- Email: [email protected]
99mTechnetium-methylene diphosphonate bone imaging using low-intensity pulsed ultrasound: promotion of bone formation during mandibular distraction osteogenesis in dogs
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British Journal of Oral and Maxillofacial Surgery 48 (2010) 94–99
99m
Technetium-methylene diphosphonate bone imaging using low-intensity pulsed ultrasound: promotion of bone formation during mandibular distraction osteogenesis in dogs
Yuxiang Ding a , Guoquan Li b , Jianhua Ao a , Libin Zhou c , Qin Ma a , Yanpu Liu a,∗ a
Department of Oral and Maxillofacial Surgery, School of Stomatology, Fourth Military Medical University (FMMU), 145 Western Changle Road, Xi’an, 710032, PR China b Department of Nuclear Medicine, Xijing Hospital, FMMU, PR China c Postgraduate Institute, FMMU, PR China Accepted 29 April 2009 Available online 30 May 2009
Abstract Our objective was to assess the value of 99m technetium-methylene diphosphonate (99m Tc-MDP) bone imaging in the use of low-intensity pulsed ultrasound to promote bony formation during mandibular distraction osteogenesis in dogs. The body of the mandibles in 7 dogs were cut between the first and the second premolar and were lengthened at the rate of 1 mm/day, twice a day, for 20 days. During the period of distraction one lateral distraction gap was irradiated with low-intensity pulsed ultrasound (LIPUS) for 10 min twice a day, and the other side was used as control. Serial radiographic inspections were made at different periods (0, 1, 2, 4, 6, 8, and 12 weeks) during the consolidation phase, followed by a plain radiograph and histological examination. The 99m Tc-MDP imaging showed that the ratio of bone formation on the LIPUS-treated side was significantly higher than that on the control side during the early period of consolidation (before the 4th week), but later this was reversed and there were no significant differences between the two sides by the 12th week. Plain radiographs and histological examination showed that the new bone on the experimental side had matured earlier than that on the control side. Radionuclide bone imaging is a good way to assess the formation of bone after distraction osteogenesis. © 2009 The British Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved. Keywords:
99m Tc-MDP
bone imaging; Low-intensity pulsed ultrasound (LIPUS); Distraction osteogenesis; Dogs
Introduction Distraction osteogenesis (DO) has become an accepted method for the treatment of numerous congenital and acquired craniofacial anomalies. However, its main disadvantage is the prolonged length time for which the distracted bony segment must be held by the distractor to facilitate the maturation and remodelling of new bone. This has a psychological effect on patients and their families because several ∗
Corresponding author. Tel.: +86 029 84772531. E-mail address: [email protected] (Y. Liu).
months are needed before the woven bone matures. Attempts to remove the distractor prematurely will result in non-union or a pathological fracture. Ilizarov1 suggested that the retention time should be not less than two or three times as long as the distraction time (usually 6–8 weeks). Long-term retention causes inconvenience and increases the cost to the hospital; complications such as pseudarthrosis, fracture, and relapse have also been reported.2,3 How to shorten the retention time and improve the mechanical properties are now our focus. Low-intensity pulsed ultrasound (LIPUS) is a well-known treatment for accelerating the healing of fractured bones.4–6 If ultrasound stimulation could accelerate the rate of callus
0266-4356/$ – see front matter © 2009 The British Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.bjoms.2009.04.029
Y. Ding et al. / British Journal of Oral and Maxillofacial Surgery 48 (2010) 94–99
formation and maturation of regenerated bone in distraction osteogenesis the fixator could be removed earlier, the period of treatment could be shortened, complications could be reduced, and patients could return to their daily activities more quickly. Some papers7–9 have also reported that LIPUS can promote the maturation of distracted bone and improve the mechanical quality of new bone, but the underlying mechanisms are still not clear. Radionuclide bone imaging is an important way of evaluating the blood supply and metabolic activity of the bone. The uptake of the radionuclide can directly reflect the local blood supply to the bone and its metabolic activity and regeneration, which can be used to monitor the remodelling processing of the new bone. In this study we have used 99m Tc-MDP imaging to evaluate the formation of bone accelerated by low-intensity pulsed ultrasound during mandibular distraction osteogenesis in dogs.
