Background A limitation of mandibular Distraction Osteogenesis (DO) is the length of time required for consolidation. This drawback subjects patients to possible pin-site infections, as well as a prolonged return to activities of normal daily living. Developing innovative techniques to abridge consolidation periods could be immensely effective in preventing these problematic morbidities. Deferoxamine (DFO) is an angiogenic activator that triggers the HIF-1α pathway through localized iron depletion. We previously established the effectiveness of DFO in enhancing regenerate vascularity at a full consolidation period (28 days) in a murine mandibular DO model. To investigate whether this augmentation in vascularity would function to accelerate consolidation, we progressively shortened consolidation periods prior to μCT imaging and biomechanical testing (BMT). Materials and Methods Three time points (14d, 21d and 28d) were selected and six groups of Sprague-Dawley rats (n=60) were equally divided into control (C) and experimental (E) groups for each time period. Each group underwent external fixator placement, mandibular osteotomy, and a 5.1mm distraction. During distraction, the experimental groups were treated with DFO injections into the regenerate gap. After consolidation, mandibles were imaged and tension tested to failure. ANOVA was conducted between groups, and p < 0.05 was considered statistically significant. Results At 14 days of consolidation the experimental group demonstrated significant increases in Bone Volume Fraction (BVF), Bone Mineral Density (BMD) and Ultimate Load (UL) in comparison to non-treated controls. The benefit of treatment was further substantiated by a striking 100% increase in the number of bony unions at this early time-period (C:4/10 vs. E:8/10). Furthermore, metrics of BVF, BMD, Yield and UL at 14 days with treatment demonstrated comparable metrics to those of the fully consolidated 28d control group. Conclusion Based on these findings, we contend that augmentation of vascular density through localized DFO injection delivers an efficient means for accelerating bone regeneration without significantly impacting bone quality or strength.

Background Radiotherapy is known to be detrimental to bone and soft-tissue repair. Bone marrow stromal cells have been shown to enhance bone regeneration during distraction osteogenesis following radiation therapy. The authors posit that transplanted bone marrow stromal cells will significantly augment the mandibular vascularity devastated by radiation therapy. Methods Nineteen male Lewis rats were split randomly into three groups: distraction osteogenesis only (n = 5), radiation therapy plus distraction osteogenesis (n = 7), and radiation therapy plus distraction osteogenesis with intraoperative placement of 2 million bone marrow stromal cells (n = 7). A mandibular osteotomy was performed, and an external fixator device was installed. From postoperative days 4 through 12, rats underwent a gradual 5.1-mm distraction followed by a 28-day consolidation period. On postoperative day 40, Microfil was perfused into the vasculature and imaging commenced. Vascular radiomorphometric values were calculated for regions of interest. An analysis of variance with post hoc Tukey or Games-Howell tests was used, dependent on data homogeneity. Results Stereologic analysis indicated significant remediation in vasculature in the bone marrow stromal cell group compared with the radiation therapy/distraction osteogenesis group. Each of five metrics idicated significant improvements from radiation therapy/distraction osteogenesis to the bone marrow stromal cell group, with no difference between the bone marrow stromal cell group and the distraction osteogenesis group. Conclusions Bone marrow stromal cells used together with distraction osteogenesis can rejuvenate radiation-impaired vasculogenesis in the mandible, reversing radiation therapy–induced isotropy and creating a robust vascular network. Bone marrow stromal cells may offer clinicians an alternative reconstructive modality that could improve the lifestyle of patients with hypovascular bone.

Background Our laboratory has previously demonstrated that Deferoxamine (DFO) promotes angiogenesis and bone repair in the setting of radiation therapy (XRT) coupled with Distraction Osteogenesis (DO). However, clinically relevant effects of deferoxamine administration on union rate, micro-Computed Tomography (μCT) and biomechanical parameters are unknown. We posit that administration of deferoxamine will increase union rate, mineralization, and strength of the regenerate in an irradiated DO model. Materials and Methods Sprague Dawley rats were randomized into three groups; DO-Control, DO-XRT, and DO-XRT-DFO. All animals underwent an osteotomy and DO across a 5.1mm distraction gap. Irradiated animals received 35Gy human-equivalent XRT 2 weeks prior to surgery and deferoxamine was injected postoperatively in the regenerate site of treatment animals. Animals were sacrificed at postoperative day 40 and mandibles harvested to determine rates of bony union as well as μCT and biomechanical parameters. Results Compared to irradiated mandibles, deferoxamine-treated mandibles exhibited higher union rate (11% vs. 92%, respectively). Across μCT and biomechanical parameters, we observed significant diminutions with administration of XRT while deferoxamine therapy resulted in significant restorations to levels of controls, with select metrics exhibiting significant increases even beyond controls. Conclusion Our data confirm that deferoxamine restores clinically relevant metrics of bony union and μCT and biomechanical parameters in a model of irradiated DO in the murine mandible. Our findings support a potential use for deferoxamine in treatment protocols to allow predictable and reliable use of DO as a viable reconstructive option in patients with head and neck cancer. Level of Evidence Animal study, not gradable for level of evidence.