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Magnetic Field and Hydrogels Could Be Used to Grow New Cartilage

by Frank Otto

MRI Knee joint or Magnetic resonance imaging sagittal view for detect tear or sprain of the anterior cruciate ligament (ACL).

Using a magnetic field and hydrogels, a team of researchers in the Perelman School of Medicine have demonstrated a new possible way to rebuild complex body tissues, which could result in more lasting fixes to common injuries, such as cartilage degeneration. This research was published in Advanced Materials.

“We found that we were able to arrange objects, such as cells, in ways that could generate new, complex tissues without having to alter the cells themselves,” says the study’s first author, Hannah Zlotnick, a graduate student in bioengineering who works in the McKay Orthopaedic Research Laboratory at Penn Medicine. “Others have had to add magnetic particles to the cells so that they respond to a magnetic field, but that approach can have unwanted long-term effects on cell health. Instead, we manipulated the magnetic character of the environment surrounding the cells, allowing us to arrange the objects with magnets.”

In humans, tissues like cartilage can often break down, causing joint instability or pain. Often, the breakdown isn’t in total, but covers an area, forming a hole. Current fixes are to fill those holes in with synthetic or biologic materials, which can work but often wear away because they are not the same exact material as what was there before. It’s similar to fixing a pothole in a road by filling it with gravel and making a tar patch: The hole will be smoothed out but eventually wear away with use because it’s not the same material and can’t bond the same way.

What complicates fixing cartilage or other similar tissues is that their makeup is complex.

“There is a natural gradient from the top of cartilage to the bottom, where it contacts the bone,” Zlotnick explains. “Superficially, or at the surface, cartilage has a high cellularity, meaning there is a higher number of cells. But where cartilage attaches to the bone, deeper inside, its cellularity is low.”

So the researchers, which included senior author Robert Mauck, PhD, director of the McKay Lab and a professor of Orthopaedic Surgery and Bioengineering, sought to find a way to fix the potholes by repaving them instead of filling them in. With that in mind, the research team found that if they added a magnetic liquid to a three-dimensional hydrogel solution, cells, and other non-magnetic objects including drug delivery microcapsules, could be arranged into specific patterns that mimicked natural tissue through the use of an external magnetic field.

Read more at Penn Medicine News.

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Neuroengineering/Bioengineering Seminar: “Photovoltaic Restoration of Sight in Age-related Macular Degeneration” (Daniel Palanker)

Daniel Palanker, PhD

The Center for Neuroengineering and Therapeutics and the Department of Bioengineering present:

Speaker: Daniel Palanker, Ph.D.
Director of the Hansen Experimental Physics Laboratory and Professor of Ophthalmology
Stanford University

Date: Wednesday, November 18, 2020
Time: 1:00-2:00 PM EST
Zoom – check email for link or contact eprince@seas.upenn.edu

Title: “Photovoltaic Restoration of Sight in Age-related Macular Degeneration”

Abstract:

Retinal degenerative diseases lead to blindness due to loss of the “image capturing” photoreceptors, while neurons in the “image-processing” inner retinal layers are relatively well preserved. Information can be reintroduced into the visual system using electrical stimulation of the surviving inner retinal neurons. We developed a photovoltaic substitute of photoreceptors which convert light into pulsed electric current, stimulating the secondary retinal neurons. Visual information captured by a camera is projected onto the retina from augmented-reality glasses using pulsed near-infrared (~880nm) light. This design avoids the use of bulky electronics and wiring, thereby greatly reducing the surgical complexity. Optical activation of the photovoltaic pixels allows scaling the number of electrodes to thousands. In preclinical studies, we found that prosthetic vision with subretinal implants preserves many features of natural vision, including flicker fusion at high frequencies (>30 Hz), adaptation to static images, antagonistic center-surround organization and non-linear summation of subunits in receptive fields, providing high spatial resolution. Results of the clinical trial with our implants (PRIMA, Pixium Vision) having 100μm pixels, as well as preclinical measurements with 75 and 55μm pixels, confirm that spatial resolution of prosthetic vision can reach the pixel pitch. Remarkably, central prosthetic vision in AMD patients can be perceived simultaneously with peripheral natural vision. For broader acceptance of this technology by patients who lost central vision due to agerelated macular degeneration, visual acuity should exceed 20/100, which requires pixels smaller than 25μm. I will describe the fundamental limitations in electro-neural interfaces and 3-dimensional configurations which should enable such a high spatial resolution. Ease of implantation of these wireless arrays, combined with high resolution opens the door to highly functional restoration of sight.

