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 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.

Maria Ovando: Research and Self-discovery

by Elisa Ludwig

Maria Ovando

The process of discovery sometimes starts with a hunch. Maria Ovando arrived at Penn Engineering with an affinity for math and science, extensive experience volunteering at her local health clinic and an assumption that she was preparing for a career in medicine. She was drawn to Penn Engineering because of the flexibility in the curriculum and the ability to both tailor her course of study and pursue cross-disciplinary subjects.

As a pre-med student, bioengineering seemed to be the natural choice for a major, but during her freshman year, Ovando found that she genuinely enjoyed bioengineering as a discipline in its own right, and only then did her future goals come into view.

“I’ve discovered that I have a passion for research, working on low-cost devices that can have a direct impact on individuals,” she says.

One of the most important opportunities she’s had at Penn is her work with Dr. Michelle J. Johnson at the Rehabilitation Robotics Lab in the Perelman School of Medicine. There, Ovando has been working to improve aspects of the Community-based Affordable Robot Exercise System, which helps stroke patients with lower extremity impairment. She’s also worked on a project that involved analyzing and reevaluating data in the early detection of cerebral palsy in infants. As an undergraduate, she found it both meaningful and moving to have a role in this groundbreaking research.

Read the full story in Penn Engineering today.

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.

Danielle Bassett and Jason Burdick are Among World’s Most Highly Cited Researchers

Danielle Bassett and Jason Burdick
Danielle Bassett and Jason Burdick

The nature of scientific progress is often summarized by the Isaac Newton quotation, “If I have seen further it is by standing on the shoulders of giants.” Each new study draws on dozens of earlier ones, forming a chain of knowledge stretching back to Newton and the scientific giants his work referenced.

Scientific publishing and referencing has become more formal since Newton’s time, with databases of citations allowing for sophisticated quantitative analyses of that flow of information between researchers.

The Institute for Scientific Information and the Web of Science Group provide a yearly snapshot of this flow, publishing a list of the researchers who are in the top 1 percent of their respective fields when it comes to the number of times their work has been cited.

Danielle Bassett, J. Peter Skirkanich Professor in the departments of Bioengineering and Electrical and Systems Engineering, and Jason Burdick, Robert D. Bent Professor in the department of Bioengineering, are among the 6,389 researchers named to the 2020 list.

Bassett is a pioneer in the field of network neuroscience, which incorporates elements of mathematics, physics,  biology and systems engineering to better understand how the overall shape of connections between individual neurons influences cognitive traits. Burdick is an expert in tissue engineering and the design of biomaterials for regenerative medicine; by precisely tailoring the microenvironment within these materials, they can influence stem cell differentiation or trigger the release of therapeutics.

Bassett and Burdick were named to the Web of Science’s 2019 Highly Cited Researchers list as well.

Originally posted in Penn Engineering Today.

Jennifer Phillips-Cremins Wins CZI Grant to Study 3D Genome’s Role in Neurodegenerative Disease

The Chan Zuckerberg Initiative’s Collaborative Pairs Pilot Project Award is part of its Neurodegeneration Challenge Network

Jennifer Phillips-Cremins, Ph.D.

Read the full story on the Penn Engineering blog.

A Record 15 BE Students Receive 2020 NSF Graduate Research Fellowships

The Department of Bioengineering at Penn is incredibly proud of its fifteen current and future graduate student recipients of the 2020 National Science Foundation Graduate Research Fellowship Program (NSF GRFP). This total surpasses last year’s record of twelve students. In addition, one current student was selected for honorable mention and one additional incoming student has been named a Fullbright Scholar.

The prestigious NSF GRFP program recognizes and supports outstanding graduate students in NSF-supported fields. Further information about the program can be found on the NSF website. BE is thrilled to congratulate our excellent students on these well-deserved accolades! Continue reading below for a list of 2020 recipients and descriptions of their research.

Current Students:

William Benman

William Benman is a Ph.D. student in the lab of Assistant Professor of Bioengineering, Lukasz Bugaj. His work in the Bugaj lab focuses on developing novel optogenetic tools to control and study cell function.

Paul Gehret

Paul Gehret is a Ph.D. student and Ashton Fellow in the lab of Riccardo Gottardi, Assistant Professor of Pediatrics at the Perelman School of Medicine. Paul works on pediatric cartilage and airway tissue engineering for children with subglottic stenosis. He and his team apply classic tissue engineering principles to the airway.

