Compact 256-channel multi-well microelectrode array system for in vitro neuropharmacology test.

Microelectrode arrays (MEAs) have been extensively used to measure extracellular spike activity from cultured neurons using multiple electrodes embedded in a planar glass substrate. This system has been implemented to investigate drug effects by detecting pharmacological perturbation reflected in spontaneous network activity. By configuring multiple wells in an MEA, a high-throughput electrophysiological assay has become available, speeding up drug tests. Despite its merits in acquiring massive amounts of electrophysiological data, the high cost and the bulky size of commercial multi-well MEA systems and most importantly its lack of customizability prevent potential users from fully implementing the system in drug experiments. In this work, we have developed a microelectrode array based drug testing platform by incorporating a custom-made compact 256-channel multi-well MEA in a standard microscope slide and commercial application-specific integrated circuit (ASIC) chip based recording system. We arranged 256 electrodes in 16 wells to maximize data collection from a single chip. The multi-well MEA in this work has a more compact design with reduced chip size compared to previously reported multi-well MEAs. Four synaptic modulators (NMDA, AMPA, bicuculline (BIC) and ATP) were applied to a multi-well MEA and neural spike activity was analyzed to study their neurophysiological effects on cultured neurons. Analyzing various neuropharmacological compounds has become much more accessible by utilizing commercially available digital amplifier chips and customizing a user-preferred analog-front-end interface design with additional benefits in reduced platform size and cost.

[1]  D. Khodagholy,et al.  Easy‐to‐Fabricate Conducting Polymer Microelectrode Arrays , 2013, Advanced materials.

[2]  G. Pazour,et al.  Ror2 signaling regulates Golgi structure and transport through IFT20 for tumor invasiveness , 2017, Scientific Reports.

[3]  B. Botterman,et al.  Carbon nanotube coating improves neuronal recordings. , 2008, Nature nanotechnology.

[4]  A. Bhardwaj,et al.  In situ click chemistry generation of cyclooxygenase-2 inhibitors , 2017, Nature Communications.

[5]  W Göpel,et al.  Strychnine analysis with neuronal networks in vitro: extracellular array recording of network responses. , 1997, Biosensors & bioelectronics.

[6]  Hongda Chen,et al.  Sodium Dodecyl Sulfate doping PEDOT to enhance the performance of neural microelectrode , 2015 .

[7]  Shimon Marom,et al.  Long-range synchrony and emergence of neural reentry , 2016, Scientific Reports.

[8]  H. Hultborn,et al.  Modulation of spontaneous locomotor and respiratory drives to hindlimb motoneurons temporally related to sympathetic drives as revealed by Mayer waves , 2015, Front. Neural Circuits.

[9]  Vijay Viswam,et al.  High-resolution CMOS MEA platform to study neurons at subcellular, cellular, and network levels. , 2015, Lab on a chip.

[10]  Edward S. Boyden,et al.  A direct-to-drive neural data acquisition system , 2015, Front. Neural Circuits.

[11]  J. Meulenbelt,et al.  Neurotoxicity screening of (illicit) drugs using novel methods for analysis of microelectrode array (MEA) recordings. , 2016, Neurotoxicology.

[12]  Jong M. Rho,et al.  Loss of the Kv1.1 potassium channel promotes pathologic sharp waves and high frequency oscillations in in vitro hippocampal slices , 2013, Neurobiology of Disease.

[13]  Giada Cellot,et al.  PEDOT:PSS Interfaces Support the Development of Neuronal Synaptic Networks with Reduced Neuroglia Response In vitro , 2016, Front. Neurosci..

[14]  Michael L. Roukes,et al.  Nanofabricated Neural Probes for Dense 3-D Recordings of Brain Activity , 2016, Nano letters.

[15]  T. Bliss,et al.  Plasticity in the human central nervous system. , 2006, Brain : a journal of neurology.

[16]  J. Olney,et al.  Excitotoxity and the NMDA receptor , 1987, Trends in Neurosciences.

[17]  A. Harsch,et al.  Odor, drug and toxin analysis with neuronal networks in vitro: extracellular array recording of network responses. , 1997, Biosensors & bioelectronics.

[18]  Allister F. McGuire,et al.  Soft conductive micropillar electrode arrays for biologically relevant electrophysiological recording , 2018, Proceedings of the National Academy of Sciences.

[19]  David C. Martin,et al.  Electrochemical deposition and characterization of poly(3,4-ethylenedioxythiophene) on neural microelectrode arrays , 2003 .

[20]  G. Gross,et al.  A new fixed-array multi-microelectrode system designed for long-term monitoring of extracellular single unit neuronal activity in vitro , 1977, Neuroscience Letters.

[21]  Steve M. Potter,et al.  Controlling Bursting in Cortical Cultures with Closed-Loop Multi-Electrode Stimulation , 2005, The Journal of Neuroscience.

[22]  Andrew F M Johnstone,et al.  Microelectrode arrays: a physiologically based neurotoxicity testing platform for the 21st century. , 2010, Neurotoxicology.

[23]  P. Renaud,et al.  Intracellular recording of cardiomyocyte action potentials with nanopatterned volcano-shaped microelectrode arrays. , 2019, Nano letters.

[24]  Robert H. Brown,et al.  Intrinsic membrane hyperexcitability of amyotrophic lateral sclerosis patient-derived motor neurons. , 2014, Cell reports.

[25]  Timothy J Shafer,et al.  Evaluation of multi-well microelectrode arrays for neurotoxicity screening using a chemical training set. , 2012, Neurotoxicology.

[26]  J. Pine Recording action potentials from cultured neurons with extracellular microcircuit electrodes , 1980, Journal of Neuroscience Methods.

