METHODS FOR PRE-STRESSING AND CAPPING BIOPROSTHETIC TISSUE

• US 20080302372A1
• Filed: 06/09/2008
• Published: 12/11/2008
• Est. Priority Date: 06/11/2007
• Status: Active Grant

• Current Assignee: Edwards Lifesciences Corporation
• Original Assignee: Edwards Lifesciences Corporation
• Inventors: Dobler, Darin, Davidson, Jim, Dove, Jeff
• Granted Patent: US 9,101,691 B2
• Time in Patent Office: Days
• US Class Current: 128/898
• 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 2210/0004 bioabsorbable
• CPC Class Codes: A61F 2210/0076 multilayered, e.g. laminated structures
• 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 2430/40 Preparation and treatment of biological tissue for implantation, e.g. decellularisation, cross-linking
• CPC Class Codes: A61L 27/3625 Vascular tissue, e.g. heart valves
• CPC Class Codes: A61L 27/3683 subjected to a specific treatment prior to implantation, e.g. decellularising, demineralising, grinding, cellular disruption/non-collagenous protein removal, anti-calcification, crosslinking, supercritical fluid extraction, enzyme treatment
• 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 is disclosed. The method includes preconditioning, pre-stressing, or pre-damaging fixed bioprosthetic tissue in a manner that mimics the damage associated with post-implant use, while, and/or subsequently applying a calcification mitigant such as a capping agent or a linking agent to the damaged tissue. The capping agent suppresses the formation of binding sites in the tissue that are exposed or generated by the damage process (service stress) and otherwise would, upon implant, attract calcium, phosphate, immunogenic factors, or other precursors to calcification. The linking agent will act as an elastic reinforcement or shock-absorbing spring element in the tissue structure at the site of damage from the pre-stressing. In one method, tissue leaflets in assembled bioprosthetic heart valves are preconditioned by simulating actual flow conditions for a predetermined number of cycles, during or after which the valve is exposed to the capping agent.

Claims

1. A method of treating bioprosthetic implant tissue to reduce in vivo calcification, comprising:

at least partially cross-linking bioprosthetic implant tissue;

then

stressing the cross-linked tissue; and

applying a calcification mitigant to the stressed, cross-linked tissue.

2. The method of claim 1, wherein the calcification mitigant comprises a capping agent solution having at least one constituent that can bind to calcium, phosphate, or immunogenic factor binding sites.

3. The method of claim 1, wherein the calcification mitigant comprises a linking agent solution including a long elastic molecule.

4. The method of claim 1, wherein the calcification mitigant comprises a capping agent 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 hydrazides,

a N,N-disuccinimidyl carbonate,

a carbodiimide,

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

an antibiotic,

a cell recruiting agent,

a hemocompatibility agent,

an antiinflammatory agent,

an antiproliferative agent,

an immunogenic suppressing agent,

a reducing agent, and

a mono-, di- or polyepoxy alkane.

5. The method of claim 1 where the calcification mitigant is delivered in one or a combination of the selected solutions:

an aqueous solution,

an organic solvent, and

an organic buffered solution.

6. The method of claim 1 where the tissue is fully cross-linked prior to stressing.

7. The method of claim 1 where the tissue comprises pre-cut heart valve leaflets mounted and flexed in a suitable flow producing apparatus.

8. The method of claim 1 where the tissue comprises bulk sheets of tissue flexed in a suitable apparatus.

9. The method of claim 1, wherein the bioprosthetic implant tissue comprises a bioprosthetic heart valve, and the step of stressing comprises subjecting the heart valve to pulsed fluid flow therethrough.

10. The method of claim 9, wherein the heart valve is subjected to pulsed fluid flow for at least 100 cycles.

11. The method of claim 9, wherein the step of stressing comprises subjecting the bioprosthetic implant tissue to a simulated post-implant physiological environment.

12. The method of claim 9, wherein the step of stressing comprises subjecting the bioprosthetic implant tissue to at least one stress-accelerating environmental parameter.

