To date, the analytical performance of intravascular chemical sensors capable of continuously monitoring blood gases (pH, P02, PCO2) and electrolytes (e.g., K(+), Ca(+2), etc.) for extended periods in critically ill patients has been limited by problems associated with initiation of thrombus on the sensor surfaces as well as localized arterial constriction that diminishes blood flow at the implant site. The goal of the proposed research program will be to explore the chemistries required to fabricate implantable electrochemical and optical blood gas and electrolyte sensors with outer polymeric films that slowly release low levels of nitric oxide (NO) locally, at the implant site. Such in-situ release of NO should prevent platelet adhesion/activation on the surface of the sensors and, concomitantly, provide a sustained release of NO or NO precursors that will serve to dilate the artery immediately surrounding the sensor, thereby maintaining blood flow. Initial studies will focus on demonstrating the feasibility of preparing functional blood gas/electrolyte sensors with outer polymer films containing novel NO donor compounds (diazeniumdiolates; stable NO-NO adducts with amines)in addition to reagents required for selective chemical sensing. These investigations will involve developing polymer formulations/configurations that provide the appropriate rates of NO release required to decrease platelet adhesion/activation yet do not interfere with the sensor's analytical performance (e.g., selectivity, drift, etc.). In addition, new, more lipophilic and polymer bonded diazeniumdiolates will be synthesized in an effort to minimize contamination of the sample phase with residual donor diamines. In-vitro and in-vivo (rabbit model) platelet adhesion studies will be used to assess the biocompatibility of the different polymer/sensing films containing the various NO-NO adducts and results will be correlated with measurements of NO gas levels at the surface of the polymer films via an electrochemical NO microsensor. In-vivo analytical performance of intravascular blood gas sensors prepared with the NO release polymers will ultimately be assessed (in dogs) without systemic anticoagulation of the animals to determine the effect of local NO release on thrombogenicity and blood flow at the implant site.
|Frost, Megan C; Rudich, Steven M; Zhang, Huiping et al. (2002) In vivo biocompatibility and analytical performance of intravascular amperometric oxygen sensors prepared with improved nitric oxide-releasing silicone rubber coating. Anal Chem 74:5942-7|
|Parzuchowski, Pawel G; Frost, Megan C; Meyerhoff, Mark E (2002) Synthesis and characterization of polymethacrylate-based nitric oxide donors. J Am Chem Soc 124:12182-91|
|Saavedra, J E; Mooradian, D L; Mowery, K A et al. (2000) Conversion of a polysaccharide to nitric oxide-releasing form. Dual-mechanism anticoagulant activity of diazeniumdiolated heparin. Bioorg Med Chem Lett 10:751-3|
|Mowery, K A; Schoenfisch, M H; Saavedra, J E et al. (2000) Preparation and characterization of hydrophobic polymeric films that are thromboresistant via nitric oxide release. Biomaterials 21:21-Sep|
|Schoenfisch, M H; Mowery, K A; Rader, M V et al. (2000) Improving the thromboresistivity of chemical sensors via nitric oxide release: fabrication and in vivo evaluation of NO-releasing oxygen-sensing catheters. Anal Chem 72:1119-26|