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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., (© 2021. The Author(s).)

Purpose: We aim to characterize the quantitative dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) parameters associated with advanced mandibular osteoradionecrosis (ORN) compared with the contralateral normal mandible., Methods and Materials: Patients with a diagnosis of advanced ORN after curative-intent radiation treatment of head and neck cancer were prospectively enrolled after institutional review board approval and study-specific informed consent were obtained. Quantitative maps generated with the Tofts and extended Tofts pharmacokinetic models were used for analysis. Manual segmentation of advanced ORN 3-dimensional volume was done using anatomic sequences to create ORN volumes of interest (VOIs). Subsequently, normal mandibular VOIs were segmented on the contralateral healthy mandible of similar volume and anatomic location to create control VOIs. Finally, anatomic sequences were coregistered to DCE sequences, and contours were propagated to the respective parameter maps., Results: Thirty patients were included. The median time to ORN diagnosis after completion of IMRT was 38 months (range, 6-184 months), whereas median time to ORN progression to advanced grade after initial diagnosis was 5.6 months (range, 0-128 months). There were statistically significant higher K trans and V e in ORN-VOIs compared with controls (0.23 vs 0.07 min -1 , and 0.34 vs 0.15; P < .0001 for both). The average relative increase of K trans in ORN-VOIs was 3.2-fold higher than healthy mandibular control VOIs. Moreover, the corresponding rise of V e in ORN-VOIs was 2.7-fold higher than in the controls. Using combined K trans and V e parameters, 27 patients (90%) had at least a 200% increase of either of the studied parameters in the ORN-VOIs compared with their healthy mandible VOIs., Conclusions: Our results confirm that there is a quantitatively significant higher degree of leakiness in the mandibular vasculature as measured using DCE-MRI parameters of areas with advanced ORN versus healthy mandible., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Osteoradionecrosis (ORN) of the mandible is a severe complication of radiotherapy for head and neck cancer and is arduously difficult to manage. Current treatment options carry risks with some patients remaining incurable. Mesenchymal stromal/stem cell (MSC) therapy has shown promising results supporting osteogenesis and regeneration of radiotherapy-damaged tissues. The aim of this study was to systematically review the literature on the safety and efficacy of MSCs in treating ORN., Methods: A systematic search was performed on MEDLINE, Embase, Cochranes Library online databases, and clinicaltrials.gov to identify preclinical and clinical studies examining the effect of MSCs on osseous healing of ORN. The preclinical studies were assessed according to the SYRCLEs guidelines and risk of bias tool., Results: Six studies (n = 142) from 5 countries were eligible for analysis. Of these four were preclinical studies and two clinical case studies. Preclinical studies found MSC treatment to be safe, demonstrating bone restorative effects and improved soft tissue regeneration. In the clinical cases, healing of bone and soft tissue was reported with no serious adverse events., Conclusion: The evidence from the included studies suggests that MSCs may have beneficial regenerative effects on the healing of ORN. None of the studies reported adverse events with the use of MSCs. More carefully controlled studies with well-identified cells are however needed to demonstrate the efficacy of MSCs in a clinical setting. Graphical abstract.

