Infection and thrombosis on intravascular catheters are major, expensive problems in medical practice. Over the last ten years we have demonstrated that surface nitric oxide (NO) release can solve these problems, using various NO donor molecules (e.g., diazeniumdiolates, S-nitrosothiols (RSNOs)) incorporated into polymeric catheter tubing. This technology is based on the fact that NO released within the sinus cavities and by neutrophils and macrophages functions as a potent natural antimicrobial and antiviral agent. Further, NO secretion by the normal endothelium prevents clotting by preventing platelet adhesion and activation. We have developed polymers that continuously produce NO to prevent biofilm formation, platelet adhesion, and thrombosis in relevant animal models of intravascular catheters. Although effective, the cost, toxicity, and preparation of the donor molecules used to date have prevented clinical application. We have recently discovered that all of the positive effects of NO release can be achieved with the NO donor molecule S-nitroso-N-acetylpenicillamine (SNAP). In contrast to earlier NO release materials, polymers that are doped/impregnated with SNAP are easy to fabricate, nontoxic, inexpensive, and very stable. We will develop new methods of fabricating NO release catheters with polymer stabilized SNAP (e.g., solvent impregnation, NO releasing multilumen catheters, etc.). The chemistry laboratory directed by Dr. Meyerhoff will create and evaluate combinations of SNAP loaded into polyurethane and silicone catheters, optimize NO release rates for 21 d, reduce leaching rates, enhance durability, and demonstrate the ability to sterilize without significant loss in NO loading Dr. Bull, a bioengineer, will model NO release from certain multi-lumen catheter configurations and also oversee testing of the physical properties of the catheters (e.g., durometer, surface roughness, etc.), in terms of potential changes in such parameters as a result of SNAP impregnation. Dr. Xi's laboratory in the School of Public Health, will examine the antimicrobial/antibiofilm activity of the new NO release catheters against several microbes known to be associated with infections caused by intravascular catheters in hospitalized patients. The large animal laboratory, directed by Dr. Bartlett, will evaluate the optimized NO secreting catheters in chronic animal testing to evaluate effect on biofilm and thrombosis formation. This bioengineering research grant (BRG) combines new basic chemistry of RSNO-based NO release agents in biomedical polymers, the bioengineering to use this chemistry to make practical devices, the microbiological studies to prove effectiveness against targeted bacterial strains, and biologic evaluation in animal models, all leading to clinical translation in four years.

Public Health Relevance

This is a bioengineering research grant (BRG) application that combines advances in the basic chemistry of nitric oxide (NO) release from S-nitrosothiol impregnated polymers with biologic evaluation of these new NO release materials' bactericidal/antithrombotic activities in animal models. Specifically, this research will focus on the development of novel intravascular catheters that secrete NO in a durable and controlled fashion, thereby solving two major clinical problems associated with existing intravascular catheter placement: infection and thrombosis.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Biomaterials and Biointerfaces Study Section (BMBI)
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Baldwin, Tim
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University of Michigan Ann Arbor
Schools of Medicine
Ann Arbor
United States
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Xu, Li-Chong; Meyerhoff, Mark E; Siedlecki, Christopher A (2018) Blood coagulation response and bacterial adhesion to biomimetic polyurethane biomaterials prepared with surface texturing and nitric oxide release. Acta Biomater :
Wang, Xuewei; Jolliffe, Aaron; Carr, Benjamin et al. (2018) Nitric oxide-releasing semi-crystalline thermoplastic polymers: preparation, characterization and application to devise anti-inflammatory and bactericidal implants. Biomater Sci 6:3189-3201
Xu, Li-Chong; Wo, Yaqi; Meyerhoff, Mark E et al. (2017) Inhibition of bacterial adhesion and biofilm formation by dual functional textured and nitric oxide releasing surfaces. Acta Biomater 51:53-65
Wo, Yaqi; Li, Zi; Colletta, Alessandro et al. (2017) Study of Crystal Formation and Nitric Oxide (NO) Release Mechanism from S-Nitroso-N-acetylpenicillamine (SNAP)-Doped CarboSil Polymer Composites for Potential Antimicrobial Applications. Compos B Eng 121:23-33
Wo, Yaqi; Brisbois, Elizabeth J; Wu, Jianfeng et al. (2017) Reduction of Thrombosis and Bacterial Infection via Controlled Nitric Oxide (NO) Release fromS-Nitroso-N-acetylpenicillamine (SNAP) Impregnated CarboSil Intravascular Catheters. ACS Biomater Sci Eng 3:349-359
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Ketchum, Alex R; Kappler, Michael P; Wu, Jianfeng et al. (2016) The preparation and characterization of nitric oxide releasing silicone rubber materials impregnated with S-nitroso-tert-dodecyl mercaptan. J Mater Chem B 4:422-430