|Year : 2009 | Volume
| Issue : 2 | Page : 141-148
|Low-intensity pulsed ultrasound: Nonunions
Bernadette G Dijkman, Sheila Sprague, Mohit Bhandari
Division of Orthopaedic Surgery, Department of Surgery and Department of Clinical Epidemiology & Biostatistics. McMaster University, 293 Wellington Street North, Suite 110, Hamilton, Ontario L8L 2X2, Canada
Click here for correspondence address and email
| Abstract|| |
Nonunions occur in 5-10% of fractures and are characterized by the failure to heal without further intervention. Low intensity pulsed ultrasound therapy has been developed as an alternative to surgery in the treatment of nonunions. We describe a systematic review on trials of low-intensity pulsed ultrasound therapy for healing of nonunions. We searched the electronic databases Medline and the Cochrane library for articles on ultrasound and healing of nonunions published up to 2008. Trials selected for the review met the following criteria: treatment of at least one intervention group with low intensity pulsed ultrasound; inclusion of patients (humans) with one or more nonunions (defined as "established" or as a failure to heal for a minimum of eight months after initial injury); and assessment of healing and time to healing, as determined radiographically. The following data were abstracted from the included studies: sample size, ultrasound treatment characteristics, nonunion location, healing rate, time to fracture healing, fracture age, and demographic information. We found 79 potentially eligible publications, of which 14 met our inclusion criteria. Of these, eight studies were used for data abstraction. Healing rates averaged 87%, (range 65.6%-100%) among eight trials. Mean time to healing was 146.5 days, (range 56-219 days). There is evidence from trials that low-intensity pulsed ultrasound may be an effective treatment for healing of nonunions. More homogeneous and larger controlled series are needed to further investigate its efficacy.
Keywords: Fracture healing, low-intensity pulsed ultrasound (LIPUS), nonunion
|How to cite this article:|
Dijkman BG, Sprague S, Bhandari M. Low-intensity pulsed ultrasound: Nonunions. Indian J Orthop 2009;43:141-8
| Introduction|| |
Nonunions occur in 5-10% of fractures and are characterized by the failure to heal without further intervention. , To avoid the risks of surgery, several alternative treatments have been developed, including electrical stimulation, extracorporeal shock wave therapy, and low-intensity pulsed ultrasound (LIPUS). LIPUS has been found to have a beneficial effect on fracture healing by increasing the quantity and strength of bony callus and by several other biological and molecular mechanisms. ,, Also, it is a safe and noninvasive treatment, since it uses mechanical energy of a low intensity, thereby not causing tissue damage. , Although many randomized controlled trials (RCTs) have been conducted investigating the effect of LIPUS on fresh fractures, ,, far less evidence is available on its efficacy on nonunions. We describe a systematic review of trials on LIPUS therapy used for healing of nonunions, to evaluate the current evidence on success rates of LIPUS therapy for nonunions. Also, we provide background information on mechanisms of LIPUS and potential factors influencing its efficacy.
| Materials and Methods|| |
We searched the electronic databases of MEDLINE and the Cochrane library for articles on ultrasound and healing of nonunions published up to 2008. The search strategy consisted of the following terms: "fracture healing," "bone graft," "bone remodeling," "nonunion," "ununited," and "ultras*," in which the wild term "*" was used to allow all terms that start with the preceding letters, such as "ultrasound" and "ultrasonography." We searched for all types of study designs (RCTs, cohort studies, case series, and case reports), and systematic reviews and meta-analyses. In addition, we searched in the bibliographies of all retrieved articles to find other relevant articles.
For each potentially eligible publication, each of the following inclusion criteria had to be met: treatment of at least one intervention group with LIPUS; inclusion of patients (humans) with one or more nonunions, as defined below; and assessment of healing and time to healing, as determined radiographically. There is no agreement among surgeons on the definition of a nonunion, ranging from 2 to 12 months after initial injury.  To make sure the studies had included true nonunions only, we chose a rather conservative cutoff point for nonunion definitions. We included studies in which a nonunion was either called "established" (a minimum of nine months after initial injury and no signs of progression in the last three months),  or defined as a fracture that had failed to heal within a minimum of 8 months after initial injury. Articles in any other language than English and articles on case reports were excluded from data abstraction.
The following data were abstracted from the included studies: study design, sample size, LIPUS treatment characteristics, nonunion location, healing rate, time to fracture healing, fracture age, and demographic information.
Reviews that were found by our search strategy were all evaluated by us on relevant information and references.
| Results|| |
We found 79 potentially eligible publications, of which 14 met our inclusion criteria and were reviewed by us. Of the 65 excluded articles, 43 did not use LIPUS as an intervention, 7 studies were excluded because they did not include nonunions, 10 were reviews, and 5 were animal or cell studies. Of the 14 included studies, 6 were excluded from the data abstraction.
