JP2001526935A - Tissue-reactive adhesive composition - Google Patents

Abstract

  (57) [Summary] The present invention relates to a biocompatible tissue-reactive composition having a functional polymer having a tissue-reactive substituent capable of forming a covalent bond with a tissue-related functional group.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD OF THE INVENTION

The present invention relates to a biocompatible tissue-reactive adhesive composition.
ctive adhesive composition) and methods for repairing damaged tissue. In particular, the present invention relates to a functional polymer having a tissue-reactive substituent capable of forming a covalent bond with a tissue associated functional group.
alized polymer) and a biocompatible tissue-reactive composition (biocompatible ti
ssue reactive composition).

[0002]

BACKGROUND OF THE INVENTION AND SUMMARY OF THE INVENTION

With the advent of significant advances in surgical technology and the development of biocompatible materials for prosthetic implants, researchers are also focusing on the development of new tissue / implant fixation techniques. One aspect of such research is formulating surgical adhesives that can be used as an alternative to, or in combination with, common mechanical fixation techniques. Recently, biocompatible adhesives for surgical use have been proposed, at least in part based on the findings obtained with natural bioadhesives, such as those produced by barnacles and the species itself. Have been proposed on the basis of proteinaceous compositions which allow them to adhere in a seemingly permanent manner to a wide variety of underwater structures. Much has been learned about the "chemistry" of such natural adhesives, and efforts are being made to utilize such chemistry for the production of surgical adhesives.

[0003] The present invention, which differs from the chemistry of marine natural adhesives, is based on the use of "chemistry" to optimize adhesion under physiological conditions. In particular, the invention is based on the reactivity of certain polymer-associated functional groups to tissue-associated functional groups. The adhesive composition reacts with a tissue in vivo and forms a covalent bond with the tissue. The functional group of the adhesive polymer component of the composition of the present invention reacts with the molecular component of the tissue and, at the same time, is transferred to the second functional group, so that at least one other functional group on the adhesive polymer and intramolecularly. Alternatively, the intermolecular reaction results in covalent bonding and "setting" of the adhesive in vivo.

[0004] According to one exemplary embodiment of the present invention, there is provided a tissue-reactive adhesive composition comprising a biocompatible polymer substituted by at least one tissue-reactive functional group.

[0005] In another example embodiment, the substituted biocompatible polymer is a monomer having at least one tissue-reactive substituent and a thiol-reactive substituent to form a tissue adhesive composition. Combined with oligomer.

In another exemplary embodiment of the present invention, the tissue adhesive composition is reduced from an effective amount to form a self-adhesive implant capable of sustained release of the biologically active ingredient in vivo. Further comprising one or more biologically active ingredients.

In another embodiment of the present invention, a tissue-reactive adhesive composition may be used alone or in combination with a mechanical fixation technique for bonding adjacent tissue surfaces or fixing an artificial implant. it can.

[0008]

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention provides a tissue adhesive composition having a biocompatible polymer having a covalently bonded tissue reactive substituent. In one embodiment, the covalent tissue-reactive substituent includes, for example, a thiolactone group of the formula:

[0009]

Embedded image

The groups react under physiological conditions with hydroxy, amino, and thiol groups associated with tissue to form the corresponding acyclic esters, amides, and thiol esters, respectively, while at the same time acyclic thiol moieties. To produce. In another example embodiment,
The biocompatible polymer component of the tissue adhesive composition of the present invention includes a tissue reactive substituent having a boric acid functional group of the formula: -B (OH) ₂ . The functional group reacts under physiological conditions with a hydroxy group associated with tissue, especially a vicinal dihydroxy functional group, to form a cyclic borate ester.
In one exemplary embodiment of the present invention, the biocompatible polymer component of the tissue adhesive composition of the present invention has the formula: wherein R and R ′ are independently hydrogen or optionally substituted C ₁ -C ₆ alkyl. Thiol-reactive substituents containing a divalent group consisting of CR = CR'- or -C−C- are also included. Such thiol-reactive substituents, including divalent olefin groups or acetylene groups, may be cyclic or non-cyclic. The structure of such a thiol-reactive group is not critical if it exhibits reactivity to the thiol function under physiological conditions to produce the corresponding sulfide group. The reaction of the thiol moiety with a thiol-reactive substituent, in the case of a tissue-associated thiol group, acts to covalently link the polymer component of the adhesive composition to the tissue. Such sulphide formation can also be effected intramolecularly or intermolecularly in the adhesive composition, for example by hydrolysis of thiol-reactive polymer-bonded substituents and polymer-bound thiolactone groups,
It occurs between thiol groups released by alcoholysis, aminolysis or thiolysis, and effectively cross-links the polymer component of the tissue adhesive composition after transplantation.

