Zenghe Liu

Miniature Amperometric Self-Powered Continuous Glucose Sensor with Linear Response

Continuous glucose measurement has improved the treatment of type 1 diabetes and is typically provided by externally powered transcutaneous amperometric sensors. Self-powered glucose sensors (SPGSs) could provide an improvement over these conventionally powered devices, especially for fully implanted long-term applications where implanted power sources are problematic. Toward this end, we describe a robust SPGS that may be built from four simple components: (1) a low-potential, wired glucose oxidase anode; (2) a Pt/C cathode; (3) an overlying glucose flux-limiting membrane; and (4) a resistor bridging the anode and cathode. In vitro evaluation showed that the sensor output is linear over physiologic glucose concentrations (2-30 mM), even at low O(2) concentrations. Output was independent of the connecting resistor values over the range from 0 to 10 MΩ. The output was also stable over 60 days of continuous in vitro operation at 37 °C in 30 mM glucose. A 5-day trial in a volunteer demonstrated that the performance of the device was virtually identical to that of a conventional amperometric sensor. Thus, this SPGS is an attractive alternative to conventionally powered devices, especially for fully implanted long-term applications.

Metabolic Biofouling of Glucose Sensors in Vivo: Role of Tissue Microhemorrhages

Objective: Based on our in vitro study that demonstrated the adverse effects of blood clots on glucose sensor function, we hypothesized that in vivo local tissue hemorrhages, induced as a consequence of sensor implantation or sensor movement post-implantation, are responsible for unreliable readings or an unexplained loss of functionality shortly after implantation. Research Design and Methods: To investigate this issue, we utilized real-time continuous monitoring of blood glucose levels in a mouse model. Direct injection of blood at the tissue site of sensor implantation was utilized to mimic sensor-induced local tissue hemorrhages. Results: It was found that blood injections, proximal to the sensor, consistently caused lowered sensor glucose readings, designated temporary signal reduction, in vivo in our mouse model, while injections of plasma or saline did not have this effect. Conclusion: These results support our hypothesis that tissue hemorrhage and resulting blood clots near the sensor can result in lowered local blood glucose concentrations due to metabolism of glucose by the clot. The lowered local blood glucose concentration led to low glucose readings from the still functioning sensor that did not reflect the systemic glucose level.

Blood-Induced Interference of Glucose Sensor Function in Vitro: Implications for in Vivo Sensor Function

Background: Although tissue hemorrhages, with resulting blood clots, are associated with glucose sensor implantation, virtually nothing known is about the impact of red blood cells and red blood cell clots on sensor function in vitro or in vivo. In these studies, we tested the hypothesis that blood can directly interfere with glucose sensor function in vitro. Methods: To test this hypothesis, heparinized human whole blood (HWB) and nonheparinized human whole blood (WB) were obtained from normal individuals. Aliquots of HWB and WB samples were also fractionated into plasma, serum, and total leukocyte (TL) components. Resulting HWB, WB, and WB components were incubated in vitro with an amperometric glucose sensor for 24 hours at 37°C. During incubation, blood glucose levels were determined periodically using a glucose monitor, and glucose sensor function (GSF) was monitored continuously as nanoampere output. Results: Heparinized human whole blood had no significant effect on GSF in vitro, nor did TL, serum, or plasma-derived clots from WB. Sensors incubated with WB displayed a rapid signal loss associated with clot formation at 37°C. The half-life was 0.8 ± 0.2 hours (n = 16) for sensors incubated with WB compared to 3.2 ± 0.5 (n = 12) for sensors incubated with HWB with a blood glucose level of approximately 100 mg/dl. Conclusion: These studies demonstrated that human whole blood interfered with GSF in vitro. These studies further demonstrated that this interference was related to blood clot formation, as HWB, serum, plasma-derived clots, or TL did not interfere with GSF in vitro in the same way that WB did. These in vitro studies supported the concept that the formation of blood clots at sites of glucose sensor implantation could have a negative impact on GSF in vivo.

Importance of interleukin-1 and interleukin-1 receptor antagonist in short-term glucose sensor function in vivo.

Background: The importance of the interleukin (IL)-1 cytokine family in inflammation and immunity is well established as a result of extensive in vitro and in vivo studies. In fact, much of our understanding of the in vivo importance of interleukin-1beta (IL-1B) is the result of research utilizing transgenic mice, such as overexpression or deficiencies of the naturally occurring inhibitor of IL-1 known as interleukin-1 receptor antagonist (IL-1RA). For the present studies, we utilized these transgenic mice to determine the role of IL-1B in glucose sensor function in vivo. Methods: To investigate the role of IL-1B in glucose sensor function in vivo, we compared glucose sensor function in transgenic mice that (1) overexpressed IL-1RA [B6.Cg-Tg(II1rn)1Dih/J] and (2) are deficient in IL-1RA (B6.129S-Il1rntm1Dih /J), with mice that have normal levels of IL-1RA (C57BL/6). Results: Our studies demonstrated that, during the first 7 days post-sensor implantation (PSI), mice deficient in IL-1RA had extensive inflammation and decreased sensor function when compared to normal or IL-1RA-overexpressing mice. Conclusion: These data directly support our hypothesis that the IL-1 family of cytokines and antagonists play a critical role in controlling tissue reactions and thereby sensor function in vivo during the first 7 days PSI.