Among the six studies excluded from the data abstraction, the study of Jones et al .  used LIPUS as an adjunctive therapy to surgery, as a result of which healing could not be ascribed to the ultrasound treatment solely. The one RCT in our review also used LIPUS as an adjunctive therapy to surgery (vascularized pedicle bone graft), but was included since it was placebo-controlled, which enables us to attribute the healing effect to the LIPUS treatment. Another study  was excluded because the authors did not define the fracture as a nonunion. Finally, four studies were excluded from data abstraction because they were case reports.
Study characteristics and methodological quality
[Table 1] presents the baseline characteristics and study design of the eight studies selected for review. ,,,,,,, One double-blinded RCT and seven case series were included, of which five were of a prospective, and two were of a retrospective design. The double-blinded RCT included 21 established nonunions of the scaphoid treated with vascularized pedicle bone graft in patients with a mean age of 26.7 years, all being male.
In all the eight reviewed studies, the investigators applied a 20-minute daily LIPUS treatment to their treatment groups, with an ultrasound signal that was composed of a burst width of 200 µs containing 1.5 MHz sine waves, with a 1 kHz frequency and an intensity of 30 mW/cm 2 . In the one included double-blinded RCT, units were externally identical for the sham and active stimulation groups, and the sham units were adjusted to give no ultrasound signal output across the transducer.
In the reviewed studies, the healing rate varied from 65.6%  to 100%; the latter success rate found in three different studies [Table 2]. ,, The study with the highest level of evidence (the double-blinded RCT) reported a healing rate of 100% of 21 scaphoid nonunions with an average fracture age of 38.4 months. A healing rate of 86% was reported by the study with the largest sample size (366 nonunions).  On average, the healing rate of nonunions after LIPUS treatment was 87% among the reviewed studies [Table 2].
Time to fracture healing
The time until union ranged from 56 to 219 days, with an average of 146.5 days in the eight included trials [Table 2]. The RCT reported a significant decrease in healing time of 38 days in the active LIPUS group compared with the placebo group (56±3.2 days compared with 94±4.8 days). Similar as to the healing rate, the average time to healing of the fracture approximates the time to healing found in the largest study (152 days). 
| Discussion|| |
Fracture healing is a highly complex process including three predominant stages, that is, the inflammatory phase, reparative phase, and remodeling phase. For this process, a large cell population (fibroblasts, macrophages, chondroblasts, osteoblasts, and osteoclasts) and the expression of relevant genes (controlling matrix production and organization, growth factors, and transcription factors) are needed at the right time and place for an undisturbed progress of fracture healing.  Considering the complexity of fracture healing, it seems plausible that 5-10% of fractures become a delayed union or nonunion. 
Nonunion - Definition
Authors disagree in the definition of a nonunion with regard to the time from injury at which a nonunion is declared, ranging from 15 weeks  to 12 months from injury.  However, they all add to their definition that all fracture repair processes have stopped. U.S. Food and Drug Administration (FDA) states that "A nonunion is considered to be established when a minimum of nine months has elapsed since injury and the fracture site shows no visibly progressive signs of healing for minimum of three months."  In addition, consensus among authors exists on the definition of an established nonunion, as being one that does not heal without operation. ,, Therefore, most studies on treatment of nonunion use a spontaneous healing rate of 0%, with which they compare the healing rate accomplished after the treatment under investigation. However, some studies have used an estimated spontaneous healing rate of 5-30% of nonunions for statistical analyses on the treatment effect. ,,
Although the cause of delayed union and nonunion is not known, several factors are associated with their occurrences. , The major factors are those that characterize the injury, such as fracture location, comminution, vascular and soft tissue damage, bone loss, and infection. Also, several patient-related factors can be recognized, such as age, comorbidity, nutrition, smoking habits, and use of alcohol or drugs.
Nonunion - Treatment
The "gold standard" or preferred option in nonunion treatment is the removal of necrotic bone tissue and stabilization with internal or external fixation devices, in most cases, accompanied by bone grafts to stimulate osteogenesis in indolent bone ends.  However, union is not always accomplished after a surgical treatment, with reported success rates varying from 68% to 96% for the first surgical procedure, depending on the fracture location and surgical method. ,,,,
Currently, several nonoperative methods have been developed for treatment of nonunions that avoid the risks associated with surgery. These alternative treatments include LIPUS, electrical stimulation, and extracorporeal shock-wave therapy. Success rates of electrical stimulation techniques on nonunions do not seem to differ greatly from those of surgical procedures, with reported rates ranging from 65% to more than 80%. ,,,, In addition, equivalent success rates (52-91%) have been reported on extracorporeal shock-wave therapy. ,,, Despite their good results and the fact that most surgeons believe that therapeutic ultrasound may assist in fracture healing, current usage of alternative treatments is rare, primarily because of the perceived lack of evidence and availability. 
