Clark T. Hung Receives UPenn Department of Orthopedic Surgery Distinguished Alumni Award

Clark T. Hung Receives UPenn Department of Orthopedic Surgery Distinguished Alumni Award

May 18, 2019

Professor Clark T. Hung, in his first presentation with his joint appointment in Orthopaedic Surgery, delivered a research seminar at UPenn this past weekend. He was awarded the Department of Orthopedic Surgery Distinguished Alumni Award (scientist). Dr. Robert L. Mauck, a previous graduate student in CEL, is now Director of the McKay Orthopaedic Research Laboratory at UPenn.

Check out the latest research from CEL published in the Journal of Orthopedic Research

Check out the latest research from CEL published in the Journal of Orthopedic Research

Cartilage Wear Particles Induce an Inflammatory Response Similar to Cytokines in Human Fibroblast-like Synoviocytes

Authors: Estell EG, Silverstein AM, Stefani RM, Lee AJ, Murphy LA, Shah RP, Ateshian GA, Hung CT.

Abstract: The synovium plays a key role in the development of osteoarthritis, as evidenced by pathological changes to the tissue observed in both early and late stages of the disease. One such change is the attachment of cartilage wear particles to the synovial intima. While this phenomenon has been well observed clinically, little is known of the biological effects that such particles have on resident cells in the synovium. The present work investigates the hypothesis that cartilage wear particles elicit a pro-inflammatory response in diseased and healthy humanfibroblast-like synoviocytes, like that induced by key cytokines in osteoarthritis. Fibroblast-like synoviocytes from 15 osteoarthritic humandonors and a subset of 3 non-osteoarthritic donors were exposed to cartilage wear particles, interleukin-1α or tumor necrosis factor-α for 6 days and analyzed for proliferation, matrix production, and release of pro-inflammatory mediators and degradative enzymes. Wear particlessignificantly increased proliferation and release of nitric oxide, interleukin-6 and -8, and matrix metalloproteinase-9, -10, and -13 in osteoarthritic synoviocytes, mirroring the effects of both cytokines, with similar trends in non-osteoarthritic cells. These results suggest that cartilage wear particles are a relevant physical factor in the osteoarthritic environment, perpetuating the pro-inflammatory and pro-degradative cascade by modulating synoviocyte behavior at early and late stages of the disease. Future work points to therapeutic strategies for slowing disease progression that target cell-particle interactions.

Lianna Gangi Publishes Undergraduate Research in Journal of Biomechanical Engineering

Lianna Gangi Publishes Undergraduate Research in Journal of Biomechanical Engineering

Title: On the Biomechanics of Cardiac S-Looping in the Chick: Insights From Modeling and Perturbation Studies

Authors: Ashok Ramasubramanian, Xavier Capaldi, Sarah A. Bradner and Lianna Gangi

Abstract: Cardiac looping is an important embryonic developmental stage where the primitive heart tube (HT) twists into a configuration that more closely resembles the mature heart. Improper looping leads to congenital defects. Using the chick embryo as the experimental model, we study cardiac s-looping wherein the primitive ventricle, which lay superior to the atrium, now assumes its definitive position inferior to it. This process results in a heart loop that is no longer planar with the inflow and outflow tracts now lying in adjacent planes. We investigate the biomechanics of s-looping and use modeling to understand the nonlinear and time-variant morphogenetic shape changes. We developed physical and finite element models and validated the models using perturbation studies. The results from experiments and models show how force actuators such as bending of the embryonic dorsal wall (cervical flexure), rotation around the body axis (embryo torsion), and HT growth interact to produce the heart loop. Using model-based and experimental data, we present an improved hypothesis for early cardiac s-looping.

Former CELer Terri-Ann Kelly, PhD Profiled on WPI Website

Former CELer Terri-Ann Kelly, PhD Profiled on WPI Website

Dr. Kelly graduated from Columbia in 2006 with her thesis titled: “Functional Tissue Engineering of Articular Cartilage: Characterization and Optimization of Chondrocyte-Seeded Agarose Hydrogels .” She now serves as lead engineer at EpiBone, spearheading the research and development of cartilage tissue products.

Eben Estell Defends his Thesis!

Eben Estell Defends his Thesis!

Eben defended his thesis, titled “Modulation of Synoviocyte Mechanotransduction in the Osteoarthritic Environment” on Friday, December 7. He will be doing his post-doc at Maine Medical Center Research Institute. Congratulations, Dr. Estell!

Thesis Abstract: The synovium is a specialized connective tissue that encapsulates diarthrodial joints like the knee, maintaining a low-friction environment for the articulating surfaces within. This tissue plays a key role in homeostasis by regulating solute transport in and out of the joint, and secreting paracrine and lubricating factors into the synovial fluid. The predominant cell type in the synovium is the fibroblast-like synoviocyte (FLS), which resides on the intimal surface of the tissue and produces lubricating molecules such as hyaluronan. Because these cells directly face the synovial fluid and apposing tissue surfaces within the joint, they are exposed to a dynamic environment of mechanical stimuli generated during daily activity. This dissertation addresses the global hypothesis that FLS are mechanosensitive to distinct modes of shear stress generated in the knee during articulation, and that modulation of this sensitivity by chemical and physical factors of the osteoarthritic (OA) environment contributes to disease progression.

