| dc.description.abstract | More than 50% of adults in the United States are afflicted with musculoskeletal disease or injury, with bone fractures being the most common musculoskeletal condition requiring medical resources. While fracture repair is often uneventful, fracture nonunion remains a significant clinical and socioeconomic burden. Nonunion can occur if a fracture is improperly stabilized or if a patient’s biological healing capacity is inadequate. Improving the mechanical stability at the fracture can reduce the risk of developing a nonunion, but some movement at the fracture site is thought to be beneficial for healing. Bone grafting can also be used to enhance fracture repair, but autograft, the current gold standard of bone graft materials, is hampered by donor site morbidity and limited supply. In this work, in vitro, in silico, and in vivo models were developed to guide the development of a novel murine fixation device and evaluate synthetic bone graft alternatives. First, a suite of finite element models was created to identify which intramedullary nail design parameters have the largest impact on interfragmentary strain in a murine transverse femoral osteotomy model, and these simulations predicted that using rigid and compliant nails would most effectively support clinically relevant studies investigating how interfragmentary strain influences fracture healing. Next, amorphous calcium polyphosphate nanoparticles were investigated as a potential alternative to autograft in a clinically relevant murine posterior lumbar fusion model, and these nanoparticles induced at least as much bone growth and spinal fusion as iliac crest bone graft from genetically identical age-matched mice. Finally, a 3D in vitro humanized model of tumor-induced bone disease was developed by dynamically culturing osteoblast, osteoclast, and metastatic cancer cells together within tissue-engineered bone constructs. This model can be used to study the impact of bone metastases and potential drug therapies, and the learnings and analytical methods from this work can be used to compare the relative cell-mediated resorption rates of different bone graft materials or guide future mechanotransduction studies. Together, the models and materials developed in this dissertation can be used to advance fixation and bone grafting strategies that account for fracture severity and patient-dependent risk factors for nonunion. | |
