More than 34 million Americans suffer from pulmonary diseases like asthma, emphysema and chronic bronchitis. While medical treatments can keep these ailments in check, there are currently no cures. Part of the reason, notes Dan Huh, is that it’s incredibly hard to study how these diseases actually work. While researchers can grow cells taken from human lungs in a dish, they cannot expect them to act like they would in the body. In order to mimic the real deal, it’s necessary to recreate the complex, 3D environment of the lung — right down to its tiny air sacs and blood vessels — and to gently stretch and release the tissue to simulate breathing.
Huh, Associate Professor in Bioengineering, is the cofounder of Vivodyne, a Penn Engineering biotech spinoff that is creating tissues like these in the lab. Vivodyne uses a bioengineering technology that Huh has been developing for more than a decade. While a postdoctoral fellow at Harvard’s Wyss Institute, he played a central role in creating a novel device called an “organ on a chip,” which, as the name implies, assembles multiple cell types on a tiny piece of engineered plastic to create an approximation of an organ.
“While those chips represented a major innovation,” says Huh, “they still weren’t truly lifelike. They lacked many of the essential features of their counterparts in the human body, such as the network of blood vessels running between different kinds of tissue, which are essential for transporting oxygen, nutrients, waste products and various biochemical signals.”
How does the placenta keep harmful substances away from developing babies while still providing proper nutrition?
(Photo: Getty Images)
The exact mechanisms remain unknown, which is why the University of Pennsylvania, Rutgers University, Tulane University, the University of North Carolina at Chapel Hill and the University of Rochester have joined together to launch a research center dedicated to solving this mystery and ensuring healthy pregnancies.
A $5 million grant from the National Institutes of Health (NIH) will help fund the Integrated Transporter Elucidation Center (InTEC), which will operate from the Rutgers Biomedical Health Sciences campus in Piscataway under the leadership of Lauren Aleksunes, a professor of pharmacology and toxicology at Rutgers’ Ernest Mario School of Pharmacy and resident scientist in the Environmental and Occupational Health Sciences Institute (EOHSI).
“Since my time working as a community pharmacist, I have found the lack of high-quality information about the safety of everyday products on the health of a pregnancy frustrating,” says Aleksunes. “People need to know whether the chemicals in their diet, personal care products and medications can impact their babies. Our goal at InTEC is to better understand how these chemicals travel in and out of the placenta and if they can reach the baby and influence their development.”
Aleksunes will study how transporter proteins carrying nutrients, dietary supplements, medications and toxic chemicals work during pregnancies. Some of the work will test how individual placenta cells respond to various stimuli in the laboratory. Others on the team will examine how environmental factors influence placental transporters during healthy and unhealthy or complicated pregnancies.
Key to this work will be Dan Huh, Associate Professor in Bioengineering in Penn Engineering, who will lead a team with an innovative approach to modeling the transfer of molecules across the human placenta.
As a pioneer of organ-on-a-chip technology, the Huh group will use a novel microengineered system in which maternal tissue engineered from a layer of primary human trophoblasts is grown adjacent to a three-dimensional network of perfusable fetal blood vessels to mimic the human placental barrier. This microphysiological system will be employed as an in vitro platform to simulate and quantitatively analyze the exchange of various substances between maternal and fetal circulation without the need for laboratory animals or placenta explants.
Penn Bioengineering is proud to congratulate Sunghee Estelle Park, Ph.D. on her appointment as Assistant Professor in the Weldon School of Biomedical Engineering at Purdue University. Park earned her Ph.D. at Penn Bioengineering, graduating in July 2023. She conducted doctoral research in the BIOLines Lab of Dan Huh, Associate Professor in Bioengineering. Her appointment at Purdue will begin January 2024.
During her Ph.D. research, Park forged a unique path that combined principles in developmental biology, stem cell biology, organoids, and organ-on-a-chip technology to develop innovative in vitro models that can faithfully replicate the pathophysiology of various human diseases. Using a microengineered model of the human retina, she discovered previously unknown roles of the MAPK, IL-17, PI3K-AKT, and TGF-β signaling pathways in the pathogenesis of age-related macular degeneration (AMD), presenting novel therapeutic targets that could be further investigated for the development of AMD treatments. More recently, she tackled a significant challenge in the organoid field, the limited tissue growth and maturity in conventional organoid cultures, by designing microengineered systems that enabled organoids to grow with unprecedented levels of maturity and human-relevance. By integrating these platforms with bioinformatics and computational analyses, she identified novel disease-specific biomarkers of inflammatory bowel disease (IBD) and intestinal fibrosis, including previously unknown link between the presence of lncRNA and the development of IBD.
