CMOS Interface for Mammalian Electrogenic Cell Interrogation

Abstract

Classical tools to record and stimulate electrogenic cells, mainly cardiac cells and neurons, are intracellular patch clamp micropipettes and extracellular microelectrode arrays (MEAs). The former has high precision while the latter is suitable for non-invasive, long-term, parallel interrogation of a large number of cells. A lot of recently developed electrophysiology tools are based on the MEA scheme by devising nano-sized structures as electrodes that can penetrate into cells and thus circumvent signal attenuation across cell membrane. These nanoelectrode arrays (NEAs) aim at combining both strengths of the classical tools, but inherently suffer from unprecedentedly high electrode impedance from the small electrode size. One important way to emolliate the intrinsic predicament is to customize signal processing electronics able to optimize the acquired signal-to-noise ratio, feasible with the help of industrialized complementary metal-oxide-semiconductor (CMOS) technology. Two generations of application-specific integrated circuits (ASICs) are designed and fabricated to advance a previously developed vertical nanowire electrode array. These CMOS-assited nanoelectrode arrays have front-end amplifiers right underneath, or nearby, the nanoelectrodes, lessening signal attenuation along the stray parasitics. Meanwhile, these arrays can achieve very high array density—32 × 32 with 126-μm pitch and 64 × 64 with 20-μm pitch, respectively—with CMOS multiplexed outputs that greatly simplify interconnects. In electrophysiology experiments, these CMOS-assited nanoelectrode arrays prove to have network-level, intracellular stimulation/recording capabilities, able to simultaneously record intracellular membrane potentials of hundreds of connected in vitro neonatal rat ventricular cardiomyocytes. We then use it to examine the effect of pharmaceuticals on the fine, important details of the cardiomyocyte network dynamics.