Abstract: Implantable Deferoxamine Facilitates Non-Vascularized Grafting in Irradiated Bone

Abstract

INTRODUCTION: The goal of this proposal is to therapeutically reverse the damaging effects of radiotherapy on bone formation and healing to enable non-vascularized grafting in irradiated bone. Utilizing a rodent model of mandibular bone grafting, we quantified metrics of diminished graft take and bone healing in response to radiation treatment. Subsequently, we utilized implantable deferoxamine (DFO)-an angiogenic stimulant, to reverse these radiation-induced detriments. We hypothesized that the addition of our proposed therapy, would evidence quantifiable degrees of remediation on the process of tissue regeneration, graft incorporation and bone healing. METHODS: Male Lewis rats received a human equivalent dose of radiotherapy (7Gy/d x 5d) to left hemi-mandibles. After recovery, a circular trephine burr (6mm) was utilized to create a critical size defect just posterior to the third molar, and a bone graft was harvested from the right hemi-mandible of the same animal and secured with a custom PLA resorbable plate. Three groups (n=8/group) of animals were investigated: Control, (irradiated) XRT and irradiated + implantable deferoxamine (DFO). Mandibles were imaged at 14, 40 and 60 days with in vivo µCT, and a 60-day healing period was allowed prior to further outcomes testing. Bony union was judged clinically by 3 blinded reviewers on a scale from 0 to 4, representing the approximate percentage of robust union formation along the circular graft-recipient site interface (e.g. 1=25%, 4=100%). Statistical comparisons were conducted with ANOVA (p<0.05). RESULTS: We observed a significant diminution of bone graft healing after radiotherapy. At 60 days, the bone volume fraction (BVF) of the XRT group decreased by 20% (p=0.001), and exhibited lower bony union scores when compared to control (p=0.005). With the addition of DFO, these findings were largely remediated. At 60 days, the BVF improved upon the XRT BVF by 12% (p=0.025), and was not different than control (p=0.282). In addition, the bony union scores of the implanted DFO group significantly improved from XRT levels (p=0.05), and were not different than control (p=0.200). CONCLUSION: Implantable DFO strongly remediates the effects of radiation on non-vascularized bone graft incorporation and healing as measured by micro-densitometry and bony union analysis. These observations are promising with regards to the potential utility of this therapy to enhance bone graft incorporation in the irradiated mandible for head and neck cancer survivors.