[0011] The inherent histocompatibility of the biocompatible polymer of the adhesive of the present invention can be measured at physiological pH such as amino, amidino, and guanidino groups in addition to tissue-reactive and / or thiol-reactive substituents. Optimization is achieved by selecting or chemically modifying the polymer to include substituents that are substantially cationic. The resulting cationic properties of the biocompatible polymer enable and indeed facilitate in vivo compatibility / affinity with endogenous tissues that are found to have aggregated anionic properties.

[0012] The tissue adhesive compositions of the present invention are based on their ability to react and covalently bind tissues in vivo, and in some embodiments, include free radical-based chemistry or undesirable chemical side-effects. It is based on its ability to perform post-implantation cross-linking, which acts to increase the adhesion and cohesion of the composition after implantation, without the need for product production and concomitant release. The tissue adhesive composition can be used to bond and repair adjacent tissue surfaces, or can be used alone or in combination with mechanical fixation techniques as a surgical adhesive for the fixation of an artificial implant. . Alternatively, the adhesive composition of the present invention can be combined with one or more biologically active compounds, such as antibodies, anti-inflammatory agents, growth factors, etc. It can be used to form a self-adhesive implant that can be sustained release.

One of the key components of the tissue adhesive composition of the present invention is a biocompatible polymer having one or more, preferably many, hydroxy, amino, carboxylic acid, and thiol functional groups associated with the tissue. is there. Importantly, the reactive polymer component of the tissue adhesive composition of the present invention is biocompatible, non-toxic and non-immunogenic in vivo, and minimally induces an inflammatory response. . Other than that,
The properties of the polymer are not critical except that it has the specific functional groups described above, or other pendant functional groups that can be chemically modified to provide the tissue-reactive or thiol-reactive substituents described above. Absent. The intermediate polymer (polymer "backbone") that is chemically modified to form the polymer component of the adhesive composition of the present invention can be a homopolymer, terpolymer, copolymer, block copolymer, or polymer. It may be in the form of a blend. These polymers are biodegradable or non-biodegradable, but are not bioerodible, that is, they are partially soluble in physiological fluids. Examples of biodegradable polymers used to synthesize the substituted polymer component of the tissue adhesive composition of the present invention include polyanhydrides, polylactic acid, polyglycolic acid, lactic acid and glycolic acid alone or caproic acid. Polyester containing a copolymer with a combination and the like, and poly (amino) acid are exemplified. Examples of other polymers used to synthesize the substituted polymer component of the tissue adhesive composition of the present invention include polyhydroxyethyl methacrylate, polymethyl methacrylate, polyacrylic acid, and also Shearwater Polymer.
Product name: Pendant poly (ethylene glycol) propionic acid (Pe
and polyethylene glycol copolymers such as a copolymer of ethylene oxide and 4,5-epoxypentanoic acid sold as ndant Poly (ethylene glycol) -propionic acid. In one embodiment, the intermediate polymer is selected such that the reactive substituent-containing polymer derivative used in the tissue adhesive composition is capable of being manually molded at a temperature in the range of about 0 ° C to 60 ° C. Is done. The substituted polymer-containing component of the composition of the present invention generally has a glass transition temperature (Tg) of less than about 90 ° C,
In one example embodiment, the glass transition temperature is less than about 40 ° C. In another example embodiment, the glass transition temperature is from about 40 ° C to about 90 ° C. The polymer component of the tissue composition of the present invention generally has a molecular weight of about 1,500 daltons to 50,000 daltons, more typically from about 1,800 daltons to about 20,000 daltons.

The polymer component of the tissue adhesive composition of the present invention is selected or synthesized to have one or more covalent tissue-reactive substituents. In one example embodiment, the tissue-reactive substituent has the formula:

Embedded image Of the formula: -B (OH) ₂ , and a thiol-reactive unsaturated hydrocarbyl substituent. Such substituted polymers can be formed from monomer components that include such substituents, or can be chemically modified to include one or more of the above tissue-reactive or thiol-reactive substituents. It can be synthesized by either reacting a polymer intermediate having a substituent. Thus, a polymer intermediate can be reacted, for example, by an alkylation or acylation reaction to covalently attach the polymer to a substituent containing the tissue-reactive or thiol-reactive moiety, for example, a pendant hydroxy or amino function. Group. Alternatively, a polymer intermediate having carboxy functionality can be reacted with, for example, an ester-forming or amide-forming compound containing one or more of the above tissue-reactive or thiol-reactive functional groups, and the tissue adhesive composition of the present invention. Such groups are covalently attached to the polymer used in.

