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

Byunggik Kim; Jong Seob Choi; Yiguang Zhu; Juhyun Kim; Ye Seul Kim; Andres Parra; Paul A Locke; Jae Ho Kim; Todd Herron; Deok-Ho Kim

doi:10.1016/j.bios.2024.117082

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

Biosens Bioelectron. 2024 Dec 25:272:117082. doi: 10.1016/j.bios.2024.117082. Online ahead of print.

Authors

Byunggik Kim¹, Jong Seob Choi², Yiguang Zhu³, Juhyun Kim⁴, Ye Seul Kim⁵, Andres Parra⁶, Paul A Locke³, Jae Ho Kim⁵, Todd Herron⁷, Deok-Ho Kim⁸

Affiliations

¹ Department of Mechanical Engineering, Johns Hopkins University, Baltimore, MD, 21218, United States.
² Division of Advanced Materials Engineering, Kongju National University, Budaedong 275, Seobuk-gu, Cheonan-si, Chungnam, 31080, Republic of Korea; Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, 21205, United States.
³ Department of Environmental Health and Engineering, Johns Hopkins University, Baltimore, MD, 21205, United States.
⁴ Emotion, Cognition and Behavior Research Group, Korea Brain Research Institute (KBRI), Daegu, 41062, Republic of Korea.
⁵ Department of Physiology, School of Medicine, Pusan National University, Yangsan, 50612, Republic of Korea.
⁶ Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, 21205, United States.
⁷ Department of Internal Medicine, University of Michigan, Ann Arbor, MI, 48109, United States.
⁸ Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, 21205, United States; Department of Medicine, Johns Hopkins University, Baltimore, MD, 21205, United States; Institute for NanoBio Technology, Johns Hopkins University, Baltimore, MD, 21218, United States; Center for Microphysiological Systems, Johns Hopkins University, Baltimore, MD, 21205, United States. Electronic address: dhkim@jhu.edu.

PMID: 39778241
DOI: 10.1016/j.bios.2024.117082

Abstract

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.

Keywords: Cardiotoxicity screening; Electrochemical topology; Human iPSC-derived cardiomyocytes; Impedance spectroscopy; Microelectrode array (MEA); NanoMEA platform.