Ss Deshpande

Vascular analysis as a proxy for mechanostransduction response in an isogenic, irradiated murine model of mandibular distraction osteogenesis.

INTRODUCTION Head and neck cancer is a debilitating and disfiguring disease. Although numerous treatment options exist, an array of debilitating side effects accompany them, causing physiological and social problems. Distraction osteogenesis (DO) can avoid many of the pathologies of current reconstructive strategies; however, due to the deleterious effects of radiation on bone vascularity, DO is generally ineffective. This makes investigating the effects of radiation on neovasculature during DO and creating quantifiable metrics to gauge the success of future therapies vital. The purpose of this study was to develop a novel isogenic rat model of impaired vasculogenesis of the regenerate mandible in order to determine quantifiable metrics of vascular injury and associated damage. METHODS Male Lewis rats were divided into two groups: DO only (n=5) AND Radiation Therapy (XRT)+DO (n=7). Afterwards, a distraction device was surgically implanted into the mandible. Finally, they were distracted a total of 5.1mm. Animals were perfused with a radiopaque casting agent concomitant with euthanasia, and subsequently demineralization, microcomputed tomography, and vascular analysis were performed. RESULTS Vessel volume fraction, vessel thickness, vessel number, and degree of anisotropy were diminished by radiation. Vessel separation was increased by radiation. CONCLUSION The DO group experienced vigorous vessel formation during distraction and neovascularization with a clear, directional progression, while the XRT/DO group saw weak vessel formation during distraction and neovascularization. Further studies are warranted to more deeply examine the impairments in osteogenic mechanotransductive pathways following radiation in the murine mandible. This isogenic model provides quantifiable metrics for future studies requiring a controlled approach to immunogenicity.

Prophylactic amifostine prevents a pathologic vascular response in a murine model of expander-based breast reconstruction

BACKGROUND Although expander-based breast reconstruction is the most commonly used method of reconstruction worldwide, it continues to be plagued with complication rates as high as 60% when radiotherapy is implemented. We hypothesized that quantitative measures of radiotherapy-induced vascular injury can be mitigated by utilizing amifostine in a murine model of expander-based breast reconstruction. METHODS 30 rats were divided into three groups: expander placement (Control), expander placement followed by radiotherapy (XRT), and expander placement followed by radiotherapy with amifostine (AMF/XRT). All groups underwent placement of a sub-latissimus tissue expander. After a 45 day recovery period, all groups underwent vascular perfusion and micro-CT analysis. RESULTS Micro-CT analysis was used to calculate vessel volume fraction (VVF), vessel number (VN), and vessel separation (VSp). A significant increase in VN was seen in the XRT group as compared to the Control (p = 0.021) and the AMF/XRT (p = 0.027). There was no difference between Control and AMF/XRT (p = 0.862). VVF was significantly higher in XRT than either Control (p = 0.043) and AMF/XRT (p = 0.040), however no difference was seen between Control and AMF/XRT (p = 0.980). VSp of XRT was smaller when compared to both Control and AMF/XRT specimens (p = 0.05 and p = 0.048, respectively), and no difference was seen between Control and AMF/XRT (p = 0.339). CONCLUSIONS Amifostine administered prior to radiotherapy preserved vascular metrics similar to those of non-radiated specimens. Elevated vascularity demonstrated within the XRT group was not seen in either the Control or AMF/XRT groups. These results indicate that amifostine protects soft tissue in our model from a radiotherapy-induced pathologic vascular response.

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 87: DEFEROXAMINE INDUCES THE RESTORATION OF MINERALIZATION METRICS 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 mandibles, clinically impactful effects of DFO on mineralization metrics have never been examined. We hypothesize DFO administration will restore the composition and mineralization of the bony regenerate in an irradiated model of DO.

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.

Abstract 42P: Deferoxamine Decreases Non-Unions and Restores Bone Quality and Biomechanical Strength in Pathologic Fracture Healing After Radiotherapy

Objective: Adjuvant radiotherapy for head and neck cancer patient management continues to be paralleled with costly and devastating bone related pathologies. Most detrimental is the development of non-unions secondary to pathologic fractures. A pharmacologic means to prevent these pathologies would be highly desirable. Deferoxamine (DFO), an angiogenic therapy, augments vascularity and subsequently enhances fracture healing when injected into a fracture callus. We posit that the untoward effects of radiotherapy on bone quality, mechanical strength and non-union formation can be mitigated with this powerful angiogenic therapy.