Advisor: Robert E. Guldberg, Ph.D. (Georgia Institute of Technology)
Johnna S. Temenoff, Ph.D. (Georgia Institute of Technology)
Krishnendu Roy, Ph.D. (Georgia Institute of Technology)
Greg Gibson, Ph.D. (Georgia Institute of Technology)
Steven L. Stice, Ph.D. (University of Georgia)
Patient-specific Approaches to Bone Regeneration
Bone is the second-most transplanted tissue after blood with more than 1.6 million bone grafting procedures performed annually in the US at a cost of over 5 billion dollars. Treatment of large bone defects in particular remains one of the most challenging problems faced by orthopedic surgeons. Current therapies include bone grafts and/or delivery of osteoinductive proteins such as bone morphogenetic protein 2 (BMP-2). Despite advances in surgical technique and medical care, many of these treatment options still exhibit high variability in healing, suggesting that patient-specific factors, such as age, gender, treatment timing, and immune status, may play a much more crucial role in treatment success than previously thought. Thus, the need to account for these patient-specific factors with more sophisticated treatment strategies has become increasingly apparent.
The main objective of this work was to use preclinical animal models to investigate the influence of patient-specific factors on bone regeneration, with a particular focus on long-term immune profile characterization as it relates to the bone healing response after treatment. The impact of age and dose on large bone defect healing was assessed using a well-established bone injury rat model along with delivery of BMP-2 in a collagen sponge, which is the current clinical standard. These results offer valuable insight on a controversial subject: the use of BMP-2 in pediatric patients. Additionally, this work sought to elucidate some of the key mechanisms that lead to impaired healing following nonunion, a significant clinical problem that still affects up to 10% of patients with long bone injuries. To accomplish this, a chronic nonunion model was established that can potentially serve as a more rigorous and clinically relevant platform for studying nonunion and testing novel therapeutics. Finally, the issue of trauma-induced immune dysregulation was evaluated in this model of nonunion as a potential harbinger of poor healing outcome. Collectively, these studies have advanced our understanding of the factors that affect bone regeneration and represent a pivotal step towards improved, more personalized treatment strategies for bone repair.