids,

HOOC-(A) _m-COOH

Here, m is 0 or 1, and A is-CH ₂-or by formula-R-CO-or

The electron attractive group of expression is explained; Here R represents to comprise the alkyl of the bivalence of 1-8 carbon atom, and R ' expression comprises the alkyl of bivalence of 1-20 carbon atom or the alkyl of halogen substitute, and X is a kind of halogen atom or nitro or cyano group, Y represents hydrogen atom, halogen atom or nitro or cyano group, n represent 0,1 or 2.The form that prepolymer is easy to decompose causes binding agent to decompose in several weeks, and the form of other prepolymer needs some months or longer time to decompose.Resolving time can be calculated by rule of thumb.Binding agent that can resorbent urethanes is at United States Patent (USP) 5,173, and people such as Itoh has done further discussion in 301, and exercise question is " surgical adhesive ", is hereby incorporated by.

The compositions that is fit to based on second composition of the medical adhesives of urethanes comprises polyhydric alcohol, as is used to form the polyhydric alcohol of prepolymer.The addition of polyhydric alcohol is based on the number of unreacted residue functional group in the prepolymer of urethanes.Perhaps, second composition of the binding agent of the oligomer of urethanes can be the cyano compound that contains the cyano group that is attached to the carbon atom that relates to polymerizable double bond, as alpha-cyanoacrylate and ester thereof.Unsaturated cyano compound specifically comprises, alpha-cyanoacrylate for example, cyano methyl acrylic acid, the methyl alpha-cyanoacrylate, methyl cyanide ylmethyl acrylic acid, ethyl alpha-cyanoacrylate, ethyl cyanide ylmethyl acrylic acid, isobutyl group cyano group acrylic acid, isobutyl cyanide ylmethyl acrylic acid, with and corresponding esters, acrylonitrile, methacrylonitrile, cyano group acrylonitrile, the mixture of cyano methyl acrylonitrile and above-mentioned substance.Such binding agent has a detailed description in the United States Patent (USP) 4,740,534 of Matsuda etc., is hereby incorporated by.The compositions of polyhydric alcohol and unsaturated cyano compound can be used as second composition or the adding ingredient of binding agent.

Usually comprise based on the adhesive composition of urethanes and to account for 20% to 90% of urethane prepolymer weight ratio, be preferably 30% to 70% weight ratio.The ratio of urethane prepolymer and unsaturated cyano compound can change to obtain required hardness.Urethanes accounts for a high proportion of application and brings stronger elasticity in binding agent.Can add catalyst if desired.

Basis be natural composition binding agent normally interior on the basis of natural binding affinity and corresponding biological respinse.Usually, one or more compositions of binding agent are a kind of protein or based on the chemical compound of albumen.The protein extensive interpretation is for having any chemical compound of polypeptide composition (as aminoacid), can comprise the derivant of native protein and the polypeptide of bonded composition covalently or non-covalently, as other polypeptide, nucleoside, the chemical compound of carbohydrate and other organic or inorganic.Protein component comprises the aminoacid with the side chain that is used to connect the functional group that remains adhesive ingredients usually.And if basal layer is crosslinked tissue, binding agent adhesive ingredients in the cross-linking reaction process can be replaced the composition that is eliminated by reaction in grassroots organization.

One type biological adhesive is based on proteinic Fibrinogen.Fibrinogen is known factor I, relates to the process of setting of natural blood.The protein thrombin from fibrinogenic one or two peptide to fibrin.Thrombin also relates to the process of setting of blood.The binding agent of various fibrin is crosslinked based on fibrin.The fibrin viscose glue is usually directed to Fibrinogen, the compositions of thrombin and factor XI, plasma thromboplastin antecedent II.Factor XI, plasma thromboplastin antecedent II also is comprised in the healing mechanism of natural wound.Factor XI, plasma thromboplastin antecedent II is a kind of known fibrin stabilizing factor, by thrombin activation, soluble fibrin is changed into undissolvable thrombosis.The polyreaction of fibrin sealant and the covalent cross-linking of collagen are connected by fluid tight with other component of organization.If Fibrinogen, a kind of composition as binding agent is united in thrombin or factor XI, plasma thromboplastin antecedent II and substrate, and the other albumen of binding agent can comprise the amount of these compositions.The final amount in binding agent of the composition of Fibrinogen, thrombin or factor XI, plasma thromboplastin antecedent II can be adjusted, and if desired, selects the character of binding agent, as intensity and/or healing time, or program easily.

People's such as Iwatsuki United States Patent (USP) 4,818,291 is being incorporated herein by reference, and it has been described fibroin and has been transformed into the fibrin viscose glue to increase its mechanical strength.Fibrin is bonding can also comprise albumin,,, is hereby incorporated by described in 976 at United States Patent (USP) 4,414 as people such as Schwarz.

