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Therapeutic Localized Iron Chelation Condenses Consolidation Periods and Enhances Regenerate Quality in Mandibular Distraction Osteogenesis
Alexis Donneys, MD, MS, Sagar S. Deshpande, BS, Catherine Tchanque-Fossuo, MD, MS, Peter Felice, MD, Kelsey L. Johnson, Deniz Sarhaddi, BA, Joseph Perosky, MS, Aaron S. Farberg, BS, Kenneth Kozloff, PhD, Steven R. Buchman, MD.
University of Michigan, Ann Arbor, MI, USA.

PURPOSE:An inherent limitation of mandibular Distraction Osteogenesis (DO) is the length of time required for successful consolidation. This drawback subjects patients to vulnerability by infection, and prolonged return to activities of normal daily living. Finding techniques to abridge consolidation periods could limit these morbidities, and further forward the immense therapeutic potential of this surgical procedure. The intricate involvement of the vascular system during bone regeneration makes it a clear target for therapeutic intervention. Deferoxamine (DFO) is an angiogenic transcriptional activator that triggers the HIF-1α pathway through a mechanism of localized Iron depletion. In our model of mandibular DO we previously established the effectiveness of DFO in enhancing vascularity at a full consolidation period (28 days). To investigate whether this augmentation in vascularity would function to accelerate consolidation without compromising regenerate quality or strength, we utilized Micro-Computed Tomography (µCT) and Biomechanical Tension Testing (BMT) at progressively shortened consolidation periods.

METHODS:
Three time points (28d, 21d and 14d) were selected and 6 groups of Sprague-Dawley rats (n=60) were 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 distraction gap. After consolidation, mandibles were imaged with μCT and subsequently potted and tension tested to failure. Radiomorphometrics and biomechanical data were calculated and statistical comparisons were conducted with the independent samples t-test. p<0.05 was considered statistically significant.

RESULTS:
At 14 days of consolidation the experimental group demonstrated a 50% increase in the number of bony unions (c:4/10 vs. e:8/10). Robust increases in Bone Volume Fraction (BVF), Bone Mineral Density (BMD) and Ultimate Load (UL) were also evident and reached statistical significance. Similar occurrences were evident at 21 days. When comparing 14d vs. 28d of consolidation without treatment, differences were noted for Total Volume (TV), Bone Volume (BV), BMD, Y, UL and Stiffness; however, with the addition of DFO therapy these differences were no longer apparent. Confidence Intervals confirmed no differences between the full consolidation period (28d) and the abridged time period (14d) at the 95th percentile for each outcome (See Table 1.* Denotes significant differences from 28d-Control. § Denotes comparison between 28d-Control vs. 14d-DFO).
Table 1: Outcome means ± standard deviations demonstrating treatment effectiveness.
28d-Control14d-Control14d-DFO§ 95% CI
TV(mm3)98±22*65±2778±24-40-3.7
BV(mm3)65±17*41±2357±19-25-9
BMD(mg/cc)554±65*467±90557±87-69-75
Y(N)48±29*18±1840±29-19.5-35
UL(N)68±34*24±2353±33-17-46
S(N/mm)795±593*258±402469±345-130-781

CONCLUSION:Clinically relevant enhancements in bone union, regenerate quality and biomechanical strength are demonstrated after localized DFO injection; furthermore, these anabolic enhancements were exploited to demonstrate acceleration of bone union at curtailed consolidation periods. We contend that augmentation of vascular density delivers a means for enhancing the mineral and biomechanical properties of bone produced by DO and may ultimately result in the ability to accelerate the procedure to the significant benefit of our patients in the future.

*Sponsored by the American Society of Maxillofacial Surgeons ®.


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