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Liver-Chip Streamlines Preclinical Drug Testing Across Species

organ chip
Organs-on-chips can house human or animal cells and mimic the 3D structure of biological tissue. | Emulate, Inc.

A team of researchers has created a "Liver-Chip" that can help predict the toxic effects of both common medications and drug candidates in rats, dogs and humans. The new organ-on-a-chip design was published in the Nov. 6 issue of Science Translational Medicine.

The Liver-Chip offers a more accurate platform for studying the toxicity of potential drugs, which are currently tested in preclinical studies using cells, rodents or other animal species. The authors believe the technology could help curb expensive and time-consuming drug failures in the clinic, which occur partly because of a lack of consistency between animal and human studies.

The scientists tested the Liver-Chip's capabilities by determining how several approved drugs, such as acetaminophen, can cause liver toxicity. The technology also detected side effects that often do not appear until the late stages of clinical trials.

The FDA and the European Medicines Agency require that drug candidates be tested in animal models to see whether and how the compounds have any serious side effects. As a result, whether a drug candidate moves on to a clinical trial often depends on its initial performance and safety record in other species, according to the study.

However, animal studies cannot always predict which compounds might cause toxicity in people. For example, an analysis of 150 drug candidates showed regulatory testing in rats and dogs could only predict 71% of adverse effects in humans.

Animal models are even less effective at predicting how drug candidates might affect the human liver. Preclinical research can help predict toxicity in organs such as the heart with relative accuracy, but a recent survey showed there was little agreement between results from humans and animals when it came to drug-induced liver injury.

Complicating the picture, scientists do not yet fully understand how both drug candidates and approved compounds can induce liver toxicity. The lack of understanding poses a challenge for regulatory agencies and consumers because the FDA prioritizes understanding the mechanisms of drug toxicity to reduce risks for patients.

All of these roadblocks contribute to costly drug failures in the clinic, according to Kyung-Jin Jang, vice president at Emulate, Inc. and lead author of the new study. Emulate is a company that specializes in organ-on-a-chip technologies, which are cell-based platforms that aim to recreate the functions of larger organs.

"Given the scale of this challenge and its negative impact on health care costs and the development of new therapeutics, there is a critical need for more predictive and human-relevant alternatives to animal models," Jang and colleagues write.

Jang's team wondered whether an organ-on-a-chip approach could offer a more realistic alternative for studying the effects of drugs. Organs-on-chips are small, fluid-based devices that can house human or animal cells and mimic the three-dimensional structure of biological tissue. They serve as a miniature representation of larger organs and can be used for various applications in medicine, such as testing new chemotherapies.

In their new study, the researchers developed and fabricated the Liver-Chip: an organ-on-a-chip platform that can be installed with different types of liver cells. Their chips can also be configured with cells from either rats, dog, or humans, allowing them to study and compare the effects of drug candidates across multiple species.

After creating the Liver-Chip, the scientists set out to demystify the liver-specific effects of some approved drugs. They began by treating rat, dog and human Liver-Chips with bosentan, a drug approved for the treatment of pulmonary hypertension, and identified the mechanism by which the drug caused toxicity in the three species at different concentrations.

The scientists then determined how high doses of the pain-reliever acetaminophen caused toxic effects on liver cells. Specifically, they observed that acetaminophen injured cells by generating harmful and highly reactive oxygen molecules, confirming previous hypotheses in the field.

Surprisingly, the Liver-Chip showed that compounds that are unsafe in animals may not necessarily be toxic in humans. In one experiment, Jang's group observed that the discontinued compound JNJ-2 caused a harmful excess of connective tissue in rat chips but did not have negative effects on human liver cells.

The platform also captured the idiosyncratic toxic effects of a failed drug candidate called TAK-875, which was tested for the treatment of type 2 diabetes. Idiosyncratic toxic effects are relatively rare and usually occur in large patient trials or in the drug's post-marketing phase, but they are often missed during early clinical testing. The Liver-Chip could therefore help researchers better understand the side effects of drug candidates throughout the drug testing process, according to the study.

"Because our chips provide a high fidelity window into biological mechanisms, we were able to answer questions about 'why' and 'where' there are differences between the human and the animal models — well beyond giving a 'yes' or 'no' answer about toxicity," said Geraldine Hamilton, president and chief scientific officer of Emulate and a senior author of the new study.

The scientists note one advantage of their chip is that it allows for continuous fluid flow in an open system. This feature ensures that all the liver cells are exposed to enough of a drug and its by-products, improving the sensitivity of the system when compared to static, non-animal liver models such as lab culture plates.

Furthermore, the chips are designed to work with instruments, software, and supporting protocols that allow human cells to properly thrive in the Liver-Chip. The system is also automated, so any scientist in any lab could apply the technology in a reproducible manner, according to Hamilton.

Hamilton sees her team's chips being used side-by-side with existing animal models to enable better predictions and translation to the clinic, as well as to reduce failure rates in drug discovery and development due to safety issues. The team also believes the Liver-Chip could be applied in other preclinical settings, such as discovering biomarkers linked to chronic liver conditions.

The scientists are ramping up the commercialization of their products so they can be applied in real-life settings. They add that a future version of the device could incorporate liver cells derived from an individual's own stem cells to better capture the biological variability of liver cells.