“…The platform can be used not only for understanding the mechanism of action for drug candidates on the basis of clinically relevant electrophysiological and histological metrics, but also for investigating basic mechanisms driving nerve pathologies, including but not limited to toxicity, demyelination, and other neurodegenerative conditions. In addition, comparison of data acquired in parallel using our Rat NoaC (RNoaC) platform 15 and HNoaC for a given drug treatment or disease, could help further close the gap between nonclinical testing and our ability to anticipate responses and potential safety risks in humans.…”
Section: Discussionmentioning
confidence: 99%
“…A dual-hydrogel scaffold was created on the membranes of Transwell® inserts (0.4 µm/PES; Corning) using a micro-photolithography technique similar to methods previously described 15 . All solutions were created with sterile-filtered PBS unless otherwise noted.…”
Development of “organ-on-a-chip” systems for neuroscience applications are lagging due in part to the structural complexity of the nervous system and limited access of human neuronal & glial cells. In addition, rates for animal models in translating to human success are significantly lower for neurodegenerative diseases. Thus, a preclinical
in vitro
human cell-based model capable of providing critical clinical metrics such as nerve conduction velocity and histomorphometry are necessary to improve prediction and translation of
in vitro
data to successful clinical trials. To answer this challenge, we present an
in vitro
biomimetic model of all-human peripheral nerve tissue capable of showing robust neurite outgrowth (~5 mm), myelination of hNs by primary human Schwann cells (~5%), and evaluation of nerve conduction velocity (0.13–0.28 m/sec), previously unrealized for any human cell-based
in vitro
system. To the best of our knowledge, this Human Nerve-on-a-chip (HNoaC) system is the first biomimetic microphysiological system of myelinated human peripheral nerve which can be used for evaluating electrophysiological and histological metrics, the gold-standard assessment techniques previously only possible with
in vivo
studies.
“…The platform can be used not only for understanding the mechanism of action for drug candidates on the basis of clinically relevant electrophysiological and histological metrics, but also for investigating basic mechanisms driving nerve pathologies, including but not limited to toxicity, demyelination, and other neurodegenerative conditions. In addition, comparison of data acquired in parallel using our Rat NoaC (RNoaC) platform 15 and HNoaC for a given drug treatment or disease, could help further close the gap between nonclinical testing and our ability to anticipate responses and potential safety risks in humans.…”
Section: Discussionmentioning
confidence: 99%
“…A dual-hydrogel scaffold was created on the membranes of Transwell® inserts (0.4 µm/PES; Corning) using a micro-photolithography technique similar to methods previously described 15 . All solutions were created with sterile-filtered PBS unless otherwise noted.…”
Development of “organ-on-a-chip” systems for neuroscience applications are lagging due in part to the structural complexity of the nervous system and limited access of human neuronal & glial cells. In addition, rates for animal models in translating to human success are significantly lower for neurodegenerative diseases. Thus, a preclinical
in vitro
human cell-based model capable of providing critical clinical metrics such as nerve conduction velocity and histomorphometry are necessary to improve prediction and translation of
in vitro
data to successful clinical trials. To answer this challenge, we present an
in vitro
biomimetic model of all-human peripheral nerve tissue capable of showing robust neurite outgrowth (~5 mm), myelination of hNs by primary human Schwann cells (~5%), and evaluation of nerve conduction velocity (0.13–0.28 m/sec), previously unrealized for any human cell-based
in vitro
system. To the best of our knowledge, this Human Nerve-on-a-chip (HNoaC) system is the first biomimetic microphysiological system of myelinated human peripheral nerve which can be used for evaluating electrophysiological and histological metrics, the gold-standard assessment techniques previously only possible with
in vivo
studies.
