Reproducing human and cross-species drug toxicities using a Liver-Chip.

Area of Science:

• Biotechnology and Pharmaceutical Sciences
• Toxicology and Drug Safety Assessment
• Organ-on-a-Chip Technology

Background:

• Current nonclinical animal models for drug toxicity testing frequently yield discordant results or fail to predict human complications, leading to costly clinical trial failures.
• There is a critical need for more predictive preclinical models to assess drug safety and efficacy in humans.

Purpose of the Study:

• To develop and validate a microengineered multi-species Liver-Chip platform for predicting human liver toxicity.
• To assess the ability of the Liver-Chip to detect various liver toxicity phenotypes and species-specific responses.

Main Methods:

• Application of microengineered Organs-on-Chips technology to create rat, dog, and human Liver-Chips.
• Incorporation of species-specific primary hepatocytes co-cultured with liver sinusoidal endothelial cells, and optionally Kupffer and hepatic stellate cells, under physiological flow.
• Treatment of Liver-Chips with tool compounds to evaluate toxicity detection capabilities.

Main Results:

• The multi-species Liver-Chip successfully detected diverse liver toxicity phenotypes, including hepatocellular injury, steatosis, cholestasis, and fibrosis.
• The platform demonstrated the ability to identify species-specific toxicities in response to various compounds.
• Results indicate improved prediction of human liver toxicity compared to traditional animal models.

Conclusions:

• The multi-species Liver-Chip represents a promising advancement in preclinical drug safety assessment.
• This technology can enhance the prediction of human liver toxicity and inform the relevance of animal study findings.
• Utilizing Liver-Chips can contribute to better determination of drug safety and human risk, potentially reducing clinical failures.