LEADING ARTICLE

Sports Med 2003; 33 (2): 95-107 0112-1642/03/0002-0095/$30.00/0 Adis Data Information BV 2003. All rights reserved.

A New Direction for Ultrasound Therapy in Sports Medicine

Stuart J. Warden1,2,3
1 2 3 Centre for Sports Medicine Research and Education, School of Physiotherapy, The University of Melbourne, Parkville, Victoria, Australia Department of Orthopaedic Surgery, Indiana University School of Medicine, Indianapolis, Indiana, USA Physiotherapy Department, Centre for Sports Sciences and Sports Medicine, Australian Institute of Sport, Bruce, Australian Capital Territory, Australia

Abstract

Ultrasound therapy is a widely available and frequently used electrophysical agent in sports medicine. However, systematic reviews and meta-analyses have repeatedly concluded that there is insufficient evidence to support a beneficial effect of ultrasound at dosages currently being introduced clinically. Consequently, the role of ultrasound in sports medicine is in question. This does not mean that ultrasound should be discarded as a therapeutic modality. However, it does mean that we may need to look in a new direction to explore potential benefits. A new direction for ultrasound therapy has been revealed by recent research demonstrating a beneficial effect of ultrasound on injured bone. During fresh fracture repair, ultrasound reduced healing times by between 30 and 38%. When applied to non-united fractures, it stimulated union in 86% of cases. These benefits were generated using low-intensity (<0.1 W/cm2) pulsed ultrasound (LIPUS), a dose alternative to that traditionally used in sports medicine. Although currently developed for the intervention of bone injuries, LIPUS has the potential to be used on tissues and conditions more commonly encountered in sports medicine. These include injuries to ligament, tendon, muscle and cartilage. This review discusses the effect of LIPUS on bone fractures, the dosages introduced and the postulated mechanisms of action. It concludes by discussing the relevance of these latest findings to sports medicine and how this evidence of a beneficial clinical effect may be implemented to intervene in sporting injuries to bone and other tissues. The aim of the paper is to highlight this latest direction in ultrasound therapy and stimulate new lines of research into the efficacy of ultrasound in sports medicine. In time this may lead to accelerated recovery from injury and subsequent earlier return to activity.

Ultrasound therapy is one of the most widely available and frequently used electrophysical agents in sports medicine. A recent survey of ultrasound use by sports physiotherapists in Australia found all therapists to have access to an ultrasound unit.[1]

These units were used on a daily basis by 84% of therapists and in a quarter of patient consultations. Given this large-scale application, ultrasound provides an economic contribution to the practice of sports medicine. This was estimated at 6.3% of the

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total income derived by Australian sports physiotherapists from standard consultations.[1] To validate such a large role for ultrasound in sports medicine it is important that interventions using this modality be evidence-based. Evidence-based medicine is the current ideal of the healthcare profession and involves the integration of individual clinical expertise with the best available external clinical evidence.[2] The latter is considered to be provided by randomised, controlled trials (RCTs).[3,4] In terms of ultrasound therapy, RCT evidence regarding its effectiveness is currently lacking. Systematic reviews and meta-analyses of ultrasound effects have repeatedly concluded that there is insufficient evidence to support the current clinical application of ultrasound.[5-8] A prominent reason for this lack of evidence is the limited number of well-designed RCTs into ultrasound effects. A recent systematic review found that, of the 35 English language RCTs investigating the clinical effects of ultrasound published between 1975 and 1999, only ten met minimal methodological standards.[7] Of these ten, only two demonstrated a beneficial ultrasound effect.[9,10] Due to the lack of evidence for a beneficial effect, the role of ultrasound therapy in clinical practice is currently in question. This does not mean that ultrasound should be discarded as a therapeutic modality. Eighty-seven percent of clinicians consider ultrasound to have a place in modern day sports medicine despite the lack of evidence.[1] This suggests that further methodologically-sound RCTs are required to establish the efficacy of ultrasound. It also suggests that we may need to look in new directions to explore the potential benefits of ultrasound given the inability of 80% of previous well-designed RCTs to elicit a beneficial effect. A potential new direction for ultrasound in sports medicine has been stimulated by recent research showing that ultrasound can have clinically significant beneficial effects on injured tissue, and in particular on fractured bone. These benefits were generated using low-intensity (<0.1 W/cm2) pulsed ultrasound (LIPUS), a dose alternative to that traditionally used in sports medicine. This perspec Adis Data Information BV 2003. All rights reserved.