Background/aim: To evaluate the association between osteoradionecrosis (ORN) of the mandible and stenosis of the external carotid artery after radiation therapy (RT) for head and neck cancer., Patients and Methods: The computed tomography images of 42 patients (36 men, six women; median age, 64.5 years) treated with RT for head and neck cancer between January 2011 and December 2015 were reviewed. The cross-sectional diameters of the bilateral external carotid arteries were measured on contrast-enhanced images taken after completion of RT., Results: Nine of the 42 included patients (21.4%) developed ORN after a median interval of 34 months from completion of RT. Univariate analysis revealed that external carotid artery diameter ≤ the median diameter was significantly associated with ORN development (p=0.008 and 0.013). In multivariate analysis, left external carotid artery diameter ≤ the median was significantly associated with ORN development (p=0.023)., Conclusion: External carotid artery stenosis was significantly associated with ORN development., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Objectives: Hypovascularisation is thought to play an important role in the pathogenesis of osteoradionecrosis. The objective of this study was to assess the microvascular system in the irradiated mandibular bone marrow., Materials and Methods: Mandibular bone biopsies were taken from 20 irradiated patients and 24 controls. Blood vessels were visualized using CD34 antibody stain to detect endothelial cells. The vascular density (VD) and vascular area fraction (VAF) were measured. Mean vessel lumen area, perimeter and diameter of the vessels were calculated for each vessel. A distinction was made between large and small vessels (cut-off point <400 µm 2 )., Results: Vascular density and vascular area fraction were lower in the irradiated group. The mean vascular perimeter and mean vascular diameter were higher in samples with a local radiation dose of ≥50 Gy, whereas the percentage of small vessels was lower. Larger vessel perimeter is associated with higher radiation dose. A longer interval between biopsy and radiotherapy is associated with a larger mean vessel perimeter and a lower percentage of small vessels., Conclusions: Radiation dosages higher than 50 Gy mainly affect the smaller vessels. With increased time after irradiation, the share of smaller vessels in the mandibular bone marrow seems to decrease. In search of the exact mechanisms of irradiation damage and osteoradionecrosis of the mandible, the role of the microvascular system in the mandibular bone marrow should be further explored., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: Approximately 5% of irradiated head and neck cancer patients develop osteoradionecrosis of the mandible. The current non-surgical treatment options for osteoradionecrosis have limited effects and are based on a small number of studies. Therefore, we aimed to enhance the understanding of the pathophysiology of osteoradionecrosis by investigating changes induced by external irradiation in mini-pigs., Methods: Sixteen Göttingen mini-pigs were divided into four groups for the application in two fractions with total equivalent radiation dosages of 25, 50, 70 Gray, and one group served as control. Thirteen weeks after irradiation, the left lateral teeth the mandible were removed and implants were placed. The pigs were sacrificed twenty-six weeks after irradiation, and the bone samples were stained with Masson's trichrome., Results: The amount of fibrosis, resorption lacunae, necrosis, and the woven/lamellar bone ratios were increased after higher radiation dosages. The diameter of the lumen of the inferior alveolar artery was reduced depending on the irradiation dosages. The rate of bone remodeling decreased after irradiation., Conclusion: Both surgery and increasing irradiation dosages cause architectural bone changes and damage the vascularization. This might result in a chronic hypoxic state of the mandibular bone. In general, the bone formation rate was markedly decreased after radiotherapy., (Copyright © 2017 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.)

Background: The purpose of this study was to compare outcomes for segmental reconstruction of the mandible between patients who underwent reconstruction with a fibula flap (group 1), and those with an alternative osseous free flap in which the fibula flap was unsuitable either for defect reasons (group 2) or in which the fibula flap could not safely be harvested because of compromised leg vessels (group 3)., Methods: One hundred fifty-two patients who underwent osseous free flap reconstruction of a mandibular segmental defect between January 2008 and June 2014 were identified from operating records. Outcomes between groups was compared., Results: The flap success rate was 97% and the late recipient-site complication rate was 19%. There was no difference in flap success or complication rates between groups., Conclusion: Bony reconstruction of the mandible can be achieved with no compromise in flap success even where preoperative vascular studies or the nature of the defect deem the fibula unsuitable. © 2017 Wiley Periodicals, Inc. Head Neck 39: 916-920, 2017., (© 2017 Wiley Periodicals, Inc.)

