A subcutaneous glucose sensor with improved longevity, dynamic range, and stability of calibration

OBJECTIVE - To evaluate the lifetime, response time, linearity glucose rang e, and calibration stability of two different types of continuous glucose s ensor implants in a dog model. RESEARCH DESIGN AND METHODS - Glucose sensors based on the enzyme electrode principle that are coupled to a radio transmitter were evaluated on the be nch cop, sterilized, and then implanted subcutaneously in nondiabetic mongr el dogs. A multichannel radio receiver and PC data processor were used to r ecord the sensor glucose data. initial early reliable sensor responsivity w as recognized by a vigorous hyperglycemic excursion after an intramuscular injection of glucagon. Periodically the dogs were made temporarily diabetic by blocking pancreatic insulin secretion by subcutaneous injection of a sy nthetic somatostatin (octreotide). By using exogenous insulin injection fol lowed by intravenous glucose infusion, glucose levels were manipulated thro ugh the entire clinical range of interest: 2.2-38.9 mmol/l (40-700 mg/dl). Every 5-10 min, reference blood glucose samples were obtained and run ill o ur hospital clinical laboratory. The glucose sensor data was evaluated by l inear least squares optimization and by the error grid method. RESULTS- Beginning as early as postimplant day 7, the in vivo performances of sensors were evaluated by using glucose infusion studies per formed ever y 1-4 weeks, Bench-top and in vivo 90% response-time sensors were in the ra nge of 4-7 min during sensor lifetime. Best-performing sensors from both ty pes are summarized as follows. The earlier-stage technology was less linear with a dynamic range of no more than 22 mmol/l glucose, had a best-case re calibration interval of 18 days, and had a maximum lifetime of 94 days. The improved later-stage technology sensors, which were constructed with the a ddition of bioprotective and angiogenic membranes, were linear over the ful l extended range of clinical interest (2.2-38.9 mmol/l [40-700 mg/dl glucos e]), had a best-case recalibration interval of 20 days, and had a maximum l ifetime of >160 days. CONCLUSIONS - Stable clinically useful sensor performance was demonstrated as early as 7 days alter implantation and for a sensor lifetime of 3-5 mont hs. This type of subcutaneous glucose sensor appears to be promising as a c ontinuous and painless long-term method for monitoring blood glucose. Speci fically sensors with top-layer materials that stimulate angiogenesis at the sensor/tissue interface may have better dynamic measurement range, longer lifetimes, and better calibration stability than our previously reported se nsors.