RAT NerveSim®

Leverage in vitro testing with a depth and accuracy typically only found in vivo

SUMMARY

Organ-on-a-chip devices have great potential to identify effects of chemical and drug exposure by mimicking in vivo physiology. These devices must be qualified, however, through comparison with the known effects of drugs already on the market. We conducted that assessment with AxoSim’s rat NerveSim, also known as its rat Nerve-on-a-Chip platform, using multiplexed analyses to determine neurotoxic effects of several cancer drugs from a mechanistic perspective.

We assessed NerveSim’s ability to screen for implications of functional and structural nerve dysfunction in chemotherapy-induced peripheral neuropathy. First, this research demonstrates that NerveSim accurately recreates axonal growth, orientation, and function analogous to mature nerve anatomy. By screening known neurotoxic compounds, we established the potential for our model to prove not only whether a drug is toxic, but to also provide insights into the mechanism of that toxicity. It’s the first 3D in vitro model to collect electrophysiological and histomorphic metrics to assess in vivo pathophysiology. NerveSim not only offers a shorter path to data, but also higher-content results.

Liana Kramer

A lot of the times the standard in vitro results, like 2D cell cultures, and even the results that you see in animal models, aren’t necessarily similar to what you see once you get up to human trials. We’re bridging that gap with 3D structures. For a drug company that wants to test whether their compounds are neurotoxic, they now have a validated tissue model.

Liana Kramer, lead author

METHODS & RESULTS

The validation paper, Modeling Chemotherapy-Induced Peripheral Neuropathy Using a Nerve-on-a-Chip Microphysiological System, shows that NerveSim can screen for peripheral neuropathy in early stages of drug development.

To put this tool to the test, we cultured embryonic rat dorsal root ganglia in NerveSim’s innovative hydrogel construct. We exposed the cultures to the chemotherapeutics bortezomib, oxaliplatin, paclitaxel, or vincristine, as well as negative controls, then electrically stimulated the ganglia to collect clinically relevant electrophysiological metrics indicative of healthy or diseased populations.

The constructs exhibited abnormalities like those seen in both humans and rats, with all chemotherapeutics decreasing nerve conduction velocity (NCV) and peak amplitude (AMP) in a concentration-dependent manner. Histopathological analysis revealed hallmarks of peripheral neuropathy. And IC50 values calculated from concentration-response curves indicate that the significant decrease in function occurred before a decrease in viability. By multiplexing these results, we found that the neurotoxic mechanism of each drug matched those seen clinically.

RELEVANCE

TESTS THAT TRANSLATE

The techniques used to show neuropathy in NerveSim are similar to those used to diagnose human neuropathy. These results support the tool’s relevance and translatability for drug development companies, especially when compared to traditional 2D cell culture studies. But the analytical advantages go even further.

With NerveSim, drug compounds can be administered for up to a month, far exceeding the days’ worth of data available via traditional in vitro tests. And the results can be much more nuanced. NerveSim is a functional model—able to distinguish different forms of toxicity, such as demyelination vs. degeneration of peripheral nerve axons vs cell cytotoxicity.

1 MONTH TO DATA

And near real-time insights, versus at least 3 months’ delay with traditional animal testing

1/5 OF THE COST

Test more compounds in parallel, compared to just 1 with in vivo assessment

3D STRUCTURE

Assess in vivo pathophysiology via rich histomorphic metrics, beyond the limits of 2D cell culture

READ THE FULL PAPER

For more details on the research, download a copy of the article here.

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