Stretchable Micro-Electrode Arrays for Electrophysiology

Abstract

A potential serious side effect of drugs is cardiotoxicity which can result in lethal heart arrhythmias. Cardiotoxicity has been the leading cause of drug withdrawals from the market in the past decades, and has been responsible for costly failures in late stage clinical trials. This highlights the unmet need in the pharmaceutical industry for more accurate and predicative cardiotoxicity screening assays. An important indication for drug-induced proarrhythmic cardiotoxicity is the prolongation of the action potential duration of the cardiomyocytes. The prolongation of the action potential duration can be detected in vitro through field potential measurements from cardiomyocytes cultured on Micro-Electrode Arrays (MEAs) when they are subjected to drug compounds. MEAs are normally fabricated on rigid substrates which precludes mechanical stretching and contraction of the cultured cardiomyocytes as it happens in vivo during diastole and systole of the heart. It has been demonstrated in the literature that cardiomyocytes can sense mechanical stretching and adapt their electrical and mechanical responses to it, through mechano-electric coupling phenomena, causing alterations of the action potential shape, duration, and rhythm. Including physiologically relevant mechanical loading of cardiomyocytes in the in vitro model, can lead to potentially more predictive screening results. In this thesis the design, fabrication and characterization of a novel platform for in vitro electrophysiological measurements is presented which allows for in situ mechanical loading of cardiomyocytes. The platform is based on pneumatically actuated Stretchable Micro-Electrode Array (SMEA) chips which are fabricated using state of the art silicon micro-fabrication technology. The main technological challenges addressed in this thesis were the mechanical design of the electrical interconnects for the stretchable devices, and the development of a manufacturable micro-fabrication technology to enable high volume production of the SMEA chips. The electrochemical and electromechanical characterization of the chips is presented, together with proof of concept field potential measurements from human stem cell derived cardiomyocytes under cyclic mechanical loading.