An NIH-designated Center of Biomedical Research Excellence (COBRE)

Research Projects 2022-25

The Delaware Center for Musculoskeletal Research Projects Awards offer needed assistance to early-career investigators on the path to research independence.

Charles Dhong, PhD
Assistant Professor
Material Science & Engineering
Biomedical Engineering
University of Delaware
Profile

Thematic area: Osteoarthritis & Diagnosis

Project title: Restoring the fixed charge density of damaged articular cartilage through synthetic aggrecan mimics

Christopher Price

Summary: Currently, there are no lasting treatments to restore degenerated articular cartilage in people with osteoarthritis. Many treatment strategies for osteoarthritis attempt to restore the extracellular matrix (ECM) to its native stiffness, but these approaches have not been successful. Instead, this project focuses on the ability for healthy cartilage to swell, which in conjunction with the stiffness of the ECM, helps support load and lower friction. The ability for cartilage to swell, or its osmotic pressure, is derived from the negatively charged sidechains of proteoglycans (aggrecan). These negatively charged groups (glycosaminoglycans) are lost in osteoarthritis. To restore the osmotic pressure, often measured as the fixed charge density, we propose developing synthetic aggrecan mimics made from polystyrene sulfonate. In conjunction with this treatment, we will develop a platform capable of resolving cartilage swelling in situ, which will help determine our treatment efficacy, while also contributing to a timeline of mechanical changes in the cartilage. To facilitate physiological relevance, our platform will evaluate swelling on full-stack equine explants. This project will first establish how typical OA-like processes, like enzymatic digestion, impact the in situ swelling in our cartilage explants. Then, we will test how more physiologically relevant OA precursors, such as mechanical injury or inflammation, lead to aberrant swelling behavior. Due to the orthogonal nature of swelling measurements to standard mechanical testing, we will be able to decouple mechanical changes derived by the osmotic pressure of the cartilage from those resulting from matrix damage. Finally, after synthesis of our polymer aggrecan mimics, we will test if our intervention can revert the swelling behavior of damaged cartilage into the swelling behavior seen in native cartilage. The impact of this work is a new treatment strategy based on the swelling behavior of cartilage: while swelling is equally important to the mechanical function of cartilage, it has not seen a similar level of research as an intervention target. We hypothesize that without restoring the swelling behavior, current OA treatment strategies are unlikely to be successful in the long term.

Research Projects 2021-24

The Delaware Center for Musculoskeletal Research Projects Awards offer needed assistance to early-career investigators on the path to research independence.

Elise Corbin, PhD
Assistant Professor
Biomedical Engineering
Materials Science and Engineering
University of Delaware
Profile

Thematic area: Disease Modeling and Tissue & Regenerative Engineering

Project title: Competition between Resistance Training and Inflammation in an On-Chip Skeletal Muscle Microtissue Model of Sepsis

Elise Corbin

Summary: Chronic and acute inflammation are significant contributors to skeletal muscle pathology in multiple diseases. Severe inflammation associated with sepsis has profound short- and long-term effects on muscle. Sepsis is characterized by a dysregulated immune response to infection that can alter muscle force generation, wasting, and bioenergetics. Survivors of sepsis have increased risk for the development of persistent acquired weakness syndromes. The inflammatory response in sepsis is mediated by the release of pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α) and interleukin 1 beta (IL-1β). While we know that sepsis-induced changes in skeletal muscle are associated with inflammation, the mechanisms underlying muscle dysfunction in sepsis are not well understood, and there is a significant need to capture the evolution of these impairments to establish effective treatment strategies. Harnessing in vitro models of cytokine-induced myopathy in human skeletal muscle can inform and elucidate fundamental mechanisms of pathology in sepsis enabling development of effective treatments. Resistance training is a widely accepted prescriptive treatment for rebuilding muscle strength and mass. However, post-recovery resistance training has minimal long-term effects in many sepsis patients, and recent studies suggest that early (pre-recovery) physical therapy may preserve muscle fiber cross-sectional area though not strength, indicating a need for further analysis of the complex evolution of sepsis. This evidence formed the cornerstone of our hypothesis that inflammation limits the therapeutic effects of resistance training, which will be tested in a 3D in vitro organoid model.