Accordingly, biocompatible polymers having, inter alia, thiol-reactive substituents can be synthesized by reacting an intermediate polymer with a compound of the formula: HL _n -X, where H is of the formula Is a thiol-reactive, unsaturated cyclic or acyclic hydrocarbyl group having a divalent group of -CR = CR'- or -C≡C-, wherein R and R 'are each independently hydrogen or optionally substituted C ₁ -C ₆ alkyl, L is a linking group, n is 0 or 1, and X is a functional group capable of forming a covalent bond with a functional group on the intermediate polymer. The nature of the linking group L is not critical and is simply any divalent group that ultimately links the thiol-reactive substituent H to the polymer. The functional group X may represent, for example, a good leaving group, in which case the polymer component is capable of substituting X and forming a covalent bond with the unsaturated hydrocarbyl group via the linker -L-. Contains a core group. Alternatively, X is a carboxy group that can be activated for acylation coupling to a hydroxy and / or amino function on the intermediate polymer, for example, by active ester formation.

[0016] Similarly, the tissue-reactive thiolactone substituent of the formula: TL-L n by using the compound of _-X can be covalently attached to the polymer, TL wherein is thiolactone moiety, L, n and X is as defined above. Boric acid substituents can also be attached to the polymer via similar reactive intermediates.

The degree of tissue reactivity and substitution with thiol-reactive substituents on the biocompatible polymer can vary over a wide range and can be selected to provide adhesive properties depending on the desired use. it can. The biocompatible polymer component of the tissue adhesive composition of the present invention must include at least one covalent tissue-reactive / thiol-reactive thiolactone substituent. Preferably, the polymer is also substituted by at least one thiol-reactive unsaturated hydrocarbyl substituent. Optionally, the polymer can be substituted with one or more boric acid substituents. In another example embodiment,
The biocompatible polymer component of the tissue adhesive composition of the present invention comprises multiple covalently bonded thiolactone groups and multiple thiol-reactive unsaturated hydrocarbyl groups, and is optionally substituted with one or more boric acid functional groups. ing. Alternatively, the biocompatible polymer component of the tissue adhesive composition of the present invention is synthesized to include a covalently reactive substituent consisting of a borate group with or without additional tissue-reactive or thiol-reactive substituents. You.

[0018] In addition to the covalently substituted biocompatible polymer described above, the tissue adhesive composition of the present invention has the formula:

Embedded image And a formula in which R and R ′ are independently hydrogen or optionally substituted C ₁ -C ₆ alkyl: —CR ＝ CR′— or —C≡C
A thiol-reactive unsaturated hydrocarbyl substituent having a divalent group of the formula: -B (
OH) ₂ to about 1% to about 60% by weight of a monomer or oligomer having at least two covalent substituents selected from the group consisting of a tissue reactive substituent comprising a borate group. You. Such monomers or oligomers generally have a molecular weight of about 100 to about 1200. The biocompatible polymer component can be mixed with the monomer or oligomer to form a solution or suspension that can be applied as a surgical adhesive to the surface of the tissue and / or the artificial implant. Alternatively, the tissue to be abutted and adhered as part of the surgical repair process may be preceded by the tissue-reactive monomer or oligomer prior to application of the tissue adhesive composition of the invention comprising a biocompatible polyfunctional polymer. Can be processed.

The tissue adhesive composition of the present invention can be used alone or in combination with mechanical / tissue fixation and repair techniques. When the tissue adhesive composition is used alone, usually, the adjacent surface is coated with the tissue adhesive composition of the present invention, and the adhesive composition in contact with the adjacent tissue surface and the tissue-reactive functional group are used. Pressing of the bonded tissue for a period of time before covalent bonding occurs maintains temporary contact of the intimate surfaces.