Bio:

Daniel Palanker is a Professor of Ophthalmology and Director of the Hansen Experimental Physics Laboratory at Stanford University. He received MSc in Physics in 1984 from the State University of Armenia in Yerevan, and PhD in Applied Physics in 1994 from the Hebrew University of Jerusalem, Israel. Dr. Palanker studies interactions of electrical field with biological cells and tissues, and develops optical and electronic technologies for diagnostic, therapeutic, surgical and prosthetic applications, primarily in ophthalmology. In the range of optical frequencies, his studies include laser-tissue interactions with applications to ocular therapy and surgery, and interferometric imaging of neural signals. In the field of electro-neural interfaces, he is developing highresolution photovoltaic retinal prosthesis for restoration of sight and implants for electronic control of organs. Several of his developments are in clinical practice world-wide: Pulsed Electron Avalanche Knife (PEAK PlasmaBlade, Medtronic), Patterened Scanning Laser Photocoagulator (PASCAL, Topcon), Femtosecond Laser-assisted Cataract Surgery (Catalys, J&J), and Neural Stimulator for enhancement of tear secretion (TrueTear, Allergan). Photovoltaic retinal prosthesis for restoration of sight (PRIMA, Pixium Vision) is in clinical trials.

See the full list of upcoming Penn Bioengineering events here.

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Immunology/BE Seminar: “Engineering Next-Generation CAR-T Cells for Cancer Immunotherapy” (Yvonne Chen)

Yvonne Chen, PhD

This event is part of the Penn Institute for Immunology Colloquium seminar series in conjunction with the Department of Bioengineering.

Speaker: Yvonne Chen, Ph.D.
Associate Professor, Microbiology, Immunology & Molecular Genetics
University of California, Los Angeles

Date: Tuesday, November 17, 2020
Time: 4:00-5:00 PM EST
This event will be held virtually on Bluejeans.

Title: “Engineering Next-Generation CAR-T Cells for Cancer Immunotherapy”

Abstract:

The adoptive transfer of T cells expressing chimeric antigen receptors (CARs) has demonstrated clinical efficacy in the treatment of advanced cancers, with anti-CD19 CAR-T cells achieving up to 90% complete remission among patients with relapsed B-cell malignancies. However, challenges such as antigen escape and immunosuppression limit the long-term efficacy of adoptive T-cell therapy. Here, I will discuss the development of next-generation T cells that can target multiple cancer antigens and resist immunosuppression, thereby increasing the robustness of therapeutic T cells against tumor defense mechanisms. Specifically, I will discuss the development of multi-input receptors and T cells that can interrogate intracellular antigens. I will also discuss the engineering of T cells that can effectively convert TGF-beta from a potent immunosuppressive cytokine into a T-cell stimulant. This presentation will highlight the potential of synthetic biology in generating novel mammalian cell systems with multifunctional outputs for therapeutic applications.

Bio:

Dr. Yvonne Chen is an Associate Professor of Microbiology, Immunology, and Molecular Genetics at the University of California, Los Angeles. She is also a faculty, by courtesy, in the Department of Chemical and Biomolecular Engineering. The Chen Laboratory focuses on applying synthetic biology and biomolecular engineering techniques to the development of novel mammalian-cell systems. The Chen Lab’s work on engineering next-generation T-cell therapies for cancer has been recognized by the NIH Director’s Early Independence Award, the NSF CAREER Award, the Hellman Fellowship, the ACGT Young Investigator Award in Cell and Gene Therapy for Cancer, the Mark Foundation Emerging Leader Award, and the Cancer Research Institute Lloyd J. Old STAR Award. Prior to joining UCLA in 2013, Yvonne was a Junior Fellow in the Harvard Society of Fellows. She received postdoctoral training at the Center for Childhood Cancer Research within the Seattle Children’s Research Institute, and in the Department of Systems Biology at Harvard Medical School. Yvonne received her B.S. in Chemical Engineering from Stanford University and her Ph.D. in Chemical Engineering from the California Institute of Technology.

