Abstract
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.
Highlights
Delayed unions and nonunions are among the most debilitating fracture pathologies affecting approximately 250,000–500,000 patients per year.[1,2,3,4,5,6] Angiogenesis and osteogenesis are intimately coupled, and impaired angiogenesis is often a predisposing factor underlying failed fracture healing
We observed a significant increase between 50 μM injected DFO (iDFO) and 100 μM hyaluronic acid (HA)-DFO at 4 h of incubation (p = 0.033) and trending increases between 50 μM iDFO and 100 μM HA-DFO at 2 and 3 h (p = 0.055 and 0.066), crylated crosslinking (See Figs 1b–d), or HA molar mass and DFO concentration (See Fig. 2) were synthesized and tested
Delayed unions and nonunions are commonly caused by conditions such as underlying vascular disease resulting from diabetes, advanced age or uremia; pathologic states that directly weaken bone such as osteoporosis; anatomic predispositions to avascular necrosis; or iatrogenic causes associated with cancer management such as chemotherapy or radiotherapy
Summary
Delayed unions and nonunions are among the most debilitating fracture pathologies affecting approximately 250,000–500,000 patients per year.[1,2,3,4,5,6] Angiogenesis and osteogenesis are intimately coupled, and impaired angiogenesis is often a predisposing factor underlying failed fracture healing. The addition of serially injected DFO in these fractures elicited remediations in metrics of vascularity, osteocyte viability, callus mineralization and biomechanical strength These remediations facilitated a 2.35-fold improvement in bone union over non-treated/irradiated controls, in a model where nonunions are the expected outcome.[26,27,28,29]. The viscoelastic characteristics of HA-DFO facilitated localized implantation, maintained the drug at the fracture site for sustained release dosing of DFO over weeks, and eliminated the potential for fracture site effusion Employing this technology in our established model of radiotherapy-induced non-unions, we investigated the therapeutic potential of HA-DFO to remediate obliterated vascularity and promote osteogenesis in the aftermath of radiation injury.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