“The unique interdisciplinary expertise I gained from these projects has shaped me into a scholar with a strong collaborative ethos, a quality I hold in high esteem as we work towards advancing our knowledge and management of health and disease,” says Park.
Her vision as an independent researcher is to become a leading faculty who makes impactful contributions to our fundamental understanding of the factors influencing the structural and functional changes of human organs in health and disease. To achieve this, she plans to lead a stem cell bioengineering laboratory with a primary focus on tissue engineering and regenerative medicine. This will involve developing human organoids-on-a-chip systems and establishing next-generation biomedical devices and therapies tailored for regenerative and personalized medicine.
“I am grateful to all my Ph.D. mentors and lab mates at the BIOLines lab and especially my advisor Dr. Dan Huh, for his exceptional guidance, unwavering support, and invaluable mentorship throughout my Ph.D. journey,” says Park. “Dan’s expertise, dedication, and commitment to excellence have been instrumental in shaping both my research and professional development, while also training me to become an independent scientist and mentor.”
Congratulations to Dr. Park from everyone at Penn Bioengineering!
With OCTOPUS, Dan Huh’s team has significantly advanced the frontiers of organoid research, providing a platform superior to conventional gel droplets. OCTOPUS splits the soft hydrogel culture material into a tentacled geometry. The thin, radial culture chambers sit on a circular disk the size of a U.S. quarter, allowing organoids to advance to an unprecedented degree of maturity.
When it comes to human bodies, there is no such thing as typical. Variation is the rule. In recent years, the biological sciences have increased their focus on exploring the poignant lack of norms between individuals, and medical and pharmaceutical researchers are asking questions about translating insights concerning biological variation into more precise and compassionate care.
What if therapies could be tailored to each patient? What would happen if we could predict an individual body’s response to a drug before trial-and-error treatment? Is it possible to understand the way a person’s disease begins and develops so we can know exactly how to cure it?
Dan Huh, Associate Professor in the Department of Bioengineering at the University of Pennsylvania’s School of Engineering and Applied Science, seeks answers to these questions by replicating biological systems outside of the body. These external copies of internal systems promise to boost drug efficacy while providing new levels of knowledge about patient health.
An innovator of organ-on-a-chip technology, or miniature copies of bodily systems stored in plastic devices no larger than a thumb drive, Huh has broadened his attention to engineering mini-organs in a dish using a patient’s own cells.
From left to right: Marc Singer, Kirsten Leute, D. Kacy Cullen, Dan Huh, Doug Smith, and Haig Aghajanian
Two Penn Bioengineering Professors have received awards in the 7th Annual Celebration of Innovation from the Penn Center for Innovation (PCI).
Dongeun (Dan) Huh, Associate Professor in the Department of Bioengineering, was named the 2022 Inventor of the Year. D. Kacy Cullen, Associate Professor of Neurosurgery with a secondary appointment in Bioengineering, accepted the Deal of the Year Award on behalf of his company Innervace along with Co-Scientific Founder Douglas H. Smith, Robert A. Groff Professor of Teaching and Research in Neurosurgery in the Perelman School of Medicine.
PCI is interdisciplinary center for technology commercialization and startups in the Penn community. Their 7th Annual Celebration, held on December 6, 2022 at the Singh Center for Nanotechnology, honored Penn researchers and inventors whose achievements were a particular highlight of the fiscal year.
Huh was honored in recognition of his “extraordinary innovations in bioengineering tools.” The Huh Biologically Inspired Engineering Systems Laboratory (BIOLines) Laboratory is a leader in tissue engineering and cell-based smart biomedical devices, particularly in the “lab-on-a-chip” field of devices which can approximate the functioning of organs. Their research has been featured by the National Science Foundation (NSF, video below) and Wired, and has received a competitive Chan Zuckerberg Initiative (CZI) grant. Most recently, their “implantation-on-a-chip” technology has been used to better understand early-stage pregnancy. Huh and former lab member Andrei Georgescu (Ph.D. in Bioengineering, 2021) founded the spinoff company Vivodyne to bring this organ-on-a-chip technology to the industry sector. Fast Company included Vivodyne in a list of “most innovative” companies.