tive will discuss the effect of ultrasound on bone fractures, the dosages introduced and the postulated mechanisms of action. It will conclude by discussing the relevance of these latest findings to sports medicine and how this evidence of a beneficial clinical effect may be implemented to intervene in sporting injuries to bone and other tissues. The aim of the paper is to highlight this latest direction in ultrasound therapy and stimulate new lines of research into the efficacy of ultrasound in sports medicine. In time this may lead to accelerated recovery from injury and subsequent earlier return to activity. 1. Beneficial Effect of Ultrasound on Bone Fractures Over the past decade ultrasound has developed into an established intervention for bone fractures. For a complete review, refer to Rubin et al.[11] and Warden et al.[12,13] In brief, during fresh fracture repair ultrasound has been shown to substantially accelerate the rate of repair. In animals, this was primarily illustrated by the enhancement of mechanical strength return following fracture.[14-18] Investigating the time course of mechanical strength return, Pilla et al.[17] found rabbit fibular osteotomies treated with active-ultrasound to achieve the mechanical strength of intact bone 17 days post-fracture. In contralateral inactive-ultrasound treated fractures, mechanical strength was regained between 23 and 28 days post-injury. This represented an acceleration in the rate of biomechanical healing by 3038% with the use of ultrasound. In humans, the most convincing evidence for the use of ultrasound during fresh fracture repair has been provided by three well-designed RCTs. The methodologies of these studies are detailed in table I. In tibial diaphyseal fractures, Heckman et al.[19] found active-ultrasound to reduce the time taken for fractures to be classified as both radiographically and clinically healed by an average of 58 days (figure 1). When compared with inactive-ultrasound treated fractures, the acceleration in repair represented a 38% reduction in healing time. Kristiansen et al.[20] found active-ultrasound reduced radiSports Med 2003; 33 (2)

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Table I. Methodological details of studies investigating the effect of ultrasound on fresh fracture repair in humans Reference Study design Fracture characteristics Closed or grade I open tibial shaft fracture. Treatable by closed reduction and cast immobilisation. Mean maximum fracture gap = 0.4cm. Mean length of fracture = 4cm. Exclusions: long fractures, large displacements, fractures of the metaphysis, most comminuted fractures Intervention and group numbers Active: cast immobilisation + active-ultrasound (n = 33). Placebo: cast immobilisation + inactiveultrasound (n = 34) Outcome measures Anteroposterior and lateral radiographs at 4, 6, 8, 10, 12, 14, 20, 33 and 52 weeks. Clinical assessment at 6 and 10 weeks, and at time of cast removal (as indicated by radiographs) Posteroanterior and lateral radiographs at each follow-up visit. Clinical assessment at each follow-up visit. Follow-up at 1, 2, 3, 4, 5, 6, 8, 12 and 16 weeks Study endpoint 3 of 4 cortices bridged on radiographical examination. Fracture stable and not painful to manual stress on clinical examination 4 of 4 cortices bridged on radiographical examination. Fracture stable and not painful to manual stress on clinical examination

Heckman et al.[19] Randomised, double-blind, placebo-controlled, prospective, multicentre

Kristiansen et al.[20]

Randomised, double-blind, placebo-controlled, prospective, multicentre

Closed, dorsally angulated, Active: cast metaphyseal fracture of the immobilisation + distal radius (within 4cm of tip) active-ultrasound [Colles fracture]. Treatable by (n = 30). Placebo: one closed reduction and below-cast immobilisation elbow cast. Intra-articular + inactiveinvolvement of radiocarpal or ultrasound (n = 31) radio-ulnar joint and concomitant ulnar styloid process fractures acceptable. Exclusions: Chauffeur, Barton, Smith fractures Stable, non-dislocated fracture through waist of scaphoid (AO classification B1 and B2). Exclusions: unstable fractures, bone pathology, greater than 10 days post-fracture Active: cast immobilisation + active-ultrasound (n = 15). Control: cast immobilisation alone (n = 14)

Mayr et al.[21]

Randomised, controlled, prospective, singlecentre

Sagittal computer tomography. Clinical healing time. Follow-up at 28 days after diagnosis and every 14 days thereafter

