From Benchtop to Body: Solution Resistance-Induced Distortion in Electrochemical, Aptamer-Based Sensors

Abstract By providing continuous, in vivo molecular measurements, electrochemical aptamer-based (EAB) sensors have the potential to improve the fidelity with which pharmaceutical drugs are administered and physiological processes are monitored. The impact of solution resistance on EAB sensor response, however, has not been systematically investigated, despite its potential to introduce systematic errors in concentration measurements. Here, we show that uncompensated solution resistance of wire-based EAB sensors can increase from a few hundred ohms in vitro up to ∼1–2 kΩ in vivo. This elevated resistance increases the RC charging time constant of the electrode interface, allowing non-faradaic charging currents to persist into the sampling window used during square wave voltammetry. As a result, capacitive currents contribute to the measured signal, distorting sensor responses whenever the interrogation frequency falls within this RC-limited charging regime. Using three representative EAB sensors, we show that changes in uncompensated solution resistance between calibration and measurement conditions can, for some sensors, cause target concentrations to be systematically underestimated, with the magnitude of this error strongly dependent on interrogation frequency. We also introduce a simple strategy by which the calibration of in vivo EAB sensors can be improved by introducing a resistor in series with the working electrode during in vitro testing. Finally, we provide further strategies by which the errors introduced by uncompensated solution resistance can be reduced to negligible levels.