Toward Autonomous Electrochemical Sensing: Advances and Challenges in Calibration-Free and Long-Duration Technologies

Abstract

Electrochemical biosensors hold promise for autonomous molecular monitoring owing to their sensitivity, electronic compatibility, and suitability for wearable, implantable, and point-of-care platforms. However, conventional operation relies on external calibration that erodes with batch-to-batch variability and environmental fluctuations, ultimately compromising long-term accuracy in complex biofluids and in vivo environments. Calibration-free electrochemical sensing addresses this challenge through three complementary strategies. First, intrinsic dual-signal encoding strategy embeds two distinct redox-reporters to generate ratiometric outputs that convert absolute faradaic currents into self-normalized readouts, thereby eliminating the need for external calibration. Second, operationally programmed self-referencing strategy extracts drift-differentiated kinetics from a single reporter by varying measurement parameters or environmental conditions. Third, interfacial engineering slows signal decay and drift at its molecular origin through coordinated optimization of redox reporters, self-assembled monolayers, protective layers and nuclease-resistant nucleic-acid scaffolds. This Account summarizes recent advances, outlines these signal- and interface-level designs and their principles, and discusses opportunities toward long-lasting autonomous biosensing in clinical settings.