Abstract
Background & Purpose
Traditional preclinical models often fail to predict human outcomes, with nearly 90% of clinical trials unsuccessful due to species differences. Peripheral nerve toxicity is particularly challenging to assess due to the complex architecture and bioelectrical conduction of nerves. This study introduces a 3D human nerve-on-a-chip model, which mimics peripheral nerve anatomy and allows for clinically relevant nerve conduction velocity (NCV) testing. The model aims to provide a predictive platform for evaluating neuropathic side effects of chemotherapy and other neurotoxic compounds.
Methods
- Model Fabrication:
- 3D spheroids of motor neurons were cultured alone (monoculture) or with Schwann cells (co-culture).
- A dual hydrogel system was used to promote axon growth and myelination.
- Electrophysiological Testing:
- NCV was recorded to assess functional nerve conduction.
- Schwann cell migration and myelination were evaluated using histological imaging.
- Drug Screening:
- Tested compounds:
- Vincristine and Teriflunomide – caused gradual NCV reduction with increasing doses.
- Paclitaxel and Bortezomib – caused a sharp NCV decline at specific concentrations.
Results
- The model successfully demonstrated functional NCV measurements in both mono- and co-culture conditions.
- Schwann cell co-culture supported nerve myelination, crucial for mimicking in vivo nerve responses.
- Neurotoxic effects of chemotherapy drugs were quantified, showing different toxicity profiles:
- Gradual vs. sudden NCV reductions, indicating varying toxicity mechanisms.
- The platform provides a predictive tool for assessing chemotherapy-induced peripheral neuropathy (CIPN).
Conclusion
The 3D human nerve-on-a-chip system offers a powerful alternative to animal models, providing clinically relevant electrophysiological metrics for drug screening and neurotoxicity assessment. The ability to quantify NCV changes makes it a valuable tool for predicting drug-induced peripheral neuropathy and optimizing therapeutic development.
