A semiconductor 96-microplate platform for electrical-imaging based high-throughput phenotypic screening.

High-content imaging for compound and genetic profiling is popular for drug discovery but limited to endpoint images of fixed cells. Conversely, electronic-based devices offer label-free, live cell functional information but suffer from limited spatial resolution or throughput. Here, we introduce a semiconductor 96-microplate platform for high-resolution, real-time impedance imaging. Each well features 4096 electrodes at 25 µm spatial resolution and a miniaturized data interface allows 8× parallel plate operation (768 total wells) for increased throughput. Electric field impedance measurements capture >20 parameter images including cell barrier, attachment, flatness, and motility every 15 min during experiments. We apply this technology to characterize 16 cell types, from primary epithelial to suspension cells, and quantify heterogeneity in mixed co-cultures. Screening 904 compounds across 13 semiconductor microplates reveals 25 distinct responses, demonstrating the platform's potential for mechanism of action profiling. The scalability and translatability of this semiconductor platform expands high-throughput mechanism of action profiling and phenotypic drug discovery applications.

A semiconductor 96-microplate platform for electrical-imaging based high-throughput phenotypic screening.

Profiling compounds and genetic perturbations via high-content imaging has become increasingly popular for drug discovery, but the technique is limited to endpoint images of fixed cells. In contrast, electronic-based devices offer label-free, functional information of live cells, yet current approaches suffer from low-spatial resolution or single-well throughput. Here, we report a semiconductor 96-microplate platform designed for high-resolution real-time impedance "imaging" at scale. Each well features 4,096 electrodes at 25 µm spatial resolution while a miniaturized data interface allows 8× parallel plate operation (768 total wells) within each incubator for enhanced throughputs. New electric field-based, multi-frequency measurement techniques capture >20 parameter images including tissue barrier, cell-surface attachment, cell flatness, and motility every 15 min throughout experiments. Using these real-time readouts, we characterized 16 cell types, ranging from primary epithelial to suspension, and quantified heterogeneity in mixed epithelial and mesenchymal co-cultures. A proof-of-concept screen of 904 diverse compounds using 13 semiconductor microplates demonstrates the platform's capability for mechanism of action (MOA) profiling with 25 distinct responses identified. The scalability of the semiconductor platform combined with the translatability of the high dimensional live-cell functional parameters expands high-throughput MOA profiling and phenotypic drug discovery applications.

An Aqueous Analog MAC Machine.

Using ions in aqueous milieu for signal processing, like in biological circuits, may potentially lead to a bioinspired information processing platform. Studies, however, have focused on individual ionic diodes and transistors rather than circuits comprising many such devices. Here a 16 × 16 array of new ionic transistors is developed in an aqueous quinone solution. Each transistor features a concentric ring electrode pair with a disk electrode at the center. The electrochemistry of these electrodes in the solution provides the basis for the transistor operation. The ring pair electrochemically tunes the local electrolytic concentration to modulate the disk's Faradaic reaction rate. Thus, the disk current as a Faradaic reaction to the disk voltage is gated by the ring pair. The 16 × 16 array of these transistors performs analog multiply-accumulate (MAC) operations, a computing modality hotly pursued for low-power artificial neural networks. This exploits the transistor's operating regime where the disk current is a multiplication of the disk voltage and a weight parameter tuned by the ring pair gating. Such disk currents from multiple transistors are summated in a global reference electrode to complete a MAC task. This ionic circuit demonstrating analog computing is a step toward sophisticated aqueous ionics.

CMOS electrochemical pH localizer-imager.

pH controls a large repertoire of chemical and biochemical processes in water. Densely arrayed pH microenvironments would parallelize these processes, enabling their high-throughput studies and applications. However, pH localization, let alone its arrayed realization, remains challenging because of fast diffusion of protons in water. Here, we demonstrate arrayed localizations of picoliter-scale aqueous acids, using a 256-electrochemical cell array defined on and operated by a complementary metal oxide semiconductor (CMOS)-integrated circuit. Each cell, comprising a concentric pair of cathode and anode with their current injections controlled with a sub-nanoampere resolution by the CMOS electronics, creates a local pH environment, or a pH "voxel," via confined electrochemistry. The system also monitors the spatiotemporal pH profile across the array in real time for precision pH control. We highlight the utility of this CMOS pH localizer-imager for high-throughput tasks by parallelizing pH-gated molecular state encoding and pH-regulated enzymatic DNA elongation at any selected set of cells.

An Atomically Thin Optoelectronic Machine Vision Processor.

2D semiconductors, especially transition metal dichalcogenide (TMD) monolayers, are extensively studied for electronic and optoelectronic applications. Beyond intensive studies on single transistors and photodetectors, the recent advent of large-area synthesis of these atomically thin layers has paved the way for 2D integrated circuits, such as digital logic circuits and image sensors, achieving an integration level of ≈100 devices thus far. Here, a decisive advance in 2D integrated circuits is reported, where the device integration scale is increased by tenfold and the functional complexity of 2D electronics is propelled to an unprecedented level. Concretely, an analog optoelectronic processor inspired by biological vision is developed, where 32 × 32 = 1024 MoS2 photosensitive field-effect transistors manifesting persistent photoconductivity (PPC) effects are arranged in a crossbar array. This optoelectronic processor with PPC memory mimics two core functions of human vision: it captures and stores an optical image into electrical data, like the eye and optic nerve chain, and then recognizes this electrical form of the captured image, like the brain, by executing analog in-memory neural net computing. In the highlight demonstration, the MoS2 FET crossbar array optically images 1000 handwritten digits and electrically recognizes these imaged data with 94% accuracy.