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

Abstract

A rat, dog, and human Liver-Chip designed using microengineered Organs-on-Chips technology recapitulates species-specific drug toxicities. Spotting species-specific toxicity Candidate drug testing using standard preclinical models cannot accurately predict which compounds are likely to cause drug-induced liver injury in humans. To improve selection of promising drug candidates, Jang et al. developed a Liver-Chip consisting of rat, dog, or human hepatocytes, endothelial cells, Kupffer cells, and stellate cells. Using the microfluidic chips, the authors confirmed mechanism of action of several known hepatotoxic drugs and an experimental compound. A second experimental compound that induced fibrosis in a rat Liver-Chip did not alter hepatocyte function in human chips, whereas a third compound demonstrated increased toxicity in a dog Liver-Chip. Results support using multispecies chips to identify species-specific differences in drug metabolism and toxicity. Nonclinical rodent and nonrodent toxicity models used to support clinical trials of candidate drugs may produce discordant results or fail to predict complications in humans, contributing to drug failures in the clinic. Here, we applied microengineered Organs-on-Chips technology to design a rat, dog, and human Liver-Chip containing species-specific primary hepatocytes interfaced with liver sinusoidal endothelial cells, with or without Kupffer cells and hepatic stellate cells, cultured under physiological fluid flow. The Liver-Chip detected diverse phenotypes of liver toxicity, including hepatocellular injury, steatosis, cholestasis, and fibrosis, and species-specific toxicities when treated with tool compounds. A multispecies Liver-Chip may provide a useful platform for prediction of liver toxicity and inform human relevance of liver toxicities detected in animal studies to better determine safety and human risk.