Continued studies aimed at preparing, characterizing and testing the in vivo thromboresistivity/biocompatibility of novel polymeric materials capable of catalytically generating nitric oxide (NO) from endogenous S- nitrosothiol (RSNO) species in blood are proposed. Results from Phase I studies have demonstrated that polymers modified with given Cu(II)-complexes as well as organoselenium (RSe) species are capable of generating physiologically relevant levels of NO when bathed in solutions containing 5M levels of RSNOs, the concentrations of RSNOs found in fresh blood. In addition, use of the same catalytic polymer chemistries to devise novel electrochemical RSNO sensors has yielded devices that respond to RSNO concentrations in whole blood, further proving the capability of these materials for generating NO when in contact with blood. Nitric oxide is well known to be a potent inhibitor of platelet activation and adhesion as well as smooth muscle cell proliferation. Hence, the local generation of NO at a polymer/blood interface should significantly reduce the risk of thrombus formation on the surface of polymer coated medical devices, including stents, vascular grafts, implanted catheters and sensors, etc. Ongoing efforts (including results from Phase I of this project and other studies) have shown clearly that NO release polymers developed earlier as well as the newer NO generating polymers do inhibit thrombus formation on the surface of implanted devices. Our goals for Phase II will now focus on: 1) further synthesizing an array of biomedical grade polyurethanes (PUs) with covalently attached Cu(II)-cyclen complexes as catalytic sites, as well as preparing/evaluating PUs with embedded Cuo micro/nanoparticles that can also generate NO from RSNOs;2) developing methods to attach RSe catalytic sites to PUs and also examining a new Layer-by-Layer (LbL) polyelectrolyte deposition method to immobilize the RSe sites on any biomedical polymer or device surface (including titanium and stainless steel);3) studying the ability of the polymer coatings devised in (1) and (2) for producing NO catalytically when in contact with various RSNOs species, and assessing changes in catalytic NO generation as a function of time (due to catalytic site leaching, poisoning, etc.);4) examining the toxicity of the new Cu and RSe-based coatings using standard ISO protocols with small animals (mice and rabbits);and 5) testing the longer-term in vivo thromboresistance of the most promising new NO generating coatings in porcine animal model of peripheral vascular grafts developed by collaborators at the University of Cincinnati Medical School. We anticipate that the studies described in this application will lead to a variety of novel biomimetic materials that will have immediate applications for preparing/coating a host of medical implants to reduce the risk of in vivo thrombosis.

Public Health Relevance

There is a great need in the biomedical community for novel polymeric coatings that can enhance the biocompatibility and functionality of a wide range of medical devices including catheters, vascular grafts, stents, in vivo chemical sensors, extracorporeal circuits, etc. Indeed, there exists a lingering risk of life- threatening thrombosis on the surface of these blood-contacting devices that continues to be a serious hazard to patients who receive such interventions. The proposed research will have an immediate impact by providing device manufacturers with new coatings that can prevent clots from forming on the surface of medical implants via spontaneous generation of nitric oxide, a potent anti-platelet agent, from a pool of endogenous S-nitrosothiol species that already exists in blood.

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Research Project (R01)
Project #
5R01EB004527-08
Application #
8241135
Study Section
Special Emphasis Panel (ZRG1-BCMB-B (02))
Program Officer
Hunziker, Rosemarie
Project Start
2004-12-01
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2014-03-31
Support Year
8
Fiscal Year
2012
Total Cost
$319,157
Indirect Cost
$69,080
Name
University of Michigan Ann Arbor
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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