Plasma modified medical devices and methods

Abstract

Coatings, devices and methods are provided, wherein the contacting surface of a medical device with at least one contacting surface for contacting a bodily fluid or tissue, wherein long-lasting and durable bioactive agents or functional groups are deposited on the contacting surface through a unique two-step plasma coating process with deposition of a thin layer of plasma coating using a silicon-containing monomer in the first step and plasma surface modification using a mixture of nitrogen-containing molecules and oxygen-containing molecules in the second step. The two-step plasma coating process enables the implantable medical device to prevent both restenosis and thrombosis under clinical conditions. The invention also relates to surface treatment of metallic and polymeric biomaterials used for making of medical devices with significantly improved clinical performance and durability.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application claims the benefit of U.S. Provisional Application No. 61 / 524,434, filed Aug. 17, 2011, which is hereby incorporated by reference herein in its entirety, including but not limited to those portions that specifically appear hereinafter, the incorporation by reference being made with the following exception: In the event that any portion of the above-referenced provisional application is inconsistent with this application, this application supercedes said above-referenced provisional application.STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT[0002]This invention was made with government support under grant No. 1R44HL097485-01A2 from the National Institutes of Health. The government has certain rights in the invention.FIELD OF THE INVENTION[0003]This invention relates to applications and methods for glow discharge plasma coatings for medical devices with improved long-term biocompatibility for clinical pract...

AI Technical Summary

Benefits of technology

[0061]It is a feature of an illustrative embodiment of the present invention to provide a novel biocompatible coating of high thrombo-resistance on the surface of metallic biomaterials of which coronary stents are made. As an environmentally benign technology, a low temperature plasma process is invented to deposit an ultra-thin (nano-scale) but continuous layer of coating, sufficient to generate the desired abrasion resistance and immobilize the bioactive functional groups created in the subsequent plasma surface treatment to prevent blood clots and restenosis, but thin enough to allow for stent expansion without cracking when delivered into patients. The plasma modified metallic surfaces exhibit the following properties: 1) non-clot formation on the NH3 / O2 plasma treated stainless steel (SS) surface, combined with increased apoptosis in smooth muscle cells (SMC), and non-inflammatory responses; 2) a thin trimethylsilane (TMS) coating followed by NH3 / O2 plasma surface modification with direct current (DC) plasma which delivers statistically significant increases in coronary artery endothelial cell (EC) attachment without promoting SMC proliferation on SS wafers at 12 weeks after plasma coating, suggesting formations of stable and durable bioactive surfaces; 3) a stainless steel stent coated with the two-step plasma coating with DC plasma which exhibits significantly less intimal hyperplasia than untreated controls in swine arteries; 4) surface bound NO functional groups which play a role similar to free NO in inhibiting fibrinogen adsorption and preventing platelet aggregation; and 5) a preferred plasma coating in thickness of 20 nm which shows robust adhesion to SS substrates and no coating cracks observed after stent expansion. In addition to application to coronary stents, the significantly improved biocompatibility for medical devices can also be employed for other implantable medical devices such as pacemakers, pulse generators, cardiac defibrillators and bio-sensors, etc.

Problems solved by technology

Coronary heart disease (CHD) caused by atherosclerosis, the narrowing of the coronary arteries due to fatty build up of plaque, remains a major healthcare problem in the US.

However, concerns were raised in recent years about the safety of DES due to a reportedly small but significantly increased risk of blood clots in the stent within 1 year after stenting (i.e. stent thrombosis).

While not frequent, late stent thrombosis is a life-threatening problem.

Each year about 600,000 Americans are getting DES [Stent facts. http: / / americanheart.mediaroom.com / ], which means that even a small increased risk could result in thousands of heart attacks and deaths.

Furthermore, the requirement for prolonged, aggressive anti-thrombotic therapy after placement of a DES (usually aspirin and clopidogrel) can introduce major complications into the management of patients who require surgical procedures (which necessitate temporary discontinuation of anti-thrombotic drugs) within the first year after PCI.

Restenosis following angioplasty, however, is a major clinical problem since the biological response to this vessel damage is stimulation of accelerated growth of arterial smooth muscle cells.

Biomater Sci Polym Ed, 21(4): 529-552, 2010], but further investigation for clinical use is needed, and recent morphology studies of biodegradable coatings have shown cracks in the coatings after stent expansion [Basalus et al.

However, no systematical study for stent application has been reported.

J Biomed Mater Res (Appl Biomater), 53: 244-251, 2000], but the polyurethane used as a sealant for the radioactive agent on the stent surface remains problematic in causing chronic inflammation.

In summary, none of those aforementioned approaches addresses both issues of late thrombosis and in-stent restenosis with one specific coating.

However, in large animal studies with this patented plasma technology, certain, often large variations have been observed on the patency of plasma treated stents after implantation, which is believed to be due to the potential instability of surface bioactivity generated by the single-step NH3 / O2 plasma surface treatment on bare stainless steel surfaces.

As discussed above, the currently available coronary stents and the methods under development for improved biocompatibility of stents have the following crucial problems: 1) existing stent procedures with BMS still experience a high incidence of restenosis; 2) although DES, in comparison with BMS, have been much more widely used due to their better ability in controlling restenosis carry the risk of developing late stent thrombosis, which is associated with a clinically significant risk of mortality; and 3) most existing coating processes investigated have the major limitation of being incapable of preventing restenosis and thrombosis at the same time.

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