Nitric oxide (NO) secretion by the normal endothelium inhibits clotting by preventing platelet activation and adhesion. Nitric oxide is also a potent antimicrobial agent and is capable of preventing/dispersing biofilms. Over the past decade, several groups, including ours, have developed novel materials 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, extracorporeal circulation loops, etc.) and wound healing bandages. 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, bandages, etc.) made with the fragile NO donors species, which are sensitive to moisture and increased temperature. To overcome this hurdle, we now propose a completely new, low cost and robust method to create a new generation of thromboresistant/bactericidal intravascular and urinary catheters, as well as other biomedical devices, via use of electrochemically modulated NO release from an inner reservoir of simple inorganic nitrite salt. One approach relies on electrochemically reducing the stable nitrite ions via electrochemical generation of transient Cu(I) ions from a metallic copper wire electrode that reduce nitrite to NO. Alternatively, we will also explore the use of soluble Cu(II)-ligand complexes that mimic the active Cu(II/I) site of nitrite reductase enzymes. These complexes can be electrochemically reduced to Cu(I) complexes that further mediate the reduction of nitrite to NO. Preliminary data already demonstrate the ability of electrochemical NO release catheters to prevent and/or disperse microbial biofilm formation in vitro and also dramatically decrease thrombus formation in vivo. Further optimization of the electrochemistry will enable detailed in vitro studies on the antimicrobial activity of the basic technology. Additionally, it will allow shrt- term (8 h) and long-term (7 and 30 d) studies of the new electrochemical NO release catheters within the veins of rabbits with the goal of evaluating the efficacy of these devices in preventing thrombosis and microbial biofilm formation in vivo. Miniaturized battery powered circuitry will be developed to aid in the longer-term studies in freely moving animals. Success of this project could lead to a new generation of low- cost catheters (both intravascular and urinary) that will dramatically reduce risk of common catheter related infections and thrombosis, and it may also provide a novel technology for creating planar NO release patches that can readily employed to promote wound healing.
This grant application focuses on the development of novel electrochemical approaches to create nitric oxide (NO) releasing catheters and the evaluation of the antithrombotic/bactericidal activity of these devices in vitro and within appropriate animal models. The controlled electrochemical release of NO from inexpensive nitrite ion reservoir within one lumen of a multi-lumen catheter will provide a low-cost/robust solution to two major clinical problems associated with existing intravascular catheter placement, thrombosis and infection, and could also be used in other biomedical devices, such as urinary catheters and wound healing patches.