Crosslinked human or animal tissue products and their methods of manufacture and use

Abstract

Degradable bioprostheses made of collagen-based material having amine-based and ester-based crosslinks are provided, as are methods for their formation and use. Some embodiments of the present invention are directed towards a method of controlling the ratio of amine-based crosslinks to ester-based crosslinks within a collagen-based material to provide a tailorably crosslinked collagen-based material. Some embodiments provide a method of making a degradable bioprosthesis involving controlling crosslinking to afford a degradable bioprosthesis that is partially crosslinked. By controlling the ratio of amine-based to ester-based crosslinks, by controlling the level of crosslinking, or by controlling both of these features, degradable bioprostheses with tailored degradation rates can be synthesized. Some embodiments of degradable bioprostheses have degradation rates that are tailored to allow their use in particular medical applications. Some embodiments are directed towards methods of use degradable bioprostheses in wound healing, tissue repair, and tissue supplementation.

What is claimed is: 
     
         1 . A degradable bioprosthesis comprising:
 a tailorably crosslinked collagen-based material,   wherein the collagen-based material comprises collagen strands that further comprise amine-based crosslinks, ester-based crosslinks, and free amines (—NH 2 );   wherein the amount of free amines on the collagen strands is between about 50% and about 85% relative to the total amount of free amines (—NH 2 ) prior to crosslinking; and   the tailorably crosslinked collagen-based material has a degradation rate between 0.2% to 1.0% per hour when subjected to a pronase digestion assay.   
     
     
         2 . The degradable bioprosthesis of  claim 1 , wherein the collagen strands are derived from animal or human pericardium. 
     
     
         3 . The degradable bioprosthesis of  claim 1 , wherein the collagen strands are derived from fascia, tendon, or cartilage. 
     
     
         4 . The degradable bioprosthesis of  claim 1 , having a shrinkage temperature (Ts) above about 70° C. 
     
     
         5 . The degradable bioprosthesis of  claim 1 , having a shrinkage temperature (Ts) between 72.54° C. and 77.22° C. 
     
     
         6 . The degradable bioprosthesis of  claim 1 , wherein the shrinkage temperature is proportional to the amount of free amines on the collagen strands. 
     
     
         7 . The degradable bioprosthesis of  claim 1 , wherein the degradation rate is proportional to the amount of free amines on the collagen strands. 
     
     
         8 . The degradable bioprosthesis of  claim 1 , wherein the ratio of amine-based crosslinks to ester-based crosslinks is about 100:1 to about 1:100. 
     
     
         9 . The degradable bioprosthesis of  claim 1 , wherein the degradable bioprosthesis comprises a flexible sheet. 
     
     
         10 . The degradable bioprosthesis of  claim 9 , wherein the flexible sheet is between about 1 cm 2  and about 500 cm 2 . 
     
     
         11 . The degradable bioprosthesis of  claim 9 , wherein the flexible sheet is treated with antimicrobial agent. 
     
     
         12 . The degradable prosthesis of  claim 1 , wherein the amine-based crosslinks are represented by Crosslink A and wherein the ester-based crosslinks are represented by Crosslink B: 
       
         
           
           
               
               
           
         
         wherein: 
            indicates collagen strands; 
       
       
         
           
           
               
               
           
         
         R 3  and R 4  are independently selected from the group consisting of —CH 2 —O—(CH 2 ) n —O—CH 2 — and —CH 2 —(O(CH 2 ) n ) m —O—CH 2 —, and 
       
       n and m are independently an integer from 1-6. 
     
     
         13 . A method of treating a tissue defect comprising:
 positioning the degradable bioprosthesis of  claim 1  at, over, or into the tissue defect.   
     
     
         14 . The method of  claim 13 , wherein the tissue defect is a defect selected from the group consisting of a tendon defect, a ligament defect, vaginal prolapse, a hernia, a tissue defect that causes urinary incontinence, a gum defect, an organ defect, a tissue defect that results from bariatric surgery, and a wound. 
     
     
         15 . A method of preparing the degradable bioprosthesis of  claim 1 , comprising:
 providing a collagen-based material;   contacting the collagen-based material with a first buffered solution with a pH between about 8.0 to about 10.5 for a first period of time to provide a treated collagen-based material, wherein the first buffered solution comprises a concentration of a first crosslinking agent;   contacting the treated collagen-based material with a second buffered solution with a pH between about 3.0 to about 5.5 for a second period of time to provide a tailorably crosslinked collagen-based material, wherein the second buffered solution comprises a concentration of a second crosslinking agent; and   isolating the tailorably crosslinked collagen-based material to provide a degradable bioprosthesis.   
     
     
         16 . The method of  claim 15 , wherein the concentration of each of the first crosslinking agent and the second crosslinking agent is independently selected to be between about 1% w/v to about 10% w/v. 
     
     
         17 . A crosslinked collagen-based material comprising Crosslink A, Crosslink B, and free amines (—NH 2 ): 
       
         
           
           
               
               
           
         
         wherein: 
            indicates collagen strands; 
       
       
         
           
           
               
               
           
         
         R 3  and R 4  are independently selected from the group consisting of —CH 2 —O—(CH 2 ) n —O—CH 2 — and —CH 2 —(O(CH 2 ) n ) m —O—CH 2 —, 
         n and m are independently an integer from 1-6, and 
         the amount of free amines (—NH 2 ) on the collagen strands is between 50% and 85% relative to the total amount of free amines (-NH 2 ) prior to crosslinking. 
       
     
     
         18 . The crosslinked collagen-derived material of  claim 17 , wherein R 3  and R 4  are the same. 
     
     
         19 . The crosslinked collagen-based material of  claim 17 , wherein the ratio of Crosslink A and Crosslink B is from about 70:30 to about 30:70. 
     
     
         20 . The crosslinked collagen-derived material of  claim 17 , wherein the crosslinked collagen-derived material has a degradation rate between about 0.2% to about 1.1% per hour when subjected to a pronase digestion assay.