Advances in large-scale electrophysiology with high-density microelectrode arrays

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.