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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL128337-03
Application #
9316710
Study Section
Biomaterials and Biointerfaces Study Section (BMBI)
Program Officer
Baldwin, Tim
Project Start
2015-08-01
Project End
2019-07-31
Budget Start
2017-08-01
Budget End
2018-07-31
Support Year
3
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Surgery
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109