3D high-density microelectrode array with optical stimulation and drug delivery for investigating neural circuit dynamics

Abstract

Investigation of neural circuit dynamics is crucial for deciphering the functional connections among regions of the brain and understanding the mechanism of brain dysfunction. Despite the advancements of neural circuit models in vitro, technologies for both precisely monitoring and modulating neural activities within three-dimensional (3D) neural circuit models have yet to be developed. Specifically, no existing 3D microelectrode arrays (MEAs) have integrated capabilities to stimulate surrounding neurons and to monitor the temporal evolution of the formation of a neural network in real time. Herein, we present a 3D high-density multifunctional MEA with optical stimulation and drug delivery for investigating neural circuit dynamics within engineered 3D neural tissues. We demonstrate precise measurements of synaptic latencies in 3D neural networks. We expect our 3D multifunctional MEA to open up opportunities for studies of neural circuits through precise, in vitro investigations of neural circuit dynamics with 3D brain models.

A multimodal 3D neuro-microphysiological system with neurite-trapping microelectrodes

“…However, exploring the functional phenotype of 3D neuronal structures requires the capability to measure the electrical activity of individual neurons with millisecond resolution 37 . Commercial MEAs for 2D cultures perform poorly for 3D cultures, while recent solutions for 3D in vitro electrophysiological recordings 18,38 are incompatible with the throughput and simple cross-platform integration required by drug discovery efforts.…”

“…The nMPS consolidates electrophysiological readout and morphological analysis in a multiwell microplate-compatible design. This represent a true novelty for 3D neuronal networks, as current 3D in vitro neuronal assays only rely on morphological 17,31 or low-throughput, invasive electrophysiological readouts 18,32 . We demonstrate the benefits of combining functional and structural assays for in vitro investigation of neurodegenerative disorders by examining the effects of rotenone on mature (more than 7 DIV) 3D neuronal cultures.…”

“…However, direct readout of electrical activitythe most relevant measure of neuronal functionremains challenging. Complex devices such as multi-shank 3D neural probes allow readout of 3D neural network activity 18 , but are poorly suited for the demands of high throughput automated culture. To fill this gap, we report here a neuro-microphysiological system (nMPS), based on 2 / 20 microelectrode arrays (MEA) and glass microfluidics 19 , capable of electrophysiological readout of 3D neuronal circuits in a microplate-compatible format.…”

Modeling Neurological Disorders in 3D Organoids Using Human-Derived Pluripotent Stem Cells

“…Recently, Soscia et al (2020) designed 3D MEAs which can provide multi-channel recordings as well as record precise signals that are appropriate to the cellular morphology, neural network dynamics, and drug responses. Recent advances of 3D MEAs have demonstrated integrated capabilities to stimulate surrounding neurons to form a neural network in real-time in such 3D neural organoid models (Shin et al, 2021). However, further refinements of these 3D MEAs, with appropriate size and density of electrodes to accommodate 3D organoids is needed.…”

Multifunctional optrode for opsin delivery, optical stimulation, and electrophysiological recordings in freely moving rats

“…To avoid these issues and allow for a single-insertion implantation surgery, it is of interest to combine fluidic, optical and electrical recording functionalities in a single device. Recently such triple-modality probes have come into focus for more efficient interrogation of neural circuitry (Canales et al, 2015;Park et al, 2017;Shin et al, 2019Shin et al, , 2021. Park et al 2017 andCanales et al 2015 integrated these modalities in flexible polymer fibers fabricated using a fiber drawing process.…”