Reher, Peter; (1999) Evidence for the use of ultrasound therapy for the management of mandibular osteoradionecrosis. Doctoral thesis (Ph.D.), University College London (United Kingdom).

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Abstract

Introduction: The treatment of mandibular osteoradionecrosis includes antibiotics and curettage, hyperbaric oxygen, surgery, and more recently, therapeutic ultrasound. The aim of this thesis was to establish the possible mechanisms of action of therapeutic ultrasound, that could explain its excellent clinical results. Material and Methods: Two ultrasound machines were evaluated, a 'traditional' (1 MHz and 3 MHz) and a 'long wave' machine (45 kHz). Ultrasound was applied to human mandibular osteoblasts, gingival fibroblasts, peripheral blood monocytes (PBMc) and mice calvaria. The following in vitro assays were performed: cell proliferation, collagen and non-collagenous protein (NCP) synthesis, bone resorption, cytokines and angiogenesis factors production using ELISA and RT-PCR techniques, and nitric oxide production. To evaluate the effects of ultrasound on angiogenesis in vivo, the chick chorioallanlbic membrane assay (CAM) was used. The use of near infrared spectroscopy (NIRS) for the measurement of radiotherapy effects in the mandible (deoxyhaemoglobin concentrations) was also evaluated. Results: Ultrasound stimulated bone formation in the mice calvaria. Cell proliferation assays showed an increase of DNA synthesis in fibroblasts and osteoblasts, up to 52%. Collagen/NCR synthesis was also enhanced, in fibroblasts up to 48%, and in osteoblasts up to 112%. Bone resorption, part of the bone turnover process, was promoted, and there is suggestion that the cyclo-oxygenase pathway is involved. In relation to cytokine production, a slight stimulation of IL-1beta was noted in all cell types. There was no difference in IL-6 and TNFalpha levels. The angiogenesis factors, IL-8 and bFGF, were significantly stimulated in osteoblasts, and VEGF was significantly stimulated in fibroblasts, osteoblasts and PBMc. RT-PCR showed that ultrasound induces mRNA transcription for several cytokines and bone related proteins, with the most evident effect being the induction of VEGF transcription in osteoblasts. The CAM assay showed that direct ultrasound application and insonated medium from fibroblasts induced angiogenesis in vivo. The best overall stimulatory intensities were 15 and 30 mW/cm2(SA) with 45 kHz ultrasound, and 0.1 and 0.4 W/cm2(SAPA) with 1 MHz ultrasound. The NIRS evaluation showed that it is very sensitive to measure deoxyhaemoglobin concentrations, however these measurements are not reproducible. No age correlations could be performed, and the differences between normal and radiotherapy mandibles was not significant because of the great variability in the measurements. Conclusions: These results show that ultrasound can correct hypocellularity, hypoxia and hypovascularity observed in osteoradionecrosis. It stimulates cell proliferation, bone formation, healing, and angiogenesis. Further in vivo experiments are recommended as well as prospective clinical trials using therapeutic ultrasound for the treatment and prevention of osteoradionecrosis, but NIRS cannot be used to measure the outcome of treatment. Therapeutic ultrasound is a viable option for the management of mandibular osteoradionecrosis, since it is effective, inexpensive and readily available.

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