In another exemplary embodiment of the present invention, the tissue adhesive composition is formulated to include one or more biologically active ingredients. The adhesive composition so formulated can be used for surgical repair or simply as a mass implant for sustained release of the biologically active ingredient. The biologically active ingredient may be selected from a wide variety of previously recognized compounds, including, for example, typical therapeutic agents such as antibiotics or anti-inflammatory agents, proteins such as growth factors or cytokines. , And D
NA or living cells. As proteins, for example, cells, serum, skin,
Bone and extracts from other tissues are included, as well as cellular or non-cellular tissue components. Therefore, suitable biologically active agents are whole blood or its components,
It can be extracted from skin, bone, cartilage, tendons, microorganisms and the like. That is, examples of the protein component include a synthetic protein, a protein produced by recombinant DNA technology, a hormone, an enzyme, albumin, or a structural protein such as keratin and collagen, a simple protein, or a glycoprotein, a mucoprotein, a lipoprotein. , A heme protein, a nucleoprotein and the like. DNA components include, for example, bone morphogenetic factors useful for bone or cartilage regeneration (
bone morphogenic protein) and transforming growth factor β. Examples of growth factors used in the tissue adhesive composition of the present invention include fibroblast growth factor, transforming growth factor, epidermal growth factor, platelet-derived growth factor, insulin-like growth factor, and the like. Growth factor binding proteins, including insulin-like growth factor binding proteins such as IGFBP3 and 5, can also be used as a component of the adhesive composition of the present invention. Examples of cells that can be used in the tissue adhesive composition of the present invention are bone marrow cells and chondrocytes. Potential osteogenic components include demineralized bone powder, cancellous bone, aspirated bone marrow, bone or chondrogenic cells, or precursors thereof. Alternatively, the compositions of the present invention can be formulated so as to contain antibacterial compounds such as gentamicin and vancomain, or known drugs such as steroidal anti-inflammatory substances such as cortisone, hydrocortisone, and synthetic prednisolone. Other optional components of the tissue adhesive composition include exogenous proteins such as gelatin or albumin, tocopherol, citric acid, butylated hydroxyanisole, butyl or hydroxytoluene, t
-Antioxidants such as butyl hydroquinone, propyl gallate, ascorbate, and other antioxidants "generally recognized as safe" by the Food and Drug Administration Can be

[0021] The tissue adhesive composition of the present invention can be used in surgical procedures to temporarily secure an artificial implant to damaged or diseased tissue. The adhesive composition is utilized to immobilize the prosthetic implant over a period of time that allows regeneration of endogenous tissue, incidental "natural" fixation of the implanted structure, or repair or healing of adjacent tissue. Accordingly, the tissue adhesive composition of the present invention may be used to provide a temporary matrix structure for the growth of chondrogenic cells, eg, for the production / regeneration of damaged cartilage structures, "felted" polylactic acid. Or it can be used to fix polyglycolic acid. The tissue adhesive composition of the present invention provides a "covalent"
"Enables temporary fixation. The adhesive composition of the present invention can be used as a surgical adhesive for a wide variety of endogenous tissue structures such as skin, cartilage, and bone.
If the implanted tissue adhesive composition includes a biologically active component, a biologically active component, the biological component is gradually released from the adhesive matrix over a period of time after implantation. Generally, the biologically active agent is used to facilitate repair of the surgical repair site, or simply to cause unnecessary infection (if the biologically active agent is an antibiotic) or inflammation (if the biologically active agent is an anti-inflammatory). (If it is an agent). In another surgical application, a tissue adhesive composition comprising a biologically active agent may be formed by simply pushing a portion of the composition into the bone defect and forming it to fit the defect. It can be used to fill defective sites.

[0022]Example 1: Adhesive based on poly (L-arginine) poly (ornithine)  All reactions were performed under a dry nitrogen atmosphere using dry degassed solvents and reagents. 3
Equivalent of maleimide propionic acid N-hydroxysuccinimide ester and 3 equivalents
Of poly L-arginine hydrochloride while stirring at room temperature with triethylamine.
Methyl sulfoxide (DMSO) solution (Sigma Chemical Co., about 1% to about 3%
Containing ornithine monomer. After about 2 hours, the resulting polymer
Dry tetrahydrofuran (THF) was added to the mixture to precipitate the
. The polymer was dried at room temperature under vacuum. Both polyarginine and polyornithine
Between the polymer and maleimidopropionic acid N-hydroxysuccinimide ester
Was determined based on the method of Ellman (Ellman, Arch. Biochem. Biophys 82, 70, 1959).
Confirmed using nitrobenzene sulfonate.

