New research on reproductive health demonstrates the first successful delivery of mRNA to placental cells to treat pre-eclampsia at its root.
Pre-eclampsia is a leading cause of stillbirths and prematurity worldwide, occurring in 3 – 8 % of pregnancies. A disorder characterized by high maternal blood pressure, it results from insufficient vasodilation in the placenta, restricting blood flow from the mother to the fetus.
Currently, a health-care plan for someone with pre-eclampsia involves diet and movement changes, frequent monitoring, blood pressure management, and sometimes early delivery of the baby. These standards of care address symptoms of the condition, not the root cause, and further perpetuate health inequity.
Now, Penn engineers are addressing this longstanding gap in reproductive health care with targeted RNA therapy.
The COVID vaccines demonstrated how lipid nanoparticles (LNPs) efficiently deliver mRNA to target cells. The success of LNPs is opening doors for a variety of RNA therapies aiming to treat the root causes of illness and disease. However, drug development and health care have consistently neglected a portion of the population in need of targeted care the most – pregnant people and their babies.
In one of the first studies of its kind, published in the Journal of the American Chemical Society,Michael Mitchell, J. Peter and Geri Skirkanich Assistant Professor of Innovation in Bioengineering, and Kelsey Swingle, Ph.D. student in the Mitchell Lab and lead author, describe their development of an LNP with the ability to target and deliver mRNA to trophoblasts, endothelial cells, and immune cells in the placenta.
Once these cells receive the mRNA, they create vascular endothelial growth factor (VEGF), a protein that helps expand the blood vessels in the placenta to reduce the mother’s blood pressure and restore adequate circulation to the fetus. The researchers’ successful trials in mice may lead to promising treatments for pre-eclampsia in humans.
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.
Bella Mirro, a fourth year student in Bioengineering who also minors in Chemistry, spoke with 34th Street Magazine about her many roles at Penn, including being Co–President of Shelter Health Outreach Program (SHOP), a Research Assistant in lab of Michal A. Elovitz, the Hilarie L. Morgan and Mitchell L. Morgan President’s Distinguished Professor in Women’s Health at Penn Medicine, and a Penn Engineering Council Marketing Team Member. In this Q&A, she discusses her research in women’s health and her passions for accessible healthcare, serving Philadelphia’s homeless community, and good food.
A study published in Nature Biomedical Engineering details a novel method for imaging the placenta in pregnant patients as well as the results of a pilot clinical study. By combining optical measurements with ultrasound, the findings show how oxygen levels can be monitored noninvasively and provides a new way to generate a better understanding of this complex, crucial organ. This research was the result of a collaboration of the groups of the University of Pennsylvania’s Arjun Yodh and Nadav Schwartz with colleagues from the Children’s Hospital of Philadelphia (CHOP) and was led by postdoc Lin Wang.
Schwartz describes the placenta as the “engine” of pregnancy, an organ that plays a crucial role in delivering nutrients and oxygen to the fetus. Placental dysfunction can lead to complications such as fetal growth restriction, preeclampsia, and stillbirth. To increase knowledge about this crucial organ, the National Institute of Child Health and Human Development launched the Human Placenta Project in 2014. One focus of the program is to develop tools to assess human placental structure and function in real time, including optical devices.
For three years, the researchers optimized the design of their instrument and tested it in preclinical settings. The process involved integrating optical fibers with ultrasound probes, exploring various ultrasound transducers, and improving the multimodal technology so that measurements were stable, accurate, and reproducible while collecting data at the bedside. The resulting instrumentation now enables researchers to study the anatomy of the placenta while also collecting detailed functional information about placenta blood flow and oxygenation, capabilities that existing commercially devices do not have, the researchers say.
Because the placenta is located far below the body’s surface, one of the key technical challenges addressed by Wang, a postdoc in Yodh’s lab, was reducing background noise in the opto-electronic system. Light is scattered and absorbed when it travels through thick tissues, Yodh says, and the key for success was to reduce background interference so that the small amount of light that penetrates deep into the placenta and then returns is still large enough for a high-quality measurement.
“We’re sending a light signal that goes through the same deep tissues as the ultrasound. The extremely small amount of light that returns to the surface probe is then used to accurately assess tissue properties, which is only possible with very stable lasers, optics, and detectors,” says Yodh. “Lin had to overcome many barriers to improve the signal-to-noise ratio to the point where we trusted our data.”
The authors are Lin Wang, Jeffrey M. Cochran, Kenneth Abramson, Lian He, Venki Kavuri, Samuel Parry, Arjun G. Yodh, and Nadav Schwartz from Penn; Tiffany Ko, Wesley B. Baker, and Rebecca L. Linn from the Children’s Hospital of Philadelphia, and David R. Busch, previously a research associate at Penn and now at the University of Texas Southwestern Medical School.
Each year, Penn Engineering’s seniors present their Senior Design projects, a year-long effort that challenges them to test and develop solutions to real-world problems, to their individual departments. The top three projects from each department go on to compete in the annual Senior Design Competition, sponsored by the Engineering Alumni Society, which involves pitching projects to a panel of judges who evaluate their potential in the market.
