Privileges & Pathways Through an Academic Career in Biomechanics: Appreciation for the 2022 ASME HR Lissner Medal

Winning an award carrying Lissner's name is itself a great honor, as Lissner was a genuine pioneer in creating the new disciplines of impact biomechanics and injury biomechanics but also in creating new equipment and measurement systems to obtain data never before acquired [1]. As outlined in an illuminating history of Lissner's legacy by Albert King and Michelle Grimm, Lissner deviated from his disciplinary strength in statics and dynamics to study skull fracture when approached by a surgeon, Dr. E Gurdjian, with an important problem. Lissner was motivated by the relationship with Gurdjian to determine magnitudes of force generating skull fracture on dry, cadaveric skulls but then continued to study crack propagation in skull fracture and eventually associated brain injury. I found this pattern driving Lissner's studies—research problems with outcomes that drive interest in new and different research problems to resonate with my own path through research. Like Lissner who “…was interested in a wide range of bio-engineering problems…”, I think my own story will reveal how bio-engineering problems of interest were driven in part by the people before me, trainees and colleagues, with study outcomes that led to a branching path through research in biomechanics.

Unlike Lissner, I started my research career immersed in biomechanics, working as part of a community of scientist-engineers asking all new questions about the mechanical behavior and failure modes for multiple tissues, including cartilage, joint capsule and intervertebral disk. I had completed my BSE in mechanical and aerospace engineering at Princeton University with lots of industry experience but no interest in working in industry. Instead, I was considering a route through medical school after returning to live with my parents in New York City. Then in 1985, Van Mow gave me the opportunity to work as a technician at his new lab at Columbia University Department of Orthopedic Surgery. He had organized a very large laboratory around teams working on problems in spine biomechanics, growth plate and articular cartilage, shoulder and hand biomechanics, and the hip. This team approach was very motivational for me with lots of opportunity for questioning, new learning and casual conversation that gave me the colleagues that would shape my journey for life. I first met three female engineers – Barbara Best (postdoctoral research associate), Wenbo Zhu (Ph.D. student) and Mary Beth Schmidt (laboratory manager)—who were all wiser and older and who gave me a vision of what was possible for me. I worked alongside all three on a multitude of experimental problems including compressive testing of the baboon endplate, rheological properties of the nucleus pulposus, and tensile testing of cartilage strips that gave me a sense of how engineering mechanics was adapted to accommodate the hydrated and “sticky” tissues of our bodies. Most of our studies were motivated by a desire to understand how the water components of soft tissues governed transient and dynamic mechanical behaviors, as Van Mow and Michael Lai were developing the mathematical framework for their comprehensive multiphasic, mixture theory (e.g., Ref. [2,3]).

By 1987, Van Mow had converted me to a Ph.D. student and I became one of a large group of students who would become life-long friends and family. This includes Kyriacos Athanasiou, Louis Soslowsky, and Gerard Ateshian (all HR Lissner medalists), as well as Nathaniel Bachrach, Boaz Cohen, and James Iatridis, all remaining active in research careers (Fig. 1). One of these students supported me on my own studies of cartilage mechanics in compression and later became my husband and father to our two children, Farshid Guilak (Fig. 2). From this initial period of trepidation and uncertainty, I emerged with a supportive community, a knowledge of an academic career path, and a doctoral thesis advancing a mathematical model to explain fluid flow-dependent and flow-independent viscoelasticity in articular cartilage [4]. Importantly, we learned that preservation of a highly organized surface zone, that was frequently lost in osteoarthritis, was important for fluid-pressurization of the cartilage layer and load support (Fig. 3).