Materials and methods Seven adult mongrel dogs, 18–24 months old, which weighed 11–16 kg (supplied by the experimental laboratory, Xijing Hospital, Fourth Military Medical University) were used in this study. They were caged individually and fed fluid food and water. Surgical procedure and distraction Each dog was anaesthetised with pentobarbital 20–30 mg/kg intravenously and halothane inhalation. Aqueous penicillin G 1,600,000 units, 0.2 ml/kg was given intramuscularly before operation, and postoperatively for 5 days. A complete osteotomy was made bilaterally between the first and second premolar, and the anterior mandible was mobilised. The intraoral distraction device was placed subsequently. After a 7-day latency period the gradual distraction was started at the rate of 0.5 mm twice a day for 20 days. After the distraction had been completed the dogs were killed at 0, 1, 2, 4, 6, 8, and 12 weeks and mandibular samples were harvested. Regular plain radiographs were taken and histological examinations made.
99m Tc-MDP
95
imaging of bone
99m Tc-MDP bone imaging was done at 0, 1, 2, 4, 6, 8, and 12
weeks of the consolidation phase. Four hours after the bolus intravenous injection of 740 MBq 99m Tc-MDP, delayed static bone scanning was obtained with 128 × 128 matrices, magnified to a multiple of 1.33 (Millennium VG5 with Hawkeye, GETM ). We used the working station (VG5 with Hawkeye, GETM ) to analyse data. For semiquantitative analysis of the delayed static image, we set the region of interest (ROI) manually on the LIPUS-stimulated distraction area, and set a symmetrical ROI on the opposite area as control. The uptake ratios of radionuclide were calculated by dividing the radioactivity counted in the LIPUS-stimulated area by that in the control area in each image. Statistical analysis Radioactivity values are expressed as mean (SD). The paired t test was used to compare data between the LIPUS-treated and control samples. Probabilities of less than 0.05 were accepted as significant.
Results The distraction area showed significant uptake of the radionuclide above those of normal bone in both treated and control sides. The counting of ROI (Table 1) showed the uptake of 99m Tc-MDP in the experimental side was significantly higher (p < 0.05) than that of the control side in the early period of consolidation (before the 4th week). However, later this was reversed, the uptake on the control side being significantly higher than that of the experimental side (p < 0.05). There were no significant differences in radioactivity between the two sides by the 12th week (Figs. 1–4).
LIPUS stimulation Ultrasound energy was provided by an ultrasound signal comprising a burst width of 200 s containing 1.5 MHz sine waves, with a repetition rate of 1 kHz and a spatial average–temporal average intensity of 40 mW/cm2 . During the distraction period one lateral distraction gap was irradiated with LIPUS for 10 min twice a day, and the other side served as control. Ultrasound gel was used as a medium and to prevent excessive heat forming from any ultrasound waves that were reflected off the bone. The ultrasound signal affected an area of 4 cm2 and so the entire distraction gap was stimulated by the ultrasound signal.
Fig. 1. 99m Tc image of the bone at the beginning of the consolidation phase (0 weeks).
96
Y. Ding et al. / British Journal of Oral and Maxillofacial Surgery 48 (2010) 94–99
Table 1 Mean (SD) radioactivity counts in the two sides of the mandible (n = 7). Consolidation time (weeks)
Experimental group
Control group
Uptake ratio
0 1 2 4 6 8 12
286.917 (59.038) 455.731 (68.085) 327.031 (51.767) 180.306 (34.614) 128.286 (22.675) 101.038 (19.100) 89.086 (16.105)
182.571 (65.699) 304.897 (65.220) 246.819 (50.100) 212.013 (40.592) 182.266 (21.557) 137.168 (17.247) 107.574 (14.885)
1.57 1.49 1.32 0.85 0.70 0.74 0.83
Histological examination showed that there were more trabeculae on the experimental side and they were thicker than those on the control side during the early period of retention (Fig. 6). However, there were no significant differences during the later period.
Discussion
Fig. 2.
99m Tc
image of the bone after 2 weeks’ consolidation.
Regular plain radiographs (Fig. 5) showed that during the early period of consolidation there was newly formed woven bone extending from both edges of the distracted gap to the central area on the experimental side, but on the control side the distracted gap was translucent. At the later time the density of the distracted bone on the experimental side was higher than that of the control side, which indicated that the new bone on the experimental side had matured earlier than that of the control side.
Fig. 3.
99m Tc
image of the bone after 4 weeks’ consolidation.
