WO1988001155A1 - Biomaterial implant with a net positively charged surface - Google Patents

Biomaterial implant with a net positively charged surface

Info

Publication number
WO1988001155A1
WO1988001155A1 PCT/US1987/002055 US8702055W WO8801155A1 WO 1988001155 A1 WO1988001155 A1 WO 1988001155A1 US 8702055 W US8702055 W US 8702055W WO 8801155 A1 WO8801155 A1 WO 8801155A1
Authority
WO
WIPO (PCT)
Prior art keywords
implant
compound
biomaterial
amino groups
biomaterial implant
Prior art date
Application number
PCT/US1987/002055
Other languages
French (fr)
Inventor
Gershon Golomb
Robert J. Levy
Original Assignee
The Children's Medical Center Corporation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by The Children's Medical Center Corporation filed Critical The Children's Medical Center Corporation
Publication of WO1988001155A1 publication Critical patent/WO1988001155A1/en

Links

Classifications

    • 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
    • A61L27/3695—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 function or physical properties of the final product, where no specific conditions are defined to achieve this
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02—Prostheses implantable into the body
    • A61F2/24—Heart valves ; Vascular valves, e.g. venous valves; Heart implants, e.g. passive devices for improving the function of the native valve or the heart muscle; Transmyocardial revascularisation [TMR] devices; Valves implantable in the body
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/34—Muscles; Smooth muscle cells; Heart; Cardiac stem cells; Myoblasts; Myocytes; Cardiomyocytes
    • 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
    • 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

Definitions

  • This invention relates to preventing calcification of bi ⁇ material implants.
  • Biomaterial implants e.g., bioprosthetic heart
  • pathologic calcification defined as the deposition of calcium phosphate mineral salts in association with a disease process. Pathologic calcification represents the main source of bioprosthetic heart valve failure.
  • the iny.ention features a biomaterial implant covalently bonded-to a compound that imparts a positive charge to the implant sufficient to substantially repel calcium ions in the environment of
  • the compound, after bonding to said implant has at least one free basic
  • the compound 25 functional group (e.g., an amino group) that imparts the positive charge to the implant; the compound has at least six amino groups; the compound has a molecular weight of greater than 600; and the compound is a polypeptide such as protamine, polylysine, or
  • the implant is made of natural tissue or collagen and is stabilized with a stabilizing reagent (e.g., glutaraldehyde) that forms a covalent bond with an amino group of the implant.
  • a stabilizing reagent e.g., glutaraldehyde
  • natural tissue refers to tissue derived from humans or animals.
  • calcification is prevented by the addition of positive charges to the implant.
  • the positive charge repels positively charged calcium ions which could otherwise attach to the implant and act as nucleation sites for calcification. Covalently bonding the compound to the implant minimizes long-term calcification because the compound remains attached to the implant.
  • Particular advantage is gained where the compound is used with implants that have been treated with gluteraldehyde, which consumes the naturally-present basic functionality (e.g., amino groups) of the implant; it is hypothesized that such consumption normally is a cause of calcification.
  • the compounds are easy to use and non-toxic.
  • biomaterial implants are produced from collagen or derived from natural tissue, e.g., porcine aortic valves or bovine pericardium, and are stabilized with glutaraldehyde, which reacts with some of the amino groups of the implants.
  • biomaterial implants include heart valves, vascular grafts, breast implants, hip and tendon prostheses, intracardiac patches, and artificial heart devices having biolized surfaces.
  • the biomaterial implants preferably are covalently bonded, prior to implantation, to a compound that has a plurality of amino groups.
  • a compound that has a plurality of amino groups When such a compound is reacted with the implant in accordance with the method described below, at least one of the amino groups covalently bonds to the implant. If the compound has more then two amino groups, some of the amino groups do not bond to the implant and thus remain free. If the compound has two amino groups,- generally only one of the amino groups bonds to the implant, thus leaving one amino group per compound free.
  • the free, unreacted amino groups are basic, i.e., are positively charged at physiological pH. The positive charge imparted to the implant by the charged amino groups inhibits calcificaion of the implant.
  • the compound is a nontoxic, water soluble, organic polymer that has a molecular weight of greater than 600, more preferably greater than 2000, and has at least 6 amino groups.
  • Such polymers molecules are efficient at spreading through the implant the positive charges associated with each molecule.
  • the biomaterial implants of the invention are prepared by contacting a conventionally fabricated biomaterial implant with the compound in a suitable aqueous buffer solution, e.g., HEPES, to allow the compound to penetrate into the tissue.
  • a suitable aqueous buffer solution e.g., HEPES
  • the pH of the buffer solution is between 7.0 and 8.0.
  • the implants are then contacted with a buffered solution of glutaraldehyde.
  • the implant can be reduced with sodium borohydride following glutaraldehyde treatment.
  • the compound covalently bonds to the implant through the glutaraldehyde, which reacts with both an amino group of the compound and an amino group of the implant.
  • the glutaraldehyde thus both stabilizes the tissue and serves as the crosslinking reagent that attaches the compound to the implant.
  • a collagen sponge treated according to the invention was prepared as follows.
  • Type I collagen " sponges were cut into small pieces
  • Biomaterial implants of the invention can be surgically implanted using conventional surgical techniques. It is believed that calcification is prevented as follows. Biomaterial implants in general are substantially composed of collagen Type I. Collagen Type I contains 30-35 lysine and hydroxylysine residues per 1000 amino acid residues; these residues have basic, positively charged amino groups. Collagen Type I also contains many acidic, negatively charged ⁇ arboxylate groups.
  • the gluteraldehyde reacts primarily with the amino group-, of the lysine and hydroxylysine residues of collagen.
  • the implant has fewer basic amino groups. Because the number of carboxylate groups is unchanged, the implant will have more of a negative charge associated with it following glutaraldehyde treatment. The increased negative charge will tend to attract Ca +2 to the implant; the most likely affinity sites for the ions are the carboxylate groups. Bonding the compound to the implant compensates for the amino groups that are consumed during glutaraldehyde treatment.
  • the amino groups effectively neutralize the acidic groups of the tissue, thus making the carboxylate groups less attractive to Ca +2.
  • the positively charged groups repel calcium ions, thus preventing the ions from interacting with the tissue.
  • the compounds can be bound to synthetic polymers used to fabricate biomaterial implants, e.g., silicone rubbers, polyurethane elastomers, and polymer hydrogels.
  • the polymers must contain suitable functional groups which are capable of covalently bonding to the compound.
  • Compounds can also be contacted with, the implant after or during the period in which the implant is treated with gluteraldehyde.
  • Compounds can be covalently bonded to the implant through standard crosslinking reagents such as 1,2 cyclohexanedione, formaldehyde, DMA, and CNBr (all of which are available from PIERCE).
  • standard crosslinking reagents such as 1,2 cyclohexanedione, formaldehyde, DMA, and CNBr (all of which are available from PIERCE).

