Effect of electrochemical topology on detection sensitivity in MEA assay for drug-induced cardiotoxicity screening.

Cardiotoxicity remains a major challenge in drug development, accounting for 45% of medication withdrawals due to cardiac ischemia and arrhythmogenicity. To overcome the limitations of traditional multielectrode array (MEA)-based cardiotoxicity assays, we developed a Nafion-coated NanoMEA platform with decoupled reference electrodes, offering enhanced sensitivity for electrophysiological measurements. The 'Decoupled' configuration significantly reduced polarization resistance (Rp) from 12.77 MΩ to 3.41 MΩ, improving charge transfer efficiency as demonstrated by electrochemical impedance spectroscopy and cyclic voltammetry. Additionally, the limit of detection significantly decreased from 0.175 MΩ (Coupled) to 0.040 MΩ (Decoupled), underscoring the system's enhanced sensitivity. Using human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), we evaluated the effects of three proarrhythmic drugs: Ranolazine, Domperidone, and Sotalol. Under the decoupled condition, the platform exhibited reductions in IC50 values for Domperidone (0.71 μM-0.29 μM), Sotalol (7.61 μM-0.27 μM), and Ranolazine (53.08 μM-5.89 μM), demonstrating significantly improved drug detection sensitivity. Longitudinal analysis revealed significant alterations in key electrophysiological parameters, including beating period (BP), field potential duration (FPD), spike slope, and amplitude, which were consistent with the known pharmacological actions of these drugs. Further validation through action potential (AP) waveform analysis showed enhanced repolarization dynamics, confirming the platform's predictive capabilities. Our findings highlight the critical role of electrochemical topology in optimizing MEA performance. The NanoMEA system, featuring decoupled Nafion-coated electrodes, represents a robust and sensitive platform for cardiotoxicity screening, setting a new standard for preclinical drug safety assessment and advancing bioelectronic device design for cardiac research.