Original Full Length ArticleDeferoxamine expedites consolidation during mandibular distraction osteogenesis☆
Introduction
Mandibular distraction osteogenesis (DO) has emerged as an efficacious surgical technique for the treatment of congenital retrognathia, micrognathia and mandibular hypoplasia. Increasing surgeon experience and device innovation has allowed for the expansion of this attractive technique throughout the craniofacial skeleton to allow for the correction of maxillary hypoplasia, midface hypoplasia and craniosynostosis [1], [2], [3], [4]. Despite these clinical advancements, the length of time required for bone consolidation continues to be a significant limitation to the widespread use of this procedure [5].
In contrast to fracture healing in which bone takes six to eight weeks to heal, DO requires device manipulation during lengthening and a subsequent consolidation period that is proportional to the amount of bone lengthening. This consolidation period ranges from approximately two to six months depending on the desired length and anatomic location of distraction [3], [6].
Numerous factors play a role in the success of DO, with blood flow as paramount to the formation of a healthy union. The importance of sufficient blood flow to the fractured ends during consolidation is related to osteoblast survival [7], [8], [9]. Osteoblast survival, in turn, relies on the close proximity of these cells to nutrient vessels (< 100 μm) [10], [11]. Studies of non-unions demonstrate ischemic, fibrous tissue; whereas healthy unions often demonstrate high levels of neovascularization and active osteogenesis [12]. The dense vascular network in the craniofacial skeleton allows for a high success rate of DO; however, improved angiogenesis would reasonably lead to faster consolidation. Improving vascularity would not only enhance osteogenesis through improved blood flow to osteoblasts, but vascular tissues themselves also secrete osteogenic cytokines such as BMP-2 and vasculogenic cytokines such as VEGFA, which have also been shown to enhance osteogenesis [13].
Other novel treatment methods of distraction optimization have been reported; however, considerable regulatory hurdles have prevented translation of these methods to the clinical arena [14], [15], [16], [17]. A therapeutic paradigm focused on the optimization of vascularity with an established, FDA approved therapy may be a strategy for distraction optimization with real translational potential.
Recent tissue engineering strategies have shed light on the use of angiogenesis and vascular augmentation as mechanisms to enhance bone regeneration in long bone murine models. Investigators have utilized deferoxamine, an iron chelator with angiogenic properties, to trigger angiogenesis and report quantifiable enhancements in vascularity at 14 days and bone quality at 28 days—a widely accepted normal time-point for expected full consolidation [9], [18]. Deferoxamine exerts its angiogenic function through the stimulation of the HIF-1 α pathway. Iron is a co-factor in a reaction that leads to the degradation of HIF-1α. In the absence of iron, the production of HIF-1 α becomes constitutive resulting in an accumulation of the factor in the nucleus. HIF-1 α then dimerizes and begins a transcriptional cascade of events leading to the production of VEGF, as well as other downstream angiogenic factors. Deferoxamine simply removes iron from this equation, thereby triggering angiogenesis and subsequently, new blood vessel formation [18], [19], [20].
We previously reported on the ability of deferoxamine to successfully augment vascularity and bone cellularity even beyond that of the normal regenerative response in our rat model of mandibular DO at a full 28 d consolidation period. Our results demonstrated a significant 40% increase in vessel number and a 45% increase in osteocytes within the regenerate site [21], [22].
In order to expand on our findings, we aim to investigate the therapeutic potential of deferoxamine to substantially shorten consolidation periods. Here we examine its utility in our model at three consecutive time-points (14 d, 21 d and 28 d). We posit that the addition of deferoxamine will allow for successful consolidation at substantially shortened time-points (14 and 21 days) without compromising regenerate quality or mechanical strength when compared to a normal, fully consolidated regenerate (28 days).
Section snippets
Experimental design
Twelve-week-old male Sprague Dawley rats weighing approximately 400 g were paired in cages and maintained in a pathogen-free environment on a 12-hour light/dark schedule. Six groups of animals (n = 60) were equally divided into control (C) and experimental (E) groups for each time-period (n = 10 per group). Three time-points of consolidation were chosen (14 d, 21 d and 28 d). The 28 d time-point was selected as a full, standard consolidation period based on what is widely accepted in the literature and
μCT results
Radiomorphometrics collected through μCT imaging revealed the clear effects of therapy at each time point (Fig. 2, Fig. 3a–c; Table 1, Table 2).
In comparison to the standard 28 d fully consolidated control (28 d C), radiomorphometric analyses of the non-treated group at 14 days (14d C) demonstrated an expected significant disparity in BVF and BMD (both were 77% of 28 d C). This difference was not apparent with deferoxamine therapy, indicating a benefit of treatment at the earliest time-point (14 d E
Discussion
In the present study we investigated the therapeutic potential of deferoxamine to accelerate regenerate consolidation after mandibular DO. While other methods to accelerate consolidation have been attempted, we specifically aimed to optimize an ongoing and well-established phenomenon occurring during distraction. Angiogenesis and vascular augmentation in response to the mechanical stretching of a callus are critical mechanisms integral to the successful regeneration of bone [10], [29], [30],
Disclosure/financial support
All authors state that they have no conflicts of interest.
Acknowledgments
The authors would like to thank Charles Roehm for fabrication of fixator devices.
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Funding was provided by the American Society of Maxillofacial Surgeons grant award to A Donneys for the proposal titled “The Effect of Deferoxamine on the Rate of Consolidation in Distraction Osteogenesis”. Further funding was provided by NIH T32-GM 008616 for A. Donneys and NIH RO1 CA 12587-01 for S. R. Buchman.