Therapeutic use of gas phase nitric oxide (NO) has several important applications in medicine. Since its first medical application more than 20 years ago, inhaled nitric oxide (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 in the treatment of chronic airway infection that occurs in cystic fibrosis, sinusitis, and tuberculosis. Further, NO added to the sweep gas in extracorporeal circulation (ECC) prevents activation of platelets (preventing thrombosis) and white blood cells (preventing systemic inflammatory response syndrome (SIRS)). Current methods of creating and monitoring gas phase NO for these applications are expensive and inconvenient owing to the instability of high concentrations of NO within conventional gas cylinders. In this combined Phase I/II STTR application, NOTA Laboratories LLC will collaborate with researchers at the University of Michigan (U of M) to further develop a completely new and very low-cost electrochemical (E-chem) based compact, portable instrument to generate high purity gas phase NO for clinical applications (NOGEN). The method is based on the E-chem reduction of simple nitrite ions to NO gas via an optimized Cu(II)-ligand complex that channels electrons from a working electrode to efficiently reduce NO2- to NO(g). In Phase I, researchers at U of M and scientists/engineers at NOTA will work together to optimize the design of the E-chem NOGEN system, in terms of key components (e.g., using various metal mesh or foam, or metal/carbon ink electrodes, an optimized gas separator made with highly NO permeable silicone hollow fibers, optimal nitrite and Cu(II)- complex levels in the solution phase, and incorporation of NO/NO2 sensors for feedback/tight control of NO production, etc.). The accuracy in creating targeted gas phase NO levels with the high purity required for medical applications will also be verified in Phase I. In Phase II, further development of a prototype product will continue with full incorporation of all the components into a single compact NOGEN unit that will have replaceable electrode and electrolyte solution modules. In addition, the new prototype NOGEN system will be tested in animal models of CPB and INO at U of M to demonstrate the clinical potential and safety of this new, low-cost system. NOTA intends to first market the NOGEN system for use in preventing platelet activation and SIRS during CPB and then pursue applications of the NOGEN system for treating neonate/adult pulmonary hypertension, and further use as a home INO unit to treat chronic lung infections in cystic fibrosis patients.

Public Health Relevance

Inhaled nitric oxide (INO) gas is used routinely to treat pulmonary hypertension in newborns as well as adult patients with lung disorders. Use of NO within the oxygenator sweep gas during cardiopulmonary bypass (CPB) surgery is known to reduce activation of white cells that can lead to systemic inflammatory response syndrome (SIRS), as well as decrease platelet activation. Current medical use of NO requires tanks of NO gas that are very costly and unstable. In this Phase I/II STTR, NOTA Laboratories LLC will collaborate with researchers at the University of Michigan to further develop a completely new, low-cost electrochemical gas phase NO generator (NOGEN) for medical applications. This application focuses on developing a compact system initially for the CPB market, where higher levels of NO may be needed, although the proposed system can also be readily designed for hospital INO therapy as well as for use at home for patients with cystic fibrosis/chronic lung infections.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Small Business Technology Transfer (STTR) Grants - Phase II (R42)
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Special Emphasis Panel (ZRG1)
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Natarajan, Aruna R
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Nota Laboratories, LLC
Ann Arbor
United States
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