Orthopedic Soft Tissue Research Program

Cartilage and Meniscal Restoration 

Ongoing projects suitable for resident involvement are focused on the following core themes:

1. Understanding the response of articular cartilage to altered loads.
   In this NIH funded project we take joint contact force data from cadaveric simulations and input them to bioreactor tissue explant models. We are studying how cartilage explants respond to loads that occur in an ACL ruptured knee. In doing so, we hope to translate contact stress data to ‘likelihood’ of damage profiles. The resident can be involved with the cadaveric studies (which use a multidirectional dynamic simulator), the analysis and interpretation of the data, or the bioreactor tissue-culture studies.
2. Scaffolds for meniscal and cartilage repair
   We are developing scaffolds that can adhere to soft tissue by chemical means, prior to cellular integration. Residents can be involved in assessing the ability of the scaffolds to withstand joint loads, to create a strong interface with articular cartilage under physiological loading conditions and to figure out how best to use the materials in a clinical environment.
3. Quantifying the effect of osteotomy on joint contact mechanics
   In this newly devised project, we aim to build patient-specific models that allow us to guide surgeons as to how degree of limb re-alignment can affect joint mechanics on a per-patient basis. Resident involvement will include working to segment geometries from scans, helping to interpret data from the computer-based models, and defining clinical relevant patient-to-patient variables to include in the models.

Enhanced Tendon-to-Bone Healing 

As a general principle, our areas of research parallel the common clinical problems that we encounter in sports medicine.  The resident could be involved in all facets of the studies, including animal surgery, tissue dissection, tissue preparation and execution of biomechanical testing, computerized image analysis of histology specimens, in vivo imaging (molecular imaging using fluorescent probes, in vivo micro CT, and in vivo MRI), data analysis, and manuscript preparation.

1. Investigation of the basic cellular and molecular mechanisms of healing between tendon and bone. We are using models of ACL reconstruction and rotator cuff repair. We are examining the role of mechanical load on the healing process. We are also planning to use transgenic mice to study the role of signaling molecules such as Indian hedgehog and scleraxis.
2. Tendonopathy: We have developed a mouse model of overuse tendonosis to study the basic cellular and molecular mechanisms involved. We will pair this work with parallel analyses of human tendinopathy samples.
3. Post-traumatic OA: We are using a mouse model to examine cell-based therapy for both prevention and treatment.
4. We are working with stem cell experts from Weill Cornell Medical College to evaluate the role of a novel cell population (activated endothelial cells) in stimulating the intrinsic stem cell niche. We are evaluating these cells in our PTOA model as well as our rotator cuff repair model.

Development of these mouse models is now allowing us to use transgenic animals. We can also now use in-vivo molecular imaging, high resolution microCT, and MRI in these animals. This imaging can then be evaluated in conjunction with our analyses at the tissue level (histology) and cellular level (molecular, gene expression analyses).

Biological Pathways in OA

1. PRP characterization and outcome analysis: This new study aims to better understand how platelet-rich plasma (PRP) treatment improves symptoms in some patients with OA. It involves the integrated efforts of the HSS Precision Medicine Laboratory and the HSS Healthcare Research Institute, with clinicians at HSS (Dr. Scott Rodeo and Dr. Brian Halpern) and Cornell-Ithaca (Dr. Lisa Fortier). Residents can (a) analyze PRP by Luminex (multiplex) approaches, (b) generate and analyze data (NanoString, RNA-seq, RTqPCR) from in vitro/cell-based systems, or (c) evaluate and analyze patients outcomes.
2. Contribution of DNA methylation to chondrocyte hypertrophy in OA: In this NIH funded project, we are studying how changes in DNA methylation (assessed in human tissues and in mouse models of OA disease) lead to abnormal gene expression, with emphasis in hypertrophy-related genes. Residents can be involved in processing (histology, immunohistochemistry, and isolation of cells and RNA/DNA) and analyzing (RNA-seq, DNA-methylation, RTqPCR) tissues retrieved from patients undergoing total knee replacement, as well in developing in vitro cell-based assays.
3. Evaluation of the role of the infrapatellar fat pad in OA disease: The infrapatellar fat pad (IFP) is a source of inflammatory factors, and its structural alterations associate with both pain and structural damage in OA patients. In this project, we will retrieve IFP from well-characterized (biomechanics and imaging) OA patients to perform detailed histological, cellular (FACS) and molecular (NanoString, RNA-seq, RTqPCR, ATAC-seq) analyses, aiming contributing factors and predictors of OA progression and/or outcomes post TKA. The residents generate and analyze data related with (a) processing IFP for histological and immunohistochemical characterization, or (b) isolating and characterizing the stromal vascular fraction at the cellular (FACS) and molecular (NanoString, ATAC-seq, RNA-seq)  levels.

Intervertebral Disc 

Several ongoing projects are focused on harnessing multiple facets of the cellular and molecular biological milieu of the spine to result in improved methods of spine fusion.  The methods being developed are tested using in vivo and tissue culture models.

Specific projects suitable for involvement of residents are:

1. Surgical delivery of small purified molecules of interest (eg. parathyroid hormone-related peptide or simvastatin): Using an in-house developed nanoparticle delivery approach, the ability of biologics to enhance fusion is being assessed.
2. Development of novel graft materials:  We are currently developing a hydrogel scaffold that will be utilized to minimize cells from being extruded from their transplanted location (posterolateral gutter or intervertebral disc space) so that the cells can provide their effects locally to where they are delivered. The scaffold is being formulated to help foster bone production, and will be optimized to have sufficient permeability to maintain viability of cells delivered yet mechanically “tough” enough to withstand forces applied to it and resist rapid dissolution.
3. Development of gene-reprogrammed cells: We are utilizing retroviral and adenoviral vectors to program target cells with genes of interest (eg. bone morphogenetic proteins, tumor necrosis factor, vascular endothelial growth factor, etc.) to study and manipulate mineralization status, permissiveness to vascular invasion, and conversion of naïve disc cells into hypertrophic chondrocyte-like cells, along with the gene regulation changes requisite.  Using site directed mutagenesis and RNA silencing, we are also developing techniques to alter the enzyme activity and expression levels of genes of interest in our models.
4. Assessing the molecular and cellular biology of primary cultures of nucleus pulposus (disc) tissue or explanted disc organ cultures. Using these models, we are assessing several factors (eg. bone growth factors, cytokines, etc) for potential roles in augmenting spinal fusion