The binding agent of other type comprises the binding agent of biotic component and synthetic ingredient.Usually, biotic component comprises protein.For example, gelatin-resin phenol aldehyde adhesive relates to gelatin-resorcinol material, and it forms by heating gelatin and Syringaresinol.Gelatin is formed by the hydrolysing activity on the albumin glue protoplasm.Formaldehyde, glutaraldehyde or its analog can be used to the crosslinked to form complete binding agent of gelatin-resorcinol material.

A kind of similar binding agent be by water miscible proteinic material and two or polymerization aldehyde formed.Protein substance can be the albumen or the proteinic mixture of purification.Preferred protein comprises albumin, comprises ovalbumin.Special preferred protein comprises and derives from human or animal's serum albumin.Suitable water miscible two-or many aldehyde comprise Biformyl and glutaraldehyde.Binding agent solidifies in acetaldehyde injection coating protein material last one minute of coating or shorter time.Such binding agent has further description in the United States Patent (USP) 5,385,606 of Kowanko, be hereby incorporated by.

Similar binding agent record in people's such as Barrows United States Patent (USP) 5,583,114 based on protein substance is hereby incorporated by.In addition, protein substance preferably includes the serum albumin as main component.Second composition comprises the bifunctional cross-linker.Preferred cross-linking agents comprises that molecular weight ranges is about Polyethylene Glycol of 1,000 to 15,000.This Polyethylene Glycol adding leaving group that can be modified, activatable crosslinking agent is in proteinic uncle or the combination of secondary amine place.Suitable leaving group for example comprises, succinic acid, and maleimide, phthamimdyl, other sulfilimine, heterocyclic leaving group such as imidazole radicals, aromatic leaving group such as Nitrobenzol separate group such as tresyl (CF with fluorinated alkyl sulfonic acid ₃-CH ₂SO ₂-O-).Linking group can combination between the pure and mild leaving group of polyester polyols.

Binding agent can comprise additive, to change the engineering properties of binding agent.The additive that is fit to comprises, for example, and implant, softening agent and stabilizing agent.Typical implant for example comprises carbon black and metal-oxide, silicate, the powder of acrylic resin powder and various potteries.Typical softening agent for example comprises, dibutylphosphoric acid ester, dioctylphosphoric acid ester, front three hydroxyphenyl phosphate ester, tri butylethyl phosphate and other ester.Be that the stabilizing agent of polymer for example comprises typically based on urethanes, the trimethyl quinol, Phenyl beta naphthylamine, p-isopropoxy-diphenylamine, hexichol-to inferior aniline etc.Can also comprise sugar as carbohydrate gum based on proteinic binding agent, glucose or sucrose are with the raising dissolubility, and stabilizing agent, comprise heparin.Fibrin glue can also comprise other composition, as fibrin decomposing inhibitor (antifibrin decomposing agents), for example, aprotinin and/or transexamic acid, and calcium chloride.

D. adhesive ingredients and basal layer combines

The binding agent of one or more compositions normally is connected with the basal layer of at least a portion.Although connected composition can comprise that more than a kind of composition, connected composition lacks a kind of neccessary composition at least in the forming process of binding agent.In other words, itself can not form complete binding agent by the connection of certain or some compositions, with other composition addition the time, forms strong adhesive bond.The adhesive ingredients that is connected with basal layer can be applied, by covalent bond and basal layer, and/or is mixed in the substrate or structure of substrate.

The additional protein of binding agent comprises the additive that all adhesive ingredients and beginning do not link to each other with basal layer.The extention of binding agent can comprise the connection adhesive ingredients of other amount.For example as coating or by covalent bond, the extention of this binding agent be introduced into the natural tissues surface or second basal layer that will be connected with this basal layer on, or be applied to the basal layer that is connected with adhesive ingredients partly on.

In case all parts of binding agent are employed, basal layer glue and natural tissues are bonding, so that basal layer is adhered on the natural tissues.The bonding strength that adhesive bond had is at least than without extention, want Senior Three doubly with the binding agent of the bonding composition of one or more conjunctive tissues.Although basal layer is adhered on the natural tissues usually, before the migration process of medical devices or among basal layer can be bonding with second basic unit.Like this, before the binding agent full solidification among or afterwards the mutual bonding preferred migration of composite substrate layer of medical adhesives in patient's body.Mutual contact has the advantage relevant with the binding agent location between application this paper process basic unit, and increases bond strength usually.

Certain that the adhesive power of the adhesive bond of the adhesive power that can be by binding agent and the remainder of binding agent is selected to be connected with basal layer or some composition.In some aspects, many appropriate ingredients can be bonding with basal layer in binding agent.For urethane adhesive, the urethanes polymer coating can be bonding with basal layer.For based on proteinic binding agent, protein usually can be bonding with basal layer.If desired, the part of binding agent can comprise a kind of coordinator of bonding composition, and the coordinator of the another kind of binding agent of the other parts of basal layer.If desired, two parts of different bonding compositions can partly or entirely be covered.

