CA2344061A1 - Crosslinking of bioprosthetic material to mitigate post-implantation calcification - Google Patents

Crosslinking of bioprosthetic material to mitigate post-implantation calcification Download PDF

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Publication number
CA2344061A1
CA2344061A1 CA002344061A CA2344061A CA2344061A1 CA 2344061 A1 CA2344061 A1 CA 2344061A1 CA 002344061 A CA002344061 A CA 002344061A CA 2344061 A CA2344061 A CA 2344061A CA 2344061 A1 CA2344061 A1 CA 2344061A1
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Canada
Prior art keywords
bioprosthesis
solution
degrees
biological tissue
weight
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CA002344061A
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French (fr)
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CA2344061C (en
Inventor
Crystal M. Cunanan
Lillian Quintero
Michael N. Helmus
Christine Loshbaugh
Chris H. Sarner
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Edwards Lifesciences Corp
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Individual
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
    • A61L27/3683—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix 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
    • A61L27/3691—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix 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 characterised by physical conditions of the treatment, e.g. applying a compressive force to the composition, pressure cycles, ultrasonic/sonication or microwave treatment, lyophilisation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
    • A61L2/0005—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts
    • A61L2/0082—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts using chemical substances
    • A61L2/0088—Liquid substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
    • A61L27/3604—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
    • A61L27/3641—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix characterised by the site of application in the body
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
    • A61L27/3641—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix characterised by the site of application in the body
    • A61L27/3645—Connective tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
    • A61L27/3683—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
    • A61L27/3683—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix 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
    • A61L27/3687—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix 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 characterised by the use of chemical agents in the treatment, e.g. specific enzymes, detergents, capping agents, crosslinkers, anticalcification agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L33/00—Antithrombogenic treatment of surgical articles, e.g. sutures, catheters, prostheses, or of articles for the manipulation or conditioning of blood; Materials for such treatment
    • A61L33/06—Use of macromolecular materials
    • A61L33/12—Polypeptides, proteins or derivatives thereof, e.g. degradation products thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2400/00—Materials characterised by their function or physical properties
    • A61L2400/02—Treatment of implants to prevent calcification or mineralisation in vivo
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/40—Preparation and treatment of biological tissue for implantation, e.g. decellularisation, cross-linking
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S623/00—Prosthesis, i.e. artificial body members, parts thereof, or aids and accessories therefor
    • Y10S623/901—Method of manufacturing prosthetic device
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S623/00—Prosthesis, i.e. artificial body members, parts thereof, or aids and accessories therefor
    • Y10S623/915—Method or apparatus for preparing biological material
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S623/00—Prosthesis, i.e. artificial body members, parts thereof, or aids and accessories therefor
    • Y10S623/915—Method or apparatus for preparing biological material
    • Y10S623/916—Blood vessel
    • Y10S623/917—Collagen
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S623/00—Prosthesis, i.e. artificial body members, parts thereof, or aids and accessories therefor
    • Y10S623/92—Method or apparatus for preparing or treating prosthetic

Abstract

A method for fixation of biological tissues, and bioprosthetic devices prepared by such method. The method generally comprises the steps of: A) fixing the tissue; B) treating the tissue with a mixture of i) a denaturant, ii) a surfactant and iii) a cross-linking agent; C) fabricating or forming t he bioprosthesis (e.g., forming the tissue and attaching any non-biological components thereto); and D) subjecting the bioprosthesis to terminal sterilization.