13. The method of claim 12 wherein the stress-accelerating environmental parameter comprises rapid pulsed fluid flow in a range of 4-1500 Hz.

14. The method of claim 12 wherein the stress-accelerating environmental parameter is an elevated temperature range of 26-65°

C.

15. The method of claim 12 wherein the stress-accelerating environmental parameter is an acidic solution of pH of 4-7.

16. The method of claim 12 wherein the stress-accelerating environmental parameter is an alkaline solution of pH 8-10.

17. The method of claim 12 wherein the stress-accelerating environmental parameter is an oxidizing solution.

18. The method of claim 12 wherein the stress-accelerating environmental parameter comprises at least two selected from the group consisting of:

rapid pulsed fluid flow in a range of 4-1500 Hz;

an elevated temperature range of 26-65°

C.;

an acidic solution of pH of 4-7;

an alkaline solution of pH 8-10; and

an oxidizing solution.

19. The method of claim 1 wherein the step of stressing is done until the newly exposed sites to be capped on the bioprosthetic tissue increase by at least 10%.

20. The method of claim 1 wherein the step of stressing is done at least until the level of damage in the bioprosthetic implant tissue increases by about 10%.

21. The method of claim 1 wherein the step of stressing is done at least until the rate of acid production in the bioprosthetic implant tissue decreases by about 10%.

22. The method of claim 1, wherein the steps of first stressing the tissue and then applying a calcification mitigant thereto are done multiple times.

23. The method of claim 1, wherein the steps of first stressing the tissue and then applying a calcification mitigant thereto are done at least twice with different calcification mitigants.

24. A method of treating bioprosthetic implant tissue to reduce in vivo calcification, comprising:

cyclic stressing the bioprosthetic implant tissue until the rate of acid production in the bioprosthetic implant tissue decreases by about 10%;

then

applying a calcification mitigant to the stressed tissue.

25. The method of claim 24, wherein the bioprosthetic implant tissue comprises a bioprosthetic heart valve, and the step of stressing comprises subjecting the heart valve to pulsed fluid flow therethrough.

26. The method of claim 24, wherein the step of stressing is done until the rate of increase of the acid level of the bioprosthetic implant tissue levels off.

27. The method of claim 24, wherein the calcification mitigant comprises a capping agent solution having at least one constituent that can bind to calcium or phosphate, and/or immunogenic binding sites.

28. The method of claim 24, wherein the calcification mitigant comprises a capping agent 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 hydrazides,

a N,N-disuccinimidyl carbonate,

a carbodiimide,

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

an antibiotic,

a cell recruiting agent,

a hemocompatibility agent,

an antiinflammatory agent,

an antiproliferative agent,

an immunogenic suppressing agent,

a reducing agent, and

a mono-, di- or polyepoxy alkane.

29. The method of claim 24, wherein the calcification mitigant comprises a linking agent solution including a long elastic molecule.

30. A method of treating a bioprosthetic heart valve to reduce in vivo calcification, comprising:

mounting a bioprosthetic heart valve in a simulated fluid flow system;

subjecting the bioprosthetic heart valve to pulsed fluid flow for at least 100 cycles;

then

applying a calcification mitigant to the bioprosthetic heart valve.

31. The method of claim 30, wherein the bioprosthetic heart valve is subjected to pulsed fluid flow for at least 100,000 cycles.

32. The method of claim 30, wherein the steps of first subjecting the bioprosthetic heart valve to pulsed fluid flow and then applying a calcification mitigant thereto are done multiple times.

33. The method of claim 30, wherein the steps of first subjecting the bioprosthetic heart valve to pulsed fluid flow and then applying a calcification mitigant thereto are done at least twice with different calcification mitigants.

34. The method of claim 30, wherein the step of subjecting is done until the rate of increase of the acid level of the bioprosthetic implant tissue levels off.

35. The method of claim 30, wherein the calcification mitigant comprises a capping agent solution having at least one constituent that can bind to calcium, phosphate, or immunogenic factor binding sites.

36. The method of claim 30, wherein the calcification mitigant comprises a linking agent solution including a long elastic molecule.