Rebecca Haley

Rebecca Haley is a Ph.D. student in the lab of Michael J. Mitchell, Skirkanich Assistant Professor of Innovation in Bioengineering. Her current project aims to use polymer and/or lipid nanoparticles for the intracellular delivery of proteins. Successful delivery of proteins (such as antibodies) in this fashion may allow for targeting of previously undruggable intracellular targets.

Patrick John Mulcahey

Patrick John Mulcahey is a Research Assistant and Graduate Student in the Children’s Hospital of Philadelphia (CHOP) Epilepsy Research Lab of Douglas A. Coulter, Professor of Pediatrics at the Perelman School of Medicine. His work focuses on developing techniques that combine electrophysiology with two-photon excitation microscopy to study a potential biomarker of the seizure onset zone in models of drug-refractory epilepsy.

Catherine Porter

Catherine Porter is a Ph.D. student in the lab of Alex J. Hughes, Assistant Professor of Bioengineering. She is working on developing high-throughput methods to produce and characterize human-cell-derived kidney organoids for disease modeling and genetic screening. Currently, she is focused on engineering physicochemical control to improve organoid homogeneity.

Sarah Shepherd

Sarah Shepherd is a Ph.D. student who is co-advised in the Michael J. Mitchell lab and the lab of David Issadore, Associate Professor of Bioengineering and Electrical and Systems Engineering (ESE). Her research aims to combine microfabrication with biomaterial design of lipid nanoparticles to address major shortcomings in the field of nanomedicine. Currently, she is prototyping a scale-up microfluidic device to produce lipid nanoparticles for gene therapy.

Michael Tobin

Michael Tobin is a Ph.D. student in the lab of Dennis E. Discher, Robert D. Bent Professor of Chemical and Biomolecular Engineering (CBE), Bioengineering, and Mechanical Engineering and Applied Mechanics (MEAM). His current research examines phenomena leading to mechano-induced genomic variation in multiple cell subtypes. Through better understanding of characteristic pathways and subsequent cell responses, he hopes to improve treatments for malignant solid tumors.

John Viola, a Ph.D. student in the Hughes lab, was listed as an honorable mention.

Incoming Students:

Additionally, eight NSF GRFP honorees from other institutions will be joining our department in the fall of 2020. We congratulate them as well and look forward to welcoming them to Penn:

Finally, incoming Ph.D. student Dora Racca was awarded a Fullbright Scholarship. Dora will will have rotations in the BIOLines Laboratory of Dongeun (Dan) Huh, Associate Professor of Bioengineering and the McKay Orthopaedic Research Laboratory of Robert Mauck, Mary Black Ralston Professor of Orthopaedic Surgery and Professor of Bioengineering.

We would like to send congratulations once again to all our current and future graduate students on another year of outstanding research!

Penn BE Alumnus Helps Develop Rapid COVID-19 Test

Spencer Glantz (left) examines a scheme for light-activated protein cleavage with Dr. Brian Chow (middle) and 2014 iGEM team member Daniel Cabrera (right).

Spencer Glantz, a graduate of the Penn Bioengineering doctoral program and former member of the Brian Chow Lab, was mentioned in a recent WHYY piece highlighting the efforts of Penn labs to develop rapid, at-home testing for COVID-19. Glantz is currently a co-leader of the molecular biology team for 4Catalyzer, a medical device incubator founded by National Medal of Technology and Innovation recipient, and sponsor of the annual Rothberg Catalyzer Makerthon competition, Jonathan Rothberg. 4Catalyzer is developing the testing technology while Penn researchers are working to evaluate its effectiveness.

Glantz defended his Ph.D. in 2017 and went on to become a postdoc at the Jackson Laboratory (JAX). He was the recipient of the NSF GRFP Fellowship, and during his doctoral work, he discovered a new class of photoreceptors useful for controlling signaling at the cell membrane with light. During his time at Penn, Glantz also mentored the university’s iGEM team, bringing the annual program devoted to undergraduate-led innovation in synthetic biology to the University of Pennsylvania.

Read the full WHYY article here.

