Foundational Engineering Theory in Design and Translation

Ramakrishnan
What a nanoparticle remembers during its journey is pictorially represented in the above figure, and this “memory” is crucial in predicting its approach to the blood vessel wall and its subsequent capture by cell surface receptors, collectively determining the efficacy of therapeutic drug delivery. Reprinted from: Ramakrishnan et al, “Motion of a nano-spheroid in a cylindrical vessel flow: Brownian and hydrodynamic interactions,” J Fluid Mech. 2017;821:117-152, with permission of Cambridge UP, owner of copyright.

A recent article coauthored by Ramakrishnan Natesan, a postdoctoral fellow in the Department of Bioengineering who works in the lab of Dr. Ravi Radhakrishnan, and published in the Journal of Fluid Mechanics provides an elegant and rigorous approach to integrate the memory, errant motion, and adhesion effects in the dynamics of colloidal nanoparticles of different sizes and shapes. The method described in the article computationally analyzes how the hydrodynamic forces are influenced by size, shape, and nature of confining boundary amidst blood flow.

In traditional modes of therapeutic treatment, such as a direct intravenous (IV) injection, only a small fraction of injected drug accesses the diseased tissue. Suboptimal therapeutic delivery represents an acute challenge by limiting the efficacy of biotherapeutics. Strategies to address and overcome this challenge may be based on theoretical and computational approaches to in order to help design innovative, quantitative, experimental methods. Targeted therapeutic delivery using nanoparticles coated with specific targeting molecules is such an approach in therapeutic and diagnostic applications.

Targeted delivery is inherently a multiscale problem: a broad range of length and time scales govern the hydrodynamic, microscopic, and molecular interactions mediating nanoparticle motion in blood flow and capture due to cell binding. The events following upon the injection of a targeted therapeutic nanoparticle bearing a drug (nanocarrier) include flow through blood vessels and maneuvering around much larger entities in the blood, such as the red blood cells. Nanoparticles eventually break free to approach the wall of the blood vessel — a phenomenon collectively known as margination.

After margination, the nanoparticle is relatively free from the influences of the blood cells but starts to “feel” the approach to the wall. It needs to get excruciatingly close to the wall to stick — a phenomenon known as adhesion or capture. In the backdrop of this arduous journey is the inescapable randomness of its motion caused by Brownian forces, an erratic form of motion that only impacts nanoscale objects. The interplay among fluid forces, Brownian fluctuations, and wall interactions shape the detailed itinerary of the nanoparticle.  How it moves at a given location and given time is intricately coupled with the motion of the surrounding fluid, namely the blood plasma, which is mostly water. Together, they decide to pave the path forward in time described by a “memory function.”

“The optimization of future drug delivery agents, such as targeted therapeutic nanocarriers, could be based on our computations,” Dr. Ramakrishnan says. “This will, in effect, establish a rational computational platform for fast tracking the clinical translation from carrier design to clinical practice.”

Chow Wins NIH Grant for Brain Study

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Brian Chow, Ph.D.

The National Institutes of Health (NIH) has awarded a grant to Brian Chow, Ph.D., an assistant professor in the Department of Bioengineering, to study ultrafast genetically encoded voltage indicators (GEVIs). GEVIs are proteins that can detect changes in the electrical output of cells and report those changes by emitting different color light. His research seeks to create GEVIs that can report these changes much more rapidly – in fact, more than a million times more quickly than the velocity of the changes themselves – and apply these ultrafast GEVIs to the study of the brain.

The NIH-funded research will build on earlier research, employing de novo fluorescent proteins (dFPs) created in Dr. Chow’s lab. These dFPs, which are totally artificial and unrelated to natural proteins, report voltage changes in neurons by changing in brightness. Working with a team of investigators that includes faculty members from the Departments of Biochemistry & Biophysics and Neuroscience, Dr. Chow hopes to develop these ultrafast GEVIs.

“Monitoring thousands of neurons in parallel will shed new light on cognition, learning and memory, mood, and the physiological underpinnings of nervous system disorders,” he says.

Dan Huh Receives $1M CRI Grant to Study Cancer

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Dan Huh, Ph.D.

Dan Huh, Wilf Family Term Assistant Professor in the Penn Department of Bioengineering, has received the Cancer Research Institute (CRI) Technology Impact Award. Dr. Huh, whose research attempts to model cancer-immune cell interactions in microphysiological systems, will receive $1 million over the next three years for direct costs of his research.

