Shreya Parchure, a recent graduate of Penn Bioengineering, was selected by a committee of faculty for a 2021 Rose Award from the Center for Undergraduate Research and Fellowships (CURF). The Rose Award recognizes outstanding undergraduate research projects completed by graduating seniors under the supervision of a Penn faculty member and carries with it a $1,000 award. Parchure’s project, titled “BDNF Gene Polymorphism Predicts Response to Continuous Theta Burst Stimulation (cTBS) in Chronic Stroke Patients,” was done under the supervision of Roy H. Hamilton, Associate Professor in Neurology and Physical Medicine and Rehabilitation and director of the Laboratory for Cognition and Neural Stimulation in the Perelman School of Medicine. Parchure’s work in Hamilton’s lab previously resulted in a 2020 Goldwater Scholarship.
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.”
A.T. Charlie Johnson, Rebecca W. Bushnell Professor of Physics and Astronomy at the Penn School of Arts & Sciences, and member of the Penn Bioengineering Graduate Group has been working with a team of researchers on a new “electronic nose” that could help track the spread of COVID-19 based on the disease’s unique odor profile. Now, similar research shows that vapors emanating from blood samples can be tested to distinguish between benign and cancerous pancreatic and ovarian cells. Johnson presented the results at the annual American Society of Clinical Oncology meeting on June 4 (Abstract # 5544):
“It’s an early study but the results are very promising,” Johnson said. “The data shows we can identify these tumors at both advanced and the earliest stages, which is exciting. If developed appropriately for the clinical setting, this could potentially be a test that’s done on a standard blood draw that may be part of your annual physical.”
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.
César de la Fuente, PhD, Presidential Assistant Professor in Bioengineering, Chemical and Biomolecular Engineering, Psychiatry, and Microbiology, was featured in the Philadelphia Business Journal’s Class of 2021 “40 Under 40” list. Currently focused on antibiotic discovery, creating tools for microbiome engineering, and low-cost diagnostics, de le Fuente pioneered the world’s first computer-designed antibiotic with efficacy in animal models.
De la Fuente was previously included in the AIChE’s “35 Under 35” list in 2020 and most recently published his work demonstrating a rapid COVID-19 diagnostic test which delivers highly accurate results within four minutes.
Read “40 Under 40: Philadelphia Business Journal’s complete Class of 2021” here.
Read other BE blog posts featuring Dr. de la Fuente here.
RAPID, a low-cost COVID-19 diagnostic test, can detect SARS-CoV-2 within four minutes with 90 percent accuracy
Even as COVID-19 vaccinations are being rolled out, testing for active infections remains a critical tool in fighting the pandemic. Existing rapid tests that can directly detect the virus rely on reverse transcription polymerase chain reaction (RT-PCR), a common genetic assay that nevertheless requires trained technicians and lab space to conduct.
Alternative testing methods that can be scaled up and deployed in places where those are in short supply are therefore in high demand.
Penn researchers have now demonstrated such a method, which senses the virus by measuring the change in an electrical signal when a piece of the SARS-CoV-2 virus binds to a biosensor in their device, which they call RAPID 1.0.
The work, published in the journal Matter, was led by César de la Fuente, a Presidential Assistant Professor who has appointments in Engineering’s departments of Chemical and Biomolecular Engineering, and Bioengineering, as well as in Psychiatry and Microbiology in the Perelman School of Medicine.
“Prior to the pandemic, our lab was working on diagnostics for bacterial infections. But then, COVID-19 hit. We felt a responsibility to use our expertise to help—and the diagnostic space was ripe for improvements,” de la Fuente said. “We feel strongly about the health inequities witnessed during the pandemic, with testing access and the vaccine rollout, for example. We believe inexpensive diagnostic tests like RAPID could help bridge some of those gaps.”
The RAPID technology uses electrochemical impedance spectroscopy (EIS), which transforms the binding event between the SARS-CoV-2 viral spike protein and its receptor in the human body, the protein ACE2 (which provides the entry point for the coronavirus to hook into and infect human cells), into an electrical signal that clinicians and technicians can detect. That signal allows the test to discriminate between infected and healthy human samples. The signal can be read through a desktop instrument or a smartphone.
Carl June, MD, the Richard W. Vague Professor in Immunotherapy in the department of Pathology and Laboratory Medicine in the Perelman School of Medicine at the University of Pennsylvania, director of the Center for Cellular Immunotherapies at Penn’s Abramson Cancer Center, and member of the Penn Bioengineering Graduate Group, received the $1 million Sanford Lorraine Cross Award for his groundbreaking work in developing chimeric antigen receptor (CAR) T cell therapy. June is a world renowned cancer cell therapy pioneer.