Previous work has demonstrated that fluid-induced shear stress, generated as synovial fluid redistributes within the capsule during articulation, is a relevant mechanical stimulus for FLS. Exposure of FLS to fluid shear has been shown to modulate downstream functions such as lubricant secretion and the release of degradative matrix-metalloproteinases as induced by the cytokine interleukin-1, the latter indicating a link between mechanotransduction and the inflammatory environment of OA. The first goal of this dissertation was to further elucidate the process of mechanotransduction by characterizing the upstream response of FLS to fluid shear, to determine the influence of interleukin-1, and investigate known potentiators of mechanotransduction as potential mechanisms of the observed cytokine modulation. The work presented herein demonstrates for the first time a robust calcium signaling response of FLS to fluid shear, a key upstream event in the mechanotransduction of physical stimuli. Furthermore, the modulation of key aspects of this response were significantly altered by pre-exposure to interleukin-1, indicating a pathologic modulation of normal mechanosensing in the OA environment. This modulation was observed in both juvenile bovine and human FLS from healthy and OA donors, and was found to be potentiated by increases in intercellular communication via gap junctions as well as modulation of the primary cilia of individual cells.

In addition to chemical factors such as cytokines, the degradation of cartilage itself produces a physical factor, in the form of wear particles, that perpetuates the OA disease state. As degrading cartilage surfaces continue to grind against each other within the joint, these particles are released into the synovial fluid and attach to the synovium. We have previously shown in a bovine model that attachment of cartilage wear particles (CWP) to FLS monolayers in static culture induces release of pro-inflammatory mediators of OA. The second goal of this dissertation was to employ a similar in vitro model with human FLS to confirm CWP modulation of downstream function in static culture, as well as calcium signaling response when exposed to fluid shear. To this end, we found that CWP attachment to human FLS monolayers induces similar pro-inflammatory release products as observed in bovine models in static culture, and significantly modulates the calcium signaling response to fluid shear.

In areas of the articulating capsule where apposing tissues slide in direct contact with each other, shear stress generated by these frictional interactions may provide a physical stimulus distinct from fluid-induced shear stress. In this case of direct interaction between surfaces, the tissue-level frictional properties may affect the magnitude of shear stress presented to the cells within the intimal layer. While previous work has characterized synovium friction properties in sliding contact against glass, relatively little is known of synovium tribology in native tissue configurations, the influence of pathologic conditions such as CWP attachment, or the consequences for mechanotransduction of FLS within the tissue. The third goal of this dissertation is thus to characterize the effect of CWP on both tissue-level mechanical properties and cell-level mechanotransduction under sliding contact. The work herein presents consistently low friction properties for synovium against other tissues within the joint such as cartilage and demonstrates a significant increase in these properties when CWP are attached. A novel bioreactor was developed to characterize the effect of sliding contact on downstream functions of FLS within explant tissues, where initial results indicated an increase in metabolic activity in FLS exposed to sliding contact against cartilage.

The research presented in this dissertation further elucidates the processes of normal synoviocyte mechanotransduction, and by demonstrating that key chemical and physical factors of the OA environment modulate both cell and tissue-level functional properties, sheds light on the mechanisms by which the synovium contributes to disease progression. This sets the foundation for future work into synovium mechanotransduction in response to distinct physical stimuli and the relationship with tissue-level mechanical properties, and points towards clinical interventions that seek to restore the normal mechanical environment of the joint.

Robert Stefani Publishes New Functional Synovium-based Model of OA in Tissue Engineering Part A

Robert Stefani Publishes New Functional Synovium-based Model of OA in Tissue Engineering Part A

Robert Stefani publishes a novel in vitro tissue engineered synovium model, validated against native explants, to investigate the structure-function of synovium through quantitative solute transport measures. The synovium envelops the diarthrodial joint and plays a key regulatory role in defining the composition of the synovial fluid through filtration and biosynthesis of critical boundary lubricants. Synovium changes often precede cartilage damage in osteoarthritis, but the mechanism by which it may contribute to disease progression has not yet been elucidated. It is anticipated that this model will support efforts to develop more effective strategies aimed at restoring joint health.

Andy J. Lee Presents Research at BMES 2018

Andy J. Lee Presents Research at BMES 2018

CEL graduate student Andy Lee presented his research at the BMES Annual Meeting in Atlanta, Georgia. In his talk, titled “SB431542-Encapsulated Microspheres as a Strategy to Prevent Arthrofibrosis,” he discussed a novel approach to deliver a sensitive TGF-β inhibitor to the synovial capsule.

Clark T. Hung Co-Inventor of Award Winning Technology

Clark T. Hung Co-Inventor of Award Winning Technology

The Missouri Osteochondral Preservation System (MOPS) won the 2018 best technology in sports medicine award, presented by Orthopedics This Week. The technology significantly extends the life of tissue allografts, with the added benefits of the use of closed containers, serum-free media that includes dexamethasone, and the ability to be stored at room temperature. MOPS was developed by MTF Biologics in conjunction with Missouri Orthopedic Institute & ConMed, with CEL Director Clark T. Hung and former CEL doctoral student Eric Lima as co-inventors and engineers.

Saiti Halder Invited to Present at SciSymp2018 Conference

Saiti Halder Invited to Present at SciSymp2018 Conference

Saiti Halder, an undergraduate researcher in CEL, will be presenting her work at the Scientista Symposium Poster Fair and Competition in Times Square on April 14. The symposium is part of SciSymp18, which celebrates "Innovation in STEM - Scientistas Advancing the Field." Great job, Saiti!