Three livers on one chip
Analysis of complex biochemical interactions in real time allows you to choose from many molecules those that will form the basis of new drugs. A group of researchers from the Wyss Institute at Harvard University has created a so-called liver-on-a-chip, which can significantly speed up the process of testing compounds for liver toxicity, necessary in the development of medicines, food and other consumer products.
The liver-on-a–chip contains two channels, one of which is lined with living organ cells, and the other with living blood vessel cells, which mimic the physiology of an entire organ and allow us to study the differences in the reaction of the rat, dog and human liver to medicinal compounds. Source: Wyss Institute.
The new liver model recreates species-specific toxic reactions that are caused by known drugs and other compounds in the liver of humans, dogs and rats. The data obtained show that the chip can be used along with animal models in preclinical studies to improve the safety of human studies and improve the results of clinical trials through the participation of safer drugs in them.
AstraZeneca Janssen, Emulate, Janssen Research & Development, LLC and the Wyss Institute have developed a species-specific liver chip containing simultaneously four different types of cells taken from the liver of rats, dogs and humans to obtain the smallest functional unit of the liver. The group injected the drug FIAU (fialuridin) into the chip. This is an infamous compound that was created in the USA for the treatment of hepatitis B and in 1992 was studied on volunteers. Despite the safety confirmed in tests on various animals, FIAU turned out to be extremely toxic to humans and led to severe liver failure and the death of a third of the volunteers. The effects of FIAU on the chip demonstrated high toxicity for human liver cells and much lower for dogs and rats, recreating the effects observed in previous studies. The researchers evaluated the liver-on-a-chip response to drug candidate molecules and saw differences in their effect on the function of human and animal liver cells, which repeat the effects observed in vivo. They also tested the underlying mechanisms of action of various drugs and were able to obtain a reaction that could not be observed using conventional cell-based systems or animal models.
From theory to practice
The liver-on-a-chip consists of a transparent flexible polymer the size of a USB stick with parallel internal channels lined with living cells. The spatial arrangement of channels and cell types accurately recreates the tissue microenvironment of human organs in vivo and demonstrates physiological reactions and disorders similar to those that occur in humans.
An image of the human part of the liver-on-a-chip, which shows the multidrug resistance-associated protein 2 (MRP2) in green color and the dye protein DAPI in blue color in the hepatocyte transport stream after 14 days in culture. Source: Emulate, Ink.
Drugs that are undergoing clinical trials are first tested on animals to make sure they are safe before being administered to humans. Liver toxicity testing in rats and dogs is standard for preclinical studies, but these tests may produce results that contradict each other. Toxicity to the human liver is one of the main reasons why drugs do not pass clinical trials.
The liver-on-a-chip study demonstrates the capabilities of this platform to provide faster identification of safe and effective therapeutic agents, ineffective or toxic drugs are rejected early in the development process. As a result, the quality and quantity of new drugs successfully researched and introduced into the clinic can be improved, and the results of patient treatment can be improved.
Microscopy of the light field of human hepatocytes in a chip after 7 days in culture. Source: Emulate, Inc.
Liver-on-a-chip is planned to be used as a human-oriented predictive model for the research, pharmaceutical, biotechnological and cosmetic industries. The authors hope to include disease modeling in the scope of the chip.
Article by K.-J. Jang et al. Reproducing human and cross-species drug toxins using a Liver-Chip is published in the journal Science Translational Medicine.
Aminat Adzhieva, portal "Eternal Youth" http://vechnayamolodost.ru based on the materials of the Wyss Institute: Liver-Chip Identifies Distinct Drug Toxins in Human, Rat, and Dog Models.