While at Columbia University, my advisor introduced me to a rheumatologist, Dr. David Howell, who explained the importance of bone, cartilage and muscle remodeling processes in veterans that were immobilized due to injury or healing. It was Dr. Howell who first introduced the biology that drove the proteolytic resorption of some extracellular matrix molecules and not others, and the mechanical signals that drove tissues to remodel with applied loading. Although not named at the time, we now call this mechanobiology research which would capture my attention for years. Dr. Howell gave me my first VA subcontract funding when I started my own laboratory at Duke University in 1995 to study disuse atrophy in canines at the Miami VA Medical Center. We developed a noncontacting method to quantify cartilage mechanics with osmotic swelling by optical tracking of fiducial cell markers and worked with a new doctoral student, Daria Narmoneva, to validate that disuse-induced changes in cartilage mechanics could be detected [5,6] (Fig. 4). This new approach allowed us to pursue studies in cartilage of small mouse models just as studying genetic mutation models of musculoskeletal disease was a blossoming field. Thus, my lab launched its first projects studying mouse cartilage mechanics with grants from the Whitaker Foundation, NSF and NIH, plus collaborations with Thomas Jefferson Hospital that introduced me to some of the world's leaders in extracellular matrix mutations. Many of the musculoskeletal tissue changes in mouse models of genetic collagen mutations were fascinating and surprising, including a finding by Ph.D. student Larry Boyd that type IX collagen mutations were associated with an early onset of intervertebral disk degeneration [7]. While we began with a research problem in articular cartilage mechanics, it was the outcomes from this study that motivated continuing work on intervertebral disk pathomechanics.

Just as Lissner was advised to pursue research problems by a clinical colleague, it was an orthopedic surgeon at Duke (T. Parker Vail) who convinced me of the importance of the meniscus in joint health. Dr. Vail had an easy time engaging my newest doctoral students in studying meniscal tears, a common pathology in young athletes (and young students studying musculoskeletal disease). Michelle LeRoux-Williams and Maureen Upton-Dreher would sign up for “team meniscus,” leading finite element modeling of the anisotropic meniscus and experimental studies of the material (and later cellular) responses to damage and loading [8–10] (Fig. 5). This venture into studying anisotropy in multiphasic cartilage tissues revealed large values for Poisson's ratio in the meniscus that were associated with rapid and high levels of pressurization load support during loading. The role of this anisotropy was also behind the thesis work of my first doctoral student, Dawn Elliott, who obtained much-needed and highly cited material properties of the annulus fibrosus as a function of orientation [11]. The lab had virtually no money to purchase testing equipment, and we all spent too much time trying to resuscitate what test equipment we could find on campus. But these projects led to early successes for my Ph.D. students and follow-on funding that would be used to purchase new equipment and expand our research directions.

Tony Baer was a doctoral student pursuing biphasic finite element modeling research with me, following up on the work of Michelle LeRoux. Tony looked at the heterogeneity of intervertebral disk cell morphology during model construction and rightfully suspected that metabolism and phenotype were not the same for all cells. In particular, cells derived from the nucleus pulposus region of the intervertebral disk resided in a unique extracellular matrix environment that gave rise to unique finite element modeling predictions of their micromechanical environment [12,13]. Following the outcomes of our modeling work, we knew we had to understand the biological responses of cells to these vastly different micromechanical cues. When given my first sizeable grant from the NIH, I had the opportunity to hire a mechanical test engineer and purchase an Instron, or hire a cell biologist and acquire a bench-top thermal cycler. Jun Chen was the risk-taking cell biologist who signed up to work alongside me for over 12 years at Duke, advancing from postdoctoral research associate to Associate Research Professor with an independent NIH-funded program on stem cell differentiation for the intervertebral disk. Prof. Chen also recruited Liufang Jing as my laboratory manager and together they tackled new protocols, from isolating primary cells from the meniscus and intervertebral disk, to characterizing mRNA and metabolomics via high through-put screening methods. Prof. Chen and Liufang supported my research program and many, many dozens of students including Tony Baer, Maureen Upton-Dreher, and Larry Boyd with their collective expertise in molecular and cell biology that enabled our early studies of isolated cellular responses to compressive and osmotic loading [14–17].