Abstract

A biomaterial implant, preferably derived from glutaraldehyde-treated animal tissue, is covalently bonded to a compound which imparts a net positive charge to the implant. Preferably, the implant is treated with a polyamino acid which has free amino groups so as to impart the net positive charge to the implant's surface.

Description

BIOMATERIAL IMPLANT WITH A NET POSITIVELY CHARGED SURFACE
Background of the Invention This invention relates to preventing calcification of biαmaterial implants.
Biomaterial implants, e.g., bioprosthetic heart
5 halves for use in human patients, are often derived from human or animal tissue. These implants generally are pre-treated with glutaraldehyde to prevent biodegradation and immunogenic responses following implantation. One problem with glutaraldehyde-treated
10 implantc is pathologic calcification, defined as the deposition of calcium phosphate mineral salts in association with a disease process. Pathologic calcification represents the main source of bioprosthetic heart valve failure.
15 Summary of the Invention
In general, the iny.ention features a biomaterial implant covalently bonded-to a compound that imparts a positive charge to the implant sufficient to substantially repel calcium ions in the environment of
20 use, i.e., sufficient to prevent calcium ions from adhering to the implant to the extent that the functioning of the implant is impaired.
In preferred embodiments, the compound, after bonding to said implant, has at least one free basic
25 functional group (e.g., an amino group) that imparts the positive charge to the implant; the compound has at least six amino groups; the compound has a molecular weight of greater than 600; and the compound is a polypeptide such as protamine, polylysine, or
30 polyargininβ; and the implant is made of natural tissue or collagen and is stabilized with a stabilizing reagent (e.g., glutaraldehyde) that forms a covalent bond with an amino group of the implant. As used herein, the term "natural tissue" refers to tissue derived from humans or animals.
According to the invention, calcification is prevented by the addition of positive charges to the implant. The positive charge repels positively charged calcium ions which could otherwise attach to the implant and act as nucleation sites for calcification. Covalently bonding the compound to the implant minimizes long-term calcification because the compound remains attached to the implant. Particular advantage is gained where the compound is used with implants that have been treated with gluteraldehyde, which consumes the naturally-present basic functionality (e.g., amino groups) of the implant; it is hypothesized that such consumption normally is a cause of calcification. The compounds are easy to use and non-toxic.
Other features and advantages of the invention will be apparent from the following description of the preferred embodiments thereof, and from the claims. Description of the Preferred Embodiments We now describe the structure, preparation, and use of preferred embodiments of the invention. Structure Preferred biomaterial implants are produced from collagen or derived from natural tissue, e.g., porcine aortic valves or bovine pericardium, and are stabilized with glutaraldehyde, which reacts with some of the amino groups of the implants. Examples of biomaterial implants include heart valves, vascular grafts, breast implants, hip and tendon prostheses, intracardiac patches, and artificial heart devices having biolized surfaces. The biomaterial implants preferably are covalently bonded, prior to implantation, to a compound that has a plurality of amino groups. When such a compound is reacted with the implant in accordance with the method described below, at least one of the amino groups covalently bonds to the implant. If the compound has more then two amino groups, some of the amino groups do not bond to the implant and thus remain free. If the compound has two amino groups,- generally only one of the amino groups bonds to the implant, thus leaving one amino group per compound free. The free, unreacted amino groups are basic, i.e., are positively charged at physiological pH. The positive charge imparted to the implant by the charged amino groups inhibits calcificaion of the implant.