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An Ecosystem of Innovation Fosters Tech-based Solutions to COVID-19 Challenges

by Erica K. Brockmeier

GRASP lab researchers (from left) Bernd Pfrommer, Kenneth Chaney, and Caio Mucchiani assembling telemedicine cart prototypes in Levine hall earlier this spring. (Image courtesy of Kenneth Chaney and Bernd Pfrommer)

Since the start of the spring, members of the Penn community have been working to combat coronavirus and its many impacts. Some people are studying COVID-19 or developing vaccines, while others are 3D-printing face shields for health care workers and delivering fall courses online.

And while innovation in health care usually brings to mind new treatments and medicines, the efforts of clinicians, engineers, and IT specialists demonstrate the importance technological infrastructure for rapidly deployable, tech-based solutions so clinicians can provide the best care to patients amid social distancing and coronavirus restrictions.

The telemedicine revolution

In late March, telemedicine was key for allowing Penn Medicine clinicians to deliver care while avoiding potentially risky in-person interactions. Chief Medical Information Officer C. William Hanson III and his team helped set up the IT infrastructure for scaling up telemedicine capabilities and provided guidance to clinicians. Thanks to the quick pivot, Penn Medicine went from 300 telemedicine visits in February to more than 7,500 visits per day in a matter of weeks.

But far from seeing telemedicine as a temporary solution during the pandemic, Hanson has been a long-time advocate for this approach to health care. In his role as liaison between clinicians and the IT community in the past 10 years Hanson, helped establish remote ICU monitoring protocols and broadened opportunities for televisits with specialists. Now, with the pandemic removing many of the previous barriers to entry, be they technical, insurance-based, or simply a lack of familiarity, Hanson believes that telemedicine is here to stay.

“As the pandemic evolved, people were aware that telemedicine could help the health care system, as well as doctors and patients, during this crisis,” he says. “Now, there are definitely places where telemedicine makes good sense, and we will continue to use that as part of our way of handling a problem.” Other benefits include removing geographic barriers to entry for new patients, reduced appointment times, increased patient satisfaction, and reduced health care provider burnout.

Simple solutions for COVID-19 challenges

As the director of Penn’s Telestroke Program, neurologist Michael Mullen has experience diagnosing from a distance. This spring, telemedicine carts his group uses were repurposed in COVID ICUs. At the same time, Mullen and group wanted to expand their ability to assess stroke patients remotely, so he reached out to Brian Litt, faculty director of Penn Health-Tech, to see how he could collaborate to create an analogous telemedicine station using readily available, cost-effective components.

Rapid and simple solutions are at the heart of Penn’s ModLab, a subgroup of the GRASP lab focused on robots made of configurable individual components. As part of a COVID-19 rapid response initiative, engineers worked with Mullen to figure out a viable solution in record time. “The idea was to make it as simple and as fast as possible,” says graduate student Caio Mucchiani. “With robotics, usually you want to make things more sophisticated, however, given the situation, we needed to know how we could use off-the-shelf components to make something.”

Fellow graduate student Ken Chaney, postdoc Bernd Pfrommer, and Mucchiani came up with a plan that replicated the required specs of the existing telemedicine carts, including state-of-the-art cameras for detailed imaging as well as a reliable, easily rechargeable battery. The team then put together 10 telemedicine carts, assembling the prototypes with social distancing and masks at the GRASP lab in early April.

While changes to treatment approaches mean that these carts still require additional field testing, Mullen is still eager to expand the program, be it for diagnosing patients safely or educating medical students in an era of social distancing. “In the setting of COVID, when everything was getting crazy, it was remarkable to see the energy that GRASP brought to help,” adds Mullen. “Everyone was really busy, and it was amazing to see this group of people who wanted to use their expertise to help.”

Continue reading at Penn Today.

NB: Brian Litt is Professor in Neurology and Bioengineering.

