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September 17, 2021

Drug testing on miniatured livers

The Kazuo Takayama lab shows the benefits of a particular polymer in drug discovery research.

Before a drug is approved for patient use, not only must its effectiveness be confirmed, but so too its safety. Liver toxicity is one of the most important safety tests conducted, because the liver is the organ responsible for metabolizing the drug. In collaboration with AGC Inc., CiRA Junior Associate Professor Kazuo Takayama and colleagues report a new liver-on-a-chip made of tetrafluoroethylene-propylene (FEPM) that offers higher accuracy for these tests.

Before it receives approval for use in patents, a typical drug will have cost several hundreds of millions of dollars for research and development. To lower this cost, researchers have developed organ-on-a-chip technology. An organ-on-a-chip is smaller than a finger and usually made of a polymer, which allows it to be manufactured into different shapes.

Inside the chip are cells and other components that make up the organ. In the case of liver-on-a-chip, this content, Takayama explains, has to recreate the real liver environment.

"To be a reliable assay for liver toxicity, the liver-on-a-chip needs to recapitulate the fluid sheer stress and mechanical strain the cells experience in the liver," he said.

Polydimethylsiloxane, or PDMS, is the most commonly used polymer for liver-on-a-chip manufacturing, because it is colorless, allowing scientists to see the cells easily; it is moldable, allowing it to form just about any desired shape; and finally, it is cheap. However, it also absorbs small drug molecules.

"Understanding what doses are safe is paramount for drug testing. Because of its absorption properties, PDMS may report tolerances that are too high," continued Takayama.

In other words, because PDMS absorbs the drug, scientists may overestimate the effective or toxic dose.

In search of an alternative material, Takayama and his colleagues settled on FEPM. This polymer is also moldable but is less absorptive of drug molecules than PDMS. However, it had never been used in a liver-on-a-chip.

Coumarin is a natural compound found in cinnamon and has several positive health attributes including anti-inflammation and anti-hypertension. At the same time, excessive intake can damage the liver. The FEMS liver-on-a-chip prepared in the new study showed a toxicity level that was 10 times less than that found with the PDMS liver-on-a-chip.

Additionally, the metabolite levels of two drugs, midazolam and bufuralol, were maintained after four hours in the FEMS liver-on-a-chip but nearly vanished in the PDMS liver-on-a-chip, demonstrating the different absorption levels of the two polymers.

Together, Takayama argues that liver-on-a-chip technology may benefit by adopting FEMS as the polymer. However, he also recognizes more study is needed.

"This is only a preliminary study to show the viability of FEMS liver-on-a-chip. More drugs should be tested before deciding how widely we can apply it to drug research," he said.

Paper Details
  • Journal: ACS Omega
  • Title: Generation of Tetrafluoroethylene-Propylene Elastomer-Based Microfluidic Devices for Drug Toxicity and Metabolism Studies
  • Authors: Emi Sano1,2, Sayaka Deguchi1,3, Naoki Matsuoka4, Masahiro Tsuda5, Mengyang Wang1,
    Kaori Kosugi1,2, Chihiro Mori2, Keisuke Yagi4, Aya Wada4, Shinsuke Yamasaki4, Tsuyoshi Kawai4, Masahide Yodogawa4, Hiroyuki Mizuguchi3, Norhito Nakazawa4, Fumiyoshi Yamashita5,
    Yu-suke Torisawa2, and Kazuo Takayama1
  • Author Affiliations:
    1. Center for iPS Cell and Application (CiRA), Kyoto University, Kyoto, Japan
    2. Department of Micro Engineering, Kyoto University, Kyoto, Japan
    3. Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan
    4. AGC Inc., Tokyo, Japan
    5. Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan
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