Claims (54)

1. A method for chemical fixation of biological tissue which contains connective tissue protein to reduce the potential for post-implantation calcification and thrombogenicity, said method comprising the steps of:
a. crosslinking the connective tissue protein within the biological tissue with a fixative agent;
b. contacting the biological tissue with a mixture of a denaturant, a surfactant and a crosslinking agent;
c. assembling the bioprosthesis by performing any required shaping of the biological tissue and attaching any non-biological components of the prosthesis to the biological tissue; and, d. subjecting, the bioprosthesis to a sterilant.
2. The method of Claim 1 wherein the fixative agent used in Step A
comprises an aldehyde.
3. The method of Claim 1 wherein the fixative agent used in Step A
is selected from the group consisting of:
a. diisocyanates, b. carbodiimides, c. photooxidation; and d. polyepoxy compounds.
4. The method of Claim 1 wherein Step A comprises immersing the biological tissue in a solution containing 0.2-2.0 % by weight glutaraldehyde for 0.5 hours-14 days at 4-37 degrees C.
5. The method of Claim 1 wherein Step A is performed prior to Step B.
6. The method of Claim 1 wherein Step B is performed before Step A.
7. The method of Claim 1 wherein Step B is performed after Step C.
8. The method of Claim 1 wherein Step B is performed before Step A and again before Step C.
9. The method of Claim 1 wherein Step B is performed before Step A and again after Step C.
10. The method of Claim 1 wherein Step B is performed after Step A
and again after Step C.
11. The method of Claim 1 wherein Step B is performed before Step A, again after Step A and again after Step C.
12. The method of Claim 1 wherein the crosslinking agent of the mixture used in Step B is an aldehyde.
13. The method of Claim 1 wherein the denaturing agent of the mixture used in Step B is an alcohol.
14. The method of Claim 1 wherein the denaturing agent of the mixture used in Step B is selected from a group consisting of:
a. acidified ethers;
b. ketones;
c. chlorofluorocarbon solvents;
d. glycols;
e. chaotropic agents; and f. high concentration salt solutions.
15. The method of Claim 1 wherein the surfactant agent of the mixture used in Step B is selected from a group consisting of:
a. anionic surfactants;
b. alkyl sulfonic acid salts;
c. non-ionic compounds; and d. alkylated phenoxypolyethoxy alcohols.
16. The method of Claim 1 wherein the mixture used in Step B is a DSC solution which comprises:

a. Formaldehyde.....................Ø1-10.0 % by weight;
b. Ethanol...............................1 % to less than 60% by weight;

and, c. Tween 80..........................Ø1-5.0% by weight.
17. The method of Claim 16 wherein the mixture used in Step B is maintained at a temperature of at least 4 degrees C but below 50 degrees C
while in contact with the biological tissue.
18. The method of Claim 1 wherein the DSC solution used in Step B
is maintained at a temperature of at least 4 degrees C but below 50 degrees C
while in contact with the biological tissue.
19. The method of Claim 1 wherein Step B comprises:
a. immersing the biological tissue in a solution containing 0.1-10.0% by weight formaldehyde, 1% to less than 60% by weight ethanol and 0.1-5.0% by weight of a surfactant; and, b. maintaining said solution at a temperature of at least 4 degrees C but below 50 degrees C for 1-36 hours.
20. The method of Claim 1 wherein the sterilant used in Step D is selected from the group of sterilants consisting of:
a. liquid sterilants; and, b. a non-contacting sterilization source.
21. The method of Claim 1 wherein Step D comprises immersing the bioprosthesis in a liquid terminal sterilization solution and heating said terminal sterilization solution to a temperature between 37-50 for a period of time sufficient to ensure the sterility of the bioprosthesis until the time of implantation.
22. The method of Claim 21 wherein Step D is carried out in a sealed container and further comprises allowing the bioprosthesis to remain within said sealed container until the time of implantation.
23. The method of Claim 21 wherein said terminal sterilization solution comprises an aqueous solution of 0.2-2.0% by weight glutaraldehyde buffered to a pH of approximately 7.4.
24. The method of Claim 21 wherein said terminal sterilization solution comprises an osmotically balanced salt solution in the absence of other chemical sterilants and wherein the solution is heated to a temperature of at least 45 degrees C.
25. The method of Claim 21 wherein the terminal sterilization solution comprises osmotically balanced salt solution in combination with at least one chemical sterilant.
26. The method of Claim 21 wherein the terminal sterilization solution comprises at least one component selected from i) a denaturant, ii) a surfactant and iii) a crosslinking agent.
27. The method of Claim 1 wherein Step D comprises:
a. dispensing into a container a quantity of a terminal sterilant solution comprising 0.2-2.0 % by weight glutaraldehyde buffered to a pH of approximately 7.4;
b. immersing the bioprosthesis in said terminal sterilant solution within said container;
c. sealing said container;
d. heating said container, and the terminal sterilant solution and bioprosfhesis contained therein, to a temperature of 37-50 degrees C for 1-6 days;

