Coating processes – Medical or dental purpose product; parts; subcombinations;... – Implantable permanent prosthesis
Reexamination Certificate
1999-02-08
2001-10-16
Nguyen, Dinh X. (Department: 3738)
Coating processes
Medical or dental purpose product; parts; subcombinations;...
Implantable permanent prosthesis
C427S002100, C427S002240
Reexamination Certificate
active
06303179
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to methods of preparing materials, preferably biocompatible materials, and typically, blood compatible materials. In particular, this invention relates to a method of attaching biomolecules, such as heparin, to the surface of a substrate through amine-functional groups, which are formed from amide-functional groups.
BACKGROUND OF THE INVENTION
The development of vascular grafts and medical devices that contact physiological fluids, particularly blood, is a rapidly developing area of medicine. This has been hampered, however, by the lack of suitable synthetic materials that are stable when contacted with such fluids.
Adverse reactions between materials and blood components are predominant factors limiting the use of synthetic materials that come into contact with physiological fluids. For example, catheters, vascular grafts, and the like, tend to serve as a nidus, or focus, for the formation of thrombi (blood clots). Initial contact of such materials with blood results in deposition of plasma proteins, such as albumin, fibrinogen, immunoglobulin, coagulation factors, and complement components. The adsorption of fibrinogen onto the surface of the material causes platelet adhesion, activation, and aggregation. Other cell adhesive proteins, such as fibronectin, vitronectin, and von Willebrand factor (vWF) also promote platelet adhesion. As a result, the continual use of anticoagulants in conjunction with the introduction of such materials to the body is often necessary.
Furthermore, complement activation occurs when materials are introduced into blood. Adsorption of large amounts of IgG, IgM, and C
3
b onto surfaces causes activation. Subsequently, complexes may be formed which contribute to undesirable immune responses, such as proteolysis, cell lysis, opsonization, anaphylaxis, and chemotaxis. As a result, these responses render such materials incompatible with the living body.
A number of approaches have been suggested to improve the biocompatibility, and even blood compatibility, of medical devices. Heparinization of polymers is one such approach. In one method, heparin is complexed with a quaternary amine prior to coating the complex onto a polymeric surface. Heparin can also be immobilized onto segmented polyurethane-urea surfaces using hydrophilic poly(ethylene oxide) spacers of different chain lengths, as disclosed in K. D. Park et al.,
J. Biomed. Mater. Res.,
22, 977-992 (1988).
Another heparinization method, which is disclosed in U.S. Pat. No. 5,229,172 (Cahalan et al.), involves initially irradiating a polymeric surface in the presence of an oxygen source and then grafting acrylamide to the irradiated surface using an acrylamide monomer and ceric ions. The grafted acrylamide surface, which can be optionally modified to include pendant functional groups such as amine and carboxyl groups, provides a suitable surface to which a biomolecule can be ionically or covalently bonded. For example, the graft can be subjected to hydrolysis in order to introduce carboxyl groups, to which spacer molecules like ethylenediamine can be coupled, using carbodiimide. To the aminated graft biomolecules such as heparin can be bound using a coupling agnet such as carbodiimide.
Although such conventional methods of attaching biomolecules, particularly heparin, to substrate surfaces have significant advantages, there is still a need for additional methods.
SUMMARY OF THE INVENTION
The present invention provides methods for attaching biomolecules, such as heparin, to substrate surfaces. Preferably, the present invention provides methods for making medical devices having biomolecules attached to (e.g., immobilized on) a substrate surface. The substrate can be made of metal or an organic polymer (i.e., a solid polymeric material).
Significantly, the present invention provides efficient methods by which biomolecules can be attached to a substrate surface containing amidefunctional groups without the need for spacers, such as ethylenediamine, and coupling agents, such as carbodiimide. Rather, the methods of the present invention provide direct conversion of amide (—C(O)NH
2
) groups to amine (—NH
3
) groups, which allows for direct attachment of biomolecules.
Specifically, the present invention provides a method of making a medical device having a biomolecule immobilized on a substrate surface. The method includes: providing a substrate having a surface comprising an amide-functional polymer; contacting the amide-functional polymer with a reaction mixture comprising a source of hydroxide ions and a source of hypohalite ions at a temperature of at least about 20° C. for a time effective to convert at least a portion of the amide-functional groups to amine-functional groups to form a substrate surface comprising an amine-functional polymer, wherein the hydroxide ions are present in a molar excess relative to the hypohalite ions and at a concentration of no more than about 0.1 M, based on the total volume of the reaction mixture; and contacting the substrate surface comprising an amine-functional polymer with a biomolecule under conditions effective to immobilize the biomolecule on the substrate surface.
The present invention also provides a method of modifying the surface characteristics of a solid polymeric material, which may or may not form a part of a medical device. The method includes: irradiating a surface of the solid polymeric material; contacting the irradiated surface with an amide-functional ethylenically unsaturated monomer and a source of oxidizing metal ions under conditions effective to graft the monomer to the irradiated surface to form an amide-functional graft polymer thereon; contacting the amide-functional graft polymer with a reaction mixture comprising a source of hydroxide ions and a source of hypohalite ions under conditions effective to convert at least a portion of the amide-functional groups to amine-functional groups to form a solid polymeric material having a surface with an amine-functional graft polymer thereon; and contacting the solid polymeric material having a surface with an amine-functional graft polymer thereon with a biomolecule under conditions effective to immobilize the biomolecule on the surface.
As used herein, a “substrate surface comprising an amidefunctional polymer” is a surface of a substrate made of a solid organic polymeric material or metal on which is coated, grafted, or otherwise adhered an organic polymer having at least amide-functional groups. A “substrate surface comprising an amine-functional polymer” is a surface of a substrate made of a solid organic polymeric material or metal on which is coated, grafted, or otherwise adhered an organic polymer having at least amine-functional groups. These polymers can also include other functional groups. The polymers having such functional groups (amide groups, amine groups, etc.) are referred to herein as “functionalized” polymers. Preferably, the functionalized polymer is a graft polymer, and more preferably, a graft hydrogel polymer. Generally, a hydrogel polymer is distinct from a solid polymeric material in the amount of water contained therein. Typically, a solid polymeric material includes less than about 10 wt-% water.
A “medical device” may be defined as a device that has surfaces that contact tissue, blood, or other bodily fluids in the course of their operation, which fluids are subsequently used in patients. This can include, for example, extracorporeal devices for use in surgery such as blood oxygenators, blood pumps, blood sensors, tubing used to carry blood or other devices that contact blood which is then returned to the patient. This can also include endoprostheses implanted in blood contact in a human or animal body such as vascular grafts, stents, pacemaker leads, heart valves, and the like that are implanted in blood vessels or in the heart. This can also include devices for temporary intravascular use such as catheters, guide wires, and the like, which are placed into the blood vessels or the heart for purposes of monitoring or repair
Cahalan Linda
Cahalan Patrick
Koulik Edouard
Verhoeven Michel
Vincent Judith
Barrett Thomas
Jaro Michael J.
Medtronic Inc
Nguyen Dinh X.
Patton Harold
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