A highly-catalytic hydrogel modified biosensor for wearable and non-invasive glucose monitoring via reverse iontophoresis

Reverse iontophoresis (RI)-based continuous glucose monitoring (CGM) is promising for wearable diabetes management; however, its clinical translation remains limited by skin irritation associated with current operation, and the challenge of accurately quantifying low-concentration glucose. Here, we present a zwitterionic enzymatic hydrogel for wearable RI-based CGM. The hydrogel provides excellent skin affinity, enabling operation under low current density conditions to alleviate irritation, while its high catalytic activity accounts for the reduced glucose flux by the low current density and ensures detection of low-concentration glucose. The highly-catalytic hydrogel is modified onto flexible electrodes to construct a glucose sensor, making high sensitivity (437.03 nA mM^-1), low detection limit (0.396 μM), and prolonged operational lifetime (69.42% retention after 30 days). The sensor is integrated with two RI electrodes to produce a glucose biosensor for wearable and non-invasive CGM. In vitro evaluation demonstrates accurate prediction of simulated subcutaneous glucose levels with a high correlation (R² = 0.968). In vivo studies in both healthy subjects and patients with diabetes further confirm the capability of the proposed biosensor in practice, showing good agreement with the blood glucose and no observable skin erythema or irritation. Clarke error grid analysis shows that 97.5% of data fall within zones A and B, with a mean absolute relative difference (MARD) of 15.41% for healthy subjects and 16.43% for patients with diabetes. The biosensor also achieves a 20/20% agreement rate of 73.75%. This work provides a broadly applicable method and platform for wearable and non-invasive biosensing.