Electrochemically Modulated Generation/Delivery of Nitric Oxide (NO) from Nitrite for Biomedical Applications.

Abstract

In this dissertation research, the development of a new electrochemically modulated NO generation/delivery approach was examined. Further, the potential application of this approach in devising advanced thromboresistant/bactericidal intravascular catheters and a new NO inhalation therapy system was explored. Nitric oxide can be generated from nitrite via two electrochemical approaches: 1) using a Cu0 wire and an applied anodic/cathodic potential pulse sequence to electrochemically reduce nitrite to NO (Chapter 2); and 2) using Pt/Au or other working electrodes and a soluble Cu(II)-ligand complex as mediator to reduce nitrite to NO (Chapter 3). The temporal pattern of NO generation can be precisely modulated in the latter system by the applied potential or current. This electrochemical NO release system was first incorporated within intravascular catheters, which exhibited much reduced clotting (~85 %) in vivo and significantly less (>99.9%) microbial biofilm in vitro compared to non-NO release control devices. Further, this NO release concept was combined with an amperometric oxygen sensor (PO2 sensor) within a dual-lumen catheter configuration (Chapter 4) for intravascular continuous monitoring of PO2 levels. Electrochemical NO release was fully compatible with PO2 sensing and yielded more accurate PO2 measurements (vs. controls) when implanted in arteries of pigs for 20 h. In Chapter 5, the electrochemical NO release catheters were used for controlled delivery of NO to elucidate the dosage effect of NO on mature P. aeruginosa biofilm. Fluxes of NO >0.5 × 10^-10 mol min-1 cm-2 showed 99% killing of the biofilm in 3 h, and such an effect was in synergy with added gentamicin. In Chapter 6, the new electrochemical NO delivery method was employed for developing a gas phase NO inhalation (INO) system. Relatively pure gas phase NO in the range of 1–150 ppmv can be created by this system. Finally, the partitioning and diffusion properties of NO within several biomedical polymers was examined (Chapter 7), with silicone rubber exhibiting the optimal transport of NO. Overall, electrochemical delivery of NO provides both a tool for fundamental biological studies, as well as a means to improve the biocompatibility of medical devices.