“…utilized a >11,000 MEA to study signal propagation along constrained rat cortical neurites in PDMS microchannels (Lewandowska et al., 2015). This platform allowed for the recording of discrete action potentials propagating from the soma to individual neurites or the axonal terminus.Figure 3Examples of Instrumented Organ-on-chip Models of the Peripheral and Central Nervous System(A and B) Extracellular activity and connectivity of compartmentalized cortical neurons via an MEA.(C and D) Extracellular recordings of neural activity and 3D connectivity via a 3D MEA.(E) Extracellular recordings and impedance detection to quantify firing frequency and cell adhesion of neuronal cells exposed to sodium valproic acid via an MEA and an interdigitated electrode structure.(F) Extracellular recordings of spontaneous and stimulated autonomic neuron activity for regulating cardiac beating via an MEA.(G) CV of myelinated and nonmyelinated sensory neurons via a microchannel-electrode approach.(H) Single-unit action potentials and CV of intact sciatic nerves exposed to ultrasound stimuli via a multi-wire electrode array.(I) CAP and CV of intact sciatic nerves via a microchannel-electrode approach.(J, K, and L) (J) CAP recording in 3D rodent sensory neuron, (K) 3D myelinated rodent sensory neurons, and (L) 3D human stem cell-derived sensory neuron models via stimulating and recording wire electrodes.Reprinted and adapted with permission from: A (Kanagasabapathi et al., 2011); B (Pan et al., 2015); C (Rowe et al., 2007); D (Musick et al., 2009); E (Koester et al., 2010a); F (Oiwa et al., 2016); G (Sakai et al., 2017); H (Chen et al., 2017); I (Gribi et al., 2018); J (Huval et al., 2015); K (Khoshakhlagh et al., 2018); and L (Sharma et al., 2019). MEA, multielectrode array; CV, conduction velocity; CAP, compound action potential.…”
Section: Cns-on-chipmentioning
confidence: 99%
“…Reprinted and adapted with permission from: A (Kanagasabapathi et al., 2011); B (Pan et al., 2015); C (Rowe et al., 2007); D (Musick et al., 2009); E (Koester et al., 2010a); F (Oiwa et al., 2016); G (Sakai et al., 2017); H (Chen et al., 2017); I (Gribi et al., 2018); J (Huval et al., 2015); K (Khoshakhlagh et al., 2018); and L (Sharma et al., 2019). MEA, multielectrode array; CV, conduction velocity; CAP, compound action potential.…”
Section: Cns-on-chipmentioning
confidence: 99%
“…Beneficially, the dual hydrogel system allows the culture to be fixed and sectioned for transmission electron microscopy (TEM) of neural culture cross-sections to investigate myelination. To further explore myelination in vitro , the platform was modified to incorporate exogenous SCs (Figure 3K) (Khoshakhlagh et al., 2018). Using a growth-restrictive PEG hydrogel to confine nerve tracts, rat neonatal SCs were encapsulated along with rat embryonic DRGs in a glycidyl methacrylate-dextran hydrogel.…”
Recent advancements in electronic materials and subsequent surface modifications have facilitated real-time measurements of cellular processes far beyond traditional passive recordings of neurons and muscle cells. Specifically, the functionalization of conductive materials with ligand-binding aptamers has permitted the utilization of traditional electronic materials for bioelectronic sensing. Further, microfabrication techniques have better allowed microfluidic devices to recapitulate the physiological and pathological conditions of complex tissues and organs in vitro or microphysiological systems (MPS). The convergence of these models with advances in biological/biomedical microelectromechanical systems (BioMEMS) instrumentation has rapidly bolstered a wide array of bioelectronic platforms for real-time cellular analytics. In this review, we provide an overview of the sensing techniques that are relevant to MPS development and highlight the different organ systems to integrate instrumentation for measurement and manipulation of cellular function. Special attention is given to how instrumented MPS can disrupt the drug development and fundamental mechanistic discovery processes.
The composition, elasticity, and organization of the extracellular matrix within the central nervous system contribute to the architecture and function of the brain. From an in vitro modeling perspective, soft biomaterials are needed to mimic the 3D neural microenvironments. While many studies have investigated 3D culture and neural network formation in bulk hydrogel systems, these approaches have limited ability to position cells to mimic sophisticated brain architectures. In this study, cortical neurons and astrocytes acutely isolated from the brains of rats are bioprinted in a hydrogel to form 3D neuronal constructs. Successful bioprinting of cellular and acellular strands in a multi‐bioink approach allows the subsequent formation of gray‐ and white‐matter tracts reminiscent of cortical structures. Immunohistochemistry shows the formation of dense, 3D axon networks. Calcium signaling and extracellular electrophysiology in these 3D neuronal networks confirm spontaneous activity in addition to evoked activities under pharmacological and electrical stimulation. The system and bioprinting approaches are capable of fabricating soft, free‐standing neuronal structures of different bioink and cell types with high resolution and throughput, which provide a promising platform for understanding fundamental questions of neural networks, engineering neuromorphic circuits, and for in vitro drug screening.
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