Usually, bonding composition is to be connected a large amount of so bonding molecules to make basal layer not easily separated in binding agent is cured the required time with basic unit.For some adhesive ingredients, bonding composition is applied directly to the bonding strength that is enough to provide effect in the selection of basal layer as coating.Be bonded into stratified bonding strength and depend on substrate and natural connection that is bonded between the branch, be bonded into the influence of the surperficial natural moistening of branch, the dissolubility of bonding composition in water and/or the influence of other similar action.

The bonding composition that connects can be connected by covalent bond or application of coatings with basal layer.Preferably, one period the composition coating stable, more preferably several days or longer time are stable under suitably storing.Coating formed after one hour at least, and sometimes in needs two hours or longer time, bonding composition and basal layer bonding is connected by various non-covalent connected modes with basal layer fully as bonding composition.To be further described below, the adhesive coatings of bonding composition and basal layer prepares before will using and stores.For bonding composition is connected with basal layer, substrate can place the solution that comprises bonding composition.Selectable, bonding composition can be brushed the surface, or uses or spray with ejector or analog.In selectable embodiment, the adhesive ingredients of this connection can join in the basal layer substrate.

In order to form the coating that contains the medical adhesives composition, this method can be selected suitable substrate and bonding composition.For example, if bonding composition and basal layer are insensitive to drying, bonding composition can add basal layer to and dry removing desolvated.Can select, bonding composition can be used as concentrated solvent and use, and keeps final composition moistening, to prevent substrate/bonding component composition desiccation.The container that is used for storing the moisture-sensitive reagent of substrate/bonding component composition is described at the U.S. PCT/US98/03519 of exercise question for " bin ", is hereby incorporated by.

In certain preferred aspects, a kind of composition of medical adhesives is connected with basal layer by covalent bond.If the bonding composition that is connected by covalent bond is a protein, there is the method for many covalent bonds to connect, rely on the character of basal layer.For being organized as the basal layer on basis, standard organize cross-linking agent can be used to covalent bond to connect,, comprise glutaraldehyde as difunctional aldehyde.Cross-linking agent is attached in the protein of adhesive ingredients and in the protein of basal epithelial cell layer.

For synthetic basal layer and protein or non-proteic adhesive ingredients, suitable crosslinking agent can be used to covalently bound.The molecule of cross-linking agent can have one or more to the active functional group of being bonded with of binding agent or one or more to the active functional group of being bonded with of basal layer.The basal layer that is fit to have can chemical crosslinking functional group.According to the character of synthetic base layer material, can select the suitable functional group of cross-linking agent.The functional group of cross-linking agent can be accredited as the functional group that can carry out chemical crosslinking with synthetic polymer.

For example, as the chlorosulfonated polyethylene of substrate, can react with the cross-linking compounds that contains alcohol or amine functional group.Like this, the chemical compound that contains aldehyde and alcohol or amine functional group can take place crosslinked between bonding composition of albumen and chlorosulfonated polyethylene substrate.Similarly, the polystyrene substrate can with halohydrocarbons reaction.Therefore, the suitable crosslinking agent that can make protein be adhered to the polystyrene substrate has aldehyde functional group and halogenated methyl functional group.

If bonding composition and substrate are covalently bound, bond condition can be adjusted to the adhesive ingredients of covalent bonds aequum, and does not make the adhesive power of deactivation composition.In order to reach this purpose, can regulate binding agent and bonding constituent concentration.The concentration that the bonding composition of albumen has in adhesive solution usually for approximately from 1ng albumen/ml to 50 μ g/ml, preferred 25ng albumen/ml is to 100 μ g/ml.Suitable concentration can be selected by experience.

For being connected of protein binder composition and basal epithelial cell layer, can under careful controlled condition, carry out with the bonding of cross-linking agent, to avoid the bond property of the bonding composition of deactivation.Particularly, crosslinkedly preferably in the weak solution of cross-linking agent, carry out, as glutaraldehyde.Crosslinked preferably at crosslinker concentration less than 0.1%, more preferably, be more preferably at 0.005% to 0.02% time and carry out less than 0.05%.According to the conventional amount used in this area, percent value is to dilute by volume according to dense percent by volume glutaraldehyde storing solution to obtain, and the glutaraldehyde storing solution is the storing solution of 50% volume ratio normally.

The crosslinked of casco composition and basal epithelial cell layer needs 5 minutes at least, normally about 15 minutes to 24 hours or longer time.Glutaraldehyde cross-linking for certain albumen and basal epithelial cell layer, observing its bondability is fast relatively with respect to crosslinking time, transferred the possession of United States Patent (USP) 09/186,810 referring to exercise question for the co-applications of " having the prosthese that connects somatomedin ", be hereby incorporated by.The preferred crosslinked time, can openly select according to this paper by rule of thumb.At preferred moderate condition as herein described, basal epithelial cell layer can not be crosslinked the obviously fixing of agent usually.

