Repair of large structural bone defects remains a major problem in orthopaedic reconstruction surgery due to the limited supply of cortical bone autograft and the poor long-term outcomes obtained with structural allografts. While there is no substitute for structural allografts, based on their biomechanical and biocompatible properties, their lack of osteogenic and osteoinductive potential, combined with the host's inability to remodel processed cortical bone, results in a high percentage of fractures. Towards elucidating the cellular and molecular mechanisms that regulate structural bone graft healing, we have developed a murine femoral segmental allograft model. Using this model we were able to demonstrate that autograft healing is superior to that observed with allografts due to the angiogenic and osteogenic activity from live periosteal cells. We have also developed novel approaches to engraft cells and/or recombinant adeno-associated viruses (rAAV) on the cortical surface of the femoral allografts. Based on this, we hypothesize that: 1) allograft healing and later repair is limited by the absence of angiogenic and osteogenic cells. 2) Revitalization of lifeless allograft using a cell based tissue engineering approach and/or AAV based gene therapy will confer angiogenic, osteogenic and remodeling properties on processed cortical bone leading to enhanced bone allograft healing. In our first Specific Aim, we will utilize our murine femoral bone graft model to perform transplantation of live isografts from C57B/6 Rosa 26A male mice to formally demonstrate the contributions of periosteal donor cells in structural bone graft revascularization, osteogenesis and remodeling, in our second Specific Aim, we will seed bone marrow stromal cells onto processed allograft to examine their efficacy on bone healing and remodeling of frozen allograft. In our third aim, we will combine stem cell engraftment and rAAV gene therapy to complement processed structural allograft with live cells and angiogenic-osteogenic signals, and compare its healing with autograft and allograft.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Skeletal Biology Structure and Regeneration Study Section (SBSR)
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Panagis, James S
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University of Rochester
Schools of Dentistry
United States
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Huang, Chunlan; Tang, Minghui; Yehling, Eric et al. (2014) Overexpressing sonic hedgehog peptide restores periosteal bone formation in a murine bone allograft transplantation model. Mol Ther 22:430-439
Krill, Kenneth T; Csencsits-Smith, Keri; Wood, Sherri C et al. (2013) Glucocorticoid-induced TNFR-related protein stimulation reverses cardiac allograft acceptance induced by CD40-CD40L blockade. Clin Dev Immunol 2013:986859
Lyu, Seungyoun; Huang, Chunlan; Yang, Hong et al. (2013) Electrospun fibers as a scaffolding platform for bone tissue repair. J Orthop Res 31:1382-9
Colnot, CĂ©line; Zhang, Xinping; Knothe Tate, Melissa L (2012) Current insights on the regenerative potential of the periosteum: molecular, cellular, and endogenous engineering approaches. J Orthop Res 30:1869-78
Wang, Qun; Huang, Chunlan; Xue, Ming et al. (2011) Expression of endogenous BMP-2 in periosteal progenitor cells is essential for bone healing. Bone 48:524-32
Yazici, Cemal; Takahata, Masahiko; Reynolds, David G et al. (2011) Self-complementary AAV2.5-BMP2-coated femoral allografts mediated superior bone healing versus live autografts in mice with equivalent biomechanics to unfractured femur. Mol Ther 19:1416-25
Li, Dan; Gromov, Kirill; Proulx, Steven T et al. (2010) Effects of antiresorptive agents on osteomyelitis: novel insights into the pathogenesis of osteonecrosis of the jaw. Ann N Y Acad Sci 1192:84-94
Liu, Yaqing; Zhang, Xinping; Xia, Younan et al. (2010) Magnetic-field-assisted electrospinning of aligned straight and wavy polymeric nanofibers. Adv Mater 22:2454-7
Wang, Qun; Huang, Chunlan; Zeng, Fanjie et al. (2010) Activation of the Hh pathway in periosteum-derived mesenchymal stem cells induces bone formation in vivo: implication for postnatal bone repair. Am J Pathol 177:3100-11
Ritchlin, Christopher T; Proulx, Steven; Schwarz, Edward S (2009) Translational perspectives on psoriatic arthritis. J Rheumatol Suppl 83:30-4

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