By: Scott Harris
If you’d read about it in a science fiction novel, you might not have believed it. Human organs and organ systems — from lungs to blood vessels to blinking eyes — bio-miniaturized and stored on a plastic chip no larger than a matchbook.
But that’s the breathing, blinking reality at the Biologically Inspired Engineering Systems (BIOLines) Laboratory in the Department of Bioengineering in the School of Engineering and Applied Sciences at the University of Pennsylvania, a bona fide pioneer of what is now widely known as “organ-on-a-chip” technology. Proponents hope these devices can one day help scientists around the world learn more about the body’s inner workings and ultimately improve disease prevention and treatment.
“The century-old practice of cell culture is to grow living cells isolated from the human body in hard plastic dishes and keep them bathed in copious amounts of culture media under static conditions, and that is drastically different than the complex, dynamic environment of native tissues in which these cell reside,” said Dan Dongeun Huh, PhD, BIOLines’ principal investigator and an associate professor of Bioengineering in Penn’s School of Engineering and Applied Science. “What makes this organ-on-a-chip technology so unique and powerful is that it enables us to reverse-engineer living human tissues using microengineered devices and mimic their intricate biological interactions and physiological functions in ways that have not been possible using traditional cell culture techniques. This represents a major advance in our ability to model and understand the inner workings of complex physiological systems in the human body.”
Generally speaking, organ-on-a-chip devices are made of clear silicone rubber — the same material used to make contact lenses — and can vary in size and design. Embedded within are microfabricated three-dimensional chambers lined with different human cell types, arranged and propagated to ultimately form a structure complex enough to actually mimic the essential elements of a functioning organ.
With partners at the Perelman School of Medicine, BIOLines recently developed a newer variation of the organ-on-a-chip: one that replicates the interface between maternal tissue and the cells of the placenta at the critical moments in early pregnancy when the embryo is implanting in the uterus. Huh and Penn Medicine physicians led a study using the “implantation-on-a-chip” to observe things that would otherwise have been virtually unobservable.
The study findings appeared this spring in the journal Nature Communications.
“With this small, quarter-sized device, we took multiple cell types that are involved in early implantation and then assessed them in the same physiological arrangement that you see in vivo,” said Monica Mainigi, MD, the study’s co-senior author and an associate professor of Obstetrics and Gynecology and the fellowship director of Reproductive Endocrinology and Infertility at the Hospital of the University of Pennsylvania. “We wanted to study how the uterus controls embryo implantation, but the current models are insufficient. This process begins very early in pregnancy before most women have even taken a pregnancy test. So, we don’t have a lot of ways to study this in humans.”
The implantation-on-a-chip uses a special fluid platform containing two chambers, one containing placental cells and the other tiny blood vessels.
“Our implantation-on-a-chip system was modeled to study the interactions between the mother and the placental tissue of the baby,” Mainigi said. “The reason we went after this question was because humans are fairly unique both in how the placenta attaches to the mother and in the interface between the maternal and placental cells.”
Prior studies have pointed to the implantation period as a potential source of serious complications later in pregnancy, including preeclampsia — a condition defined as elevated blood pressure, and sometimes protein in urine, during pregnancy. Mainigi and her colleagues used the implantation-on-a-chip device to investigate how different factors, like environment or the presence of immune cells, can affect the implantation process.
Among other findings, the study revealed previously unknown effects of pre-implantation maternal immune cells on extravillous trophoblasts or EVTs, which are a certain kind of placental cell involved in implantation. In addition to the results themselves, Huh and Mainigi said, the study served to establish the implantation-on-a-chip as a novel tool in pregnancy research.
“Now that we’ve shown the relevance of this system, we can look at the individual cell types and really get a much better understanding of what each individual cell type is doing,” Mainigi said.
The Future for Organs-on-a-Chip
Back in 2010, Huh helped develop the first ever organ-on-a-chip model: a respiring lung. Ever since, Huh and his BIOLine colleagues have been trailblazers in the field, now having developed about 15 different replications of human organs and other tissue systems, from bone marrow to intestines to a mouth complete with tiny teeth.
The next step, Huh said, is to take these exceedingly delicate devices and make them more scalable, reproducible, and accessible.
“A fundamental challenge we face is to convert these models into practical tools that can be used for routine experiments in the hands of biomedical researchers without engineering expertise,” Huh said. “The complexity of organ chips is what makes them exciting and powerful, but this also poses major challenges to translating the technology into industry and academic practice, which I believe is the reason why this technology has had little impact on real-world applications. This fundamental problem motivated us to develop an entirely different, highly advanced in vitro platform that makes it possible to produce realistic living human tissues on a large scale and in a fully automated manner and to run hundreds of experiments on the same device and to do so without human error.”
Vivodyne, a Penn startup company co-founded by Huh and funded last year by venture capitalist firm Kairos Ventures, has entered into licenses with Penn to some of the “organ-on-a-chip” technologies and will attempt to further develop the devices and make them even more readily available to researchers.
“An important goal is to get these organ-chip models out of the labs of developers and into the hands of end users in pharmaceutical companies, clinical laboratories, academic research groups, and so on,” Huh said. “We believe that our technology will be a game changer and provide unprecedented opportunities to generate large amounts of high-quality, human-relevant data that we desperately need to, for example, make accurate, reliable preclinical predictions during drug development or to understand complex disease processes in the human body.”
At this point, especially after the success of implantation-on-a-chip, there’s no reason not to keep thinking big.
“Critically, in time, we hope to use our technology to test therapeutics,” Mainigi said. “Potentially, we can identify patients at high risk for poor pregnancy outcomes and have a therapy that could decrease these risks. To do this we need to understand the complicated process of embryo implantation. These are the kinds of questions we want to figure out.”
University of Pennsylvania Financial Disclosure: Penn and Dr. Huh each own equity interests in Vivodyne. Penn and Dr. Huh may receive in the future, license-related financial consideration related to the licensing of certain Penn intellectual property to Vivodyne.