Preferably, the compound is a nontoxic, water soluble, organic polymer that has a molecular weight of greater than 600, more preferably greater than 2000, and has at least 6 amino groups. Such polymers molecules are efficient at spreading through the implant the positive charges associated with each molecule.
Examples of such polymers include protamine (which is comprised of approximately 80% arginine residues, each of which has a free amino group), polylysine (each lysine residue having a free amino group), polyarginine, polymyxin, and polyornithine, or their pharmaceutically acceptable salts, e.g., sulfates, chlorides, or nitrates. Preparation In general, the biomaterial implants of the invention are prepared by contacting a conventionally fabricated biomaterial implant with the compound in a suitable aqueous buffer solution, e.g., HEPES, to allow the compound to penetrate into the tissue. The pH of the buffer solution is between 7.0 and 8.0. The implants are then contacted with a buffered solution of glutaraldehyde. To stabilize the covalent bonding between the compound and the biomaterial implant, the implant can be reduced with sodium borohydride following glutaraldehyde treatment.
It is believed that the compound covalently bonds to the implant through the glutaraldehyde, which reacts with both an amino group of the compound and an amino group of the implant. The glutaraldehyde thus both stabilizes the tissue and serves as the crosslinking reagent that attaches the compound to the implant.
A collagen sponge treated according to the invention was prepared as follows.
Type I collagen"sponges were cut into small pieces
(1 5 cm) and immersed for 24 hrs. in 10 ml of a solution containing 10% protamine sulfate (available from Sigma Chemical Co., St. Louis, MO, catalog no. P 4380) and 5 ml HEPES buffer
(pH = 7.5) (available from Sigma Chemical Co., catalog no. H 3375). Analytical grade glutaraldehyde was then added to a concentration of 0.2%, and the resulting solution incubated for 96 hrs, after which the sponges were rinsed free of buffer solution and reduced with sodium borohydride. The sponges were then rinsed and dried. Use The biomaterial implants of the invention can be surgically implanted using conventional surgical techniques. It is believed that calcification is prevented as follows. Biomaterial implants in general are substantially composed of collagen Type I. Collagen Type I contains 30-35 lysine and hydroxylysine residues per 1000 amino acid residues; these residues have basic, positively charged amino groups. Collagen Type I also contains many acidic, negatively charged σarboxylate groups.
When a biomaterial implant is treated with gluteraldehyde to stabilize the implant, the gluteraldehyde reacts primarily with the amino group-, of the lysine and hydroxylysine residues of collagen. As a result, following the reaction, the implant has fewer basic amino groups. Because the number of carboxylate groups is unchanged, the implant will have more of a negative charge associated with it following glutaraldehyde treatment. The increased negative charge will tend to attract Ca +2 to the implant; the most likely affinity sites for the ions are the carboxylate groups. Bonding the compound to the implant compensates for the amino groups that are consumed during glutaraldehyde treatment. The amino groups effectively neutralize the acidic groups of the tissue, thus making the carboxylate groups less attractive to Ca +2. In addition, the positively charged groups repel calcium ions, thus preventing the ions from interacting with the tissue.
Other Embodiments
Other embodiments are within the following claims. For example, the compounds can be bound to synthetic polymers used to fabricate biomaterial implants, e.g., silicone rubbers, polyurethane elastomers, and polymer hydrogels. The polymers must contain suitable functional groups which are capable of covalently bonding to the compound.
Compounds can also be contacted with, the implant after or during the period in which the implant is treated with gluteraldehyde.
Compounds can be covalently bonded to the implant through standard crosslinking reagents such as 1,2 cyclohexanedione, formaldehyde, DMA, and CNBr (all of which are available from PIERCE).