Pyrophosphate, the diphosphonates, and their 99m Tc-labelled compounds are known to adsorb strongly to the surface of apatite crystals. Uptake of 99m Tc-MDP results from a number of factors including the affinity of the tracer for bone mineral, the metabolic activity of osteogenesis, local alterations in blood flow and blood supply, and the effects of trauma in general.10–12 These factors govern the uptake of the tracer during the distraction period, when continuous distraction induces serious damage in the tissue. Any factor that causes osteoblasts to proliferate and osteogenesis to be accelerated will result in increased uptake and accumulation of 99m Tc-MDP. In the imaging of bone, therefore, the distribution of 99m Tc-MDP can not only show the skeletal contour but can also indirectly reflect any local change in blood supply and the metabolic activity of osteogenesis. We used 99m Tc-MDP bone imaging to record the changes in the local blood supply and osteogenic activity of the
Fig. 4.
99m Tc
image of the bone after 8 weeks’ consolidation.
Y. Ding et al. / British Journal of Oral and Maxillofacial Surgery 48 (2010) 94–99
97
Fig. 5. Plain radiographs of the consolidation phase. (A) control side (the distracted gap was translucent) at the beginning of consolidation (0 weeks). (B) LIPUS-treated side (newly formed woven bone extending from both edges of the distracted gap to the central area) at the beginning of consolidation (0 weeks). (C) control side (the central area of distraction gap still translucent) at 2 weeks. (D) LIPUS-treated side (the distraction gap was bridged by newly generated trabeculae) at 2 weeks.
Fig. 6. Histological picture of distracted bone, there were more trabeculae on the experimental side and they were thicker than on the control side: (A) control side at 1 week. (B) LIPUS-treated side at 1 week. (C) control side at 2 weeks. (D) LIPUS-treated side at 2 weeks. Haematoxylin and eosin, original magnification of all four slides × 10.
98
Y. Ding et al. / British Journal of Oral and Maxillofacial Surgery 48 (2010) 94–99
distracted bone area under the stimulus of the LIPUS. From the delayed imaging at the different consolidation times (0, 1, 2, 4, 6, 8, and 12 weeks after distraction) we found different processes of formation and remodelling of new bone. The results showed that the radionuclide uptake reached its maximum around the 1st week of consolidation. The counting of radionuclide density in ROI showed that the uptake of 99m Tc-MDP on the experimental side was significantly higher than that of the control side during the early period of consolidation. We noted at the same time that the LIPUSstimulated area had more blood supply and metabolic activity. During 20 days of distraction, LIPUS radiation 10 min twice a day improved the healing and osteogenesis of the new bone. LIPUS is a form of mechanical energy that is transmitted through and into biological tissues as an acoustic pressure wave, and it has been widely used in medicine for diagnosis and treatment. Application of LIPUS (<50 mW/cm2 ) was thought to have little thermal effect and to produce stable cavitation and streaming. Blood supply is closely related to osteogenesis. The thermal and streaming effect of LIPUS increased the local blood supply to the distracted area and increased the formation of bone. It has been hypothesised that the stimulatory effect of LIPUS may be the result of the increased formation of new blood vessels,13 the increased secretion of prostaglandin E2,14 the increased secretion of growth factors,15 and may be related to the piezoelectric properties of biological tissue.16 Electric potential produced by LIPUS through the piezoelectric effect may increase the formation of bone and accelerate bony healing.17,18 The acoustic pressure waves can also facilitate fluid flow which, in turn, increases the nutrient delivery and waste removal (acoustic streaming phenomenon), which stimulate proliferation and differentiation of the fibroblasts, chondroblasts, and osteoblasts.19,20 In addition, the acoustic pressure waves produce microstress fields, which results in a mechanical response of the bone that is analogous to the phenomena described by Wolf’s law.21 Small temperature fluctuations (<1 ◦ C) develop as a result of the conversion of ultrasound energy to heat. Some enzymes, such as collagenase and alkaline phosphatase, are exquisitely sensitive to these small variations, so ultrasound may also facilitate some enzymatic processes.22 LIPUS improved the healing and osteogenesis processing by increasing cell proliferation and differentiation, and bone metabolic activity. Later during the consolidation phase the uptake of 99m TcMDP on the control side was significantly higher than that on the experimental side. In addition, the area of accumulated tracer was reduced, particularly at the two ends of the distracted gap on the experimental side. The reduction in uptake of 99m Tc-MDP might have been caused by the change in bone metabolism from net formation to remodelling. This would mean that at the time of the consolidation, the new bone on the experimental side had matured and remodelled earlier than that on the control side. At the end
of consolidation (12 weeks) there were no significant differences in the radionuclide density between the two sides. Radiographic and histological examinations showed the same results as bone imaging, in that the new bone on the experimental side had matured earlier than that on the control side.