Justin Parreno, PhD
Assistant Professor
Biological Sciences
Biomedical Engineering
University of Delaware
Profile

Thematic area: Articular cartilage

Project title: Cytoskeletal Mechanisms that Regulate Chondrocyte Architecture and Phenotype

Justin Parreno

Summary: Osteoarthritis (OA) is an irreversible, debilitating, and chronic disease. Current OA treatments are either surgical or aimed at pain with poor long-term reparative outcomes. Thus, there is a need to develop new OA treatments. Targeting the actin cytoskeleton in chondrocytes may be a promising strategy for treatments against OA. Actin is an abundant, ubiquitously expressed protein in cells that exists as globular (G-) molecules which polymerize to form filamentous (F-) actin. Proper F-actin organization into diverse higher order structures is required for the maintenance of chondrocyte morphology which determines phenotype. Despite strong links between actin reorganization and the chondrocyte phenotype it remains unclear if targeting actin reorganization is a feasible strategy against OA. This is due in large part to two critical knowledge gaps: 1) It remains unclear how specific deregulated F-actin populations (i.e. stress fibers) can be abolished, while retaining other vital F-actin networks (i.e. cortical actin). To fill this knowledge gap, a greater understanding on the regulation of F-actin networks by actin binding proteins is needed. 2) It is unclear if F-actin reorganization occurs and plays a role in OA pathogenesis in native chondrocytes. Previous studies have determined that treatment of chondrocyte with inflammatory mediators results in reorganization of cortical F-actin networks into stress fibers. However, these studies were performed on in vitro cultured cells. It is unknown if F-actin occurs in vivo. To assess actin reorganization in cartilage, the development of new high-to-super resolution imaging methodology of chondrocytes within native cartilage is required. Our long-term goal is to enable actin-based interventions against OA.

Pilots 2022-23

The Delaware Center for Musculoskeletal Research Pilot Awards offer needed assistance to early-career investigators on the path to research independence.

Emily Day, PhD
Associate Professor
Biomedical Engineering
Material Science & Engineering
University of Delaware
Profile

Thematic area: Nanomedicine and osteoporosis

Project title: Membrane-wrapped nanoparticles for targeted cargo delivery to mesenchymal stem cells

Charles Dhong

Summary: This project seeks to develop a biologically inspired nanomedicine that enables safe and effective treatment of osteoporosis, a devastating disease that affects over 10 million Americans annually. The proposed technology consists of cargo-loaded polymer nanoparticles that are wrapped with membranes derived from mesenchymal stem cells (MSCs), which are the precursors to bone-forming osteoblasts. We postulate that the unique proteins expressed on the MSC membrane surface will enable the MSC membrane-wrapped nanoparticles (MWNPs) to selectively bind and deliver cargo to MSCs both in vitro and in vivo. By manipulating MSCs through drug or nucleic acid delivery, it may be possible to enhance osteoblast activity and thereby improve bone density and decrease the risk of fractures. Towards this goal, we propose to (1) evaluate the ability of MSC MWNPs to bind and enter MSCs in vitro without inducing cellular toxicity and (2) demonstrate that MSC MWNPs, but not non-targeted polymer NPs, preferentially interact with MSCs versus hematopoietic stem cells (HSCs) in vitro. Validating the MSC MWNPs can effectively target MSCs in vitro will support future in vivo evaluation and development of this platform for treatment of osteoporosis and other bone diseases

X. Lucas Lu, PhD
Associate Professor
Mechanical Engineering
University of Delaware
Profile

Thematic area: Cartilage biomechanics

Project title: Resveratrol for the Protection of Osteocyte Mechanotransduction

Christopher Price

Summary: This project aims to study the potential of using resveratrol as a food supplement to reduce
postmenopausal bone loss. Resveratrol is a natural antioxidant presented in the skin of grapes, red wine,
and berries. Many studies in cancer and anti-aging research have revealed the health beneficial effects of
resveratrol. A recent clinical trial showed that resveratrol can slow down bone loss in postmenopausal
women. We have found that resveratrol can attach on collagen molecules and protect collagen fibrils from
enzymatic degradation. Resveratrol can also inhibit the activities of matrix metalloproteinases. Based on
these finding, we propose to test a new bone-protective mechanism of resveratrol, i.e., resveratrol can
protect the integrity of the osteocyte pericellular matrix post menopause by simultaneously strengthening
the collagen fibrils and inhibiting collagen degradation. We will first test the hypothesis using an
ovariectomized mouse model. The mice received resveratrol in food are expected to have higher density
of PCM tethers and more robust responses under loading. The unique protective mechanisms of
resveratrol will then be defined using cell and bone explant culture models. MMP activity assays will be
performed to determine the inhibition efficacy of resveratrol on various MMPs. The outcome of this project
could motivate resveratrol consumption in the population who are suffering from or at a high risk of bone
loss. The project aligns with the DCMR missions that include the “identifying potential therapeutic
intervention” to improve skeletal health.