e. cooling said container, and the terminal sterilant solution and bioprosthesis contained therein, to room temperature; and, f. allowing said container to remain sealed until it is desired to implant the bioprosthesis in a mammalian patient.
28. A bioprosthesis comprising biological tissue having reduced potential for post-implantation calcification and thrombogenicity which has been fixed and sterilized by a method which comprises the steps of:
a. crosslinking the connective tissue protein within the biological tissue with a fixative agent;
b. contacting the biological tissue with a mixture of a denaturant, a surfactant and a crosslinking agent;
c. assembling the bioprosthesis by performing any required shaping of the biological tissue and attaching any non-biological components of the prosthesis to the biological tissue; and, d. subjecting the bioprosthesis to a sterilant.
29. The bioprosthesis of Claim 28 wherein the fixative agent used in Step A comprises an aldehyde.
30. The bioprosthesis of Claim 28 wherein the aldehyde fixative agent used in Step A is selected from the group consisting of:
a. diisocyanates, b. carbodiimides, c. photooxidation; and d. polyepoxy compounds.
31. The bioprosthesis of Claim 28 wherein Step A comprises immersing the biological tissue in a solution containing 0.2-2.0 % by weight glutaraldehyde for 0.5 hours-14 days at 4-37 degrees C.
32. The biopmsthesis of Claim 28 wherein Step A is performed prior to Step B.
33. The bioprosthesis of Claim 28 wherein Step B is performed before Step A.
34. The bioprosthesis of Claim 28 wherein Step B is performed after Step C.
35. The bioprosthesis of Claim 28 wherein Step B is performed before Step A and before Step C.
36. The bioprosthesis of Claim 28 wherein Step B is performed before Step A and again after Step C.
37. The bioprosthesis of Claim 28 wherein Step B is performed after Step A and again after Step C.
38. The bioprosthesis of Claim 28 wherein Step B is performed before Step A, again after Step A and again after Step C.
39. The bioprosthesis of Claim 28 wherein the crosslinking agent of the mixture used in Step B is an aldehyde.
40. The bioprosthesis of Claim 28 wherein the denaturing agent of the mixture used in Step B is an alcohol.
41. The bioprosthesis of Claim 28 wherein the denaturing agent of the mixture used in Step B is selected from a group consisting of:
a. acidified ethers;
b. ketones;
c. chlorofluorocarbon solvents;
d. glycols;
e. chaotropic agents; and f. high concentration salt solutions.
42. The bioprosthesis of Claim 28 wherein the surfactant agent of the mixture used in Step B is selected from a group consisting of:
a. anionic surfactants;
b. alkyl sulfonic acid salts;
c. non-ionic compounds; and d. alkylated phenoxypolyethoxy alcohols.
43. The bioprosthesis of Claim 28 wherein the mixture used in Step B is a DSC solution which comprises:
a. Formaldehyde.....................Ø1-10.0 % by weight;
b. Ethanol...............................1% to less than 60% by weight;
and, c. Tween 80..........................Ø1-5.0% by weight.
44. The bioprosthesis of Claim 43 wherein the mixture used in Step B is maintained at a temperature of at least 4 degrees C but below 50 degrees C
while in contact with the biological tissue.
45. The bioprosthesis of Claim 28 wherein the mixture used in Step B is maintained at a temperature of at least 4 degrees C but below 50 degrees C
while in contact with the biological tissue.
46. The bioprosthesis of Claim 28 wherein Step B comprises:
a. immersing the biological tissue in a solution containing 0.1-10.0% by weight formaldehyde, 1% to less than 60% by weight ethanol and 0.1-5.0% by weight of a surfactant; and, b. maintaining said solution at a temperature of at least 4 degrees C but below 50 degrees C for 1-36 hours.
47. The bioprosthesis of Claim 28 wherein the sterilant used in Step D is selected from the group of sterilants consisting of:
a. liquid sterilants; and, b. a non-contacting sterilization source.
48. The bioprosthesis of Claim 28 wherein Step D comprises immersing the bioprosthesis in a liquid terminal sterilization solution and heating said terminal sterilization solution to a temperature between 37-50 for a period of time sufficient to ensure the sterility of the bioprosthesis until the time of implantation.
49. The bioprosthesis of Claim 48 wherein Step D is carried out in a sealed container and further comprises allowing the bioprosthesis to remain within said sealed container until the time of implantation.
50. The bioprosthesis of Claim 48 wherein said terminal sterilization solution comprises an aqueous solution of 0.2-2.0% by weight glutaraldehyde buffered to a pH of approximately 7.4.
51. The bioprosthesis of Claim 48 wherein said terminal sterilization solution comprises an osmotically balanced salt solution in the absence of other chemical sterilants and wherein the solution is heated to a temperature of at least 45 degrees C.
52. The bioprosthesis of Claim 48 wherein the terminal sterilization solution comprises osmotically balanced salt solution in combination with at least one chemical sterilant.
53. The bioprosthesis of Claim 48 wherein the terminal sterilization solution comprises at least one component selected from i) a denaturant, ii) a surfactant and iii) a crosslinking agent.
54. The bioprosthesis of Claim 28 wherein Step D comprises:
a. dispensing into a container a quantity of a terminal sterilant solution comprising 0.2-2.0 % by weight glutaraldehyde buffered to a pH of approximately 7.4;
b. immersing the bioprosthesis in said terminal sterilant solution within said container;
c. sealing said container;
d. heating said container, and the terminal sterilant solution and bioprosthesis contained therein, to a temperature of 37-50 degrees C for 1-6 days;
e. cooling said container, and the terminal sterilant solution and bioprosthesis contained therein, to room temperature; and, f. allowing said container to remain sealed until it is desired to implant the bioprosthesis in a mammalian patient.
CA2344061A 1998-09-21 1999-09-20 Crosslinking of bioprosthetic material to mitigate post-implantation calcification Expired - Lifetime CA2344061C (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US09/157,546 1998-09-21
US09/157,546 US6214054B1 (en) 1998-09-21 1998-09-21 Method for fixation of biological tissues having mitigated propensity for post-implantation calcification and thrombosis and bioprosthetic devices prepared thereby
PCT/US1999/021707 WO2000016820A1 (en) 1998-09-21 1999-09-20 Crosslinking of bioprosthetic material to mitigate post-implantation calcification

