The development and eventual approval of modern drugs is hugely reliant on animal models and human clinical trials, but for some time now scientists have been working on an alternative and more expedient approach. By recreating the functions of various organs on small devices known as Organ Chips or Organs-on-a-chip, researchers hope to greatly reduce the time and cost of testing new drugs for safety and efficacy. Now, scientists at Harvard’s Wyss Institute have pieced together 10 of them to create a functioning Body-on-Chips platform that can offer new and comprehensive insights into how prospective drugs will behave throughout the human body.
The aim of the research project was to not just recreate the complicated functions of 10 different human organs, but to connect them up via fluidic pathways to observe how the flow of simulated blood impacts the entire system. A drug may appear safe when screened in the kidneys, for example, but could create side effects in other organs. The idea with these Body-on-Chips systems is to sniff out such dangers earlier on in the testing process.
Back in 2017, we looked at a “Body-on-a-Chip" system from scientists at Wake Forest Institute for Regenerative Medicine, which combined several organ models into the one system. The Wyss Institute’s builds on this by offering a more complete picture, with the scientists focusing on two aspects of drug behavior in particular.
The first is known as pharmacokinetics (PK), which revers to how a drug is absorbed, distributed, metabolized and excreted by the human body, which ultimately determines the drug levels left in the blood. The other is known as pharmacodynamics (PD), which refers to the way a drug impacts its target organs, including both the mechanics of how it works and any potential side effects.
Like others we’ve looked at in the past, the Organ Chips making up the Body-on-Chips system are microfluidic devices around the size of a memory stick. A pair of parallel channels are separated by a porous membrane, with cells specific to the organ populating one side and vascular cells mimicking a blood vessel on the other.
These organs-on-chips are connected by vascular channels that transfer fluid between them to mimic blood flow through the human body. In this way, scientists are able to observe how drugs impact PK and PD, with the team using computational modeling to predict how they might impact the entire human body.
“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,” says co-first author Richard Novak. “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.”
In one experiment, the scientists used the modular platform to connect Organ Chips simulating the gut, the liver and a kidney. Nicotine was added to gut chip to mimic oral administration of the drug, from where it was passed through the intestinal wall, through the vascular system to the liver to be metabolized, and onward to the kidney where it was excreted. An analysis using mass spectrometry followed, with the team confirming the drug’s journey and its effects closely resembled that seen in actual humans.
“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,” says Ben Maoz, a co-first author.
In another experiment, the team observed the effects of a common chemotherapy drug called cisplatin that can cause toxicity in kidney and bone marrow. The Body-on-Chips platform again proved to be an accurate model.
“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,” says co-first author Anna Herland.
The research was published across two studies in the journal Nature Biomedical Engineering (1, 2), and the video below offers a look at the Body-on-Chips platform in action, with an instrument called the “Interrogator” linking together the various Organ Chips making up the system.
Source: Wyss Institue