# US 11,305,036 B2 · Bioprosthetic tissue having a reduced propensity for in vivo calcification

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- Number: US 11,305,036 B2
- Document ID: US11305036B2
- Status: Granted
- Kind: B2
- Application number: 16/595,089
- Filed: 2019-10-07
- Published: 2020-02-06
- Granted: 2022-04-19
- Earliest claimed: 2007-06-11
- Assignees: Edwards Lifesciences Corporation
- Applicants: Edwards Lifesciences Corporation
- Inventors: James A. Davidson; Jeffrey S. Dove; Darin P. Dobler
- Web page: https://patentgrep.com/patent/US11305036B2

## CPC

- A61L 27/3625: {Vascular tissue, e.g. heart valves}
- A61F 2/2412: {with soft flexible valve members, e.g. tissue valves shaped like natural valves}
- 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}
- A61L 27/3687: {characterised by the use of chemical agents in the treatment, e.g. specific enzymes, detergents, capping agents, crosslinkers, anticalcification agents}
- 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}
- A61L 27/507: {for artificial blood vessels (apparatus for applying cells on a blood vessel prosthesis A61F2/062)}
- A61F 2210/0004: bioabsorbable
- A61F 2210/0076: multilayered, e.g. laminated structures
- A61L 2400/02: Treatment of implants to prevent calcification or mineralisation in vivo
- A61L 2430/20: for reconstruction of the heart, e.g. heart valves
- A61L 2430/40: Preparation and treatment of biological tissue for implantation, e.g. decellularisation, cross-linking
- 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 (preservation of bodies or disinfecting characterised by the agents employed A01N; preserving, e.g. sterilising, food or foodstuffs A23; preparations for medical, dental or toiletry purposes A61K)
- A61F: FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS (dental prosthetics A61C)

## Abstract

A bioprosthetic tissue having a reduced propensity to calcify in vivo, the bioprosthetic tissue. The bioprosthetic tissue comprises an aldehyde cross-linked and stressed bioprosthetic tissue comprising exposed calcium, phosphate or immunogenic binding sites that have been reacted with a calcification mitigant. The bioprosthetic tissue has a reduced propensity to calcify in vivo as compared to aldehyde cross-linked bioprosthetic tissue that has not been stressed and reacted with the calcification mitigant.

## Claims

### Claim 1

A method of treating a cross-linked bioprosthetic tissue to reduce in vivo calcification, the method comprising:
immersing a cross-linked bioprosthetic tissue in a solution comprising a calcification mitigant; and
stressing the cross-linked bioprosthetic tissue by subjecting the cross-linked bioprosthetic tissue to pulsed fluid flow in the solution comprising the calcification mitigant;
wherein the stressing produces localized micro collagen fibril damage at sites of flexion and acid binding sites; and
wherein the calcification mitigant couples with the acid binding sites to produce capped acid binding sites.

### Claim 2 (depends on 1)

The method of claim 1, wherein the calcification mitigant 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 α-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 antiinflammatory agent, an anti-proliferative agent, an immunogenic suppressing agent, a reducing agent, and a mono-, di- or polyepoxy alkane.

### Claim 3 (depends on 2)

The method of claim 2, wherein:
the calcification mitigant is an amine; and
the amine is an ethanolamine.

### Claim 4 (depends on 2)

The method of claim 2, wherein:
the calcification mitigant is an amino sulfonate; and
the amino sulfonate is a taurine.

### Claim 5 (depends on 1)

The method of claim 1, wherein the solution comprises one or more selected from the group consisting of: an aqueous solution, an organic solvent, and an organic buffered solution.

### Claim 6 (depends on 1)

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

### Claim 7 (depends on 6)

The method of claim 6, wherein the aldehyde is a glutaraldehyde.

### Claim 8 (depends on 1)

The method of claim 1, wherein the bioprosthetic tissue is one or more selected from the group consisting of: cardiac valves, blood vessels, skin, dura mater, pericardium, small intestinal submucosa, ligaments, and tendons.

### Claim 9 (depends on 1)

The method of claim 1, wherein the bioprosthetic tissue comprises precut heart valve leaflets mounted and flexed in a suitable flow-producing apparatus.

### Claim 10 (depends on 1)

The method of claim 1, wherein the stressing causes the bioprosthetic tissue to flex repeatedly.

### Claim 11 (depends on 10)

The method of claim 10, wherein the stressing comprises subjecting the bioprosthetic tissue to at least 100 cycles of the pulsed fluid flow.

### Claim 12 (depends on 10)

The method of claim 10, wherein the stressing comprises subjecting the bioprosthetic tissue to a simulated post-implant physiological environment.

### Claim 13 (depends on 10)

The method of claim 10, wherein the stressing comprises subjecting the bioprosthetic tissue to at least one stress-accelerating environmental parameter.

### Claim 14 (depends on 13)

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

### Claim 15 (depends on 13)

The method of claim 13, wherein the stress-accelerating environmental parameter is an elevated temperature range of 26° C. to 65° C.

### Claim 16 (depends on 13)

The method of claim 13, wherein the stress-accelerating environmental parameter is an acidic solution having a pH in a range of 4 to 7.

### Claim 17 (depends on 13)

The method of claim 13, wherein the stress-accelerating environmental parameter is an alkaline solution having a pH in a range of 8 to 10.

### Claim 18 (depends on 13)

The method of claim 13, wherein the stress-accelerating environmental parameter is an oxidizing solution.

### Claim 19 (depends on 1)

An implant comprising a cross-linked bioprosthetic tissue treated according to the method of claim 1.

### Claim 20 (depends on 1)

A bioprosthetic heart valve comprising a cross-linked bioprosthetic tissue treated according to the method of claim 1.