Background: The purpose of this study was to measure the histologic and histomorphometric effects of parathyroid hormone (PTH) treatment on irradiated bone undergoing distraction osteogenesis (DO)., Methods: Thirty-four rats were divided into 3 groups. The control group underwent DO and the radiation control group underwent radiotherapy (RT) before DO. The PTH group underwent RT and received PTH during DO. Quantitative histology and histomorphometry were performed., Results: RT resulted in a depletion of osteocytes and increase in empty lacunae. Treatment with PTH resulted in an increase in osteocyte counts and decrease in empty lacunae (p < .05), restoring osteocytes to levels seen in nonradiated bone (p = .121). RT decreased bone volume to tissue volume (BV-TV) ratio and increased osteoid volume to tissue volume (OV-TV) ratio, signifying increased immature bone formation. PTH treatment restored OV-TV ratio to that observed in nonradiated bone., Conclusion: PTH treatment of irradiated bone enhanced bone regeneration and restored osteocyte counts and OV-TV ratio to levels comparable to nonradiated bone. © 2016 Wiley Periodicals, Inc. Head Neck 39: 464-470, 2017., (© 2016 Wiley Periodicals, Inc.)

Background: This study aimed to analyze differences in necrotic changes between cortical and cancellous bone in resection margins after segmental mandibulectomy for advanced mandibular osteoradionecrosis., Methods: Anteroposterior bone specimens from eleven patients who underwent segmental mandibulectomy with simultaneous free fibula flap reconstruction for advanced osteoradionecrosis were analyzed histopathologically for the presence of necrotic bone based on the presence of blood vessels within Haversian canals., Results: Ten of eleven (91%) cortices near the inferior border of the mandible at the anterior margins were necrotic. All cancellous bones at the anterior margins were viable. Seven of eleven (64%) cortices near the inferior border of the mandible at the posterior margins were necrotic. Three of eleven (27%) cancellous bones at the posterior margins were necrotic., Conclusion: Necrotic changes are more prevalent in cortices than in cancellous bones in mandibular osteoradionecrosis, probably due to a decrease of periosteal blood supply caused by radiotherapy.

Objectives: To develop an animal model of mandibular osteoradionecrosis (ORN) using a high-energy radiation source (as used in human therapeutics) and to assess the role of tooth extraction on ORN development., Materials and Methods (study Design): Ten animals were irradiated with a single 35- or 50-Gy dose. Three weeks later, the second left mandibular molar was extracted from three animals in each group. Nine weeks after irradiation, the animals were euthanized, with an injection of contrast agent in the bloodstream to highlight vascularization. Mandibles were harvested and studied using micro-CT, histology, tartrate-resistant acid phosphatase activity and scanning electron microscopy., Results: This study demonstrates that a single 50-Gy dose associated with molar extraction is necessary for ORN development. In these conditions, absence of healing of the mucosa and bone, dental effects, fibrosis, an increase in osteoclast activity and a decrease in vascularization were observed. We also determined that molar extraction increases the impact of the cellular effects of radiation., Conclusion: The mandibular ORN animal model was validated after 50-Gy irradiation and molar extraction. The results of this study therefore support an animal ORN model and tissue engineering strategies will now be developed to regenerate bone for patients with head and neck cancer., (Copyright © 2015 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.)

Background: Radiotherapy is known to be detrimental to bone and soft-tissue repair. Bone marrow stromal cells have been shown to enhance bone regeneration during distraction osteogenesis following radiation therapy. The authors posit that transplanted bone marrow stromal cells will significantly augment the mandibular vascularity devastated by radiation therapy., Methods: Nineteen male Lewis rats were split randomly into three groups: distraction osteogenesis only (n = 5), radiation therapy plus distraction osteogenesis (n = 7), and radiation therapy plus distraction osteogenesis with intraoperative placement of 2 million bone marrow stromal cells (n = 7). A mandibular osteotomy was performed, and an external fixator device was installed. From postoperative days 4 through 12, rats underwent a gradual 5.1-mm distraction followed by a 28-day consolidation period. On postoperative day 40, Microfil was perfused into the vasculature and imaging commenced. Vascular radiomorphometric values were calculated for regions of interest. An analysis of variance with post hoc Tukey or Games-Howell tests was used, dependent on data homogeneity., Results: Stereologic analysis indicated significant remediation in vasculature in the bone marrow stromal cell group compared with the radiation therapy/distraction osteogenesis group. Each of five metrics idicated significant improvements from radiation therapy/distraction osteogenesis to the bone marrow stromal cell group, with no difference between the bone marrow stromal cell group and the distraction osteogenesis group., Conclusions: Bone marrow stromal cells used together with distraction osteogenesis can rejuvenate radiation-impaired vasculogenesis in the mandible, reversing radiation therapy-induced isotropy and creating a robust vascular network. Bone marrow stromal cells may offer clinicians an alternative reconstructive modality that could improve the lifestyle of patients with hypovascular bone.