Innervace, represented by Cullen and Smith, took home the Deal of the Year award in recognition of its “successful Series A funding.” Innervace is another Penn spinoff which develops “anatomically inspired living scaffolds for brain pathway reconstruction.” Innervace raised up to $40 million in Series A financing to “accelerate a new cell therapy modality for the treatment of neurological disorders.” The Cullen Lab at Penn Medicine combines neuroengineering, regenerative medicine, and the study of neurotrauma to improve understanding of neural injury and develop cutting-edge neural tissue engineering-based treatments to promote regeneration and restore function.
Read the full list of 2022 PCI Award winners here.
Dan Huh’s BIOLines Lab develops several different kinds of organ-on-a-chip systems, such as this blinking-eye-on-a-chip.
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, Ph.D., 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.
Congratulations to the two Bioengineering students to receive 2022 National Science Foundation Graduate Research Fellowship Program (NSF GRFP) fellowships. The prestigious NSF GRFP program recognizes and supports outstanding graduate students in NSF-supported fields. The eighteen Penn 2022 honorees were selected from a highly-competitive pool of over 12,000 applications nationwide. Further information about the program can be found on the NSF website.
Gianna Therese Busch, PhD student, Bioengineering
Gianna is a member of the systems biology lab of Arjun Raj, Professor in Bioengineering and Genetics. Her research focuses on single-cell differences in cancer metabolism and drug resistance.
Shawn Kang, BSE/MSE, Bioengineering (’22)
Shawn conducted research in the BIOLines Lab of Dan Huh, Associate Professor in Bioengineering, where he worked to develop more physiologically relevant models of human health and disease by combining organs-on-a-chip and organoid technology.
The following Bioengineering students also received Honorable Mentions: Michael Steven DiStefano, PhD student Rohan Dipak Patel, PhD student Abraham Joseph Waldman, PhD student
Andrei Georgescu (left) and Dan Huh developed several organ-on-a-chip platforms in Huh’s lab. Their spin-off company, Vivodyne, aims to use the technology as a scalable alternative to animal testing in the pharmaceutical industry.
With Vivodyne, Associate Professor in the Department of Bioengineering Dan Huh is translating the organs-on-chips technology into a promising industry venture. Using microfluidic structures that mimic aspects of human physiology, organs-on-chips allow scientists to test therapies on lab-grown human cells. Vivodyne specifically focuses on designing organs-on-chips to create a scalable alternative for pharmaceutical drug testing on animals.
Fast Company now lists it as one of “the 10 most innovative companies with fewer than 10 employees,” saying “Vivodyne is helping major pharmaceutical companies like GlaxoSmithKline quickly adopt viable alternatives for testing drugs on monkeys.”
Vivodyne, launched in 2021, has created a platform that allows fully automated, complex studies at a far larger scale and lower cost than would be possible with manual experimentation, so pharmaceutical companies can actually test lab-made organs instead of animals in their drug-development processes. When done by hand, only 20 to 40 living tissue samples can be managed in parallel; Vivodyne’s instrument can cultivate, dose, and image more than 2,000 living tissues at once. The company, which raised $4 million in seed funding last year, says its instruments currently play pivotal roles in clinical drug testing for respiratory diseases, cancer treatment, vaccine development, diabetes therapies, and maternal medicine. GlaxoSmithKline, one of Vivodyne’s clients, estimates that for some projects the lab-grown tissues may displace as much as 80% of its animal testing. The company’s ultimate goal? “To supplant the vast majority of animal testing within the next decade,” says CEO Andrei Georgescu.
Bioengineering’s Dan Huh and colleagues have developed a number of organ-on-a-chip devices to simulate how human cells grow and perform in their natural environments. Their latest is a muscle-on-a-chip, which carefully captures the directionality of muscle cells as they anchor themselves within the body. See the full infographic at the bottom of this story. (Illustration by Melissa Pappas).
Studying drug effects on human muscles just got easier thanks to a new “muscle-on-a-chip,” developed by a team of researchers from Penn’s School of Engineering and Applied Science and Inha University in Incheon, Korea.
Muscle tissue is essential to almost all of the body’s organs, however, diseases such as cancer and diabetes can cause muscle tissue degradation or “wasting,” severely decreasing organ function and quality of life. Traditional drug testing for treatment and prevention of muscle wasting is limited through animal studies, which do not capture the complexity of the human physiology, and human clinical trials, which are too time consuming to help current patients.
