New Chair for Biomedical Engineering

New Chair for Biomedical Engineering

Renowned inventor Kristi Kiick takes the helm of growing department

Kristi Kiick, the Blue and Gold Distinguished Professor of Materials Science and Engineering at the University of Delaware, is the new chair of the Department of Biomedical Engineering, effective December 1, 2020.

Kiick is an internationally recognized inventor and an expert in the design and synthesis of biologically inspired and biologically produced materials, developing materials for treating wounds, arthroses, and surgically manipulated blood vessels.  She served as the Associate Director of the BME program in 2010-2011, working with the Director, Jill Higginson, a professor of mechanical engineering and biomedical engineering, and now associate dean for graduate and postgraduate education in the College of Engineering.

A Fellow of the American Chemical Society and a member of the National Academy of Inventors, Kiick has published nearly 175 articles, book chapters, and patents, and has delivered over 200 invited and award lectures. Kiick’s honors have included several awards (Camille and Henry Dreyfus Foundation New Faculty, Beckman Young Investigator, National Science Foundation CAREER, DuPont Young Professor, and Delaware Biosciences Academic Research Award, Leverhulme Trust Visiting Professor, Fulbright Scholar) as well as induction as a Fellow of the American Institute for Medical and Biological Engineering and of the American Chemical Society Division of Polymer Chemistry. She also serves on the advisory and editorial boards for multiple international journals and research organizations.

From 2011 to 2019, Kiick served as the deputy dean of the College of Engineering. In this role, she worked with stakeholders across the university and region to develop interdisciplinary graduate and research partnerships with various industries and national laboratories. She also focused efforts internally to strengthen the college’s intellectual and physical infrastructure.

From July 2019 through July 2020, Kiick studied in the United Kingdom through a Leverhulme Visiting Professorship, which provides funds for eminent scholars to visit the UK, and a Fulbright Award, one of the most prestigious international scholarship opportunities.

“Kristi is a highly regarded scholar and innovator, and a proven leader,” said Levi Thompson, Dean of the College of Engineering. “I cannot think of a person better suited to lead our Department of Biomedical Engineering into its next phase of growth for impact.”

“It is a great honor to have the opportunity to work with the BME faculty, staff, and students,” said Kiick. “The department has a wonderful foundation and trajectory, and I am looking forward to working collaboratively with the department and its partners to further extend BME’s impact.”

A growing department

For the last decade, the biomedical engineering department, established in 2010, has been led by founding department chair Dawn Elliott, Blue and Gold Distinguished Professor of Biomedical Engineering.

The department has grown rapidly, accommodating up to 100 new students each fall, plus a thriving graduate program. It is rated among the top one-third of all biomedical engineering departments nationwide.

Under Elliott’s leadership, the department has recruited award-winning faculty, four of whom have received prestigious NSF CAREER Awards within the past three years.

Students and alumni are thriving as well. For example, 95 percent of biomedical engineering alumni who received a bachelor’s degree from 2015 to 2019 are employed or pursuing higher education. They’re working in 49 states and 94 countries around the world.

“Dawn has been a tremendous leader. She took an idea and helped turn it into the research and education powerhouse that our biomedical engineering department is today,” said Thompson.

Doctoral Dissertation Defense  –  Omar Ambrocio Banda

Doctoral Dissertation Defense – Omar Ambrocio Banda

BME PhD Candidate, Omar Ambrocio Banda, will be defending his dissertation

TITLE:

Reference-free Traction Force Microscopy to Investigate Cell Adhesion and Mechanotransduction 

When:   Thursday, October 29, 2020 @ 9:00 am
Where:  Zoom Meeting: https://udel.zoom.us/j/95950766250     Password: BANDA
Committee Chair:   John Slater, PhD
Committee:   Dawn Elliott, PhD, Jeffrey Caplan, PhD, Darrin Pochan, PhD

ABSTRACT:

Physical stimuli present in the extra-cellular domain influence cell-fate decisions. Understanding the mechanisms of these signaling pathways may provide better strategies for guiding cell-fate decisions in clinically relevant cell populations. In these populations, batch-to-batch variations between cellular doses negatively impact both consistency and efficacy of therapeutic doses of cells. Altogether, this results in reduced numbers of emergent therapies in clinical trials. Of the many types of mechanical stimuli which can affect cells, one promising avenue capable of clinical intervention has been control of the physical properties of the substrate on which cells are cultured. Substrate properties such as stiffness and adhesive ligand presentation dictate how cells can adhere and have demonstrated impacts on important cell-fate decisions, such as cellular proliferation and differentiation. While the mechanisms of this route of mechanotransduction are not well understood, it is evident that signaling through these pathways requires cell adhesion to the substrate followed by cytoskeletal contraction. The overall goal of this research is to design, develop and validate a platform capable of approximating the magnitude of these contractile forces to determine the relationship between cell generated forces and cell-fate decisions.

