Collaboration : Enhancing Bone Regeneration by Mimicking the Osteogenic Niche
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abstract
Of the 13 million yearly fractures that occur in the United States, about 10% fail to repair and in extreme cases result in immobility or amputation. While autologous bone grafts are the most effective method to heal complex defects, the available graft material is limited, and the procedure involves additional surgery known to cause chronic donor-site pain in many patients. Human mesenchymal stem cells (hMSCs) have been intensely investigated for their ability to promote bone healing, but results have been variable and disappointing. This is at least partly due insufficient retention of hMSCs at the site of injury for sufficient time to achieve engraftment and promote repair. In an attempt to solve these problems, hMSCs have been treated with the small molecule PPARã inhibitor GW9662 to produce osteogenically-enhanced hMSCs (OEhMSCs). These OEhMSCs produce extracellular matrix (hMatrix) that dramatically increases hMSC retention and osteorepair in calvarial defects. The central hypothesis for this project is that an injectable microsphere vehicle co-administering GW9662, hMatrix and hMSCs will promote osteo-repair through a mechanism that involves extended hMSC retention, trophic factor secretion and paracrine activation of the host stroma. To test this, composite microspheres will be constructed and assessed for GW9662 delivery and hMatrix presentation to hMSCs in culture, as well as for their ability to promote repair of critical-sized defects in a mouse calvarial model. Finally, soluble factors secreted by hMSCs responsible for promoting osteoregeneration will be identified. These studies will lay the groundwork for translating this novel hMSC-based method for osteo-repair to the clinic. Successful completion of this project could lead to a revolutionary new method for bone repair that could effectively dismiss the need for autologus bone graft in regenerative orthopedics. These studies are based on the concept that providing an in vivo-like microenvironment stimulates hMSCs to behave as they do during normal tissue generation. This concept applies to hMSC-mediated healing in general, thus the knowledge gained from the proposed studies may eventally be applied to the regeneration of other tissue targets. The methods and concepts used to construct and evaluate the microsphere composites will be broadly disseminated in journals and conferences and incorporated into courses taught at Texas A&M. The PI has a record of successfully mentoring undergraduate researchers from underrepresented populations in his lab; the proposed project will provide additional opportunities for undergraduate research in the laboratory. As part of the project, two graduate students will be supported for their doctoral studies. The PI and the graduate students will each participate in outreach to high schools in the greater Houston area and develop media for broad use in the Texas school system.
