Abstract

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Background & Purpose

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Traditional preclinical drug development models, including 2D cell cultures and animal models, often fail to predict neurotoxicity and peripheral neuropathy in human patients. Microphysiological systems (MPS) offer a promising alternative by mimicking in vivo nerve function. 28bio developed NerveSim®, a cutting-edge peripheral nerve-on-a-chip platform integrating embedded electrode arrays (EEAs) to measure electrophysiology-based functional responses. This study evaluates the ability of NerveSim® to detect electrophysiological changes in response to neurotoxic compounds, such as Paclitaxel (PTX), a chemotherapy drug known for causing peripheral neuropathy.

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Methods

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1. NerveSim® Fabrication & Culture:
   
   1. Custom 24-well plates with 10 microelectrodes per well for stimulation and recording.
   2. Rat dorsal root ganglia (DRG) spheroids cultured on microelectrode arrays for 35 days to guide axonal growth.
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2. Electrophysiological Testing:
   
   1. Compound Action Potentials (CAPs): Measured nerve conduction velocity (NCV), amplitude, and stimulus-response characteristics.
   2. Paclitaxel (PTX) Dosing:
      
      1. 200 nM and 500 nM PTX applied for 7 days to assess dose-dependent toxicity.
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3. Data Analysis:
   1. Peak detection, conduction velocity, and amplitude analysis.
   2. Velocity Density Index (VDI): Measured electrophysiological activity at various stimulus currents.

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Results

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• Electrophysiology Findings:
  
  • Time-delayed CAP responses confirmed the functional activity of peripheral nerve cultures.
  • Higher PTX doses resulted in dose-dependent declines in nerve conduction velocity and amplitude.
  • Significant reductions in VDI at high stimulus currents (48 µA), indicating PTX-induced axonopathy and reduced excitability.
• Morphological Changes:
  
  • Axonal retraction was observed in high PTX doses, demonstrating structural degeneration of neurons.

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Conclusion

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The NerveSim® platform successfully models human-relevant peripheral nerve function and offers high-content electrophysiological readouts for drug screening applications. The study confirms its value for detecting neurotoxic effects in compounds like Paclitaxel. Future work aims to expand compound screening to generate predictive neurotoxicity and neuroprotection profiles for drug development.