References 1. Ilizarov GA. The tension-stress effect on the genesis and growth of tissues. Part I. The influence of stability of fixation and soft-tissue preservation. Clin Orthop Relat Res 1989;238:249–81. 2. Swennen G, Schliephake H, Dempf R, Schierle H, Malevez C. Craniofacial distraction osteogenesis: a review of the literature. Part 1. Clinical studies. Int J Oral Maxillofac Surg 2001;30:89–103. 3. Mommaerts MY, Spaey YJ, Soares PE, Correia PE, Swennen GR. Morbidity related to transmandibular distraction osteogenesis for patients with developmental deformities. J Craniomaxillofac Surg 2008;36:192–7. 4. Heybeli N, Yesildag A, Oyar O, Gulsoy UK, Tekinsoy MA, Mumcu EF. Diagnostic ultrasound treatment increases the bone fracture healing rate in an internally fixed rat femoral osteotomy model. J Ultrasound Med 2002;21:1357–63. 5. Busse JW, Bhandan M, Kulkarni AV, Tunks E. The effect of low-intensity pulsed ultrasound therapy on time to fracture healing: a meta-analysis. CMAJ 2002;166:437–41. 6. Nolte PA, van de Krans A, Patka P, Janssen IM, Ryaby JP, Albers GH. Low-intensity pulsed ultrasound in the treatment of nonunions. J Trauma 2001;51:693–702. 7. Shimazaki A, Inui K, Azuma Y, Nishimura N, Yamano Y. Low-intensity pulsed ultrasound accelerates bone maturation in distraction osteogenesis in rabbits. J Bone Joint Surg 2000;82(B):1077–82. 8. Machen MS, Tis JE, Inoue N, Meffert RH, Chao EY, McHale KA. The effect of low intensity pulsed ultrasound on regenerate bone in a less-than-rigid biomechanical environment. Biomed Mater Eng 2002;12:239–47. 9. Tsumaki N, Kakiuchi M, Sasaki J, Ochi T, Yoshikawa H. Low-intensity pulsed ultrasound accelerates maturation of callus in patients treated with opening-wedge high tibial osteotomy by hemicallotasis. J Bone Joint Surg 2004;86A:2399–405. 10. Kanishi D. 99 mTc-MDP accumulation mechanisms in bone. Oral Surg Oral Med Oral Pathol 1993;75:239–46. 11. Genant HK, Bautovich GJ, Singh M, Lathrop KA, Harper PV. Boneseeking radionuclides: an in vivo study of factors affecting skeletal uptake. Radiology 1974;113:373–82. 12. Siegel BA, Donovan RL, Alderson PO, Mack GR. Skeletal uptake of 99 mTc-diphosphonate in relation to local bone blood flow. Radiology 1976;120:121–3. 13. Young SR, Dyson M. The effect of therapeutic ultrasound on angiogenesis. Ultrasound Med Biol 1990;16:261–9. 14. Sun JS, Tsuang YH, Lin FH, Liu HC, Tsai CZ, Chang WH. Bone defect healing enhanced by ultrasound stimulation: an in vitro tissue culture model. Biomed Mater Res 1999;46:253–61. 15. Ito M, Azumaa Y, Ohtaa T, Komoriyaa K. Effects of ultrasound and 1,25-dihydroxyvitamin D3 on growth factor secretion in co-cultures of osteoblasts and endothelial cells. Ultrasound Med Biol 2000;26: 161–6. 16. Duarte LR. The stimulation of bone growth by ultrasound. Arch Orthop Trauma Surg 1983;101:153–9. 17. Hagiwara T, Bell WH. Effect of electrical stimulation on mandibular distraction osteogenesis. J Craniofac Surg 2000;28:12–9. 18. Zorlu U, Tercan M, Ozyazgan I, et al. Comparative study of the effect of ultrasound and electrostimulation on bone healing in rats. Am J Phys Med Rehabil 1998;77:427–32.
Y. Ding et al. / British Journal of Oral and Maxillofacial Surgery 48 (2010) 94–99 19. Hadjiargyrou M, McLeod K, Ryaby JP, Rubin C. Enhancement of fracture healing by low intensity ultrasound. Clin Orthop Relat Res 1998;355(suppl.):216–29. 20. Rubin C, Bolander M, Ryaby JP, Hadjiargyrou M. The use of lowintensity ultrasound to accelerate the healing of fractures. J Bone Joint Surg 2001;83A:259–70.
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21. Rubin CT, Hausman MR. The cellular basis of Wolff’s law: transduction of physical stimuli to skeletal adaptation. Rheum Dis Clin North Am 1988;14:503–17. 22. Wu J, Du G. Temperature elevation in tissues generated by a focused Gaussian ultrasonic beam at a tissue-bone interface. J Acoust Soc Am 1990;87:2748–55.