“This award will provide us with an exciting opportunity to explore the potential of our organ-on-a-chip technology for the study of cancer immunotherapy, which is one of the most promising yet poorly understood clinical strategies for cancer treatment,” Dr. Huh said. “I am honored to receive this major award and excited with the prospect of contributing to this rapidly emerging area of medicine using innovative bioengineering technologies.”

Join us in congratulating Dr. Huh!

How Cells Spread in Fibrous Environments

New research by faculty in the University of Pennsylvania Department of Bioengineering is examining the interplay between cells and their environment and how they impact the cells’ ability to grow and spread, showing that stiffness is not the only factor researchers should consider when studying this process.

The relationship between cellular adhesion and spread is a key factor in cancer metastasis. Better understanding of this dynamic would improve diagnosis of the disease and provide a potential target in combating it; reducing the ability of cells to grip their environment could keep them contained.

 

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Vivek Shenoy (left) and Jason Burdick

The study, published in the Proceedings of the National Academy of Sciences, was led by Vivek Shenoy, professor in the Department of Materials Science and Engineering, co-director of Penn’s Center for Engineering Mechanobiology, and a secondary faculty member in the Department of Bioengineering, along with Xuan Cao and Ehsan Ban, members of his lab. They collaborated with Jason Burdick, professor in the Department of Bioengineering, Boston University’s Christopher Chen, the University of Michigan’s Brendon Baker and the University of Hong Kong’s Yuan Lin.

This collaboration reflects work of The Center for Engineering Mechanobiology, a National Science Foundation-funded Science and Technology Center that supports interdisciplinary research on the way cells exert and are influenced by the physical forces in their environment.

​​​​​​​Previous work from Shenoy’s group has shown that the relationship between cancer cells and the extracellular matrix is dynamic, containing feedback mechanisms that can change the ECM’s properties, including overall stiffness. One earlier study investigated how cancer cells attempt to strike a balance in the density of the fibrous netting surrounding them. If there are too few fibers to grip, the cells can’t get enough traction to move. If there are too many, the holes in the net become too small for the cells to pass through.

Read more at the Penn Engineering blog.

Bassett on Improvements in Executive Function

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Danielle Bassett, Ph.D.

Danielle Bassett, Eduardo D. Glandt Faculty Fellow and Associate Professor in the departments of Bioengineering and Electrical and Systems Engineering, recently collaborated with colleagues from the Perelman School of Medicine on a study that looks at how brain networks change as children develop into adolescence. Bassett’s previous work on applying network science principles to neuroscience has suggested that the organization of these networks helps lead to “cognitive control” and that they reorganize as children age, improving executive function.

In a new paper published in Current Biology, Bassett and her colleagues delve deeper into the network changes that lead to this improvement.

“The work,” Bassett says, “significantly extends our understanding of the role of modular network organization in development, and its importance for executive function.”

Margulies Named BME Chair at GA Tech/Emory

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Susan Margulies, Ph.D.

Susan S. Margulies, Ph.D., currently professor of bioengineering at the University of Pennsylvania, has been named the Wallace H. Coulter Chair of the Department of Biomedical Engineering at Georgia Tech/Emory University and the Georgia Research Alliance Eminent Scholar in Injury Biomechanics. Her appointment begins August 1.

Dr. Margulies’s history at Penn goes back to 1982, she arrived at Penn to earn a master’s degree in the bioengineering department, followed by her Ph.D. in 1987. In 1993, she returned to Penn as an assistant professor, with promotion to associate in 1998 and full professor in 2004.

“At GT-Emory BME I will lead 72 faculty and 1,500 students, and look forward to creating impact in a new environment,” Dr. Margulies says. “As a Penn alum and emeritus faculty member, my ties here run deep. I look forward to keeping in touch.”

Dr. Margulies’s has deep roots at Penn indeed, and her accomplishments are broad and distinctive. They include:

  • Creating new faculty mentoring programs across the university, including the Penn Faculty Pathways program
  • Originating the Penn Forum for Women Faculty, a key campus resource for discussion and collaboration
  • Chairing the Faculty Senate
  • Teaching a broad number of courses spanning Introduction to Bioengineering through to Pedagogical Methods in Engineering Education
  • Establishing many new research initiatives that extended into Children’s Hospital of Philadelphia and significant relationships with industry
  • Activity with several national leadership positions

On Dr. Margulies’s departure, David Meaney, the department chair, said, “We will miss Susan’s wisdom and insight, but we wish her the very best in her next step.”

Center for Curiosity Partners with Bioengineering

by Perry Zurn and Dani Bassett

Do not stop to think about the reasons for what you are doing, about why you are questioning. The important thing is not to stop questioning. Curiosity has its own reasons for existence. One cannot help but be in awe when he contemplates the mysteries of eternity, of life, of the marvelous structure of reality. It is enough if one tries merely to comprehend a little of this mystery each day. Never lose a holy curiosity.