Mechanisms of LIPUS on fracture healing
Ultrasound, a form of mechanical energy that can be transmitted in organisms as high-frequency acoustical pressure waves, has been widely used as a therapeutic, operative, and diagnostic tool. , Used with an intensity of 1-3 W/cm 2 , ultrasound can cause considerable heat in tissues and is therefore used to decrease joint stiffness and improve muscle mobility.  For diagnostic or imaging purposes, even lower ultrasound intensities (1-50 mW/cm 2 ) are used, which are considered nonthermal and nondestructive.  Although the absorption of the energy from LIPUS causes very little (<1ºC) heating, some enzymes, such as matrix metalloproteinase (MMP) -1, or collagenase, are sensitive to this variation in temperature. , Therefore, ultrasound may alter enzymatic processes associated with fracture healing. In addition, an increased blood flow to dissipate the accumulated heat and return the tissue to homeostatic levels has been attributed to the small increase in temperature. 
Next to thermal effects, LIPUS induced bone osteogenesis may also be ascribed to nonthermal processes, including acoustic streaming and cavitation. Cavitation "involves the pulsation of gas or vapor-filled voids in a sound field''  with the accumulation of gas and formation of gas bubbles.  At the surface of such a gas bubble, acoustic streaming can occur,  which has been found to affect diffusion rates and membrane permeability. 
Duarte was the first to develop the LIPUS (intensity 30 mW/cm 2 ) for fracture repair and demonstrate in an experimental animal study with 45 rabbits that this therapy caused a significant increase of callus.  Later, Pilla et al . demonstrated that LIPUS (20 minutes daily, 200 µs burst of 1.5 MHz sine waves repeated at 1 kHz) with an intensity of 30mW/ cm 2 not only had an effect on the quantity of callus, but also significantly increases the mechanical strength and stiffness of the callus. 
Although it is still not completely understood by which specific mechanism LIPUS accelerates and enhances the fracture repair process, there are indications that it has influence on the different stages of the healing process, including signal transduction, gene expression, and blood flow.  As suggested by several in vivo experimental studies, LIPUS rather affects the earlier inflammation or callus formation stage than the later occurring remodeling phase. , The increased quantity of callus after LIPUS treatment has been shown by histological analysis to be due to increased endochondral bone formation processes.  Pilla et al.  found that torque and torsional stiffness of osteotomies were significantly greater in the LIPUS treated group compared with the untreated group in the first three weeks after surgery, but there was no difference between the groups at 4 weeks follow-up. This confirms the hypothesis that LIPUS treatment only stimulates the earlier phases of fracture healing. Also in another animal osteotomy model, LIPUS treatment was found to increase bone mineral density at 75 days after surgery, but this effect was not seen at 120 days after surgery. 
In vitro studies have shown that ultrasound can induce conformational changes in the cell membrane, resulting in changes in ionic permeability , and second messenger activity. , However, if the ultrasound signal influences the rate of healing, it must also show an effect on the expression of specific genes involved in the healing process. Using differential mRNA display on callus material from a rat bilateral femur fracture,  it was shown that several genes were upregulated during exposure to ultrasound. These include genes encoding for the matrix protein osteopontin and a growth factor inducible gene that plays a role during chondrogenesis.
Additionally, ultrasound has been shown to increase angiogenesis. In vitro cell studies have demonstrated that LIPUS exposure leads to an increased expression of vascular endothelial growth factor-A levels in osteoblasts.  Also, LIPUS has been shown to increase the production of fibroblast growth factor and interleukin-8 in osteoblasts and periostal cells. , These cytokines stimulate and are necessary for angiogenesis, which is a key component in the earliest stages of bone repair. The role of LIPUS in angiogenesis is supported by the observation that factors diminishing blood flow (smoking, vascular problems, diabetes) have a negative influence on fracture healing.
In the fracture repair process, proliferation of osteoblasts and chondrocytes serves as a trigger for the following sequential cellular events.  Takayama et al . found a substantial effect of LIPUS on the differentiation of rat osteosarcoma cells, but no effect on the proliferation of these cells.  Therefore, it seems unlikely that LIPUS can initiate the fracture repair process, which might be the reason that LIPUS has yet been used more on fresh fracture than on nonunions. 
Multiple animal studies have been conducted to examine the effect of LIPUS on fracture repair. These studies include the investigation of the macroscopic effect of LIPUS on fracture models, but also research at the extracellular and intracellular level. In most animal nonunion models, segmental bone resection has been used to induce a nonunion. Takikawa et al . evaluated the effect of LIPUS on rat tibial nonunions by placing a portion of the tibialis muscle within the fracture site, preventing the two ends of the bone from bridging.  Using this technique, the nonunion was believed to more accurately mimic a clinical nonunion. Results of this study showed that 50% of LIPUS-treated nonunions healed after 6 weeks, compared with none of the tibial fractures in the control group.
Using a bilateral closed femoral fracture model in rats, Azuma et al . tried to determine the influence of LIPUS at different stages of fracture healing.  They found that union was accelerated regardless of the duration or timing of the treatment. This animal experiment suggests that no specific stage of fracture healing is more sensitive than another, and therefore that LIPUS might be useful in every stage of fracture repair.
