Compositions and systems for forming crosslinked biomaterials and methods of preparation and use

Abstract

Crosslinkable compositions are provided that readily crosslink in situ to provide biocompatible, nonimmunogenic crosslinked materials that may be used as adhesive compositions. The compositions comprise collagen and a plurality of crosslinkable components having reactive functional groups thereon, with the functional groups selected so as to enable inter-reaction between the components, i.e., crosslinking. Methods for preparing and using the compositions are also provided. Exemplary uses include tissue augmentation, biologically active agent delivery, bioadhesion, prevention of adhesions following surgery or injury, and coating of surgically acceptable patches and solid implants, the latter including sutures.

1 - 56 . (canceled) 
     
     
         57 . A composition comprising:
 (a) a first crosslinkable component having m nucleophilic groups, wherein m≧2;   (b) a second crosslinkable component having n electrophilic groups capable of reaction with the m nucleophilic groups to form covalent bonds, wherein n≧2 and m+n≧4; and   (c) a visualization agent,   wherein each of the first and second crosslinkable components is biocompatible, synthetic, and nonimmunogenic, and crosslinking of the composition results in a biocompatible, nonimmunogenic, crosslinked matrix.   
     
     
         58 . The composition of  claim 57  wherein at least one of the first crosslinkable component and the second crosslinkable component is combined with the visualization agent. 
     
     
         59 . The composition of  claim 57  wherein the visualization agent is combined with the crosslinked matrix. 
     
     
         60 . The composition of  claim 57  wherein the visualization agent is an imaging agent. 
     
     
         61 . The composition of  claim 57  wherein the visualization agent is a colorant. 
     
     
         62 . (canceled) 
     
     
         63 . The composition of  claim 57  wherein the each nucleophilic group is independently a thiol, amino or hydroxyl group. 
     
     
         64 . The composition of  claim 57  wherein the electrophilic group is a succinimidyl group, a succinimidyl carbonate group, a maleimidyl group, —COOH, —CHO, 
       
         
           
           
               
               
           
         
         —N═C═O or —SO 2 CH—CH 2 . 
       
     
     
         65 . The composition of  claim 57  wherein m is 4 and n is 4. 
     
     
         66 . The composition of  claim 57  each of the first and second crosslinkable components independently include a hydrophilic polymer. 
     
     
         67 . The composition of  claim 66  wherein the hydrophilic polymer is branched polyalkylene oxide. 
     
     
         68 . The composition of  claim 57  further comprising a therapeutically effective amount of a biologically active agent selected from the group consisting of enzymes, receptor antagonists, receptor agonists, hormones, growth factors, autogenous bone marrow, antibiotics, antimicrobial agents, antibodies, cells and genes. 
     
     
         69 . (canceled) 
     
     
         70 . The composition of  claim 57  wherein one or both of the first and second crosslinkable components are in a dry powder form. 
     
     
         71 . A kit comprising:
 a first container housing a first crosslinkable component having m nucleophilic groups, wherein m≧2, and optionally a first visualization agent;   a second container housing a second crosslinkable component having n electrophilic groups capable of reaction with the m nucleophilic groups to form covalent bonds and optionally a second visualization agent, wherein n≧2 and m+n≧4, and wherein the electrophilic group is independently amino or thiol groups; and   wherein each of the first and second crosslinkable components is biocompatible, synthetic, and nonimmunogenic, and crosslinking of the composition results in a biocompatible, nonimmunogenic, crosslinked matrix.   
     
     
         72 . A composition comprising:
 a) a first crosslinkable component having m nucleophilic groups, wherein m≧2; and   (b) a second crosslinkable component having n electrophilic groups capable of reaction with the m nucleophilic groups to form covalent bonds, wherein n≧4, wherein the first crosslinkable component is a naturally occurring protein or recombinant protein, and the second crosslinkable component includes a synthetic hydrophilic polymer.   
     
     
         73 . The composition of  claim 72  wherein the first crosslinkable component is natural or recombinant albumin, collagen, fibrin or fibrinogen. 
     
     
         74 . The composition of  claim 72  wherein the electrophilic groups are the same or different and independently succinimidyl groups, succinimidyl carbonate groups, or maleimidyl groups. 
     
     
         75 . The composition of  claim 74  wherein the electrophilic groups form one or more covalent bonds with the naturally occurring protein or recombinant protein. 
     
     
         76 . The composition of  claim 72  wherein the synthetic hydrophilic polymer is a branched polyalkylene oxide. 
     
     
         77 . The composition of  claim 76  wherein the second crosslinkable component includes a tetra-functionalized branched polyethylene glycol having a pentaerythritol core. 
     
     
         78 . The composition of  claim 72  further comprising a colorant. 
     
     
         79 . The composition of  claim 72  further comprising a therapeutically effective amount of a biologically active agent. 
     
     
         80 . The composition of  claim 79  wherein the biologically active agent is selected from the group consisting of enzymes, receptor antagonists, receptor agonists, hormones, growth factors, autogenous bone marrow, antibiotics, antimicrobial agents, antibodies, cells and genes. 
     
     
         81 . (canceled) 
     
     
         82 . A device comprising:
 an implant selected from sutures, surgically acceptable patches, artificial blood vessels, artificial heart valves, vascular grafts, vascular stents, vascular stent/graft combinations, bone implants, cartilage implants, artificial joints, bone prostheses, retaining pins, cranial plates, ophthalmic shields, corneal lenticules, breast implants, and drug delivery devices;   a coating composition coated on the implant, wherein the coating composition is formed by crosslinking (a) a first crosslinkable component having m nucleophilic groups, wherein m≧2; (b) a second crosslinkable component having n electrophilic groups, wherein n≧2 and m+n≧4, wherein the m nucleophilic groups and the n electrophilic groups form covalent bonds.   
     
     
         83 . The device of  claim 82 , wherein the nucleophilic groups of the first crosslinkable component are selected from —NH 2 , —NHR 4 , —N(R 4 ) 2 , —SH, —OH, —COOH, —C 6 H 4 —OH, —PH 2 , —PHR 5 , —P(R 5 ) 2 , —NH—NH 2 , —CO—NH—NH 2 , and —C 5 H 4 N, wherein R 4  and R 5  are C 1 -C 12  hydrocarbyl. 
     
     
         84 . The device of  claim 82 , wherein the electrophilic groups of the second crosslinkable component are amino-reactive groups or sulfhydryl-reactive groups. 
     
     
         85 . The device of  claim 84 , wherein the electrophilic groups are selected from carboxylate esters, succinimidyl groups, succinimidyl carbonate groups, maleimidyl groups, carboxylic acids, acid chloride groups, anhydrides, ketones, aldehydes, halides, isocyanates, isothiocyanates, epoxides, activated hydroxyl groups, and olefins. 
     
     
         86 . The device of  claim 82  wherein at least one of the first and second crosslinkable component includes a synthetic hydrophilic polymer. 
     
     
         87 . The device of  claim 86  wherein the synthetic hydrophilic polymer is branched polyalkylene oxide. 
     
     
         88 . The device of  claim 87  wherein the synthetic hydrophilic polymer includes a tetra-functionalized branched polyethylene glycol having a pentaerythritol core. 
     
     
         89 . The device of  claim 82 , wherein the composition further comprises a biologically active agent. 
     
     
         90 . The device of  claim 89 , wherein the biologically active agent is selected from the group consisting of enzymes, receptor antagonists, receptor agonists, hormones, growth factors, autogenous bone marrow, antibiotics, antimicrobial agents, antibodies, cells and genes. 
     
     
         91 . (canceled)