Pre-stressing and capping bioprosthetic tissue

• US 10,434,218 B2
• Filed: 01/24/2018
• Issued: 10/08/2019
• Est. Priority Date: 06/11/2007
• Status: Expired due to Fees

• Current Assignee: Edwards Lifesciences Corporation
• Original Assignee: Edwards Lifesciences Corporation
• Inventors: Davidson, James A., Dove, Jeffrey S., Dobler, Darin P.
• Primary Examiner(s): Moloye, Titilayo
• Application Number:
  US15/879,339
• Publication Number:
  US 20180147323A1
• Time in Patent Office: 622 Days
• 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 bioprosthetic tissue for implantation in a subject, the bioprosthetic tissue comprising:

a cross-linked bioprosthetic tissue that has been subjected to pulsed fluid flow to produce localized micro collagen fibril damage at sites of flexion and acid binding sites at the sites of flexion; and

one or more capping agents coupled to the acid binding sites to produce capped acid binding sites prior to implantation into the subject;

wherein a content of the acid binding sites is at least 10% in the cross-linked bioprosthetic tissue comprising localized micro collagen fibril damage at sites of flexion than in a cross-linked bioprosthetic tissue not having localized micro collagen fibril damage at sites of flexion; and

wherein the cross-linked bioprosthetic tissue comprising localized micro collagen fibril damage at sites of flexion and capped acid binding sites has a reduced propensity to calcify in vivo as compared to the cross-linked bioprosthetic tissue not having micro collagen fibril damage at sites of flexion and having capped acid binding sites.

2. The bioprosthetic tissue of claim 1, wherein the bioprosthetic tissue is one or a combination selected from the group consisting of:

pericardium, porcine valves, blood vessels, skin, dura matter, small intestinal mucosa, ligaments, and tendons.

3. The bioprosthetic tissue of claim 2, wherein the bioprosthetic tissue is a pericardium and the pericardium is a bovine pericardium.

4. The bioprosthetic tissue of claim 1, wherein the bioprosthetic tissue is cross-linked with an aldehyde.

5. The bioprosthetic tissue of claim 4, where in the aldehyde is a glutaraldehyde.

6. The bioprosthetic tissue of claim 1, wherein the one or more capping agents is one or more selected from the group consisting of:

an amine, an amino acid, an amino sulfonate, a hydrophilic multifunctional polymer, a hydrophobic multifunctional polymer, an alpha-dicarbonyl, a hydrazide, an N, N-disuccinimidyl carbonate, a carbodiimide, a 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.

7. The bioprosthetic tissue of claim 6, wherein the capping agent is an amine and the amine is an ethanolamine.

8. The bioprosthetic tissue of claim 6, wherein the capping agent is an amino sulfonate and wherein the amino sulfonate is a taurine.

9. An implant comprising the bioprosthetic tissue of claim 1.

10. A bioprosthetic heart valve comprising the bioprosthetic tissue of claim 1.

11. The bioprosthetic tissue of claim 1, wherein the pulsed fluid flow is at least 100 cycles.

12. The bioprosthetic tissue of claim 11, wherein the pulsed fluid flow is at least 100,000 cycles.

13. The bioprosthetic tissue of claim 1, wherein the pulsed fluid flow is in the range of 4 Hz to 1,500 Hz.