Evaluating Drug Toxicity On A Chip

Scientists in Japan have invented a ‘body-on-a-chip’ device that can be used for pre-clinical testing of drug side effects.

AsianScientist (Aug. 31, 2017) – In a study published in the journal Royal Society of Chemistry Advances, scientists in Japan have designed a ‘body-on-a-chip’ device that can be used to identify and evaluate the toxic side effects of drugs.

Before a drug goes to clinical trial, its safety profile must be well investigated to avoid adverse patient responses. Conventional screening protocols for drug side effects often depend on animal models, although in recent years, microfluidic devices have been developed to allow on-chip testing using human cells.

In this study, researchers at Kyoto University’s Institute for Integrated Cell-Material Sciences (iCeMS) in Japan designed a small ‘body-on-a-chip’ device that can be used for pre-clinical testing of drug toxicity. The device improves on the design of current microfluidic devices and offers promise for the next generation of pre-clinical drug tests.

The device is smaller than a microscope glass slide, containing six tiny chambers arranged in pairs, with each pair of chambers connected by microchannels. The movement of liquid into these microchannels is controlled by a series of port inlets and valves. A pneumatic pump pushes fluid through the channels and creates a flow. Each pair of chambers and their separate microchannel system constitute one test bed. The researchers called their device the integrated heart/cancer on a chip (iHCC).

The researchers, led by Professor Ken-ichiro Kamei of iCeMS, used the iHCC to test the toxicity of the anti-cancer drug doxorubicin on heart cells. They first tested doxorubicin’s effects on heart cells and liver cancer cells cultured separately in small wells. The drug produced the expected anti-cancer effect on the cancer cells without causing damage to the heart cells.

They then ran the test using the iHCC device. Heart cells were placed in one chamber while liver cancer cells were placed in the other. Doxorubicin was introduced into cell culture medium circulating through a closed-loop system of microchannels that connects the two chambers, mimicking the blood’s circulatory system. In this way, the drug flows unidirectionally in a continuous loop through both chambers.

The team found signs of toxicity in both cancer and heart cells. They thus hypothesized that a compound, doxorubicinol, which is a metabolic byproduct of doxorubicin interacting with cancer cells, was causing the toxic effect. To test this, they added doxorubicinol to heart cells and liver cancer cells cultured separately in small wells. Doxorubicinol was toxic to the heart cells but not to the cancer cells.

When the researchers added doxorubicin alone to the liver cancer cells, the amount of doxorubicinol produced was too small to be toxic to the heart cells. The researchers suspected that this was due to the large volume of cell culture medium needed for the well-based tests, which diluted the metabolite.

In contrast, when they introduced doxorubicin into the iHCC, the metabolite was not diluted when moving through the microchannel circulation system because a smaller volume of cell culture was used. As a result, the toxic effect of this metabolite on the heart cells could be observed.

The study is a proof-of-concept of how such ‘body-on-the-chip’ devices could be used to investigate the toxic side effects of anti-cancer drugs on heart cells before proceeding on to expensive clinical trials.

The article can be found at: Kamei et al. (2017) Integrated Heart/cancer on a Chip to Reproduce the Side Effects of Anti-cancer Drugs in vitro.


Source: Kyoto University.
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