Members of the research team include (from left to right) Xuexiang Han, Michael J. Mitchell, Ningqiang Gong, Lulu Xue, Sarah J. Shepherd, and Rakan El-Mayta.
Since the success of the COVID-19 vaccine, RNA therapies have been the object of increasing interest in the biotech world. These therapies work with your body to target the genetic root of diseases and infections, a promising alternative treatment method to that of traditional pharmaceutical drugs.
Lipid nanoparticles (LNPs) have been successfully used in drug delivery for decades. FDA-approved therapies use them as vehicles for delivering messenger RNA (mRNA), which prompts the cell to make new proteins, and small interfering RNA (siRNA), which instruct the cell to silence or inhibit the expression of certain proteins.
The biggest challenge in developing a successful RNA therapy is its targeted delivery. Research is now confronting the current limitations of LNPs, which have left many diseases without an effective RNA therapy.
Liver fibrosis occurs when the liver is repeatedly damaged and the healing process results in the accumulation of scar tissue, impeding healthy liver function. It is a chronic disease characterized by the buildup of excessive collagen-rich extracellular matrix (ECM). Liver fibrosis has remained challenging to treat using RNA therapies due to a lack of delivery systems for targeting activated liver-resident fibroblasts. Both the solid fibroblast structure and the lack of specificity or affinity to target these fibroblasts has impeded current LNPs from entering activated liver-resident fibroblasts, and thus they are unable to deliver RNA therapeutics.
To tackle this issue and help provide a treatment for the millions of people who suffer from this chronic disease, Michael Mitchell, J. Peter and Geri Skirkanich Assistant Professor of Innovation in the Department of Bioengineering, and postdoctoral fellows Xuexiang Han and Ningqiang Gong, found a new way to synthesize ligand-tethered LNPs, increasing their selectivity and allowing them to target liver fibroblasts.
Lulu Xue, Margaret Billingsley, Rakan El-Mayta, Sarah J. Shepherd, Mohamad-Gabriel Alameh and Drew Weissman, Roberts Family Professor in Vaccine Research and Director of the Penn Institute for RNA Innovation at the Perelman School of Medicine, also contributed to this work.
CPE4H is one of the focal points of Penn Engineering signature initiative on Engineering Health.
The Penn Center for Precision Engineering for Health (CPE4H) was established late last year to accelerate engineering solutions to significant problems in healthcare. The center is one of the signature initiatives for Penn’s School of Engineering and Applied Science and is supported by a $100 million commitment to hire faculty and support new research on innovative approaches to those problems.
Acting on that commitment, CPE4H solicited proposals during the spring of 2022 for seed grants of $80K per year for two years for research projects that address healthcare challenges in several key areas of strategic importance to Penn: synthetic biology and tissue engineering, diagnosis and drug delivery, and the development of innovative devices. While the primary investigators (PIs) for the proposed projects were required to have a primary faculty appointment within Penn Engineering, teams involving co-PIs and collaborators from other schools were eligible for support. The seed program is expected to continue for the next four years.
“It was a delight to read so many novel and creative proposals,” says Daniel A. Hammer, Alfred G. and Meta A. Ennis Professor in Bioengineering and the Inaugural Director of CPE4H. “It was very hard to make the final selection from a pool of such promising projects.”
Judged on technical innovation, potential to attract future resources, and ability to address a significant medical problem, the following research projects were selected to receive funding.
Evolving and Engineering Thermal Control of Mammalian Cells
Led by Lukasz Bugaj, Assistant Professor in Bioengineering, this project will engineer molecular switches that can be toggled on and off inside mammalian cells at near-physiological temperatures. Successful development of these switches will provide new ways to communicate with cells, an advance that could be used to make safer and more effective cellular therapies. The project will use directed evolution to generate and find candidate molecular tools with the desired properties. Separately, the research will also develop new technology for manipulating cellular temperature in a rapid and programmable way. Such devices will enhance the speed and sophistication of studies of biological temperature regulation.
A Quantum Sensing Platform for Rapid and Accurate Point-of-Care Detection of Respiratory Viral Infections
Combining microfluidics and quantum photonics, PI Liang Feng, Professor in Materials Science and Engineering and Electrical and Systems Engineering, Ritesh Agarwal, Professor in Materials Science Engineering, and Shu Yang, Joseph Bordogna Professor in Materials Science and Engineering and Chemical and Biomolecular Engineering, are teaming up with Ping Wang, Professor of Pathology and Laboratory Medicine in Penn’s Perelman School of Medicine, to design, build and test an ultrasensitive point-of-care detector for respiratory pathogens. In light of the COVID-19 pandemic, a generalizable platform for rapid and accurate detection of viral pathogenesis would be extremely important and timely.
