Long-term non-invasive interrogation of human dorsal root ganglion neuronal cultures on an integrated microfluidic multielectrode array platform
Abstract
Scientific studies in drug development and toxicology rely heavily on animal models, which often inaccurately predict the true response for human exposure. This may lead to unanticipated adverse effects or misidentified risks that result in, for example, drug candidate elimination. The utilization of human cells and tissues for in vitro physiological platforms has become a growing area of interest to bridge this gap and to more accurately predict human responses to drugs and toxins. The effects of new drugs and toxins on the peripheral nervous system are often investigated with neurons isolated from dorsal root ganglia (DRG), typically with one-time measurement techniques such as patch clamping. Here, we report the use of our multi-electrode array (MEA) platform for long-term noninvasive assessment of human DRG cell health and function. In this study, we acquired simultaneous optical and electrophysiological measurements from primary human DRG neurons upon chemical stimulation repeatedly through day in vitro (DIV) 23. Distinct chemical signatures were noted for the cellular responses evoked by each chemical stimulus. Additionally, the cell viability and function of the human DRG neurons were consistent through DIV 23. To the best of our knowledge, this is the first report on long-term measurements of the cellmore »
- Authors:
-
- Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)
- Anabios, Inc., San Diego, CA (United States)
- Publication Date:
- Research Org.:
- Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States)
- Sponsoring Org.:
- USDOE National Nuclear Security Administration (NNSA)
- OSTI Identifier:
- 1467804
- Report Number(s):
- LLNL-JRNL-674199
Journal ID: ISSN 0003-2654; ANALAO; 796995
- Grant/Contract Number:
- AC52-07NA27344
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Analyst
- Additional Journal Information:
- Journal Volume: 141; Journal Issue: 18; Journal ID: ISSN 0003-2654
- Publisher:
- Royal Society of Chemistry
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES
Citation Formats
Enright, H. A., Felix, S. H., Fischer, N. O., Mukerjee, E. V., Soscia, D., Mcnerney, M., Kulp, K., Zhang, J., Page, G., Miller, P., Ghetti, A., Wheeler, E. K., and Pannu, S. Long-term non-invasive interrogation of human dorsal root ganglion neuronal cultures on an integrated microfluidic multielectrode array platform. United States: N. p., 2016.
Web. doi:10.1039/c5an01728a.
Enright, H. A., Felix, S. H., Fischer, N. O., Mukerjee, E. V., Soscia, D., Mcnerney, M., Kulp, K., Zhang, J., Page, G., Miller, P., Ghetti, A., Wheeler, E. K., & Pannu, S. Long-term non-invasive interrogation of human dorsal root ganglion neuronal cultures on an integrated microfluidic multielectrode array platform. United States. https://doi.org/10.1039/c5an01728a
Enright, H. A., Felix, S. H., Fischer, N. O., Mukerjee, E. V., Soscia, D., Mcnerney, M., Kulp, K., Zhang, J., Page, G., Miller, P., Ghetti, A., Wheeler, E. K., and Pannu, S. Tue .
"Long-term non-invasive interrogation of human dorsal root ganglion neuronal cultures on an integrated microfluidic multielectrode array platform". United States. https://doi.org/10.1039/c5an01728a. https://www.osti.gov/servlets/purl/1467804.
