CHIP-BASED artificial organs such as this ‘liver,’ could one day replace animal experiments, researchers hope..
(photo credit: HEBREW UNIVERSITY)
Instead of carrying out experimentation on animals to determine whether a drug or cosmetic is safe for humans, the Hebrew University of Jerusalem and Germany’s Fraunhofer Institute for Cell Therapy and Immunology have joined together to successfully create a liver-on-chip device that mimics human physiology.
While safety evaluation is a critical part of drug and cosmetic development, there has been a growing understanding in recent years that animal experiments do not always accurately predict the human response.
The main problem in replacing animal experiments with other models is that human cells rarely survive more than a few days outside the body. The Israeli-German research therefore fills an urgent need. “The liver organs we created were less than a millimeter in diameter and survived for more than a month,” Prof. Yaakov Nahmias, the study’s lead author and director of Hebrew University’s Alexander Grass Center for Bioengineering said.
While other groups showed similar results, the breakthrough came when the groups added nanotechnology-based sensors to the mix, Nahmias said. “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.” The addition of nanotechnology-based optoelectronic sensors to the living tissues enabled the group to identify a new mechanism of acetaminophen (Tylenol or Excedrin) toxicity.
“Because we placed sensors inside the tissue, we could detect small and fast changes in cellular respiration that nobody else could,” Nahmias said. “Suddenly nothing we saw made sense.” The researchers discovered that acetaminophen blocked respiration much faster and at a much lower dose than previously believed. The current understanding was that acetaminophen broke down into a toxic compound, called NAPQI, before damaging 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 half a century 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 side-effects of the drug.
“This is a fascinating study”, said Prof. Oren Shibolet, head of the liver unit at Tel Aviv Sourasky Medical Center and one of the leading experts on drug-induced liver injury (who was not part of the original study). “We knew that acetaminophen can cause nephrotoxicity [toxicity to the kidneys] 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 will soon follow. The global market for the technology has shown a double-digit annual growth rate in the last three years and is predicted to grow to $17 billion by 2018.
Yissum, Hebrew University’s Research & Development Company and Fraunhofer, Europe’s largest application-oriented research organization, submitted a joint provisional patent application earlier this year and are actively seeking industrial partners.