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Principal Investigator: Nicolai Lehnert
Organization: UNIVERSITY OF MICHIGAN AT ANN ARBOR
Fiscal Year: 2024
Award: $481,657
Funding agency: National Heart Lung and Blood Institute
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.
Terms: <Acceleration><Air><Airway infections><Animal Model><Animal Models and Related Studies><Anti-viral Agents><Antibiotic Resistance><Antiseptics><Area><Arteries><Attention><Bacteria><Bacterial Infections><Blood><Blood Clotting><Blood Reticuloendothelial System><Blood coagulation><Blood leukocyte><COVID-19 infection><COVID-19 virus infection><COVID19 infection><Catheters><Chronic><Clotting><Coagulation><Coagulation Process><Complex><Copper><Cu element><Cystic Fibrosis><Dedications><Devices><Diffusion><Dioxygen><Effectiveness><Electrodes><Elements><Endogenous Nitrate Vasodilator><Endothelium-Derived Nitric Oxide><Enzyme Gene><Enzymes><Ethene Homopolymers><Ethylene Homopolymers><Ethylene Polymers><Extracorporeal Circulation><Family suidae><Fiber><Gases><Generations><Goals><Grant><H-bond><Hospitals><Hydrogen Bonding><Hydrophobicity><Immobilization><Infection><Infection prevention><Inhalation><Inhaling><Intensive Care><Ions><Leukocytes><Leukocytes Reticuloendothelial System><Ligands><Local Anti-Infective Agents><Lung><Lung Grafting><Lung Respiratory System><Lung Transplantation><M tuberculosis infection><M. tb infection><M. tuberculosis infection><M.tb infection><M.tuberculosis infection><MTB infection><Marrow leukocyte><Mediator><Medical><Medicine><Membrane><Methods><Microbial Biofilms><Microcid><Mononitrogen Monoxide><Mucoviscidosis><Mycobacterium tuberculosis (MTB) infection><Mycobacterium tuberculosis infection><NIH><NO2><National Institutes of Health><Neonatology><Nitric Oxide><Nitric Oxide Donors><Nitrites><Nitrogen><Nitrogen Dioxide><Nitrogen Monoxide><Nitrogen Peroxide><Nitrogen Protoxide><Output><Ovine><Ovis><Oxidases><Oxidation-Reduction><Oxygenators><Patients><Performance><Phase><Physiologic><Physiological><Pigs><Platelet Activation><Polyethylenes><Polymers><Polythene><Porosity><Prevent infection><Prevention><Production><Publications><Pulmonary Graft><Pulmonary Hypertension><Pulmonary Transplant><Pulmonary Transplantation><Reaction><Redox><Research><Resistance to antibiotics><Resistant to antibiotics><Respiratory Infections><Respiratory Tract Infections><Risk Reduction><SARS-CoV-2 infection><SARS-CoV2 infection><Safety><Scientific Publication><Sepsis><Severe acute respiratory syndrome coronavirus 2 infection><Sheep><Silicones><Sinusitis><Stream><Suidae><Surface><Swine><System><Systemic Inflammatory Response Syndrome><TB infection><Technology><Testing><Therapeutic Uses><Thrombosis><Time><Topical Anti-Infective Agents><Tube><Tuberculosis><United States National Institutes of Health><Vasodilating Agent><Vasodilator Agents><Vasodilator Drugs><Vasodilators><Veins><White Blood Cells><White Cell><anti-microbial><anti-viral compound><anti-viral drugs><anti-viral medication><anti-viral therapeutic><anti-virals><antibiotic drug resistance><antibiotic resistant><antimicrobial><bacteria infection><bacterial disease><biofilm><blood infection><bloodstream infection><carboxylate><catalyst><catheter related infection><coronavirus disease 2019 infection><cost><diffused><diffuses><diffusing><diffusions><disseminated TB><disseminated tuberculosis><endothelial cell derived relaxing factor><fighting><glucose oxidase><iNO><improved><infected with COVID-19><infected with COVID19><infected with SARS-CoV-2><infected with SARS-CoV2><infected with coronavirus disease 2019><infected with severe acute respiratory syndrome coronavirus 2><infection due to Mycobacterium tuberculosis><infection risk><inhaled nitric oxide><lung failure><lung transplant><membrane structure><model of animal><novel><orthopedic freezing><ovine animal model><ovine model><oxidation reduction reaction><polymer><polymeric><porcine><portability><prevent><preventing><pulmonary><pulmonary failure><reduce risk><reduce risks><reduce that risk><reduce the risk><reduce these risks><reduces risk><reduces the risk><reducing risk><reducing the risk><risk-reducing><scaffold><scaffolding><sheep model><suid><thrombotic disease><thrombotic disorder><tuberculosis infection><tuberculous spondyloarthropathy><voltage><white blood cell><white blood corpuscle>