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Chip Device More Accurate for Drug Toxicity Than Animals

Liver chip device

Liver chip device (Wyss Institute, Harvard University)

7 Nov. 2019. A plastic chip device lined with liver cells is shown to better predict drug toxicity in humans than lab animals, including drugs that progressed to failed clinical trials. An industry-academic team describes the device and test results in yesterday’s issue of the journal Science Translational Medicine (paid subscription required).

Researchers from the company Emulate Inc. in Boston, with colleagues from the Wyss Institute for Biologically Inspired Engineering at Harvard University and other drug maker and academic labs are seeking better ways to test new drugs before reaching human clinical trials. Regulatory authorities in the U.S. and Europe require drug candidates first be tested for toxicity with animals, such as rodents and dogs, before progressing to clinical trials. But the authors cite a study showing of 150 drugs causing adverse effects in humans, only 71 percent predicted these reactions during animal tests.

This lack of predictability is a particular problem with liver injury from drug toxicity, thus the researchers created a plastic microfluidic chip, about the size of a flash memory drive, with channels and wells simulating liver functions. The Wyss Institute is a pioneer in designing organs-on-chip devices, and the company Emulate Inc. is a spin-off enterprise that licenses the institute’s technology for further development and commercialization.

The liver chip device in the study contains two main channels, with one channel containing hepatocytes, functioning liver cells, and the other channel emulating blood vessels in the liver. The two channels are separated with a membrane of extracellular matrix, the framework material in cells. The team created different liver chip devices for rats, dogs, and humans and tested physiological functioning of the devices, including production of the protein albumin, an indicator of liver health. Later versions of the chips added liver-specific cells including stellate cells that regulate vitamin A levels and Kupffer cells, white blood cells in the immune system that interact with liver functions.

The team tested the liver chip with drugs known to cause toxic reactions in the liver. One of those drugs is bosentan, designed to treat high blood pressure in the vessels that carry blood to the lungs. Bosentan is toxic to humans, but not in rats or dogs. Tests show the liver chip show varying potency and albumin production for the different species, with toxicities changing by the concentration of bosentan administered. Another drug known to cause liver damage with excessive doses is the pain-killer acetaminophen, often sold over-the-counter. The liver chip also shows toxic effects with high concentrations of acetaminophen.

In addition, the researchers tested the human liver chip with three drugs that showed no liver toxicity in animal tests, but had to be withdrawn when liver damage occurred in patients during clinical trials: fialuridine for treating hepatitis-B, fasiglifam or TAK-875 for type 2 diabetes, and an unspecified experimental drug. In all three cases, the human liver chip indicated toxic reactions that were not predicted when previously tested with animals.

Geraldine Hamilton, the president of Emulate Inc. and the study’s senior author says in a company statement that the liver chip can “identify possible safety issues in humans earlier and more reliably in the drug discovery and development process, with the goal of enabling the design and selection of drug candidates that have a higher potential of success in human clinical trials.”

Don Ingber, director of the Wyss Institute and scientific founder of Emulate Inc. notes in an institute statement that the liver chip, “shows the power of this technology to provide insight into human-relevant responses where current preclinical animal models often fail.” If confirmed by others, adds Ingber, “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.”

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