Tetra-Polyethylene Glycol Hydrogel Coating Enhances the Performance and Stability of Electrochemical Sensors in Complex Biological Matrices

Electrochemical aptamer-based (EAB) sensors promise real-time, reagent-free drug and biomarker monitoring, but protein adsorption and enzymatic degradation of their target-recognizing aptamers rapidly depress their signal and induce drift in complex matrices, such as saliva or undiluted whole blood. Size-excluding hydrogels offer an approach to reducing these effects, but the problem remains of achieving long-duration operation without significantly throttling the analyte transport or electron transfer to the electrode. In response, here we show that a tetra-poly(ethylene glycol) (tetra-PEG) hydrogel coating forms a soft, highly hydrated, ∼31 nm mesh network that excludes large glycoproteins and cellular components, reduces drift while preserving electron transfer, and enables acceptably rapid small-molecule access. Specifically, in undiluted saliva and bovine blood, this coating reduces electrode fouling and helps sustain EAB performance. For example, in undiluted whole blood at 37 °C, hydrogel-protected sensors exhibit lower drift over 8 h (∼5.7 vs ∼25.1% for unprotected controls) while maintaining a comparable signal gain across the tested vancomycin concentrations. It thus appears that the tetra-PEG hydrogel network can balance antifouling efficacy and nuclease resistance with electron transfer compatibility, suggesting that it may prove to be a practical route to long-duration, in-matrix, and, ultimately, in vivo monitoring using EAB sensors.