For based on basal epithelial cell layer, the solution that contains adhesive ingredients preferably is cushioned under near the physiology pH value, and the pH value scope is from about 6.0 to 8.5, and preferred scope is from about 6.9 to 7.5.Suitable buffer for example can be based on following chemical compound: phosphate, borate, bicarbonate, carbonate, two methyl-arsinic acid salt, citrate and other organic buffer liquid such as trihydroxymethylaminomethane (TRIS), N-(colamine) piperazine-N '-(2-ethanesulfonic acid) (HEPES) and morpholine propane sulfonic acid (MOPS).

In selectable embodiment, the photochemistry coupling can be used to induce the covalent coupling of bonding composition and basal layer.The photochemistry coupling is that for example, ultraviolet is to form the reaction intermediate of some functional group on the basis of using high-octane light.These intermediate products can form carbon-carbon bond between two compositions.Aryl ketones functional group is particularly suitable therein.When carrying out the photochemistry coupling, in the covalent bond of cross-linking agent between bonding composition and basal layer not necessarily.

The photochemistry coupling can be used to being connected of bonding composition of albumen and basal epithelial cell layer.As, for example, people's such as Dunkirk J.Biomaterials Applications 6:131-156 (1991) is hereby incorporated by.Because the yet crosslinked usually tissue of photochemistry coupling, this tissue can or can be not crosslinked respectively yet, i.e. photofixation.Selectable, the photochemistry coupling junctional complex with before the casco composition is connected, afterwards or among all can be used for being connected of junctional complex and tissue.

Ultraviolet can be used to the crosslinked of various synthetic polymers and basal layer.Particularly, when the ray that is exposed to owing to free radical mechanism, ethene polymers carries out crosslinked.Cross-linking agent can with known photoactive those uses.In addition, the side-chain radical of various polymer can be used for photoreaction and for example comprise alkynes, anthracene, Bendioxide bithiophene, chalcone derivative, cinnamate, Herba Lysimachiae foenum-graeci element, dibenzazepine, hexichol cyclopropylene carboxylate, episulfide, maleimide, stibazole, stilbene, 1,2,3-thiadiazoles, and thymus pyrimidine.Therefore, substrate polymer and/or bonding composition can comprise that these can carry out the group of photoactivation.

In the preferred embodiment that can select, the medical adhesives composition can join in the structure/substrate of biocompatibility substrate when basal layer forms.Particularly, at the reasonable time of substrate preparation, a certain amount of medical adhesives composition can be mixed with the composition of basal layer, forms mixture.When basal layer was formed, basal layer was included in the molecular structure of medical adhesives composition.Therefore, part or all of final basal layer comprises the bonding composition of medical science that distributes by basal layer substrate.Several parts and/or which floor this biocompatibility basal layer can comprise, several parts that can form the biocompatibility basal layer and/or which floor the bonding composition of medical science only be distributed in like this.

The basal layer of polymer can form by conventional polymerization process.Polymer can be synthetic polymer or natural polymer, as the collagen protein that is purified.Base material can be selected so that the composition work in-process of surgery glue is not decomposed.For example, if adhesive ingredients to thermo-responsive, can be selected the processing method of basal layer, do not need adhesive ingredients is joined in the hot radical bottom material.In this situation, can wait with the solvent molding method to replace thermoforming process.Can select the concentration of adhesive ingredients by rule of thumb, provide enough bonding after adding with all the other compositions, finish with the adhesive bond of natural tissues or other basal layer bonding at binding agent.

E. the adherent formation of adhesive bond

The remainder of binding agent can add by all means.For example, the extention of binding agent can directly be applied on a part of natural tissues or second basal layer (first basal layer is used on it).Second basal layer can comprise or not comprise the adhesive ingredients of connection.Selectable, with before the natural tissues or second basal layer contact, this binding agent can be applied on the basal layer of the adhesive ingredients with connection at this basal layer.The remainder of medical adhesives can be used from device by brush on its surface, or contains in the solution of other composition by basal layer immersion that will be suitable, or as hydrosol injection etc.The denseness of the other part of medical adhesives can show that it is specially adapted to use.

The other part of binding agent generally includes one or more other adhesive ingredients, and it does not comprise the adhesive ingredients that is connected with basal layer.The other part of this binding agent can comprise one or more adhesive ingredients that are connected with basal layer of other amount.The other part of this binding agent can comprise additive.

If the other part of this binding agent is forming adhesive bond in conjunction with before being applied to the natural tissues or second basal layer, the bonded formation of adhesive bond relates to the combination of the heterogeneity of binding agent.If the other part of this binding agent puts on the coordinator of adhesive group bottom, its final structure can be had any different with the coating of binding agent.Therefore, binding agent is any method of application of part in addition, and the final structure of basal layer and binding agent is distinguished mutually with the complete blended additive coating of binding agent, comprises all the components of mixed adhesive.

