Patient-specific approaches to bone regeneration

Abstract

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.