Stock material or miscellaneous articles – Composite
Reexamination Certificate
2000-09-15
2002-08-27
Boykin, Terressa M. (Department: 1711)
Stock material or miscellaneous articles
Composite
Reexamination Certificate
active
06440565
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to surface-modified metallic materials for medical purposes, in particular materials for use in circulatory medical devices. More specifically, the present invention relates to surface-modified metallic materials prepared by coating a thin film of gold or silver on the surface of metallic substrates, attaching to said thin film functional sulfur compounds having high adsorptivity, and chemically bonding sulfonated poly(ethylene oxide) (PEO) (alternatively, referred to as poly(ethylene) glycol, PEG) to functional groups of said sulfur compounds. The materials of the invention have remarkably improved antithrombogenicity and biocompatibility and thus are especially useful for medical devices such as prosthetic cardiac valves, stents and catheters.
2. Description of the Prior Art
Prosthetic cardiac valves have been implanted and used as substitutes for cardiac valves that have been impaired through hereditary or acquired means. Examples of prosthetic cardiac valves include valves made from tissues and mechanical valves made from metallic materials such as titanium. The tissue valves have good biocompatibility but have a drawback in that their internal durability is inferior due to calcification. The mechanical valves have excellent durability but are defective in that they may be accompanied by the formation of thrombus, requiring the patient to take anticoagulants throughout his or her life. Intensive research has been conducted in the art in order to improve the antithrombogenicity of mechanical valves. But because the formation of thrombus is a normal physiological phenomenon, it is impossible to completely prevent it. Moreover, the formation mechanism of thrombus has not yet been completely explained.
In order to treat the stricture of the coronary arteries, a percutaneous transluminal coronary angioplasty in which blood vessels are expanded by inserting intraaortic baloon catheters into the coronary arteries has been commonly used. This angioplasty has produced relatively good results, and its operation method and apparatus have been continuously developed. However, problems such as chronic closure and restenosis are still unsolved.
Stents are metallic implants in the form of a spring which are inserted into blood vessels to keep them expanded after the angioplasty has been carried out in order to prevent restenosis. Recently, the use of stents has increased. Stents are made from stainless steel, tantalum or titanium-nickel alloys and the like, and various types of stents, such as balloons or tubes have been developed and used. However, it has been found that the effort to prevent restenosis meets with failure about 20% to 30% of the time, even in cases when stents are implanted. It has been also ascertained that the main cause of such failure are restenosis, which is caused by an acute and chronic thrombus formation and the proliferation of smooth muscle cells in the internal walls of blood vessels from the wounds inflicted when inserting stents. The inherent properties of metals make it easy for thrombus to easily form on the surface thereof. Metal surfaces generally have a positive charge and, thus, exhibit high interreactivity with blood having a negative charge. Also, it has been ascertained that metals have high critical surface tension and thus are easily susceptible to the formation of thrombus, as noted by M.F.A. Goosen, et al. in Biomaterials, 17, 685-694 (1996).
U.S. Pat. No. 5,824,045, granted to E. Alt, and U.S. Pat. No. 5,976,169, granted to M. A. Imran, disclose attempts to improve the antithrombogenicity and to reduce allergic reactions of stents made from stainless steel and the like, by vapor deposition of a thin film of gold, platinum, silver or an alloy thereof on the surface of stents. However, these attempts have failed to provide a superior antithrombogenicity effect.
Also, U.S. Pat. No. 5,919,126 granted to A. J. Annini, discloses stents for the prevention of the restenosis by beta-ray emission, which are prepared by vapor deposition of a thin film of gold, platinum, titanium, nickel or the like on the surface thereof made from stainless steel, titanium or nickel-titanium alloy, and then by implanting radioisotopes to the film.
Further, many studies have been made in the art wherein polymers are coated on the surface of metallic materials which are to be used in the preparation of mechanical valves and stents in order to improve their antithromgenicity. For example, a method comprising the covering of the metallic surface with nylon mesh (See T. Yoshioka, et al., Am. J. Radiol., 15, 673-676, 1988), or a method comprising the coating of the metallic surface with silicone (See T. Roeren, et al., Radiology 174, 1069, 1990) or polyurethane (See I. K. De Scheerder, et al., J. Am. Coll. Cardiol 23, 186A, 1994) have been proposed, but these methods have not produced satisfactory results.
Further, there are proposed methods comprising the coating of the metallic surface with polymers having grafted heparin as an anticoagulant (See S. Stheth, et al., J. Am. Coll. Cardiol 23, 187A, 1994), with fibrin (See R. S. Schwartz, et al., J. Am. Coll. Cardiol 19, 171A, 1992), or with polymers containing agents such as dexamethasone (See A. M. Lincoff, et al., J. Am. Coll. Cardiol 23, 18A, 1994) such that the agents can be released slowly. However, these methods also failed to obtain the desired results.
In order to enhance the antithromgenicity of metallic materials for medical uses, many studies have been made with respect to anionic surfaces or structures having hydrophilic, hydrophobic and hydrophilic/hydrophobic micro-domains. It has been reported that a PEO-grafted surface prevents the adhesion of blood components such as proteins and blood platelets thereto and thus improves the antithromgenicity thereof (See J. D. Andrade, et al., Biomaterials 11, 455, 1990). It has also been reported that the PEO-grafted surface largely reduces the adhesion and spreading of cells as well as the adhesion and infection of bacteria (See J. A. Hubbell, et al., Biomaterials 13, 417, 1992).
Because metals have no functional groups that are chemically active, unlike polymers, i.e., organic materials, it is impossible to chemically modify them. There are some examples where PEO, poly(vinyl alcohol) or similar hydrophilic polymers have been applied to the surface of metals, especially stents, in order to modify the surface (See U.S. Pat. No. 5,843,172, granted to J. Y. Yan and U.S. Pat. No. 5,897,911, granted to J. P. Loeffler). However, because the polymers were simply coated on the metal surface, adhesive strength is poor and the antithromgenicity is below the desired level.
M. Grunze, et al. studied and reported that in a PEO self-assembled monolayer wherein the PEO is grafted to the surface of gold or silver film by means of sulfur compounds, the adsorption of protein is reduced (See J. Phys. Chem. B, 102, 426-436, 1998). Similar studies are in progress. However, it is impossible to obtain a practically applicable level of antithromgenicity, and there have been no reports on its commercialization.
We, the present inventors, found that the grafting of sulfonated poly(ethylene oxide) to the surface of polymers adds antithrombotic effects of the sulfonate group to the non-adhesion property of the PEO, thereby highly enhancing the antithrombogenicity and biocompatibility of the surface of the polymers (See Korean Patent. No. 62,921 to Y. H. Kim et al.).
The present inventors have now found that excellent antithrombogenicity and biocompatibility of metals can be obtained by chemically binding sulfonated PEO through sulfur compounds to thin film of gold or silver that is then stably coated on the surface of the metals. In other words, the present inventors have solved the problems mentioned above by discovering a thin film of gold or silver that could be stably coated on a metallic surface; sulfur compounds that form charge transfer complexes with said thin films and are strongly adsorbed onto the films; an
Ahn Dong-Jun
Kim Soo-Hyun
Kim Young-Ha
Lee Won-Kyu
Park Ki-Dong
Boykin Terressa M.
Korea Institute of Science and Technology
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