Capping Bioprosthetic Tissue to Reduce Calcification

• US 20090164005A1
• Filed: 12/18/2008
• Published: 06/25/2009
• Est. Priority Date: 12/21/2007
• Status: Active Grant

• Current Assignee: Edwards Lifesciences Corporation
• Original Assignee: Edwards Lifesciences Corporation
• Inventors: Dobler, Darin, Dove, Jeffery, Wright, Gregory A., Davidson, Jim
• Granted Patent: US 8,357,387 B2
• Time in Patent Office: Days
• US Class Current: 623/2.130
• CPC Class Codes: A61F 2/0095 Packages or dispensers for prostheses or other implants for intraocular lenses A61F2/1691; for dental surgery A61C19/02
• CPC Class Codes: A61F 2/2412 with soft flexible valve members, e.g. tissue valves shaped like natural valves check valves with flexible valve members in general F16K15/14
• CPC Class Codes: A61F 2/2415 Manufacturing methods
• CPC Class Codes: A61F 2/2418 Scaffolds therefor, e.g. support stents
• CPC Class Codes: A61L 2400/02 Treatment of implants to prevent calcification or mineralisation in vivo
• CPC Class Codes: A61L 2430/20 for reconstruction of the heart, e.g. heart valves
• CPC Class Codes: A61L 27/3604 characterised by the human or animal origin of the biological material, e.g. hair, fascia, fish scales, silk, shellac, pericardium, pleura, renal tissue, amniotic membrane, parenchymal tissue, fetal tissue, muscle tissue, fat tissue, enamel
• CPC Class Codes: A61L 27/3625 Vascular tissue, e.g. heart valves
• CPC Class Codes: A61L 27/3629 Intestinal tissue, e.g. small intestinal submucosa
• CPC Class Codes: A61L 27/3687 characterised by the use of chemical agents in the treatment, e.g. specific enzymes, detergents, capping agents, crosslinkers, anticalcification agents
• CPC Class Codes: A61L 27/3691 characterised by physical conditions of the treatment, e.g. applying a compressive force to the composition, pressure cycles, ultrasonic/sonication or microwave treatment, lyophilisation
• CPC Class Codes: A61L 27/507 for artificial blood vessels apparatus for applying cells on a blood vessel prosthesis A61F2/062

Abstract

A treatment for bioprosthetic tissue used in implants or for assembled bioprosthetic heart valves to reduce in vivo calcification. The method includes applying a calcification mitigant such as a capping agent or an antioxidant to the tissue to specifically inhibit oxidation in tissue. Also, the method can be used to inhibit oxidation in dehydrated tissue. The capping agent suppresses the formation of binding sites in the tissue that are exposed or generated by the oxidation and otherwise would, upon implant, attract calcium, phosphate, immunogenic factors, or other precursors to calcification. In one method, tissue leaflets in assembled bioprosthetic heart valves are pretreated with an aldehyde capping agent prior to dehydration and sterilization.

Claims

1. A method of mitigating calcification in bioprosthetic implant tissue, comprising:

a) treating bioprosthetic implant tissue with a capping agent that reacts with functional groups on said tissue, and

b) dehydrating the tissue with a non-aqueous solution.

2. The method of claim 1, wherein said functional groups are aldehyde groups.

3. The method of claim 1, wherein said functional groups are carboxylic acid groups.

4. The method of claim 1, wherein the capping agent is selected from the group consisting of:

an amine,

an amino acid,

an amino sulfonate,

a hydrophilic multifunctional polymer,

a hydrophobic multifunctional polymer,

α

-dicarbonyl,

a hydrazide,

a N,N-disuccinimidyl carbonate,

a carbodiimide,

2-chloro-1-methylpyridinium iodide (CMPI),

an antibiotic,

a cell recruiting agent,

a hemocompatibility agent,

an antiinflamatory agent,

an antiproliferative agent,

an immunogenic suppressing agent,

a short chain carbohydrate,

a reducing agent, and

a mono-, di- or polyepoxy alkane.

5. The method of claim 1, wherein the capping agent is delivered in a) an aqueous solution, b) an organic solvent, c) an anhydrous, polyhydric alcohol solution;

or d) mixtures thereof.

6. The method of claim 1, wherein said tissue comprises pre-cut heart valve leaflets mounted and treated as a whole valve.

7. The method of claim 1, wherein said tissue comprises bulk sheets of tissue.

8. The method of claim 1, wherein said capped tissue is dehydrated in a glycerol solution.

9. The method of claim 1, wherein said capped tissue is dehydrated in a glycerol/ethanol solution.

10. The method of claim 1, where the dehydration solution contains a water-soluble wax.

11. The method of claim 1, wherein the capping agent can react with calcium, phosphate, or immunogenic factor binding sites on the tissue.

12. The method of claim 1, wherein the capping agent prevents oxidative damage from free radicals or ionizing radiation.

13. A bioprosthetic implant tissue, comprising:

a) bioprosthetic implant tissue that has been treated with a capping agent which reacts with functional groups on said tissue, and

b) dehydrated with a non-aqueous solution.

14. The tissue of claim 13, wherein said functional groups are aldehyde groups.

15. The tissue of claim 13, wherein said functional groups are carboxylic acid groups.

16. The tissue of claim 13, wherein the capping agent is selected from the group consisting of:

an amine,

an amino acid,

an amino sulfonate,

a hydrophilic multifunctional polymer,

a hydrophobic multifunctional polymer,

α

-dicarbonyl,

a hydrazide,

a N,N-disuccinimidyl carbonate,

a carbodiimide,

2-chloro-1-methylpyridinium iodide (CMPI),

an antibiotic,

a cell recruiting agent,

a hemocompatibility agent,

an antiinflamatory agent,

an antiproliferative agent,

an immunogenic suppressing agent,

a short chain carbohydrate,

a reducing agent, and

a mono-, di- or polyepoxy alkane.

17. The tissue of claim 13, wherein the capping agent is delivered in a) an aqueous solution, b) an organic solvent, c) an anhydrous, polyhydric alcohol solution;

or mixtures thereof.

18. The tissue of claim 13, which comprises pre-cut heart valve leaflets mounted and treated as a whole valve.

19. The tissue of claim 13, which comprises bulk sheets of tissue.

20. The tissue of claim 13, wherein said capped tissue is dehydrated in a glycerol solution.

21. The tissue of claim 13, wherein said capped tissue is dehydrated in a glycerol/ethanol solution.

22. The tissue of claim 13, where the dehydration solution contains a water-soluble wax.

23. The tissue of claim 13, wherein the capping agent can react with calcium, phosphate, or immunogenic factor binding sites on the tissue.

24. The tissue of claim 13, wherein the capping agent prevents oxidative damage from free radicals or ionizing radiation.

25. A bioprosthetic heart valve, comprising:

bioprosthetic implant tissue that has been treated with a capping agent,

wherein, said tissue is dehydrated with a glycerol solution.

26. The bioprosthetic heart valve of claim 25, wherein said heart valve is a percutaneous heart valve, transapical heart valve, or transfemoral heart valve.