Ferroximend Improves Nonvascularized Bone Graft Incorporation in the Irradiated Rat Mandible

The purpose of this work is to therapeutically reverse the damaging effects of radiotherapy on bone graft incorporation to enable nonvascularized bone grafting (NVBG) in the irradiated mandible. While NVBG has lost favor as a surgical reconstructive method in irradiated bone, it offers advantages to the current gold standard free tissue transfer, as it is less invasive and avoids the need for complex microsurgery. Therapeutically, fortifying the NVBG technique with angiogenic stimulants may offer avenues for the reintroduction of this practical method of surgical reconstruction.Utilizing a rodent model of mandibular bone grafting and established standard outcome measures, we quantified metrics of diminished graft take and bone healing as a consequence of radiotherapy (XRT). We hypothesized that the addition of Ferroximend, a novel implantable formulation of angiogenic deferoxamine conjugated to hyaluronic acid, would demonstrate substantial, clinically relevant degrees of remediation on the process of bone graft incorporation in the aftermath of radiation injury.

Three groups of Lewis rats were investigated (n = 8/group): control, XRT, and Ferroximend (FER). The XRT and FER groups received a human equivalent dose of 70 gray (Gy) of radiotherapy to left hemi-mandibles. In all groups, a circular 6-mm critical sized defect was created and repaired with a bone graft. Mandibles were imaged at 15, 40, and 60 days with in vivo μCT and radiomorphometrics were analyzed. Upon harvest, bony union was assessed by 3 blinded reviewers prior to biomechanical testing.

Radiation impaired bone graft incorporation as evidenced by diminished radiomorphometrics and biomechanical metrics at 40 and 60 days. Ferroximend implantation after radiotherapy significantly improved radiomorphometrics and metrics of biomechanical strength when compared to irradiated, nonimplanted animals. Notably, the bony union percentage of the FER group demonstrated both statistical and clinically significant improvement when compared to the XRT group (89% vs 39%, respectively) and was not significantly different than control animals (94%).

Our results suggest that the implantation of Ferroximend during NVBG reconstruction can remediate the damaging effects of radiotherapy. Upon clinical translation, countless patients may benefit from the successful reintroduction of nonvascularized bone grafting as a reconstructive option in oncologic reconstruction after radiotherapy.