A cross-disciplinary Penn team is pioneering a new approach to peripheral nerve repair.
In a new publication in the journal npjRegenerative Medicine, a team of Penn researchers from the School of Dental Medicine and the Perelman School of Medicine “coaxed human gingiva-derived mesenchymal stem cells (GMSCs) to grow Schwann-like cells, the pro-regenerative cells of the peripheral nervous system that make myelin and neural growth factors,” addressing the need for regrowing functional nerves involving commercially-available scaffolds to guide nerve growth. The study was led by Anh Le, Chair and Norman Vine Endowed Professor of Oral Rehabilitation in the Department of Oral and Maxillofacial Surgery/Pharmacology at the University of Pennsylvania School of Dental Medicine, and was co-authored by D. Kacy Cullen, Associate Professor in Neurosurgery at the Perelman School of Medicine at Penn and the Philadelphia Veterans Affairs Medical Center and member of the Bioengineering Graduate Group:
D. Kacy Cullen (Image: Eric Sucar)
“To get host Schwann cells all throughout a bioscaffold, you’re basically approximating natural nerve repair,” Cullen says. Indeed, when Le and Cullen’s groups collaborated to implant these grafts into rodents with a facial nerve injury and then tested the results, they saw evidence of a functional repair. The animals had less facial droop than those that received an “empty” graft and nerve conduction was restored. The implanted stem cells also survived in the animals for months following the transplant.
“The animals that received nerve conduits laden with the infused cells had a performance that matched the group that received an autograft for their repair,” he says. “When you’re able to match the performance of the gold-standard procedure without a second surgery to acquire the autograft, that is definitely a technology to pursue further.”
Read the full story and view the full list of collaborators in Penn Today.
George Floyd’s murder had an undeniable emotional impact on people around the world, as evidenced by this memorial mural in Berlin, but quantifying that impact is challenging. Researchers from Penn Engineering and Stanford have used a computational approach on U.S. survey data to break down this emotional toll along racial and geographic lines. Their results show a significantly larger amount of self-reported anger and sadness among Black Americans than their White counterparts. (Photo: Leonhard Lenz)
The murder of George Floyd, an unarmed Black man who was killed by a White police officer, affected the mental well-being of many Americans. The effects were multifaceted as it was an act of police brutality and example of systemic racism that occurred during the uncertainty of a global pandemic, creating an even more complex dynamic and emotional response.
Because poor mental health can lead to a myriad of additional ailments, including poor physical health, inability to hold a job and an overall decrease in quality of life, it is important to understand how certain events affect it. This is especially critical when the emotional burden of these events falls most on demographics affected by systemic racism. However, unlike physical health, mental health is challenging to characterize and measure, and thus, population-level data on mental health has been limited.
To better understand patterns of mental health on a population scale, Penn Engineers Lyle H. Ungar, Professor of Computer and Information Science (CIS), and Sharath Chandra Guntuku, Research Assistant Professor in CIS, take a computational approach to this challenge. Drawing on large-scale surveys as well as language analysis in social media through their work with the World Well-Being Project, they have developed visualizations of these patterns across the U.S.
Their latest study involves tracking changes in emotional and mental health following George Floyd’s murder. Combining polling data from the U.S. Census and Gallup, Guntuku, Ungar and colleagues have shown that Floyd’s murder spiked a wave of unprecedented sadness and anger across the U.S. population, the largest since relevant data began being recorded in 2009.
New collaborative research describes how electrons move through two different configurations of bilayer graphene, the atomically-thin form of carbon. These results provide insights that researchers could use to design more powerful and secure quantum computing platforms in the future.
“Today’s computer chips are based on our knowledge of how electrons move in semiconductors, specifically silicon,” says first and co-corresponding author Zhongwei Dai, a postdoc at Brookhaven. “But the physical properties of silicon are reaching a physical limit in terms of how small transistors can be made and how many can fit on a chip. If we can understand how electrons move at the small scale of a few nanometers in the reduced dimensions of 2-D materials, we may be able to unlock another way to utilize electrons for quantum information science.”
When a material is designed at these small scales, to the size of a few nanometers, it confines the electrons to a space with dimensions that are the same as its own wavelength, causing the material’s overall electronic and optical properties to change in a process called quantum confinement. In this study, the researchers used graphene to study these confinement effects in both electrons and photons, or particles of light.
