Date of Award
Doctor of Philosophy
Comparative and Experimental Medicine
David E. Anderson
Alexandru Biris, Madhu Dhar, David Harper, Pierre-Yves Mulon, H. Steve Adair
Regenerative therapies, or bone substitutes, for long bone fractures are on the verge of becoming standard practice. Development of a wide variety of synthetic materials has been undertaken in effort to improve healing of debilitating fractures. An ideal bone substitutes would mimic natural bone physiology. The form and function of long bones must first be understood in order to create the ideal regenerative material. From there, basic fracture healing provides key insights as to where and how fractures may advance to stages of non-healing. The ideal bone substitute would be both osteo-inductive and osteo-conductive. An effective material to promote bone healing in large defects has yet to be developed, and large animal preclinical models are lacking. Few large animal studies looking at bone regeneration exceed ninety days making long-term osseointegration of the bone substitute difficult. One of the most studied platforms for synthetic bone substitutes are nanohydroxyapatite and polyurethane composites due to their biocompatibility and bioresorbability. The studies detailed here focus on the biological assessment of a bone substitute that contains polyurethane, nanohydroxyapatite, and decellularized bone particles. A multitude of in vivo assessments were carried out to assess the impact of the bone substitute on a novel preclinical large animal model of long term bone healing. Baseline gait assessment characteristics were able to be determined for goat models relating to apparently healthy goats prior to the start of the bone healing model. Positive results were associated with long term integration of the bone substitute when the material was impregnated with the growth factor bone morphogenetic protein-2. The most catastrophic complication of any bone substitute used for long bone fractures, infection was encountered. Phenotypic and whole genomic characterization of the Staphylococcal associated infections, and subsequent osteomyelitis, were performed. It was recognized that there was an initial bone proliferation associated with Staphylococcus aureus associated osteomyelitis cases. The successful large animal preclinical model may provide an alternative to study bone substitutes. Conventional fixation methodologies may be removed, after sufficient healing time, to allow for further investigation into the integration and rehabilitation of the bone substitute with the native bone.
Rifkin, Rebecca Elaine, "Osseointegration of Complex Scaffolds. " PhD diss., University of Tennessee, 2020.