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Refining the mandibular osteoradionecrosis rat model by in vivo longitudinal µCT analysis.

ABSTRACT: Osteoradionecrosis (ORN) is one of the most feared side effects of radiotherapy following cancers of the upper aero-digestive tract and leading to severe functional defects in patients. Today, our lack of knowledge about the physiopathology restricts the development of new treatments. In this study, we refined the ORN rat model and quantitatively studied the progression of the disease. We tested the impact of radiation doses from 20 to 40 Gy, delivered with incident 4MV X-ray beams on the left mandible of the inbred Lewis Rat. We used micro-computed tomography (µCT) to obtain in vivo images for longitudinal bone imaging and ex vivo images after animal perfusion with barium sulphate contrast agent for vessel imaging. We compared quantification methods by analyzing 3D images and 2D measurements to determine the most appropriate and precise method according to the degree of damage. We defined 25 Gy as the minimum irradiation dose combined with the median molar extraction necessary to develop non-regenerative bone necrosis. µCT image analyses were correlated with clinical and histological analyses. This refined model and accurate methods for bone and vessel quantification will improve our knowledge of the progression of ORN pathology and allow us to test the efficacy of new regenerative medicine procedures.

SUBMITTER: Dos Santos M

PROVIDER: S-EPMC8594779 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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Refining the mandibular osteoradionecrosis rat model by in vivo longitudinal µCT analysis.

Dos Santos Morgane M Demarquay Christelle C Ermeneux Louis L Aberkane Fazia F Bléry Pauline P Weiss Pierre P Milliat Fabien F Mathieu Noëlle N

Scientific reports 20211115 1

Osteoradionecrosis (ORN) is one of the most feared side effects of radiotherapy following cancers of the upper aero-digestive tract and leading to severe functional defects in patients. Today, our lack of knowledge about the physiopathology restricts the development of new treatments. In this study, we refined the ORN rat model and quantitatively studied the progression of the disease. We tested the impact of radiation doses from 20 to 40 Gy, delivered with incident 4MV X-ray beams on the left m ...[more]

PMID: 34782666

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Project description:BackgroundOsteoradionecrosis (ORN) is a serious complication of radiotherapy for head and neck cancer. There is currently a lack of data on the dynamic expression of genes related to bone remodeling during the development of mandibular ORN. This study aimed to establish an animal model of ORN in Sprague Dawley (SD) rats, detect the expression of genes related to bone metabolism, observe morphological changes, and clarify the mechanism of ORN.MethodsA total of 24 male SD rats in group 1 were randomly divided into four groups (n=6/group): group a, normal control; group b, simple tooth extraction; group c, simple radiation; and group d, radiation extraction group. The right mandible of rats in groups c and d was irradiated with a single dose of 35 Gy. The right mandibles were taken from each group for morphological observation 90 days after irradiation. SD rats in group 2 (n=144) were randomly divided into four groups (in similar fashion to group 1 but with groups a', b', c', and d'). Samples were collected at six time points after irradiation. Histopathological changes were observed, and Western blotting (WB) was used to analyze protein expression.ResultsThe formation of dead bone and pathological fracture was visible under micro-computed tomography (micro-CT), and tissue biopsy showed late fibrosis repair. In group d', osteogenesis and osteoclasis coexisted in the early irradiation stage. Vascular endothelial growth factor (VEGF) receptor expression was lower in groups c' and d' than in group a'. On day 45, runt-related transcription factor 2 (RUNX2) expression in group d' was lower than that in the other groups. The ratio of receptor activator of nuclear factor-κβ ligand to osteoprotegerin (RANKL:OPG) differed significantly among groups b', c', and d' on the 45th day (d' > c' > b').ConclusionsRadiation and vascular function damage resulted in the lower expression of VEGF. The first 15 days after radiation was mainly characterized by new bone formation. After 15 days, bone resorption increased. Tooth extraction trauma can aggravate the bone metabolism imbalance and promote ORN occurrence. These findings shed light on the mechanism of ORN.

Project description:BackgroundOsteoradionecrosis (ORN) of the mandible is a severe complication of radiation therapy in head and neck cancer patients. Treatment of advanced stage mandibular osteoradionecrosis may consist of segmental resection and osseous reconstruction, often sacrificing the inferior alveolar nerve (IAN). New computer-assisted surgery (CAS) techniques can be used for guided IAN preservation and 3D radiotherapy isodose curve visualization for patient specific mandibular resection margins. This study introduces a novel treatment concept combining these CAS techniques for treatment of advanced stage ORN.MethodsOur advanced stage ORN treatment concept includes consecutively: 1) determination of the mandibular resection margins using a 3D 50 Gy isodose curve visualization, 2) segmental mandibular resection with preservation of the IAN with a two-step cutting guide, and 3) 3D planned mandibular reconstruction using a hand-bent patient specific reconstruction plate. Postoperative accuracy of the mandibular reconstruction was evaluated using a guideline. Objective and subjective IAN sensory function was tested for a period of 12 months postoperatively.ResultsFive patients with advanced stage ORN were treated with our ORN treatment concept using the fibula free flap. A total of seven IANs were salvaged in two men and three women. No complications occurred and all reconstructions healed properly. Neither non-union nor recurrence of ORN was observed. Sensory function of all IANs recovered after resection up to 100 percent, including the patients with a pathologic fracture due to ORN. The accuracy evaluation showed angle deviations limited to 3.78 degrees. Two deviations of 6.42° and 7.47° were found. After an average of 11,6 months all patients received dental implants to complete oral rehabilitation.ConclusionsOur novel ORN treatment concept shows promising results for implementation of 3D radiotherapy isodose curve visualization and IAN preservation. Sensory function of all IANs recovered after segmental mandibular resection.

Dataset Information

Refining the mandibular osteoradionecrosis rat model by in vivo longitudinal µCT analysis.

Publications

Refining the mandibular osteoradionecrosis rat model by in vivo longitudinal µCT analysis.

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