The work relied upon two advances developed independently at Penn and Brookhaven. Researchers at Penn, including Zhaoli Gao, a former postdoc in the lab of Charlie Johnson who is now at The Chinese University of Hong Kong, used a unique gradient-alloy growth substrate to grow graphene with three different domain structures: single layer, Bernal stacked bilayer, and twisted bilayer. The graphene material was then transferred onto a special substrate developed at Brookhaven that allowed the researchers to probe both electronic and optical resonances of the system.
“This is a very nice piece of collaborative work,” says Johnson. “It brings together exceptional capabilities from Brookhaven and Penn that allow us to make important measurements and discoveries that none of us could do on our own.”
A new study from the Addiction, Health, & Adolescence (AHA!) Lab at the Annenberg School for Communication at the University of Pennsylvania found that men are over-cited and women are under-cited in the field of Communication. The researchers’ findings indicate that this problem is most persistent in papers authored by men.
“Despite known limitations in their use as proxies for research quality, we often turn to citations as a way to measure the impact of someone’s research,” says Professor David Lydon-Staley, “so it matters for individual researchers if one group is being consistently under-cited relative to another group. But it also matters for the field in the sense that if people are not citing women as much as men, then we’re building the field on the work of men and not the work of women. Our field should be representative of all of the excellent research that is being undertaken, and not just that of one group.”
The AHA! Lab is led by David Lydon-Staley, Assistant Professor of Communication and former postdoc in the Complex Systems lab of Danielle Bassett, J. Peter Skirkanich Professor in Bioengineering and in Electrical and Systems Engineering in the School of Engineering and Applied Science. Dr. Bassett and Bassett Lab members Dale Zhou and Jennifer Stiso, graduate students in the Perelman School of Medicine, also contributed to the study.
Scanning electron microscope images of endotracheal tubes at three levels of magnification. After 24 hours of Staphylococcus epidermidis exposure, tubes coated with the researchers’ AMPs (right) showed decreased biofilm production, as compared with tubes coated with just polymer (center) and uncoated tubes (left).
Endotracheal tubes are a mainstay of hospital care, as they ensure a patient’s airway is clear when they can’t breathe on their own. However, keeping a foreign object inserted in this highly sensitive part of the anatomy comes is not without risk, such as the possibility of infection, inflammation and a condition known as subglottic stenosis, in which scar tissue narrows the airway.
Broad-spectrum antibiotics are one way to mitigate these risks, but come with risks of their own, including harming beneficial bacteria and contributing to antibiotic resistance.
With this conundrum in mind, Riccardo Gottardi, Assistant Professor of Pediatrics at the Children’s Hospital of Philadelphia (CHOP) and of Bioengineering at Penn Engineering, along with Bioengineering graduate students and lab members Matthew Aronson and Paul Gehret, are developing endotracheal tubes that can provide a more targeted antimicrobial defense.
In a proof-of-concept study published in the journal The Laryngoscope, the team showed how a different type of antimicrobial agent could be incorporated into the tubes’ polymer coating, as well as preliminary results suggesting these devices would better preserve a patient’s microbiome.
Instead, the investigators explored the use of antimicrobial peptides (AMPs), which are small proteins that destabilize bacterial membranes, causing bacterial cells to fall apart and die. This mechanism of action allows them to target specific bacteria and makes them unlikely to promote antimicrobial resistance. Prior studies have shown that it is possible to coat endotracheal tubes with conventional antibiotics, so the research team investigated the possibility of incorporating AMPs into polymer-coated tubes to inhibit bacterial growth and modulate the upper-airway microbiome.
The researchers, led by Matthew Aronson, a graduate student in Penn Engineering’s Department of Bioengineering, tested their theory by creating a polymer coating that would release Lasioglossin-III, an AMP with broad-spectrum antibacterial activity. They found that Lasio released from coated endotracheal tubes, reached the expected effective concentration rapidly and continued to release at the same concentration for a week, which is the typical timeframe that an endotracheal is used before being changed. The investigators also tested their drug-eluting tube against airway microbes, including S. epidermidis, S. pneumoniae, and human microbiome samples and observed significant antibacterial activity, as well as prevention of bacterial adherence to the tube.
Read “CHOP Researchers Develop Coating for Endotracheal Tubes that Releases Antimicrobial Peptides” at CHOP News.
