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Kafe 바로가기국가/구분 | United States(US) Patent 등록 |
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국제특허분류(IPC7판) |
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출원번호 | US-0135507 (2008-06-09) |
등록번호 | US-9101691 (2015-08-11) |
발명자 / 주소 |
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출원인 / 주소 |
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대리인 / 주소 |
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인용정보 | 피인용 횟수 : 0 인용 특허 : 245 |
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-impla
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.
1. A method of treating bioprosthetic implant tissue to reduce in vivo calcification, comprising: at least partially cross-linking bioprosthetic implant tissue with glutaraldehyde or other aldehyde containing agents; then stressing the cross-linked tissue by repeatedly flexing it, wherein the stress
1. A method of treating bioprosthetic implant tissue to reduce in vivo calcification, comprising: at least partially cross-linking bioprosthetic implant tissue with glutaraldehyde or other aldehyde containing agents; then stressing the cross-linked tissue by repeatedly flexing it, wherein the stressing is performed to expose potential binding sites for calcification; and applying a calcification mitigant to the stressed, cross-linked tissue, thereby reducing in vivo calcification of the bioprosthetic implant. 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 containing two or more reactive functional groups specific for tissue functional groups produced by the stressing. 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 step of stressing comprises subjecting the bioprosthetic implant tissue to pulsed fluid flow to cause the tissue to repeatedly flex. 10. The method of claim 9, wherein the step of stressing comprises subjecting the tissue to at least 100 cycles of the pulsed fluid flow. 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 performed 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 performed 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 performed 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 performed multiple times. 23. The method of claim 1, wherein the steps of first stressing the tissue and then applying a calcification mitigant thereto are performed at least twice with different calcification mitigants. 24. A method of treating bioprosthetic implant tissue to reduce in vivo calcification, comprising: cyclically stressing a glutaraldehyde or other aldehyde-fixed bioprosthetic implant tissue by repeatedly flexing it to produce additional acid binding sites until the rate of acid production in the bioprosthetic implant tissue decreases by at least 10%; then applying a calcification mitigant to the stressed tissue, thereby reducing in vivo calcification of the bioprosthetic implant. 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 to cause the tissue to repeatedly flex. 26. The method of claim 24, wherein the step of stressing is performed 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 containing two or more reactive functional groups specific for tissue functional groups produced by the stressing. 30. A method of treating a bioprosthetic heart valve to reduce in vivo calcification, comprising: mounting a bioprosthetic heart valve comprising a pericardial tissue in a simulated fluid flow system; subjecting the bioprosthetic heart valve to at least 100 cycles of pulsed fluid flow to cause the pericardial tissue to repeatedly flex and to produce additional acid binding sites on the pericardial tissue; and applying a calcification mitigant to the bioprosthetic heart valve, thereby reducing in vivo calcification of the bioprosthetic heart valve. 31. The method of claim 30, wherein the bioprosthetic heart valve is subjected to at least 100,000 cycles of the pulsed fluid flow. 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 performed multiple times. 33. The method of claim 30, wherein the steps of subjecting the bioprosthetic heart valve to pulsed fluid flow and applying a calcification mitigant thereto are performed at least twice with different calcification mitigants. 34. The method of claim 30, wherein the step of subjecting is performed 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 containing two or more reactive functional groups specific for tissue functional groups produced by the subjecting. 37. The method of claim 1, wherein the calcification mitigant comprises a capping agent, where the capping agent is an amine. 38. The method of claim 24, wherein the calcification mitigant comprises a capping agent, where the capping agent is an amine. 39. The method of claim 30, wherein the step of subjecting the bioprosthetic heart valve to pulsed fluid flow and applying a calcification mitigant thereto are performed simultaneously. 40. The method of claim 24, wherein the bioprosthetic implant tissue is pericardium. 41. A method of treating a biological implant tissue to reduce in vivo calcification comprising: at least partially-crosslinking biological implant tissue with glutaraldehyde or other aldehyde containing agents; stressing the biological implant tissue by subjecting the tissue to pulsed fluid flow to cause the tissue to repeatedly flex and to produce acid binding sites on the tissue; and applying a calcification mitigant to the tissue, thereby reducing in vivo calcification of the biological implant. 42. The method of claim 41, wherein the stressing comprises subjecting the tissue to at least 100 cycles of the pulsed fluid flow. 43. The method of claim 42, wherein the stressing comprises subjecting the tissue to at least 100,000 cycles of the pulsed fluid flow. 44. The method of claim 41, wherein the stressing comprises subjecting the biological implant tissue to at least one stress-accelerating environmental parameter. 45. The method of claim 41, wherein the stressing is performed at least until the rate of acid production in the biologic implant tissue decreases by at least 10%. 46. The method of claim 41, wherein the calcification mitigant is provided in one or a combination of an aqueous solution, an organic solvent, and an organic buffered solution. 47. The method of claim 41, wherein the calcification mitigant comprises a capping agent solution having at least one constituent that binds calcium, phosphate, or immunogenic factor binding sites. 48. The method of claim 41, wherein the calcification mitigant comprises a linking agent comprising a long elastic molecule containing two or more reactive functional groups. 49. The method of claim 41, 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 hydrazide, a N,N-disuccimidyl carbonate, a carbodiimide, 2-chloro-1-methylpyridinium iodide (CMPI), an antibiotic, a cell recruiting agent, a hemocompatibility agent, an anti-inflammatory agent, an antiproliferative agent, an immunogenic suppressing agent, a reducing agent, and a mono-, di- or polyepoxy alkane. 50. The method of claim 41, wherein the steps of stressing the tissue and then applying the calcification mitigant are performed multiple times.
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