Double cross-linkage process to enhance post-implantation bioprosthetic tissue durablity

Abstract

Bioprosthetic tissues and methods for making same, comprising fixing bioprosthetic implant tissue by treatment with 0.1 to 10 wt. % glutaraldehyde at elevated temperature, capping said fixed tissue by treatment with a diamine crosslinking agent, and treating said capped tissue with about 0.6 wt. % glutaraldehyde.

What is claimed is: 
     
         1 . A packaged bioprosthetic device comprising:
 a dry collagenous tissue comprising at least first and second sets of crosslinkages, wherein the first set of crosslinkages is provided between free amine functional groups on the collagenous tissue, wherein the second set of crosslinkages is provided between free aldehyde functional groups, and wherein at least a portion of the water initially present in the dry collagenous tissue has been replaced with glycerol; and   a packaging containing the dry collagenous tissue.   
     
     
         2 . The packaged bioprosthetic device of  claim 1 , wherein the first set of crosslinkages is provided by reaction of a first dialdehyde with the free amine functional groups. 
     
     
         3 . The packaged bioprosthetic device of  claim 2 , wherein the first dialdehyde is glutaraldehyde. 
     
     
         4 . The packaged bioprosthetic device of  claim 1 , wherein the second set of crosslinkages is provided by reaction of a diamine with the free aldehyde functional groups. 
     
     
         5 . The packaged bioprosthetic device of  claim 4 , wherein the diamine is one or more selected from the group consisting of: a polyetheramine and a lysine. 
     
     
         6 . The packaged bioprosthetic device of  claim 4 , wherein the second set of crosslinkages includes Schiff bases. 
     
     
         7 . The packaged bioprosthetic device of  claim 6 , wherein the Schiff bases are reduced by a reducing agent. 
     
     
         8 . The packaged bioprosthetic device of  claim 7 , wherein the reducing agent is a borohydride. 
     
     
         9 . The packaged bioprosthetic device of  claim 8 , wherein the borohydride is one or more selected from the group consisting of: sodium borohydride, potassium borohydride and cyanoborohydride. 
     
     
         10 . The packaged bioprosthetic device of  claim 4 , further comprising a third set of crosslinkages. 
     
     
         11 . The packaged bioprosthetic device of  claim 10 , wherein the third set of crosslinkages is provided between free amine functional groups on the collagenous tissue, free amine functional groups of the diamine, or free amine functional groups on the collagenous tissue and the diamine. 
     
     
         12 . The packaged bioprosthetic device of  claim 11 , wherein the third set of crosslinkages is provided by reaction of a second dialdehyde with the free amine functional groups on the collagenous tissue, the free amine functional groups of the diamine, or both. 
     
     
         13 . The packaged bioprosthetic device of  claim 12 , wherein the second dialdehyde is glutaraldehyde. 
     
     
         14 . The packaged bioprosthetic device of  claim 1 , wherein the second set of crosslinkages is provided between free aldehyde functional groups on the collagenous tissue. 
     
     
         15 . The packaged bioprosthetic device of  claim 1 , wherein the collagenous tissue is selected from the group consisting of bovine pericardium, porcine tissue, blood vessels, skin, dura mater, pericardium, small intestinal submucosa, tissue heart valves, ligaments, and tendons. 
     
     
         16 . The packaged bioprosthetic device of  claim 1 , wherein the collagenous tissue is a native valve treated and mounted as a whole valve. 
     
     
         17 . The packaged bioprosthetic device of  claim 1 , wherein the bioprosthetic device is a bioprosthetic heart valve and the dry collagenous tissue form leaflets of the bioprosthetic heart valve. 
     
     
         18 . The packaged bioprosthetic device of  claim 17 , wherein the packaged dry collagenous tissue is sterilized. 
     
     
         19 . The packaged bioprosthetic device of  claim 18 , wherein the packaged dry collagenous tissue is sterilized with ethylene oxide. 
     
     
         20 . The packaged bioprosthetic device of  claim 19 , wherein the packaging comprises a double sterile barrier packaging.