@article{osti_1467804,
title = {Long-term non-invasive interrogation of human dorsal root ganglion neuronal cultures on an integrated microfluidic multielectrode array platform},
author = {Enright, H. A. and Felix, S. H. and Fischer, N. O. and Mukerjee, E. V. and Soscia, D. and Mcnerney, M. and Kulp, K. and Zhang, J. and Page, G. and Miller, P. and Ghetti, A. and Wheeler, E. K. and Pannu, S.},
abstractNote = {Scientific studies in drug development and toxicology rely heavily on animal models, which often inaccurately predict the true response for human exposure. This may lead to unanticipated adverse effects or misidentified risks that result in, for example, drug candidate elimination. The utilization of human cells and tissues for in vitro physiological platforms has become a growing area of interest to bridge this gap and to more accurately predict human responses to drugs and toxins. The effects of new drugs and toxins on the peripheral nervous system are often investigated with neurons isolated from dorsal root ganglia (DRG), typically with one-time measurement techniques such as patch clamping. Here, we report the use of our multi-electrode array (MEA) platform for long-term noninvasive assessment of human DRG cell health and function. In this study, we acquired simultaneous optical and electrophysiological measurements from primary human DRG neurons upon chemical stimulation repeatedly through day in vitro (DIV) 23. Distinct chemical signatures were noted for the cellular responses evoked by each chemical stimulus. Additionally, the cell viability and function of the human DRG neurons were consistent through DIV 23. To the best of our knowledge, this is the first report on long-term measurements of the cell health and function of human DRG neurons on a MEA platform. Future generations will include higher electrode numbers in customized arrangements as well as integration with different tissue types on a single device. This platform will provide a valuable testing tool for both rodent and human cells, enabling a more comprehensive risk assessment for drug candidates and toxicants.},
doi = {10.1039/c5an01728a},
journal = {Analyst},
number = 18,
volume = 141,
place = {United States},
year = {Tue Jun 28 00:00:00 EDT 2016},
month = {Tue Jun 28 00:00:00 EDT 2016}
}
Web of Science
Works referenced in this record:
Long-term electrophysiological activity and pharmacological response of a human induced pluripotent stem cell-derived neuron and astrocyte co-culture
journal, January 2014
- Odawara, A.; Saitoh, Y.; Alhebshi, A. H.
- Biochemical and Biophysical Research Communications, Vol. 443, Issue 4
Emergence of Rich-Club Topology and Coordinated Dynamics in Development of Hippocampal Functional Networks In Vitro
journal, April 2015
- Schroeter, M. S.; Charlesworth, P.; Kitzbichler, M. G.
- Journal of Neuroscience, Vol. 35, Issue 14
Microelectrode arrays: A physiologically based neurotoxicity testing platform for the 21st century☆
journal, August 2010
- Johnstone, Andrew F. M.; Gross, Guenter W.; Weiss, Dieter G.
- NeuroToxicology, Vol. 31, Issue 4
Investigating neuronal activity with planar microelectrode arrays: achievements and new perspectives
journal, August 2005
- Morin, Fabrice O.; Takamura, Yuzuru; Tamiya, Eiichi
- Journal of Bioscience and Bioengineering, Vol. 100, Issue 2
Bayesian Modeling and Classification of Neural Signals
journal, September 1994
- Lewicki, Michael S.
- Neural Computation, Vol. 6, Issue 5
An innovations approach to fault detection and diagnosis in dynamic systems
journal, September 1971
- Mehra, R. K.; Peschon, J.
- Automatica, Vol. 7, Issue 5
Neural spike sorting under nearly 0-dB signal-to-noise ratio using nonlinear energy operator and artificial neural-network classifier
journal, January 2000
- Kyung Hwan Kim,
- IEEE Transactions on Biomedical Engineering, Vol. 47, Issue 10
P2X receptors in peripheral neurons
journal, October 2001
- Dunn, Philip M.; Zhong, Yu; Burnstock, Geoffrey
- Progress in Neurobiology, Vol. 65, Issue 2
Pentobarbital-activated Cl− channels in cultured adult and embryonic human DRG neurons
journal, November 2000
- Valeyev, Alexander Y.; Hackman, John C.; Holohean, Alice M.
- Developmental Brain Research, Vol. 124, Issue 1-2
Automatic spike detection based on adaptive template matching for extracellular neural recordings
journal, September 2007
- Kim, Sunghan; McNames, James
- Journal of Neuroscience Methods, Vol. 165, Issue 2
The Influence of Neuronal Density and Maturation on Network Activity of Hippocampal Cell Cultures: A Methodological Study
journal, December 2013
- Biffi, Emilia; Regalia, Giulia; Menegon, Andrea
- PLoS ONE, Vol. 8, Issue 12
A generalized likelihood ratio approach to the detection and estimation of jumps in linear systems
journal, February 1976
- Willsky, A.; Jones, H.
- IEEE Transactions on Automatic Control, Vol. 21, Issue 1
Cannabinoid receptor CB2 localisation and agonist-mediated inhibition of capsaicin responses in human sensory neurons
journal, January 2008
- Anand, Uma; Otto, William R.; Sanchez-Herrera, Daniel
- Pain, Vol. 138, Issue 3
On-chip in vitro cell-network pre-clinical cardiac toxicity using spatiotemporal human cardiomyocyte measurement on a chip
journal, April 2014
- Kaneko, Tomoyuki; Nomura, Fumimasa; Hamada, Tomoyo
- Scientific Reports, Vol. 4, Issue 1
HIV-1 viral protein R causes peripheral nervous system injury associated with in vivo neuropathic pain
journal, November 2010
- Acharjee, Shaona; Noorbakhsh, Farshid; Stemkowski, Patrick L.