Objectives: Both osteoradionecrosis (ORN) and bisphosphonate associated osteonecrosis of the jaws (BRONJ) present clinically as regions of exposed necrotic bone. The study aimed to demonstrate the histopathological differences behind the observed clinical similarities., Study Design: Ten ORN specimens and ten BRONJ specimens were used, as well as ten samples of normal mandibular bone as control. Two bone-specific stainings were used, i.e. Sirius Red for the study of the relative presence of collagen types I and III and toluidine blue for the study the osteon density., Results: The Red Green Blue (RGB)-analysis of the specimens stained with Sirius Red identified significant differences between the chromatic patterns observed in bone preparations of patients suffering from ORN when compared to both BRONJ and control samples. Moreover, the osteon density of the BRONJ samples was significantly lower when compared to ORN and normal bone samples., Conclusions: The demonstrated differences in the bone architecture and in the bone collagen content between the two pathological conditions most likely reflect underlying pathophysiological differences.

Background: Despite widespread use of adjuvant irradiation for head and neck cancer, the extent of damage to the underlying bone is not fully understood but is associated with pathologic fractures, nonunion, and osteoradionecrosis. The authors' laboratory previously demonstrated that radiation significantly impedes new bone formation in the murine mandible. We hypothesize that the detrimental effects of human equivalent radiation on the murine mandible results in a dose-dependent degradation in traditional micro-computed tomography (micro-CT) metrics., Methods: Fifteen male Sprague-Dawley rats were randomized into 3 radiation dosage groups: low (5.91 Gy), middle (7 Gy), and high (8.89 Gy), delivered in 5 daily fractions. These dosages approximated 75%, 100%, and 150%, respectively, of the biologically equivalent dose that the human mandible receives during radiation treatment. Hemimandibles were harvested 56 days after radiation and scanned using micro-CT. Bone mineral density, tissue mineral density, and bone volume fraction were measured along with microdensitometry measurements., Results: Animals demonstrated dose-dependent adverse effects of mucositis, alopecia, weight loss, and mandibular atrophy with increasing radiation. Traditional micro-CT parameters were not sensitive enough to demonstrate statistically significant differences between the radiated groups; however, microdensitometry analysis showed clear differences between radiated groups and statistically significant changes between radiated and nonradiated groups., Conclusions: The authors report dose-dependent and clinically significant adverse effects of fractionated human equivalent radiation to the murine mandible. The authors further report the limited capacity of traditional micro-CT metrics to adequately capture key changes in bone composition and present microdensitometric histogram analysis to demonstrate significant radiation-induced changes in mineralization patterns.

Radiotherapy is widely used in the treatment of head and neck cancers. Its major adverse effect is osteoradionecrosis, which can occur during the whole life of the patient, involving the vital prognosis. The aim of the study was to develop a model for irradiation of the rabbit mandible in order to have a better knowledge of radiotherapy-induced bone alterations and thus a better prevention and treatment of osteoradionecrosis. The control group consisted in 7 rabbits and was used to assess anatomical and histological parameters of the rabbit's mandible. A first group of 14 rabbits was weekly irradiated at doses of 5.5 Gy during 5 weeks, at a total dose of 46.8Gy. Sacrifices were done at 1 week, 4 weeks, 12 weeks and 24 weeks. As histological analysis did not reveal statistical differences with the control group, a second group (3 rabbits) was weekly irradiated at 8.0, 8.5 and 9 Gy during 5 weeks. The first histological results seem to show vascular alterations, bone cells decrease and alterations of bone architecture. The role of intra alveolar collagen sponges, PRF®, ultrasounds and stem cells in bone regeneration after radiotherapy will be further studied.