Animal studies are commonly used as an intermediate between cell studies and clinical studies. For example, the increased angiogenesis findings in cell studies are supported by Rawool et al. , who used midshaft ulnar fractures in dogs and found a threefold increase in blood flow after LIPUS treatment for one week of  minutes daily.
With the first clinical application of their developed LIPUS signal, Xavier and Duarte obtained a healing rate of 70% in 26 nonunions.  Since then, most studies have been performed to study the effect of LIPUS on healing of fresh fractures, many in a randomized controlled fashion. The first double-blind RCT of LIPUS on fresh tibial fractures was performed by Heckman et al ., who's results showed a significant (38%) reduction in time to healing in the LIPUS treatment group compared to the control group.  Several other studies have reported similar favorable results. , Busse et al . conducted a meta-analysis of the available RCTs on the effect of LIPUS on healing time of fresh fractures.  Review of the pooled data from the three studies included in the analysis revealed a difference of 64 days between the LIPUS treatment and control groups.
Almost no RCTs have been conducted to study the effect of LIPUS on healing of nonunions, since it is generally considered unethical to conduct placebo-controlled studies on their treatment. Namely, this would mean denying a patient a treatment of his nonunion for another six to nine months.  Therefore, most studies on treatment of nonunions use self-paired controlled designs. These designs are valid and medically appropriate to study treatment effects in medical conditions with unfavorable prognoses, such as nonunions, which fail to heal without any further treatment.  The effectiveness of the LIPUS treatment can be estimated by the healed status change, where the patient serves as his or her own control.  In addition, self-pairing offers the advantage of minimizing sources of variability between the treatment and control groups, which minimizes confounding bias. ,
Despite the lack of evidence from RCTs, the use of LIPUS for the treatment of established nonunions has been approved by the FDA in February 2000,  based on the results of three prospective self-paired studies. ,, The average healing rate of these studies was 81.2% among nonunions with a mean fracture age of 21.3 months.
Healing rate and time to healing
In our review, we found an average healing rate of 87% of nonunions among eight studies, which is comparable to the 85% healing rate among 700 nonunions reported in a registry of all orthopedic prescription use of LIPUS since FDA approval of Exogen's Sonic Accelerated Fracture Healing System (SAFHS) (Exogen, Inc, Piscataway, NJ) for marketing.  In addition, Rubin et al . reported a similar healing rate in their own review of the prescription use registry as of June 2000.  The 1546 nonunions had a healing rate of 83%, with an average time to healing of 172 days, which is comparable to the mean healing time of the included studies from our review (146.5 days). Although the RCT from our review reported a 100% healing rate for both the active and placebo group, a significant difference in time to healing was demonstrated, favoring the active LIPUS treatment group. 
Factors influencing healing rate
The largest study reviewed by us  contained 366 nonunions of various bones and found a healing rate of 86%. Because various bones were investigated and the sample size was relatively large, separate healing rates for the different locations of nonunions could be calculated, ranging from 69% for humeral nonunions to 100% for scaphoid nonunions. This is consistent with the results of Ricardo et al .,  who also found a 100% healing rate in 21 scaphoid nonunions. Scaphoid nonunions do not only seem to heal more often, but also in a shorter time, as Pigozzi et al . demonstrated a significant shorter healing time in scaphoid nonunions than in the nonunions located elsewhere. 
In the study of Mayr et al .  it was observed that the success rate consistently decreased from 97% among 20-year-old patients to 71% among 70-year-old patients. Further, they found a variation in healing rates depending on the use of described drugs. For example, in patients treated with calcium channel blockers, the nonunions healed in only 63%.
With respect to the effect of smoking on the healing rate of nonunions, different studies show conflicting results. Mayr et al .  found a healing rate of 79% among active smokers, compared with 89% among those who stopped smoking and 87% who never smoked. However, the comparison of smoking strata in the study of Nolte et al .  was significant ( P < 0.05), with healing rates of 60%, 82% and 100% among active smokers, those who stopped smoking, and nonsmokers, respectively.
Jingushi et al .  recommend in their article to start with LIPUS treatment within 6 months of the most recent operation. This recommendation is based on their findings of a significant higher healing rate for those with a shorter time period between the most recent operation and start of LIPUS treatment, with rates decreasing from 89.7% for a time period of three to six months to 52.6% for ≥12 months. However, Gebauer et al .  did not find a difference in healing rate between nonunions with a last procedure interval of 120-365 days and 366-730 days (88% and 100%, respectively).