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Through Brain Imaging Analysis in Rats, Penn Researchers Show Potential to Predict Whether Pain Will be Acute or Persistent

Beth Winkelstein, Megan Sperry, and Eric Granquist

Pain may be a universal experience, but what actually causes that experience within our brains is still poorly understood. Pain often continues long after the relevant receptors in the body have stopped being stimulated and can persist even after those receptors cease to exist, as is the case with “phantom limb” pain.

The exact experience an individual will have after a painful incident comes down to the complex, variable connections formed between several different parts of the brain. The inability to predict how those connections will form and evolve can make pain management a tricky, frustrating endeavor for both healthcare providers and patients.

Now, a team of Penn researchers has shown a way to make such predictions from the pattern of neural connections that begin to take shape soon after the first onset of pain. Though their study was conducted in rats, it suggests that similar brain imaging techniques could be used to guide treatment decisions in humans, such as which individuals are most likely to benefit from different drugs or therapies.

The study, published in the journal Pain, was led by Beth Winkelstein, Eduardo D. Glandt President’s Distinguished Professor in Penn Engineering’s Department of Bioengineering and Deputy Provost of the University of Pennsylvania, along with Megan Sperry, then a graduate student in her lab. Eric Granquist, Director of the Center for Temporomandibular Joint Disease at the Hospital of the University of Pennsylvania in the Department of Oral & Maxillofacial Surgery, and assistant professor of Oral & Maxillofacial Surgery in Penn’s School of Dental Medicine, also contributed to the research.

“Our findings provide the first evidence that brain networks differ between acute and persistent pain states, even before those different groups of rats actually show different pain symptoms,” says Winkelstein.

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

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Ravi Radhakrishnan Adapts Multiscale Modeling Course

 

Ravi Radhakrishnan, PhD

Ravi Radhakrishnan, Professor and Chair of the Department of Bioengineering and Professor in Chemical and Biomolecular Engineering, is among the many faculty who quickly adapted their courses to an online format in the wake of the COVID-19 pandemic. Now, a recent publication in the American Institute of Chemical Engineers (AIChE) Journal reflects one of these revamped courses. The course BE 559: “Multiscale Modeling of Chemical and Biological Systems” provides theoretical, conceptual, and hands-on modeling experience on three different length and time scales: (1) electronic structure (A, ps); (2) molecular mechanics (100A, ns); and (3) deterministic and stochastic approaches for microscale systems (um, sec). During the course, students gained hands-on experience in running codes on real applications together with the following theoretical formalisms: molecular dynamics, Monte Carlo, free energy methods, deterministic and stochastic modeling. The transition to the online format was greatly facilitated by a grant from the Extreme Science and Engineering Discovery Environment (XSEDE) which provided cloud and supercomputing resources to the students facilitating the computational laboratory experience. Radhakrishnan’s article, “A survey of multiscale modeling: Foundations, historical milestones, current status, and future prospects,” reviews the foundations, historical developments, and current paradigms in multiscale modeling (MSM).

Radhakrishnan aspires to modernize computational science, integrating Multiscale Modeling and Data Science for Biological and Biomedical Science & Engineering. His team does so by integrating multiphysics modeling, computing, data science to tackle applications. The integrative approach is pictorially depicted here in terms of modeling different length and timescales using techniques such as molecular dynamics of atomistic systems, Brownian dynamics of coarse-grained systems, and field equations governing continuum scales of macroscopic systems.

Read the full article in the AIChE Journal: https://doi.org/10.1002/aic.17026

Funding source: National Institutes of Health, Grant/Award Number: CA227550

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Brianne Connizzo Appointed Assistant Professor at Boston University

by Mahelet Asrat

Brianne Connizzo, PhD

The Department of Bioengineering is proud to congratulate alumna Brianne Connizzo, PhD on her appointment as a tenure-track Assistant Professor in the Department of Biomedical Engineering in the College of Engineering at Boston University. Connizzo’s appointment will begin in January 2021, after completing her work as a postdoctoral researcher in Biological Engineering at MIT under the supervision of Alan J. Grodzinsky, ScD, Professor of Biological, Electrical, and Mechanical Engineering.

