Abstract
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 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 to assess in vivo pathophysiology. Here we culture embryonic rat dorsal root ganglia (DRG) in the construct to demonstrate its potential to screen for implications of nerve dysfunction in chemotherapy-induced peripheral neuropathy (CIPN). RNoaC constructs containing DRG explants from E15 rat pups were exposed to the chemotherapeutics bortezomib, oxaliplatin, paclitaxel or vincristine for 7 days. Then, axons were electrically stimulated to collect nerve conduction velocity (NCV) and peak amplitude (AMP), which are clinical electrophysiological metrics indicative of healthy or diseased populations. All chemotherapeutics decreased NCV and AMP in a concentration-dependent manner. At high drug concentrations, NCV and AMP were 10-60% lower than control values. Histopathological analysis revealed hallmarks of peripheral neuropathy. IC50 values calculated from concentration-response curves indicate that the significant decrease in function occurred before a decrease in viability. Our data suggest that electrophysiology recordings collected from our RNoaC platform can closely track subtle pathological changes in nerve function. The ability to collect clinically relevant data from RNoaC suggests it can be an effective tool for in vitro preclinical screening for peripheral neuropathy.
Highlights
Experimental drugs have unacceptably high attrition rates during development, from discovery to clinical trials and to market, with only 9.6% of drugs successfully reaching patients (Thomas, 2016)
We show that the rat nerve-on-a-chip (RNoaC) tissues exhibit histopathological hallmarks of neuropathy and that the platform is compatible with common in vitro techniques (Fig. 1)
3.1 Electrophysiological activity of evoked nerve constructs is sensitive to drug exposure Compound action potentials (CAPs) were measured from RNoaC constructs by electrically stimulating axons distally while recording extracellular field potentials at the ganglion
Summary
Experimental drugs have unacceptably high attrition rates during development, from discovery to clinical trials and to market, with only 9.6% of drugs successfully reaching patients (Thomas, 2016). Patients with CIPN may experience a range of sensory symptoms including spontaneous tingling, burning pain, and joint and muscle pain in the distal extremities in a “glove and stocking” distribution (Peters et al, 2007). Often, these side effects discourage patient use of the drug, leading to delays or limited dosages and even discontinued treatment altogether (Staff et al, 2017). Drugs with neurotoxic side effects reaching market approval is attributed to a lack of reliable screens for drug candidate neurotoxicity
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