On-Device Calibration of Organic Electrochemical Transistor Biosensors for Advancing Alzheimer’s Diagnostics

Alzheimer's disease is a progressive form of dementia, which affects more than 50 million people worldwide and is expected to impact three times more by 2050. Although its cause and progression mechanisms are still not fully understood, Alzheimer’s disease has been associated with the misregulation of certain biomarkers.¹ The quantification of these biomarkers requires expensive elaborate equipment, substantial experience, and time-consuming analysis due to their sub-nanomolar concentrations in blood. A much faster, cost-effective, and more convenient <i>in-vitro</i> method with very high sensitivity and good specificity is needed to advance Alzheimer’s research and diagnostics.<br/><br/> Organic electrochemical transistors (OECTs) have emerged as a promising point-of-care testing platform for enzymatic biosensing due to their exceptional signal amplification properties, stability in aqueous environments, and biocompatibility.²However, due to their high sensitivity, OECTs are susceptible to signal drifts caused by changes in the surrounding environment, such as variations in pH levels, temperature fluctuations, and the presence of interfering species in the sample of interest. In this work we present a new OECT configuration design to achieve real-time on-device calibration. This configuration is designed to effectively compensate for signal drifts and faulty analyte detection, thereby ensuring stability and reliable results.<br/><br/> Three-terminal OECTs have been designed and microfabricated with a poly(3,4-ethylenedioxythiophene) polystyrene sulfonate (PEDOT: PSS) channel. This ion permeable channel is extremely sensitive to biochemical reactions occurring in the electrolyte placed directly on top of the device for testing.² The design of the device incorporates two gates, and it has been optimised to create highly sensitive enzymatic sensors.³ An enzyme is immobilised via bioconjugation on the first gate electrode, while the second gate electrode acts as a reference. The system is tested in real-time by addition of varying concentrations of the target compound in the electrolyte, while the changes in current are recorded. This test allowed the on-device calibration of our OECTs, enabling the reliable measurement of the compound with high sensitivity and specificity. This is a new promising platform for achieving stability against signal drifts in the OECTs and robustness against interfering analytes in enzymatic sensors, outlining the pathway to very high sensitivity and low limit of detection of brain biomarkers.<br/><br/>1. Michel, Claire H., et al. Extracellular Monomeric Tau Protein is Sufficient to Initiate the Spread of Tau Protein Pathology. <i>Journal of Biological Chemistry</i>, 289.2, 956–967 (2014).<br/>2. D. A. Bernards and G. G. Malliaras. Steady-State and Transient Behavior of Organic Electrochemical Transistors. <i>Advanced Functional Materials</i>, 17.17, 3538–3544 (2007).<br/>3. Cicoira, Fabio, et al. Influence of Device Geometry on Sensor Characteristics of Planar Organic Electrochemical Transistors.” <i>Advanced Materials, </i>22.9, 1012–1016 (2010)