This year’s panel included 42 judges, 21 in-person and 21 online, who weighed in on 18 projects. Each winning team received a $2,000 prize, generously sponsored by Penn Engineering alumnus Kerry Wisnosky.
This year, Bioengineering teams won two of the four interdepartmental awards.
Technology & Innovation Award
This award recognized the team whose project represents the highest and best use of technology and innovation to leverage engineering principles.
Winner: Team Modulo Prosthetics Department: Bioengineering Team Members: Alisha Agarwal, Michelle Kwon, Gary Lin, Ian Ong, Zachary Spalding Mentor: Michael Hast Instructors: Sevile Mannickarottu, David Meaney, Michael Siedlik Abstract: Modulo Prosthetic is an adjustable, low-cost, thumb prosthetic with integrated haptic feedback that attaches to the metacarpophalangeal (MCP) joint of partial hand amputees and assists in activities of daily living (ADLs).
This award recognizes the team which most professionally and persuasively presents their group project to incorporate a full analysis of their project’s scope, advantages and challenges, as well as addresses the research’s future potential and prospects for commercialization.
Winner: Team ReiniSpec Department: Bioengineering Team Members: Caitlin Frazee, Caroline Kavanagh, Ifeoluwa Popoola, Alexa Rybicki, Michelle White Mentor: JeongInn Park Instructors: Sevile Mannickarottu, David Meaney, Michael Siedlik Abstract: ReiniSpec is a redesigned speculum to improve the gynecological exam experience, increasing patient comfort with a silicone shell and using motorized arm adjustments to make it easily adjustable for each patient, while also incorporating a camera, lights, and machine learning to aid in better diagnosis by gynecologists.
After a year of hybrid learning, Penn Bioengineering (BE) seniors were excited to return to the George H. Stephenson Foundation Educational Laboratory & Bio-MakerSpace for Senior Design (BE 495 & 496), a two-semester course in which students work in teams to conceive, design and pitch their capstone projects in bioengineering. This year’s projects include tools for monitoring health, software to improve communication for the healthcare and supply chain industries, and devices to improve patient care for women and underrepresented minorities.
The three winning teams went on to compete in the annual interdepartmental Senior Design Competition sponsored by the Penn Engineering Alumni Society. BE took home two of the four interdepartmental awards: Team Modulo Prosthetics won the “Technology and Innovation Prize,” recognizing the project which best represents the highest and best use of technology and innovation to leverage engineering principles; and Team ReiniSpec won the “Leadership Prize,” which recognizes the team which most professionally and persuasively presents their group project to incorporate a full analysis of their project scope, advantages, and challenges, and addresses the commercialization and future potential of their research.
All BE teams were also required to submit their projects to local and national competitions, and were met with resounding success. “The creativity and accomplishment of this Senior Design class is really unparalleled,” said David Meaney, Solomon R. Pollack Professor in Bioengineering, Senior Associate Dean of Penn Engineering, and instructor for Senior Design. “The number of accolades received by these students, as well as the interest in transforming their ideas into real products for patients, reached a new level that makes us extremely proud.”
Keep reading for a full list of this year’s projects and awards.
Team 1 – MEViD
MEViD (Multichannel Electrochemical Viral Diagnostic) is a modular, low cost device that leverages electrochemistry to rapidly diagnose viral diseases from saliva samples.
Team members: Yuzheng (George) Feng, Daphne Kontogiorgos-Heintz, Carisa Shah, Pranshu Suri, & Rachel Zoneraich
MOD EZ-IO is a low-cost, novel intraosseous drill that uses force and RPM readings to alert the user via an LED when they have breached cortical bone and entered cancellous bone, guiding proper IO placement.
Team members: Gregory Glova, Kaiser Okyan, Patrick Paglia, Rohan Vemu, & Tshepo Yane
CliniCall helps streamline and centralize communication channels, offering a real-time monitoring device that enables on-site/attending physicians to communicate with on-call physicians through a livestream of patients and data.
Team members: Neepa Gupta, Santoshi Kandula, Sue Yun Lee, & Ronil Synghal
Team 5 – PneuSonus
PneuSonus is a low-cost, user-friendly wearable strap that aids in detecting pediatric pneumonia by using frequency analysis of sound waves transmitted through the lungs to identify specific properties related to fluid presence, a valid indicator specific to pneumonia.
Team members: Iman Hossain, Kelly Lopez, Sophia Mark, Simi Serfati, & Nicole Wojnowski
Team 6 – Chrysalis
Chrysalis is a smart swaddle system comprising an electric swaddle and accompanying iOS application that comforts neonatal abstinence syndrome infants via stochastic resonance and maternal heartbeat vibrational patterns to reduce opioid withdrawal symptoms without pharmacological intervention or constant nurse oversight as well as streamlines the Eat, Sleep, Console documentation process for nurses.
Team members: Julia Dunn, Rachel Gu, Julia Lasater, & Carolyn Zhang
Modulo Prosthetic is an adjustable, low-cost, thumb prosthetic with integrated haptic feedback that attaches to the metacarpophalangeal (MCP) joint of partial hand amputees and assists in activities of daily living (ADLs).