–Albert Einstein1

This haunting passage prompts a series of difficult questions. Should we ever worry about where our curiosity goes? Is it true that curiosity is an end in itself? Or, are its justifications so obvious to us as to go unquestioned? Have we lost our sense of mystery? What makes curiosity holy? Einstein himself did not study curiosity, nor could he revolutionize the field of curiosity studies, which is just coming into its own today. But he does capture the compulsion of curiosity and its tantalizing promise.

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Kushal Sacheti, Founder and Director of the Center for Curiosity

The Center for Curiosity was established in New York in 2014 by Kushal Sacheti, a diamond merchant who was formerly an engineer. Its mission is to advance both the academic study of curiosity and the public practice of curiosity. A year after its founding, the first of its satellite centers was established at the University of Pennsylvania, in the School for Social Policy and Practice, under the leadership of Dean John Jackson, Jr. It is here that Mr. Sacheti’s dream of uniting engineering and curiosity came alive.

Given her work on the network neuroscience of human learning, Dr. Danielle Bassett, Associate Professor of Bioengineering, was one of the first faculty spotlighted in Penn’s Center for Curiosity seminar series. Her talk, “Flexible Brain Network Dynamics During Learning,” so perfectly represented the Center’s mission that she was quickly appointed to its advisory board. Shortly thereafter, Dr. Bassett invited the Center’s two postdoctoral fellows, Dr. Arjun Shankar and Dr. Perry Zurn, to lead curiosity workshops at the 2016 Penn Network Visualization program. This program provides young artists the opportunity to understand and creatively reimagine network science. Dr. Zurn’s seminar on structural models of curiosity, coupled with Dr. Shankar’s workshop on the affective elements of curiosity, inspired program fellows to explore curiosity not only in network science, but also in their own artistic praxis.

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Dr. Arjun Shankar, Center for Curiosity, Postdoctoral Fellow
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Dr. Perry Zurn, Center for Curiosity, Postdoctoral Fellow
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Dr. Danielle Bassett (left) and Dr. Susan Engel (right) at the Curiosity Across the Disciplines Symposium, December 9, 2016

 

 

 

 

 

 

 

 

Behind Dr. Bassett’s Network Visualization program is a passion for thinking between the arts and sciences and a conviction that they are richer enterprises together. An even broader commitment to interdisciplinarity energizes Penn’s Center for Curiosity. Last December, Drs. Zurn and Shankar organized the Curiosity Across the Disciplines symposium. This day-long event explored the concept of curiosity across major academic disciplines (history, medicine, ecology, neuroscience, psychology, education, anthropology, comparative literature, ethnic studies, political philosophy, and film). As presenters (including Dr. Bassett) reflected on their fields’ contributions to curiosity studies, as well as the role of curiosity in their own scholarship, a deeper, shared conversation emerged about how curiosity can help us to collectively navigate the scientific, educational, and political challenges of our times.

The collaboration between Penn’s Center for Curiosity and the Department of Bioengineering has really only begun. This fall, Drs. Zurn and Bassett are co-organizing a symposium on The Network Neuroscience of Curiosity. Speakers will include Dr. Danielle Bassett, Dr. David Danks (Carnegie Mellon University), Dr. Jacqueline Gottlieb (Columbia University), and Dr. Celeste Kidd (University of Rochester). And, as a long-term project, they have started a conversation about reinvigorating the Bioengineering curriculum with an emphasis on student curiosity and creativity. Sharing Penn’s commitment to community outreach, moreover, the Center for Curiosity and Department of Bioengineering are also in conversation with Westtown School about building an art- and science-centered curiosity initiative there.

If indeed one cannot help but be curious about life and its mysterious design, that journey is perhaps best undertaken together—Einstein’s fabled solipsism notwithstanding. This exciting new partnership at Penn is yet another step in that direction.

1 Albert Einstein, Statement to William Miller, as quoted in LIFE magazine (2 May 1955); reprinted in Joseph S. Willis, Finding Faith in the Face of Doubt: A Guide for Contemporary Seekers (Quest Books, 2001), 58; and William Hermanns, Einstein and the Poet: In Search of the Cosmic Man (1983; Brandon Books, 2013), 138.

Margulies Among Recipients of Award to Study Concussions

How can physicians and engineers help design athletic equipment and diagnostic tools to better protect teenaged athletes from concussions? A unique group of researchers with neuroscience, bioengineering and clinical expertise are teaming up to translate preclinical research and human studies into better diagnostic tools for the clinic and the sidelines as well as creating the foundation for better headgear and other protective equipment.