As suspected, we found that cells of the disk responded to physical stimuli with vastly different metabolic behaviors. Doctoral students, Chris Gilchrist and Li Cao, believed spatially varying cell-matrix interactions to be key to this finding. Indeed, Chris showed that nucleus pulposus cells use unexpected integrin-pairs to bind to extracellular matrix proteins [18], and revealed the surprising presence of multiple laminins in these regions [19] (Fig. 6). While studying why and which laminins were present in the disk and how they regulated disk cell biology, Chris documented a very novel role for substrate stiffness in regulating nucleus pulposus cell biology with stiffnesses less than 0.5 kPa required to preserve cell phenotype [20,21]. How this phenomena is transduced to the cells would become the subject of research led by Duke student Priscilla Hwang, postdoctoral researcher associate Bailey Fearing, and Washington University student Julie Speer that would reveal how YAP/TAZ, cadherins and cell motility play a role in maintaining cell health [22–24]. Leading with the observation that mechanics regulates cell biology led us to ever new questions about the underlying mechanisms, and we were always fortunate to assemble the multidisciplinary expertise to undertake these goals.

In 2005, an opportunity to advance translational research in partnership with the Coulter Foundation was presented to the Duke department of biomedical engineering. This partnership – the Duke-Coulter Translational Research Partnership - was solidified in 2006 and really pushed me to consider how to translate my own fundamental research into products supporting repair for the intervertebral disk and cartilage. I found myself working with biomaterials scientists for the first time (Mark Grinstaff, Ashutosh Chilkoti, Stephen Craig) to design crosslinkable materials for repairing cartilage defects and delivering cells to the degenerated intervertebral disk. Our earliest work here involved design of tunable in situ crosslinked hydrogels guided by mechanical property goals to support cell viability, crosslinking to native tissue and mechanical load support [25,26]. Key to success of these projects was my recruiting a totally different type of trainee to the lab with a materials science or chemistry background. I had not the textbook knowledge nor experience to bridge the mechanics-materials divide, but had the tremendously good fortune to recruit Dana Nettles, Helawe Betre, S. Kenny Roberts, Aubrey Francisco, S. Michael Sinclair, Mohammed Shamji, Timothy Mwangi, Samuel Adams, Jr., Isaac Karikari, and Devin Bridgen to this challenge (Fig. 7). Over the years, this team engineered novel extracellular matrix (hyaluronan, laminin, elastin) presenting or drug presenting (inflammatory antagonists) gelling systems with a focus on increasing the residence time of the delivered cells and drugs at the defect site [27–32]. We focused on in situ gelling systems that were cleared slowly from the injected site (e.g., elastin-like polypeptide fusion proteins for drug delivery) or integrated with the adjacent and native tissue to avoid displacement during degradation (e.g., chemically crosslinked systems for cell delivery). The translational aspect of this work made it easy to recruit new trainees to the team and to interact with interested industry parties. When moving to Washington University in 2015, it was easy again to recruit Ian Berke, Marcos Barcellona, Julie Speer, Xiahong Tan and postdoctoral researchers Era Jain and Deepanjali Patil to these translational research projects, continuing our focus on cell and drug delivery for treating musculoskeletal pathologies [33–35].

Each of our translational research projects followed fundamental discovery of tissue biomechanics and extracellular matrix structure. In the case of intra-articular drug delivery in the treatment of osteoarthritis, we could engineer multiple drug carriers but never understand the processes governing drug uptake or drug clearance due to a lack of fundamental knowledge of tissue biomechanics and structure. While most of what we delivered was cleared through the joint lining tissue, or synovium, not enough was understood about the morphology, physical properties or solute diffusivities of synovium to be able to predict depot outcomes or guide drug depot design. With the support of doctoral students Young Guang, Alexandra Davis and postdoctoral research associate Milad Rohanifar, we returned to fundamental mechanics testing of synovium coupled with finite element modeling of solute and fluid transport (Fig. 8). This time, we were not writing our own code in C++ or comsol but benefited from the extensive efforts of my long-time colleague, Gerard Ateshian, who developed open-source FEBio along with Steve Maas and Jeff Weiss [36]. This transformative development allowed us to quickly code unsteady diffusive transport and compressive loading of the synovium to determine the diffusivity of multiple size solutes through human and animal synovium [37–39]. These newly obtained mechanical properties of diffusivity, hydraulic permeability, compressive modulus and Poisson's ratio, now guide our understanding of a role for intra-articular fluid pressure, tissue thickness and layers, and cellularity in both health and disease. Will we use this knowledge to design model-informed modifications to drugs and depots to inform new therapeutic solutions? Right now, I'm just enjoying the return to the roots of my career in biomechanics with fundamental studies of tissue properties that bring new discoveries and surprising insights each day.

