Abstract
Background & Purpose
Neurological drug development faces high failure rates (94%) due to poor translation from preclinical models to human outcomes. Peripheral neuropathy is difficult to assess using 2D cell cultures or animal models, as they fail to replicate 3D nerve structure and functional electrophysiology. To address this, 28bio developed NerveSim®, a microphysiological system (MPS) that models peripheral nerve function using rat or human-derived cells. This platform enables electrophysiology-based screening for neurotoxicity, neuroprotection, and neurorehabilitation.
Methods
- NerveSim® Fabrication:
- Peripheral nerve spheroids were derived from rat dorsal root ganglia (DRG) cells or human iPSC-derived sensory neurons.
- Cells were grown in custom media for 28-42 days to support axonal growth and nerve conduction.
- Electrophysiology Testing:
- Embedded Electrode Arrays (EEAs): A 24-well culture plate with 10 electrodes per well recorded nerve signals.
- Compound Action Potential (CAP) Analysis:
- Metrics included nerve conduction velocity (NCV), peak response amplitude (AMP), activity-dependent slowing (ADS), and threshold stimulus strength (TSS).
- Drug Screening:
- Tested compounds:
- Paclitaxel (PTX) and Vincristine (Vn): Known to cause peripheral neuropathy.
- Electrophysiology was recorded before, during, and after dosing to track functional deficits over time.
Results
- Electrophysiology Findings:
- Nerve conduction velocity (NCV) decreased before cell viability loss, indicating early detection of neuropathy.
- Vincristine caused a rapid decline in distal nerve responses, while Paclitaxel reduced both proximal and distal responses over time.
- Neurotoxicity Mechanisms:
- Electrophysiology metrics revealed distinct neurotoxic signatures, differentiating compounds by their impact on nerve conduction, ion channel function, and axonal health.
- Species-Specific Differences:
- Rat vs. Human NerveSim® models showed similarities and differences in neurotoxic responses, highlighting the importance of human-based models for drug screening.
Conclusion
The NerveSim® platform provides a scalable, automated system for electrophysiology-based neurotoxicity screening. By mimicking in vivo nerve function, it enables clinically relevant insights into drug-induced neuropathy. Future studies aim to expand compound screening libraries and build a predictive neurotoxicity database based on electrophysiological responses.
