Thromboresistant/Bactericidal Intravascular Catheters Based on Electrochemical Nitric Oxide Generation

University Of Michigan At Ann Arbor, Ann Arbor MI

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Abstract

? DESCRIPTION (provided by applicant): Blood/material interaction is critical to the success of implantable medical devices including catheters, stents, grafts, and extracorporeal artificial organs, which are used in millions of patients every day. There are two major limiting factors to clinical application of blood-contacting materials: 1) platelet activation and thrombosis, and 2) infection. Nitric oxide (NO) secretion by the normal endothelium inhibits clotting by preventing platelet activation and adhesion. Further, NO is released by neutrophils and macrophages, which functions as a potent antimicrobial agent and is capable of preventing/dispersing biofilms. Over the past decade, novel materials have been developed that continuously secrete NO from various NO donors (S-nitrosothiols and diazeniumdiolates) embedded within polymers to prevent platelet adhesion, thrombosis and microbial biofilm formation on the surface of a number of biomedical devices (e.g., intravascular catheters/sensors, ECC loops, etc.). However, to date, there have not been any commercial applications of this technology owing to the high cost of preparing and shipping commodity devices (e.g., catheters) made with the fragile NO donors species, which are sensitive to moisture and increased temperature. The goal of this proposal is to overcome these hurdles by developing and optimizing a completely new, low cost, and robust generation of thromboresistant/bactericidal intravascular catheters via the use of electrochemically modulated NO release from an inner reservoir of simple inorganic nitrite salt. Soluble Cu(II)-ligand complexes, that mimic the active Cu(II/I) site of nitrite reductase enzymes, will be electrochemically reduced to Cu(I) complexes that can further mediate the reduction of nitrite to NO. Optimization of the electrochemistry will enable detailed in vitro studies of the NO release and antimicrobial activity of the new catheters. Additionally, short-term (8 h) and long-term (10 d) studies of the new electrochemical NO release catheters within the veins of rabbits will be conducted, with the goal of evaluating the efficacy of these devices in preventing thrombosis and bacterial adhesion in vivo. Success of this project could lead to a new generation of low-cost intravascular catheters that will dramatically reduce risk of common catheter related infections and thrombosis.