Enhanced cardiomyocyte structural and functional anisotropy through synergetic combination of topographical, conductive, and mechanical stimulation

Abstract

Drug-induced cardiotoxicity, a significant concern in the pharmaceutical industry, often results in the withdrawal of drugs from the market. The main cause of drug-induced cardiotoxicity is the use of immature cardiomyocytes during in vitro drug screening procedures. Over time, several methods such as topographical, conductive, and mechanical stimulation have been proposed to enhance both maturation and contractile properties of these cardiomyocytes. However, the synergistic effects of integrating topographical, conductive, and mechanical stimulation for cardiomyocyte maturation remain underexplored and poorly understood. To address this limitation, herein, we propose a grooved polydimethylsiloxane (PDMS) membrane embedded with silver nanowires (AgNWs–E-PDMS). The proposed AgNWs–E-PDMS membrane enhances the maturation of cardiomyocytes and provides a more accurate evaluation of drug-induced cardiotoxicity. When subjected to 10% tensile stress on the AgNWs–E-PDMS membrane, cardiomyocytes displayed substantial enhancements. Specifically, the contraction force, sarcomere length, and connexin-43 (Cx43) expression are increased by 2.0-, 1.5-, and 2.4-times, respectively, compared to the control state. The practical feasibility of the proposed device as a drug screening platform is demonstrated by assessing the adverse effects of lidocaine on cardiomyocytes. The contraction force and beat rate of lidocaine treated cardiomyocytes cultured on the AgNWs–E-PDMS membrane under mechanical stimulation decreased to 0.9 and 0.64 times their initial values respectively, compared to 0.6 and 0.51 times in the control state. These less pronounced changes in the contraction force and beat rate signify the superior drug response in the cardiomyocytes, a result of their enhanced maturation and growth on the AgNWs–E-PDMS membrane combined with mechanical stimulation.