Abstract
Background & Purpose
Preclinical drug development often fails due to poor translation from animal models to human physiology. Peripheral neuropathy, a common side effect of chemotherapy, requires better predictive models for neurotoxicity screening. Nerve-on-a-Chip, a microphysiological system developed by 28bio, mimics peripheral nerve anatomy and function, enabling early detection of nerve dysfunction. This study assesses the impact of four chemotherapy drugs on nerve function using electrophysiology, metabolic assays, and histology.
Methods
- Nerve-on-a-Chip Fabrication:
- Rat dorsal root ganglia (DRG) explants were cultured in a dual hydrogel system for 28 days.
- Chemotherapy Drug Exposure (7 days):
- Bortezomib (BZ) – Proteasome inhibitor
- Oxaliplatin (OX) – DNA replication inhibitor
- Paclitaxel (PTX) – Microtubule stabilizer
- Vincristine (VN) – Microtubule formation inhibitor
- Neurotoxicity Assessments:
- Electrophysiology: Nerve conduction velocity (NCV) measured functional deficits.
- Metabolic Assays: CCK-8 assay determined cell viability.
- Histology & Imaging:
- Myelin Basic Protein (MBP) staining assessed myelination.
- Mitochondrial membrane potential (TMRE) dye analyzed metabolic activity.
Results
- Early Detection of Neuropathy:
- NCV decreased before cell viability loss, showing early functional impairment.
- Drug-Specific Neurotoxicity:
- BZ and OX significantly reduced electrical activity and viability.
- PTX and VN caused demyelination without reducing mitochondrial activity.
- Histology Findings:
- PTX and VN exposure led to MBP reduction, confirming demyelination.
- BZ and OX affected mitochondrial activity, impacting neuron survival.
Conclusion
The Nerve-on-a-Chip platform effectively detects early-stage peripheral neuropathy using electrophysiology and histology. The system provides a clinically relevant, non-animal model for predicting neurotoxicity in chemotherapy drugs. Future studies aim to enhance automated electrophysiology measurements and expand the database of neurotoxic compounds.
