Penn Engineers’ New Bioprinting Technique Allows for Complex Microtissues

by Evan Lerner

Jason Burdick, Andrew C. Daly and Matthew Davidson

Bioprinting is currently used to generate model tissues for research and has potential applications in regenerative medicine. Existing bioprinting techniques rely on printing cells embedded in hydrogels, which results in low-cell-density constructs that are well below what is required to grow functional tissues. Maneuvering different kinds of cells into position to replicate the complex makeup of an organ, particularly at organlike cell densities, is still beyond their capabilities.

Now, researchers at the School of Engineering and Applied Science have demonstrated a new bioprinting technique that enables the bioprinting of spatially complex, high-cell-density tissues.

Using a self-healing hydrogel that allows dense clusters of cells to be picked and placed in a three-dimensional suspension, the researchers constructed a model of heart tissue that featured a mix of cells that mimic the results of a heart attack.

The study was led by Jason Burdick, Robert D. Bent Professor in the Department of Bioengineering, and Andrew C. Daly, a postdoctoral researcher in his lab. Fellow Burdick lab postdoc Matthew Davidson also contributed to the study, which has been published in the journal Nature Communications.

Even without a bioprinter, groups of cells can be made to clump into larger aggregates, known as spheroids. For Burdick and colleagues, these spheroids represented a potential building block for a better approach to bioprinting.

“Spheroids are often useful for studying biological questions that rely on the cells’ 3D microenvironments or in the construction of new tissues,” says Burdick. “However, we’d like to produce even higher levels of organization by ‘printing’ different kinds of spheroids in specific arrangements and have them fuse together into structurally complex microtissues.”

Read more at Penn Engineering Today.

Penn Dental, Penn Engineering Unite to Form Center for Innovation & Precision Dentistry

by Beth Adams

With the shared vision to transform the future of oral health care, Penn Dental Medicine and Penn’s School of Engineering and Applied Sciences have united to form the Center for Innovation & Precision Dentistry (CiPD). The new Center marked its official launch on January 22 with a virtual program celebrating the goals and plans of this unique partnership. Along with the Deans from both schools, the event gathered partners from throughout the University of Pennsylvania and invited guests, including the National Institute of Dental and Craniofacial Research Director (NIDCR) Dr. Rena D’Souza and IADR Executive Director Chris Fox.

Conceived and brought to fruition by co-directors Dr. Michel Koo of Penn Dental Medicine and Dr. Kathleen Stebe of Penn Engineering, the CiPD is bridging the two schools through cutting-edge research and technologies to accelerate the development of new solutions and devices to address unmet needs in oral health, particularly in the areas of dental caries, periodontal disease, and head and neck cancer. The CiPD will also place a high priority on programs to train the next generation of leaders in oral health care innovation.

“We have a tremendous global health challenge. Oral diseases and craniofacial disorders affect 3.5 billion people, disproportionately affecting the poor and the medically and physically compromised,” says Dr. Koo, Professor in the Department of Orthodontics and Divisions of Community Oral Health and Pediatric Dentistry, in describing their motivation to form the Center. “There is an urgent need to find better ways to diagnose, prevent, and treat these conditions, particularly in ways that are affordable and accessible for the most susceptible populations. That is our driving force for putting this Center together.”

“We have united our schools around this mission,” adds Dr. Stebe, Richer & Elizabeth Goodwin Professor in the Department of Chemical and Biomolecular Engineering. “We have formed a community of scholars to develop and harness new engineering paradigms, to generate new knowledge, and to seek new approaches that are more effective, precise, and affordable to address oral health. More importantly, we will train a new community of scholars to impact this space.”

Born through Interdisciplinary Research

A serendipitous connection born through Penn’s interdisciplinary research environment itself brought Drs. Koo and Stebe together more than five years ago, an introduction that would eventually lead to creating the CiPD.

Dr. Tagbo Niepa, now assistant professor at the University of Pittsburgh, came to Penn Engineering in 2014 as part of Penn’s Postdoctoral Fellowship for Academic Diversity, an initiative from the office of the Vice Provost for Research. His studies on the microbiome led him to reach out to Dr. Stebe and Dr. Daeyeon Lee (also at Penn Engineering), and to connect them to Dr. Koo, initiating collaboration between their labs.