The first objective of this research was to develop a physical platform capable of recapitulating physical aspects of native extra-cellular matrix, including stiffness and ligand presentation, in a tunable way. In addition, the platform needed modular support for fiducial marks which could be used for identifying deformations in the materials. These design criteria were accomplished using a light catalyzed poly(ethylene glycol) diacrylate (PEGDA) hydrogel system, coupled with multiphoton lithography to generate fiducial markers within a base PEGDA hydrogel. We demonstrate the versatility of this system to generate a wide variety of fluorescently labeled cellular substrates with tunable stiffness and ligand presentation. We debut the platform’s capabilities by demonstrating control over adhesive-ligand concentrations as well as spatial distribution to control cell adhesion in various cell types, while simultaneously supporting fluorescent tracking of substrate deformation.

The second objective of this research was to develop the software tools necessary for high-throughput analysis of cell-generated forces. Existing platforms to study cellular traction forces—collectively referred to as traction force microscopy (TFM)—all suffer from low experimental throughput, often as low as 1-5 cells per sample. While there are many contributors to this low yield, the majority of these contributing factors can be circumvented through the implementation of reference-free schemata in place of traditional approaches. We highlight here several reference-free solutions made possible using computer algorithms to identify, catalogue, track and predict fiducial marker location and reference coordinates. Using these computational methods, we demonstrate the full implementation of a reference-free TFM platform with a competitive resolving power for cellular tractions. We demonstrate the inherent compatibility of this platform with existing computational methods for the conversion of marker displacements to material stresses and cellular tractions. We also demonstrate the ability to generate these traction profiles in a fully automated and high-throughput manner.

The final objective of this research was to implement the platform to approximate cell-generated forces alongside measures of activation of Focal Adhesion Kinase (FAK). FAK is a signaling kinase found in focal adhesions and is associated with regulation of cell-fate decisions such as migration, proliferation, and differentiation. Simulations of FAK interactions, as well as single protein force measurements, suggest that FAK kinase activity may be linked to the application of force across its structure after incorporating into focal adhesions. If true, FAK may serve as an early mechano-sensor in a variety of pathways. Here we demonstrate the ability to measure FAK phosphorylation at the pFAK576/577 Tyr residues with simultaneous measures of cellular traction. We demonstrate that these measures can be performed with sufficient accuracy and high-throughput to make meaningful conclusions about mechanotransduction in cellular models. We are the first to report that FAK phosphorylation is upregulated during early cell spreading, coinciding with increased stress on focal adhesions. While further testing is needed to verify our hypothesis linking adhesion tension to pFAK, these results and the methodologies presented here will guide future studies into the function of FAK as an early mechanosensor and provide the framework to explore other mechanically active proteins, such as paxillin.

        Altogether, this work satisfies the need for platforms capable of supporting quantification of cell generated forces paired with measures of protein recruitment and activation. The knowledge gained from these studies will fuel the development of better strategies to isolate, culture and expand clinically relevant cell populations for cell-based therapeutics.

Engineering Leader

Engineering Leader

Ten years ago, award-winning mentor Dawn Elliott founded UD’s biomedical engineering department

Dawn Elliott is having a banner year. As an academic, she’s winning awards, reaching milestones and receiving major kudos from students and colleagues who’ve benefited from her leadership. And yet, she’s not all that interested in talking about triumphs. For all her professional prowess, she’d much rather chat about mistakes.

“In science, you experience more failure than success,” said Elliott, a Blue and Gold Distinguished Professor of Biomedical Engineering at the University of Delaware. “And you learn more from it as well.”

In 2010, Elliott founded UD’s Department of Biomedical Engineering, which she chairs. With help from UD and College of Engineering leadership, she made it her mission to hire a dynamic faculty — 50 percent women — who would feel a sense of ownership in building a robust program from the ground up. Her efforts paid off. In its infancy, the unit had the capacity to enroll 40 eager undergraduates — now, it accommodates up to 100 new students each fall, plus a thriving graduate program. It is rated among the top one-third of all biomedical engineering departments nationwide.

According to her colleagues, this rapid growth is partially due to Elliott’s position as president of the Biomedical Engineering Society — heading this international body of more than 7,500 distinguished members continues to bring great visibility to the program. But this growth is also due to Elliott’s on-campus leadership.