Versatile Coacervating Peptides as Carriers and Synthetic Organelles for Cell Engineering
PI Amish Patel, Associate Professor in Chemical and Biomolecular Engineering, and Matthew C. Good, Associate Professor of Cell and Developmental Biology in the Perelman School of Medicine and in Bioengineering, will design and create small proteins that self-assemble into droplet-like structures known as coacervates, which can then pass through the membranes of biological cells. Upon cellular entry, these protein coacervates can disassemble to deliver cargo that modulates cell behavior or be maintained as synthetic membraneless organelles. The team will design new chemistries that will facilitate passage across cell membranes, and molecular switches to sequester and release protein therapeutics. If successful, this approach could be used to deliver a wide range of macromolecule drugs to cells.
Towards an Artificial Muscle Replacement for Facial Reanimation
Cynthia Sung, Gabel Family Term Assistant Professor in Mechanical Engineering and Applied Mechanics and Computer Information Science, will lead a research team including Flavia Vitale, Assistant Professor of Neurology and Bioengineering, and Niv Milbar, Assistant Instructor in Surgery in the Perelman School of Medicine. The team will develop and validate an electrically driven actuator to restore basic muscle responses in patients with partial facial paralysis, which can occur after a stroke or injury. The research will combine elements of robotics and biology, and aims to produce a device that can be clinically tested.
“These novel ideas are a great way to kick off the activities of the center,” says Hammer. “We look forward to soliciting other exciting seed proposals over the next several years.”
She joins 28 early-career scientists from around the world in this year’s cohort, with each receiving support for one to two years, $100,000 in salary support per year, individualized mentoring, and a series of professional development sessions as they pivot to the next stages of their research agendas.
The fellowship is a program of Schmidt Futures, the philanthropic initiative of Eric and Wendy Schmidt that aims to tackle society’s toughest challenges by supporting interdisciplinary researchers at the start of their careers.
“Our latest group of Schmidt Science Fellows embodies our vision for this Program at its inception five years ago,” says Eric Schmidt, co-founder of Schmidt Futures and former CEO and Chairman of Google. “We find the most talented next-generation leaders from around the world and back these impressive young adults with the resources and networks they need to realize their full potential while addressing some of the big scientific questions facing the world. Congratulations to the 2022 Schmidt Science Fellows, I am excited to see where your science takes you and what you will achieve.”
Working at the intersection of materials science, biology, and applied clinical research, Zlotnick’s postdoctoral work will involve developing advanced bioprinting techniques for regenerative medicine. Such advances are necessary to recreate the multi-cellular composition of orthopedic tissues, such as those found in the knee joint. Lab-grown tissue models can then be used to broaden our understanding of how degenerative diseases progress after injury, limit the need for animal models, and serve as a platform for therapeutic discovery.
Savan Patel, a junior studying Bioengineering and Finance in the Jerome Fisher Management and Technology dual degree program, was selected as the recipient of the 2022 C. William Hall Scholarship from the Society for Biomaterials. The C. William Hall Scholarship is named in honor of the Society for Biomaterials’ first president and is awarded annually “to a junior or senior undergraduate pursuing a bachelor’s degree in bioengineering or a related discipline focusing on biomaterials.” As this year’s recipient, Savan will receive complimentary membership to the Society and will have expenses paid to the Society’s annual meeting being held April 27-30, 2022 in Baltimore, Maryland.
Savan is currently a member of the lab of Michael J. Mitchell, Skirkanich Assistant Professor of Innovation in Bioengineering. Savan’s research interests lie in the interface of drug delivery and immunoengineering with a particular focus on T cell delivery. His current project involves the use of modified cholesterol molecules to improve the delivery of nucleic acids (i.e., mRNA) to cell populations using lipid nanoparticles.
Lipid nanoparticles (LNPs) are a clinically proven delivery platform for nucleic acid therapeutics. One drawback of these particles is their high cellular recycling rate. Savan and the members of the Mitchell lab are working to reduce this recycling by leveraging cellular processes and incorporating modified molecules into our lipid nanoparticle formulations. The focus of Savan’s project is on modifying cholesterol, a molecule that is important to both our LNP formulations and cell membranes. The goal is to generate a more potent delivery platform to improve current therapeutics.
Following graduation, Savan intends to pursue a Ph.D. in Bioengineering.
Michael Mitchell, Skirkanich Assistant Professor of Innovation in the Department of Bioengineering, has been awarded the 2022 Society for Biomaterials (SFB) Young Investigator Award for his “outstanding achievements in the field of biomaterials research.”
The Society for Biomaterials is a multidisciplinary society of academic, healthcare, governmental and business professionals dedicated to promoting advancements in all aspects of biomaterial science, education and professional standards to enhance human health and quality of life.
Mitchell, whose research lies at the interface of biomaterials science, drug delivery, and cellular and molecular bioengineering to fundamentally understand and therapeutically target biological barriers, is specifically being recognized for his development of the first nanoparticle RNAi therapy to treat multiple myeloma, an incurable hematologic cancer that colonizes in bone marrow.
“Before this, no one in the drug delivery field has developed an effective gene delivery system to target bone marrow,” said United States National Medal of Science recipient Robert S. Langer in Mitchell’s award citation. “Mike is a standout young investigator and leader that intimately understands the importance of research and collaboration at the interface of nanotechnology and medicine.”
Academic recipients of the SFB Young Investigator Award should not exceed the rank of Assistant Professor and must not be tenured at the time of nomination. The award includes a $1,000 endowment.
Earlier this year, Penn President Amy Gutmann and Vijay Kumar, Nemirovsky Family Dean of Penn’s School of Engineering and Applied Science, announced a $100 million commitment to accelerate innovations in medical technologies. Called the Center for Precision Engineering for Health (CPE4H), the initiative aims to bring together researchers from a wide range of fields to develop customizable biomaterials and implantable devices that can be tailored for individualized diagnostics, treatments and therapies.
Now, Daniel A. Hammer, Alfred G. and Meta A. Ennis Professor in Penn Engineering’s Departments of Bioengineering and Chemical and Biomolecular Engineering, has been named CPE4H’s inaugural director.
“Penn is a unique environment where innovations in healthcare can emerge very rapidly, as we’ve seen with the development of CAR-T cancer immunotherapy, and the design and delivery of mRNA vaccines,” Hammer says. “Engineering plays a central role in making those technologies functional and maximizing their impact, and CPE4H is a golden opportunity to take these technologies to the next level in a way that actually helps people.”
Speaker: Samir Mitragotri, Ph.D.
Hiller Professor of Bioengineering and Hansjorg Wyss Professor of Biologically Inspired Engineering
John A. Paulson School of Engineering and Applied Sciences
Harvard University
Date: Thursday, November 18, 2021
Time: 3:30-4:30 PM EST
Zoom – check email for link or contact ksas@seas.upenn.edu
This seminar will be held virtually, but students registered for BE 699 can gather to watch in Moore 216.
Abstract: Ionic liquids, the liquid salts comprising organic anions and cations, offer exciting opportunities for several therapeutic applications. Their tunable properties offer control over their design and function. Starting with biocompatible ions, we synthesized a library of ionic liquids and explored them for various drug delivery applications. Ionic liquids provided unique advantages including overcoming the biological transport barriers of skin, buccal mucosa and the intestinal epithelium. At the same time, they also stabilized proteins and nucleic acids and enabled the delivery of biologics across these barriers. Ionic liquids also provided unique biological functions including adjuvancy towards vaccines and antimicrobial function. I will present an overview of the design features of ionic liquids and novel biomedical applications enabled by these unique materials.
Samir Mitragotri Bio: Samir Mitragotri is the Hiller Professor of Bioengineering and Wyss Professor of Biologically Inspired Engineering at Harvard University. His research is focused on transdermal, oral, and targeted drug delivery systems. He is an elected member of the National Academy of Engineering, National Academy of Medicine and National Academy of Inventors. He is also a foreign member of Indian National Academy of Engineering. He is also an elected fellow of AAAS, CRS, BMES, AIMBE, and AAPS. He is an author of over 350 publications, an inventor on over 200 patent/patent applications, and a Clarivate Highly Cited Researcher. He received his BS in Chemical Engineering from the Institute of Chemical Technology, India and a PhD in Chemical Engineering from the Massachusetts Institute of Technology. He is the Editor-in-Chief of AIChE’s and SBE’s journal Bioengineering and Translational Medicine.
Speaker: Susan N. Thomas, Ph.D.
Woodruff Associate Professor of Mechanical Engineering
Parker H. Petit Institute of Bioengineering and Bioscience
Georgia Institute of Technology
Date: Thursday, September 23, 2021
Time: 3:30-4:30 PM EDT
Zoom – check email for link or contact ksas@seas.upenn.edu
This virtual seminar will be held over Zoom. Students registered for BE 699 can gather to watch live in Moore 216, 200 S. 33rd Street.
Abstract: Lymph nodes mediate the co-mingling of cells of the adaptive system to coordinate adaptive immune response. Drug delivery principles and technologies our group has developed to leverage the potential of lymph nodes as immunotherapeutic drug targets to augment anti-cancer therapeutic effects will be described.
Susan Thomas Bio: Susan Napier Thomas is a Woodruff Associate Professor with tenure of Mechanical Engineering in the Parker H. Petit Institute of Bioengineering and Bioscience at the Georgia Institute of Technology where she holds adjunct appointments in Biomedical Engineering and Biological Science and is a member of the Winship Cancer Institute of Emory University. Prior to this appointment, she was a Whitaker postdoctoral scholar at École Polytechnique Fédérale de Lausanne and received her B.S. in Chemical Engineering cum laude from the University of California Los Angeles and her Ph.D. as in Chemical & Biomolecular Engineering as an NSF Graduate Research Fellow from The Johns Hopkins University. For her contributions to the emerging field of immunoengineering, she has been honored with the 2018 Young Investigator Award from the Society for Biomaterials for “outstanding achievements in the field of biomaterials research” and the 2013 Rita Schaffer Young Investigator Award from the Biomedical Engineering Society “in recognition of high level of originality and ingenuity in a scientific work in biomedical engineering.” Her interdisciplinary research program is supported by multiple awards from the National Cancer Institute, the Department of Defense, the National Science Foundation, and the Susan G. Komen Foundation, amongst others.
The junior year BE-MAD lab series includes modules on dialysis, drug delivery, insect limb control, microfluidics, cell-cell communication, ECG analysis (pictured here), and spectroscopy. (Image: Bioengineering Educational Lab)
While the majority of courses remained online this spring, a small number of lab-based undergraduate courses were able to resume limited in-person instruction. One course was BE 310, the second semester of the Bioengineering Modeling, Analysis, and Design lab sequence. Better known as BE-MAD, this junior-year bioengineering course was able to bring students back to the teaching lab safely this spring while adapting its curriculum to keep remote learners engaged with hands-on lab modules at home.
An Essential Step Towards Becoming a Bioengineer
After learning the basics of chemistry, physics, biology, and math during freshman year and studying bioengineering fundamentals throughout sophomore year, BE-MAD is designed to provide essential hands-on experience to bioengineering majors during their junior years. In BE-MAD, students integrate what they’ve learned so far in the classroom to addressing complex, real-world problems by breaking down the silos that exist across different STEM fields.
“Usually what we hear from students is that this BE 309/310 sequence is when they really feel like they are engineers,” says Brian Chow, one of the BE 310 instructors. “They can put what they learn in classes to work in some practical setting and applied context.”
BE-MAD is also an important course to prepare students for senior design and is designed to be a “safe space to fail,” allowing students to build confidence through trial and error within a supportive environment, explains Sevile G. Mannickarottu, director of the educational laboratories. “We’re trying to build skills needed for senior year as well as teaching students how to think critically about problems by pulling together the materials they’ve learned all in one place,” he says. “By senior year, we want them to, when presented with a problem, not be afraid.”
Adapting BE-MAD for Both Remote and Hybrid Instruction
Traditionally, the BE-MAD lab is taught in the George H. Stephenson Foundation Educational Laboratory & Bio-MakerSpace, the primary bioengineering teaching lab, and includes modules on dialysis, drug delivery, insect limb control, microfluidics, cell-cell communication, ECG analysis, and spectroscopy. In the fall, the first lab in the series (BE-309) pivoted to remote learning using video tutorials of lab experiments and providing real data to students for analysis.
This spring, with more aspects of on-campus life able to reopen, the Educational Laboratory staff and BE-MAD instructors developed protocols in collaboration with David Meaney, Penn Engineering senior associate dean and an instructor for BE 309, and Penn’s Environmental Health and Radiation Safety office to safely reopen the teaching lab and Bio-MakerSpace for both BE-310 and for bioengineering senior design students.
The BE-MAD lab was also recreated on Gather.Town, an online video chat platform where students can speak with group members or instructors. Student groups also had their own tables where they could meet virtually to work on data analysis and lab report writing.
To continue to meet the needs of remote students, BE 310 instructor Lukasz Bugaj says that the curriculum was adapted to be two parallel courses—one that could be done entirely at home and the other in-person. The challenge was to adjust the content so that it could be completed either in-person or virtually, and could be switched from in-person to virtual at a moment’s notice because of COVID precautions, all while maximizing the hands-on experience, says Bugaj. “That’s a real credit to the lab staff of Sevile and Michael Patterson, who put a lot of work into revamping this entire class.”
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.