“Tagbo embodies what we are trying to do with the CiPD,” recalls Dr. Stebe. “He had initiative, he identified new tools and important context, and he did good science that may help us understand how to interrupt the disease process and identify new underlying mechanisms that can inspire new therapies.” Dr. Niepa worked on applying microfluidics and engineering to study the oral microbiome and better understand how the interactions between fungi and bacteria could impact dental caries.

“Upon meeting Michel, we became excited about the possibilities of bringing talent from the two schools together,” notes Dr. Stebe. A 2018 workshop organized by Drs. Koo and Stebe and funded by Penn’s Vice Provost of Research explored the potential for expanding cross-school research. “We invited researchers from dental medicine and engineering as well as relevant people from the arts and sciences to see if we could find a way to collaborate to advance oral and craniofacial health,” says Dr. Koo. “That was the catalyst for the Center; after the workshop, we put together a task force which would become the core members of the CiPD.”

In addition to Drs. Koo and Stebe, the CiPD Executive Committee includes Associate Directors Dr. Henry Daniell, Vice-Chair and W.D. Miller Professor, Department of Basic & Translational Sciences, Penn Dental Medicine, and Dr. Anh Le, Chair and Norman Vine Endowed Professor of Oral Rehabilitation, Department of Oral and Maxillofacial Surgery / Pharmacology, Penn Dental Medicine; as well as Dr. Andrew Tsourkas, Professor, Department of Bioengineering, Co-Director, Center for Targeted Therapeutics & Translational Nanomedicine (CT3N) and Chemical and Nanoparticle Synthesis Core, Penn Engineering; and Dr. Jason Moore, Edward Rose Professor of Informatics, Director of the Penn Institute for Biomedical Informatics. The core members of CiPD include 26 faculty from across both Penn Dental Medicine and Penn Engineering, and also from the Schools of Medicine and Arts & Sciences.

Read the full story in Penn Today.

Penn Bioengineers Develop Implantable Living Electrodes

Living Electrode Panels (image courtesy of the Cullen Lab)

Connecting the human brain to electrical devices is a long-standing goal of neuroscientists, bioengineers, and clinicians, with applications ranging from deep brain stimulation (DBS) to treat Parkinson’s disease to more futuristic endeavors such as Elon Musk’s NeuraLink initiative to record and translate brain activity. However, these approaches currently rely on using implantable metallic electrodes that inherently provoke a lasting immune response due to their non-biological nature, generally complicating the reliability and stability of these interfaces over time. To address these challenges, D. Kacy Cullen, Associate Professor in Neurosurgery and Bioengineering, and Dayo Adewole, a doctoral candidate in Bioengineering, worked with a multi-disciplinary team of collaborators to develop the first “living electrodes” as an implantable, biological bridge between the brain and external devices. In a recent article published in Science Advances, the team demonstrated the fabrication of hair-like microtissue comprised of living neuronal networks and bundled tracts of axons the signal sending fibers of the nervous system protected within soft hydrogel cylinders. They showed that these axon-based living electrodes could be fully controlled and monitored with light thus eliminating the need for electrical contact and are capable of surviving and forming synapses with the brain as demonstrated in an adult rat model. While further advancements are necessary prior to clinical use, the current findings provide the foundation for a new class of “living electrodes” as a biological intermediary between humans and devices capable of leveraging natural mechanisms to potentially provide a stable interface for clinical applications.

Cullen has a primary appointment in the Department of Neurosurgery in the Perelman School of Medicine, with a secondary appointment in the Department of Bioengineering in the School of Engineering and Applied Science, and an appointment in the Corporal Michael J. Crescenz VA Medical Center in Philadelphia.

Penn Engineering and CHOP Researchers Identify Nanoparticles that Could Be Used in Therapeutic mRNA Delivery before Birth

by Evan Lerner

William H. Peranteau, Michael J. Mitchell, Margaret Billingsley, Meghana Kashyap, and Rachel Riley (Clockwise from top left)

Researchers at Children’s Hospital of Philadelphia and the School of Engineering and Applied Science at the University of Pennsylvania have identified ionizable lipid nanoparticles that could be used to deliver mRNA as part of fetal therapy. The proof-of-concept study, published today in Science Advances, engineered and screened a number of lipid nanoparticle formulations for targeting mouse fetal organs and has laid the groundwork for testing potential therapies to treat genetic diseases before birth.

