Israeli-German Partnership Aims To Replace Animal Experiments With Advanced Liver-On-Chip Devices

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Bionic Liver Micro-Organs Explain Off-Target Toxicity of Acetaminophen (Tylenol)

Liver-on-chip device and microscopic image of bionic liverJerusalem, August 17, 2015 — Safety evaluation is a critical part of drug and cosmetic development. In recent years there is a growing understanding that animal experiments fail to predict the human response, necessitating the development of alternative models to predict drug toxicity.

The recent tightening of European regulations preventing the cosmetic industry from using animals in research and development, blocks companies like L'Oréal and Estée Lauder from developing new products, bringing massive investment into this field.

The main challenge in replacing animal experiments is that human cells seldom survive more than a few days outside the body. To address this challenge, scientists at the Hebrew University of Jerusalem and the Fraunhofer Institute for Cell Therapy and Immunology in Germany partnered to create a liver-on-chip device mimicking human physiology.

“The liver organs we created were less than a millimeter in diameter and survive for more than a month,” said Prof. Yaakov Nahmias, the study’s lead author and Director of the Alexander Grass Center for Bioengineering at the Hebrew University.

Hebrew University liver-on-chip device

While other groups showed similar results, the breakthrough came when the groups added nanotechnology-based sensors to the mix. “We realized that because we are building the organs ourselves, we are not limited to biology, and could introduce electronic and optical sensors to the tissue itself. Essentially we are building bionic organs on a chip,” said Nahmias.

The addition of nanotechnology-based optoelectronic sensors to the living tissues enabled the group to identify a new mechanism of acetaminophen (Tylenol) toxicity.

“Because we placed sensors inside the tissue, we could detect small and fast changes in cellular respiration that nobody else could,” said Nahmias. “Suddenly nothing we saw made sense”. The authors discovered that acetaminophen blocked respiration, much faster and at a much lower dose than previously believed. The current understanding was that acetaminophen was broken to a toxic compound, called NAPQI, before damaging the cells. As the liver could naturally deactivate NAPQI, damage was thought to occur only at high doses and in cases of diseased or compromised liver function.

The current study, released online in the leading journal Archives of Toxicology, turns 50 years of research on its head. The authors found that acetaminophen itself can stop cellular respiration in minutes, even in the absence of NAPQI, explaining much of the off target effects of the drugs.

“This is a fascinating study”, said Prof. Oren Shibolet, Head of the Liver Unit at the Tel-Aviv Sourasky Medical Center, and one of the leading experts on drug-induced liver injury, who was not involved in the original study. “We knew that acetaminophen can cause nephrotoxicity as well as rare but serious skin reactions, but up until now, we didn’t really understand the mechanism of such an effect. This new technology provides exceptional insight into drug toxicity, and could in fact transform current practice.”

The results mark the first discovery of a new toxicity mechanism using the newly emerging human-on-a-chip technology, suggesting that the development of alternative models for animal testing is just around the corner. The global market of this technology is estimated to grow to $17 billion by 2018, showing a double-digit annual growth rate in the last three years.

Yissum, the Research and Development Company of the Hebrew University, together with the Fraunhofer Institute for Cell Therapy and Immunology (IZI-BB) in Germany submitted a joint provisional patent application earlier this year and are actively seeking industrial partners.

Other co-authors participating in the study include Danny Bavli, Gahl Levy, Elishai Ezra, and Dr. Merav Cohen from the Hebrew University; Dr. Sebastian Prill, Dr. Magnus S. Jaeger, and Dr. Claus Duschl from the Fraunhofer Institute; Prof. Michael Schwarz from the University of Tuebingen; and Dr. Elmar Schmälzlin, developer of the OPAL system and co-founder of Colibri Photonics.

The work was funded by the European Research Council; the British Council BIRAX Regenerative Medicine initiative; the HeMibio consortium funded by the European Commission and Cosmetics Europe as part of the SEURAT-1 cluster; and the generous gift of Sam and Rina Frankel.

Prof. Yaakov Nahmias is the Director of the Alexander Grass Center for Bioengineering at the Hebrew University of Jerusalem. The Center brings together top scientists who work on the development of transformative technologies. Projects include nanotechnology-based diagnostic devices, innovative medical devices, advanced computational models, and microchip alternatives for animal and human testing. The center’s BioDesign Medical Innovation program has received international acclaim for producing several award-winning spin-off companies in its three years of operation. For more information, go to http://cbsh.cs.huji.ac.il.

Fraunhofer is Europe’s largest application-oriented research organization. Its research efforts are geared entirely to people’s needs: health, security, communication, energy and the environment. As a result, the work undertaken by its researchers and developers has a significant impact on people’s lives.

Yissum Research Development Company of the Hebrew University of Jerusalem Ltd. was founded in 1964 to protect and commercialize the Hebrew University’s intellectual property. Products based on Hebrew University technologies that have been commercialized by Yissum currently generate $2 Billion in annual sales. Ranked among the top technology transfer companies in the world, Yissum has registered 9,150 patents covering 2,575 inventions; has licensed out 825 technologies and has spun out 110 companies. Yissum’s business partners span the globe and include companies such as Novartis, Microsoft, Johnson & Johnson, Merck, Intel, Teva, ICL and many more. More information at http://www.yissum.co.il.

Citation:

S. Prill, D. Bavli, G. Levy, E. Ezra, E. Schmälzlin, M.S. Jaeger, M. Schwarz, C. Duschl, M. Cohen, Y. Nahmias, Real-time monitoring of oxygen uptake in hepatic bioreactor shows CYP450-independent mitochondrial toxicity of acetaminophen and amiodarone. Arch Toxicol. (2015) [Epub ahead of print]

To contact Prof. Yaakov Nahmias: ynahmias@cs.huji.ac.il or (857) 222-1954 (USA)

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