“Sanford Health, the only health system in the country to award a $1 million prize for achievements in the medical sciences, announced the award on April 13 at a special ceremony in Sioux Falls, South Dakota. The biennial award recognizes life-changing breakthroughs and bringing emerging transformative medical innovations to patients.
‘This is a well-deserved and exciting award for one of Penn’s most distinguished faculty members, whose pioneering research has reshaped the fight against cancer and brought fresh hope for both adults and children with the disease,’ said J. Larry Jameson, MD, PhD, Executive Vice President of the University of Pennsylvania for the Health System and Dean of the Perelman School of Medicine. ‘His contributions truly have been transformative for patients across the globe and taken the field of oncology in new and powerful directions.'”
As we age, the cushioning cartilage between our joints begins to wear down, making it harder and more painful to move. Known as osteoathritis, this extremely common condition has no known cure; if the symptoms can’t be managed, the affected joints must be surgically replaced.
Now, researchers are exploring whether their specially designed nanoparticles can deliver a new inflammation inhibitor to joints, targeting a previously overlooked enzyme called sPLA2.
The normal function of sPLA2 is to provide lipids (fats) that promote a variety of inflammation processes. The enzyme is always present in cartilage tissue, but typically in low levels. However, when the researchers examined mouse and human cartilage taken from those with osteoarthritis, disproportionately high levels of the enzyme were discovered within the tissue’s structure and cells.
“This marked increase strongly suggests that sPLA2 plays a role in the development of osteoarthritis,” said the study’s corresponding author, Zhiliang Cheng, PhD, a research associate professor of Bioengineering. “Being able to demonstrate this showed that we were on the right track for what could be a potent target for the disease.”
The next step was for the study team – which included lead author Yulong Wei, MD, a researcher in Penn Medicine’s McKay Orthopaedic Research Laboratory – to put together a nanoparticle loaded with an sPLA2 inhibitor. This would block the activity of sPLA2 enzyme and, they believed, inflammation. These nanoparticles were mixed with animal knee cartilage in a lab, then observed as they diffused deeply into the dense cartilage tissue. As time progressed, the team saw that the nanoparticles stayed there and did not degrade significantly or disappear. This was important for the type of treatment the team envisioned.
New research from Robert Mauck, Mary Black Ralston Professor in Orthopaedic Surgery and Bioengineering and Director of Penn Medicine’s McKay Orthopaedic Research Laboratory, announces a “new biosealant therapy may help to stabilize injuries that cause cartilage to break down, paving the way for a future fix or – even better – begin working right away with new cells to enhance healing.” Their research was published in Advanced Healthcare Materials. The study’s lead author was Jay Patel, a former postdoctoral fellow in the McKay Lab and now Assistant Professor at Emory University and was contributed to by Claudia Loebel, a postdoctoral research in the Burdick lab and who will begin an appointment as Assistant Professor at the University of Michigan in Fall 2021. In addition, the technology detailed in this publication is at the heart of a new company (Forsagen LLC) spun out of Penn with support from the Penn Center for Innovation (PCI) Ventures Program, which will attempt to spearhead the system’s entry into the clinic. It is co-founded by both Mauck and Patel, along with study co-author Jason Burdick, Professor in Bioengineering, and Ana Peredo, a PhD student in Bioengineering.
César de la Fuente, Ph.D., a Presidential Assistant Professor in Psychiatry, Microbiology, and Bioengineering, is leading a team to develop an electrode that can be easily printed at low cost to provide COVID-19 test results from your smart phone.
A recent Penn Medicine blog post surveys the efforts across Penn and the Perelman School of Medicine to develop novel says to detect SARS-CoV-2 and features several Department of Bioengineering faculty and Graduate Group members, including César de la Fuente, Presidential Assistant Professor in Psychiatry, Microbiology, and Bioengineering; Arupa Ganguly, Professor in Genetics; A.T. Charlie Johnson, Rebecca W. Bushnell Professor in Physics and Astronomy; Lyle Ungar, Professor in Computer and Information Science; and Ping Wang, Associate Professor in Pathology and Laboratory Medicine.
Read “We’ll Need More than Vaccines to Vanquish the Virus: New COVID-19 Testing Technology at Penn” by Melissa Moodyin Penn Medicine News.
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