[0023] The resulting intermediate polymer product is dissolved in dry DMSO and 1 equivalent of D
, L homocysteine thiolactone hydrochloride (HCTL), and 2 equivalents of ethyl-3
-(3-Dimethylamino-propyl) carbodiimide was added with stirring.
After about 10 minutes, 6 equivalents of DMSO containing dry pyridine were added, and the resulting solution was stirred at room temperature under an atmosphere of dry nitrogen for about 12-18 hours.
The resulting functional polymer was precipitated with THF, collected and dried at room temperature and under high vacuum.

The polymer product (hereinafter “poly (Arg) -TL”) was stored as a dry powder. A gel is formed 10 to 15 minutes after dissolving the polymer in water. Gel formation is thought to be the result of hydrolysis of the thiolactone ring of homothiolactone and subsequent crosslinking of the polymer.

The adhesive properties of poly (Arg) -TL were determined by a tensile test based on the following method.

A plurality of glass slides were immersed in a heated sulfuric acid bath for 10 minutes for cleaning. The slide was rinsed with ultrapure water. They were then placed in warm ammonium hydroxide: hydrogen peroxide (4: 1 by volume) for 1 minute. Rinse the glass slide again with ultrapure water,
It was further dried with filtered nitrogen.

[0027] Water swelled chondroitin sulfate (CS) was used as a test substrate to simulate wet tissue. The washed glass slide was pretreated with an aminosilane coating. An aqueous solution of CS was applied to a pre-treated glass slide (4.83 cm ² exposed area). A CS film was provided on the glass slide by gelation of CS.

Prior to testing, CS films cast on glass were placed in a 100% humidity chamber for 30 minutes. poly (Arg) -TL was sprinkled on one of the CS coated glass slides. A second CS-coated glass slide was placed on the first glass slide and the two slides were pressed together with a force of about 15 Newton for either 30 or 90 minutes. Next, using a test apparatus, slide the two slides to about 9
Stress and strain were measured by separating at an angle of 0 °. The separation speed is 0.5mm /
Minutes.

The results of the adhesion test of poly (Arg) -TL are shown in Tables 1 and 2. poly (Arg
) -TL is a poly () which does not react with either maleimidopropionic acid N-hydroxysuccinimide ester or D, L-homocysteinethiolactone hydrochloride.
L-arginine) -poly (ornithine) copolymer [poly (Arg) -poly (Or)
n)]. For CS coated glass slides
The adhesive strength of the poly (Arg) -TL adhesive composition is between 9.4 Newtons and 22.5
9 Newton range. This indicates that poly (Arg) -poly which did not show any adhesive properties when tested on CS coated glass slides based on the above procedure
In contrast to (Orn).

TABLE 1 Poly (Ar on swelled CS coated glass slides performed after 30 minutes at 15 N pressure
g) -TL adhesion test Test pArgTL Maximum force on slide 1 on slide 2 Failure to failureAmt of CS Amt of CS (mg) CS of Amt (mg) (N) Distance (mm)  1 4.7 10 10 21.48 0.45 2 4.7 10 20 12.39 0.33 3 3.8 10 10 12.85 0.42 4 8 20 20 14.23 0.49 5 13.3 35 35 18.3 0.53

TABLE 2 Poly (Arg) on swollen CS coated glass slides performed after 90 minutes at 15N pressure
-TL Adhesion Test Test pArgTL Maximum Force on Slide 2 on Slide 1 Failure to FailureAmt of CS Amt of CS (mg) CS of Amt (mg) (N) Distance (mm)  1 4.4 20 20 9.4 0.48 2 8.2 40 20 13.28 0.74 3 5 10 10 22.59 0.74

[0032]Example 2 Synthesis of Adhesive Based on Polyethylene Glycol  2. an average molecular weight of 5000 daltons and an average of 3.
Poly (ethylene glycol) propyl containing 79 pendant propionic acid groups
Onic acid (sold by Shearwater Polymers, Inc.) was dissolved in dimethylformamide (DMF). DL-homocysteine thiolactone (1.9 equivalents) and 4-
(4-N-maleimidophenyl) -butanoic acid hydrazide (1.9 eq.) At room temperature
It was added with stirring. Cool the resulting mixture to 0 ° C. and add 7.6 eq.
Of ethyl-3 (3-dimethylaminopropyl) carbodiimide was added. 30
After minutes, the reaction mixture was warmed to room temperature and the mixture was further stirred at room temperature for 12 hours. Conclusion
The resulting functional polymer is precipitated by the addition of diethyl ether,
The limer was collected and further dried under vacuum at room temperature. Use dry functional polymer
Until it was stored in the desiccator.