- The FASEB Journal, Vol. 24, Issue 11
Mechanisms of Prolonged Presynaptic Ca2+ Signaling and Glutamate Release Induced by TRPV1 Activation in Rat Sensory Neurons
journal, May 2008
- Medvedeva, Y. V.; Kim, M. -S.; Usachev, Y. M.
- Journal of Neuroscience, Vol. 28, Issue 20
GABAA receptor subunit mRNA expression in cultured embryonic and adult human dorsal root ganglion neurons
journal, April 2004
- Maddox, Floyd N.; Valeyev, Alexander Y.; Poth, Kevin
- Developmental Brain Research, Vol. 149, Issue 2
Particle filtering-based fault detection in non-linear stochastic systems
journal, January 2002
- Kadirkamanathan, V.; Li, P.; Jaward, M. H.
- International Journal of Systems Science, Vol. 33, Issue 4
TRPA1 receptor localisation in the human peripheral nervous system and functional studies in cultured human and rat sensory neurons
journal, June 2008
- Anand, U.; Otto, W. R.; Facer, P.
- Neuroscience Letters, Vol. 438, Issue 2
Sodium channel β1 and β2 subunits parallel SNS/PN3 α-subunit changes in injured human sensory neurons
journal, January 2001
- Coward, K.; Jowett, A.; Plumpton, C.
- Neuroreport, Vol. 12, Issue 3
A new approach to neural cell culture for long-term studies
journal, September 2001
- Potter, Steve M.; DeMarse, Thomas B.
- Journal of Neuroscience Methods, Vol. 110, Issue 1-2
Model-based failure detection for cylindrical shells from noisy vibration measurements
journal, December 2014
- Candy, J. V.; Fisher, K. A.; Guidry, B. L.
- The Journal of the Acoustical Society of America, Vol. 136, Issue 6
Evidence for Cholinergic Synapses Between Dissociated Rat Sympathetic Neurons in Cell Culture
journal, September 1974
- O'Lague, P. H.; Obata, K.; Claude, P.
- Proceedings of the National Academy of Sciences, Vol. 71, Issue 9
Cytosine arabinoside affects the heat and capsaicin receptor TRPV1 localisation and sensitivity in human sensory neurons
journal, April 2008
- Anand, Uma; Otto, William R.; Bountra, Chas
- Journal of Neuro-Oncology, Vol. 89, Issue 1
A general-purpose system for long-term recording from a microelectrode array coupled to excitable cells
journal, June 1993
- Martinoia, S.; Bove, M.; Carlini, G.
- Journal of Neuroscience Methods, Vol. 48, Issue 1-2
Human sensory neurons: Membrane properties and sensitization by inflammatory mediators
journal, January 2014
- Davidson, Steve; Copits, Bryan A.; Zhang, Jingming
- Pain, Vol. 155, Issue 9
Detection, classification, and superposition resolution of action potentials in multiunit single-channel recordings by an on-line real-time neural network
journal, May 1997
- Chandra, R.; Optican, L. M.
- IEEE Transactions on Biomedical Engineering, Vol. 44, Issue 5
GDNF and its receptor component Ret in injured human nerves and dorsal root ganglia
journal, January 1998
- Bär, K. J.; F. Saldanha, G. J.; Kennedy, A. J.
- NeuroReport, Vol. 9, Issue 1
The effect of neurotrophic factors on morphology, TRPV1 expression and capsaicin responses of cultured human DRG sensory neurons
journal, May 2006
- Anand, U.; Otto, W. R.; Casula, M. A.
- Neuroscience Letters, Vol. 399, Issue 1-2
Human embryonic stem cell-derived neuronal cells form spontaneously active neuronal networks in vitro
journal, July 2009
- Heikkilä, Teemu J.; Ylä-Outinen, Laura; Tanskanen, Jarno M. A.