British Journal of Oral and Maxillofacial Surgery 48 (2010) 94–99
99m
Technetium-methylene diphosphonate bone imaging using low-intensity pulsed ultrasound: promotion of bone formation during mandibular distraction osteogenesis in dogs
Yuxiang Ding a , Guoquan Li b , Jianhua Ao a , Libin Zhou c , Qin Ma a , Yanpu Liu a,∗ a
Department of Oral and Maxillofacial Surgery, School of Stomatology, Fourth Military Medical University (FMMU), 145 Western Changle Road, Xi’an, 710032, PR China b Department of Nuclear Medicine, Xijing Hospital, FMMU, PR China c Postgraduate Institute, FMMU, PR China Accepted 29 April 2009 Available online 30 May 2009
Abstract Our objective was to assess the value of 99m technetium-methylene diphosphonate (99m Tc-MDP) bone imaging in the use of low-intensity pulsed ultrasound to promote bony formation during mandibular distraction osteogenesis in dogs. The body of the mandibles in 7 dogs were cut between the first and the second premolar and were lengthened at the rate of 1 mm/day, twice a day, for 20 days. During the period of distraction one lateral distraction gap was irradiated with low-intensity pulsed ultrasound (LIPUS) for 10 min twice a day, and the other side was used as control. Serial radiographic inspections were made at different periods (0, 1, 2, 4, 6, 8, and 12 weeks) during the consolidation phase, followed by a plain radiograph and histological examination. The 99m Tc-MDP imaging showed that the ratio of bone formation on the LIPUS-treated side was significantly higher than that on the control side during the early period of consolidation (before the 4th week), but later this was reversed and there were no significant differences between the two sides by the 12th week. Plain radiographs and histological examination showed that the new bone on the experimental side had matured earlier than that on the control side. Radionuclide bone imaging is a good way to assess the formation of bone after distraction osteogenesis. © 2009 The British Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved. Keywords:
99m Tc-MDP
bone imaging; Low-intensity pulsed ultrasound (LIPUS); Distraction osteogenesis; Dogs
Introduction Distraction osteogenesis (DO) has become an accepted method for the treatment of numerous congenital and acquired craniofacial anomalies. However, its main disadvantage is the prolonged length time for which the distracted bony segment must be held by the distractor to facilitate the maturation and remodelling of new bone. This has a psychological effect on patients and their families because several ∗
Corresponding author. Tel.: +86 029 84772531. E-mail address: [email protected] (Y. Liu).
months are needed before the woven bone matures. Attempts to remove the distractor prematurely will result in non-union or a pathological fracture. Ilizarov1 suggested that the retention time should be not less than two or three times as long as the distraction time (usually 6–8 weeks). Long-term retention causes inconvenience and increases the cost to the hospital; complications such as pseudarthrosis, fracture, and relapse have also been reported.2,3 How to shorten the retention time and improve the mechanical properties are now our focus. Low-intensity pulsed ultrasound (LIPUS) is a well-known treatment for accelerating the healing of fractured bones.4–6 If ultrasound stimulation could accelerate the rate of callus
0266-4356/$ – see front matter © 2009 The British Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.bjoms.2009.04.029
Y. Ding et al. / British Journal of Oral and Maxillofacial Surgery 48 (2010) 94–99
formation and maturation of regenerated bone in distraction osteogenesis the fixator could be removed earlier, the period of treatment could be shortened, complications could be reduced, and patients could return to their daily activities more quickly. Some papers7–9 have also reported that LIPUS can promote the maturation of distracted bone and improve the mechanical quality of new bone, but the underlying mechanisms are still not clear. Radionuclide bone imaging is an important way of evaluating the blood supply and metabolic activity of the bone. The uptake of the radionuclide can directly reflect the local blood supply to the bone and its metabolic activity and regeneration, which can be used to monitor the remodelling processing of the new bone. In this study we have used 99m Tc-MDP imaging to evaluate the formation of bone accelerated by low-intensity pulsed ultrasound during mandibular distraction osteogenesis in dogs.