Connizzo got her BS in Engineering Science from Smith College (the first all women’s engineering program in the country) where she graduated in 2010 with highest honors. During her time there, she worked in the laboratory of Borjana Mikic, Rosemary Bradford Hewlett 1940 Professor of Engineering. While working in the lab, she explored the role of myostatin deficiency on Achilles tendon biomechanics and built mechanical testing fixtures for submerged testing of biological tissues. Connizzo continued along this path during her graduate studies in Bioengineering at Penn while working with Louis J. Soslowsky, Fairhill Professor in Orthopaedic Surgery and Professor in Bioengineering, at the McKay Orthopaedic Research Laboratory. Her thesis work focused on the dynamic re-organizations of collagen during tendon loading in the rotator cuff, developing a novel AFM-based method for measuring collagen fibril sliding along the way. During her time at Penn, Connizzo also served as the Social Chair for the Graduate Association of Bioengineers (GABE) and the Graduate Student Engineering Group (GSEG), both of which play a vital role in representing graduate students across the School of Engineering and Applied Sciences. She completed her PhD in Bioengineering in 2015 and then pursued her postdoctoral studies at MIT, focusing on fluid flow during compressive loading and developing novel explant culture models to explore real-time extracellular matrix turnover. For her work she was awarded both an NIH F32 postdoctoral fellowship and the NIH K99/R00 Pathway Independence Award, which are just a few of her long list of impressive accomplishments.

Although Connizzo’s interests in soft tissue mechanobiology span development, injury, and disease, her more recent work has targeted how aging influences tendon function and biology. With a fast-growing active and aging population, she believes that identifying the cause and contributors of age-related changes is critical to finding treatments and therapies that could prevent tendon disease, and thus improve overall population healthspan and quality of life. The primary objectives of the Connizzo Lab at Boston University will be to harness novel in vitro and in vivo models to study cell-controlled extracellular matrix remodeling and tissue biomechanics and to better understand normal tendon maintenance and the initiation of tendon damage in the context of aging.

“I am so grateful to have had the guidance of my mentors and peers at Penn during my doctoral studies, and even more thankful that many of those relationships remain a significant part of my support system to this day,” Connizzo says. “I’m really looking forward to this next chapter — to all the successes and failures in pursuing the science, to building a community at BU and in my own laboratory, and to supporting the next generation of brilliant young scientists.”

Congratulations Dr. Connizzo from everyone at Penn Bioengineering!

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Engineering Bacteria-Killing Molecules from Wasp Venom

César de la Fuente, PhD

César de la Fuente a Presidential Assistant Professor in the Perelman School of Medicine’s departments of Psychiatry and Microbiology and Engineering’s department of Bioengineering, has racked up accolades for his innovative, computational approach to discovering new antibiotics.

Now, in his most recent study, de la Fuente has shown how these vital drugs might be derived from wasp venom.

The study, published in The Proceedings of the National Academy of Sciences, involved altering a highly toxic small protein from a common Asian wasp species, Vespula lewisii, the Korean yellow-jacket wasp. The alterations enhanced the molecule’s ability to kill bacterial cells while greatly reducing its ability to harm human cells. In animal models, de la Fuente and his colleagues showed that this family of new antimicrobial molecules made with these alterations could protect mice from otherwise lethal bacterial infections.

There is an urgent need for new drug treatments for bacterial infections, as many circulating bacterial species have developed a resistance to older drugs. The U.S. Centers for Disease Control & Prevention has estimated that each year nearly three million Americans are infected with antibiotic-resistant microbes and more than 35,000 die of them. Globally the problem is even worse: Sepsis, an often-fatal inflammatory syndrome triggered by extensive bacterial infection, is thought to have accounted for about one in five deaths around the world as recently as 2017.

“New antibiotics are urgently needed to treat the ever-increasing number of drug-resistant infections, and venoms are an untapped source of novel potential drugs. We think that venom-derived molecules such as the ones we engineered in this study are going to be a valuable source of new antibiotics,” says de la Fuente.

De la Fuente and his team started with a small protein, or “peptide,” called mastoparan-L, a key ingredient in the venom of Vespula lewisii wasps. Mastoparan-L-containing venom is usually not dangerous to humans in the small doses delivered by wasp stings, but it is quite toxic. It destroys red blood cells, and triggers a type of allergic/inflammatory reaction that in susceptible individuals can lead to a fatal syndrome called anaphylaxis—in which blood pressure drops and breathing becomes difficult or impossible.