Week in BioE (July 9, 2018)

A New Treatment for Joint Dysfunction

TMD is a common condition affecting movement of the jaw

Medical researchers have long been baffled by the need to find safe and effective treatment for a common condition called temporomandibular joint dysfunction (TMD). Affecting around twenty-five percent of the adult population worldwide, TMD appears overwhelmingly in adolescent, premenopausal women. Many different factors such as injury, arthritis, or grinding of the teeth can lead to the disintegration of or damage to the temporomandibular joint (TMJ), which leads to TMD, although the root cause is not always clear. A type of temporomandibular disorder,  TMD can result in chronic pain in the jaw and ears, create difficulty eating and talking, and even cause occasional locking of the joint, making it difficult to open or close one’s mouth.  Surgery is often considered a last resort because the results are often short-lasting or even dangerous.

The state of TMD treatment may change with the publication of a study in Science Translational Medicine. With contributions from researchers at the University of California, Irvine (UCI), UC Davis, and the University of Texas School of Dentistry at Houston, this new study has successfully implanted engineered discs made from rib cartilage cells into a TMJ model. The biological properties of the discs are similar enough to native TMJ cells to more fully reduce further degeneration of the joint as well as potentially pave the way for regeneration of joints with TMD.

Senior author Kyriacos Athanasiou, PhD, Distinguished Professor of Biomedical Engineering at UCI, states the next steps for the team of researchers include a long-term study to ensure ongoing effectiveness and safety of the implants followed by eventual clinical trials. In the long run, this technique may also prove useful and relevant to the treatment of other types of arthritis and joint dysfunction.

Advances in Autism Research

Currently, diagnosis of autism spectrum disorders (ASD) has been limited entirely to clinical observation and examination by medical professionals. This makes the early identification and treatment of ASD difficult as most children cannot be accurately diagnosed until around the age of four, delaying the treatment they might receive. A recent study published in the journal of Bioengineering & Translational Medicine, however, suggests that new blood tests may be able to identify ASD with a high level of accuracy, increasing the early identification that is key to helping autistic children and their families. The researchers, led by Juergen Hahn, PhD, Professor and Department Head of Biomedical Engineering at the Rensselaer Polytechnic Institute, hope that after clinical trials this blood test will become commercially available.

In addition to work that shows methods to detect autism earlier, the most recent issue of Nature Biomedical Engineering includes a study to understand the possible causes of autism and, in turn, develop treatments for the disease. The breakthrough technology of Cas9 enzymes allowed researchers to edit the genome, correcting for symptoms that appeared in mice which resembled autism, including exaggerated and repetitive behaviors. This advance comes from a team at the University of California, Berkeley, which developed the gene-editing technique known as CRISPR-Gold to treat symptoms of ASD by injecting the Cas9 enzyme into the brain without the need for viral delivery. The UC Berkeley researchers suggest in the article’s abstract that these safe gene-editing technologies “may revolutionize the treatment of neurological diseases and the understanding of brain function.” These treatments may have practical benefits for the understanding and treatment of such diverse conditions as addiction and epilepsy as well as ASD.

Penn Professor’s Groundbreaking Bioengineering Technology

Our own D. Kacy Cullen, PhD, was recently featured in Penn Today for his groundbreaking research which has led to the first implantable tissue-engineered brain pathways. This technology could lead to the reversal of certain neurodegenerative disorders, such as Parkinson’s disease.

With three patents, at least eight published papers, $3.3 million in funding, and a productive go with the Penn Center for Innovation’s I-Corps program this past fall, Dr. Cullen is ready to take this project’s findings to the next level with the creation of a brand new startup company: Innervace. “It’s really surreal to think that I’ve been working on this project, this approach, for 10 years now,” he says. “It really was doggedness to just keep pushing in the lab, despite the challenges in getting extramural funding, despite the skepticism of peer reviewers. But we’ve shown that we’re able to do it, and that this is a viable technology.” Several Penn bioengineering students are involved in the research conducted in Dr. Cullen’s lab, including doctoral candidate Laura Struzyna and recent graduate Kate Panzer, who worked in the lab all four years of her undergraduate career.

In addition to his appointment as a Research Associate Professor of Neurosurgery at the Perelman School of Medicine at the University of Pennsylvania, Dr. Cullen also serves as a member of Penn’s Department of Bioengineering Graduate Group Faculty, and will teach the graduate course BE 502 (From Lab to Market Place) for the BE Department this fall 2018 semester. He also serves as the director for the Center of Neurotrauma, Neurodegeneration, and Restoration at the VA Medical Center.