Materials and methods Seven adult mongrel dogs, 18–24 months old, which weighed 11–16 kg (supplied by the experimental laboratory, Xijing Hospital, Fourth Military Medical University) were used in this study. They were caged individually and fed fluid food and water. Surgical procedure and distraction Each dog was anaesthetised with pentobarbital 20–30 mg/kg intravenously and halothane inhalation. Aqueous penicillin G 1,600,000 units, 0.2 ml/kg was given intramuscularly before operation, and postoperatively for 5 days. A complete osteotomy was made bilaterally between the first and second premolar, and the anterior mandible was mobilised. The intraoral distraction device was placed subsequently. After a 7-day latency period the gradual distraction was started at the rate of 0.5 mm twice a day for 20 days. After the distraction had been completed the dogs were killed at 0, 1, 2, 4, 6, 8, and 12 weeks and mandibular samples were harvested. Regular plain radiographs were taken and histological examinations made.
99m Tc-MDP
95
imaging of bone
99m Tc-MDP bone imaging was done at 0, 1, 2, 4, 6, 8, and 12
weeks of the consolidation phase. Four hours after the bolus intravenous injection of 740 MBq 99m Tc-MDP, delayed static bone scanning was obtained with 128 × 128 matrices, magnified to a multiple of 1.33 (Millennium VG5 with Hawkeye, GETM ). We used the working station (VG5 with Hawkeye, GETM ) to analyse data. For semiquantitative analysis of the delayed static image, we set the region of interest (ROI) manually on the LIPUS-stimulated distraction area, and set a symmetrical ROI on the opposite area as control. The uptake ratios of radionuclide were calculated by dividing the radioactivity counted in the LIPUS-stimulated area by that in the control area in each image. Statistical analysis Radioactivity values are expressed as mean (SD). The paired t test was used to compare data between the LIPUS-treated and control samples. Probabilities of less than 0.05 were accepted as significant.
Results The distraction area showed significant uptake of the radionuclide above those of normal bone in both treated and control sides. The counting of ROI (Table 1) showed the uptake of 99m Tc-MDP in the experimental side was significantly higher (p < 0.05) than that of the control side in the early period of consolidation (before the 4th week). However, later this was reversed, the uptake on the control side being significantly higher than that of the experimental side (p < 0.05). There were no significant differences in radioactivity between the two sides by the 12th week (Figs. 1–4).
LIPUS stimulation Ultrasound energy was provided by an ultrasound signal comprising a burst width of 200 s containing 1.5 MHz sine waves, with a repetition rate of 1 kHz and a spatial average–temporal average intensity of 40 mW/cm2 . During the distraction period one lateral distraction gap was irradiated with LIPUS for 10 min twice a day, and the other side served as control. Ultrasound gel was used as a medium and to prevent excessive heat forming from any ultrasound waves that were reflected off the bone. The ultrasound signal affected an area of 4 cm2 and so the entire distraction gap was stimulated by the ultrasound signal.
Fig. 1. 99m Tc image of the bone at the beginning of the consolidation phase (0 weeks).
96
Y. Ding et al. / British Journal of Oral and Maxillofacial Surgery 48 (2010) 94–99
Table 1 Mean (SD) radioactivity counts in the two sides of the mandible (n = 7). Consolidation time (weeks)
Experimental group
Control group
Uptake ratio
0 1 2 4 6 8 12
286.917 (59.038) 455.731 (68.085) 327.031 (51.767) 180.306 (34.614) 128.286 (22.675) 101.038 (19.100) 89.086 (16.105)
182.571 (65.699) 304.897 (65.220) 246.819 (50.100) 212.013 (40.592) 182.266 (21.557) 137.168 (17.247) 107.574 (14.885)
1.57 1.49 1.32 0.85 0.70 0.74 0.83
Histological examination showed that there were more trabeculae on the experimental side and they were thicker than those on the control side during the early period of retention (Fig. 6). However, there were no significant differences during the later period.
Discussion
Fig. 2.
99m Tc
image of the bone after 2 weeks’ consolidation.
Regular plain radiographs (Fig. 5) showed that during the early period of consolidation there was newly formed woven bone extending from both edges of the distracted gap to the central area on the experimental side, but on the control side the distracted gap was translucent. At the later time the density of the distracted bone on the experimental side was higher than that of the control side, which indicated that the new bone on the experimental side had matured earlier than that of the control side.
Fig. 3.
99m Tc
image of the bone after 4 weeks’ consolidation.
Pyrophosphate, the diphosphonates, and their 99m Tc-labelled compounds are known to adsorb strongly to the surface of apatite crystals. Uptake of 99m Tc-MDP results from a number of factors including the affinity of the tracer for bone mineral, the metabolic activity of osteogenesis, local alterations in blood flow and blood supply, and the effects of trauma in general.10–12 These factors govern the uptake of the tracer during the distraction period, when continuous distraction induces serious damage in the tissue. Any factor that causes osteoblasts to proliferate and osteogenesis to be accelerated will result in increased uptake and accumulation of 99m Tc-MDP. In the imaging of bone, therefore, the distribution of 99m Tc-MDP can not only show the skeletal contour but can also indirectly reflect any local change in blood supply and the metabolic activity of osteogenesis. We used 99m Tc-MDP bone imaging to record the changes in the local blood supply and osteogenic activity of the
Fig. 4.
