To date, efforts to develop clinically viable in vivo chemical sensors for real-time monitoring of blood gases, electrolytes, glucose, lactate, etc. in critically ill hospital patients have been stymied by the inaccurate analytical results obtained owing to sensor biocompatibility problems (cell adhesion, thrombus formation, inflammatory response, etc.). The goal of this research program is to explore and optimize the chemistries required to fabricate in vivo chemical sensors with outer polymeric coatings that slowly release or generate low levels of nitric oxide (NO). The local release/generation of NO mimics the chemistry that occurs at the inner walls of all healthy blood vessels (NO production by endothelium) and is expected to greatly enhance the biocompatibility and concomitant analytical performance of the implanted sensors. Indeed, results during the first 3 phases of NIH support have clearly demonstrated that in situ release and/or generation of NO significantly reduces surface thrombus formation and improves in the in vivo analytical accuracy of intravascular oxygen sensors, and also reduces inflammatory response for glucose sensors implanted subcutaneously. Newly developed NO generating polymers, based on spontaneous catalytic decomposition of endogenous S-nitrosothiols (RSNOs) at immobilized Cu(II) or organoselenium (RSe) sites, are potentially the most attractive coatings for preparation implanted sensors. However, any significant variability in endogenous levels of RSNOs in blood may ultimately dictate whether these NO generation type polymers can provide results equivalent to NO release coatings (with NO donors doped or covalently linked to polymers). Therefore, in the final phase of studies, the most promising NO release and NO generation coatings will be evaluated side-by-side via in vivo studies with coated sensors implanted intravascularly (arteries and veins) within pigs and rabbits. Beyond oxygen sensors, greater emphasis will be placed on also demonstrating improved biocompatibility/performance for intravenous glucose and lactate electrochemical sensors prepared with these coatings. Such sensors are sorely needed in the ICU and other critical care hospital units where tight glycemic control of patients significantly improves outcomes, and where trends in blood lactate levels are viewed as an important prognosticator of patient recovery. Measurements of RSNO species in the test animals with improved electrochemical RSNO sensors will also be carried out to assess whether there is a clear correlation in analytical performance/thrombus formation for sensors prepared with the NO generating coatings vs. measured RSNO blood levels. The ability to reliably measure critical care analytes (blood gases, electrolytes, metabolites) in blood continuously at a patient's bedside is the "holy grail" for biomedical sensor technology, and this goal can only be achieved when sensor performance is not compromised by biocompatibility issues. Hence, the success of this research will have significant impact in the ability improve the quality of health care for critically ill patients.

Public Health Relevance

The ability to accurately measure critical care analytes (blood gases, electrolytes, glucose, lactate, urea, etc.) in blood continuously at a patient's bedside with intravascular sensors is the "holy grail" for biomedical sensor technology. This goal can only be achieved when sensor performance is not compromised by biocompatibility issues that result in thrombus formation on the surface of the sensors, yielding inaccurate measurements of target analytes. Hence, success of the proposed research program will have significant impact on the ability enhance the quality of health care for critically ill patients by providing an approach (NO release/generation polymeric coatings) to dramatically improve the biocompatibility and concomitant analytical performance of miniaturized chemical sensing catheters implanted within blood vessels.

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Research Project (R01)
Project #
5R01EB000783-15
Application #
8204837
Study Section
Special Emphasis Panel (ZRG1-BCMB-B (02))
Program Officer
Korte, Brenda
Project Start
1998-01-01
Project End
2013-12-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
15
Fiscal Year
2012
Total Cost
$319,368
Indirect Cost
$103,098
Name
University of Michigan Ann Arbor
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Ren, Hang; Wu, Jianfeng; Colletta, Alessandro et al. (2016) Efficient Eradication of Mature Pseudomonas aeruginosa Biofilm via Controlled Delivery of Nitric Oxide Combined with Antimicrobial Peptide and Antibiotics. Front Microbiol 7:1260
Ren, Hang; Bull, Joseph L; Meyerhoff, Mark E (2016) Transport of Nitric Oxide (NO) in Various Biomedical grade Polyurethanes: Measurements and Modeling Impact on NO Release Properties of Medical Devices. ACS Biomater Sci Eng 2:1483-1492
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 Mater Biol Med 4:422-430
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Ren, Hang; Coughlin, Megan A; Major, Terry C et al. (2015) Improved in vivo performance of amperometric oxygen (PO2) sensing catheters via electrochemical nitric oxide generation/release. Anal Chem 87:8067-72
Zheng, Zheng; Ren, Hang; VonWald, Ian et al. (2015) Highly sensitive amperometric Pt-Nafion gas phase nitric oxide sensor: Performance and application in characterizing nitric oxide-releasing biomaterials. Anal Chim Acta 887:186-91
Brisbois, Elizabeth J; Davis, Ryan P; Jones, Anna M et al. (2015) Reduction in Thrombosis and Bacterial Adhesion with 7 Day Implantation of S-Nitroso-N-acetylpenicillamine (SNAP)-Doped Elast-eon E2As Catheters in Sheep. J Mater Chem B Mater Biol Med 3:1639-1645
Ren, Hang; Colletta, Alessandro; Koley, Dipankar et al. (2015) Thromboresistant/anti-biofilm catheters via electrochemically modulated nitric oxide release. Bioelectrochemistry 104:10-6

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