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CA2344061A1 true CA2344061A1 (en) 2000-03-30
CA2344061C CA2344061C (en) 2010-07-06

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US (4) US6214054B1 (en)
EP (1) EP1098670B1 (en)
JP (1) JP2002526206A (en)
AT (1) ATE243537T1 (en)
AU (1) AU767210B2 (en)
BR (1) BR9914008A (en)
CA (1) CA2344061C (en)
DE (1) DE69909096T2 (en)
WO (1) WO2000016820A1 (en)

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US6214054B1 (en) * 1998-09-21 2001-04-10 Edwards Lifesciences Corporation Method for fixation of biological tissues having mitigated propensity for post-implantation calcification and thrombosis and bioprosthetic devices prepared thereby
WO2000064371A1 (en) * 1999-04-27 2000-11-02 The Children's Hospital Of Philadelphia Stabilization of implantable bioprosthetic devices
WO2001015628A2 (en) * 1999-09-01 2001-03-08 Edwards Lifesciences Corporation In vivo screening methods for predicting calcification of implantable prosthetic material
US6458155B1 (en) * 2000-09-01 2002-10-01 Edwards Lifesciences Corporation Fresh donor heart valve sizer and method of use
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US6214054B1 (en) 2001-04-10
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US8236241B2 (en) 2012-08-07
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