Usually, the other part of binding agent was added before the interface just forms, though precise time can be regulated according to various factors.The factor of relevant time comprises fixed rate, the time of surgical procedure and under environmental condition the stability of separated component, as the humidity of using.The scope of preferred adhesive hardening time is from about 1 minute to 5 hours, more preferably from about 5 minutes to 1 hour, preferably from about 5 minutes to 30 minutes.After the other part of medical adhesives was applied, basal layer contacted on required junction point with the natural tissues or second basal layer.When this adhesive bond is applied to the bonded normal pressure of adhesive bond in conjunction with bearing, and do not need other support, this binding agent is full solidification just.Normal pressure can cover many effective ranges.For example, pressure is quite low or for the relative height of the bonding support of cardiac valve annulus prosthese for the bonding support of surgical patch.Work as full solidification, adhesive strength level that binding agent reached and the desired the same durability that has.

For the initial curing of binding agent, the nursing staff can keep basal layer in a certain position, to reach full solidification for a long time.Can select, wrench or paperclip or analog can be used to basal layer is remained on a certain position.These can use the binding agent with fast setting speed.Can select, or in addition, the line of some stitching usefulness or seam are ordered and can be used to basal layer is remained on a certain position.The degree that suture and seam are ordered is still less used than medical adhesives usually.Sew up and/or restriction that seam is ordered to use be to solidify the stable of early stage adhesive bond in order to provide, prevent from that adhesive bond is bonded to break.

The character of adhesive bond

After the other part of binding agent is used, contain at basal layer and natural tissues or other between basal layer of the part of surgery glue at least, between basal layer and natural tissues or other basal layer, form connection, sealing or adhesive bond combination.Any connection characteristics about the binding site between natural tissues/second basal layer and first basal layer are not represented in the existence of adhesive bond.Its junctional complex can relate to " no suturing with thread management connects " between natural tissues/second basal layer and first basal layer, makes to be slick connection between two materials.

This binding agent is included in the overlay area of the binding agent between first basal layer and tissue or other basal layer.Adhesive bond preferably has associative key intensity and is at least 75g/cm ², be more preferably 100g/cm at least ²Because can not measure the intensity of patient's real adhesive bond, the intensity between the equivalent of the equivalent of the intensity reference basal layer of key and the true adhesive bond of natural tissues.With reference to figure 3, bond strength is by forming measured key between the adhesive bond 150 at the covering edge of basal layer part 152 and cambium 154, and tissue that promptly need not fixed non-degraded makes basal layer 152 and tissue 154 negative drawings in adhesive bond 150.If suitably, different basal layeres can be used for substituting tissue, as suitable.Be fixed in clip 160,162 from the stretched edge of adhesive bond, between 164,166.

Bond substrates layer 152,154 is positioned at clip 160,162, between 164,166, is stretched, and referring to Fig. 3, stretches from adhesive bond 150 all directions, ruptures under shearing force up to adhesive bond.The adhesive bond intensity of shearing force (fracture strength) value when the adhesive bond fracture for measuring.Although the actual adhesion key is not two-dimentional, and is promptly planar, bond strength is to estimate by the concordance of the adhesive bond of two dimension.If form good hemorrhage or liquid seal thing around the adhesive bond, the two-dimentional bond strength that the bond strength of non-two-dimentional adhesive bond roughly is equivalent to adhesive bond bonded area counit area usually multiplies each other.

For the biocompatibility adhesive bond, it is when basal layer and tissue link together in the natural agglutination that adhesive bond is absorbed preferred time phase again.Like this, binding agent is replaced by natural tissues, and does not contain complete adhesive bond.Various reabsorption rates can make binding agent keep time enough at least by experience adjustments so that the bond strength of adhesive bond be do not have destroyed.The length of wound healing time can depend on the suffered pressure of size and wound tissue of the size of wound.For example, organizing is stressed hardly may cure after several days, was possible need the long relatively time when tissue is subjected to certain pressure.

G. biological activity additive

Binding agent can comprise biological response and change agent.The biological response change agent that is included in the binding agent can cause discharging gradually biological response change agent, if particularly binding agent is can be resorbent by biology.Be fit to biological response change agent and comprise for example antibacterial, anticalcification agent and somatomedin.Usually, the other parts of additive and additive merge local the use, although if adhesive bonding method also is protein additive and basal layer bonding, the protein additive also can be bonding with basal layer.