“The role of a chair isn’t just to build their own career; it’s to build the career of every person in the department,” said Emily Day, associate professor of biomedical engineering who has worked with Elliott since 2013. “So you need someone who is incredibly selfless, and that’s Dawn. She does whatever she can to get us the resources we need for success.”

Under the department’s purview is Elliott’s own laboratory, which focuses on the functionality of orthopedic soft tissues — her research is pushing the scientific community closer to understanding and addressing chronic back pain. She’s had more than 150 peer-reviewed papers published, collaborated on the creation of two patents and spearheaded several breakthroughs in the field. Among them? The development of a better method for seeing into the human spine as it functions.

“What sets my group apart is the way we combine experiments, imaging and modeling,” Elliott said. “Sometimes, people have a deep expertise in one of these areas, but when you integrate them all together you can address your problem in a more holistic way. An advantage of working at UD is access to the bioimaging and MRI centers here — these core facilities are top in the nation and very accessible to faculty. At other institutions, resources like this are often sequestered for use only by certain people.”

Throughout her academic life, Elliott has taken students under her wing, mentoring them in and out of the lab. She served on the board of The Perry Initiative, a nonprofit co-founded by UD professor Jenni Buckley that inspires young women to be leaders in the fields of orthopedic surgery and engineering. In recent years, Elliott’s received national recognition for outstanding mentorship (see: here and here). Now, she is being honored yet again, this time by the American Society of Mechanical Engineers (ASME). In June, the global association announced Elliott would receive the prestigious Robert M. Nerem Education and Mentorship Medal for being a tireless champion of students.

“She is a big reason why I decided to pursue a career in academia,” said Grace O’Connell, who nominated Elliott for the award. An associate professor of mechanical engineering at the University of California Berkeley, she studied under Elliott at her previous appointment at the University of Pennsylvania. “For her, it’s not just about the nuts and bolts of the research, but really looking at giving back to the scientific community — and reshaping the community itself. Now that I am in the academy and learning my own mentorship style, taking bits and pieces of what I’ve learned from Dawn, I’ve grown to really appreciate the emotional part that she puts into listening to her mentees.”

Elliott will be the first to tell you — and here is where that comfort with admitting missteps comes in — she wasn’t always the world’s best adviser. It took some time at the beginning of her career to realize that “not all students were just like me,” she said. “We’re not all motivated by the same things. I like to get an early start, others work best late at night; I thought everyone working toward a PhD wanted to be a professor, but there are many different career paths. Over time, I’ve learned from the unique perspective that every student brings, and I’ve changed my mentoring style.”

Talking openly about mistakes is something Elliott encourages from all her mentees. At a weekly meeting of her research team, one of the items on the agenda is to share slipups made in the previous seven days, whether that’s breaking a piece of lab equipment, failing to properly record the steps of an experiment or forgetting about an appointment (it happens even to the organized, science-minded set).

“We’ve found that this has made a huge difference,” Elliott said. “It helps everyone understand that other people make mistakes, too. Oftentimes, it’s easy to feel like you’re all alone in screwing up and you can’t do anything right. So this becomes a bonding — and a learning — opportunity.”

Babak Safa

“Dawn Elliott is a leader,” said Babak Safa (pictured), who earned a doctorate in mechanical engineering from UD in 2019. “As a boss, you feel she’s in the same boat with you, pushing the envelope by your side. She’s an asset to our community and our society.”

Take Babak Safa, who completed his doctoral dissertation on tendon damage mechanics at UD in 2019. When he struggled a couple of times to get his first theoretical paper through the peer-review process, he found comfort in Elliott’s don’t-get-discouraged philosophy. She normalized rejection — and reworking — as part of the process. Eventually, the paper was published.

“Dawn models persistence, perseverance and having faith in the work that you’re doing,” said Safa, now a postdoctoral fellow at the Georgia Institute of Technology. “She taught me how to make my contribution without being easily intimidated.”

But Elliott’s guidance went beyond academics.

“I can remember in 2016 when the travel ban was signed,” Safa added. “UD has a sizable Iranian graduate student population, and we were all in a state of panic. This was devastating — to devote years of your life to science and not know if you were going to be able to continue your studies. I remember having a meltdown, and Dawn reassured me that we were in this together. She was going to do everything in her power to make sure I completed my PhD. It was the best thing that could have happened to me during those uncertain days.”

