Human body-on-chip platform could speed up drug testing

Two new studies published on 27 January in Nature Biomedical Engineering have demonstrated the incredible potential of rapidly emerging ‘organ-on-chip’ (organ chip) technologies (1, 2). The so-called ‘Interrogator’ system links together various organ chips to create a whole human body-on-chip, which could accelerate the drug discovery process and reduce animal testing.

Modern drug development relies on animal models and human clinical trials, which are hugely time-consuming and costly — often in the billions of euros — not to mention the ethical considerations. Furthermore, only around 13.8 per cent of all tested drugs actually obtain approval and eventually reach the clinic. To overcome these limitations and accelerate drug discovery, scientists are developing organ-on-chip technologies.

The first single organ-on-chip of a lung was proposed in 2010 by Prof Donald Ingber and his team at the Wyss Institute of Harvard University, reported in Science (3). Now, the team of researchers and their collaborators have managed to piece together up to 10 different organ-on-a-chip models, including the intestine, liver, kidney, heart, lung, skin, blood-brain barrier, and brain, to create a complete human body-on-a-chip platform. This could allow scientists to observe the possible whole-body impact of candidate drugs or treatments.

The chips themselves around the size of a memory stick and made of clear flexible polymer. Each chip contains two channels separated by a membrane. Since all organs are connected by blood vessels, one channel contains cells of a particular organ while the other channel contains vascular cells to mimic blood vessels, which can communicate through pores in the membrane. Then, the vascular channels of various chips are connected to create an interconnected body-on-chip system.

The vascular system plays an important role in how independent organs respond to a particular drug. So, using this approach, the scientists hope to observe two important aspects of drug behaviour: pharmacokinetics (how the drug is absorbed, distributed, and metabolised by the body) and pharmacodynamics (how the drug works on the target organ).

Co-author Dr Richard Novak explained in a statement: “In this study, we serially linked the vascular channels of eight different organ chips, including intestine, liver, kidney, heart, lung, skin, blood-brain barrier and brain, using a highly optimized common blood substitute, while independently perfusing the individual channels lined by organ-specific cells.

“The instrument maintained the viability of all tissues and their organ-specific functions for over three weeks and, importantly, it allowed us to quantitatively predict the tissue-specific distribution of a chemical across the entire system.”

To test the platform, in a second study, they predicted changes in certain drug levels over time, as well as organ-specific toxicities, and compared the results to levels previously measured in human patients. First, the researchers modelled the effects of ingesting nicotine — nicotine chewing gum using the body-on-chip platform by connecting the human gut, liver, and kidney chips.

“The resulting calculated maximum nicotine concentrations, the time needed for nicotine to reach the different tissue compartments, and the clearance rates in the liver chips in our in vitro-based in silico model mirrored closely what had been measured previously in patients,” said co-first author Ben Maoz, formerly at the Weiss Institute and currently assistant professor at Tel Aviv University in Israel.

Then, they looked undesirable toxicity in the kidney and bone marrow due to commonly used chemotherapy drug, cisplatin. The body-on-chip platform produced accurate quantitative information on how the is metabolized and cleared by the liver and kidney.

“Our analysis recapitulates the pharmacodynamic effects of cisplatin in patients, including a decrease in numbers of different blood cell types and an increase in markers of kidney injury”, explained co-first author Dr Anna Herland at the KTH Royal Institute of Technology in Stockholm, Sweden.

(1) Novak, R. et al. Robotic fluidic coupling and interrogation of multiple vascularized organ chips. Nature Biomedical Engineering (2020). DOI: 10.1038/s41551-019-0497-x

(2) Herland, A. et al. Quantitative prediction of human pharmacokinetic responses to drugs via fluidically coupled vascularized organ chips. Nature Biomedical Engineering (2020). DOI: 10.1038/s41551-019-0498-9

(3) Huh, D. et al. Reconstituting Organ-Level Lung Functions on a Chip. Science (2010). DOI: 10.1126/science.1188302