! 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 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 yet been any commercial applications of this technology owing to the high cost of preparing and shipping commodity devices made with the fragile NO donors species, which are often sensitive to moisture and increased temperature. To overcome this hurdle, we now propose a completely new, low cost and robust alternate method to create a new generation of thromboresistant/bactericidal intravascular and urinary catheters, as well as other biomedical devices. This approach is based on the use of electrochemically modulated NO release from an inner reservoir of a simple inorganic nitrite salt. The most promising approach toward this goal is to utilize 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) species that further mediate the one electron reduction of nitrite to NO. Substantive preliminary data are already in hand (based on a R-56 bridge award) demonstrating the ability of such electrochemical NO release catheters to prevent and/or disperse microbial biofilm formation in vitro and also substantially decrease thrombus formation in vivo. Further optimization of the electrochemistry, especially identifying new Cu(II)-ligand complexes that have high efficiency in mediating the reduction of nitrite to NO, and modeling/testing the NO release profiles of this approach in a dual-lumen catheter configuration is needed to enable extensive in vitro and in vivo studies. In vitro testing will focus on examining the antimicrobial activity of the basic technology, especially with respect to activity against microbes commonly associated with intravascular and urinary catheter induced clinical infections. Additionally, the proposed research will include studies of the new electrochemical NO release catheters within the veins/arteries sheep (14 d) with the goal of evaluating the efficacy of these devices in preventing thrombosis and microbial biofilm formation in vivo. An in vivo comparison study of the intravascular antimicrobial activity of the new electrochemical NO release catheters vs. commercial antibiotic impregnated catheters will also be conducted. A miniaturized battery powered circuitry will be developed to aid in the 14 d studies in fully awake sheep. Success of this project could lead to a new generation of low-cost catheters (both intravascular and urinary) that will dramatically reduce the risk of common catheter related infections as well as thrombosis. !

Public Health Relevance

This grant application focuses on the development of a novel electrochemical approach to create nitric oxide (NO) releasing catheters and the evaluation of the antithrombotic/bactericidal activity of these devices in vitro and within an appropriate animal model. 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. This new technology could also be used in many other biomedical devices such as urinary catheters, intravascular chemical sensors, and wound healing patches.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL132037-02
Application #
9405609
Study Section
Bioengineering, Technology and Surgical Sciences Study Section (BTSS)
Program Officer
Luksenburg, Harvey
Project Start
2017-01-01
Project End
2020-12-31
Budget Start
2018-01-01
Budget End
2018-12-31
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
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