Multi species live-chip model for drug toxicity evaluation

Multi species live-chip model for drug toxicity evaluation


Among the numerous microengineered Organ-on-a-Chip (Organ Chip) models developed, the Liver Chip is of special interest to a number of industries because the real-time analysis of complex biochemical interactions could greatly enhance the liver toxicity testing that is ubiquitous in the development of drugs, foods, and other consumer products.

Emulate, Inc., a company spun out from the Wyss Institute to commercialize the Organ Chip technology, announced a new study based on work begun at the Wyss Institute and advanced at the company with biopharmaceutical industry partners showing that its Liver-Chip model recreates species-specific toxicity responses that known tool and drug compounds induce in human, dog, and rat livers. The data indicate that the Liver-Chip could potentially be used alongside animal models in preclinical testing to improve safety predictions in humans, with the aim of better clinical trial outcomes and safer drugs. The research is published in Science Translational Medicine.

The researchers engineered a species-specific Liver-Chip with up to four different cell types found in the livers of rats, dogs, and humans to approximate the liver's smallest functional unit. The team first exposed the Liver-Chip to FIAU, a compound known to cause liver toxicity in humans, and observed much lower and varying degrees of toxicity in the dog and rat chips than in the human chips, recreating what had been observed in previous animal studies. When the researchers tested the Liver Chip's responses to different drug candidate molecules, they saw differences in the drugs' impact on the function of human versus animal liver cells that recapitulated those seen in vivo. They were also able to test underlying mechanisms of action for the different drugs and gain insights that were not possible to observe with conventional cell-based systems or animal models.

Most drugs that enter clinical trials are first tested in animals to ensure they are safe before being administered to humans. Testing for liver toxicity in rats and dogs is standard for the majority of drug candidates in preclinical studies, but these tests can produce results that conflict with each other and with the responses later seen in humans. Human liver toxicity is one of the primary reasons why drugs fail in clinical trials.

The research with the Liver-Chip demonstrates how this platform could help ensure that safe and effective therapeutics are identified sooner, and ineffective or toxic ones are rejected early in the development process. As a result, the quality and quantity of new drugs moving successfully through the pipeline and into the clinic may be increased, regulatory decision-making could be better informed, and patient outcomes could be improved. Advancing the assessment of drug safety and efficacy is a goal shared by collaborators.

The Liver-Chip is based on technology consists of a clear, flexible polymer about the size of a USB drive with parallel internal channels that are lined with living cells. The spatial arrangement of the channels and cell types more accurately recreates the tissue microenvironment of human organs in vivo, and exhibits physiological responses and disease states that are similar to those that occur in humans. A wide variety of Organ Chips, including lung, intestine, brain, kidney, bone marrow, and liver were developed before commercialization efforts moved to Emulate, which extended and refined the work into Organ-Chips that they commercialized and continue to develop.

Emulate is now marketing its Organ-Chips as predictive human-relevant models to investigators across the research, pharmaceutical, biotechnology, and cosmetics industries, and plans to expand their offerings into disease modeling in the future.

"This work represents a major achievement for the Organ Chip field because it shows the power of this technology to provide insight into human-relevant responses where current preclinical animal models often fail. This needs to be evaluated and confirmed by others, but if it is, then this could change the way drugs are developed around the world and help begin to reduce the numbers of animals that are used in drug development efforts worldwide," said co-author.

https://wyss.harvard.edu/news/liver-chip-identifies-distinct-drug-toxicities-in-human-rat-and-dog-models/

https://stm.sciencemag.org/content/11/517/eaax5516



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