Team members: Alisha Agarwal, Michelle Kwon, Gary Lin, Ian Ong, & Zachary Spalding
COR-ASSIST by Cygno Technologies is a low-cost intra-aortic balloon enhancement that directly supports heart function by increasing cardiac output to 2.8L/min, at a much lower cost and bleeding risk than the current Impella cardiac assist device.
Team members: Francesca Cimino, Allen Gan, Shawn Kang, Kristina Khaw, & William Zhang
Pedalytics Footwear is a rechargeable sandal that continuously monitors foot health and prevents diabetic foot ulcer formation by novelly tracking three key metrics indicative of ulceration, temperature, oxygen saturation, and pressure, and sending alerts to patients via the Pedalytics app when metric abnormalities are detected.
Team members: Samantha Brosler, Constantine Constantinidis, Quincy Hendricks, Ananyaa Kumar, & María José Suárez
ReiniSpec is a redesigned speculum to improve the gynecological exam experience, increasing patient comfort with a silicone shell and using motorized arm adjustments to make it easily adjustable for each patient, while also incorporating a camera, lights, and machine learning to aid in better diagnosis by gynecologists.
Team members: Caitlin Frazee, Caroline Kavanagh, Ifeoluwa Popoola, Alexa Rybicki, & Michelle White
While reflecting on her undergraduate journey at Penn, senior Yasmina Al Ghadban says that she has a “ton of memories” she will take with her: lifelong friends made and skills developed through coursework, research, and teaching experiences, the chance to engage with public health communities on campus, and traveling for courses and internships. “That’s the beauty of Penn,” she says. “There’s just so many opportunities everywhere.”
As a double major in bioengineering and psychology, Al Ghadban, who is from Beirut, has certainly taken advantage of many such opportunities. Now, she is poised to leverage her “interdisciplinary lens” towards a future career in public health.
Looking for a place to grow and become more independent, Al Ghadban decided to come to Penn after graduating from the International College in Lebanon. After taking an introduction to bioengineering course during her freshman year, she became enthralled by the hands-on nature of the program and enrolled in the School of Engineering and Applied Science. “I really enjoyed working with circuits and Arduino, being able to synthesize things, and I felt like being in engineering was the place where I was going to gain the most skills,” she says.
Al Ghadban is applying those skills as she completes her senior design project. She and a team of four seniors are building an autonomous robot equipped with Lidar sensors that it uses to create a map of a physical space. The team also programmed their robot to recognize high-touch surfaces that it then disinfects with UV light. “It’s a technology that is completely autonomous, cheaper than what’s on the market, and doesn’t put people at risk when they go in to disinfect,” she says. The team recently put the finishing touches on the project and presented their robot as part of a demonstration on April 14.
In addition to her degree in engineering, Al Ghadban’s interests in public and mental health spurred her to take courses and eventually pursue a double major in psychology, a field that she sees as complementary to engineering. “In psychology, we focus a lot on research and study design, research bias, and these things are similar in engineering and psychology,” she says. “Overall, I think they gave me different perspectives in terms of problem solving, and it’s nice to have that interdisciplinary lens.”
One place where Al Ghadban was able to use this interdisciplinary lens was while working as an research assistant in the Rehabilitation Robotics Lab with Michelle Johnson during her sophomore year. “The focus of the lab is to create robots for post-stroke rehabilitation, and the robotics part is very engineering-focused, but there is another part where people struggle doing the exercises,” she says. “Being able to engage with people and increasing their likelihood of doing that intervention, you rely on a lot from psychology, like interventions from positive psychology or research on how people stay engaged.”
Originally from Matawan, NJ, Riley has been an NIH Postdoctoral Fellow in the Mitchell Lab since 2018. Her move to a faculty position at Rowan marks a return, as she received her B.S. in Civil and Environmental Engineering there in 2012. Riley went on to receive her Ph.D. in Biomedical Engineering in 2018 at the University of Delaware with Emily Day, Ph.D. before joining the lab of Michael J. Mitchell, Ph.D., Skirkanich Assistant Professor of Innovation, later that year. The Mitchell Lab’s research lies at the interface of biomaterials science, drug delivery, and cellular and molecular bioengineering to fundamentally understand and therapeutically target biological barriers.
“Rachel has had a prolific academic career at the University of Delaware and at Penn, launching several exciting research projects and mentoring the next generation of STEM researchers,” Mitchell says. “I’m very hopeful that her new position as an Assistant Professor of Biomedical Engineering at Rowan University will permit her to engineer new drug delivery technologies for women’s health applications.”
Research in the Riley Lab at Rowan will explore how nanoparticle drug delivery technologies can be engineered specifically for applications in women’s health. They will use nanoparticles as tools to study and treat gynecological cancers, fetal diseases, and pregnancy complications. Riley’s ultimate goal is to gain a fundamental understanding of how nanoparticle structure influences delivery to gynecological tissues to enable them to take an engineering approach to tackle new applications in women’s health.
Riley says that she is committed to supporting women and minorities in STEM disciplines and she looks forward to continuing collaborations with Penn and starting new collaborations with researchers at Cooper Medical School at Rowan University (CMSRU). Congratulations, Dr. Riley!