An organ-on-a-chip is a micro physiological system – a small cell culture chip that can mimic the structure and function of living human tissue. Organs-on-chips are helpful in terms of drug testing, and may one day even render animal testing non-essential, which would be great news. However, these small systems are not foolproof, and it’s just as important to test how the body as a whole reacts and responds to drugs as it is to test individual organs themselves. Scientists at the Wake Forest Institute for Regenerative Medicine (WFIRM), with the Wake Forest Baptist Medical Center, have used 3D printing technology to create micro hearts, livers, and lungs that could be used for new drug testing. These micro 3D organs, or organoids, are then combined in a monitored system, known as a body-on-a-chip, so researchers can replicate how the human body as a whole responds to medications.
In addition to advancing personalized medicine, increasing drug discovery, and decreasing animal testing, the goal of WFIRM’s body-on-a-chip work is to lower the approximately $2 billion price and 90% failure rate that pharmaceutical companies have to deal with while they’re working to develop new medications.
Anthony Atala, M.D., director of the institute and senior researcher on the multi-institution project, said, “There is an urgent need for improved systems to accurately predict the effects of drugs, chemicals and biological agents on the human body.”
Currently, new drug compounds are screened in the lab on human cells, and tested on animals after the screening; however, neither offers an accurate representation of how the drug compounds affect human organs. The research team recently published a paper on their work, titled “Multi-tissue interactions in an integrated three-tissue organ-on-a-chip platform,” in Scientific Reports; co-authors include Aleksander Skardal, Sean V. Murphy, Mahesh Devarasetty, Ivy Mead, Hyun-Wook Kang, Young-Joon Seol, Yu Shrike Zhang, Su-Ryon Shin, Liang Zhao, Julio Aleman, Adam R. Hall, Thomas D. Shupe, Andre Kleensang, Mehmet R. Dokmeci, Sang Jin Lee, John D. Jackson, James J. Yoo, Thomas Hurting, Ali Khademhosseinl, Shay Soker, Colin E. Bishop, and Atala.
The abstract reads, “Few engineered model systems, including the growing variety of organoid and organ-on-a-chip platforms, have so far reflected the interactive nature of the human body. To address this challenge, we have developed an assortment of bioengineered tissue organoids and tissue constructs that are integrated in a closed circulatory perfusion system, facilitating inter-organ responses. We describe a three-tissue organ-on-a-chip system, comprised of liver, heart, and lung, and highlight examples of inter-organ responses to drug administration. We observe drug responses that depend on inter-tissue interaction, illustrating the value of multiple tissue integration for in vitro study of both the efficacy of and side effects associated with candidate drugs.”
The team engineered 3D organoids and connected them on one platform to monitor their functions. Cell types found in human tissue were used to make the organ structures, using 3D printing technology and other fabrication methods as well. The team chose to make lungs because they are the “point of entry” for both aerosol drugs and toxic particles; hearts and livers were made for the system due to the fact that toxicity in them “is a major reason for drug candidate failures and drug recalls.”
Once the researchers placed the organoids in a sealed system, which was monitored in real time with a camera, they used drugs to test their similarity to real organs. A nutrient-filled liquid which circulates throughout the system to keep the organoids from dying was used to add drug therapies – for instance, a high dose of a common pain reliever was given to the micro-liver, and then the scientists introduced a second drug to counteract the first drug’s toxic effects.
Skardal, a PhD and assistant professor who was also the paper’s lead author, explained, “The data shows a significant toxic response to the drug as well as mitigation by the treatment, accurately reflecting the responses seen in human patients.”
New drug candidates, and even drugs that have been approved, can have toxic side effects in organs and tissues that the drugs don’t even target, which is why the scientists also experimented with the body-on-a-chip system to make sure it would replicate a real multi-organ response.
“If you screen a drug in livers only, for example, you’re never going to see a potential side effect to other organs. By using a multi-tissue organ-on-a-chip system, you can hopefully identify toxic side effects early in the drug development process, which could save lives as well as millions of dollars,” said Skardal.
The team introduced a cancer-treating drug into the system that was known to cause lung scarring. While a control experiment with the drug and a micro-heart showed no side effects, it had a toxic side effect on the organoid when the drug was tested in the body-on-a-chip, and the micro-heart eventually stopped beating.
Other research teams have combined cells from different organs into a similar system in the past, but this project was the first successful one using higher functioning and more accurate 3D organ structures. The WFIRM researchers are now working on speeding up the system for large-scale drug screening, as well as adding more organs, and they have also filed several patent applications for the technology.
Skardal said, “This was completely unexpected, but it’s the type of side effect that can be discovered with this system in the drug development pipeline.”
“Eventually we expect to demonstrate the utility of a body-on-a-chip system containing many of the key functional organs in the human body. This system has the potential for advanced drug screening and also to be used in personalized medicine — to help predict an individual patient’s response to treatment,” said Atala.
The body-on-a-chip project was funded by the Defense Threat Reduction Agency.
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