Andrea Lee

“Dawn Elliott allows students to explore what they’re interested in,” said Andrea Lee (pictured), who earned a doctorate in biomedical engineering from UD in 2018. “I know in some labs, the principal investigator is more interested in their own vision, and students may not have as much freedom. But Dawn was open to trying many different avenues. She’s the best professor-mentor a person can hope for.”

Andrea Lee, who earned a doctorate from UD in 2018, had a similar experience when Elliott served as lead researcher on her dissertation project involving tendon degeneration.

“When you’re working with someone for four years, you’re going to have personal stuff that comes up,” said Lee, an associate medical director for the VMLY&R healthcare marketing company in Manhattan. “I got into two car accidents in the span of six months, and the stress of it — dealing with lawyers and insurance — broke me in a way. She was there to talk to me and really listen. Because I was living by myself — my family is in Korea — I really appreciated having that support.”

Recently, while giving an acceptance speech for her most recent mentorship award, Elliott stepped outside the boundaries of her laboratory duties once again — addressing the ASME community via Zoom, she devoted her talk to racial inequalities in academia and the responsibility successful white academics in particular have to acknowledge, and to fix, these disparities. Naturally, she led by acknowledging mistakes she has made in the past. Among them? Being oblivious to her own white privilege for much of her life.

“Meritocracy, in which success and status and life depend largely on my individual talents and abilities and efforts, is largely a myth,” she said. “Much of my success and status is unearned by being born into this system.”

In the next 10 years, Elliott said she will continue using her platform to raise awareness for biases that creep into all University settings, and she will work to grow the department she founded at UD a decade ago — she’s hoping to acquire funding for a new center for musculoskeletal research. Most of all, she’s looking forward to seeing the future successes of her students, and, of course, helping them through those inevitable failures, too — inside the lab and out.

“Dawn cares about your career development, your research knowledge and your place in the field,” Safa said. “But she cares about you on a personal level, too. If she’s working with you, you’re growing in all aspects of your life. I’m a better person because of her.”

Doctoral Dissertation Defense  –  Ashutosh Parajuli

Doctoral Dissertation Defense – Ashutosh Parajuli

BME PhD Candidate, Ashutosh Parajuli, will be defending his dissertation

TITLE:

Mechanical Adaptation of Diabetic and Perlecan Deficient Skeletons

When:   Friday, August 7, 2020 @ 2:00 pm
Where:  Zoom Meeting: https://udel.zoom.us/j/8914904609
Committee Chair:   Dr. Liyun Wang
Committee:   Dr. X. Lucas Lu, Dr. Catherine B Kirn-Safran, Dr. Mary C. Farach-Carson, Dr. Ryan Zurakowski, Dr. X. Sherry Liu

ABSTRACT:

Bone, a “smart material”, keeps adapting its structure and mass under mechanical cues to meet its load-bearing function in the body. This amazing capability arises from its living cellular residents, whose sensitivity to mechanical and chemical signals, along with cell-cell communication over time and space, result in an adaptive mechanism, encoded in genes and yet modulated by environments, which works efficiently to ensure the proper maintenance of healthy adult skeleton. However, this robust adaptive process could be impaired by diseases. The overall objective of my thesis was to investigate how diabetes (a metabolic disease condition) and perlecan deficiency (a rare genetic condition, Schwartz-Jampel Syndrome) alter the adaptive response of skeleton to mechanical loading or disuse. The clinical motivation of this line of research is to maximize the anabolic potentials of mechanical stimulation in promoting bone health, a strategy complementary to pharmaceutical interventions.

Given our lab’s interest on osteocytes, the primary mechanosensing cells in bone and the master orchestrator of bone remodeling, I focused my investigations on how hyperglycemia (a complication of uncontrolled diabetes) affects the sensitivity of osteocytes and bone tissue to mechanical loading. I further investigated the effects of deficiency of perlecan, a critical component of osteocyte mechanosensing pericellular complex, on bone cells and bone tissue responses to the removal of loading and subsequent reloading. My results demonstrated the robustness of bone formation driven by mechanical loading in mice with normal or mild diabetes (40% elevated blood glucose), while sever diabetes (>200% elevation) completely abolished bone formation and inhibited osteocyte’s intracellular calcium and other responses to fluid flow. With decreased perlecan content in bone, a severe osteoporotic skeletal phenotype was seen in the trabecular bone compartments of the perlecan deficient mouse mutants. This phenotype was present for both axial bone (vertebrate) and long bones (femur and tibia) and progressively worsen with age, primary due to the upregulation of osteoclastogenesis. Also, for the first time, we found that the perlecan deficient mice, although lost bone similarly as wild type under hindlimb suspension, could partially recover from the bone loss after re-ambulation.

