A Donneys

Deferoxamine administration delivers translational optimization of distraction osteogenesis in the irradiated mandible

Background: The authors’ laboratory has previously demonstrated that deferoxamine promotes angiogenesis and bone repair in the setting of radiation therapy coupled with distraction osteogenesis. However, clinically relevant effects of deferoxamine administration on union rate and micro–computed tomographic and biomechanical parameters are unknown. The authors posit that administration of deferoxamine will increase union rate, mineralization, and strength of the regenerate in an irradiated distraction osteogenesis model. Methods: Sprague-Dawley rats were randomized into three groups: distraction osteogenesis–control, distraction osteogenesis–radiation therapy, and distraction osteogenesis–radiation therapy–deferoxamine. All animals underwent an osteotomy and distraction osteogenesis across a 5.1-mm distraction gap. Irradiated animals received 35-Gy human-equivalent radiation therapy 2 weeks before surgery, and deferoxamine was injected postoperatively in the regenerate site of treatment animals. Animals were killed on postoperative day 40, and mandibles were harvested to determine rates of bony union and micro–computed tomographic and biomechanical parameters. Results: Compared with irradiated mandibles, deferoxamine-treated mandibles exhibited a higher union rate (11 percent versus 92 percent, respectively). Across micro–computed tomographic and biomechanical parameters, significant diminutions were observed with administration of radiation therapy, whereas deferoxamine therapy resulted in significant restoration to levels of controls, with select metrics exhibiting significant increases even beyond controls. Conclusions: The authors’ data confirm that deferoxamine restores clinically relevant metrics of bony union and micro–computed tomographic and biomechanical parameters in a model of irradiated distraction osteogenesis in the murine mandible. Their findings support a potential use for deferoxamine in treatment protocols to allow predictable and reliable use of distraction osteogenesis as a viable reconstructive option in patients with head and neck cancer.

50B: DOSE RESPONSE DEGRADATION OF BIOMECHANICAL PROPERTIES OF THE MURINE MANDIBLE FOLLOWING HUMAN EQUIVALENT RADIATION

Background: Radiation (XRT) can be exceedingly detrimental to bone resulting in an unacceptably high incidence of devastating complications such as osteoradionecrosis and pathologic fractures. Unfortunately, there is precious little data regarding the dose response of XRT on the structural integrity of the mandible. The purpose of this study was to determine the biomechanical properties of the murine mandible at different human equivalent XRT dosages. Our overall goal is to both determine a dosage window by which therapeutic radiation minimizes its functional degradation of bone as well as develop treatments to mitigate those effects.

PTH Therapy Reverses Radiation Induced Non Union and Normalizes Radiomorphometrics in a Murine Mandibular Model of Distraction Osteogenesis

IntroductIon: The use of mandibular distraction osteogenesis for tissue replacement after oncologic resection or for defects caused by osteoradionecrosis has been described in limited clinical utility. Previous laboratory work has shown that radiation causes decreased union formation, decreased cellularity and decreased mineral density in an animal model of mandibular distraction osteogenesis. Our global hypothesis is that radiation induced bone damage is partly driven by the pathologic depletion of both the number and function of osteogenic cells. Parathyroid Hormone (PTH) is an FDAapproved anabolic hormonal therapy that has demonstrated efficacy for increasing bone mineral density for the treatment of osteoporosis. We posit that intermittent systemic administration of PTH will serve as a stimulant to cellular function which will act to reverse radiation induced damage and enhance bone regeneration in a murine mandibular model of DO.

196A: EVALUATION OF RADIATION INDUCED VASCULAR DAMAGE IN MANDIBULAR DISTRACTION OSTEOGENESIS

Purpose: The use of Mandibular Distraction Osteogenesis (DO) for tissue replacement after oncologic resection in head and neck cancer (HNC) could have immense therapeutic ramifications. Unfortunately, the ravaging effects of radiation (XRT) on new bone formation have heretofore precluded the use of DO as a viable option for HNC reconstruction. Our hypothesis is that the pathologic effects of XRT on the microvasculature of the mandible impede new bone formation during DO. Our specific aim is to determine and directly measure the effect of XRT on the vascularity of the regenerate after human equivalent doses to the murine mandible.

Abstract 79: deferoxamine in combination with adipose-derived stromal cells rescues mineralization and improves union rate in the treatment of established radiotherapy induced non-unions.