99m Tc
image of the bone after 8 weeks’ consolidation.
Y. Ding et al. / British Journal of Oral and Maxillofacial Surgery 48 (2010) 94–99
97
Fig. 5. Plain radiographs of the consolidation phase. (A) control side (the distracted gap was translucent) at the beginning of consolidation (0 weeks). (B) LIPUS-treated side (newly formed woven bone extending from both edges of the distracted gap to the central area) at the beginning of consolidation (0 weeks). (C) control side (the central area of distraction gap still translucent) at 2 weeks. (D) LIPUS-treated side (the distraction gap was bridged by newly generated trabeculae) at 2 weeks.
Fig. 6. Histological picture of distracted bone, there were more trabeculae on the experimental side and they were thicker than on the control side: (A) control side at 1 week. (B) LIPUS-treated side at 1 week. (C) control side at 2 weeks. (D) LIPUS-treated side at 2 weeks. Haematoxylin and eosin, original magnification of all four slides × 10.
98
Y. Ding et al. / British Journal of Oral and Maxillofacial Surgery 48 (2010) 94–99
distracted bone area under the stimulus of the LIPUS. From the delayed imaging at the different consolidation times (0, 1, 2, 4, 6, 8, and 12 weeks after distraction) we found different processes of formation and remodelling of new bone. The results showed that the radionuclide uptake reached its maximum around the 1st week of consolidation. The counting of radionuclide density in ROI showed that the uptake of 99m Tc-MDP on the experimental side was significantly higher than that of the control side during the early period of consolidation. We noted at the same time that the LIPUSstimulated area had more blood supply and metabolic activity. During 20 days of distraction, LIPUS radiation 10 min twice a day improved the healing and osteogenesis of the new bone. LIPUS is a form of mechanical energy that is transmitted through and into biological tissues as an acoustic pressure wave, and it has been widely used in medicine for diagnosis and treatment. Application of LIPUS (<50 mW/cm2 ) was thought to have little thermal effect and to produce stable cavitation and streaming. Blood supply is closely related to osteogenesis. The thermal and streaming effect of LIPUS increased the local blood supply to the distracted area and increased the formation of bone. It has been hypothesised that the stimulatory effect of LIPUS may be the result of the increased formation of new blood vessels,13 the increased secretion of prostaglandin E2,14 the increased secretion of growth factors,15 and may be related to the piezoelectric properties of biological tissue.16 Electric potential produced by LIPUS through the piezoelectric effect may increase the formation of bone and accelerate bony healing.17,18 The acoustic pressure waves can also facilitate fluid flow which, in turn, increases the nutrient delivery and waste removal (acoustic streaming phenomenon), which stimulate proliferation and differentiation of the fibroblasts, chondroblasts, and osteoblasts.19,20 In addition, the acoustic pressure waves produce microstress fields, which results in a mechanical response of the bone that is analogous to the phenomena described by Wolf’s law.21 Small temperature fluctuations (<1 ◦ C) develop as a result of the conversion of ultrasound energy to heat. Some enzymes, such as collagenase and alkaline phosphatase, are exquisitely sensitive to these small variations, so ultrasound may also facilitate some enzymatic processes.22 LIPUS improved the healing and osteogenesis processing by increasing cell proliferation and differentiation, and bone metabolic activity. Later during the consolidation phase the uptake of 99m TcMDP on the control side was significantly higher than that on the experimental side. In addition, the area of accumulated tracer was reduced, particularly at the two ends of the distracted gap on the experimental side. The reduction in uptake of 99m Tc-MDP might have been caused by the change in bone metabolism from net formation to remodelling. This would mean that at the time of the consolidation, the new bone on the experimental side had matured and remodelled earlier than that on the control side. At the end
of consolidation (12 weeks) there were no significant differences in the radionuclide density between the two sides. Radiographic and histological examinations showed the same results as bone imaging, in that the new bone on the experimental side had matured earlier than that on the control side.