──────────────────────────────────────────────────続 き Continuation of front page (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE ), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE , KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG, US, UZ, VN, YU, ZW (71) Applicant 700 Orthopaedic Drive, Warsaw, IN 46581, U.S.A. S. A. (72) Inventor Dengue Z David David United States, 46032 Indiana, Gold Finch Drive, Carmel, 13722 (72) Inventor Peterson Dale Earl United States, 46032 Indiana, Carmel, Leeds Circle 488 (72) Invention Glancy Todd P. United States, 47728 Indiana, Fairmount, 4240 e-1050 es (no address) (72) Inventor Stap Samuel I United States, 60208 Illinois, Evanston, Apartment 1608, Chicago Avenue 1630 F-term (reference) 4C081 AC04 BA16 CA081 CA191 CA211 CA241 DA11 4J001 DA01 EA33 EE72A EE72C EE85A EE85C JA18 JB07 JB50 4J002 AA031 BG011 BG051 BG071 CF001 CH021 CK021CA03J01 AL01 GB01

Claims (13)

[Claims] 1. The formula: embedded image A tissue adhesive composition having a biocompatible polymer comprising a covalently bonded tissue-reactive substituent. 2. The biocompatible polymer has the formula: —CR ＝ CR′— or —C≡, wherein R and R ′ are independently hydrogen or optionally substituted C ₁ -C ₆ alkyl.
The tissue adhesive composition according to claim 1, comprising a covalently bonded thiol-reactive substituent containing a C- divalent group. 3. The method according to claim 1, wherein the biocompatible polymer is a polyamino acid, a polyethylene glycol copolymer, a polyester, a polyurethane, a polyacrylic acid, a polyhydroxyethyl methacrylate, or a polymethyl methacrylate. Tissue adhesive composition. 4. The tissue adhesive composition according to claim 1, wherein the biocompatible polymer further comprises a covalent tissue-reactive substituent having a boric acid group of the formula: —B (OH) _2. object. 5. The tissue adhesive composition according to claim 1, wherein the biocompatible polymer further comprises a covalent substituent that is substantially cationic at physiological pH. 6. The tissue adhesive composition of claim 4, wherein said biocompatible polymer further comprises a covalent substituent that is substantially cationic at physiological pH. 7. The tissue adhesive composition according to claim 1, wherein the biocompatible polymer has a glass transition temperature of less than about 40 ° C. 8. The tissue adhesive composition according to claim 5, wherein the biocompatible polymer has a glass transition temperature of about 40 ° C. to about 90 ° C. 9. The formula: embedded image And a divalent of the formula: -CR = CR'- or -C≡C-, wherein R and R 'are independently hydrogen or optionally substituted C ₁ -C ₆ alkyl. And at least two covalent substituents selected from the group consisting of: a covalent thiol-reactive substituent comprising a group and a tissue-reactive substituent comprising a borate group of the formula: -B (OH) _2. 3. The tissue adhesive composition of claim 1 or 2 further comprising from about 60% to about 60% by weight of the monomer or oligomer. 10. The tissue adhesive composition according to claim 1, further comprising a biologically active agent. 11. A tissue adhesive composition comprising a biocompatible polymer comprising a covalently bonded tissue reactive substituent having a borate group of the formula: -B (OH) ₂ . 12. A tissue repair method using a biocompatible adhesive to bond adjacent tissue surfaces, wherein the biocompatible adhesive is used as the biocompatible adhesive.
, Claim 4, Claim 5, Claim 6, Claim 7, Claim 8, Claim 9, Claim 10
A method for repairing a tissue, wherein the improvement is to include the adhesive composition according to claim 11. 13. The method of claim 1, further comprising pretreating said adjacent tissue surface with a monomer or oligomer having at least two covalent substituents, wherein one of said at least two covalent substituents has the formula: -B (OH). _And the other is a borate group of the formula: A thiol-reactive substituent, the thiol-reactive substituents are C ₁ -C ₆ alkyl R and R 'are substituted individually hydrogen or optionally formula: -CR = CR'-
13. The method according to claim 12, comprising a divalent group of -C≡C-.