Claims

_ _ _Claims
1. A biomaterial implant covalently bonded to a compound that imparts a positive charge to said implant sufficient to substantially repel calcium ions in the environment of use.
2. The biomaterial implant of claim 1 wherein said compound, when bonded to said implant, has at least one free basic functional group that imparts said positive charge to said implant.
3. The biomaterial implant of claim 2 wherein said functional group is an amino group.
4. The biomaterial implant of .claim 1 wherein said compound has at least 6 amino groups.
5. The biomaterial implant of claim 1 wherein said compound has a molecular weight greater than about
600.
6. The biomaterial implant of claim 1 wherein said compound comprises protamine, polylysine, or polyarginine, or a pharmaceutically acceptable salt thereof.
7. The biomaterial implant of claim 1 wherein said compound comprises a polypeptide.
8. The biomaterial implant of claim 1 wherein said implant is stabilized with a stabilizing reagent that forms a covalent bond with an amino group of said implant.
9. The biomaterial implant of claim 8 wherein said stabilizing reagent is glutaraldehyde.
10. The biomaterial implant of claim 8 wherein said implant comprises natural tissue or collagen.
11. A method of inhibiting calcification of a biomaterial implant comprising the steps of providing a basic compound; and covalently bonding a sufficient amount of said compound to said implant to impart a positive charge to said implant.
12. The method of claim 11 further comprising the step of treating said implant with glutaraldehyde.
13. The method of claim 11 wherein said compoumd comprises protamine, polylysine, or polyarginine, or a -pharmaceutically acceptable salt thereof.
14. The method of claim 11 wherein said compound comprises a polypeptide.
15. The method of claim 11 wherein said compound has a molecular weight greater than about 600.
16. The method of claim 11 wherein said implant comprises natural tissue or collagen.
17. The method of claim 11 wherein said compound has at least two amino groups.
18. The method of claim 10 wherein said compound has at least six amino groups.
PCT/US1987/002055 1986-08-20 1987-08-20 Biomaterial implant with a net positively charged surface WO1988001155A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US89836186A 1986-08-20 1986-08-20
US898,361 1986-08-20

Publications (1)

Publication Number Publication Date
WO1988001155A1 true WO1988001155A1 (en) 1988-02-25

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1987/002055 WO1988001155A1 (en) 1986-08-20 1987-08-20 Biomaterial implant with a net positively charged surface

Country Status (4)

Country Link
EP (1) EP0277995A4 (en)
JP (1) JPH01500730A (en)
IL (1) IL83592A0 (en)
WO (1) WO1988001155A1 (en)

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0364517A1 (en) * 1988-02-03 1990-04-25 Biomedical Design Inc Prevention of prosthesis calcification.
US5480963A (en) * 1994-07-22 1996-01-02 United States Surgical Corporation Absorbable copolymers derived from tricarboxylic acids and surgical articles made therefrom
WO1997027886A1 (en) * 1996-02-05 1997-08-07 St. Jude Medical, Inc. Calcification-resistant biomaterials
US6193749B1 (en) 1996-02-05 2001-02-27 St. Jude Medical, Inc. Calcification-resistant biomaterials
US6254635B1 (en) 1998-02-02 2001-07-03 St. Jude Medical, Inc. Calcification-resistant medical articles
WO2001058503A1 (en) * 2000-02-09 2001-08-16 The Children's Hospital Of Philadelphia Stabilization of implantable bioprosthetic tissue
US6302909B1 (en) 1996-07-31 2001-10-16 St. Jude Medical, Inc. Calcification-resistant biomaterials
US8565872B2 (en) 2004-07-12 2013-10-22 Medtronic ATS Medical, Inc. Anti-coagulation and demineralization system for conductive medical devices
US8653632B2 (en) 2007-03-28 2014-02-18 Medtronic Ats Medical Inc. System and method for conditioning implantable medical devices
US9649499B2 (en) 2007-03-28 2017-05-16 Medtronic ATS Medical, Inc. Method for inhibiting platelet interaction with biomaterial surfaces
US9844667B2 (en) 2006-04-12 2017-12-19 Medtronic Ats Medical Inc. System for conditioning surfaces in vivo
CN111569152A (en) * 2020-05-28 2020-08-25 四川大学 Biological valve with anticoagulation and calcification resistance and preparation method thereof