A collaborative study finds that deeper regions of the brain encode visual information more slowly, enabling the brain to identify fast-moving objects and images more accurately and persistently.
by Erica K. Brockmeier
Busy pedestrian crossing at Hong Kong
New research from the University of Pennsylvania, the Scuola Internazionale Superiore de Studi Avanzati (SISSA), and KU Leuven details the time scales of visual information processing across different regions of the brain. Using state-of-the-art experimental and analytical techniques, the researchers found that deeper regions of the brain encode visual information slowly and persistently, which provides a mechanism for explaining how the brain accurately identifies fast-moving objects and images. The findings were published in Nature Communications.
Understanding how the brain works is a major research challenge, with many theories and models developed to explain how complex information is processed and represented. One area of particular interest is vision, a major component of neural activity. In humans, for example, there is evidence that around half of the neurons in the cortex are related to vision.
Researchers are eager to understand how the visual cortex can process and retain information about objects in motion in a way that allows people to take in dynamic scenes while still retaining information about and recognizing the objects around them.
“One of the biggest challenges of all the sensory systems is to maintain a consistent representation of our surroundings, despite the constant changes taking place around us. The same holds true for the visual system,” says Davide Zoccolan, director of SISSA’s Visual Neuroscience Laboratory. “Just look around us: objects, animals, people, all on the move. We ourselves are moving. This triggers rapid fluctuations in the signals acquired by the retina, and until now it was unclear whether the same type of variations apply to the deeper layers of the visual cortex, where information is integrated and processed. If this was the case, we would live in tremendous confusion.”
Experiments using static stimuli, such as photographs, have found that information from the sensory periphery are processed in the visual cortex according to a finely tuned hierarchy. Deeper regions of the brain then translate this information about visual scenes into more complex shapes, objects, and concepts. But how this process works in more dynamic, real-world settings is not well understood.
To shed light on this, the researchers analyzed neural activity patterns in multiple visual cortical areas in rodents while they were being shown dynamic visual stimuli. “We used three distinct datasets: one from SISSA, one from a group in KU Leuven led by Hans Op de Beeck and one from the Allen Institute for Brain Science in Seattle,” says Zoccolan. “The visual stimuli used in each were of different types. In SISSA, we created dedicated video clips showing objects moving at different speeds. The other datasets were acquired using various kinds of clips, including from films.”
Next, the researchers analyzed the signals registered in different areas of the visual cortex through a combination of sophisticated algorithms and models developed by Penn’s Eugenio Pasini and Vijay Balasubramanian. To do this, the researchers developed a theoretical framework to help connect the images in the movies to the activity of specific neurons in order to determine how neural signals evolve over different time scales.
“The art in this science was figuring out an analysis method to show that the processing of visual images is getting slower as you go deeper and deeper in the brain,” says Balasubramanian. “Different levels of the brain process information over different time scales; some things could be more stable, some quicker. It’s very hard to tell if the time scales across the brain are changing, so our contribution was to devise a method for doing this.”
Vijay Balasubramanian is the Cathy and Marc Lasry Professor in the Department of Physics and Astronomy in the School of Arts & Sciences and a member of the Penn Bioengineering Graduate Group at the University of Pennsylvania.
Colin Huber, a Ph.D. candidate in Bioengineering studying head impact biomechanics and concussion in sports at the Center for Injury Research and Prevention (CIRP) at the Children’s Hospital of Philadelphia (CHOP), recently published “Variations in Head Impact Rates in Male and Female High School Soccer” in Medicine & Science in Sports & Exercise with colleagues from CHOP’s Minds Matter Concussion Frontier Program and the CIRP.
Colin’s paper, the goal of which was to compare “to compare head impact exposure rates (head impacts/exposure period) in male and female high school soccer by using multiple methodological approaches,” was recently profiled in the Penn Engineering Research & Innovation Newsletter.
Michael Mitchell, Sarah Shepherd and David Issadore pose with their new device.
The COVID vaccines currently being deployed were developed with unprecedented speed, but the mRNA technology at work in some of them is an equally impressive success story. Because any desired mRNA sequence can be synthesized in massive quantities, one of the biggest hurdles in a variety of mRNA therapies is the ability to package those sequences into the lipid nanoparticles that deliver them into cells.
Now, thanks to manufacturing technology developed by bioengineers and medical researchers at the University of Pennsylvania, a hundred-fold increase in current microfluidic production rates may soon be possible.
The researchers’ advance stems from their design of a proof-of-concept microfluidic device containing 128 mixing channels working in parallel. The channels mix a precise amount of lipid and mRNA, essentially crafting individual lipid nanoparticles on a miniaturized assembly line.
