Treating biological tissues to mitigate post-implantation calcification

• US 8,236,241 B2
• Filed: 05/04/2007
• Issued: 08/07/2012
• Est. Priority Date: 09/21/1998
• Status: Expired due to Fees

• Current Assignee: Edwards Lifesciences Corporation
• Original Assignee: Edwards Lifesciences Corporation
• Inventors: Carpentier, Alain F., Carpentier, Sophie, Cunanan, Crystal M., Quintero, Lillian J., Helmus, Michael N., Loshbaugh, Christine, Sarner, H. Chris
• Primary Examiner(s): Joyner, Kevin
• Application Number:
  US11/744,614
• Publication Number:
  US 20070255423A1
• Time in Patent Office: 1,922 Days
• Field of Search: 422/28, 623/23.72
• US Class Current: 422/28
• CPC Class Codes: A61L 2/0088 Liquid substances
• CPC Class Codes: A61L 2400/02 Treatment of implants to prevent calcification or mineralisation in vivo
• CPC Class Codes: A61L 2430/40 Preparation and treatment of biological tissue for implantation, e.g. decellularisation, cross-linking
• 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 27/3641 characterised by the site of application in the body materials for artificial blood vessels A61L27/507; materials for use in artificial skin A61L27/60
• CPC Class Codes: A61L 27/3645 Connective tissue
• 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 33/12 Polypeptides, proteins or derivatives thereof , e.g. degradation products thereof
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: Y10S 623/901 Method of manufacturing prosthetic device
• CPC Class Codes: Y10S 623/915 Method or apparatus for preparing biological material
• CPC Class Codes: Y10S 623/917 Collagen
• CPC Class Codes: Y10S 623/92 Method or apparatus for preparing or treating prosthetic

Abstract

A method of treating a biological tissue including crosslinking with glutaraldehyde; immersing the biological tissue in a first solution containing glutaraldehyde and heat in the first solution to a temperature of about 50° C. for a first period of time; immersing the biological tissue in a second solution containing a mixture of a crosslinking agent, a denaturing agent and a surfactant; and immersing the biological tissue in a sterilizing solution containing glutaraldehyde and heating the sterilizing solution to a temperature of 37.5±2.5° C. for a sterilizing period of time. The method may include a terminal sterilization step in a method for fixation of biological tissues, and bioprosthetic devices may be prepared by such fixation method. The fixation method may include the steps of A) fixing the tissue, B) treating the tissue with a mixture of i) a denaturant, ii) a surfactant and iii) a crosslinking agent, C) fabricating or forming the bioprosthesis (e.g., forming the tissue and attaching any non-biological components thereto) and D) subjecting the bioprosthesis to the terminal sterilization method.

Claims

1. A method of treating biological tissue for making a bioprosthesis which contains connective tissue protein to reduce the potential for post-implantation calcification and thrombogenicity, comprising:

a) contacting the biological tissue with a first solution containing a surfactant and a denaturing agent selected from the group consisting of formaldehyde, ethanol, isopropanol, acetone, methyl ethyl ketone, a lower alkyl ether, a glycol, a chaotropic agent, and a highly concentrated salt solution;

b) fixing the tissue of step (a) by immersing said tissue in a buffered fixative solution containing a crosslinking agent for 0.5 hours to 14 days at 4-37°

C.;

c) contacting the fixed tissue of step (b) with more of said first solution,

d) heating the tissue of step (c) in a buffered solution containing a crosslinking agent to about 50°

C.;

e) assembling a bioprosthesis by attaching any non-biological components of the prosthesis to the tissue of step (d);

f) contacting the assembled bioprosthesis of step (e) with more of said first solution, and

g) sterilizing the bioprosthesis of step (f) by immersing the bioprosthesis in a sterilizing solution containing glutaraldehyde, and heating said sterilizing solution to 37.5±

2.5°

C. for a sterilizing period of time.

2. The method of claim 1, wherein the period of time in step (b) is between 2 to 24 hours.

3. The method of claim 1, wherein the crosslinking agent of the fixative solution is glutaraldehyde.

4. The method of claim 1, wherein the sterilizing period of time is between 1-6 days.

5. The method of claim 1, wherein the biological tissue is pericardium and the bioprosthesis is a heart valve.

6. The method of claim 1, wherein the sterilizing step is carried out in a sealed container and the method further comprises storing the bioprosthesis within the sealed container.

7. The method of claim 1, wherein the sterilizing solution contains glutaraldehyde in a concentration of about 0.625 weight percent.

8. The method of claim 1, wherein the sterilization solution is buffered to a pH of approximately 7.4.

9. The method of claim 1, wherein the sterilizing step is carried out in a sealed container and the method further comprises allowing the bioprosthesis to remain within said sealed container until the time of implantation.