Implantable Amperometric Glucose/Lactate Sensors with Nitric Oxide Release/ Generation Coatings for Enhanced Biocompatibility and Needle-Type Glucose Sensor for Tear Glucose Measurements.

Abstract

One of the greatest technological challenges of implantable biosensors is the biocompatibility problem that arises after implantation. Nitric oxide (NO) is known as a potent anti-thrombus and anti-inflammatory agent released by healthy endothelial cells. Hence, this dissertation research focuses on developing novel NO releasing/generating coatings to enhance the biocompatibility of implantable glucose/lactate sensors. A non-invasive method for detecting tear glucose levels is also proposed as a potential substitute for blood glucose measurements.

Novel NO releasing coatings are developed by doping poly(lactide-co-glycolide) (PLGA) with NO donors and top-coating with PurSil which can release NO > 1 × 10-10 mol min-1cm-2 for at least 7 days. Intravenous amperometric needle-type glucose/lactate sensors prepared with such coatings have excellent in vitro analytical performance. Glucose sensors with NO release show significantly enhanced hemocompatibility when implanted in rabbit veins for 8 h, with minimized thrombus formation on their surfaces and greater accuracy in measuring blood glucose levels, as evaluated using a Clarke error grid analysis.

Nitric oxide generating coatings, including Cu(II)-cyclen polyurethanes, Cu0 nanoparticle-doped polyurethanes and 100 bilayers of organoselenium-linked polyethyleneimine (SePEI) and alginate (Alg), are employed on glucose/lactate sensors. These coatings all enable the sensors to generate NO from endogenous S-nitrosothiols (RSNOs), but there is some influence on the analytical performance of the sensors. Preliminary in vivo experiments indicated the possible need for additional RSNOs to generate sufficient NO fluxes.

An amperometric needle-type tear glucose sensor is described and employed in conjunction with a 0.84 mm i.d. capillary tube to collect 4-5 μL tear fluid. The sensor possesses excellent selectivity for glucose over potential electroactive interferent species, including ascorbic acid and uric acid. Further, the new sensor is optimized to achieve very low detection limits of 1.5 ± 0.4 μM of glucose (S/N=3) with a sensitivity of 0.019 ± 0.009 nA/μM (n=4). The glucose sensor is employed to measure tear glucose levels in anesthetized rabbits over 8 h while also measuring the blood glucose values. A strong correlation between tear and blood glucose levels is found, suggesting that electrochemical measurement of tear glucose concentrations is a potential substitute for blood glucose measurements.