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

High Resolution Image Download MS PowerPoint Slide Conspectus 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.