First time 70% or more cortical bridging observed on computed tomography examination. Time from start of treatment to removal of cast (clinical healing time)

ographical and clinical healing times in fractures of the distal radius by an average of 37 days when compared with inactive-ultrasound treated fractures. This also represented a reduction of 38% in healing time. Most recently, Mayr et al.[21] demonstrated scaphoid fractures treated with active-ultrasound healed 19 days earlier than inactive-ultrasound treated fractures, an acceleration of 30%. Combining the outcomes of these clinical trials, ultrasound is observed to accelerate the rate of fresh tibial, radial and scaphoid fracture repair by 3038%. This correlates well with the aforementioned acceleration in the rate of biomechanical healing observed in animals. Pooling the results of the 158 fractures investigated, a weighted average effect size can be calculated at 6.41 (95% CI =
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1.0111.81).[22] This converts into a mean difference in healing time of 64 days between the active- and inactive-ultrasound treated groups;[22] a difference which not only has benefits in terms of reductions in patient morbidity, but also economic benefits.[23] In addition to its beneficial effects on fresh fractures, ultrasound has also been shown to facilitate healing in fractures displaying delayed- and nonunion.[24-27] In a fracture non-union model in rodents, Takikawa et al.[27] found 6 weeks of activeultrasound to stimulate union in 50% of fractures. This compared with a 0% union rate in contralateral fractures treated with inactive-ultrasound. With lengthier intervention, it is possible that ultrasound may have stimulated union in more than 50% of fractures. Clinically, ultrasound has been found to
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stimulate union in 91% of fractures displaying delayed-union (n = 951; average fracture interval = 151 days) and 86% of fractures displaying nonunion (n = 366; average fracture interval = 755 days).[25] These fractures covered a range of skeletal sites (table II). 2. Ultrasound Dosage Introduced During Fracture Repair The results of studies into the effect of ultrasound on fractured bone are interesting from the perspective that therapists have traditionally been instructed to avoid the application of ultrasound to bone. When ultrasound is applied to bone there is an inherent risk of tissue damage. Resulting from bones high absorption coefficient, high relative acoustic impedance and ability to propagate shear waves, ultrasound has selective interfacial effects at the bone surface.[28] When superclinical dosages are used these effects can generate considerable tissue damage, including premature closure, slipping and displacement of epiphyseal growth plates, bone sclerosis, diaphyseal fractures and fibrosis, and delayed healing during fracture repair.[29,30] This explains why bone is directly treated with ultrasound by less than 7% of therapists in clinical practice.[1] Given the benefits of ultrasound observed during fracture repair, yet inherent risk of tissue damage, it is reasonable to question how it is possible to safely introduce ultrasound to bone. This has been achieved by substantially changing the ultrasound dose introduced from that traditionally introduced in

Days to clinical and radiological healing (mean SD)

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Active-ultrasound treated Inactive-ultrasound treated

200

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* *

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0 Tibial diaphysis Distal radius Scaphoid

Fig. 1. Effect of ultrasound on fresh tibial diaphyseal,[19] distal radius[20] and scaphoid[21] fracture repair in humans. * Indicates p < 0.01.

clinical practice. Clinically, ultrasound is introduced at an intensity commonly in the range of 0.52 W/ cm2.[1] In comparison, in investigations into the therapeutic effect of ultrasound on bone a spatialaverage temporal-average intensity (ISATA) of below 0.1 W/cm2 has predominantly been used, with the most common ISATA introduced being 0.03 W/ cm2.[13] The ISATA refers to the average ultrasound power output over the area of the ultrasound beam (spatial-average) and the average of this intensity over a complete pulse cycle (ultrasound on and off period; temporal-average). The low ISATA introduced during fracture repair is coupled with a pulsing regimen of 1:4 (duty factor = 0.20). Using such LIPUS, heat generation at the soft tissue-bone

Table II. Effect of low-intensity pulsed ultrasound on non-united fractures at different skeletal sites[25] Fracture site Clavicle Humerus Radius/radius-ulna Scaphoid Femur Tibia/tibia-fibula Metatarsal Foot Other Total Healed/treated 8/10 33/48 21/22 24/24 57/66 105/120 14/18 18/20 34/38 314/366 Healing rate (%) 80 69 95 100 86 88 78 90 89 86 Average healing time (mean no. of days SD) 181 39 174 20 117 16 123 12 157 10 166 11 117 17 138 18 131 13 152 5 Average fracture age (days) 435 596 690 513 813 734 634 871 551 755

