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In vivo glucose sensor nitric oxide (NO) release is a means of mediating the inflammatory response that may cause sensor/tissue interactions and degraded sensor performance. The NO release (NOr) sensors were prepared by doping the outer polymeric membrane coating of previously reported needle-type electrochemical sensors with suitable lipophilic diazeniumdiolate species. The Clarke error grid correlation of sensor glycemia estimates versus blood glucose measured in Sprague-Dawley rats yielded 99.7% of the points for NOr sensors and 96.3% of points for the control within zones A and B (clinically acceptable) on Day 1, with a similar correlation for Day 3. Histological examination of the implant site demonstrated that the inflammatory response was significantly decreased for 100% of the NOr sensors at 24 h. The NOr sensors also showed a reduced run-in time of minutes versus hours for control sensors. NO evolution does increase protein nitration in tissue surrounding the sensor, which may be linked to the suppression of inflammation. This study further emphasizes the importance of NO as an electroactive species that can potentially interfere with glucose (peroxide) detection. The NOr sensor offers a viable option for in vivo glucose sensor development.

The changes in plasma glucose concentration and in interstitial glucose concentration, determined with a miniaturized subcutaneous glucose sensor, were investigated in anesthetized nondiabetic rats. Interstitial glucose was estimated through two different calibration procedures. First, after a glucose load, the magnitude of the increase in interstitial glucose, estimated through a one-point calibration procedure, was 70% of that in plasma glucose. We propose that this is due to the effect of endogenous insulin on peripheral glucose uptake. Second, during the spontaneous secondary decrease in plasma glucose after the glucose load, interstitial glucose decreased faster than plasma glucose, which may also be due to the effect of insulin on peripheral glucose uptake. Third, during insulin-induced hypoglycemia, the decrease in interstitial glucose was less marked than that of plasma glucose, suggesting that hypoglycemia suppressed transfer of glucose into the interstitial tissue; subsequently, interstitial glucose remained lower than plasma glucose during its return to basal value, suggesting that the stimulatory effect of insulin on peripheral glucose uptake was protracted. If these observations obtained in rats are relevant to human physiology, such discrepancies between plasma and interstitial glucose concentration may have major implications for the use of a subcutaneous glucose sensor in continuous blood glucose monitoring in diabetic patients.

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After 40 years of research and development, today continuous glucose monitoring (CGM) is demonstrating the benefit it provides for millions with diabetes. To provide in vivo accuracy, new permselective membranes and mediated systems have been developed to prevent enzyme saturation and to minimize interference signals. Early in vivo implanted sensor research clearly showed that the foreign body response was a more difficult issue to overcome. Understanding the biological interface and circumventing the inflammatory response continue to drive development of a CGM sensor with accuracy and reliability performance suitable in a closed-loop artificial pancreas. Along with biocompatible polymer development, other complimentary algorithm and data analysis techniques have improved the performance of commercial systems significantly. For example, the mean average relative difference of Dexcom's CGM system improved from 26 to 14% and its use-life was extended from 3 to 7 d. Significant gains in usability, including size, flexibility, insertion, calibration, and data interface, have been incorporated into new generations of commercial CGM systems. Besides Medtronic, Dexcom, and Abbott, other major players are also investing in CGM. Becton Dickinson is conducting clinical trials with an optical galactose glucose binding system. Development of fully implanted sensor systems fulfills the desire for a discreet, reliable CGM system. Research continues to find innovative ways to help make living with diabetes easier and more normal, and new segments are being pursued (intensive care unit, surgery, behavior modification) in which CGM is being utilized.