Improved hemocompatibility and analytical performance of intravascular oxygen sensors via nitric oxide (NO) releasing catheters

Abstract

Event Abstract Back to Event Improved hemocompatibility and analytical performance of intravascular oxygen sensors via nitric oxide (NO) releasing catheters Elizabeth Brisbois1, Hang Ren2, Madeline Mccabe2, Terry C. Major1, Mark E. Meyerhoff2 and Robert H. Bartlett1 1 University of Michigan, Surgery, United States 2 University of Michigan, Chemistry, United States Introduction: Continuous monitoring of blood analytes (e.g., blood gases, pH, glucose, lactate, etc.) could provide valuable information needed for the diagnosis and treatment of patients. However, implantable biosensors and other blood-contacting devices suffer from two major clinical problems: clotting and infection. Thrombus formation on implantable sensors can severely impact their accuracy due to the metabolic activity of adhered cells altering the local levels of the analytes. One approach to improving hemocompatibility is the development of polymers that mimic the NO release from the normal endothelium (NO surface flux of 0.5-4x10-10 mol cm-2 min-1) that is a known potent inhibitor of platelet adhesion/activation and endogenous antimicrobial agent. One approach has been the development of NO releasing polymers by incorporation of NO donor molecules, such as S-nitrosothiols (RSNOs) [1]-[3]. However, many RSNO-based polymers have been limited by rapid leaching, low synthetic yields, and instability during storage. Recent work has shown that incorporating S-nitroso-N-acetylpenicillamine (SNAP) within hydrophobic polymers creates materials with long-term NO release and excellent storage stability [4]. In this study, a novel solvent swelling technique is used to load the walls of catheters with SNAP. The SNAP-based catheters are used to fabricate intravascular oxygen (PO2) sensors and their biocompatibility is evaluated in a rabbit model. Methods: The SNAP-based catheters were prepared by swelling silicone rubber catheters in a tetrahydrofuran solution containing SNAP. Control and SNAP-based catheters were used to fabricate the Clark-style amperometric PO2 sensors. The catheter lumen was filled with 0.15 M KCl in 0.1 M bicarbonate/carbonate buffer (pH 10). A Pt and a Ag/AgCl wire were inserted in the catheter lumen, and both ends of the catheter were sealed with silicone rubber. The PO2 sensors were soaked in 10 mM PBS, 100µM EDTA at 37 °C. NO release from the SNAP-based PO2 sensors under physiological conditions was determined via a chemiluminescence NO analyzer (Sievers280i, Boulder, CO). Sensors were calibrated by immersing in PBS and bubbling with O2 (0-100%). A potential of -0.7 V was applied to the Pt working electrode and the current was recorded. A rabbit model (sensors placed in veins) was used to evaluate the effects on thrombus formation and analytical PO2 sensing performance, as compared to a blood gas analyzer. After 7 h, the sensors were explanted, pictures were taken of the thrombus, and the 2D representation of the thrombus area was determined with the NIH ImageJ software. Results: The SNAP-based PO2 sensors can release NO under physiological conditions for up to 2 weeks (Fig. 1). During in vitro calibrations, the SNAP-based and control sensors had similar responses to various levels of oxygen in terms of sensitivity and response times (Fig. 2). Control (without NO release) and SNAP-based PO2 sensors were evaluated in a rabbit model. The SNAP-based PO2 sensors were found to accurately measure the PO2 levels in blood (within 10% of a standard benchtop blood gas analyzer). At the end of 7 h, the SNAP-based PO2 sensors were also found to have significantly reduced thrombus formation (as compared to controls). Conclusions: NO releasing catheters can be prepared with a novel solvent swelling technique that loads the walls of existing/commercial silicone rubber catheter tubing with SNAP. These SNAP-based catheters can be used to fabricate intravascular PO2 sensors with enhanced hemocompatibility properties and more accurate PO2 measurements. The NO release levels observed from the SNAP-based PO2 sensors are expected to also possess antimicrobial properties against bloodborne pathogens (e.g., S. aureus, S. epidermidis) [5],[6]. The SNAP solvent swelling technique also has the potential of improving the hemocompatibility of other blood-contacting devices (e.g., catheters, extracorporeal circuits, etc.). This work was supported in part by the University of Michigan Postdoctoral Translational Scholars Program (UL1TR000433) and NIH grant R01HL128337.