Electrophysiology Read-Out Tools for Brain-on-Chip Biotechnology

Abstract

Brain-on-Chip (BoC) biotechnology is emerging as a promising tool for biomedical and pharmaceutical research applied to the neurosciences. At the convergence between lab-on-chip and cell biology, BoC couples in vitro three-dimensional brain-like systems to an engineered microfluidics platform designed to provide an in vivo-like extrinsic microenvironment with the aim of replicating tissue- or organ-level physiological functions. BoC therefore offers the advantage of an in vitro reproduction of brain structures that is more faithful to the native correlate than what is obtained with conventional cell culture techniques. As brain function ultimately results in the generation of electrical signals, electrophysiology techniques are paramount for studying brain activity in health and disease. However, as BoC is still in its infancy, the availability of combined BoC–electrophysiology platforms is still limited. Here, we summarize the available biological substrates for BoC, starting with a historical perspective. We then describe the available tools enabling BoC electrophysiology studies, detailing their fabrication process and technical features, along with their advantages and limitations. We discuss the current and future applications of BoC electrophysiology, also expanding to complementary approaches. We conclude with an evaluation of the potential translational applications and prospective technology developments.

A Cerebral Organoid Connectivity Apparatus to Model Neuronal Tract Circuitry

“…Brain on a Chip (BoC) systems represent a frontier for modeling the brain in a physiologically relevant setting with key clinical applications in disease modeling and pharmacological screening [15]. Herein, two versions of an in vitro BoC model of three-dimensional neural circuitry between hiPSC-derived CO cultures are presented and their potential to interface with common neuronal characterization techniques, such as calcium imaging, immunolabeling, and viral tracing, are demonstrated.…”

“…While these 2D compartmentalized systems are useful for modeling axonal injury and neuronal communication at the single-axon level, they do not accurately reflect the complex three-dimensional (3D) in vivo brain environment in terms of cytoarchitecture and input from multiple cell types. Emerging BoCs are designed to recapitulate the native brain architecture by engineering 3D cerebral systems in microfabricated platforms, which can provide an extrinsic microenvironment reminiscent of the in vivo state [15].…”

Brain-on-a-Chip: Characterizing the next generation of advanced in vitro platforms for modeling the central nervous system

“… 66 , and 140–144 for reviews of the various tools available for OoC systems, in general, and see Ref. 35 for specific discussion of Brain-on-a-Chip systems). Some sensors, such as MEA (for electrophysiology) and TEER (for permeability), can be integrated into the chip.…”

Editorial for the Special Issue on Microfluidic Brain-on-a-Chip

“…This new class of microsystems will serve pharmaceutical as well as nervous system health-tech approaches of the future. Such future technology perspective on AI-based algorithms, which run on implantable biohybrid integrated electronic systems to treat neurodegenerative diseases, are envisaged here, in this special issue, already in the review on electrophysiology read-out tools for brain-on-chip biotechnology by Forro et al [ 20 ].…”

“…Raaijmakers et al [ 29 ] provide us, in this special issue, insights in software-driven labor reduction in live-cell calcium imaging applications for brain-on-chips. Additionally, the contribution by Forro et al [ 20 ] discusses the most recent developments of brain model read-outs utilizing electrical means.…”