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Conventional opaque electrodes in microelectrode array (MEA) technology obstruct the view of cells in their immediate vicinity (e.g., ≈50 µm) from which the strongest extracellular action potentials are recorded. This limitation has been overcome by transparent graphene electrodes which allow for optical access essential for novel applications such as optogenetics and calcium imaging. Downscaling, necessary for high resolution single‐unit electrophysiological recordings, has been a significant challenge due to inferior electrochemical impedance and correspondingly lower signal‐to‐noise ratio. Here, the combination of graphene with the conductive polymer poly(3,4‐ethylenedioxythiophene) polystyrene sulfonate (PEDOT:PSS) as a transparent microelectrode material for in vitro MEAs is presented and their application with optical imaging and electrophysiology is demonstrated. Optimal graphene/PEDOT:PSS microelectrodes display transparencies of 84% over the visible spectrum and impedance magnitude of (166 ± 13) kΩ at 1 kHz. The balance of transparency and 1 kHz impedance can be tuned from ≈90% and 700 kΩ to 50% and 42 kΩ.

Three-dimensional cell technologies as pre-clinical models are emerging tools for mimicking the structural and functional complexity of the nervous system. The accurate exploration of phenotypes in engineered 3D neuronal cultures, however, demands morphological, molecular and especially functional measurements. Particularly crucial is measurement of electrical activity of individual neurons with millisecond resolution. Current techniques rely on customized electrophysiological recording set-ups, characterized by limited throughput and poor integration with other readout modalities. Here we describe a novel approach, using multiwell glass microfluidic microelectrode arrays, allowing non-invasive electrical recording from engineered 3D neural tissues. We demonstrate parallelized studies with reference compounds, calcium imaging and optogenetic stimulation. Additionally, we show how microplate compatibility allows automated handling and high-content analysis of human induced pluripotent stem cell–derived neurons. This microphysiological platform opens up new avenues for high-throughput studies on the functional, morphological and molecular details of neurological diseases and their potential treatment by therapeutic compounds.

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Organoids are emerging in vitro models of human physiology. Neural models require the evaluation of functional activity of single cells and networks, which is best measured by microelectrode arrays. The characteristics of organoids clash with existing in vitro or in vivo microelectrode arrays. With inspiration from implantable mesh electronics and growth of organoids on polymer scaffolds, we fabricated suspended hammock-like mesh microelectrode arrays for neural organoids. We have demonstrated the growth of organoids enveloping these meshes, their cultivation for at least nine months, and could measure spontaneous electrical activity within organoids. Our concept should enable a new class of microelectrode arrays for in vitro models of three-dimensional electrically active tissue.

Objective. While the positive correlation between impedance and noise of microelectrodes is well known, their quantitative relationship is too rarely described. Knowledge of this relationship provides useful information for both microsystems engineers and electrophysiologists. Approach. We discuss the physical basis of noise in recordings with microelectrodes, and compare measurements of impedance spectra to noise of microelectrodes. Main results. Microelectrode recordings intrinsically include thermal noise, v t = 4 k B T ∫ Re ( Z ) d f 1 / 2 , with the real component of impedance integrated over the recording frequency band. Impedance spectroscopy allows the quantitative prediction of thermal noise. Optimization of microelectrode noise should also consider the contribution of amplifier noise. These measures enable a quantitative evaluation of microelectrodes’ recording quality which is more informative than common but limited comparisons based on the impedance magnitude at 1 kHz. Significance. Improved understanding of the origin of microelectrode noise will support efforts to produce smaller yet low noise microelectrodes, capable of recording from higher numbers of neurons. This tutorial is relevant for single microelectrodes, tetrodes, neural probes and microelectrode arrays, whether used in vitro or in vivo.

Recording neural signals from delicate autonomic nerves is a challenging task that requires the development of a low-invasive neural interface with highly selective, micrometer-sized electrodes. This paper reports on the development of a three-dimensional (3D) protruding thin-film microelectrode array (MEA), which is intended to be used for recording low-amplitude neural signals from pelvic nervous structures by penetrating the nerves transversely to reduce the distance to the axons. Cylindrical gold pillars (Ø 20 or 50 µm, ~60 µm height) were fabricated on a micromachined polyimide substrate in an electroplating process. Their sidewalls were insulated with parylene C, and their tips were optionally modified by wet etching and/or the application of a titanium nitride (TiN) coating. The microelectrodes modified by these combined techniques exhibited low impedances (~7 kΩ at 1 kHz for Ø 50 µm microelectrode with the exposed surface area of ~5000 µm²) and low intrinsic noise levels. Their functionalities were evaluated in an ex vivo pilot study with mouse retinae, in which spontaneous neuronal spikes were recorded with amplitudes of up to 66 µV. This novel process strategy for fabricating flexible, 3D neural interfaces with low-impedance microelectrodes has the potential to selectively record neural signals from not only delicate structures such as retinal cells but also autonomic nerves with improved signal quality to study neural circuits and develop stimulation strategies in bioelectronic medicine, e.g., for the control of vital digestive functions.