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 - 15 . (canceled) 
     
     
         16 . A device for preparing a crosslinkable composition that crosslinks in situ following administration to a patient to form a heterogeneous, crosslinked biomaterial composition, comprising:
 a first storage containing an aqueous suspension of a biomaterial comprised of a biocompatible polymer containing nucleophilic groups; and   a second storage containing an 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 are each capable of covalently crosslinking the biomaterial but are not reactive with respect to each other,   wherein, the crosslinkable composition is formed upon combining the aqueous suspension of the biomaterial in the first storage and the admixture of the hydrophilic crosslinking agent and the hydrophobic crosslinking agent in the second storage.   
     
     
         17 . The device of  claim 16  wherein the biocompatible polymer in the first storage is: fibrillar collagen, succinylated collagen, methylated collagen, denatured collagen, hyaluronic acid, chondroitin sulfate A, chondroitin sulfate C, dermatan sulfate, keratin sulfate, keratosulfate, chitin, chitosan, heparin or mixtures thereof. 
     
     
         18 . The device of  claim 16  wherein the admixture in the second storage is dry powder. 
     
     
         19 . The device of  claim 16 , wherein the biomaterial has primary amino groups. 
     
     
         20 . The device of  claim 19 , wherein the biomaterial is selected from collagen and glycosaminoglycans. 
     
     
         21 . The device of  claim 20 , wherein the biomaterial is collagen. 
     
     
         22 . The device of  claim 21 , wherein the biomaterial is fibrillar collagen. 
     
     
         23 . The device of  claim 21 , wherein the biomaterial is nonfibrillar collagen. 
     
     
         24 . The device of  claim 16 , wherein said hydrophilic crosslinking agent is PEG succinimidyl glutarate, PEG succinimidyl, PEG succinimidyl succinamide, or PEG succinimidyl carbonate. 
     
     
         25 . The device of  claim 16 , wherein said hydrophilic crosslinking agent is PEG succinimidyl glutarate. 
     
     
         26 . The device of  claim 16 , wherein the hydrophobic crosslinking agent is a hydrophobic polymer derivatized to contain two or more succinimidyl groups. 
     
     
         27 . The device of  claim 26 , wherein said hydrophobic crosslinking agent is selected from disuccinimidyl suberate, bis(sulfosuccinimidyl) suberate, dithiobis(succinimidylpropionate), bis(2-succinimidooxycarbonyloxy) ethyl sulfone, and 3,3′-dithiobis(sulfosuccinimidylpropionate). 
     
     
         28 . The device of  claim 27 , wherein said hydrophobic crosslinking agent is disuccinimidyl suberate.