- Experimental Neurology, Vol. 218, Issue 1
Two-dimensional monitoring of spiking networks in acute brain slices
journal, January 2002
- Egert, Ulrich; D., Heck; A., Aertsen
- Experimental Brain Research, Vol. 142, Issue 2
Characterizing Human Stem Cell–derived Sensory Neurons at the Single-cell Level Reveals Their Ion Channel Expression and Utility in Pain Research
journal, August 2014
- Young, Gareth T.; Gutteridge, Alex; Fox, Heather DE
- Molecular Therapy, Vol. 22, Issue 8
Capsaicin-sensitive and -insensitive vagal bronchopulmonary C-fibres in the mouse
journal, August 2003
- Kollarik, M.; Dinh, Q. T.; Fischer, A.
- The Journal of Physiology, Vol. 551, Issue 3
Human cell-based micro electrode array platform for studying neurotoxicity
journal, January 2010
- Ylä-Outinen, Laura
- Frontiers in Neuroengineering, Vol. 3
An SCN9A channelopathy causes congenital inability to experience pain
journal, December 2006
- Cox, James J.; Reimann, Frank; Nicholas, Adeline K.
- Nature, Vol. 444, Issue 7121
A new interpretation of nonlinear energy operator and its efficacy in spike detection
journal, January 1998
- Mukhopadhyay, S.; Ray, G. C.
- IEEE Transactions on Biomedical Engineering, Vol. 45, Issue 2
A review of methods for spike sorting: the detection and classification of neural action potentials
journal, January 1998
- Lewicki, Michael S.
- Network: Computation in Neural Systems, Vol. 9, Issue 4
Dissociated Neurons and Glial Cells Derived from Rat Inferior Colliculi after Digestion with Papain
journal, December 2013
- Kaiser, Odett; Aliuos, Pooyan; Wissel, Kirsten
- PLoS ONE, Vol. 8, Issue 12
Nociceptors: the sensors of the pain pathway
journal, November 2010
- Dubin, Adrienne E.; Patapoutian, Ardem
- Journal of Clinical Investigation, Vol. 120, Issue 11
Differential expression of the capsaicin receptor TRPV1 and related novel receptors TRPV3, TRPV4 and TRPM8 in normal human tissues and changes in traumatic and diabetic neuropathy
journal, May 2007
- Facer, Paul; Casula, Maria A.; Smith, Graham D.
- BMC Neurology, Vol. 7, Issue 1
Responses of adult human dorsal root ganglion neurons in culture to capsaicin and low pH
journal, January 1996
- Baumann, Thomas K.; Burchiel, Kim J.; Ingram, Susan L.
- Pain, Vol. 65, Issue 1
Spike detection methods for polytrodes and high density microelectrode arrays
journal, November 2014
- Swindale, Nicholas V.; Spacek, Martin A.
- Journal of Computational Neuroscience, Vol. 38, Issue 2
Are animal models predictive for humans?
journal, January 2009
- Shanks, Niall; Greek, Ray; Greek, Jean
- Philosophy, Ethics, and Humanities in Medicine, Vol. 4, Issue 1
The Role of Body-on-a-Chip Devices in Drug and Toxicity Studies
journal, August 2011
- Esch, M. B.; King, T. L.; Shuler, M. L.
- Annual Review of Biomedical Engineering, Vol. 13, Issue 1
Intraneuronal angiotensinergic system in rat and human dorsal root ganglia
journal, June 2010
- Patil, Jaspal; Schwab, Alexander; Nussberger, Juerg
- Regulatory Peptides, Vol. 162, Issue 1-3
Two tetrodotoxin-resistant sodium channels in human dorsal root ganglion neurons
journal, November 1999
- Dib-Hajj, S. D.; Tyrrell, L.; Cummins, T. R.
- FEBS Letters, Vol. 462, Issue 1-2
Immunolocalization of SNS/PN3 and NaN/SNS2 sodium channels in human pain states
journal, January 2000
- Coward, K.; Plumpton, C.; Facer, P.
- Pain, Vol. 85, Issue 1
Nociceptor-specific gene deletion reveals a major role for Nav1.7 (PN1) in acute and inflammatory pain
journal, August 2004
- Nassar, M. A.; Stirling, L. C.; Forlani, G.
- Proceedings of the National Academy of Sciences, Vol. 101, Issue 34
Cortical cultures coupled to Micro-Electrode Arrays: A novel approach to perform in vitro excitotoxicity testing
journal, January 2012
- Frega, Monica; Pasquale, Valentina; Tedesco, Mariateresa
- Neurotoxicology and Teratology, Vol. 34, Issue 1
Advantages of using microfabricated extracellular electrodes for in vitro neuronal recording
journal, October 1995
- Breckenridge, L. J.; Wilson, R. J. A.; Connolly, P.