[27]  Åsa Johansson,et al.  Corrigendum: 1000 Genomes-based meta-analysis identifies 10 novel loci for kidney function , 2017, Scientific Reports.

[28]  Michela Chiappalone,et al.  Effects of antiepileptic drugs on hippocampal neurons coupled to micro-electrode arrays , 2013, Front. Neuroeng..

[29]  Carmen Bartic,et al.  Spine-shaped gold protrusions improve the adherence and electrical coupling of neurons with the surface of micro-electronic devices , 2009, Journal of The Royal Society Interface.

[30]  Aline Gangnery,et al.  Towards the Determination of Mytilus edulis Food Preferences Using the Dynamic Energy Budget (DEB) Theory , 2014, PloS one.

[31]  Tanja Neumann,et al.  Replica-moulded polydimethylsiloxane culture vessel lids attenuate osmotic drift in long-term cell cultures , 2009, Journal of Biosciences.

[32]  John P. John,et al.  Assessing Neurocognition via Gamified Experimental Logic: A Novel Approach to Simultaneous Acquisition of Multiple ERPs , 2016, Front. Neurosci..

[33]  Liang Guo,et al.  A PDMS-Based Integrated Stretchable Microelectrode Array (isMEA) for Neural and Muscular Surface Interfacing , 2013, IEEE Transactions on Biomedical Circuits and Systems.

[34]  Katharina Lilienthal,et al.  A novel 384-multiwell microelectrode array for the impedimetric monitoring of Tau protein induced neurodegenerative processes. , 2017, Biosensors & bioelectronics.

[35]  Jakob Voigts,et al.  Neural ensemble communities: open-source approaches to hardware for large-scale electrophysiology , 2015, Current Opinion in Neurobiology.

[36]  Eran Stark,et al.  Large-scale, high-density (up to 512 channels) recording of local circuits in behaving animals. , 2014, Journal of neurophysiology.

[37]  Wolfgang Eberle,et al.  Synaptic dysfunction in hippocampus of transgenic mouse models of Alzheimer's disease: A multi-electrode array study , 2011, Neurobiology of Disease.

[38]  Nancy Kopell,et al.  Close-Packed Silicon Microelectrodes for Scalable Spatially Oversampled Neural Recording , 2015, IEEE Transactions on Biomedical Engineering.

[39]  M. Kummu,et al.  How Close Do We Live to Water? A Global Analysis of Population Distance to Freshwater Bodies , 2011, PloS one.

[40]  G. Grest,et al.  Corrigendum: Superfast assembly and synthesis of gold nanostructures using nanosecond low-temperature compression via magnetic pulsed power , 2017, Nature Communications.

[41]  Danny Eytan,et al.  Dynamics and Effective Topology Underlying Synchronization in Networks of Cortical Neurons , 2006, The Journal of Neuroscience.

[42]  Sabine Schmidt,et al.  A novel 96-well multielectrode array based impedimetric monitoring platform for comparative drug efficacy analysis on 2D and 3D brain tumor cultures. , 2015, Biosensors & bioelectronics.

[43]  Michela Chiappalone,et al.  Cortical cultures coupled to micro-electrode arrays: a novel approach to perform in vitro excitotoxicity testing. , 2012, Neurotoxicology and teratology.

[44]  U. Frey,et al.  Tracking axonal action potential propagation on a high-density microelectrode array across hundreds of sites , 2013, Nature Communications.

[45]  Bruce C Wheeler,et al.  Novel MEA platform with PDMS microtunnels enables the detection of action potential propagation from isolated axons in culture. , 2009, Lab on a chip.

[46]  Yi Du,et al.  Corrigendum: 3D hierarchical porous graphene aerogel with tunable meso-pores on graphene nanosheets for high-performance energy storage , 2016, Scientific Reports.

[47]  Eduardo Serrano,et al.  Characterization of a clinical olfactory test with an artificial nose , 2011, Front. Neuroeng..

[48]  J. Y. Lettvin,et al.  Comments on Microelectrodes , 1959, Proceedings of the IRE.

[49]  Kenta Shimba,et al.  Axonal conduction slowing induced by spontaneous bursting activity in cortical neurons cultured in a microtunnel device. , 2015, Integrative biology : quantitative biosciences from nano to macro.

[50]  Sabine Schmidt,et al.  Real-time monitoring of relaxation and contractility of smooth muscle cells on a novel biohybrid chip. , 2010, Lab on a chip.

[51]  Shao-Wei Lu,et al.  Design and fabrication of novel three-dimensional multi-electrode array using SOI wafer , 2006 .

[52]  Baljit S. Khakh,et al.  Neuromodulation by Extracellular ATP and P2X Receptors in the CNS , 2012, Neuron.

[53]  Jakob Voigts,et al.  Open Ephys electroencephalography (Open Ephys  +  EEG): a modular, low-cost, open-source solution to human neural recording , 2017, Journal of neural engineering.

[54]  M. Stelzle,et al.  PEDOT–CNT Composite Microelectrodes for Recording and Electrostimulation Applications: Fabrication, Morphology, and Electrical Properties , 2012, Front. Neuroeng..

[55]  Dong-il Dan Cho,et al.  Fabrication of pyramid shaped three-dimensional 8 × 8 electrodes for artificial retina , 2006 .

[56]  Leslie M. Loew,et al.  Computational neurobiology is a useful tool in translational neurology: the example of ataxia , 2014, Front. Neurosci..

[57]  J. A. Varela,et al.  Shielded Coaxial Optrode Arrays for Neurophysiology , 2016, Front. Neurosci..