Objective: Descriptions of mandibular distraction osteogenesis for tissue replacement after oncologic resection or for defects caused by osteoradionecrosis have been limited. Previous work demonstrated radiation decreases union formation, cellularity and mineral density in mandibular distraction osteogenesis. The authors posit that intermittent systemic administration of parathyroid hormone will serve as a stimulant to cellular function, reversing radiation-induced damage and enhancing bone regeneration., Methods: Twenty male Lewis rats were randomly assigned to three groups: group 1 (radiation and distraction osteogenesis, n = 7) and group 2 (radiation, distraction osteogenesis, and parathyroid hormone, n = 5) received a human-equivalent dose of 35 Gy of radiation (human bioequivalent, 70 Gy) fractionated over 5 days. All groups, including group 3 (distraction osteogenesis, n = 8), underwent a left unilateral mandibular osteotomy with bilateral external fixator placement. Distraction osteogenesis was performed at a rate of 0.3 mm every 12 hours to reach a gap of 5.1 mm. Group 2 was injected with parathyroid hormone (60 µg/kg) subcutaneously daily for 3 weeks after the start of distraction osteogenesis. On postoperative day 40, all left hemimandibles were harvested. Biomechanical response parameters were generated. Statistical significance was considered at p ≤ 0.05., Results: Parathyroid hormone-treated mandibles had significantly higher failure load and higher yield than did untreated mandibles. However, these values were still significantly lower than those of nonirradiated mandibles., Conclusions: The authors have successfully demonstrated the therapeutic efficacy of parathyroid hormone to stimulate and enhance bone regeneration in their irradiated murine mandibular model of distraction osteogenesis. Anabolic regimens of parathyroid hormone, a U.S. Food and Drug Administration-approved drug on formulary, significantly improve outcomes in a model of postoncologic craniofacial reconstruction.

Objectives: Osteoradionecrosis (ORN) is common in the jaws after radiotherapy. We hypothesized that the mandible is more susceptible to ORN than the tibia, based on site disparity in hypoxic, hypocellular, and hypovascular tissue breakdown., Study Design: Twelve rats received 50 Gy irradiation to mandible or tibia; 4 of the rats further received minor surgical trauma to the irradiated sites. Structural and cellular skeletal changes were assessed with computerized tomography, histology, and immunostaining., Results: Mandible developed ORN with 70% mean bone loss 10 weeks after irradiation (P < .05), whereas tibia was structurally and radiologically intact 20 weeks after irradiation. Hypocellularity, hypoxia, and oxidative stress were higher in irradiated mandible (P < .001) than tibia (P < .01) but vascular damage was similar at both skeletal sites. Combined effects of radiation and minor trauma promoted mandibular alveolar bone loss and tibial fracture., Conclusions: ORN has a more rapid onset in mandible than in tibia in the rat., (Copyright © 2013 Elsevier Inc. All rights reserved.)

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.

Objective: To develop a rat model of mandibular osteoradionecrosis(ORN) that uses novel micro-computed tomography bone volume analysis and detailed histology to provide a more effective, quantifiable, and standardized way to study ORN in vivo., Study Design: Animal model., Setting: Academic medical center., Subjects and Methods: Modifications to our previously published rat model of mandibular ORN were done to develop an ideal protocol consisting of 10 rats (6 experimental and 4 controls) with their left middle mandibular molar removed 7 days after either 20 Gy high dose rate brachytherapy or sham irradiation. Rats were sacrificed 21 days after extraction for landmark defined bone volume and histologic analysis., Results: A standardized method of quantification was achieved in all samples. The radiated group (XRT) had a mean bone volume/total volume (BV/TV) of 13.8% compared to 65.9% for controls (P < .001). There were increases in osteoclasts and fibrosis, decreases in osteoblasts,and less bone in radiated samples with a mean (SD)of 5.91 (3.77) osteoclasts/high-powered field (HPF) and 4.00(1.83) osteoblasts/HPF in XRT samples compared to 1.08(1.08) osteoclasts/HPF and 22.49 (6.00) osteoblasts/HPF for controls (P <.001)., Conclusion: Our updated model continues to be clinically analogous to human mandibular ORN and improves the radiologic and histologic analysis of bony defects, providing a method for quantification of bone loss. Further cell-specific staining, including immunohistochemistry, can be used with this model to study potential cellular mechanisms of mandibular ORN and test any future therapeutic options.