Mastoparan-L (mast-L) also is known for its moderate toxicity to bacterial species, making it a potential starting point for engineering new antibiotics. But there are still some unknowns, including how to enhance its anti-bacterial properties, and how to make it safe for humans.

Continue reading at Penn Medicine News.

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Brian Litt Receives NIH Pioneer Award to Develop Implantable Neurodevices

Brian Litt, MD

Brian Litt, professor in Engineering’s Department of Bioengineering and the Perelman School of Medicine’s departments of Neurology and Neurosurgery, has received a five-year, $5.6 million Pioneer Award from the National Institutes of Health, which will support his research on implantable devices for monitoring, recording and responding to neural activity.

The Pioneer Award is part of the agency’s High-Risk, High-Reward Research Program honoring exceptionally creative scientists. It challenges investigators to pursue new research directions and develop groundbreaking, high-impact approaches to a broad area of biomedical or behavioral science. Litt’s neurodevice research represents a new frontier in addressing a wide variety of neurological conditions.

In epilepsy, for example, these devices would predict and prevent seizures; in Parkinson’s patients, implants will measure and communicate with patients to improve mobility, reduce tremor and enhance responsiveness. Other implants might improve hearing or psychiatric symptoms by querying patient perceptions, feelings, and altering stimulation patterns algorithmically to improve them

Continue reading about Litt’s Pioneer Award at Penn Medicine News.

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New Research from Penn Engineering and MIT Shows How Nanoparticles Can Turn Off Genes in Bone Marrow

Michael Mitchell
Michael Mitchell, PhD

by Evan Lerner

Using specialized nanoparticles, researchers from Penn Engineering and the Massachusetts Institute of Technology (MIT) have developed a way to turn off specific genes in cells of bone marrow, which play an important role in producing blood cells. These particles could be tailored to help treat heart disease or to boost the yield of stem cells in patients who need stem cell transplants.

This type of genetic therapy, known as RNA interference, is usually difficult to target to organs other than the liver, where nanoparticles would tend to accumulate. The researchers were able to modify their particles in such a way that they would accumulate in the cells found in the bone marrow.

In a recent Nature Biomedical Engineering study, conducted in mice, the researchers showed that they could use this approach to improve recovery after a heart attack by inhibiting the release of bone marrow blood cells that promote inflammation and contribute to heart disease.

“If we can get these particles to hit other organs of interest, there could be a broader range of disease applications to explore, and one that we were really interested in in this paper was the bone marrow. The bone marrow is a site for hematopoiesis of blood cells, and these give rise to a whole lineage of cells that contribute to various types of diseases,” says Michael Mitchell, Skirkanich Assistant Professor of Innovation in Penn Engineering’s Department of Bioengineering, one of the lead authors of the study.

Marvin Krohn-Grimberghe, a cardiologist at the Freiburg University Heart Center in Germany, and Maximilian Schloss, a research fellow at Massachusetts General Hospital (MGH), are also lead authors on the paper, which appears today in Nature Biomedical Engineering. The paper’s senior authors are Daniel Anderson, a professor of Chemical Engineering at MIT and a member of MIT’s Koch Institute for Integrative Cancer Research and Institute for Medical Engineering and Science, and Matthias Nahrendorf, a professor of Radiology at MGH.

Mitchell’s expertise is in the design of nanoparticles and other drug delivery vehicles, engineering them to cross biological barriers that normally block foreign agents. In 2018, he received the NIH Director’s New Innovator Award to support research on delivering therapeutics to bone marrow, a key component of this new study.

The researchers have shown they can deliver nanoparticles to the bone marrow, influencing their function with RNA silencing. At top right, the bone marrow is not yet treated with particles that turn off a gene called SDF1. At bottom right, the number of neutrophils (blue) decreases, indicating that they have been released from bone marrow after treatment. At left, treatment with a control nanoparticle does not affect the number of neutrophils before and after treatment.

Read the full story at Penn Engineering Today.