A Multimodal CMOS MEA for High-Throughput Intracellular Action Potential Measurements and Impedance Spectroscopy in Drug-Screening Applications

Abstract

Multi-electrode arrays (MEAs) are a candidate technology to screen cardiotoxicity <italic xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">in vitro</i> because they enable noninvasive recording of cardiac beating rate, electrical field potential duration, and other parameters. In this paper, we present an active MEA chip featuring 16 384 electrodes, 1024 simultaneous readout channels, and 64 stimulation units (SUs) to enable six different cell-interfacing modalities: extracellular and intracellular recording, current and voltage stimulation, fast impedance motoring, and impedance spectroscopy (IS). The chip was designed and fabricated in a 0.13- <inline-formula xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink"> <tex-math notation="LaTeX">$\mu \text{m}$ </tex-math></inline-formula> Al CMOS technology, and the electrodes were fabricated on top of the silicon substrate using biocompatible TiN. Measurement results show a total input-referred noise of <inline-formula xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink"> <tex-math notation="LaTeX">$7.5 \pm 0.6~\mu \text{V}_{\mathrm{rms}}$ </tex-math></inline-formula> and <inline-formula xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink"> <tex-math notation="LaTeX">$12.0 \pm 2.4~\mu \text{V}_{\mathrm {rms}}$ </tex-math></inline-formula> for the action potential and full bands, respectively, with a total power consumption of 95 mW for 1024 readout channels. We have experimentally validated the CMOS MEA in <italic xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">in vitro</i> experiments, demonstrating all the different modalities. This novel platform will potentially enable high-throughput electrical activity monitoring and drug screening of cardiomyocytes.