Three-dimensional, multifunctional neural interfaces for cortical spheroids and engineered assembloids

Abstract

Three-dimensional (3D), submillimeter-scale constructs of neural cells, known as cortical spheroids, are of rapidly growing importance in biological research because these systems reproduce complex features of the brain in vitro. Despite their great potential for studies of neurodevelopment and neurological disease modeling, 3D living objects cannot be studied easily using conventional approaches to neuromodulation, sensing, and manipulation. Here, we introduce classes of microfabricated 3D frameworks as compliant, multifunctional neural interfaces to spheroids and to assembloids. Electrical, optical, chemical, and thermal interfaces to cortical spheroids demonstrate some of the capabilities. Complex architectures and high-resolution features highlight the design versatility. Detailed studies of the spreading of coordinated bursting events across the surface of an isolated cortical spheroid and of the cascade of processes associated with formation and regrowth of bridging tissues across a pair of such spheroids represent two of the many opportunities in basic neuroscience research enabled by these platforms.

A method for three-dimensional single-cell chronic electrophysiology from developing brain organoids

“…Plotting spiking rate per neuron as a function of FWHm -1 further revealed the positive correlation between narrowing and spiking activity of single units. While the increase in mean firing rate and signal power has been previously reported 1,21,25 , the narrowing of spikes' depolarization in brain organoids generated from hiPSCs is reported for the first time due to the ability to form direct contact between electrodes and neurons in 3D brain organoids. This result also agrees with previous findings for hiPSC-induced 2D neuron cultures 42 .…”

“…Electrical measurement techniques such as 2D microelectrode arrays (MEA) 15,16 and patch-clamp 17,18 have been applied to measure the functional development of brain organoids, but they can only capture the activities from the bottom surface of brain organoids [19][20][21] or assay one cell at a time with cell membrane disruption. The recent development of 3D bioelectronics enables 3D interfaces with brain organoids 1,19,[21][22][23][24][25] . However, they can only contact organoids at the surface by flexible electronics or penetrate organoids invasively by rigid probes, which cannot further accommodate volume and morphological changes of brain organoids during development.…”

Light-weight Electrophysiology Hardware and Software Platform for Cloud-Based Neural Recording Experiments

“…with other devices have shown, it should be applicable to measurements of 3D brain organoids, which are becoming and increasingly popular model for studying human brain tissue development and function [5,[37][38][39][40][41][42]. Many electrode probes have been designed to interface with tissues to provide measurement points for voltage recordings [15,33,34,43,44]. Future work on Piphys would involve expanding the number of different electrodes types for long-term culture of the biological sample through collaborations with other research groups.…”

“…Piphys can be used with a wide range of electrode probes including, but not limited to, rigid 2D and flexible 3D microelectrode arrays (MEAs) [33], silicon probes [34], and tetrodes. The system is built for long-term experiments with the goal of full automation using programs that can optimize experimental variables.…”

Human brain organoid networks

“…Neurons within these 3D assemblies generate action potentials upon depolarization 6 , display excitatory and inhibitory post synaptic currents 7 and exhibit spontaneous network activity as measured by calcium imaging 6,[8][9][10] and by extracellular field potential recordings from a small number of electrodes 5,[11][12][13][14] . Progress in the development of flexible electronics have also enabled three-dimensional readout of electrical activity across the surface of an organoid 15 , and recent work has extended the activity repertoire of organoids to include rhythmic activity over a range of oscillatory frequencies 10,16 . However, technological limitations have restricted broadband detection of electrical activity to small numbers of neurons.…”