New Prosthetics Will Have the Ability to Feel Pain

New research from the Department of Biomedical Engineering at Johns Hopkins University (JHU) has found a way to address one of the difficult aspects of amputation: the inability for prosthetic limbs to feel. This innovative electronic dermis is worn over the prosthetic, and can detect sensations (such as pain or even a light touch), which are conveyed to the user’s nervous system, closing mimicking skin. The findings of this study were recently published in the journal Science Robotics.

While one might wonder at the value of feeling pain, both researchers and amputees verify that physical sensory reception is important both for the desired realism of the prosthetic or bionic limb, and also to alert the wearer of any potential harm or damage, the same way that heat can remind a person to remove her hand from a hot surface, preventing a potential burn. Professor Nitish Thakor, PhD, and his team hope to make this exciting new technology readily available to amputees.

People and Places

Women are still vastly outnumbered in STEM, making up only twenty percent of the field, and given the need for diversification, researchers, educators, and companies are brainstorming ways to proactively solve this problem by promoting STEM subjects to young women. One current initiative has been spearheaded by GE Healthcare and Milwaukee School of Engineering University (MSOE) who are partnering to give middle school girls access to programs in engineering during their summer break at the MSOE Summer STEM Camp, hoping to reduce the stigma of these subjects for young women. GE Girls also hosts STEM programs with a number of institutions across the U.S.

The National Science Policy Network (NSPN) “works to provide a collaborative resource portal for early-career scientists and engineers involved in science policy, diplomacy, and advocacy.” The NSPN offers platforms and support including grant funding, internships, and competitions. Chaired and led by emerging researchers and professors from around the country, including biomedical engineering PhD student Michaela Rikard of the University of Virginia, the NSPN seeks to provide a network for young scientists in the current political climate in which scientific issues and the very importance of the sciences as a whole are hotly contested and debated by politicians and the public. The NSPN looks to provide a way for scientists to have a voice in policy-making. This new initiative was recently featured in the Scientific American.

Upon its original founding in 2000, the Bill and Melinda Gates Foundation has included the eradication of malaria as part of its mission, pledging around $2 billion to the cause in the years since. One of its most recent initiatives is the funding of a bioengineering project which targets the type of mosquitoes which carry the deadly disease. Engineered mosquitoes (so-called “Friendly Mosquitoes”) would mate in the wild, passing on a mosquito-killing gene to their female offspring (only females bite humans) before they reach maturity. While previous versions of “Friendly Mosquitoes” have been met with success, concerns have been raised about the potential long-term ecological effects to the mosquito population. UK-based partner Oxitec expects to have the new group ready for trials in two years.

 

Shoddy Science Uncovered in New Research

by Linda Tunesi

shoddy science
Konrad Kording, Ph.D.

Konrad Kording, professor in the Department of Bioengineering, and colleagues have a new technique for identifying fraudulent scientific papers by spotting reused images. Rather than scrap a failed study, for example, a researcher might attempt to pass off images from a different experiment to give the false impression that their own was a success.

Kording, a Penn Integrates Knowledge (PIK) Professor who also has an appointment in the Department of Neuroscience in Penn’s Perelman School of Medicine, and his collaborators developed an algorithm that can compare images across journal articles and detect such replicas, even if the image has been resized, rotated, or cropped.

They describe their technique in a paper recently published on the BioRxiv preprint server.

“Any fraudulent paper damages science,” Kording says. “In biology, many times fraud is detected when someone looks at a few papers and says ‘hey, these images look a little similar.’ We reckoned we could make an algorithm that does the same thing.”

“Science depends on building upon other people’s work,” adds Daniel Acuna, lead author on the paper, and a student in Kording’s lab at Northwestern University at the time the study was conducted. “If you cannot trust other people’s work, the scientific process collapses and, worse, the general public loses trust in us. Some websites were doing this, anonymously, but at a painstakingly slow rate.” Acuna is now an assistant professor in the School of Information Studies at Syracuse University.

While much of Kording’s work focuses on using data science to understand the brain, he is also curious about the process of research itself, or, as he puts it, “the science of science.” One of the Kording lab’s previous projects closely analyzed common methods of neuroscience research, and another turned a mirror on itself, describing how to structure a scientific paper.

Continued at the Penn Engineering Medium blog.