Could a series of linked organ-on-a-chip systems be the future of quantitative pharmacokinetics?

“The instrument maintained the viability of all tissues and their organ-specific functions for over 3 weeks and, importantly, it allowed us to quantitatively predict the tissue-specific distribution of a chemical across the entire system.” – Richard Novak, Wyss Institute

A collaborative team of researchers based at the Wyss Institute for Biologically Inspired Engineering at Harvard University (MA, USA) has developed a series of linked organ-on-a-chip systems that could be used to quantitatively predict drug pharmacokinetics, addressing some of the limitations of preclinical studies.

The team, based at the Wyss Institute and featuring scientists from a range of institutions and industry, has reported its findings in two back-to-back publications in Nature Biomedical Engineering [1,2].

The first article presents a modular ‘body-on-chips’ platform, which sees multiple organ-on-a-chip systems linked by a newly engineered ‘interrogator’ system. The organ-on-a-chip systems are microfluidic devices constructed from clear polymer, approximately the size of a computer memory stick.

The organ-on-a-chip systems feature two parallel hollow channels, separated by a porous membrane. On one side of the porous membrane organ-specific cells are cultured. On the other side, vascular endothelial cells are cultured. Each channel is independently perfused with a specific cell medium and the porous membrane allows the exchange of molecules such as cytokines, drugs, breakdown products and growth factors across the membrane.

The newly developed interrogator instrument is engineered to culture up to ten different organ-on-a-chip systems and sequentially transfer fluids between them, mimicking human blood flow between the different organs of the body. In the first study, the interrogator instrument allowed the team to successfully culture, perfuse and link the vascular channels of eight different organ-on-a-chip systems.

Co-first author on both studies, Richard Novak (Wyss Institute) explained: “In this study [1], 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 3 weeks and, importantly, it allowed us to quantitatively predict the tissue-specific distribution of a chemical across the entire system.”

Having successfully demonstrated the viability of the interrogator instrument, the team moved on to probe the ability of the system to predict quantitative pharmacokinetics and pharmacodynamics.

In the second study [2], the interrogator instrument was used to support two configurations of three different organ-on-a-chip systems. The organ chips were linked to each other and to a central arterio-venous fluid mixing reservoir.

In a system featuring a gut-on-a-chip, a liver-on-a-chip and a kidney-on-a-chip, the researchers added nicotine to the gut-on-a-chip to simulate oral administration.

Using MS analysis and a newly developed biomimetic scaling approach – capable of translating organ-on-a-chip dimensions to human organ dimensions – the team quantified nicotine levels in the system. This computational approach, combined with the linked organ-on-a-chip system data, demonstrated the ability to model human drug uptake and metabolism for the first time. The system successfully predicted quantitative pharmacokinetic parameters observed in previous human clinical trials.

“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,” commented Ben Maoz, co-first author on the second study (Tel Aviv University).

In a second configuration, comprising linked liver- kidney and bone marrow-on-a-chip systems, the team investigated cisplatin.

Co-first author of the second study [2], Anna Herland, KTH Royal Institute of Technology and Karolinska Institute (both Stockholm, Sweden), explained: “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. In addition, the in vitro-to-in vivo translation capabilities of the system produced quantitative information on how cisplatin is metabolized and cleared by the liver and kidney, which will make it suitable for more refined predictions of drug absorption, distribution, metabolism, excretion and toxicity.”

The team hope that this demonstration of biomimicry will garner interest from the pharmaceutical industry and lead to widespread improvements in preclinical pharmacokinetic and pharmacodynamic studies.

Sources: [1] Novak R, Ingram M, Ingber DE et al. Robotic fluidic coupling and interrogation of multiple vascularized organ chips. Nat Biomed Eng. doi:10.1038/s41551-019-0497-x (2020)(Epub ahead of print); [2] Herland A, Maoz B, Ingber DE et al. Quantitative prediction of human pharmacokinetic responses to drugs via fluidically coupled vascularized organ chips. Nat Biomed Eng. doi:10.1038/s41551-019-0498-9 (2020)(Epub ahead of print); https://wyss.harvard.edu/news/human-body-on-chip-platform-enables-in-vitro-prediction-of-drug-behaviors-in-humans/; www.aftau.org/weblog-medicine–health?&storyid4704=2510&ncs4704=3