Comparative Analysis of Chemotherapy-Induced Peripheral Neuropathy in Bioengineered Sensory Nerve Tissue Distinguishes Mechanistic Differences in Early-Stage Vincristine-, Cisplatin-, and Paclitaxel-Induced Nerve Damage

Chemotherapy-induced peripheral neuropathy (CIPN) is a well-known, potentially permanent side effect of widely used antineoplastic agents. The mechanisms of neuropathic progression are poorly understood, and the need to test efficacy of novel interventions to treat CIPN continues to grow. Bioengineered microphysiological nerve tissue (nerve on a chip) has been suggested as an in vitro platform for modeling the structure and physiology of in situ peripheral nerve tissue. Here, we find that length-dependent nerve conduction and histopathologic changes induced by cisplatin, paclitaxel, or vincristine in rat dorsal root ganglion-derived microphysiological sensory nerve tissue recapitulate published descriptions of clinical electrophysiological changes and neuropathologic biopsy findings in test animals and human patients with CIPN. We additionally confirm the postulated link between vincristine-induced axoplasmic transport failure and functional impairment of nerve conduction, the postulated paclitaxel-induced somal toxicity, and identify a potential central role of gliotoxicity in cisplatin-induced sensory neuropathy. Microphysiological CIPN combines the tight experimental control afforded by in vitro experimentation with clinically relevant functional and structural outputs that conventionally require in vivo models. Microphysiological nerve tissue provides a low-cost, high-throughput alternative to conventional nonclinical models for efficiently and effectively investigating lesions, mechanisms, and treatments of CIPN. Neural microphysiological systems are capable of modeling complex neurological disease at the tissue level offering unique advantages over conventional methodology for both testing and generating hypotheses in neurological disease modeling.

Automated summary

The research shows that using microphysiological nerve tissue can replicate the clinical electrophysiological changes and neuropathologic biopsy findings of chemotherapy-induced peripheral neuropathy in both animals and human patients. This approach combines the tight experimental control of in vitro experimentation with the clinically relevant functional and structural outputs typically seen in in vivo models.