Advantages and disadvantages of LIPUS
The primary advantage of LIPUS is the fact that it is a safe, noninvasive treatment which prevents patients from surgical risks. , However, this also accounts for other alternative treatments of fracture healing, including extracorporeal shock wave therapy and electrical stimulation. Although similar healing rates have been found for all three (LIPUS, shock wave therapy, ,,, and electrical stimulation ,,,, ) alternative methods, LIPUS has some advantages over the other two treatment options, i.e., no hospital admission is required for LIPUS, which is in contrast with shock wave therapy.  Compliance rates are high, with a daily treatment session duration of only 20 minutes, compared with many hours for electrical or electromagnetic stimulation. 
Although LIPUS treatment is relatively expensive, total costs are still lower than those associated with surgical interventions, with an estimated overall cost saving of US$13,000-15,000 per patient. 
Despite the fact that the need for additional surgery is eliminated, nonunions treated with LIPUS still require an average of five months to heal [Table 1]. However, considering that established nonunions already failed to heal for approximately 9 months, this time is reasonable, also because daily activities can be continued during the time of treatment.
There are some limitations in this review. First, only one randomized controlled double-blinded trial was included. This RCT had a small sample size and included only scaphoid nonunions, which limits the generalizability of its results. Most included trials were self-paired case series without blinding, raising the potential for measurement bias. However, confounding bias was minimized, as the patients served as their own control. The disadvantage of a self-paired design is, however, that it is not possible to compare LIPUS with either no further treatment or with other treatments in the same or comparable patients. To assess the comparative efficacy of LIPUS nonunions, LIPUS treatment should rather be compared with a surgical treatment, such as internal fixation.  This study design would be ethically acceptable, since surgery is the current gold standard for the treatment of nonunions.
Second, the average healing rate reported in this review might not be valid, because the studies are heterogeneous regarding nonunion location and patient population. On the other hand, this healing rate might be generalizable to a large population of nonunions, as studies on various bones were included in this review.
Also, the included studies mostly contained a small or very small sample size, except for one.  Therefore, it is questionable to what extent their separate results can be used in deciding whether to use LIPUS as a treatment for nonunions. Thus, it would be desirable to pool data from these small sample sized studies. However, since there is little homogeneity among the current published trials on LIPUS treatment of nonunions, no meta-analysis has been performed in this area yet.
| Conclusion|| |
With an average healing rate of approximately 87%, LIPUS appears to be a safe and cost-effective alternative to surgery for the treatment of nonunions. Although the exact mechanism of LIPUS on fracture healing is still unknown, several biological and physical changes have been recognized. Several factors have been demonstrated that may impair the effect of LIPUS on fracture healing. However, still substantially high healing rates have been observed when impairing factors were present. The main advantage of LIPUS is the avoidance of surgical risks and morbidity, without a decrease in healing rate. Although similar success rates have been demonstrated for other alternative fracture healing treatments, LIPUS has the additional advantages over electrical stimulation and extracorporeal shock wave therapy of shorter daily treatment duration, and the application on an outpatient basis, respectively. Unfortunately, almost no RCTs or large case series are performed on this issue, and pooling of the available small-sized case series is not valid due to heterogeneity among the studies. Therefore, more homogeneous and larger controlled series or RCTs are needed to investigate the efficacy of LIPUS in nonunions.
| References|| |
|1.||Einhorn TA. Enhancement of fracture-healing. J Bone Joint Surg Am 1995;77:940-56. |
