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Research Areas:
 

Musculoskeletal Tissue Regeneration

Repair of cartilage injuries remains a tremendous challenge, despite the development of surgical treatments such as microfracture and autologous chondrocyte implantation. These surgical procedures provide symptomatic relief of joint pain, but result in fibrous tissue that degenerates within several years. One of the fundamental challenges in the engineering of musculoskeletal tissues for regenerative medicine is the design of an appropriate 3-D scaffold, combined with an appropriate cell source. Our group is studying a biologically functional 3D-microenvironment for bone marrow stromal cells within self-assembling peptide hydrogel scaffolds that can stimulate chondrogenesis and cartilage neotissue production in vivo.  Collaborations with clinical veterinary laboratories enable direct testing of our approach in small and large animal models of defect repair (rabbit and horse). Equine models of cartilage repair have been recognized to have specific advantages for translation to human cartilage resurfacing. The horse provides the closest approximation to humans in terms of cartilage thickness and mechanical loading, directly relevant to pre-clinical human studies. Recent discoveries have shown that binding and tethering of chondrogenic factors (TGF-β1, IGF-1) within the self-assembling peptide gels before assembly resulted in reversible adsorption and sustained delivery to encapsulated BMSCs, which then undergo chondrogenic differentiation. In addition, the peptide gel alone showed improved filling of full-thickness osteochondral defects and improved cartilage repair in rabbits.


AFM-Based Molecular Imaging and Nanomechanics of Extracellular Matrix

We are utilizing molecular scale atomic force microscopy, high resolution- and lateral force spectroscopy to investigate the nanoscale structure and mechanical properties of extracellular matrix molecules such as aggrecan, a critically important matrix constituent of cartilage, intervertebral discs, and other tissues subjected to compressive loading. AFM images of aggrecan provide detailed structural information, including the ultrastructure of the aggrecan core protein and the spatial distribution of long chain glycosaminoglycans attached to the core protein. These features cannot be assessed by conventional biochemical means. In collaboration with Professor Christine Ortiz (DMSE), we are studying age- and disease-related changes in human aggrecan structure and associated changes in nanoscale compressibility and lateral deformability. Such changes may be directly linked to known differences in the deformational behavior of human cartilage in health and disease, such as occurs in the in early stages of osteoarthritis. These studies are combined with state-of-the-art biochemical and molecular biological analyses of such extracellular matrix molecules. Recent discoveries include the finding that aggrecan synthesized by adult marrow-derived stromal cells resembles aggrecan from young growth cartilage, suggesting that BMSCs are promising candidates for cartilage tissue engineering.


Traumatic Joint Injury

Joint injury caused by mechanical overload in vivo results in acute damage to cartilage and surrounding joint tissues. An inflammatory response accompanies acute injury, characterized by increased levels of pro-inflammatory cytokines in the synovial fluid (e.g., IL-1, IL-6, TNF-α) as well as increased levels of extracellular matrix fragments. Injury and prolonged inflammatory insult significantly increases the risk of developing arthritis. We have developed in vitro models that emulate injury to the whole joint, including incubation of injured cartilage in the presence of exogenous cytokines, and co-culture of injured cartilage in the presence of synovial tissue explants which secrete catabolic factors that can act on cartilage. Collaborations with the pharma and biotech industries are aimed at testing the hypotheses that (1) cartilage mechanical injury in the presence of inflammatory factors results in a synergistic degradation of cartilage matrix, and (2) that selected pro-anabolic and anti-catabolic treatments (e.g., small molecule enzyme inhibitors and biologic (antibody) cytokine blockers) can ameliorate cartilage degradation. A multi-targeted systems biology approach is used to studying fundamental mechanisms underlying tissue degradation. In parallel, we are initiating tests of this approach using mouse mimics of injury in vivo.

Drug Delivery for Osteoarthritis

Osteoarthritis (OA) affects millions of people worldwide but no disease modifying OA drug has been approved by the FDA for clinical purposes yet. One of the biggest challenges is to devise a method for local and safe delivery of potential therapeutics into cartilage to minimize their systemic side effects. Intra-articular drug delivery for local treatment of OA remains inadequate because these drugs get cleared out rapidly from the joint via vasculature or lymphatics. We are developing particle based drug delivery mechanisms for treating post-traumatic OA. Since cartilage is heavily negatively charged, it offers a unique opportunity to utilize electrostatic interactions to augment transport, binding and retention of drug carrying particles. This project focuses on: (1) Determination of the size range of drug carrying particles that can penetrate into the dense matrix of cartilage tissue using in-vitro cartilage OA models (normal cartilage explants are treated with catabolic agents and/or injury to mimic early stages of OA); (2) investigation of effects of electrostatic interactions on the partitioning, uptake and binding of drug carrying particles within cartilage; (3) bringing candidate drug-carrier moieties into animal models of post-traumatic OA. We are currently using Avidin, a positively charged protein as a nanoparticle carrier for delivering dexamethasone (DEX) and IGF-1 in an ACL injury based rabbit OA model; additional carriers are under investigation.

See the Center for Biomedical Engineering website for additional information.

 



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