Abstract

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Neurological drug development faces significant challenges due to high costs and low clinical trial success rates. More predictive preclinical models are needed to enhance translational success. NerveSim®, a novel human Nerve-on-a-Chip platform, provides a microphysiological system (MPS) that mimics human peripheral nerve physiology, enabling high-throughput neurotoxicity screening. This platform integrates induced pluripotent stem cell (iPSC)-derived neurons and primary human Schwann cells, forming a functional 3D nerve model capable of electrophysiological and morphological assessments.

NerveSim® employs multi-electrode array (MEA) technology to record compound action potentials (CAPs) at multiple locations, allowing longitudinal functional neurotoxicity assessment. Additionally, a novel live-cell imaging analysis quantifies axonal morphological changes over time. The platform was tested with chemotherapeutic compounds, demonstrating its ability to detect drug-induced neurotoxicity through both functional and structural endpoints. These findings establish NerveSim® as a powerful tool for evaluating neurotoxic effects in drug discovery, reducing reliance on animal models and improving preclinical prediction.

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Key Learnings

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• Enhanced Predictive Power – NerveSim® improves translational accuracy compared to traditional animal models, offering human-relevant neurotoxicity insights.

• Functional & Morphological Assessments – The platform enables electrophysiological (CAP-based) and morphological (axon fragmentation) screening, providing a comprehensive toxicity profile.

• High-Throughput Capability – The 24-well format increases efficiency, making large-scale neurotoxicity screening feasible.

• Differentiated Chemotherapeutic Toxicity – Results showed distinct neurotoxic effects between auristatins, maytansinoids, vinca alkaloids, and ADCs, highlighting the importance of multidimensional toxicity assessments.

• Non-Invasive, Longitudinal Analysis – The system allows for repeated measures over time, minimizing variability and improving drug candidate evaluation.

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Methods

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Electrophysiological Neurotoxicity Testing

• CAPs were recorded from 10 embedded electrodes along the NerveSim® channel.

• Stimuli (1–48 µA) were applied at multiple locations, generating a velocity envelope for nerve conduction analysis.

• The velocity density index (VDI) quantified changes in nerve function pre- and post-drug exposure.

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Morphological Neurotoxicity Analysis

• Live-cell imaging captured axonal morphology over time.

• Automated segmentation quantified fiber length, number, and fragmentation.

• The nerve degeneration index (NDI) was calculated to assess structural damage.

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Toxicity Assessment & IC50 Calculation

• Chemotherapeutic compounds (auristatins, maytansinoids, vinca alkaloids, ADCs) were tested.

• Electrophysiology and imaging-based IC50 values were compared for sensitivity and agreement.

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Conclusion

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NerveSim® represents a breakthrough in neurotoxicity screening, providing clinically relevant, high-throughput, and multidimensional assessments of drug-induced nerve damage. By integrating functional and morphological data, this human-relevant in vitro platform accelerates drug discovery while reducing reliance on animal models.

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Sharma, A. D., McCoy, L., Jacobs, E., Willey, H., Behn, J. Q., Nguyen, H., Bolon, B., Curley, J. L., & Moore, M. J. (2019). Engineering a 3D functional human peripheral nerve in vitro using the Nerve-on-a-Chip platform. Scientific Reports, 9, 8921.