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interface has been shown both theoretically[31] and experimentally[17,32] to be insignificant (<1.0C). Similarly, the risk for tissue damaging inertial cavitation is negligible.[31] In addition to a different intensity from that being introduced clinically, the mode by which ultrasound is introduced during fracture repair varies from traditional ultrasound therapy theory and application. Therapists are traditionally instructed to use a dynamic (moving) treatment head when introducing ultrasound. This is in an attempt to evenly distribute areas of high local acoustic pressure (hot-spots) resulting from uneven vibration of the piezoelectric crystal (transducer) and wave interference within the near field of the ultrasound beam.[28] In comparison, LIPUS during fracture repair is introduced using a stationary treatment head over the fracture site. This is possible without a risk of tissue damage due to the combination of the low ISATA being introduced and the low beam non-uniformity ratio (BNR) of the ultrasound treatment heads being used. The BNR refers to the ratio between the spatial-peak and spatial-average intensities within the ultrasound beam. During fracture repair the ultrasound treatment heads being used have a BNR of less than 4. As the ISATA being used during fracture repair is most commonly 0.03 W/cm2, this means that the spatial-peak intensity within the ultrasound beam is less than 0.12 W/cm2, a value low enough to not pose any tissue damage risk. The low ISATA introduced during fracture repair coupled with the low BNR of the ultrasound treatment heads being used enables ultrasound to be introduced to bone with no known risk of tissue damage. However, these dosage features are unable to fully explain why LIPUS has such a beneficial effect in bone repair studies, in comparison to the frequent lack of an ultrasound effect found in studies using conventional therapeutic intensities. Two additional features of the dose introduced that potentially contribute to the beneficial effect of LIPUS during fracture repair are the duration and frequency of ultrasound introduction. During fracture repair ultrasound is introduced daily for 20 minutes. In comparison, in clinical practice ultrasound is intro Adis Data Information BV 2003. All rights reserved.

duced for 5 minutes per intervention[1] and, presumably, no more than 3 times per week. Likewise, in the methodologically-sound RCTs that failed to establish a beneficial effect, ultrasound was introduced infrequently for treatment periods of less than 10 minutes.[7] Given the beneficial effect of ultrasound observed when used for longer durations and introduced more frequently, it is possible that ultrasound introduction has traditionally been too short and too infrequent to permit a suitable cellular response and subsequent tissue effect. Supporting this theory, the two methodologically-sound RCTs demonstrating beneficial ultrasound effects at conventional therapeutic intensities introduced ultrasound frequently (5 times per week) for lengthy treatment durations (15 minutes).[9,10] Similarly, the theory is supported by a recent study investigating the effect of LIPUS on cartilage repair in rabbits.[33] By increasing the duration of daily ultrasound intervention (up to a maximum of 40 minutes) increasing advantages in terms of histologic signs of repair were found. 3. Mechanism for Beneficial Ultrasound Effect During Fracture Repair Ultrasound at low intensities can be safely applied to bone using a stationary treatment head with no known risk of tissue damage. However, considering that the intensity being introduced during fracture repair is within the traditional diagnostic ultrasound range, a range previously considered to have minimal biological effect and no therapeutic value, it is valid to consider how LIPUS induces its therapeutic effect. Unfortunately, this is currently not known. The predominant reason for this is the fact that it is not known how ultrasound signals are transduced in vivo to produce a cellular response. This results from a dearth of a priori mechanistic hypotheses in reporting ultrasound biological effects.[34] Despite the lack of supportive evidence establishing underlying biophysical effects, the beneficial effect of LIPUS observed in fracture repair studies may have resulted from three main mechanisms. The first relates to ultrasound being a form of
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mechanical stimulation. Ultrasound can be described as longitudinal mechanical waves. A mechanical wave is one in which energy is transmitted by the movement of particles within the medium through which the wave is travelling. Given the inherent mechanosensitivity of bone, it has been suggested that the micro-mechanical loading exerted by ultrasound is potentially the mechanism for the beneficial effect of LIPUS during fracture repair.[11,33,35,36] This is possible with recent research showing bone to be responsive to very low magnitude (5 microstrain), high frequency (30Hz) mechanical loading.[37] However, the frequency of loading associated with ultrasound is a number of magnitudes higher and its loading magnitude lower than that introduced in traditional mechanical loading studies. In addition, mechanical loading associated with LIPUS has been found to be unable to induce adaptation in intact bone.[38,39] Although this latter finding may have been influenced by the inability of ultrasound to effectively penetrate the outer bone cortex due to its acoustic properties, the theory that LIPUS generates mechanically-induced bone adaptation during fracture repair remains unresolved. The second possible mechanism for the observed beneficial effect of LIPUS in the treatment of bone fractures is the generation of ultrasound unique phenomena. In addition to being described as mechanical waves, ultrasound can equivalently be described as alternating pressure waves. These may generate unique phenomena, such as stable cavitation and microstreaming within the propagating tissues.[40] Although the occurrence and significance of these phenomena in vivo has been disputed,[41] their therapeutic potential may be in the generation of shear forces on cellular membranes. These forces may influence the cellular cytoskeleton to directly alter gene expression.[42] Alternatively, they may influence transmembrane cellular channels resulting in the altered transport of ions across the membrane and a subsequent cellular response.[42-44] However, as with the theory that ultrasound is a mechanical stimulus, this proposed mechanism for the benefi Adis Data Information BV 2003. All rights reserved.