|2.||Brashear HR. Treatment of ununited fractures of the long bones; diagnosis and prevention of non-union. J Bone Joint Surg Am 1965;47:174-8. |
|3.||Duarte LR. The stimulation of bone growth by ultrasound. Arch Orthop Trauma Surg 1983;101:153-9. |
|4.||Pilla AA, Mont M, Nasser PR, Khan SA, Figueiredo M, Kaufman JJ, Siffert RS. Non-invasive low-intensity pulsed ultrasound accelerates bone healing in the rabbit. J Orthop Trauma 1990;4:246-53. |
|5.||Yang KH, Parvizi J, Wang SJ, Lewallen DG, Kinnick RR, Greenleaf JF, Bolander ME. Exposure to low-intensity ultrasound increases aggrecan gene expression in a rat femur fracture model. J Orthop Res 1996;14:802-9. |
|6.||Rutten S, Nolte PA, Guit GL, Bouman DE, Albers GH. Use of low-intensity pulsed ultrasound for posttraumatic nonunions of the tibia: a review of patients treated in the Netherlands. J Trauma 2007;62:902-8. |
|7.||Brown BS. How safe is diagnostic ultrasonography? Can Med Assoc J 1984;131:307-11. |
|8.||Leung KS, Lee WS, Tsui HF, Liu PP, Cheung WH. Complex tibial fracture outcomes following treatment with low-intensity pulsed ultrasound. Ultrasound Med Biol 2004;30:389-95. |
|9.||Kristiansen TK, Ryaby JP, McCabe J, Frey JJ, Roe LR. Accelerated healing of distal radial fractures with the use of specific, low-intensity ultrasound. A multicenter, prospective, randomized, double-blind, placebo-controlled study. J Bone Joint Surg Am 1997;79:961-73. |
|10.||Busse JW, Bhandari 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. |
|11.||Bhandari M, Guyatt GH, Swiontkowski MF, Tornetta P 3rd, Sprague S, Schemitsch EH. A lack of consensus in the assessment of fracture healing among orthopaedic surgeons. J Orthop Trauma 2002;16:562-6. |
|12.||Premarket Approval P900009/Supplement 6, Summary of safety and effectiveness data. Low-intensity pulsed ultrasound device for the noninvasive treatment of nonunions. Exogen, a Smith and Nephew Company; 2000. |
|13.||Jones CP, Coughlin MJ, Shurnas PS. Prospective CT scan evaluation of hindfoot nonunions treated with revision surgery and low-intensity ultrasound stimulation. Foot Ankle Int 2006;27:229-35. |
|14.||Fujioka H, Tsunoda M, Noda M, Matsui N, Mizuno K. Treatment of ununited fracture of the hook of hamate by low-intensity pulsed ultrasound: a case report. J Hand Surg [Am] 2000;25:77-9. |
|15.||Ricardo M. The effect of ultrasound on the healing of muscle-pediculated bone graft in scaphoid non-union. Int Orthop 2006;30:123-7. |
|16.||Nolte PA, van der Krans A, Patka P, Janssen IM, Ryaby JP, Albers GH. Low-intensity pulsed ultrasound in the treatment of nonunions. J Trauma 2001;51:693-703. |
|17.||Jingushi S, Mizuno K, Matsushita T, Itoman M. Low-intensity pulsed ultrasound treatment for postoperative delayed union or nonunion of long bone fractures. J Orthop Sci 2007;12:35-41. |
|18.||Gebauer D, Mayr E, Orthner E, Ryaby JP. Low-intensity pulsed ultrasound: effects on nonunions. Ultrasound Med Biol 2005;31:1391-402. |
|19.||Gebauer D, Correll J. Pulsed low-intensity ultrasound: a new salvage procedure for delayed unions and nonunions after leg lengthening in children. J Pediatr Orthop 2005;25:750-4. |
|20.||Mayr E, Frankel V, Rüter A. Ultrasound--an alternative healing method for nonunions? Arch Orthop Trauma Surg 2000;120:1-8. |
|21.||Pigozzi F, Moneta MR, Giombini A, Giannini S, Di Cesare A, Fagnani F, et al . Low-intensity pulsed ultrasound in the conservative treatment of pseudoarthrosis. J Sports Med Phys Fitness 2004;44:173-8. |
|22.||Hadjiargyrou M, McLeod K, Ryaby JP, Rubin C. Enhancement of fracture healing by low intensity ultrasound. Clin Orthop Relat Res 1998;355:S216-29. |
|23.||Sarathy MP, Madhavan P, Ravichandran KM. Nonunion of intertrochanteric fractures of the femur. J Bone Joint Surg 1994;77B:90-2. |
|24.||Sarmiento A, Gersten LM, Sobol PA, Shankwiler JA, Vangsness CT. Tibial shaft fractures treated with functional braces. J Bone Joint Surg Br 1989;71:602-9. |
|25.||Mandt PR, Gershuni DH. Treatment of nonunion of fractures in the epiphyseal-metaphyseal region of long bones. J Orthop Trauma 1987;1:141-51. |
|26.||Forshed DL, Dalinka M, Mitchell E, Brighton CT, Alani A. Radiological evaluation of treatment of nonunion or fractures by electrical stimulation. Radiology 1978;128:629-34. |
|27.||Scott G, King JB. A prospective, double-blind trial of electrical capacitive coupling in the treatment of non-union of long bones. J Bone Joint Surg Am 1994;76:820-6. |
