Use of hydrophobic crosslinking agents to prepare crosslinked biomaterial compositions

Abstract

The present invention discloses novel crosslinked biomaterial compositions which are prepared using hydrophobic polymers as a crosslinking agent. Preferred hydrophobic polymers are those that contain two or more reactive succinimidyl groups, including disuccinimidyl suberate, bix(sulfosuccinimidyl)suberate, and dithiobis(succinimidylpropionate). Crosslinked biomaterial compositions prepared using mixtures of hydrophobic and hydrophilic crosslinking agents are also disclosed. The compositions of the present invention can be used to prepare formed implants for use in a variety of medical applications.

1 . A system for preparing a crosslinkable composition that crosslinks in situ following administration to a patient to form a heterogenous, crosslinked biomaterial composition, comprising: 
 an aqueous suspension of a biomaterial comprised of a biocompatible polymer containing nucleophilic groups; and    an admixture of hydrophilic crosslinking agent and a hydrophobic crosslinking agent containing up to about 14 carbon atoms and comprised of a polyacid esterfied with reactive moieties selected from the group consisting of succinimidyl groups and sulfonsuccinimidyl groups, wherein the hydrophilici crosslinking agent and the hydrophobic crosslinking agent are each capable of covalently crosslinking the biomaterial but are not reactive with respect to each other.    
     
     
         2 . A system for preparing an injectable, crosslinkable collagen composition that crosslinks in situ following administration to a patient to form a heterogenous, crosslinked collagen composition, comprising: 
 an aqueous suspension of a biomaterial selected from the group consisting of fibrillar collagen, succinylated collagen, methylated collagen, denatured collagen, hyaluronic acid, chondroitin sulfate A, chondroitin sulfate C, dermatan sulfate, keratin sulfate, keratosulfate, chitin, chitosan, heparin and mixtures thereof;    a dry admixture of a hydrophilic crosslinking agent and a hydrophobic crosslinking agent containing up to about 14 carbon atoms and comprised of a polyacid esterified with reactive moieties selected from the group consisting of succinimidyl groups and sulfosuccinimidyl groups, wherein the hydrophilic crosslinking agent and the hydrophobic crosslinking agent each capable of covalently crosslinking the biomaterial but are not reactive with respect to each other.    
     
     
         3 . A method for introducing an implant of a crosslinked biomaterial composition into the body of a mammalian patient, comprising: 
 (a) admixing (i) an aqueous suspension of a biomaterial comprised of a biocompatible polymer containing nucleophilic groups, (ii) a hydrophilic crosslinking agent, and (iii) a hydrophobic crosslinking agent containing up to about 14 carbon atoms and comprised of a polyacid esterified with reactive moieties selected from the group consisting of succinimidyl groups and sulfosuccinimidyl groups, wherein the hydrophilic crosslinking agent and the hydrophobic crosslinking agent are each capable of covalently crosslinking the biomaterial but are not reactive with respect to each other;    (b) placing the crosslinkable admixture prepared in step (a) into the body of the patient; and    (c) allowing the admixture to crosslink in situ.    
     
     
         4 . The method of  claim 3 , wherein step (b) is carried out by injection.  
     
     
         5 . The method of  claim 4 , wherein the injection is subcutaneous.  
     
     
         6 . The method of  claim 5 , wherein the subcutaneous injection is at a dermal site in need of correction.  
     
     
         7 . The method of  claim 3 , wherein step (b) comprises application of the crosslinkable admixture to a soft tissue site in need of augmentation.  
     
     
         8 . The method of  claim 3 , wherein step (b) comprises application of the crosslinkable admixture to a hard tissue site in need of augmentation.  
     
     
         9 . The method of  claim 3 , wherein the admixture prepared in step (a) further comprises ceramic materials, and step (b) comprises application of the crosslinkable admixture to the stie of a bone defect.  
     
     
         10 . The method of  claim 3 , wherein the admixture prepared in step (a) further comprises ceramic materials, and step (b) comprises application of the crosslinkable admixture to the site of a bone defect.  
     
     
         11 . The method of  claim 3 , wherein the admixture prepared in step (a) further comprises ceramic materials, and step (b) comprises application of the crosslinkable admixture to the stei of a cartilage defect.  
     
     
         12 . A crosslinked implant prepared by the process of  claim 3 .  
     
     
         13 . A method for providing a crosslinked, nonimmunogenic biomaterial coating on the surface of a preformed synthetic implant, comprising: 
 (a) admixing (i) an aqueous suspension of a biomaterial comprised of a biocompatible polymer containing nucleophilic groups, (ii) hydrophilic crosslinking agent, and (iii) a hydrophobic crosslinking agent containing up to about 14 carbon atoms and comprised of a polyacid esterified with reactive moieties selected from the group consisting of succinimidyl groups and sulfosuccinimidyl groups, wherein the hydrophilic crosslinking agent and the hydrophobic crosslinking agent are each capable of covalently crosslinking the biomaterial but are not reactive with respect to each other;    (b) coating a preformed synthetic implant with the crosslinkable admixture prepared in step (a); and    (c) allowing the coating to crosslink in place.    
     
     
         14 . The method of  claim 13 , wherein step (b) is carried out by brushing, painting, extrusion, or dipping.  
     
     
         15 . A nonimmunogenic implant prepared by the process of  claim 13.