Approximately 6.3 million fractures occur in the U.S. annually, with 5–10% resulting in debilitating nonunions. A major limitation to achieving successful bony union is impaired neovascularization. To augment fracture healing, we designed an implantable drug delivery technology containing the angiogenic stimulant, deferoxamine (DFO). DFO activates new blood vessel formation through iron chelation and upregulation of the HIF-1α pathway. However, due to its short half-life and rapid clearance, maintaining DFO at the callus site during peak fracture angiogenesis has remained challenging. To overcome these limitations, we composed an implantable formulation of DFO conjugated to hyaluronic acid (HA). This compound immobilizes DFO within the fracture callus throughout the angiogenic window, making it a high-capacity iron sponge that amplifies blood vessel formation and prevents nonunions. We investigated implanted HA-DFO’s capacity to facilitate fracture healing in the irradiated rat mandible, a model whereby nonunions routinely develop secondary to obliteration of vascularity. HA-DFO implantation significantly improved radiomorphometrics and metrics of biomechanical strength. In addition, HA-DFO treated mandibles exhibited a remarkable 91% bone union rate, representing a 3.5-fold improvement over non-treated/irradiated controls (20% bone union rate). Collectively, our work proposes a unique methodology for the targeted delivery of DFO to fracture sites in order to facilitate neovascularization. If these findings are successfully translated into clinical practice, millions of patients will benefit from the prevention of nonunions.

在美国，每年大约发生630万例骨折，其中5％至10％导致骨折的骨不连贯。获得成功的骨结合的主要限制是新血管形成受损。为了增强骨折愈合，我们设计了一种包含血管生成兴奋剂去铁胺（DFO）的可植入药物输送技术。DFO通过铁螯合和HIF-1α途径的上调激活新血管的形成。但是，由于其半衰期短和清除快，在峰值骨折血管生成过程中将DFO维持在愈伤组织部位仍然具有挑战性。为了克服这些限制，我们组成了与透明质酸（HA）偶联的DFO的可植入制剂。该化合物将DFO固定在整个血管生成窗口的骨折the内，使其成为高容量的海绵铁，可扩大血管形成并防止骨不连。我们研究了植入的HA-DFO促进受辐照的大鼠下颌骨骨折愈合的能力，该模型是不愈合通常在血管闭塞后继发发展的模型。HA-DFO植入显着改善了放射形态学和生物力学强度指标。此外，HA-DFO处理的下颌骨表现出了显着的91％的骨结合率，比未处理/照射的对照（20％的骨结合率）提高了3.5倍。总的来说，我们的工作提出了一种独特的方法，可将DFO定向输送到骨折部位，以促进新血管形成。如果这些发现成功地转化为临床实践，那么数百万的患者将从预防骨不连中受益。