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.
We present a nontraditional fabrication
technique for the realization
of three-dimensional (3D) microelectrode arrays (MEAs) capable of
interfacing with 3D cellular networks in vitro. The
technology uses cost-effective makerspace microfabrication
techniques to fabricate the 3D MEAs with 3D printed base
structures with the metallization of the microtowers and conductive
traces being performed by stencil mask evaporation techniques. A biocompatible
lamination layer insulates the traces for realization of 3D microtower
MEAs (250 μm base diameter, 400 μm height). The process
has additionally been extended to realize smaller electrodes (30 μm
× 30 μm) at a height of 400 μm atop the 3D microtower
using laser micromachining of an additional silicon dioxide (SiO2) insulation layer. A 3D microengineered, nerve-on-a-chip in vitro model for recording and stimulating electrical
activity of dorsal root ganglion (DRG) cells has further been integrated
with the 3D MEA. We have characterized the 3D electrodes for electrical,
chemical, electrochemical, biological, and chip hydration stability
performance metrics. A decrease in impedance from 1.8 kΩ to
670 Ω for the microtower electrodes and 55 to 39 kΩ for
the 30 μm × 30 μm microelectrodes can be observed
for an electrophysiologically relevant frequency of 1 kHz upon platinum
electroless plating. Biocompatibility assays on the components of
the system resulted in a large range (∼3%–70% live cells),
depending on the components. Fourier-transform infrared (FTIR) spectra
of the resin material start to reveal possible compositional clues
for the resin, and the hydration stability is demonstrated in in-vitro-like conditions for 30 days. The fabricated 3D
MEAs are rapidly produced with minimal usage of a cleanroom and are
fully functional for electrical interrogation of the 3D organ-on-a-chip
models for high-throughput of pharmaceutical screening and toxicity
testing of compounds in vitro.
CIPN), which is rapidly induced after the administration of anti-cancer drugs (Argyriou et al., 2012; Cavaletti and Marmiroli, 2010). Patients with CIPN may experience a range of sensory symptoms including spontaneous tingling, burning pain, and joint and muscle pain in the distal extremities in a "glove and stocking" distribution (Peters et al., 2007). Often, these side effects discourage patient use of the drug, leading to delays or limited dosages and even discontinued treatment altogether (Staff et al., 2017). In some patients, these symptoms resolve following discontinuation of therapy, but an estimated 30% of patients are left with permanent symptoms that affect their overall quality of life (Rivera and Cianfrocca, 2015). Drugs with neurotoxic side effects reaching market approval is attributed to a lack of reliable screens for drug candidate neurotoxicity.Traditional methods for studying neuronal damage and screening neurotoxicity have largely relied on cell and animal models
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