MEA-integrated cantilever platform for comparison of real-time change in electrophysiology and contractility of cardiomyocytes to drugs

Abstract

Drug-induced cardiotoxicity is a potentially severe side effect that can alter the contractility and electrophysiology of the cardiomyocytes. Cardiotoxicity is generally assessed through animal models using conventional drug screening platforms. Despite significant developments in drug screening platforms, the difficulty in measuring electrophysiology and contractile profile together affects the investigation of cardiotoxicity in potential drugs. Some drugs can prove to be more toxic to contractility than electrophysiology, which demands the need for a reliable, dual, and simultaneous drug screening platform. Herein, we propose the microelectrode array integrated SU-8 cantilever for dual and simultaneous measurement of electrophysiology and contractility of cardiomyocytes. The SU-8 cantilever is integrated with microelectrode array (C-MEA) using conventional photolithographic techniques. Drug tests are conducted to verify the feasibility of the C-MEA platform using three cardiovascular drugs. Clinically recognized drugs, quinidine and verapamil, are used to activate both the hERG channel and the contractile characteristics of cardiomyocytes. The effect of ion channel blockers on the field potential duration (FPD) of the cardiomyocytes is compared with several contractility-based parameters. The contraction-relaxation duration (CRD) profile is relatively close to that of FPD in tested drugs (half-maximal (IC50) toxicities are 1.093 μM (FPD) and 1.924 μM (CRD) for quinidine and 166.2 nM (FPD) and 459.4 nM (CRD) for verapamil). Blebbistatin, a known myosin II inhibitor, primarily affects the contractile profile of cardiomyocytes but not their field potential, with no evident correlation between contractility and field potential profiles. The proposed cantilever-based mechano-electrophysiology measurements platform provides a promising and accurate means to assess cardiotoxicity.