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Susan Margulies, PhD

The study will be led by three coinvestigators: Susan Margulies, the Robert D. Bent Professor of Bioengineering at the University of Pennsylvania’s School of Engineering and Applied Science (right); Kristy Arbogast, co-scientific director of the Center for Injury Research and Prevention at the Children’s Hospital of Philadelphia; and Christina Master, a primary care sports medicine specialist and concussion researcher at CHOP. They will use a new $4.5 million award from the National Institute of Neurological Disorders and Stroke.

The five-year project focuses specifically on developing a suite of quantitative assessment tools to enhance accuracy of sports-related concussion diagnoses, with a focus on objective metrics of activity, balance, neurosensory processing, including eye tracking, and measures of cerebral blood flow. These could also provide prognoses of the time-to-recovery and safe return-to-play for youth athletes. Researchers will examine such factors such as repeated exposures and direction of head motion. In addition, they will also look at sex-specific data to see how prevention and diagnosis strategies need to be tailored for males and females.

The multidisciplinary research team believes this study will result in post-concussion metrics that can provide objective benchmarks for diagnosis, a preliminary understanding of the effect of sub-concussive hits, the magnitude and direction of head motion and sex on symptom time course, as well as markers in the bloodstream that relate to functional outcomes.

Knowing the biomechanical exposure and injury thresholds experienced by different player positions can help sports organizations tailor prevention strategies and companies to create protective equipment design for specific sports and even specific positions.

The study will enroll research participants from The Shipley School, a co-ed independent school in suburban Philadelphias, and from CHOP’s Concussion Care for Kids: Minds Matter program which annually sees more than 2,500 patients with concussion in the Greater Delaware Valley region.

The study is funded by the National Institutes of Health.

Allen Foundation Awards Major Grant to Study Concussions

Faculty members in the Department of Bioengineering at the University of Pennsylvania are among the recipients of a major $9.25 million grant from the Paul G. Allen Family Foundation to study the mechanism underlying concussion and to investigate possible interventions.

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David Meaney, PhD, Solomon R. Pollack Professor and Chair of the Bioengineering Department (above left), is one of two principal investigators, with Douglas H. Smith, MD,  professor of neurosurgery at Penn’s Perelman School of Medicine (above right). In addition, Danielle S. Bassett, PhD, Eduardo D. Glandt Faculty Fellow and Associate Professor (below left), Dongeun (Dan) Huh, PhD, Wilf Family Term Assistant Professor (below center), and David Issadore, PhD, assistant professor (below right), all of BE Department, are co-investigators. The Allen Foundation grant also involves investigators from Columbia University (Barclay Morrison, Ph.D.), Duke University (Cameron Bass, Ph.D.), and Children’s Hospital of Philadelphia (Akiva Cohen, Ph.D.).

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Selected from a large national pool of applicants, the Allen Foundation grant will bring together new technology platforms developed by Drs. Huh and Issadore to study how concussions occur at the microtissue scale and release markers of rewiring  during recovery. Network theory models from Dr. Bassett’s group will provide an entirely new view on how concussion recovery occurs at all scales in the brain. The overall impact of the project will be to move away from the widely held perspective that all concussions should be treated identically and towards a view that concussions can follow several recovery pathways, some of which must be monitored closely in the days to weeks following injury.

Danielle Bassett on Social Networks, Brain Activity

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Danielle Bassett, PhD
Danielle Bassett, Eduardo D. Glandt Faculty Fellow and Associate Professor in the departments of Bioengineering and Electrical and Systems Engineering, recently collaborated with colleagues from the Annenberg School for Communication and elsewhere, applying her network science approach to the brain to a study of social networks.

When someone talks about using “your network” to find a job or answer a question, most people understand that to mean the interconnected web of your friends, family, and acquaintances. But we all have another key network that shapes our life in powerful ways: our brains.

In the brain, impulses whiz from one brain region to another, helping you formulate all of your thoughts and decisions. As science continues to unlock the complexities of the brain, a group of researchers has found evidence that brain networks and social networks actually influence and inform one another.

The study, published today in the Proceedings of the National Academy of Sciences looked at the brain’s response to social exclusion under fMRI, particularly in the mentalizing system, which includes separate regions of the brain that help us consider the views of others.

It found that people who show greater changes in connectivity in their mentalizing system during social exclusion compared to inclusion tend to have a less tightly knit social network — that is, their friends tend not to be friends with one another. By contrast, people with more close-knit social networks, in which many people in the network tend to know one another, showed less change in connectivity in their mentalizing regions.

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