“This is an important first step in identifying nonviral mediated approaches for delivering cutting-edge therapies before birth,” said co-senior author William H. Peranteau, MD, an attending surgeon in the Division of General, Thoracic and Fetal Surgery and the Adzick-McCausland Distinguished Chair in Fetal and Pediatric Surgery at CHOP. “These lipid nanoparticles may provide a platform for in utero mRNA delivery, which would be used in therapies like fetal protein replacement and gene editing.”

Michael J. Mitchell, Skirkanich Assistant Professor of Innovation in Penn Engineering’s Department of Bioengineering, is the other co-senior author of the study. The co-first authors are Mitchell Lab members Rachel Riley, a postdoctoral fellow, and Margaret Billingsley, a graduate student, and Peranteau Lab member Meghana Kashyap, a research fellow.

Recent advances in DNA sequencing technology and prenatal diagnostics have made it possible to diagnose many genetic diseases before birth. Some of these diseases are treated by protein or enzyme replacement therapies after birth, but by then, some of the damaging effects of the disease have taken hold. Thus, applying therapies while the patient is still in the womb has the potential to be more effective for some conditions. The small fetal size allows for maximal therapeutic dosing, and the immature fetal immune system may be more tolerant of replacement therapy.

Read the full story in Penn Engineering Today.

NB: Rachel Riley is now Assistant Professor in Biomedical Engineering at Rowan University.

Studying ‘Hunters and Busybodies,’ Penn and American University Researchers Measure Different Types of Curiosity

by Melissa Pappas

Knowledge networks were created as participants browsed Wikipedia, where pages became nodes and relatedness between pages became edges. Two diverging styles emerged — “the busybody” and “the hunter.” (Illustrations by Melissa Pappas)

Curiosity has been found to play a role in our learning and emotional well-being, but due to the open-ended nature of how curiosity is actually practiced, measuring it is challenging. Psychological studies have attempted to gauge participants’ curiosity through their engagement in specific activities, such as asking questions, playing trivia games, and gossiping. However, such methods focus on quantifying a person’s curiosity rather than understanding the different ways it can be expressed.

Efforts to better understand what curiosity actually looks like for different people have underappreciated roots in the field of philosophy. Varying styles have been described with loose archetypes, like “hunter” and “busybody” — evocative, but hard to objectively measure when it comes to studying how people collect new information.

A new study led by researchers at the University of Pennsylvania’s School of Engineering and Applied Science, the Annenberg School for Communication, and the Department of Philosophy and Religion at American University, uses Wikipedia browsing as a method for describing curiosity styles. Using a branch of mathematics known as graph theory, their analysis of curiosity opens doors for using it as a tool to improve learning and life satisfaction.

The interdisciplinary study, published in Nature Human Behavior, was undertaken by Danielle Bassett, J. Peter Skirkanich Professor in Penn Engineering’s Departments of Bioengineering and Electrical and Systems Engineering, David Lydon-Staley, then a post-doctoral fellow in her lab, now an assistant professor in the Annenberg School of Communication, two members of Bassett’s Complex Systems Lab, graduate student Dale Zhou and postdoctoral fellow Ann Sizemore Blevins, and Perry Zurn, assistant professor from American University’s Department of Philosophy.

“The reason this paper exists is because of the participation of many people from different fields,” says Lydon-Staley. “Perry has been researching curiosity in novel ways that show the spectrum of curious practice and Dani has been using networks to describe form and function in many different systems. My background in human behavior allowed me to design and conduct a study linking the styles of curiosity to a measurable activity: Wikipedia searches.”

Zurn’s research on how different people express curiosity provided a framework for the study.

Read the full story in Penn Engineering Today.

Penn, Carnegie Mellon and Johns Hopkins to Develop New Turing Tests, Investigate How AI Can Become More Like Biological Intelligence

by Evan Lerner

While artificial intelligence is becoming a bigger part of nearly every industry and increasingly present in everyday life, even the most impressive AI is no match for a toddler, chimpanzee, or even a honeybee when it comes to learning, creativity, abstract thinking or connecting cause and effect in ways they haven’t been explicitly programmed to recognize.

This discrepancy gets at one of the field’s fundamental questions: what does it mean to say an artificial system is “intelligent” in the first place?

Konrad Kording, Timothy Verstynen, Joshua T. Vogelstein, and Leyla Isik (clockwise from top left)

Seventy years ago, Alan Turing famously proposed such a benchmark; a machine could be considered to have artificial intelligence if it could successfully fool a person into thinking it was a human as well. Now, many artificial systems could pass a “Turing Test” in certain limited domains, but none come close to imitating the holistic sense of intelligence we recognize in animals and people.