I hope to have conveyed how many people accompanied me on my journey through an academic research career in biomechanics at Columbia, Duke and now Washington University in St. Louis. But even those three institutional names convey the privilege that has boosted me through this journey, beginning as a first-generation college student at Princeton. So when asked to participate in program development for undergraduate and graduate education, faculty governance, strategic planning, and departmental growth at Duke, I felt deeply committed to give back. Both at Duke and at Washington University, I have engaged with hundreds of undergraduates in the classroom and brought my excitement for biomechanics into their studies. And each year and each semester those students show me how to be a better teacher, a better mentor and a better campus citizen – the drive for a better world in our engineering students is infectious and critical to my daily rewards as faculty. I also contributed to ASME as an Associate Editor for the Journal of Biomechanical Engineering and on the awards committees, but was reprimanded as an assistant professor for not belonging to the Biomedical Engineering Society (I had joined a BME department and they wanted 100% faculty participation). So very early on, I began my career of service to BMES contributing to meeting organization, student affairs, on the board of directors and running the publications board, eventually following my department chair (George Truskey) and former Lissner Medalists (Kyriacos Athanasiou and Shu Chien) into the role of Society president. With resources newly available to me, I was eager to contribute to Society change through a partnership with the National Society for Black Engineers, and by organizing new award categories and philanthropic activities. Now as department chair at Washington University in St. Louis, I continue to mobilize resources and inspire our marvelous team of faculty, students and staff to create and grow new programs that improve opportunities for all. This has included faculty mentoring programs, campus-wide discussions around engineering education and race, launching of new training programs (Rising BME Scholars program, and new REU and T32 programs) the creation of new research centers (Center for Women's Health Engineering, Center for Cellular Condensates) and lots of faculty growth. Leadership affords us the possibility to build the world that we dream, and I've carried many lessons from my own experiences to dream up an engineering community that welcomes and nourishes all.

As I try to thank my many mentors, trainees and cheerleaders, I am remiss in not sharing appreciation for the talented staff at Duke University and Washington University in St. Louis and the many funding agencies that have supported my research program. It is staggering to contemplate how many individuals from students to staff, faculty collaborators and colleagues, and family have contributed to my standing today. I want to reserve a special shout-out to my husband who has been a steady supporter as a research collaborator and team member, but also as a sounding board for the ideas and challenges we face as citizens and leaders in our lives. Also a toast to the professional women in my life, the friends in my community in North Carolina and in St. Louis, and those that shared with me in the joy and responsibility of raising children together that have been a source of strength and support always. Finally, a special note of appreciation to the women engineering peers that walked the same path as did I from student to independent researcher, building a community that has collaborated to change the narrative around success and achievement and what it means to be a mentor. Some of these women (notably Jennifer Wayne and Rita Patterson) organized an ASME women's networking group that I remember as just a drink at the bar in a Vail resort in 2005, to a program event now attended by hundreds each summer. Their organizational efforts further point to the importance of having multidisciplinary teams of friends and family to navigate our path through the profession. I'm glad to be part of such a strong and committed “village” of bio-engineers and happy for the many moments of joy and surprise that came with it.

Thank you again for this honor.

The datasets generated and supporting the findings of this article are obtainable from the corresponding author upon reasonable request.