Development of a Rat Model of Mandibular Irradiation Sequelae for Preclinical Studies of Bone Repair.

ABSTRACT

Repairing mandibular bone defects after radiotherapy of the upper aerodigestive tract is clinically challenging. Although bone tissue engineering has recently generated a number of innovative treatment approaches for osteoradionecrosis (ORN), these modalities must be evaluated preclinically in a relevant, reproducible, animal model. The objective of this study was to evaluate a novel rat model of mandibular irradiation sequelae, with a focus on the adverse effects of radiotherapy on bone structure, intraosseous vascularization, and bone regeneration. Rats were irradiated with a single 80 Gy dose to the jaws. Three weeks after irradiation, mandibular bone defects of different sizes (0, 1, 3, or 5 mm) were produced in each hemimandible. Five weeks after the surgical procedure, the animals were euthanized. Explanted mandibular samples were qualitatively and quantitatively assessed for bone formation, bone structure, and intraosseous vascular volume by using micro-computed tomography, scanning electron microscopy, and histology. Twenty irradiated hemimandibles and 20 nonirradiated hemimandibles were included in the study. The bone and vessel volumes were significantly lower in the irradiated group. The extent of bone remodeling was inversely related to the defect size. In the irradiated group, scanning electron microscopy revealed a large number of polycyclic gaps consistent with periosteocytic lysis (described as being pathognomonic for ORN). This feature was correlated with elevated osteoclastic activity in a histological assessment. In the irradiated areas, the critical-sized defect was 3 mm. Hence, our rat model of mandibular irradiation sequelae showed hypovascularization and osteopenia. Impact statement Repairing mandibular bone defects after radiotherapy of the upper aerodigestive tract is clinically challenging. Novel tissue engineering approaches for healing irradiated bone must first be assessed in animal models. The current rat model of mandibular irradiation sequelae is based on tooth extraction after radiotherapy. However, the mucosal sequelae of radiotherapy often prevent the retention of tissue-engineered biomaterials within the bone defect. We used a submandibular approach to create a new rat model of mandibular irradiation sequelae, which enables the stable retention of biomaterials within the bone defect and should thus facilitate the assessment of bone regeneration.