Understanding how AI might someday be more like this kind of biological intelligence — and developing new versions of the Turing Test with those principles in mind — is the goal of a new collaboration between researchers at the University of Pennsylvania, Carnegie Mellon University and Johns Hopkins University.

The project, called “From Biological Intelligence to Human Intelligence to Artificial General Intelligence,” is led by Konrad Kording, a Penn Integrates Knowledge Professor with appointments in the Departments of Bioengineering and Computer and Information Science in Penn Engineering and the Department of Neuroscience at Penn’s Perelman School of Medicine. Kording will collaborate with Timothy Verstynen of Carnegie Mellon University, as well Joshua T. Vogelstein and Leyla Isik, both of Johns Hopkins University, on the project.

Read the full story on Penn Engineering Today.

Bioengineering Faculty Contribute to New Treatment That “Halts Osteoarthritis-Like Knee Cartilage Degeneration”

A recent study published in Science Translational Medicine announces a discovery which could halt cartilage degeneration caused by osteoarthritis: “These researchers showed that they could target a specific protein pathway in mice, put it into overdrive and halt cartilage degeneration over time. Building on that finding, they were able to show that treating mice with surgery-induced knee cartilage degeneration through the same pathway via the state of the art of nanomedicine could dramatically reduce the cartilage degeneration and knee pain.” This development could eventually lead to treating osteoarthritis with injection rather than more complicated surgery.

Among a team of Penn Engineering and Penn Medicine researchers, the study was co-written by Zhiliang Cheng, Research Associate Professor in Bioengineering, Andrew Tsourkas, Professor in Bioengineering, and Robert Mauck, Mary Black Ralston Professor in Bioengineering and Orthopaedic Surgery. The lead author was Yulong Wei of the Department of Orthopaedic Surgery and the McKay Orthopaedic Research Laboratory.

Read the press release in Penn Medicine News.

Engineering and Medicine Researchers Collaborate on Studies of Genome Folding in Health and Disease

(Left to right) Top row: Jennifer E. Phillips-Cremins, Rajan Jain, and Eric Joyce. Middle row: Melike Lakadamyali, Golnaz Vahedi, and Gerd Blobel. Bottom row: Bomyi Lim, Arjun Raj, and Stanley Qi.

Popular accounts of the human genome often depict it as a long string of DNA base pairs, but in reality the genome is separated into chromosomes that are tightly twisted and coiled into complex three-dimensional structures. These structures create a myriad of connections between sites on the genome that would be distant from one another if stretched out end-to-end. These “long range interactions” are not incidental — they regulate the activity of our genes during development and can cause disease when disrupted.

Now two teams of researchers at the Perelman School of Medicine at the University of Pennsylvania, each led by Jennifer E. Phillips-Cremins,  associate professor and Dean’s Faculty Fellow in the Department of Bioengineering at the School of Engineering and Applied Science and of Genetics at the Perelman School of Medicine have been awarded grants totaling $9 million from the National Institutes of Health (NIH), as part of a major NIH Common Fund initiative to understand such 3D-genomic interactions.

The initiative, known as the 4D Nucleome Program, broadly aims to map higher-order genome structures across space and time, as well as to understand how the twists and loops of the DNA sequence govern genome function and cellular phenotype in health and disease.

Read the full story in Penn Engineering Today.

N.B.: In addition to Phillips-Cremins, collaborators include Arjun Raj, Professor in Bioengineering and Genetics, and Bioengineering Graduate Group Members Melike Lakadamyali, Associate Professor in Physiology, and Bomyi Lim, Assistant Professor in Chemical and Biomolecular Engineering.

Guest Post: Penn Bioengineering Lab Classes in the Time of Coronavirus

By Solumtochukwu (Somto) Egboga

Stephenson Lab student employees (L to R): Seth Fein (BSE 20, MSE 21), Nicole Wojnowski (BSE 22), and Somto Egboga (MSE 21)

Since the country began shutting down in March, I have joined the majority of the world in calling the times “unprecedented”: The word, which I rarely used before the pandemic, is now a staple of my lockdown lexicon. In March, we all got the email that changed the trajectory of the rest of our semester and the school year. Since then, COVID-19 has been impacting lives here at Penn, around the nation, and the world. Hanging out with friends and family on Zoom, managing work and school from home, social distancing, wearing masks everywhere, and constantly washing hands have been the reality of our new normal for months.