This increased speed may not be the only benefit; more precisely controlling the nanoparticles’ size could make treatments more effective. The researchers tested the lipid nanoparticles produced by their device in a mouse study, showing they could deliver therapeutic RNA sequences with four-to-five times greater activity than those made by conventional methods.
The study was led by Michael Mitchell, Skirkanich Assistant Professor of Innovation in Penn Engineering’s Department of Bioengineering, and David Issadore, Associate Professor in Penn Engineering’s Department of Bioengineering, along with Sarah Shepherd, a doctoral student in both of their labs. Rakan El-Mayta, a research engineer in Mitchell’s lab, and Sagar Yadavali, a postdoctoral researcher in Issadore’s lab, also contributed to the study.
They collaborated with several researchers at Penn’s Perelman School of Medicine: postdoctoral researcher Mohamad-Gabriel Alameh, Lili Wang, Research Associate Professor of Medicine, James M. Wilson, Rose H. Weiss Orphan Disease Center Director’s Professor in the Department of Medicine, Claude Warzecha, a senior research investigator in Wilson’s lab, and Drew Weissman, Professor of Medicine and one of the original developers of the technology behind mRNA vaccines.
“We believe that this microfluidic technology has the potential to not only play a key role in the formulation of current COVID vaccines,” says Mitchell, “but also to potentially address the immense need ahead of us as mRNA technology expands into additional classes of therapeutics.”
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.
Researchers from Penn and CHOP detail the mechanism by which HIV infection blocks the maturation process of brain cells that produce myelin, a fatty substance that insulates neurons.
A confocal microscope image shows an oligodendrocyte in cell culture, labeled to show the cell nucleus in blue and myelin proteins in red, green, and yellow. Researchers from Penn and CHOP have shown that HIV infection prevents oligodendrocytes from maturing, leading to a reduction in white matter in the brain. (Image: Raj Putatunda)
It’s long been known that people living with HIV experience a loss of white matter in their brains. As opposed to gray matter, which is composed of the cell bodies of neurons, white matter is made up of a fatty substance called myelin that coats neurons, offering protection and helping them transmit signals quickly and efficiently. A reduction in white matter is associated with motor and cognitive impairment.
Earlier work by a team from the University of Pennsylvania and Children’s Hospital of Philadelphia (CHOP) found that antiretroviral therapy (ART)—the lifesaving suite of drugs that many people with HIV use daily—can reduce white matter, but it wasn’t clear how the virus itself contributed to this loss.
In a new study using both human and rodent cells, the team has hammered out a detailed mechanism, revealing how HIV prevents the myelin-making brain cells called oligodendrocytes from maturing, thus putting a wrench in white matter production. When the researchers applied a compound blocking this process, the cells were once again able to mature.
“Even when people with HIV have their disease well-controlled by antiretrovirals, they still have the virus present in their bodies, so this study came out of our interest in understanding how HIV infection itself affects white matter,” says Kelly Jordan-Sciutto, a professor in Penn’s School of Dental Medicine and co-senior author on the study. “By understanding those mechanisms, we can take the next step to protect people with HIV infection from these impacts.”
“When people think about the brain, they think of neurons, but they often don’t think about white matter, as important as it is,” says Judith Grinspan, a research scientist at CHOP and the study’s other co-senior author. “But it’s clear that myelination is playing key roles in various stages of life: in infancy, in adolescence, and likely during learning in adulthood too. The more we find out about this biology, the more we can do to prevent white matter loss and the harms that can cause.”
Jordan-Sciutto and Grinspan have been collaborating for several years to elucidate how ART and HIV affect the brain, and specifically oligodendrocytes, a focus of Grinspan’s research. Their previous work on antiretrovirals had shown that commonly used drugs disrupted the function of oligodendrocytes, reducing myelin formation.
In the current study, they aimed to isolate the effect of HIV on this process. Led by Lindsay Roth, who recently earned her doctoral degree within the Biomedical Graduate Studies group at Penn and completed a postdoctoral fellowship working with Jordan-Sciutto and Grinspan, the investigation began by looking at human macrophages, one of the major cell types that HIV infects.
Kelly Jordan-Sciutto is vice chair and professor in the University of Pennsylvania School of Dental Medicine’s Department of Basic & Translational Sciences and is director of Biomedical Graduate Studies. She is a member of the Penn Bioengineering Graduate Group.