An “organ-on-a-chip” approach can solve these problems. By growing real human cells within microfabricated devices, an organ-on-a-chip provides a way for scientists to study replicas of human organs outside of the body.
Using their new muscle-on-a-chip, the researchers can safely run muscle injury experiments on human tissue, test targeted cancer drugs and supplements, and determine the best preventative treatment for muscle wasting.
Dan Huh, Ph.D.
This research was published in Science Advances and was led by Dan Huh, Associate Professor in the Department of Bioengineering, and Mark Mondrinos, then a postdoctoral researcher in Huh’s lab and currently an Assistant Professor of Biomedical Engineering at Tulane University. Their co-authors included Cassidy Blundell and Jeongyun Seo, former Ph.D. students in the Huh lab, Alex Yi and Matthew Osborn, then research technicians in the Huh lab, and Vivek Shenoy, Eduardo D. Glandt President’s Distinguished Professor in the Department of Materials Science and Engineering. Lab members Farid Alisafaei and Hossein Ahmadzadeh also contributed to the research. The team collaborated with Insu Lee and professors Sun Min Kim and Tae-Joon Jeon of Inha University.
In order to conduct meaningful drug testing with their devices, the research team needed to ensure that cultured structures within the muscle-on-a-chip were as close to the real human tissue as possible. Critically, they needed to capture muscle’s “anisotropic,” or directionally aligned, shape.
“In the human body, muscle cells adhere to specific anchor points due to their location next to ligament tissue, bones or other muscle tissue,” Huh says. “What’s interesting is that this physical constraint at the boundary of the tissue is what sculpts the shape of muscle. During embryonic development, muscle cells pull at these anchors and stretch in the spaces in between, similar to a tent being held up by its poles and anchored down by the stakes. As a result, the muscle tissue extends linearly and aligns between the anchoring points, acquiring its characteristic shape.”
The team mimicked this design using a microfabricated chip that enabled similar anchoring of human muscle cells, sculpting three-dimensional tissue constructs that resembled real human skeletal muscle.
The National Science Foundation’s CAREER Award is given to early-career researchers in order to kickstart their careers in innovative and pivotal research while giving back to the community in the form of outreach and education. Alex Hughes, Assistant Professor in Bioengineering and in Cell and Developmental Biology, is among the Penn Engineering faculty members who have received the CAREER Award this year.
Hughes plans to use the funds to develop a human kidney model to better understand how the development of cells and tissues influences congenital diseases of the kidney and urinary tract.
The model, known as an “organoid,” is a lab-grown piece of human kidney tissue on the scale of millimeters to centimeters, grown from cultured human cells.
“We want to create a human organoid structure that has nephrons, the filters of the kidney, that are properly ‘plumbed’ or connected to the ureteric epithelium, the tubules that direct urine towards the bladder,” says Hughes. “To achieve that, we have to first understand how to guide the formation of the ureteric tubule networks, and then stimulate early nephrons to fuse with those networks. In the end, the structures will look like ‘kidney subunits’ that could potentially be injected and fused to existing kidneys.”
The field of bioengineering has touched on questions similar to those posed by Hughes, focusing on drug testing and disease treatment. Some of these questions can be answered with the “organ-on-a-chip” approach, while others need an even more realistic model of the organ. The fundamentals of kidney development and questions such as “how does the development of nephrons affect congenital kidney and urinary tract anomalies?” require an organoid in an environment as similar to the human body as possible.
“We decided to start with the kidney for a few reasons,” says Hughes. “First, because its development is a beautiful process; the tubule growth is similar to that of a tree, splitting into branches. It’s a complex yet understudied organ that hosts incredibly common developmental defects.
“Second,” he says, “the question of how things form and develop in the kidney has major medical implications, and we cannot answer that with the ‘organ-on-a-chip’ approach. We need to create a model that mimics the chemical and mechanical properties of the kidney to watch these tissues develop.”
The fundamental development of the kidney can also answer other questions related to efficiency and the evolution of this biological filtration system.
“We have the tendency to believe that systems in the human body are the most evolved and thus the most efficient, but that is not necessarily true,” says Hughes. “If we can better understand the development of a system, such as the kidney, then we may be able to make the system better.”
Hughes’ kidney research will lay the foundation for broader goals within regenerative medicine and organ transplantation.
Shawn Kang, BSE/MSE, Bioengineering (’22)
