The Impact of Injury-Associated Anemia and its Treatment on Fracture Healing

Project Summary 78.2 million lower extremity fractures occurred globally in 2019, of which 5-10% resulted in delayed or failed healing. Further, fractures with vascular injuries have poor healing at higher rates (up to 46%), emphasizing the importance of oxygen delivery to the injured region during healing. Recent clinical studies found injury-associated anemia—hemoglobin (Hb) < 12 g/dL—is present in ~95% of lower extremity orthopaedic trauma patients. Due to decreased Hb, anemia is characterized by lower tissue oxygenation levels and increased systemic inflammation, both of which are linked to impaired bone healing. While blood transfusions remain the current standard of care for injury-associated anemia, they demonstrate less than 1% efficacy, whereas intravenous iron therapy (IVIT) achieves ~80% success in chronic anemia cases but remains unexplored in orthopaedic trauma management. To determine the impact of injury-associated anemia on bone healing, I developed a novel murine model of femur fracture with injury-associated anemia. Using this model, I demonstrated that moderate anemia (7 < Hb < 12 g/dL) reduces regenerating bone volume after injury, suggesting that anemia contributes to impaired bone healing. However, the underlying cause of impaired bone healing in the presence of injury-associated anemia and how to manage injury-associated anemia after injury have not been studied. Thus, the overarching objective of this study is to identify how injury-associated anemia affects bone healing processes and determine if IVIT treatment can facilitate successful bone healing. First, I will determine the impact of injury- associated anemia on temporal inflammation, hypoxia, and bone regeneration following fracture. In the second aim, I will establish the efficacy of IVIT in facilitating bone regeneration via resolution of orthopaedic injury- induced anemia. The research outcomes of this work will 1) provide insight into the biological effects by which injury-associated anemia impedes bone regeneration and 2) inform the translation of IVIT into the orthopaedic clinical setting to support bone healing. This work will inform clinicians on how management of injury-associated anemia can improve patient care after orthopaedic trauma. The proposed studies will be performed at Oregon Health and Science University, a world-class training environment with strong clinical collaborations. Drs. Karina Nakayama (sponsor) and Nick Willett (co-sponsor) have developed a comprehensive training plan to support my professional and technical development including skills in mentorship and scientific communication in addition to technical skills including multiparameter flow cytometry and dimensionality reduction techniques for multivariate analysis. Drs. Nakayama and Willett are engaged mentors with expertise in the research of musculoskeletal injuries and treatments. Dr. Willett offers access to cutting-edge biomedical innovation and collaborations at the University of Oregon. Dr. Nakayama, Dr. Willett, and my established history of productive collaboration through routine in-person and virtual meetings will ensure this proposal’s success. This research setting and their expert guidance will enable collaborative, impactful, & innovative research.