Featured Investigators

Chelsea Bahney, PhD 

Building a Better Bone:

Promoting Endochondral Ossification to Stimulate Vascularized Bone Regeneration

 

My research focuses on developing therapeutic strategies that recapitulate the normal sequence of fracture repair to improve clinical outcomes in bone regeneration. Cartilage is the natural precursor of bone during embryonic development, limb growth, and fracture repair. However, current therapies to treat challenging bone defects or stimulate de novo bone regeneration transplant bone to promote the process of intramembranous ossification. This approach fails to stimulate adequate angiogenesis within the bone graft, resulting in limited osteogenesis, poor osseointegration, and ostenecrosis: as a result clinical failure rates are estimated between 16-35%.

The conceptual foundation of my laboratory is that we can improve vascularized bone regeneration by using tissue engineering strategies to promote endochondral ossification. We propose engineering a cartilage template that will stimulate angiogenesis and osteogenesis for improved clinical outcomes in bone regeneration. Our preliminary pre-clinical studies have validated this approach and demonstrated that cartilage promotes a highly vascularized and integrated bone regenerate that outperforms allograft and is not significantly different than the gold standard bone allograft.1 (FIG 1)

The research efforts supported by the CCMBM Pilot grant aim to translate these preclinical data by developing an endochondral cartilage graft appropriate for human use. Using the CCMBM core facilities we are using novel analytical tools to understand how bioactivity of different types of cartilage vary and how to optimize this tissue for a safe and efficacious cartilage allograft. This research aims to understand how the extracellular matrix of cartilage plays a role in regulating either a stable articular phenotype that can be used for articular cartilage repair, compared to cartilages that stimulate bone formation.

Figure 1: Endochondral Cartilage Grafts Promote Vascularized Cartilage Regeneration.
Endochondral cartilage grafts were isolated from the cartilage phase of fracture callus (top) and transplanted into critical sized segmental defect in an externally stabilized murine tibia (bottom). (A-C) Safranin-O staining shows loss of cartilage, while (E-G) Masson’s Trichrome staining demonstrates conversion to a traeculated bone state during the time course of healing (A&E) 7, (B&F) 14, or (C&G). (D) µCT image of tibia defect 4 weeks post-surgically demonstrates integrated bone formation. (H) PECAM staining indicates extensive re-vascularization in the graft. “cb” = cortical bone (host), “graft” = transplanted fracture callus cartilage.

LITERATURE CITED
1  Bahney CS, Hu DP, Taylor AJ, Ferro F, Britz HM, Hallgrimsson B, Johnstone B, Miclau T, Marcucio RS. (2013) Stem cell derived endochondral cartilage stimulates bone healing by tissue transformation. J Bone Miner Res. Epub 2013 Nov 21. Doi: 10.1002/jbmr.2148; PMID: 24259230

 

 

Chelsea Bahney, PhD
Assistant Professor, Orthopaedic Surgery

Research Interests: Endochondral bone regeneration, tissue engineering, polytrauma, chondrocyte transformation, stem cell therapies.

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Xiaojuan Li, PhD and Benjamin Ma, MD

In search of preventive measures for post-traumatic osteoarthritis: Synovial fluid characterization after anterior cruciate ligament injuries using novel techniques and approaches

The research efforts supported by the CCMBM Pilot grant aim to translate these preclinical data by developing an endochondral cartilage graft appropriate for human use. Using the CCMBM core facilities we are using novel analytical tools to understand how bioactivity of different types of cartilage vary and how to optimize this tissue for a safe and efficacious cartilage allograft. This research aims to understand how the extracellular matrix of cartilage plays a role in regulating either a stable particular phenotype that can be used for articular cartilage repair, compared to cartilages that stimulate bone formation.

We are exploring the role of inflammation on the development of posttraumatic osteoarthritis after ACL injury and reconstruction. Synovial fluid from these patients might tell us what inflammation does to the knee joint years after surgery.  

 

We are following a cohort of patients who were recruited at the time of their acute ACL injury and are now 2-3 years out from ACL reconstruction. We have collected a myriad of data at multiple time points: biomechanics, quantitative MR, and 3D motion analysis, to name a few.

 

Our present topic focuses on synovial fluid drawn from these patients at the time of their ACL reconstruction. The biochemical profiles of synovial fluid can tell us great details about the cartilage as the body attempts to heal from injury. The inflammatory process at the time of injury has been proposed as a possible contributor to rapid cartilage degeneration that may lead to posttraumatic osteoarthritis. Our preliminary data shows high concentrations of cytokines and markers of cartilage turnover after injury. Some of these seem to correspond to synovitis on MRI and T1ρ relaxation times in the cartilage.

