Continuous Monitoring of Glucose in Subcutaneous Tissue Using Microfabricated Differential Affinity Sensors

Objective: We describe miniaturized differential glucose sensors based on affinity binding between glucose and a synthetic polymer. The sensors possess excellent resistance to environmental disturbances and can potentially allow wireless measurements of glucose concentrations within interstitial fluid in subcutaneous tissue for long-term, stable continuous glucose monitoring (CGM).

Methods: The sensors are constructed using microelectromechanical systems (MEMS) technology and exploit poly(N-hydroxy-ethyl acrylamide-ran-3-acrylamidophenylboronic acid) (PHEAA-ran-PAAPBA), a glucose-binding polymer with excellent specificity, reversibility, and stability. Two sensing approaches have been investigated, which respectively, use a pair of magnetically actuated diaphragms and perforated electrodes to differentially measure the glucose-binding-induced changes in the viscosity and permittivity of the PHEAA-ran-PAAPBA solution with respect to a reference, glucose-unresponsive polymer solution.

Results: In vivo characterization of the MEMS affinity sensors were performed by controlling blood glucose concentrations of laboratory mice by exogenous glucose and insulin administration. The sensors experienced an 8-30 min initialization period after implantation and then closely tracked commercial capillary glucose meter readings with time lags ranging from 0-15 min during rapid glucose concentration changes. Clarke error grid plots obtained from sensor calibration suggest that, for the viscometric and dielectric sensors, respectively, approximately 95% (in the hyperglycemic range) and 84% (ranging from hypoglycemic to hyperglycemic glucose concentrations) of measurement points were clinically accurate, while 5% and 16% of the points were clinically acceptable.

Conclusions: The miniaturized MEMS sensors explore differential measurements of affinity glucose recognition. In vivo testing demonstrated excellent accuracy and stability, suggesting that the devices hold the potential to enable long-term and reliable CGM in clinical applications.