PurPose: Radiotherapy induced non-unions occurring in the head and neck cancer patient population are a devastating morbidity that can cause significant functional deficits, persistent pain and often have a dreadful impact on quality of life. Twenty-three percent of patients with advanced osteoradionecrosis proceed to develop pathologic fractures and associated non-unions. Unfortunately, clinicians have few efficacious treatment options for this catastrophic problem. Previously, we have demonstrated a reproducible non-union rate of approximately 75–80% in a non-treated, rat model of pathologic fracture healing after radiotherapy. Here, we report the utilization of a therapeutic strategy, combining adipose-derived stromal cells (ADSCs) with deferoxamine (DFO) to treat established non-unions in this validated model. Our hypothesis is that ADSCs will act to replenish cellular volume, while DFO will function to augment angiogenesis at the site of the non-union, thereby improving mineralization metrics and union formation after treatment.

Abstract 83: improved biomechanical metrics in the treatment of radiotherapy-induced non-unions with a novel combination therapy.

PurPose: Radiation-induced non-unions are complex morbidities with limited management solutions. In prior studies we have utilized a rat model of mandibular fracture healing after a Human Equivalent Dose of Radiotherapy (HEDR), and have established a reproducible non-union rate of approximately 75–80%. In this study, we sought to combine adipose-derived stem cells (ADSCs) with deferoxamine in order to treat established non-unions in our model. We posit that ADSCs will act as a cellular replacement, while DFO will function to enhance angiogenesis at the non-union site, resulting in improvements in biomechanical metrics after treatment.

Abstract 80: Parathyroid Hormone Remediates Radiation Damage in a Murine Model of Distraction Osteogenesis via Histological Evaluation.

PurPose: Radiation is known to be detrimental to bone and soft tissue repair, resulting in an unacceptably high incidence of devastating wound healing complications. This is effected through a mechanism of both direct cellular and vascular depletion. We sought to utilize an anabolic regimen of parathyroid hormone (PTH), an FDA-approved bone therapeutic, to remediate this deficiency. The purpose of this study was to allow for the successful utility of distraction osteogenesis in an irradiated field utilizing an intermittent regimen of PTH for the purpose of craniofacial reconstruction in head and neck cancer victims.

Abstract 53: prophylactic amifostine preserves the biomechanical properties of irradiated bone in the murine mandible.

ConClusion: An expanded krox20 expression domain at the embryonic stage of fgfr1b mRNA injected embryos suggests that this mutation has activating character in zebrafish, indicating a conserved role of fgfr1 in cranial suture development among vertebrates. The effects of genetic manipulation on adult suture phenotype will be assessed through histological analysis, skeletal morphology, and cell proliferation will be studied in our transgenic fgfr1b embryos. This zebrafish model of CS will advance our understanding of the role of Fgfr1b in cranial suture morphogenesis and the etiology of the disorder. In the future, it can be used for genetic and chemical screens to search for genetic modifiers and therapeutic agents that alter CS. 53 Prophylactic amifostine Preserves the Biomechanical Properties of irradiated Bone in the Murine Mandible

Abstract 62: A NOVEL COMBINATION OF AMIFOSTINE PROPHYLAXIS AND ANGIOGENIC DEFEROXAMINE PROTECTS AND RESTORES BIOMECHANICAL PROPERTIES OF BONE IN PATHOLOGIC FRACTURE HEALING AFTER RADIOTHERAPY

Purpose: Pathologic fractures and associated non-unions after radiotherapy for Head and Neck cancer pose a complex management dilemma for reconstructive surgeons. We have previously demonstrated a partial remediation of biomechanical strength and bony union formation with Deferoxamine (DFO), an angiogenic factor, in a murine model of fracture healing following radiotherapy. The purpose of this study was to investigate the synergistic potential of Amifostine (AMF), a cytoprotectant, in combination with DFO to produce a more robust biomechanical construct and predictable rate of bony union.

Abstract 211: DEFEROXAMINE RESTORES BIOMECHANICAL PROPERTIES AND POTENTIATES UNION OF IRRADIATED BONE IN DISTRACTION OSTEOGENESIS

Background: Our laboratory has shown the iron-chelating agent Deferoxamine (DFO) promotes angiogenesis and bone repair in the setting of radiation therapy (XRT) coupled with Distraction Osteogenesis (DO). While these studies demonstrate DFO improves vascular and histologic metrics for irradiated bone, the clinically impactful effect of DFO on union formation and biomechanics has never been examined. We hypothesize DFO administration will increase bony union and strengthen Biomechanical Properties (BPs) of the regenerate in an irradiated DO model.