Sunday, 30 June 2019 22:46

Human-on-a-chip model to measure the therapeutic index Featured

The start-up company Hesperos, Inc. based in Orlando, Florida, together with the University of Central Florida and the pharmaceutical company Roche has presented a new Body-on-a-Chip model with which both the efficacy of a drug and the toxicity can be measured in heart and liver as well as in target cells.

With its body-on-a-Chip developments, the team from Orlando has focused on the measurement of functionality. The company pursues the philosophy of constructing an organ simulation in the simplest form while maintaining the functions of interest, the complexity will only be added when needed.

Led by chief scientist Prof. James Hickman the team of Hesperos Inc in Florida has now developed a chip system configuration with which not only the efficacy of pharmaceuticals can be measured, but also their toxicity (therapeutic range). The therapeutic range (or index) defines the ratio of effective dosage (ED50) to lethal dosage (LD50) and therefore provides information about the application safety of a drug.

The Hesperos scientists have established a reconfigurable multi-organ system that has been used to measure the efficacy and other effects of anti-cancer drugs in two different cancer-derived models (bone marrow cell lines and breast or vulvar cancer cells). Since in most cases drugs are only converted into effective or harmful form through the liver it is necessary to integrate liver tissue respectively cells into the organ combination.

In the first system with two bone marrow cancer cell lines and liver cells, the scientists were able to assess the efficacy of the combination of two cytostatic drugs (imatinib and diclofenac). Thereby the researchers could observe dose-dependent toxicity of Diclofenac because of a protein adduct formation in the liver cells.

The second approach was concerned with the therapy of multidrug-resistant breast and vulva cancer cells. With the help of a substance that inhibited the multidrug resistance protein 1 in the cells, the desired effect was achieved in the multi-resistant cancer cells. However, it was also important to assess the impact of the combination therapy on the heart function: With the Body-on-a-Chip system, the scientists could investigate the effect on, for example, the beat frequency. The integrated functional readouts allowed a determination of an impairment of the electrical and the force function of the heart cells as a reaction on the drug combination.

Besides, high-performance liquid chromatography, in combination with mass spectrometry (HPLC-MS) was used to measure the area under the curve (AUC) from the recirculating medium in the system which is a measure of the drug burden in terms of time. The application of numerical fluid dynamics (CFD modeling) enabled a prediction of an in vitro pharmacokinetic-like AUC of drugs circulating in the system.

All cells and tissues used remained viable and functional for the 7-day experimental period. The long-term viability and function were proven for up to 28 days.

Original publication:
McAleer, CW, Long, CJ, Elbrecht, D, Sasserath, T, Bridges, LR, Rumsey, JW, Martin, C, Schnepper, M, Wang, Y, Schuler, F, Roth, AB, Funk, C, Shuler, ML & Hickman, JJ (2019). Multi-organ system for the evaluation of efficacy and off-target toxicity of anticancer therapeutics. Sci Transl Med. 11 (497). pii: eaav1386. doi: 10.1126/scitranslmed.aav1386.

Press release and further information about Hesperos: