A pair of proteins, YAP and TAZ, has been identified as conductors of bone development in the womb and could provide insight into genetic diseases such as osteogenesis imperfecta, known commonly as “brittle bone disease.” This research, published in Developmental Cell and led by members of the McKay Orthopaedic Research Laboratory of the Perelman School of Medicine, adds understanding to the field of mechanobiology, which studies how mechanical forces influence biology.
“Despite more than a century of study on the mechanobiology of bone development, the cellular and molecular basis largely has remained a mystery,” says the study’s senior author, Joel Boerckel, an associate professor of orthopaedic surgery. “Here, we identify a new population of cells that are key to turning the body’s early cartilage template into bone, guided by the force-activated gene regulating proteins, YAP and TAZ.”
In these super-resolution images of tendon cell nuclei, the color coding represents chromatin density map, from low density in blue to high density in red. Comparing a healthy human tendon cell nucleus (left) to one diagnosed with tendinosis (right) shows that disease alters the spatial localization and compaction of chromatin.
In a recent study published in Nature Biomedical Engineering, the team detailed what they found when they closely observed the nucleus of cells inside connective tissues deteriorating as a result of tendinosis, which is the chronic condition that results from a tendon repeatedly suffering small injuries that don’t heal correctly. Using the latest super-resolution imaging techniques, they found that the tendon cells involved in maintaining the tissue’s structure in a diseased microenvironment improperly reorder their chromatin — the DNA-containing material that chromosomes are composed of — when attempting to repair.
This and other findings highlighted in the report point to the possibility of new treatments, such as small-molecule therapies, that could restore order to the affected cells.
“Interestingly, we were able to explain the role of mechanical forces on the 3-D organization of chromatin by developing a theory that integrates fundamental thermodynamic principles (physics) with the kinetics of epigenetic regulation (biology),” said study co-author and CEMB Director Vivek Shenoy in a news release from Penn Medicine News.
The CEMB, one of 18 active interdisciplinary research centers funded by the National Science Foundation’s Science and Technology Center (STC) program, brings together dozens of researchers from Penn Engineering and the Perelman School of Medicine, as well as others spread across campus and at partner institutions around the world.
With its funding recently renewed for another five years, the CEMB has entered into a new phase of its mission, centered on the nascent concept of “mechanointelligence,” which is exemplified by studies like this one. While mechanobiology is the study of the physical forces that govern the behavior of cells and their communication with their neighbors, mechanointelligence adds another layer of complexity: attempting to understand the forces that allow cells to sense, remember and adapt to their environments.
Ultimately, harnessing these forces would allow researchers to help multicellular organisms — plants, animals and humans — better adapt to their environments as well.
This story originally appeared in Penn Engineering Today.
Vivek Shenoy is Eduardo D. Glandt President’s Distinguished Professor in Materials Science and Engineering, Bioengineering, and in Mechanical Engineering and Applied Mechanics.
The dynamics governing mechanointelligence vary greatly along time- and length-scales, so detailed models of individual cells and their components are necessary to connect the effects of their physical environments to the downstream effects those forces have on biological processes.
The National Science Foundation’s Science and Technology Center (STC) program is its flagship funding mechanism for organizing interdisciplinary research on cutting-edge topics. Penn’s Center for Engineering MechanoBiology (CEMB) is one of the 18 active STCs, bringing together dozens of researchers from Penn Engineering and the Perelman School of Medicine, as well as others spread across campus and at partner institutions around the world.
With its NSF funding now renewed for another five years, the Center is entering into a new phase of its mission, centered on the nascent concept of “mechanointelligence.”
Mechanobiology is the study of the physical forces that govern the behavior of cells and their communication with their neighbors. Mechanointelligence adds another layer of complexity, attempting to understand the forces that allow cells to sense, remember and adapt to their environments.
Ultimately, harnessing these forces would allow researchers to help multicellular organisms — plants, animals and humans — better adapt to their environments as well.
“Mechanointelligence is a key element of a cell’s ability to survive and reproduce,” says CEMB Director and Eduardo D. Glandt President’s Distinguished Professor Vivek Shenoy. “Just like with complex organisms, a cell’s ‘fitness’ depends on its environment, and adapting means rewiring how its genes are expressed.”
Vivek Shenoy is Eduardo D. Glandt President’s Distinguished Professor in Materials Science and Engineering, Bioengineering and Mechanical Engineering and Applied Mechanics.
As part of a major University-wide investment in science, engineering, and medicine, the Innovation in Data Engineering and Science Initiative aims to help Penn become a leader in developing data-driven approaches that can transform scientific discovery, engineering research, and technological innovation.
From smartphones and fitness trackers to social media posts and COVID-19 cases, the past few years have seen an explosion in the amount and types of data that are generated daily. To help make sense of these large, complex datasets, the field of data science has grown, providing methodologies, tools, and perspectives across a wide range of academic disciplines.
As part of its $750 million investment in science, engineering, and medicine, the University has committed to supporting the future needs of this field. To this end, the Innovation in Data Engineering and Science (IDEAS) initiative will help Penn become a leader in developing data-driven approaches that can transform scientific discovery, engineering research, and technological innovation.
“The IDEAS initiative is game-changing for our University,” says President Amy Gutmann. “This new investment allows us to boost our interdisciplinary efforts across campus, recruit phenomenal additional team members, and generate an even more sound foundation for discovery, experimentation, and design. This initiative is a clear statement that Penn is committed to taking data science head-on.”
“One of the unique things about data science and data engineering is that it’s a very horizontal technology, one that is going to be impacting every department on campus,” says George Pappas, Electrical and Systems Engineering Department chair. “When you have a horizontal technology in a competitive area, we have to figure out specific areas where Penn can become a worldwide leader.”
To do this, IDEAS aims to recruit new faculty across three research areas: artificial intelligence (AI) to transform scientific discovery, trustworthy AI for autonomous systems, and understanding connections between the human brain and AI.
In the area of neuroscience and how the human brain is similar to AI and machine learning approaches, research from PIK Professor Konrad Kording and Dani Bassett’sComplex Systems lab exemplifies the types of cross-disciplinary efforts that are essential for addressing complex questions. By recruiting additional faculty in this area, IDEAS will help Penn make strides in bio-inspired computing and in future life-changing discoveries that could address cognitive disorders and nervous system diseases.
A colorized microscope image of an osteosarcoma shows how cellular fibers can transfer physical force between neighboring nuclei, influencing genes. The Penn Anti-Cancer Engineering Center will study such forces, looking for mechanisms that could lead to new treatments or preventative therapies.
Advances in cell and molecular technologies are revolutionizing the treatment of cancer, with faster detection, targeted therapies and, in some cases, the ability to permanently retrain a patient’s own immune system to destroy malignant cells.
However, there are fundamental forces and associated challenges that determine how cancer grows and spreads. The pathological genes that give rise to tumors are regulated in part by a cell’s microenvironment, meaning that the physical push and pull of neighboring cells play a role alongside the chemical signals passed within and between them.
The Penn Anti-Cancer Engineering Center (PACE) will bring diverse research groups from the School of Engineering and Applied Science together with labs in the School of Arts & Sciences and the Perelman School of Medicine to understand these physical forces, leveraging their insights to develop new types of treatments and preventative therapies.
The Center’s founding members are Dennis Discher, Robert D. Bent Professor with appointments in the Departments of Chemical and Biomolecular Engineering (CBE), Bioengineering (BE) and Mechanical Engineering and Applied Mechanics (MEAM), and Ravi Radhakrishnan, Professor and chair of BE with an appointment in CBE.
Discher, an expert in mechanobiology and in delivery of cells and nanoparticles to solid tumors, and Radhakrishnan, an expert on modeling physical forces that influence binding events, have long collaborated within the Physical Sciences in Oncology Network. This large network of physical scientists and engineers focuses on cancer mechanisms and develops new tools and trainee opportunities shared across the U.S. and around the world.
Lukasz Bugaj, Alex Hughes, Jenny Jiang, Bomyi Lim, Jennifer Lukes and Vivek Shenoy (Clockwise from upper left).
Among the PACE Center’s initial research efforts are studies of the genetic and immune mechanisms associated with whether a tumor is solid or liquid and investigations into how physical stresses influence cell signaling.
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.
Manuela Teresa Raimondi was appointed Visiting Professor in Bioengineering in the Associated Faculty of the School of Engineering and Applied Science for the 2020-2021 academic year. Raimondi received her Ph.D. in Bioengineering in 2000 from Politecnico di Milano, Italy. She is currently a Full Professor of Bioengineering at Politecnico di Milano in the Department of Chemistry, Materials and Chemical Engineering “G. Natta”, where she teaches the course “Technologies for Regenerative Medicine” in the Biomedical Engineering graduate program.
Raimondi is the founder and Director of the Mechanobiology Lab and of the Interdepartmental Live Cell Imaging lab. She has pioneered the development of cutting edge tools for cell modelling, ranging from micro-engineered stem cell niches, to miniaturized windows for in vivo intravital imaging, to microfluidic culture systems to engineer tissue-equivalents and organoids for cell modelling and drug discovery. Her platforms are currently commercialized by her start-up, MOAB srl. Her research is funded by the European Research Council (ERC), by The National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs), by the European Commission, and by the European Space Agency.
“Getting to Penn was quite the challenge with the various travel restrictions and the pandemic, but I am used to overcoming adverse odds and I am really excited to be here now,” says Dr. Raimondi. “In this challenging time, when many new barriers are coming up, I think building bridges and new scientific collaborations is even more important. I very much look forward to being part of the Penn research community.”
Dr. Raimondi with host Riccardo Gottardi, PhD on Smith Walk
During her sabbatical at Penn, Raimondi is investigating her hypothesis that stem cells pluripotency reprogramming can be guided by mechanical cues. Over the past five years, she has cultured many different stem cell types in the “Nichoids,” the synthetic stem cell niche she developed, and gathered robust evidence on how physical constraints at the microscale level upregulate pluripotency. Raimondi is hosted in the Bioengineering and Biomaterials Lab of Riccardo Gottardi, Assistant Professor in Bioengineering and in Pediatrics at the Perelman School of Medicine, where she is helping to refine human stem cell sources that could be minimally manipulated for translational tissue engineering for a safe and effective use in regenerative therapies, as a key issue for clinical translation is the maintenance or enhancement of multipotency during cell expansion without exogenous agents or genetic modification.
“Dr. Raimondi is a trailblazer in Italy in regenerative medicine who has introduced many new concepts in a sometimes musty academic environment and has shattered a number of glass ceilings,” says Dr. Gottardi. “I think her sabbatical at Penn is a great opportunity for her and for the Penn community to build new and exciting trans-Atlantic collaborations.”
Speaker: Christopher J. Hernandez, Ph.D.
Professor, Sibley School of Mechanical and Aerospace Engineering, Cornell University
Adjunct Scientist, Hospital for Special Surgery
Date: Thursday, February 4, 2021
Time: 3:00-4:00 PM EST
Zoom – check email for link or contact ksas@seas.upenn.edu
The idea that mechanical stresses influence the growth and form of organs and organisms originated in the 1800s and is the basis for the modern study of biomechanics and mechanobiology. Biomechanics and mechanobiology are well studied in eukaryotic systems, yet eukaryotes represent only a small portion of the diversity and abundance of life on Earth. Bacteria exhibit broad influences on human health (as both pathogens and as beneficial components of the gut microbiome) and processes used in biotechnology and synthetic biology. Over the past eight years my group has explored mechanobiology within individual bacteria and the effects of changes in the composition of commensal bacterial communities on the biomechanics in the musculoskeletal system.
The ability of the bacteria to not only resist mechanical loads (biomechanics) but also to respond to changes in the mechanical environment (mechanobiology) is necessary for survival. Here I describe a novel microfluidic platform used to explore the biomechanics and mechanobiology of individual, live bacteria. I discuss work from my group demonstrating that mechanical stress within the bacterial cell envelope can influence the assembly and function of multicomponent efflux pumps used by bacteria to resist toxins and antibiotics. Additionally, I share some of our more recent work showing that mechanical stress and strain within the bacterial cell envelope can stimulate a bacterial two-component system controlling gene expression. Our findings demonstrate that bacteria, like mammalian cells, have mechanosensitive systems that are key to survival.
In musculoskeletal disease, bacteria are commonly viewed as sources of infection. However, in the past decade the studies by my group and others have suggested that commensal bacteria – the microbiome – can modulate the pathogenesis of musculoskeletal disorders. My group is among the first to study the effects of the gut microbiome on orthopaedic disorders. Here I provide an introduction to the microbiome and current concepts of how modifications to the gut microbiome could influence the musculoskeletal system. Specifically, I discuss studies from my group which are the first to demonstrate that the gut microbiome influences bone biomechanics and the development of infection of orthopaedic implants.
Bio:
Dr. Hernandez is Professor in the Sibley School of Mechanical and Aerospace Engineering at Cornell University and is an Adjunct Scientist at the Hospital for Special Surgery. Dr. Hernandez is a Fellow of the American Institute for Medical and Biological Engineering (AIMBE), the American Society of Mechanical Engineers (ASME), and the American Society for Bone and Mineral Research (ASBMR). He is the 2018 recipient of the Fuller Albright Award for Scientific Excellence from the American Society for Bone and Mineral Research. He has served on the Board of Directors of the Orthopaedic Research Society and the American Society for Bone and Mineral Research. His laboratory’s research currently focuses on the effects of the microbiome on bone and joint disorders, periprosthetic joint infection and the biomechanics and mechanobiology of bacteria.
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!
When cells move throughout the body, they do so by dragging themselves, using molecular “arms” to pull themselves closer to where they need to be while unlatching themselves from the area they’re moving away from. In a recent study, Penn Engineers looked at a few mechanobiological factors that help regulate cells’ migration towards their destination, providing new insight into the gene expression feedback loops that keep them from getting stuck.
Joel Boerckel and Devon Mason
The research was led by Joel Boerckel, Assistant Professor of Orthopaedic Surgery in the Perelman School of Medicine and in Bioengineering in Penn Engineering, and bioengineering graduate student Devon Mason. Co-authors include bioengineering graduate student Joseph Collins and researchers from the University of Notre Dame, Indiana University and Purdue University.
Speaker: 