Antibacterial comprises, for example, and the antibiotic of organic chemical reagent and the antibacterial of metal ion.Organic antibiotic for example comprises penicillin etc.The antibacterial of metal ion for example comprises Ag, Au, Pt, Pd, Ir, Cu, Sn, Sb, Pb, Bi, Zn ion and combination thereof.The antibacterial of metal ion and the bonding of prosthese, the part of prosthese or prosthese can be soaked in the liquid of the antibacterial of metal ion, as silver nitrate solution.Selectable, this solution can be by spraying, and brushing or similar mode are applied to basal layer.

Can select, the antibacterial of metal ion can be the form of saline solution of antibacterial of the metal ion of low solubility.Argentiferous chemical compound is by preferred especially.Suitable silver compound for example comprises silver chloride, Silver monobromide, silver iodide, Disilver carbonate and silver phosphate.Suitable copper compound for example comprises copper stearate and cupric phosphate.Suitable zinc compound for example comprises zinc stearate and zinc phosphate.Similarly, suitable palladium compound for example comprises palladium.

The application of the antibiotics of metal ion has further reduced the risk that infects, and is called in name in the United States Patent (USP) 08/974,992 of " medical product and metal antibacterial element bonding " to describe, and is hereby incorporated by.The antibiotic of metal ion can be used external memory structure transmission, is called in the United States Patent (USP) 08/787,139 of " argentiferous transmission system " as the name people such as Tweden and describes, and is hereby incorporated by.

Certain thanks to polyvalent metal ion can be effectively in the calcification that reduces prosthese.Preferred calcification ion for example comprises aluminium ion (Al ^{+ 3}) and iron ion (Fe ^{+ 3}).Other suitable metal ion for example comprises manganese ion, zinc ion, gallium ion, lanthanum ion and beryllium ion.For multivalence calcification metal ion is introduced in the prosthese, the part of prosthese or prosthese can be contained the ionic liquid of calcification and be soaked into.For example, aluminum nitrate or ferric nitrate can be employed.Perhaps,, make the calcification ion, contact with prosthese or part prosthese as insoluble relatively mineralization by the anion that brings Selection In to calcification ionically-soluble saline solution.For example, can precipitate aluminum palmitate by adding Palmic acid from aluminum chloride aqueous solution, iron phosphate can be precipitated from the solution of iron chloride.

In addition, shown that external memory structure can be used to transmit polyvalent cation.Referring to people's such as Schroeder United States Patent (USP) 08/690,661, exercise question is hereby incorporated by for " calcification-inhibition biological substance ".The ionic external memory structure of calcification with storage can combine with the deposit that contains the antibacterial metal element.

Biological response changes agent can become a kind of somatomedin.Particularly preferred somatomedin for example comprises VEGF (VEGF).VEGF promotes the propagation of the endotheliocyte of vascular tissue.VEGF be a kind of can be comprised in basal layer or with adhesive ingredients that adherent other composition is connected in protein.The exercise question that is combined in people such as Carlyle of VSG and prosthese has further description in the United States Patent (USP) 09/014,087 and 09/186,810 of " prosthese with relative growth factor ", at this two is incorporated herein by reference.

H. store, packing is distributed and application

Bonding composition is adhered on the basal layer, and improved basal layer can be stored.Preferably make contamination by micro drop to minimum storage.For example, improvement can store in the container of drying, sealing the insensitive basal layer of dampness.Can select, the basal layer of improvement can with listerine be stored in aseptic, the sealing container in.The character of listerine should be compatible with basal layer, and can keep the activity of adhesive ingredients.For example, the crosslinked basal epithelial cell layer that contains the bonding composition of protein can be stored in rare glutaraldehyde water solution.Should be taken into account the loss in time of bonded adhesive ingredients in advance, or the efficient of bonded adhesive ingredients may be fallen.The additive that comprises antioxidant as ascorbic acid, can be added in the storage solutions, to reduce the reduction of the efficient of bonding composition in storage process.

About distributing, the basal layer of improvement can be placed in the also aseptic container of sealing.Container indicates the date usually, and this date has reflected and considers the longest holding time of advising behind degraded that adhesive ingredients is possible and the other factors.This container package comprises the description of suitable use basal layer and the label of suitable and/or needs.This container is assigned to medical worker, is used for suitable medical procedures.。If the medical science material is stored in the liquid, medical worker takes out it back before use and cleans substrate from storage capsule.All the other compositions can not distribute with the basal layer of improveing yet.If all the other compositions do not distribute with modified basal layer, in some cases, this residual components can be used as isolating adhesive product and buys separately.

Can select, basal layer can from the transferred product to the hospital or other long-range place improve.Under certain conditions, the basal layer of improvement only can be stored the very short time before use.Under certain conditions, basal layer and bonding composition need be improved the basal layer of using separately or together.Suitable description can with basal layer, one or more bonding composition/parts, or the compositions of above-mentioned substance is distributed together.For the storage of short-term, the basal layer of improvement can be kept at the solution that is used for improveing basal layer.Perhaps, the basal layer of improvement can be used after the basal layer improvement is finished immediately.

