Alternative to animal testing

‘Human-on-a-chip’ models evaluate systemic toxicity

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ORLANDO, Fla.—Animal activists decry the use of animals as lab test subjects for obvious reasons. Researchers have another issue: animal tests make therapies look promising in the lab, but often fail when eventually tried in humans.
A collaborative effort of the cosmetic company L’Oreal, biotech firm Hesperos Inc. and the University of Central Florida (UCF) has made progress in reducing the reliance on animal testing in drug and cosmetics development.
“If we can prove that the data from our method are better, we can eventually eliminate animal testing,” said Hesperos chief scientist James J. Hickman, who is a professor at UCF’s NanoScience Technology Center. He estimated that the result could be a $2-billion to $10-billion industry, representing a paradigm shift in toxicity testing.
Replacing animal models as test subjects in drug and cosmetics development is one step closer to reality with the successful testing of multi-organ “human-on-a-chip” models to summarize the 28-day experiments used in animals to evaluate the systemic toxicity of drug and cosmetic compounds. The collaboration’s four-organ in-vitro model system is said to be able to realistically replicate in-vivo responses to sustained drug dosing of human cells.
The microfluidic device with interlinking modules containing human-derived heart, liver, skeletal muscle and nervous system cells was able to maintain cellular viability and record cellular function in real-time for 28 days. As reported in the peer-reviewed journal Advanced Functional Materials, “Body-on-a-Chip or Human-on-a-Chip platforms … are capable of reproducing organ-like functions and allowing organ-to-organ communication, as in vivo models do, by linking different organ representatives together under the same blood flow surrogate. By integrating BioMicroElectroMechanical Systems (BioMEMs) with cellular constructs, organ function features can be recreated and monitored.”
Hickman emphasized that this is important because the toxicity and efficacy of new compounds are studied upon both acute (single administration at high concentrations over a short-term period) and chronic (repeated or continuous administration at lower concentrations over an extended period) exposures. Whereas organ-on-a-chip models have previously been used for mechanism of action validation (efficacy) and acute toxicity screening, they have not been suitable for long-term studies due to short half-lives, lack of organ-organ communication and outcomes that are difficult to extrapolate to human organ functions.
The Hesperos system overcomes these limitations with a model that enables interaction between its tiny organs, cultured in a serum-free blood surrogate solution from real human cells, in a way that realistically replicates system body responses to any compounds introduced to it and “conferring a higher fidelity to predict human outcomes,” according to the Advanced Functional Materials article. The system can also non-invasively evaluate the electrical activity of neurons and cardiac cells, as well as the mechanics of cardiac and skeletal muscle contractions. Such monitoring of cellular function is crucial in chronic toxicity testing, as it emulates in-vivo function.
To be able to reach the 28-day testing milestone, Hesperos engineers used computational fluid dynamic modeling to modify their existing multi-organ models. They made them smaller, improved their flow characteristics and incorporated more functional measurements.
“Systems are operated by gravity without using pumps,” Hickman said. “Cells are all talking to each other. They are monitored with functional readouts without harming the cells.”
He added, “We have created a valuable tool to model the pharmacokinetics and pharmacodynamics profile of known drugs, in line with ICH (International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use) guidelines. In the future, it could also be used to generate mechanistic models to predict the outcome of unknown drugs, and in other precision medicine applications.”
Hesperos has been working for four years to characterize an individual’s biology with human-on-a-chip microfluidic systems. In nine years of collaborations, founders Michael L. Shuler and James J. Hickman have developed everything from individual organ-on-a-chip constructs to fully functional, interconnected multi-organ systems.
In an attempt to revolutionize toxicology testing as well as efficacy evaluation for drug discovery, the company has created pumpless platforms with serum-free cellular mediums that allow multi-organ system communication and integrated computational modeling of live physiological responses utilizing functional readouts from neurons, cardiac, muscle, barrier tissues and neuromuscular junctions, as well as responses from liver, pancreas and barrier tissues. Created from human stem cells, the fully human systems are the first in-vitro solutions that accurately utilize in-vitro systems to predict in-vivo functions without the use of animal models, Hickman said.

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