Complementary Metal-Oxide-Semiconductor (CMOS) Bio-electronic Interface for Cell-based Phenotypic Drug Screening

Abstract

Microelectrode Array (MEA) has been widely researched and with some commercial usage in measuring electrical properties and behavior of cardiac and neuronal networks, thanks to its low cost and parallelism compared to traditional patch clamp. Integration of Complementary Metal-Oxide-Semiconductor (CMOS) technology with MEA allows further miniaturization of the electrodes, improvement on the spatial resolution and the signal-to-noise ratio and enabling highly-paralleled real-time measurement and stimulation. CMOS-MEA, therefore, becomes an excellent research tool for in vitro electrophysiology studies, usually with a single-well device to measure and perform manual electrical stimulation on one cell culture at a time. Furthermore, CMOS-MEA also improves the multi-parametric label-free readouts on general cells from commercially available MEAs, opening the potential applications into phenotypic drug discovery. This dissertation discusses the design and development of two CMOS-MEA Integrated Circuit (IC) systems. First, an extension of two previously published CMOS nanoelectrode array (CNEA) systems, the 3rd generation of CNEA, is presented. The 3rd generation of CNEA features 1,024 pixels capable of simultaneously recording, on-chip action potential detection, on-chip inter-pixel feedback decision, and arbitrary stimulation pattern generation. The on-chip action potential detection and inter-pixel feedback decision making allow a stimulation pattern to be generated and applied to an arbitrary pixel within a microsecond from an action potential detected on another pixel. This capability makes the 3rd generation CNEA a perfect candidate for Spike-Timing-Dependent-Plasticity (STDP) studies in neuronal networks. The majority focus of this dissertation would be on the multiwell version of the CNEA (Multiwell Platform). The Multiwell Platform contains 24 custom design ICs interlinked onto a custom interposer printed circuit board (PCB), creating 96 identical wells and their associated circuitries into a standard form factor wellplate. Each well contains 4,096 pixels and 256 readout channels capable of scanning through the entire pixel array with arbitrary square patterns. The unique design and functionalities of the Multiwell Platform enable parallel measurements on multiple biological-relevant parameters on general cells and therefore enable high-throughput phenotypic drug screening applications.