Methods for stabilizing a bioprosthetic tissue by chemical modification of antigenic carbohydrates

Abstract

Methods are provided herein for modifying antigenic carbohydrate epitopes within a xenographic bioprosthetic tissue by oxidation of vicinal diols to form aldehydes or acids and subsequence reductive amination of aldehydes to form stable secondary amines, or amidation or esterification of acids to form stable amides or esters. Advantageously, methods provided herein mitigate the antigenicity of the bioprosthetic tissue while leaving the overall tissue structure substantially undisturbed, and thereby enhance the durability, safety and performance of the bioprosthetic implant.

What is claimed: 
     
         1 . A method for improving the performance of a bioprosthetic implant, the method comprising:
 treating a bioprosthetic tissue with an oxidizing agent that selectively oxidizes antigenic carbohydrates having vicinal diols to produce free aldehyde or acid moieties on the antigenic carbohydrate.   
     
     
         2 . The method of  claim 1 , further comprising fixing the bioprosthetic tissue with a fixation agent before treating the bioprosthetic tissue with the oxidizing agent. 
     
     
         3 . The method of  claim 2 , wherein the fixation agent is selected from the group consisting of: an aldehyde, a formaldehyde, a dialdehyde, a glutaraldehyde, a polyaldehyde, a diisocyanate, a hexamethylene diisocyanate, a diacid, a diamine with a carbodiimide, a 1-ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride (EDC), a dipeoxy, and combinations thereof. 
     
     
         4 . The method of  claim 1 , further comprising treating the bioprosthetic tissue with a bioburden reduction solution before treating the bioprosthetic tissue with the oxidizing agent. 
     
     
         5 . The method of  claim 4 , wherein the bioburden reduction solution comprises formaldehyde. 
     
     
         6 . The method of  claim 1 , further comprising treating the bioprosthetic tissue with a capping agent after treating the bioprosthetic tissue with the oxidizing agent. 
     
     
         7 . The method of  claim 6 , wherein the capping agent blocks, removes or alters a functional group that would have an adverse effect on the bioprosthesis properties. 
     
     
         8 . The method of  claim 7 , wherein the capping agent is a primary amine or an alcohol which combines with the aldehyde or acid to form an imine, amide or ester. 
     
     
         9 . The method of  claim 7 , wherein the capping agent is selected from the group consisting of: an ethanolamine, a taurine, an amino sulfate, a dextran sulfate, a chrondroitin sulfate, a polyvinyl alcohol, a polyethyleneimine, an alpha-dicarbonyl, an amino acid, a glycine, a lysine, an alkoxy alkyl amine, a 2-methoxyethylamine, an alkyl amine, a hydroxylamine, an aminoether, an amino sulfonate, an ethylamine, a propylamine, a N-hydroxysuccinamide (NHS), a N-hydroxysulfosuccinamide (NHSS), a hydrazide, an oxirane, and combinations thereof. 
     
     
         10 . The method of  claim 1 , further comprising treating the bioprosthetic tissue with a stabilizing agent. 
     
     
         11 . The method of  claim 10 , wherein the stabilizing agent reacts with the free aldehyde or acids or is a reducing agent. 
     
     
         12 . The method of  claim 10 , wherein the stabilizing agent is one or more selected from the group consisting of: a sodium borohydride, a sodium cyanoborohydride, a lithium aluminum hydride, a carbodiimide, a 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), a pyridine, a 2-chloro 1-methylpyridinium iodide (CMPI), and a Mukaiyama condensation reagent. 
     
     
         13 . The method of  claim 1 , wherein the oxidizing agent is a periodate or acetate. 
     
     
         14 . The method of  claim 13 , wherein the periodate is a sodium periodate. 
     
     
         15 . The method of  claim 1 , further comprising treating the tissue with a secondary oxidizing agent to convert the aldehydes to acids. 
     
     
         16 . The method of  claim 15 , wherein the secondary oxidizing agent is a sodium chlorite or hydrogen peroxide. 
     
     
         17 . The method of  claim 16 , further comprising capping the acids with a capping agent to form an ester, the capping agent being selected from the group consisting of N-hydroxysuccinamide and N-hydroxysulfosuccinamide. 
     
     
         18 . The method of  claim 17 , further comprising treating the tissue with a carbodiimide stabilizing agent to convert the ester to an amide. 
     
     
         19 . The method of  claim 18 , wherein the carbodiimide stabilizing agent is 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC). 
     
     
         20 . The method of  claim 1 , further comprising decellularizing the bioprosthetic tissue before treating the bioprosthetic tissue with the oxidizing agent.