Background: Treatment of oral cavity cancer may require variable extent of mandibular resection. Marginal mandibulectomy is a controversial technique in providing oncologic resection margin. This study analyzes the efficacy of local oncologic control and the morbidity of marginal mandibulectomy in oral cavity carcinoma. Nononcologic complication of osteoradionecrosis is discussed., Methods: A retrospective cohort study analyzed clinicopathologic features of 43 patients with oral cavity cancer who underwent marginal mandibulectomy. Histologic mandibular invasion was examined as a function of local control and contribution to osteoradionecrosis., Results: Bone invasion was present in 16.3% of patients with marginal mandibulectomy. Local control rates were 85.7% in the bone invasion group and 77.8% in the no bone invasion group (p = .7). Osteoradionecrosis rates were 16.7% and 17.6%, respectively (p = .96). There was no significant difference between the 2 groups., Conclusions: Marginal mandibulectomy is oncologically sound in providing a safe resection margin in oral cavity cancer abutting or superficially invading the mandible., (Copyright © 2010 Wiley Periodicals, Inc.)

The present experimental study sought to determine the effect of high-dose irradiation on the rat mandible in order to establish an experimental model of radiogenic bone damage. The left mandibles of 20 adult Wistar rats were irradiated (single fraction 1500cGy, total dose 60Gy) by means of a hypofractionated stereotactic radiotherapy (hfSRT) over a period of 6 weeks. Follow-up was 6 weeks (group 1, n=10) and 12 weeks (group 2, n=10). The contralateral mandibles as well as 5 non-irradiated animals served as controls. Primary endpoints were fibrosis, loss of cell count, decreased immunohistochemical labelling for bone morphogenetic protein-2 (BMP-2) and osteocalcin as well as increased expression of transforming growth factor (TGF-beta). Cell loss, progressive fibrosis, and focal necrosis were detected in all irradiated sites. Quantitative measurement revealed 32.0+/-8.7% and 37.3+/-9.5% empty osteocyte lacunae for groups 1 and 2 resp., compared to 16.3+/-4.7% and 18.9+/-4.9% on the contralateral side and 7.9+/-1.7% for unirradiated controls (Mann-Whitney U test; p<.01). BMP-2 and osteocalcin labelling showed a marked decrease in irradiated and contralateral sides while TGF-beta was expressed strongly in irradiated sites only (for all p<.05). External hypofractionated irradiation with a total dose of 60Gy is feasible in rats and yields all histologic changes attributed to osteoradionecrosis (ORN) after a follow-up of 6 weeks. The irradiation protocol is suitable for an assessment of regenerative options in severe radiogenic bone damage. As a split mouth design entails major inaccuracies healthy animals have to be used as controls.

The potential of distraction osteogenesis in mandibular reconstruction has been limited by its questionable efficacy in previously irradiated bone. The possible osteogenetic effect of recombinant human basic fibroblast growth factor (bFGF) on lengthening of irradiated mandibles was investigated in beagle dogs. We studied nine adult dogs which underwent a full course of external beam radiation therapy (60 Gy/30 fractions). Six months after completion of radiotherapy, the molars were extracted bilaterally followed by bone lengthening of the mandible using an intraoral device. On postoperative day 3 and 7 we injected 10 micrograms bFGF into the osteotomy site of each right hemimandible. The left sides were used as controls. The time course in ossification of the distracted area was evaluated at 2, 4, and 6 weeks after completion of bone lengthening. The radiographs of the newly formed bone tissue were measured by digital image analysis. Corresponding to the radiographic findings, the histological examination of the removed jaws showed an earlier and more intensive bone formation in the treated side after 2, 4, and 6 weeks compared to the control side. We conclude that bFGF promotes the ossification of distracted mandibles after radiation therapy in dogs.

