Dose-Response Effect of Human Equivalent Radiation in the Murine Mandible: Part I. A Histomorphometric Assessment

Tchanque-Fossuo, Catherine N.; Monson, Laura A.; Farberg, Aaron S.; Donneys, Alexis; Zehtabzadeh, Aria J.; Razdolsky, Elizabeth R.; Buchman, Steven R.

doi:10.1097/prs.0b013e31821741d4

Cited by 46 publications

(58 citation statements)

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“…Previously, we have reported on a group of experiments establishing the outcomes of a human equivalent dose of radiation in the rat mandible [17][18][19]. The administration of 35 Gy of radiation, fractionated over 5 days, mimics a clinical course of adjuvant radiation therapy for HNC and is a bioequivalent to 70 Gy to a human mandible.…”

Section: Introductionmentioning

confidence: 99%

Stem Cell Therapy Remediates Reconstruction of the Craniofacial Skeleton After Radiation Therapy

Deshpande

Gallagher

Donneys

et al. 2013

Stem Cells and Development

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This study utilized transplanted bone marrow stromal cells (BMSCs) as a cellular replacement therapy to remedy radiation-induced injury and restore impaired new bone formation during distraction osteogenesis (DO). BMSC therapy brought about the successful generation of new bone and significantly improved both the rate and quality of a bony union of irradiated, distracted [X-ray radiation therapy (XRT)/DO] murine mandibles to the level of nonirradiated DO animals. The bone mineral density and bone volume fraction were also significantly improved by the BMSC replacement therapy showing no difference when compared to nonirradiated animals. Finally, a biomechanical analysis examining the yield, failure load, and ultimate load also demonstrated a significantly improved structural integrity in BMSC-treated XRT/DO mandibles over XRT/DO alone. These results indicate that administration of BMSCs intraoperatively to a radiated distraction gap can function as an adequate stimulant to rescue the ability for irradiated bone to undergo DO and produce a healed regenerate of a vastly superior quality and strength. We believe that the fundamental information on the optimization of bone regeneration in the irradiated mandible provided by this work has immense potential to be translated from the bench to the bedside to lead to improved therapeutic options for patients suffering from the disastrous sequelae of radiation therapy.

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Section: Introductionmentioning

confidence: 99%

Stem Cell Therapy Remediates Reconstruction of the Craniofacial Skeleton After Radiation Therapy

Deshpande

Gallagher

Donneys

et al. 2013

Stem Cells and Development

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“…This radiation protocol has been performed for several years at the Department of Radiation Oncology. 5–8 …”

Section: Methodsmentioning

confidence: 99%

“…Subcutaneous infusion of buprenorphine (0.15 m/kg) with 10 cc of lactated Ringer’s solution was given to any rats exhibiting signs of radiation-induced discomfort. 5–8 …”

Section: Methodsmentioning

confidence: 99%

“…The posterior hemimandible was potted first at a depth determined to match the location of the region of interest that has been used by our laboratory in the past to look at distraction osteogenesis. 5–8 Specifically, the region of interest was located 5.1 mm behind the last mandibular molar. The anterior hemimandible was potted next by fully burying the third molar in the potting medium.…”

Section: Methodsmentioning

confidence: 99%

“…In this study, we evaluated the dynamics and pathologic effects of radiation dose on the murine mandible using human equivalent radiation. 5 Our specific aim was to assess the effect of radiation on the biomechanical properties of the murine mandible in a dose-response manner at 75, 100, and 150 percent of the dose that a human would receive in standard treatment for head and neck cancer. In conventional squamous cell cancer treatment, the human mandible receives a biologically equivalent dose of 116.66 Gy 3 or an isodose of 100 percent, which approximates to our experimental fractionation scheme of 7Gy delivered in five daily fractions.…”

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Dose-Response Effect of Human Equivalent Radiation in the Murine Mandible