Although my results provide experimental evidence that metabolic and matrix perturbations like diabetes and Schwartz-Jampel Syndrome negatively affect bone, bone cells, and bone adaptation process, the robustness of the bone adaptation process is also evident in the load-induced bone formation found in mildly diabetic mice and the surprising recovery from bone loss after re-loading of perlecan deficient mice. Despite the experiments were performed in mice, these findings could provide insights on managing bone health in patients suffering diabetes (e.g., getting the blood sugar level in control) or Schwartz-Jampel Syndrome (e.g., engaging moderate exercise). Overall, my thesis supports that exercise is a potent anabolic stimulus to bone. Unlocking or restoring its power by regulating the underlying mechanisms could be an effective way to promote bone health.

Doctoral Dissertation Defense  –  Ryan C. Locke

Doctoral Dissertation Defense – Ryan C. Locke

BME PhD Candidate, Ryan C. Locke, will be defending his dissertation

TITLE:

Preclinical Translation of Therapeutic Interventions for Tendon Injury

When:   Friday, August 7, 2020 @ 10:00 am
Where:  Zoom Meeting ID: 986 5266 3559
Password: Locke1
Committee Chair:   Megan Killian, PhD.
Committee:   Dawn Elliott, PhD., April Kloxin, PhD., Karin Silbernagel, PhD.

ABSTRACT:

The burden of injury to tendon and the attachment between tendon and bone (i.e., the tendon-bone attachment) on quality of life, disability, health care, and the economy is significant. Unfortunately, current therapeutic interventions have high re-injury rates and do not restore the optimized multiscale structure and function of the healthy tendon or attachment. Investigations are needed to further develop and validate methods to prevent re-injury and improve tendon and attachment healing. The overall goal of this dissertation was to improve the preclinical translation of therapeutic interventions for tendon and attachment injury. The body of work in this dissertation helps to translate therapeutic interventions for tendon and attachment injury by establishing (1) an improved animal model of attachment injury, (2) success criteria for preclinical translation of hydrogels for tendon repair, (3) the safety and efficacy of a clinically available therapy, and (4) biomarkers of tendon injury.

The first aim of this research was to develop and validate a rat model of localized and partial-thickness attachment injury. The first part of this aim established the multiscale biomechanical properties of the attachment with and without localized defects ex vivo. Biomechanical tests validated that strain concentrations localize at the defect site, suggesting that defects may propagate in vivo. The final part of this aim established the cellular, structural, and biomechanical healing capacity of the attachment in vivo. Collectively, this aim established that the attachment has limited healing capacity and validated this animal model for continued preclinical translation of therapeutic interventions for improving the healing capacity of the attachment.

A weak scar tissue forms following tendon and attachment injury due to poor cell-mediated repair. Engineered cell-instructive cues within synthetic hydrogels are promising therapeutic strategies for tissue regeneration. However, the soft mechanical integrity of hydrogels raises concern about the functional application of hydrogels in mechanically demanding environments like tendon and attachment repair. In the second aim, we developed rigorous success criteria for preclinical testing of hydrogels in mechanically demanding environments by systematic review of the literature. Subsequently, using our success criteria, we demonstrated the preclinical efficacy of multi-functional synthetic hydrogels for tendon repair. This aim indicated the promise for continued preclinical translation of synthetic hydrogels for tissue regeneration.

Therapeutic interventions that alter the normal cellular response to injury may cause undesired effects in vivo. Therefore, in vivo investigations are needed to validate the safety and efficacy of cell-targeted therapies. The third aim of this dissertation evaluated the preclinical safety and efficacy of near-infrared light therapy during both tendon maturation and following injury in vivo. This aim showed that light therapy may be a beneficial therapy for tendon injury because it mildly improved the biomechanical properties of tendon healing without any adverse effects.

Prognostic biomarkers of tendon injury may help to improve clinical decisions for treatment. Currently, several biomarkers of tendon injury exist, however a need exists to determine whether biomarkers are pathological or necessary adaptations to injury. The final aim investigated metabolic biomarkers following mature tendon injury in comparison to normal tendon growth. In this aim, we identified several biomarkers of tendon injury that were not expressed during normal tendon growth.

This dissertation is significant in that I not only advanced knowledge of the characteristics of attachment healing but also helped to advance the preclinical translation of therapeutic interventions for tendon healing and repair. In summary, in my dissertation work, I aimed to answer fundamental questions about therapeutic interventions for tendon injury to increase the likelihood for successful preclinical translation and to ultimately reduce the time from bench to bedside.