Embodiment

Present embodiment is to increase for the covalently bound bond strength that causes to the tissue bond composition of the composition that fiber binder is described.

Sample obtains from the main artery wall of pig.From valve take out identical blood vessel cut about two sections large artery trunks of 2cm * 6cm.Before cutting sample, the length dimension of every section blood vessel is corresponding to the basic orientation of blood vessel.12 large artery trunks segments (six pairs) are crosslinked and are stored in per 0.9% saline, and (Deerfield IL) contains about 3 weeks of glutaraldehyde of percent 0.5 for saline, Baxter Health Care Corp..The preparation of glutaraldehyde solution is every liter diluted 50% by volume of a glutaraldehyde storing solution.

Prepare 18 noncrosslinking large artery trunks segments (from nine couple of aortic nine parts).Six segments (three pairs) are placed in 0.9% the saline of 50ml spends the night.Other six large artery trunks segments (three pairs) are put in the saline that contains fibrin spends the night, and other six large artery trunks segments (three pairs) are put in the saline of fibrinogen (80% activity, promptly agglomerative) spends the night.Deshydremia fibrin solution is by obtaining in the salt that 5.0g fibrin (obtaining Sigma ChemicalCompany, lot 110H9304 from bovine blood) is dissolved in 100ml 0.9%.Similarly, the formation of fibrinogen solution is by (Sigma Chemical lot64H9300) is dissolved in and obtains in the salt of 100ml 0.9% with the 5.0g Fibrinogen.Then, the large artery trunks segment of store overnight is put in glutaraldehyde respectively and was accounted in the phosphate buffer of 0.5% volume ratio two hours in fibrin or fibrinogen solution.At the glutaraldehyde saline solution after two hours, take out sample and 0.1 mole tris buffer (tris of high purification, three (methylol) aminomethane, Gibco BRL, LifeTechnologies, Inc., Grand Island, NY) in incubation 1 hour.

Deriving from the viscose glue that the crosslinked or noncrosslinking segment of same blood vessel contained binding agent accordingly combines.About 2 square centimeters binding agent is applied to a surface of organizing pulsating end.Binding agent is a kind of fibrin glue (CryoSeal ^TMFrom Thermo Genesis Corp, Rancho Cordova, CA, use the fibrin preparation of 5,000 units/5ml Park Davis, Moms Plains, NJ), be bonded to alpha-cyanoacrylate ester gum Duro except three pairs of crosslinked large artery trunks segments (being labeled as CY/x-linked) ^(Super Glue, Hartford, CT) on.This fibrin viscose glue sample is marked as FG, and the crosslinking Treatment of tissue is labeled as " x-linked ", untreated being expressed as " fresh ", and Fibrinogen is handled is expressed as " fibrinogen ", and fibrin is handled is expressed as " fibrin ".The fibrin viscose glue is used by two spouts, and it merges multiple composition before use by single pipe.Sample is capped, and binding agent was allowed to solidify about 20 minutes.

At Instron 501b Load Cell, (Research Triangle Park NC) goes up the adherent intensity of test to Model Sintech 1/s from the Sintech Divisionof MTS Systems Corporation.Two conjunctive tissue segments are fixed on load cell, and adhesive bond is applied power.On this structure, measure and to produce the load that enough shearing forces are separated adhesive bond, roughly as shown in Figure 3.

The result lists in table 1, and meansigma methods shows in Fig. 4.

Table 1

Sample	Sequence number	Intensity (1bs)	Intensity (g)	????g/cm 2
					??CY/x-linked	???1	????4.40	????969.76	????484.88
	???2	????5.70	????1256.28	????628.14
						???3	????7.40	????1630.96	????815.48
	Meansigma methods	????5.83	????1285.67	????642.83
						??Std. ??Dev.	????1.50	????331.58	????165.79
??FG/x-linked	???1	????0.40	????88.16	????44.08
						???2	????0.30	????66.12	????33.06
	???3	????0.20	????44.08	????22.04
						Meansigma methods	????0.30	????66.12	????33.06
	???Std. ???Dev.	????0.10	????22.04	????11.02
					??FG/fresh	???1	????0.40	????88.16	????44.08
	???2	????0.60	????132.24	????66.12
						???3	????0.50	????110.20	????55.10
	Meansigma methods	????0.50	????110.20	????55.10
						???Std. ???Dev.	????0.10	????22.04	????11.02
??FG/fibrinogen	???1	????1.40	????308.56	????154.28
						???2	????2.20	????484.88	????242.44
	???3	????2.30	????506.92	????253.46
						Meansigma methods	????1.97	????433.45	????216.73
	???Std. ???Dev.	????0.49	????108.72	????54.36
					??FG/fibrin	???1	????1.00	????220.40	????110.20
	???2	????0.50	????110.20	????55.10
						???3	????0.80	????176.32	????88.16
	Meansigma methods	????0.77	????168.97	????84.49
						???Std. ???Dev.	????0.25	????55.47	????27.73

Synthetic cyanoacrylate has the strongest bonding.Before the fibrin viscose glue is used, segment is used crosslinked Fibrinogen, cause almost 4 times of tearing strength increases.Covalently bound the causing of fibrin increases, but not remarkable on the degree statistics that increases.Therefore, the covalent bond of viscose glue composition can cause the obvious increase of key bonding strength.

