Abstract
Background & Purpose
The failure rate of neurological drugs exceeds 94%, largely due to ineffective preclinical models. Current drug testing relies on animal studies and 2D cell cultures, which lack scalability and fail to replicate human nerve function. To address this, 28bio developed NerveSim®, a 3D microphysiological system (MPS) that models peripheral nerve function using rat or human-derived cells. This study evaluates NerveSim®’s electrophysiological capabilities for compound screening, neurotoxicity detection, and neurorehabilitation research.
Methods
- NerveSim® Fabrication & Culture:
- Peripheral nerve spheroids were created from rat dorsal root ganglia (DRG) cells or human iPSC-derived sensory neurons.
- Cells were cultured on a custom 24-well plate with embedded electrode arrays (EEAs) for 28-42 days to promote axonal growth.
- Electrophysiology Testing:
- Stimulation & Recording: NerveSim® samples were electrically stimulated at multiple sites, while nearby electrodes recorded compound action potentials (CAPs).
- Key metrics measured:
- Nerve conduction velocity (NCV)
- Peak response amplitude (AMP)
- Threshold stimulus strength (TSS)
- Neurotoxicity Screening:
- Tested compounds:
- Paclitaxel (PTX) and Vincristine (Vn): Chemotherapy drugs known for inducing peripheral neuropathy.
- Electrophysiological responses were recorded before, during, and after dosing to track changes in nerve function.
Results
- Electrophysiology Findings:
- NCV reductions occurred before cell viability loss, enabling early detection of neuropathic effects.
- High-dose Paclitaxel led to significant declines in nerve conduction across all velocity bins, while low doses selectively affected medium-speed responses.
- Vincristine caused a time-dependent decrease in electrophysiological activity, correlating with neurotoxic effects.
- Functional Insights:
- Human iPSC NerveSim® models responded to capsaicin by increasing spontaneous electrophysiological activity, demonstrating pain-associated nerve activation.
- Spatial electrophysiology analysis showed that distal nerve responses declined earlier than proximal responses in neurotoxic conditions.
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Conclusion
The NerveSim® platform provides a scalable, automated system for high-throughput electrophysiology-based neurotoxicity screening. By mimicking in vivo nerve function, it offers clinically relevant insights into neurotoxicity, neuroprotection, and pain research. Future efforts will focus on expanding compound screening datasets to build a predictive neurotoxicity database for drug development.