Tchanque-Fossuo

Monson

Farberg

et al. 2011

Plastic and Reconstructive Surgery

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Background Despite the widespread use of adjuvant irradiation for head and neck cancer, the extent of damage to the underlying bone is not well understood. However, patients can suffer serious clinical consequences, including pathologic fractures, nonunion, and osteoradionecrosis. The authors’ specific aim was to objectively quantify the human equivalent radiation dose-response effect of radiation on the biomechanical properties of the murine mandible. Methods Twelve Sprague-Dawley rats were randomized into three radiation dosage groups—low (5.91 Gy), middle (7 Gy), and high (8.89 Gy)—delivered in five daily fractions. The fractionation regimen was used to approximate 75, 100, and 150 percent, respectively, of the bioequivalent dose humans receive in conventional head and neck cancer treatment. Fifty-six days after irradiation, hemimandibles were loaded to failure in a uniaxial tension at 0.5 mm/second. Load displacement curves were analyzed for yield and breaking load, and values were considered statistically significant at p < 0.05. Results The authors’ data demonstrated a statistically significant decrease in the yield and breaking load metrics. The authors’ reported averages for low, middle, and high radiation dosages were 162, 136, and 69 N, respectively, for yield; and 215, 211, and 141 N, respectively, for breaking load. Both of these quantitative biomechanical properties were diminished in a dose-response pattern. Conclusions In this article, the authors report a dose-response effect in the degradation of the biomechanical properties of the mandible after fractionated human equivalent radiation. The authors’ findings and model can now be used to formulate therapies aimed at remediating those effects and augmenting bone regeneration and healing after adjuvant radiotherapy in head and neck cancer patients.

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Role of parathyroid hormone therapy in reversing radiation‐induced nonunion and normalization of radiomorphometrics in a murine mandibular model of distraction osteogenesis

et al. 2013

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Background The use of mandibular distraction osteogenesis (MDO) for tissue replacement after oncologic resection or for defects caused by osteoradionecrosis has been described but, in fact, has seen limited clinical utility. Previous laboratory work has shown that radiation (XRT) causes decreased union formation, decreased cellularity, and decreased mineral density in an animal model of MDO. 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 a U.S. Food and Drug Administration-approved anabolic hormonal therapy that has demonstrated efficacy for increasing bone mineral density for the treatment of osteoporosis. We postulate that intermittent systemic administration of PTH will serve as an anabolic stimulant to cellular function that will act to reverse radiation-induced damage and enhance bone regeneration in a murine mandibular model of DO. Methods A total of 20 isogenic male Lewis rats were randomly assigned into 3 groups. Group 1 (XRT-DO, n = 7) and group 2 (XRT-DO-PTH, n = 5) received a human bioequivalent dose of 70 Gy fractionated over 5 days. All groups including group 3 (DO, n = 8) underwent a left unilateral mandibular osteotomy with bilateral external fixator placement. Four days later, mandibular DO was performed at a rate of 0.3 mm every 12 hours to reach a maximum gap of 5.1 mm. Group 2 was injected PTH (60 μg/kg) subcutaneously daily for 3 weeks following the start of MDO. On postoperative day 41, all left hemimandibles were harvested. Micro-CT at 45-μm voxel size was performed and radiomorphometrics parameters of bone mineralization were generated. Union quality was evaluated on a 4-point qualitative grading scale. Radiomorphometric data were analyzed using 1-way ANOVA, and union quality assessment was analyzed via the Mann–Whitney test. Statistical significance was considered at p ≤ .05. Results Groups 1 and 2 appropriately demonstrated clinical signs of radiation-induced stress ranging from alopecia to mucositis. Union quality was significantly higher in PTH-treated XRT-DO animals, compared with XRT-DO group animals (p = .02). Mineralization metrics, including bone volume fraction (BVF) and bone mineral density (BMD), also showed statistically significant improvement. The groups that were treated with PTH showed no statistical differences in union or radiomorphometrics when compared with DO in nonradiated animals. Conclusion We have successfully demonstrated the therapeutic efficacy of PTH to stimulate and enhance bone regeneration in our irradiated murine mandibular model of DO. Our investigation effectively resulted in statistically significant increases in BMD, BVF, and clinical unions in PTH-treated mandibles. PTH demonstrates immense potential to treat clinical pathologies where remediation of bone regeneration is essential.

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Dose-Response Effect of Human Equivalent Radiation in the Murine Mandible: Part I. A Histomorphometric Assessment

Cited by 46 publications

References 18 publications

Stem Cell Therapy Remediates Reconstruction of the Craniofacial Skeleton After Radiation Therapy

Stem Cell Therapy Remediates Reconstruction of the Craniofacial Skeleton After Radiation Therapy

Dose-Response Effect of Human Equivalent Radiation in the Murine Mandible

Role of parathyroid hormone therapy in reversing radiation‐induced nonunion and normalization of radiomorphometrics in a murine mandibular model of distraction osteogenesis

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