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Nitric Oxide Generating Coatings for Implantable Biomedical Devices

Himabindu Nandivada1, Hsien-Yeh Chen1, Sangyeul Hwang2, Cortney White3, Melissa M. Reynolds3, Scott I. Merz3, Mark E. Meyerhoff2, and Joerg Lahann4. (1) Chemical Engineering Department, University of Michigan, 2300 Hayward St, 3434 G.G Brown, Ann Arbor, MI 48109, (2) Chemistry Department, University of Michigan, Ann Arbor, MI, (3) MC3 Corp., 3550 W. Liberty Rd., Suite 3, Ann Arbor, MI 48103, (4) University of Michigan, Dept. of Chemical Engineering, 3074 H.H. Dow Bldg., Ann Arbor, MI 48109-2136

The incompatibility of most implantable device materials with human blood and tissue is the major cause of complications in patients, which ultimately leads to functional device failure. Research has shown that nitric oxide (NO) is a potent inhibitor of platelet function and smooth muscle cell proliferation and is therefore an interesting naturally occurring drug candidate to combat adverse human body responses to foreign biomedical implants. NO is generated within endothelial cells that line the walls of all blood vessels, so by mimicking the healthy endothelium, NO-generating materials can exhibit blood compatibility. It has been recently shown that NO can be generated in vivo from endogenous NO precursors such as nitrite and nitrosothiols, already present in the blood, via the catalytic action of copper(II) ions.[1] Herein we present coatings that contain immobilized Cu(II)-complex sites as biomimetic catalysts. These coatings were synthesized by covalently attaching the Cu(II)-complex sites to a vapor-based polymer. Using poly(4-benzoyl-p-xylylene-co-p-xylylene) as the adhesion layer, a hydrogel containing Cu(II)-chelating sites was attached to the substrate. The solution containing the copper polymethacrylates was photopolymerized and concomitantly crosslinked by photoactivating the CVD polymer, thus creating a crosslinked hydrogel attached to the CVD polymer. The resulting coating was characterized using FTIR spectroscopy. Surfaces were analyzed for copper content using X-ray photoelectron spectroscopy (XPS).The NO generating capacity of these surfaces was measured using standard chemiluminescence detection. We also found that during in vitro experiments, these coatings were able to convert nitrosothiols into NO under physiological conditions (37oC, pH 7.4). On the other hand, polymer coated samples, that did not contain the Cu(II) complex did not generate significant levels of NO. This technology could be applicable to a wide range of implantable biomedical devices including intravascular catheters, implantable sensors, pacemaker leads, vascular grafts and cardiovascular stents.

References: [1] S-Y. Hwang, W. Cha, M. E. Meyerhoff, Polymethacrylates with a covalently linked Cu(II)-Cyclene complex for in situ generation of nitric oxide from nitrosothiols in blood, Angew. Chemie. Int. Ed. 2006, 118, 2811-2814.