A Fully Flexible Conductive Hydrogel Composite Electrode Integrated with Gold Nanoparticles and a Dual Activation−Regeneration Sensing Strategy for Continuous <i>In Vivo</i> Glucose Monitoring

The need for skin compatible continuous glucose monitoring (CGM) systems with high accuracy and stability has driven advancements in flexible microneedle-based sensors. Current solid microneedle-based CGMs face significant challenges, including enzyme instability and skin irritation. Hydrogel microneedles (HMNs), which become flexible after skin penetration, offer a promising alternative by reducing tissue irritation and improving skin integration. However, further optimization of hydrogel compositions is needed to enhance conductivity, stability, and long-term glucose monitoring performance. This study presents a new enzyme-free HMN-based CGM sensor, combining poly(3,4-ethylenedioxythiophene) sulfonate (PEDOT:PSS), gold nanoparticles (AuNPs), and polyvinylpyrrolidone (PVP). A new dual activation−regeneration strategy was employed to enhance the sensitivity and stability of glucose measurements for continuous monitoring. The proposed fully flexible CGM device, termed the HMN-P4Au sensor, was validated in vivo using a diabetic rat model, demonstrating a mean absolute relative difference (MARD) of 14.5% compared to standard glucometers. Notably, the sensor maintained stable readings with less than 14% signal degradation over 3 days. To examine the translational potential of the HMN-P4Au sensor, the gold-based sensing strategy was further evaluated in pig models, confirming its ability to reliably track both increases and decreases in glucose levels.