It has been almost ten months since the World Health Organization declared COVID-19 a pandemic and this has posed a global crisis like nothing most of us have experienced in our lifetime. At Penn, the campus community including students and staff have rallied to keep each other safe, all while doing what is possible to ensure that lectures, teaching, and research are possible in ways that uphold the university’s mission of “strengthening the quality of education and producing innovative research and models of healthcare delivery by fostering a vibrant inclusive environment and fully embracing diversity.”

BE students Alexa Rybicki, Ifeoluwa Popoola, and Caitlin Frazee meet for BE 309 in the Gather.Town virtual lab space.

In Penn Engineering’s Bioengineering Department, the Stephenson Foundation Educational Laboratory & Bio-MakerSpace has been at the heart of ensuring that lab-based classes run as smoothly as possible given the circumstances. First off, during the summer, the lab launched a Slack site that not only kept students engaged and connected through fun, daily “Questions of the Day” but also gave them the opportunity to reach out to our staff and obtain their expertise for coursework and personal projects. The staff at the Stephenson Lab also supported and continue to support Senior Design students (BE 495) with their projects by ordering, receiving, packaging, arranging pickups, or mailing supplies needed to complete their Senior Design projects. In addition, class time takes place using Gather.Town to recreate our Bio-MakerSpace virtually. In other classes, video tutorials of some of the experiments students were missing out on were produced over the summer and made available to students so they could learn by seeing what the lab staff were doing in the videos. For the Bioengineering Modeling, Analysis, and Design (BE MAD) class (BE 309), in addition to videos, our lab Engineer, Michael Patterson, developed software through which students can enter design criteria and have experimental data emailed to them.

Picking up lab supplies outside in the Engineering complex

The staff at the lab also supported a Rehabilitation Engineering course (BE 514) taught by Michelle Johnson, Associate Professor in Physical Medicine and Rehabilitation and Bioengineering, by putting together supplies that enabled students in the class to reengineer toy bunny rabbits to be more accessible to children with disabilities. Optical Microscopy (BE 518), another Bioengineering course, taught by Christopher Fang-Yen, Associate Professor in Bioengineering and Neuroscience, offers students an introduction to the fundamental concepts of optics and microscopy. The staff at the lab put together kits and made them available for pickup by the students in the class.

In a time when the shape of education looks vastly different from what we anticipated this year, the Bio-MakerSpace has been instrumental in ensuring that students still have access to resources that make their learning experience an enriching one. In these unprecedented times, the lab has been able to encourage students to keep up and be engaged with their coursework while also fostering creativity in students, virtually and remotely. While we may not know what life after the pandemic will look like, one thing to be sure of is that the Stephenson Lab will always be a reliable place for Penn students to get support for personal projects and coursework when needed.

Solumtochukwu (Somto) Egboga is a Master’s Student in Bioengineering, graduating December 2020. She also is a student employee for the Stephenson Foundation Bioengineering Laboratory & Bio-MakerSpace.

Using Lung-on-a-chip Technology to Find Treatments for Chlorine Gas Exposure

Huh’s organ-on-a-chip devices contain human cells, allowing for experiments that could not otherwise be practically or ethically performed.

Chlorine gas is a commonly used industrial chemical. It is also highly toxic and potentially deadly; it was used as a chemical weapon in both World War I and the Syrian Civil War and has led to multiple deaths from industrial accidents. Mixing certain household cleaners can also produce the toxic gas, leading to lasting lung injuries for which there are currently no effective treatments.

Now, researchers at Penn Engineering and Penn’s Perelman School of Medicine are collaborating with BARDA, the U.S. Office of Health and Human Services’ Biomedical Advanced Research and Development Authority, to address this need using their lung-on-a-chip technology.

The laboratory of Dan Huh, associate professor in the Department of Bioengineering, has developed a series of organ-on-a-chip platforms. These devices incorporate human cells into precisely engineered microfluidic channels that mimic an organ’s natural environment, providing a way to conduct experiments that would not otherwise be feasible.

Dan Huh
Dan Huh, PhD

Huh’s previous research has involved using a placenta-on-a-chip to study which drugs are able to reach a developing fetus; investigating microgravity’s effect on the immune system by sending one of his chips to the International Space Station; and testing treatments for dry eye disease using an eye-on-a-chip, complete with a mechanical blinking eyelid.

Read the full story on Penn Engineering Today. Media contact Evan Lerner.