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US4378224A (en) * 1980-09-19 1983-03-29 Nimni Marcel E Coating for bioprosthetic device and method of making same
US4521564A (en) * 1984-02-10 1985-06-04 Warner-Lambert Company Covalent bonded antithrombogenic polyurethane material
US4553974A (en) * 1984-08-14 1985-11-19 Mayo Foundation Treatment of collagenous tissue with glutaraldehyde and aminodiphosphonate calcification inhibitor

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IN157379B (en) * 1981-04-30 1986-03-15 Extracorporeal Med Spec
US4402697A (en) * 1982-08-25 1983-09-06 Extracorporeal Medical Specialties, Inc. Method for inhibiting mineralization of natural tissue during implantation

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US4378224A (en) * 1980-09-19 1983-03-29 Nimni Marcel E Coating for bioprosthetic device and method of making same
US4521564A (en) * 1984-02-10 1985-06-04 Warner-Lambert Company Covalent bonded antithrombogenic polyurethane material
US4553974A (en) * 1984-08-14 1985-11-19 Mayo Foundation Treatment of collagenous tissue with glutaraldehyde and aminodiphosphonate calcification inhibitor

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Title
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See also references of EP0277995A4 *

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0364517A4 (en) * 1988-02-03 1991-01-16 Biomedical Design, Inc. Prevention of prosthesis calcification
EP0364517A1 (en) * 1988-02-03 1990-04-25 Biomedical Design Inc Prevention of prosthesis calcification.
US5480963A (en) * 1994-07-22 1996-01-02 United States Surgical Corporation Absorbable copolymers derived from tricarboxylic acids and surgical articles made therefrom
WO1997027886A1 (en) * 1996-02-05 1997-08-07 St. Jude Medical, Inc. Calcification-resistant biomaterials
US6193749B1 (en) 1996-02-05 2001-02-27 St. Jude Medical, Inc. Calcification-resistant biomaterials
US6302909B1 (en) 1996-07-31 2001-10-16 St. Jude Medical, Inc. Calcification-resistant biomaterials
US6254635B1 (en) 1998-02-02 2001-07-03 St. Jude Medical, Inc. Calcification-resistant medical articles
US6391538B1 (en) 2000-02-09 2002-05-21 The Children's Hospital Of Philadelphia Stabilization of implantable bioprosthetic tissue
WO2001058503A1 (en) * 2000-02-09 2001-08-16 The Children's Hospital Of Philadelphia Stabilization of implantable bioprosthetic tissue
US6824970B2 (en) 2000-02-09 2004-11-30 The Children's Hospital Of Philadelphia Stabilization of implantable bioprosthetic tissue
US8565872B2 (en) 2004-07-12 2013-10-22 Medtronic ATS Medical, Inc. Anti-coagulation and demineralization system for conductive medical devices
US9844667B2 (en) 2006-04-12 2017-12-19 Medtronic Ats Medical Inc. System for conditioning surfaces in vivo
US10406355B2 (en) 2006-04-12 2019-09-10 Medtronic Vascular, Inc. System for conditioning surfaces in vivo
US8653632B2 (en) 2007-03-28 2014-02-18 Medtronic Ats Medical Inc. System and method for conditioning implantable medical devices
US9649499B2 (en) 2007-03-28 2017-05-16 Medtronic ATS Medical, Inc. Method for inhibiting platelet interaction with biomaterial surfaces
US11020515B2 (en) 2007-03-28 2021-06-01 Medtronic ATS Medical, Inc. Method for inhibiting platelet interaction with biomaterial surfaces
US11850335B2 (en) 2007-03-28 2023-12-26 Medtronic ATS Medical, Inc. Method for inhibiting platelet interaction with biomaterial surfaces
CN111569152A (en) * 2020-05-28 2020-08-25 四川大学 Biological valve with anticoagulation and calcification resistance and preparation method thereof
WO2021239080A1 (en) * 2020-05-28 2021-12-02 杭州启明医疗器械股份有限公司 Biological heart valve with both anticoagulation and anti-calcification properties, and preparation method therefor

Also Published As

Publication number Publication date
JPH01500730A (en) 1989-03-16
EP0277995A1 (en) 1988-08-17
EP0277995A4 (en) 1989-11-07
IL83592A0 (en) 1988-01-31

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