|28.||Sharrard WJ. A double-blind trial of pulsed electromagnetic fields for delayed union of tibial fractures. J Bone Joint Surg Br 1990;72:347-55. |
|29.||Simon SR. Orthopaedic Basic Science. American Academy of Orthopaedic Surgeons; Rosemont (IL):1994. |
|30.||Weber BG, Cech O. Pseudoarthrosis. Bern: Hans Huber Publishers; 1976. |
|31.||Healy WL, Jupiter JB, Kristiansen TK, White RR. Nonunion of the proximal humerus. A review of 25 cases. J Orthop Trauma 1990;4:424-31. |
|32.||Barquet A, Fernandez A, Luvizio J, Masliah R. A combined therapeutic protocol for aseptic nonunion of the humeral shaft: a report of 25 cases. J Trauma 1989;29:95-8. |
|33.||Ballmer FT, Ballmer PM, Mast JW, Ganz R. Results of repositioning osteotomies in delayed healing or pseudarthrosis of the proximal femur. Unfallchirurg 1992;95:511-7. |
|34.||Boyd HB, Lipinski SW, Wiley JH. Observations of nonunion of the shafts of the long bones, with a statistical analysis of 842 patients. J Bone Joint Surg 1961;43A:159-62. |
|35.||Broderson MP, Sim FH. Surgical management of delayed union and nonunion of the tibia. Orthopaedics 1981;4:1361-8. |
|36.||Brighton CT, Black J, Friedenberg ZB, Esterhai JL, Day LJ, Connoly JF. A multicenter study of the treatment of nonunion with constant direct current. J Bone Joint Surg Am 1981;63:2-13. |
|37.||Connolly JF. Selection, evaluation and indications for electrical stimulation of ununited fractures. Clin Orthop Relat Res 1981;161:39-53. |
|38.||Bassett CA, Mitchell SN, Gaston SR. Treatment of ununited tibial diaphyseal fracture treatment with pulsing electromagnetic fields. J Bone Joint Surg Am 1981;63:511-23. |
|39.||Heckman JD, Ingram AJ, Dan Lloyd RD, Luck JV Jr, Mayer PW. Nonunion treatment with pulsed electromagnetic fields. Clin Orthop Relat Res 1981;161:58-66. |
|40.||Longo JA . Successful treatment of recalcitrant nonunions with combined magnetic field stimulation. In: Szabó Z, editor. Surgical Technology International VI: Orthopaedic Surgery. San Francisco: Universal Medical Press; 1997. p. 397-403. |
|41.||Rompe JD, Eysel P, Hopf C, Vogel J, Küllmer K. Stoβwellenapplikation bei gestφrter Knochenheilung: Eine kritische Bestandsaufnahme. Unfallchirurg 1997;100:845-9. |
|42.||Schleberger R. Anwendung der extracorporalen Stoβwelle am Stützund Bewegungsapparat im mittelenergetischen Bereich. In: Chaussy C, Eisenberger F, Jochum D, Willert D, editors. Die Stoβwelle- Forschung und Klinik. Tübingen: Attempto; 1995. p. 166-74. |
|43.||Wirsching RP, Eich W, Misselbeck E. Langzeitergebnisse nach extrakorporaler Stoβwellentherapie bei Pseudarthrosen. Stoβwelle 1998;1:22-6. |
|44.||Wang CJ, Chen HS, Chen CE, Yang KD. Treatment of nonunions of long bone fractures with shock waves. Clin Orthop Relat Res 2001;387:95-101. |
|45.||Busse JW, Bhandari M. Therapeutic ultrasound and fracture healing: a survey of beliefs and practices. Arch Phys Med Rehabil 2004;85:1653-6. |
|46.||Maylia E, Nokes LD. The use of ultrasonics in orthopaedics - a review. Technol Health care 1999;7:1-28. |
|47.||Ziskin MC. Application of ultrasound in medicine-comparison with other modalities. In: Rapacholi MH, Grandolfo M, Rindi A, editors. Ultrasound: Medical applications, Biological Effects, and Hazard potential. New York: Plenum Press; 1987. p. 49. |
|48.||Dyson M. Therapeutic application of ultrasound. In: Nyborg WL, Ziskin MC, editors. Biological effects of ultrasound. New York: Churchill Livingstone; 1985. p. 121-33. |
|49.||Welgus HG, Jeffrey JJ, Eisen AZ. Human skin fibroblast collagenase. Assessment of activation energy and deuterium isotope effect with collagenous substrates. J Biol Chem 1981;256:9516-21. |
|50.||Welgus HG, Jeffrey JJ, Eisen AZ, Roswit WT, Stricklin GP. Human skin fibroblast collagenase: interaction with substrate and inhibitor. Coll Relat Res 1985;5:167-79. |
|51.||Khan Y, Laurencin CT. Fracture repair with ultrasound: clinical and cell-based evaluation. J Bone Joint Surg Am 2008;90:138-44. |
|52.||Webster DF, Pond JB, Dyson M, Harvey W. The role of cavitation in the in vitro stimulation of protein synthesis in human fibroblasts by ultrasound. Ultrasound Med Biol 1978;4:343-51. |
|53.||Watson T. The role of electrotherapy in contemporary physiotherapy practice. Man Ther 2000;5:132-41. |
|54.||Dyson M, Suckling J. Stimulation of tissue repair by ultrasound: a survey of the mechanisms involved. Physiotherapy 1978;64:105-8. |
|55.||Dyson M. Non-thermal cellular effects of ultrasound. Br J Cancer Suppl 1982;5:165-71. |
