Bioprosthetic tissue having a reduced propensity for in vivo calcification

Abstract

A bioprosthetic tissue having a reduced propensity to calcify in vivo, the bioprosthetic tissue. The bioprosthetic tissue comprises an aldehyde cross-linked and stressed bioprosthetic tissue comprising exposed calcium, phosphate or immunogenic binding sites that have been reacted with a calcification mitigant. The bioprosthetic tissue has a reduced propensity to calcify in vivo as compared to aldehyde cross-linked bioprosthetic tissue that has not been stressed and reacted with the calcification mitigant.

What is claimed is: 
     
         1 . A method of treating a cross-linked bioprosthetic tissue comprising:
 subjecting the cross-linked bioprosthetic tissue to a first stress cycle, wherein the first stress cycle comprises subjecting the cross-linked bioprosthetic tissue to a pulsed fluid flow to produce acid binding sites; and   exposing the cross-linked bioprosthetic tissue to a first calcium mitigant to couple with the acid binding sites and produce capped acid binding sites.   
     
     
         2 . The method of  claim 1 , wherein the pulsed fluid flow is provided by a solution comprising the first calcium mitigant. 
     
     
         3 . The method of  claim 1 , wherein the exposing is performed after the subjecting. 
     
     
         4 . The method of  claim 1 , further comprising subjecting the cross-linked bioprosthetic tissue to a second stress cycle, wherein the second stress cycle comprises subjecting the cross-linked bioprosthetic tissue to a stress-accelerating environmental parameter selected from the group consisting of: a second pulsed fluid flow, an elevated temperature in the range of 26-65° C., an acidic solution having a pH in the range of 4-7, an alkaline solution having a pH in the range of 8-10, and an oxidizing solution. 
     
     
         5 . The method of  claim 4 , further comprising exposing the cross-linked bioprosthetic tissue to a second calcium mitigant. 
     
     
         6 . The method of  claim 5 , wherein the second calcium mitigant is different from the first calcium mitigant. 
     
     
         7 . The method of  claim 5 , wherein the exposing the cross-linked bioprosthetic tissue to the second calcium mitigant is performed after subjecting the cross-linked bioprosthetic tissue to the second stress cycle. 
     
     
         8 . The method of  claim 4 , wherein the stress-accelerating environmental parameter is the second pulsed fluid flow. 
     
     
         9 . The method of  claim 8 , wherein the second pulsed fluid flow is provided in a range of 4 Hz to 1500 Hz. 
     
     
         10 . The method of  claim 4 , wherein the stress-accelerating environmental parameter is the elevated temperature in the range of 26-65° C. 
     
     
         11 . The method of  claim 4 , wherein the stress-accelerating environmental parameter is the acidic solution having a pH in the range of 4-7. 
     
     
         12 . The method of  claim 4 , wherein the stress-accelerating environmental parameter is the alkaline solution having a pH in the range of 8-10. 
     
     
         13 . The method of  claim 4 , wherein the stress-accelerating environmental parameter is the oxidizing solution. 
     
     
         14 . The method of  claim 1 , wherein the first calcium mitigant is one or more selected from the group consisting of: an amine, an amino acid, an amino sulfonate, a hydrophilic multifunctional polymer, a hydrophobic multifunctional polymer, an α-dicarbonyl, a hydrazide, an N,N-disuccinimidyl carbonate, a carbodiimide, a 2-chloro-1-methylpyridinium iodide (CMPI), an antibiotic, a cell recruiting agent, a hemocompatibility agent, an anti-inflammatory agent, an anti-proliferative agent, an immunogenic suppressing agent, a reducing agent, and a mono-, di- or polyepoxy alkane. 
     
     
         15 . The method of  claim 14 , wherein:
 the first calcium mitigant is an amine; and   the amine is an ethanolamine.   
     
     
         16 . The method of  claim 14 , wherein:
 the first calcium mitigant is an amino sulfonate; and   the amino sulfonate is a taurine.   
     
     
         17 . The method of  claim 1 , wherein:
 the pulsed fluid flow is performed in a solution; and   the solution comprises an aqueous solution, an organic solvent, or an organic buffered solution.   
     
     
         18 . The method of  claim 1 , wherein the bioprosthetic tissue is cross-linked with an aldehyde. 
     
     
         19 . The method of  claim 18 , wherein the aldehyde is a glutaraldehyde. 
     
     
         20 . The method of  claim 1 , wherein the cross-linked bioprosthetic tissue comprises one or more selected from the group consisting of: cardiac valves, blood vessels, skin, dura mater, pericardium, small intestinal submucosa, ligaments, and tendons.