Modeling chemotherapy-induced peripheral neuropathy using a Nerve-on-a-chip microphysiological system

• Published in: ALTEX, alternatives to animal experimentation Vol. 37; no. 3; p. 350
• Main Authors: Kramer, Liana, Nguyen, Hieu T, Jacobs, Elizabeth, McCoy, Laurie, Curley, J Lowry, Sharma, Anup D, Moore, Michael J
• Format: Journal Article
• Language: English
• Published: Germany Springer Spektrum 01.01.2020
• Subjects: Analysis; Chemotherapy; Vincristine; myelin; organs-on-chips; neurotoxicity; nerve conduction; in vitro
• ISSN: 1868-596X; 1868-596X
• DOI: 10.14573/altex.2001181

Organ-on-a-chip devices that mimic in vivo physiology have the potential to identify effects of chemical and drug exposure in early preclinical stages of drug development while relying less heavily on animal models. We have designed a hydrogel rat nerve-on-a-chip (RNoaC) construct that promotes axon growth analogous to mature nerve anatomy and is the first 3D in vitro model to collect electrophysiological and histomorphic metrics that are used to assess in vivo pathophysiology. Here we culture embryonic rat dorsal root ganglia (DRG) in the construct to demonstrate its potential as a preclinical assay for screening implications of nerve dysfunction in chemotherapy-induced peripheral neuropathy (CIPN). RNoaC constructs containing DRG explants from E15 rat pups were exposed to common chemotherapeutics: bortezomib, oxaliplatin, paclitaxel, or vincristine. After 7 days of treatment, axons were electrically stimulated to collect nerve conduction velocity (NCV) and the peak amplitude (AMP), which are two clinical electrophysiological metrics indicative of healthy or diseased populations. We observed decreased NCV and AMP in a dose-dependent manner across all drugs. At high drug concentrations, NCV and AMP were lower than control values by 10-60%. Histopathological analysis revealed that RNoaC exhibit hallmarks of peripheral neuropathy. IC50 values calculated from dose-response curves indicate significant decrease in function occurs before decrease in viability. Our data suggest electrophysiology recordings collected from our RNoaC platform can closely track subtle pathological changes in nerve function. The ability to collect clinically relevant data from RNoaCs suggests it can be an effective tool for in vitro preclinical screening of peripheral neuropathy.