ABSTRACT Therapeutic use of nitric oxide (NO) gas has several important applications in medicine. Inhaled NO (INO) has become a mainstay of intensive care for lung failure patients. As a pulmonary vasodilator, INO is essential in neonatology, lung transplantation, and pulmonary hypertension. As an inhaled antiseptic agent, NO has been proposed to treat chronic airway infection that occurs in cystic fibrosis, sinusitis, tuberculosis and COVID-19 infections. NO added to the sweep gas in extracorporeal circulation (ECC) prevents activation of platelets (preventing thrombosis) and white blood cells (preventing systemic inflam- matory response syndrome [SIRS]). Current methods of creating NO gas are extremely expensive owing to its instability at high concentrations within conventional gas cylinders. The use of NO to prevent intra- vascular (IV) catheter related infections and clotting has received considerable attention, including the incorporation of NO donors into IV catheter walls that dramatically reduces the risk of infection and thrombosis on catheter surfaces. Via prior NIH grants, we have developed a completely new and very low-cost electrochemical (E-chem) method to generate high purity NO gas (E-NOgen) for both inhalation and ECC applications, as well as to release NO from IV catheter surfaces. The method is based on the E-chem reduction of nitrite ions to NO gas via novel Cu(II)-ligand complexes. For gas phase NO genera- tion, a solution of nitrite and Cu(II) complex is circulated through a chamber with large area working and counter electrodes to generate the NO (by applying fixed current or voltage). The circulating solution is passed through a gas-exchange unit made with silicone or microporous polyethylene fibers so that the NO can permeate the fibers into a recipient stream of N2 gas for medical use. For the catheters, the Cu(II)- ligand complex and nitrite ions are contained in one lumen of a multi-lumen catheter with tiny wire electrodes to generate NO that then passes through all of the catheter walls to prevent infection/clotting. The major challenge in both of these applications is the effect of dioxygen (O2), decreasing the efficiency of NO generation by reacting with the intermediate Cu(I)-ligand species and by reacting with NO within the catheter walls or gas exchanger tubing, thereby greatly decreasing the total level of NO generated. In the proposed R01 grant, we will prepare a host of new Cu(II)-ligand complexes that have much lower O2 sensitivity and thereby enable higher levels of NO to be generated in the presence of ambient and physiological (arterial blood) levels of O2 for both the INO generator and IV catheter technology. We will optimize the reduction potential of the complexes to decrease O2 sensitivity and use ligands that provide hydrogen-bonding interactions to accelerate nitrite reduction. Further, for the IV catheters, immobilized oxidase enzymes on the outer surface and new materials will be explored to great...