References 1. Ilizarov GA. The tension-stress effect on the genesis and growth of tissues. Part I. The influence of stability of fixation and soft-tissue preservation. Clin Orthop Relat Res 1989;238:249–81. 2. Swennen G, Schliephake H, Dempf R, Schierle H, Malevez C. Craniofacial distraction osteogenesis: a review of the literature. Part 1. Clinical studies. Int J Oral Maxillofac Surg 2001;30:89–103. 3. Mommaerts MY, Spaey YJ, Soares PE, Correia PE, Swennen GR. Morbidity related to transmandibular distraction osteogenesis for patients with developmental deformities. J Craniomaxillofac Surg 2008;36:192–7. 4. Heybeli N, Yesildag A, Oyar O, Gulsoy UK, Tekinsoy MA, Mumcu EF. Diagnostic ultrasound treatment increases the bone fracture healing rate in an internally fixed rat femoral osteotomy model. J Ultrasound Med 2002;21:1357–63. 5. Busse JW, Bhandan M, Kulkarni AV, Tunks E. The effect of low-intensity pulsed ultrasound therapy on time to fracture healing: a meta-analysis. CMAJ 2002;166:437–41. 6. Nolte PA, van de Krans A, Patka P, Janssen IM, Ryaby JP, Albers GH. Low-intensity pulsed ultrasound in the treatment of nonunions. J Trauma 2001;51:693–702. 7. Shimazaki A, Inui K, Azuma Y, Nishimura N, Yamano Y. Low-intensity pulsed ultrasound accelerates bone maturation in distraction osteogenesis in rabbits. J Bone Joint Surg 2000;82(B):1077–82. 8. Machen MS, Tis JE, Inoue N, Meffert RH, Chao EY, McHale KA. The effect of low intensity pulsed ultrasound on regenerate bone in a less-than-rigid biomechanical environment. Biomed Mater Eng 2002;12:239–47. 9. Tsumaki N, Kakiuchi M, Sasaki J, Ochi T, Yoshikawa H. Low-intensity pulsed ultrasound accelerates maturation of callus in patients treated with opening-wedge high tibial osteotomy by hemicallotasis. J Bone Joint Surg 2004;86A:2399–405. 10. Kanishi D. 99 mTc-MDP accumulation mechanisms in bone. Oral Surg Oral Med Oral Pathol 1993;75:239–46. 11. Genant HK, Bautovich GJ, Singh M, Lathrop KA, Harper PV. Boneseeking radionuclides: an in vivo study of factors affecting skeletal uptake. Radiology 1974;113:373–82. 12. Siegel BA, Donovan RL, Alderson PO, Mack GR. Skeletal uptake of 99 mTc-diphosphonate in relation to local bone blood flow. Radiology 1976;120:121–3. 13. Young SR, Dyson M. The effect of therapeutic ultrasound on angiogenesis. Ultrasound Med Biol 1990;16:261–9. 14. Sun JS, Tsuang YH, Lin FH, Liu HC, Tsai CZ, Chang WH. Bone defect healing enhanced by ultrasound stimulation: an in vitro tissue culture model. Biomed Mater Res 1999;46:253–61. 15. Ito M, Azumaa Y, Ohtaa T, Komoriyaa K. Effects of ultrasound and 1,25-dihydroxyvitamin D3 on growth factor secretion in co-cultures of osteoblasts and endothelial cells. Ultrasound Med Biol 2000;26: 161–6. 16. Duarte LR. The stimulation of bone growth by ultrasound. Arch Orthop Trauma Surg 1983;101:153–9. 17. Hagiwara T, Bell WH. Effect of electrical stimulation on mandibular distraction osteogenesis. J Craniofac Surg 2000;28:12–9. 18. Zorlu U, Tercan M, Ozyazgan I, et al. Comparative study of the effect of ultrasound and electrostimulation on bone healing in rats. Am J Phys Med Rehabil 1998;77:427–32.
Y. Ding et al. / British Journal of Oral and Maxillofacial Surgery 48 (2010) 94–99 19. Hadjiargyrou M, McLeod K, Ryaby JP, Rubin C. Enhancement of fracture healing by low intensity ultrasound. Clin Orthop Relat Res 1998;355(suppl.):216–29. 20. Rubin C, Bolander M, Ryaby JP, Hadjiargyrou M. The use of lowintensity ultrasound to accelerate the healing of fractures. J Bone Joint Surg 2001;83A:259–70.
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21. Rubin CT, Hausman MR. The cellular basis of Wolff’s law: transduction of physical stimuli to skeletal adaptation. Rheum Dis Clin North Am 1988;14:503–17. 22. Wu J, Du G. Temperature elevation in tissues generated by a focused Gaussian ultrasonic beam at a tissue-bone interface. J Acoust Soc Am 1990;87:2748–55.