|56.||Hantes ME, Mavrodontidis AN, Zalavras CG, Karantanas AH, Karachalios T, Malizos KN. Low-intensity transosseous ultrasound accelerates osteotomy healing in a sheep fracture model. J Bone Joint Surg Am 2004;86A:2275-82. |
|57.||Wang SJ, Lewallen DG, Bolander ME, Chao EY, Ilstrup DM, Greenleaf JF. Low intensity ultrasound treatment increases strength in a rat femoral fracture model. J Orthop Res 1994;12:40-7. |
|58.||Ryaby JT, Bachner EJ, Bendo JA, Dalton PF, Tannenbaum S, Pilla AA. Low intensity pulsed ultrasound increases calcium incorporation in both differentiating cartilage and bone cell cultures. Trans Orthop Res Soc 1989;14:15. |
|59.||Chapman IV, MacNally NA, Tucker S. Ultrasound-induced changes in rates of influx and efflux of potassium ions in rat thymocytes in vitro. Ultrasound Med Biol 1980;6:47-58. |
|60.||Ryaby JT, Mathew J, Pilla AA, Duarte-Alves P. Low-intensity pulsed ultrasound modulates adenylate cyclase activity and transforming growth factor beta synthesis. In: Brighton CT, Pollack SR, editors. Electromagnetics in medicine and biology. San Francisco: San Francisco Press; 1991. p. 95-100. |
|61.||Ryaby JT, Mathew J, Duarte-Alves P. Low intensity pulsed ultrasound affects adenylate cyclase activity and TGF-β synthesis in osteoblastic cells. Trans Orthop Res Soc 1992;7:590. |
|62.||Wang FS, Kuo YR, Wang CJ, Yang KD, Chang PR, Huang YT, et al . Nitric oxide mediates ultrasound-induced hypoxia-inducible factor-1a activation and vascular endothelial growth factor-A expression in human osteoblasts. Bone 2004;35:114-23. |
|63.||Leung KS, Cheung WH, Zhang C, Lee KM, Lo JK. Low intensity pulsed ultrasound stimulates osteogenic activity of human periosteal cells. Clin Orthop Relat Res 2004;418:253-9. |
|64.||Reher P, Elbeshir el-NI, Harvey W, Meghji S, Harris M. The stimulation of bone formation in vitro by therapeutic ultrasound. Ultrasound Med Biol 1997;23:1251-8. |
|65.||Iwaki A, Jingushi S, Oda Y, Izumi T, Shida JI, Tsuneyoshi M, et al . Localization and quantifi cation of proliferating cells during rat fracture repair - detection of proliferating cell nuclear antigen by immunohistochemistry. J Bone Miner Res 1997;12:96-102. |
|66.||Takayama T, Suzuki N, Ikeda K, Shimada T, Suzuki A, Maeno M, et al. Low-intensity pulsed ultrasound stimulates osteogenic differentiation in ROS 17/2.8 cells. Life Sci 2007;80:965-71. |
|67.||Takikawa S, Matsui N, Kokubu T, Tsunoda M, Fujioka H, Mizonu K, et al. Low-intensity pulsed ultrasound initiates bone healing in rat nonunion fracture model. J Ultrasound Med 2001;20:197-205. |
|68.||Azuma Y, Ito M, Harada Y, Takagi H, Ohta T, Komoriya K, et al . Low-intensity pulsed ultrasound accelerates rat femoral fracture healing by acting on various cellular reactions involved in fracture repair. Unpublished data. |
|69.||Rawool NM, Goldberg BB, Forsberg F, Winder AA, Hume E. Power Doppler assessment of vascular changes during fracture treatment with low-intensity ultrasound. J Ultrasound Med 2003;22:145-53. |
|70.||Xavier CAM, Duarte LR. Estimulaca ultrasonic de calo osseo: applicaca clinica. Rev Brasileira Orthop 1983;18:73-80. |
|71.||Heckman JD, Ryaby JP, McCabe J, Frey JJ, Kilcoyne RF. Acceleration of tibial fracture-healing by non-invasive, low-intensity pulsed ultrasound. J Bone Joint Surg Am 1994;76:26-34. |
|72.||Colton T. Statistics in Medicine. Boston: Little, Brown and Co; 1974. |
|73.||Frankel VH, Mizuno K. Management of non-union with pulsed, low-intensity ultrasound therapy - international results. Surg Technol Int 2002;10:195-200. |
|74.||Rubin C, Bolander M, Ryaby JP, Hadjiargyrou M. The use of low-intensity ultrasound to accelerate the healing of fractures. J Bone Joint Surg Am 2001;83A:259-70. |
|75.||Aaron RK, Ciombor DM, Jolly G. Stimulation of experimental endochondral ossification by low-energy pulsing electromagnetic fields. J Bone Miner Res 1989;4:227-33. |
|76.||Heckman JD, Sarasohn-Kahn J. The economics of treating tibia fractures. The cost of delayed unions. Bull Hosp Jt Dis 1997;56:63-72. |
|77.||Malizos KN, Hantes ME, Protopappas V, Papachristos A. Low-intensity pulsed ultrasound for bone healing: an overview. Injury 2006;37:S56-62. |
Department of Clinical Epidemiology and Biostatistics, McMaster University, 293 Wellington Street North, Suite 110, Hamilton, Ontario L8L 2X2.
Source of Support: None, Conflict of Interest: None
[Table 1], [Table 2]
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