A detailed functional characterization of electrogenic cells, such as neurons and cardiomyocytes, by means of high-density microelectrode arrays (HD-MEAs) has emerged as a powerful approach for inferring cellular phenotypes and elucidating fundamental mechanisms underlying cellular function. HD-MEAs have been applied across a range of disciplines, including neurodevelopmental research, stem cell biology, and pharmacology, and more recently in interdisciplinary work at the intersection of biomedical engineering, computer science, and artificial intelligence (AI). Innovations in chip design, fabrication, recording capabilities, and data processing have significantly advanced the functionality of HD-MEAs. Today's chips allow the study of cellular function across scales and at high throughput. They enable the analysis of multi-parametric functional phenotypes over extended time and facilitate monitoring the effects of targeted perturbations on cellular behavior. In this Tutorial Review, we will first survey the advances in HD-MEA design and their readout and stimulation capabilities. We will then abstract studies that used HD-MEAs in combination with other experimental techniques to probe biologically relevant cellular and subcellular features, with an emphasis on in vitro applications of HD-MEAs. Thereafter, we will cover analytical techniques that are essential for analyzing and characterizing HD-MEA data. Finally, we will address current limitations of HD-MEAs and discuss potential future developments.

The performances of microelectrode arrays for neural interfaces strongly depend on electrode design. Due to a lack of simulation tools, electrode engineers often have to refine new designs empirically. This process requires setups of electrical and electrophysiological hardware that are not specific to electrode testing and unnecessarily costly. We propose a low-cost testbed for specifically targeting metrics relevant to electrode performance and functions, which relies on an off-the-shelf measurement tool and only on components necessary for such testing. We experimentally demonstrate the platform by characterizing microelectrodes by means of impedance spectroscopy and recording the extracellular action potentials from in vitro primary rat neurons.

Electrode designs and materials have become an increasingly important performance driver for microelectrode arrays, which are among the essential tools for cellular electrophysiology. Ongoing works have continuously innovated over a diverse range of electrode shapes, sizes, and materials. The large design and fabrication parameter space represents rich opportunities for optimizing performance and functionalities as well as a challenge for electrode developers due to a lack of predictive simulation software to aid design works. Electrode prototypes often need to be fabricated, empirically evaluated, and iteratively optimized at significant cost. Efficient hardware testing solutions to aid the development of new electrodes, especially at an early stage when the number of candidate designs is still high, are therefore increasingly important. Here, we propose and implement a cost-effective testbed platform, which is aimed at obtaining first-order characteristics from electrode prototypes to inform early-stage screening and refinement. Upon testing with microfabricated electrodes, the platform was shown to achieve an impedance measurement accuracy comparable to commercial equipment and effectively recorded extracellular action potentials of in vitro rat cortical neurons. By providing relevant electrode testing at a significantly lower cost, in a more compact form, and with greater ease of assembly, compared to existing hardware solutions, the presented testbed can meaningfully lower entry barriers for the development of new array-based electrophysiological microelectrodes.