 

Synovial fluid NMR spectra show us another way of measuring inflammation and degradation by characterizing the metabolic profiles of tissues. Advantages of NMR techniques include the need for small amounts of sample for analysis (20ul), its non-destructive nature, and its high throughput without the need for pre-selection of analytical parameters or sample derivatization procedures.

 

 

 

 

Xiaojuan Li, PhD
Professor, Radiology

Research Interests: Medical imaging, MRI, MR spectroscopic imaging,  clinically oriented quantitative imaging, cartilage degeneration,  osteoarthritis, joint injury, rheumatoid arthritis, marrow adiposity and  osteoporosis; MR techniques, musculoskeletal applications, arthritis

 

 

Benjamin Ma, MD
Professor, Orthopaedic Surgery

Research Interests: Non-invasive monitoring of joint condition, biomarkers, joint fluid assays & analysis, correlation of objective biomarkers with patient-reported outcomes.

 

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Aaron Fields, PhD 

Endplate dysfunction in disc degeneration:

Investigating solute transport kinetics, disc cell viability, and new imaging methods

Why do some discs degenerate while others don’t? Knowledge from this research will advance our understanding of disc degeneration etiology and will help guide new prevention strategies, diagnostics and therapeutics. My broad research interests relate to structure-function relationships in musculoskeletal tissues. One specific focus is the cartilage endplate (CEP), which is a thin layer of cartilage that separates the intervertebral disc cells from their nutrient supply. Decline in nutrient supply is believed to be an important reason why disc cells fail to remodel their matrix. With support from the CCMBM Pilot and Feasibility grant program, we’re combining advanced microscopy techniques, new clinical imaging tools and a novel diffusion chamber to establish the effects of CEP structure on nutrient transport and disc cell function (Figure). The long-term hypothesis of this work is that a new MR imaging sequence that we developed to non-invasively assess CEP permeability can forecast which discs will degenerate and which will benefit from treatment. For this work, I’m collaborating with Dr. Roland Krug (Department of Radiology and Biomedical Imaging), an expert on MR pulse sequence development for musculoskeletal tissues.

Figure 1: (Left) Fluorescence recovery after photobleaching is used to measure solute transport kinetics in the CEP. The rate of fluorescence intensity recovery relates to CEP permeability  (Right) Diffusion chambers mimic the diffusion-limited nutrient environment of the disc and allow us to evaluate the effect of CEP permeability on disc cell viability and function. Disc cells are loaded into the chambers. Glucose diffuses from media through CEP samples at the open sides of the chambers. CEP permeability, which controls nutrient supply, and cell density, which determines nutrient demand affect the viable distance; see live/dead transition in the micrograph taken from the boxed region.

 

 

Aaron Fields, PhD
Assistant Professor, Orthopaedic Surgery

Research Interests: spine, biomechanics, intervertebral disc degeneration, osteoporosis, low back pain, finite element analysis.

 

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Xuhui Liu, MD

Neuro-regulation of osteoporosis and heterotopic ossification after spinal cord injury

 

 

 

The long-term goal of this research project is to understand the mechanism of central nerve system regulating skeletal system health. My research focuses on the molecular mechanisms of skeletal muscle atrophy, degradation and heterotopic ossification after direct and indirect injuries. My research focuses on key molecular pathways involved in skeletal muscle atrophy, fibrosis and fat infiltration, including Akt/mTOR, TGFβ and PPARg pathways. A significant part of my research program focuses on the transcriptional and post-transcriptional regulation of ECM remolding enzymes, such as MMP-2 in skeletal muscle injury and regeneration. I am also interested in the role of complement and other immuno system in heterotopic ossification in muscle. The goal of my research is to gain a better understanding of the underlining molecular mechanisms of muscle atrophy, degradation and ossification after injuries, as so to develop effective treatments for these muscle disorders. Physiological and pathological muscle-bone interaction is within my central interests of research. In the past a few years, I have developed a novel murine model of spinal cord injury (SCI)-induced HO, in which we have found significantly altered myokine expression in muscle, along with the development of osteoporosis and HO. In this proposed project, we will determine the role of central nerve system in regulating bone and muscle physiology in a murine model.

 

 

Xuhui Liu, MD
Associate Professor, Orthopaedic Surgery​

Research Interests: Atrophy, skeletal muscle, matrix metalloproteinases, gene transcription regulation, ligament and tendon, rotator cuff, articular cartilage, muscle fat infiltration, mesenchymal stem cell, heterotrophic ossification, osteoporosis.

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