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

Abstract

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.

Predicting Glucose Sensor Behavior in Blood Using Transport Modeling: Relative Impacts of Protein Biofouling and Cellular Metabolic Effects

“…11 This group also conducted in vivo studies on the role of erythrocyte-embedded clots on sensor function in mice. 12 Similar to Klueh and coauthors, 11,12 in the current study, the effects of protein biofouling and cellular accumulation on glucose concentration near a sensor were observed experimentally by recording the changes in response of commercially available Medtronic MiniMed SofSensors in heparinized whole blood and various blood constituents. Numerical simulations were then used to further predict mechanistic scenarios that could be used to explain the experimental observations.…”

Analysis: On the Path to Overcoming Glucose-Sensor-Induced Foreign Body Reactions

“…As such, the mouse allows investigators to transcend simple histopathology studies with the identification of the cells, mediators, and mechanisms that can be targeted to overcome the tissue reactions that limit sensor function and lifespan in vivo. In fact, using various mouse models of CGM our laboratory demonstrated the critical role of mast cells, 1 macrophages, 6 and cytokines and cytokine inhibitors 6 as well as the importance of glucose metabolism by red blood cells (microhemorrhage) 2 and by inflammatory cells recruited to the site of sensor implantation. Inflammatory cells at the site of device location are detrimental to its functionality since inflammatory cells are metabolically very active.…”

“…In previous studies using a continuous glucose sensor mouse model, our laboratory demonstrated the critical role of inflammatory cells contributing to the sensor performance variation in vivo. [1][2][3] The preeminent role of the mouse is the result of large number of mutant and transgenic mice and related tools (e.g., recombinant proteins, antibodies, and drugs). These tools can provide important insight into tissue reactions and glucose sensor function and have only recently been appreciated.…”

“…Accumulation of vascular cells (e.g., leukocytes or red blood cells) within the implantation site can create "metabolic barriers" to glucose diffusion to the implanted sensor and result in deceptively low and delayed glucose readings by the sensor. [1][2][3] Sensor-associated fibrosis not only compromises sensor function by slowing glucose diffusion within the implantation site, but even more profoundly, fibrosis impacts sensor function by inducing blood vessel regression at the implantation site. Glucose sensors, unlike many other implantable devices, require a close proximity to blood vessels to determine real-time blood glucose levels.…”

Electrochemical biochip for applications to wireless and batteryless monitoring of free-moving mice

“…More recent devices have shown detection of other endogenous metabolites (e.g., lactate, glutamate, and ATP) [11] though not within the same sensing platform. However, all these more recent developments still present electrical cables through the animals' skin [9]- [12], which allow only limited movement in the animal cage. In 2012, a novel system to transmit power and receive data on completely free-moving animals has been proposed [13], and at the end of last year the possibility of the integration with a fully implantable and biocompatible multi-panel array sensor has been proposed [14].…”