Above-mentioned described embodiment has explained the present invention but has not limited the present invention.Enforcement embodiment in addition is in following claim.Though the present invention describes with reference to preferred embodiment, those skilled in the art can make a change aspect form and the details, and without departing from the spirit and scope of the present invention.

Claims (31)

1. the compositions of a basal layer/adhesive ingredients, it comprises first basal layer of a kind of composition with the medical adhesives that is covalently bound to basal layer.

2. compositions as claimed in claim 1, wherein said adhesive ingredients comprises a kind of protein.

3. compositions as claimed in claim 2, wherein said protein comprises Fibrinogen.

4. compositions as claimed in claim 2, wherein said protein comprises albumin.

5. compositions as claimed in claim 1, wherein said medical adhesives composition comprises the prepolymer of urethanes.

6. compositions as claimed in claim 1, wherein said first basal layer comprises tissue.

7. compositions as claimed in claim 6, wherein said tissue comprises crosslinked tissue.

8. compositions as claimed in claim 1, wherein said first basal layer comprises synthetic substrate.

9. one kind is fixed in the method for second basal layer with first basal layer, and this method comprises that all the other compositions with the compositions of claim 1 and medical adhesives contact with second basal layer, to form adhesive bond.

10. method as claimed in claim 9, wherein said second basal layer comprises tissue.

11. method as claimed in claim 8, wherein said first basal layer comprise many layers.

12. bonding system, it comprises first basal layer of the protein ingredient with medical adhesives, wherein described protein ingredient forms coating on first basal layer protein ingredient contacts above 1 hour with first basal layer after, with the second medical adhesives composition, wherein the application of the second surgical operation glue composition between first basal layer and second basal layer causes forming adhesive bond after curing.

13. bonding system as claimed in claim 12, wherein said medical adhesives comprise a kind of resorbent compositions.

14. bonding system as claimed in claim 12, the wherein said first surgical glue water constituent is covalently bound on described first basal layer.

15. bonding system as claimed in claim 12, at least a portion of wherein said first basal layer has the coating that contains resorbable polymers, this resorbable polymers contains the first surgical operation glue composition that is added into wherein, so that the first surgical operation glue composition is connected with basal layer.

16. bonding system as claimed in claim 12, wherein said first basal layer comprises a kind of crosslinked tissue.

17. bonding system as claimed in claim 12, wherein said first basal layer comprises a kind of synthetic substrate.

18. bonding system as claimed in claim 12, wherein said second basal layer comprises natural tissues.

19. one kind is fixed in the method for second basal layer with first basal layer, this method comprises the composition that merges in the described system of claim 11, and to form adhesive bond, at least a portion of second composition that makes surgical operation glue is between first and second basal layeres.

20. method as claimed in claim 19, first basal layer of wherein said coating with bonding composition are stored in before forming adhesive bond in sealing, the aseptic container.

21. a method for preparing first basal layer that is used to be adhered to second basal layer, this method comprise medical adhesives composition and fixed compound are applied at least a portion of first basal layer.

22. method as claimed in claim 21, wherein said fixed compound is a cross-linking reagent.

23. method as claimed in claim 21, wherein said fixed compound impel the composition of surgical operation glue to be covalently bound on first basal layer.

24. method as claimed in claim 21, wherein said fixed compound are can resorbent polymer.

25. a basal layer comprises that a kind of medical adhesives composition is added in the matrix components of this basal layer.

26. basal layer as claimed in claim 25, the matrix components of wherein said basal layer comprises synthetic chemical compound.

27. basal layer as claimed in claim 25, the matrix components of wherein said basal layer comprises natural polymer.

28. a method that forms basal layer comprises that a kind of of the part of a kind of composition by medical adhesives and this basal layer becomes phase-splitting to mix, and to form mixture, makes up this basal layer from mixture.

29. the formation method of a prosthese, this method comprises:

First basal layer and second basal layer are fixed with medical adhesives, and wherein said first basal layer contains relevant adhesive ingredients, and wherein said binding agent remainder is between first and second basal layeres.

30. method as claimed in claim 29 further comprises basal layer is implanted in patient's body, wherein saidly carried out before being implanted in the binding agent full solidification.

31. method as claimed in claim 29 further comprises basal layer is implanted in patient's body, wherein saidly carried out after being implanted in the binding agent full solidification.

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