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 greatly reduce the levels of
O2 in the catheter walls. Testing of such catheters in the arteries/veins of pigs and sheep will be conducted.