We undertook a microradiographic study in osteoradionecrotic mandibular bone to estimate the number of vascular channels in the compact bone, number of resorption areas, and number of regeneration areas. Normal mandibles had a similar number of vascular channels/vision field compared with compact bone in other parts of the body. Irradiation itself did not significantly alter this number. After osteoradionecrosis had developed in the mandible, the number of vascular channels increased (p = 0.02). Treatment with hyperbaric oxygen further increased the number of vascular channels/vision field (p < 0.003). The normal mandible had no resorptive or regenerative areas, either before or after radiotherapy. The osteoradionecrotic mandible, however, had an increased number of resorptive as well as regenerative areas/vision field. Fluorescence as an indication of incorporation of tetracycline was seen in the regenerative areas of all osteoradionecrotic specimens treated with doxycycline. The process started from the vascular channels, periosteum, and endosteum. We conclude that the compact bone of mandibular osteoradionecrosis has high metabolic activity with active resorption and regeneration of bone and the limitation of the blood supply through cortical vascular channels, seems to be only one of many important factors.

In the experiment, both 180 kV X-ray and cobalt-60 radiation were delivered to right mandibles of 128 guinea-pigs with different dose (1000 cGy x 4, 800 cGy x 4, 600 cGy x 4, 400 cGy x 4 within 1 week). Dental extractions were conducted 1, 3, 5 months after radiation and the irradiated animals were examined by using microvascular corrosion castings of mandibles. It was found that the number of capillaries reduced and microvascular networks broke off after radiation with small veins shrinking subsequently while the alterations of arteries were slight. This result indicated that capillary was the most vulnerable part to the damage of radiation in the vascular system. In addition the defects of vascular networks around the non-healing tooth extraction sites were also discovered with irregularly capillary proliferation in the periphery of the lesion. The phenomena suggested that microcirculation failure induced by trauma-repairing process lead to occurRence of osteoradionecrosis of jaws.

Osteoradionecrosis is a severe complication of radiation therapy for cancer. Prevention of osteoradionecrosis is most important as the condition may be chronic, progressive and lead to pathologic fracture. The clinical experience at the Cancer Control Agency of British Columbia with 26 cases in approximately 1000 patients treated with radical radiation therapy to the head and neck region is presented and discussed. A clinical classification system is proposed to provide a guide for treatment selection, and to allow classification for research purposes.

Fragments of the lower jaw from 42 patients with carcinoma of the oral cavity or oropharynx, and treated primarely with fraction radiotherapy, were excised for radiation osteonecrosis 6 month to 10 years after irradiations. The excised specimens are X-rayed before being coated with methylmetacrylate. They are then cut into thick sections along lines detailled on the X-ray films. The sections are trimmed to 80 microns and examined microradiographically. Two observations are sufficient to demonstrate destruction or reorganisation of the bone tissue. Reabsorption of unusual appearance is seen around the Haversian canals. The newly formed tissue resembles either embryonic bone matter, or lamellar tissue as seen in osteomyelitis.

The presenting characteristics and clinical courses of 60 patients with mandibular bone infections are described. Fifteen of the patients had posttraumatic osteomyelitis, 13 had odontogenic osteomyelitis, and 28 had osteoradionecrosis. Most infections (93%) were polymicrobial, and anaerobes played an important role. Types of surgical procedures and use of adjunctive hyperbaric oxygen are described. There were minimal differences in presentation or response to treatment between these four different groups. A clinical staging system for mandibular bone infections is proposed and results of treatment are retrospectively analyzed by stage. The results support the concept that initial treatment planning can be safely and successfully based on the stage of the disease.