- Journal of Neuroscience Research, Vol. 42, Issue 2
Angiotensin II type 2 receptor (AT 2 R) localization and antagonist-mediated inhibition of capsaicin responses and neurite outgrowth in human and rat sensory neurons : AT
journal, December 2012
- Anand, U.; Facer, P.; Yiangou, Y.
- European Journal of Pain, Vol. 17, Issue 7
TRPV3 is a temperature-sensitive vanilloid receptor-like protein
journal, June 2002
- Smith, G. D.; Gunthorpe, M. J.; Kelsell, R. E.
- Nature, Vol. 418, Issue 6894
In vitro pharmacologic testing using human induced pluripotent stem cell-derived cardiomyocytes
journal, August 2009
- Tanaka, Tomofumi; Tohyama, Shugo; Murata, Mitsushige
- Biochemical and Biophysical Research Communications, Vol. 385, Issue 4
Activation of ATP P2X receptors elicits glutamate release from sensory neuron synapses
journal, October 1997
- Gu, Jianguo G.; MacDermott, Amy B.
- Nature, Vol. 389, Issue 6652
Alphaxalone Activates a Cl − Conductance Independent of GABA A Receptors in Cultured Embryonic Human Dorsal Root Ganglion Neurons
journal, July 1999
- Valeyev, Alexander Y.; Hackman, John C.; Holohean, Alice M.
- Journal of Neurophysiology, Vol. 82, Issue 1
GABA-Induced Cl − Current in Cultured Embryonic Human Dorsal Root Ganglion Neurons
journal, July 1999
- Valeyev, Alexander Y.; Hackman, John C.; Holohean, Alice M.
- Journal of Neurophysiology, Vol. 82, Issue 1
Pharmacologically novel GABA receptor in human dorsal root ganglion neurons
journal, November 1996
- Valeyev, A. Y.; Hackman, J. C.; Wood, P. M.
- Journal of Neurophysiology, Vol. 76, Issue 5
Intracellular Features Predicted by Extracellular Recordings in the Hippocampus In Vivo
journal, July 2000
- Henze, Darrell A.; Borhegyi, Zsolt; Csicsvari, Jozsef
- Journal of Neurophysiology, Vol. 84, Issue 1
Works referencing / citing this record:
Evaluation of in vitro neuronal platforms as surrogates for in vivo whole brain systems
journal, July 2018
- Belle, Anna M.; Enright, Heather A.; Sales, Ana Paula
- Scientific Reports, Vol. 8, Issue 1
Role of extrinsic mechanical force in the development of the RA-I tactile mechanoreceptor
journal, July 2018
- Pham, Trung Quang; Kawaue, Takumi; Hoshi, Takayuki
- Scientific Reports, Vol. 8, Issue 1
A flexible 3-dimensional microelectrode array for in vitro brain models
journal, January 2020
- Soscia, David A.; Lam, Doris; Tooker, Angela C.
- Lab on a Chip, Vol. 20, Issue 5
Adult mouse sensory neurons on microelectrode arrays exhibit increased spontaneous and stimulus-evoked activity in the presence of interleukin-6
journal, September 2018
- Black, Bryan J.; Atmaramani, Rahul; Kumaraju, Rajeshwari
- Journal of Neurophysiology, Vol. 120, Issue 3
Controlled placement of multiple CNS cell populations to create complex neuronal cultures
journal, November 2017
- Soscia, D.; Belle, A.; Fischer, N.
- PLOS ONE, Vol. 12, Issue 11
Microdevice Platform for In Vitro Nervous System and Its Disease Model
journal, September 2017
- Choi, Jin-Ha; Cho, Hyeon-Yeol; Choi, Jeong-Woo
- Bioengineering, Vol. 4, Issue 4
Evaluation of in vitro neuronal platforms as surrogates for in vivo whole brain systems
journal, July 2018
- Belle, Anna M.; Enright, Heather A.; Sales, Ana Paula
- Scientific Reports, Vol. 8, Issue 1
Role of extrinsic mechanical force in the development of the RA-I tactile mechanoreceptor
journal, July 2018
- Pham, Trung Quang; Kawaue, Takumi; Hoshi, Takayuki
- Scientific Reports, Vol. 8, Issue 1