cial effect of LIPUS during fracture repair remains unclear. The third and final mechanism by which LIPUS may have its beneficial effect during fracture repair is through the generation of localised heat at the fracture site. Ultrasound energy generates alternating waves of compression and rarefaction in the propagating medium resulting in increased molecular motion. This leads to increased molecular vibration and collisions, and subsequent heat generation.[28] Although this heating effect when using LIPUS is small, some enzymes are exquisitely sensitive to small variations in temperature.[45] Thus, it is possible that the small degree of heating associated with LIPUS may contribute to its beneficial effect during fracture repair. However, this mechanism lacks support from a recent study by Chang et al.[15] They found that ultrasound therapy augmented fracture repair but an equivalent level of hyperthermia generated with microwave therapy did not. Consequently, as with the previous two mechanisms, this potential mechanism for the beneficial effect of LIPUS during fracture repair is not established. Despite the underlying biophysical mechanism/s of action of ultrasound during fracture repair not being known, a number of studies[42,44,46-55] have investigated potential cellular processes influenced by LIPUS. In vitro, LIPUS has been shown to directly influence a number of cells associated with the repair process (table III). These changes suggest that ultrasound may have direct effects on the reparative processes of angiogenesis, chondrogenesis and osteogenesis. Although the potentiation of cavitation and microstreaming in vitro necessitates caution when extrapolating in vitro findings to the in vivo environment,[46] these in vitro results suggest that multiple cells involved in fracture repair are potentially responsive to LIPUS. This is supported by in vivo investigation. Principally, Azuma et al.[14] showed LIPUS to influence multiple cellular reactions during fresh fracture repair. This was evident by the advancement of healing irrespective of the phase of repair during which ultrasound was introduced (figure 2). Overall, it appears that ultrasound
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Table III. In vitro effects of low-intensity pulsed ultrasound Cell type Fibroblasts Endothelial Chondrocytes Osteoblasts Reference 47 48 49 42 44 50 47 51 52 46 53 54 55 Findings Collagen synthesis PDGF with co-introducton of vitamin D3 Aggrecan mRNA and proteoglycan synthesis Intracellular calcium and proteoglycan synthesis Calcium incorporation Adenylate cyclase and TGF production, response to parathyroid hormone Collagen and non-collagenous protein synthesis, IL-1, bFGF and VEGF production PGE2 production and regulation of COX-2 mRNA cfos, IGF-I, osteocalcin and bone sialoprotein mRNA expression cfos, COX-2, alkaline phosphatase and osteocalcin mRNA expression Osteoblast proliferation, alkaline phosphatase, PGE2 and TNF cfos, COX-2, IGF-I and osteocalcin, stimulation of p38 MAPK and upstream effector, PI3K NO and PGE2 production

Bone rudiments 56 Length of calcified diaphysis bFGF = basic fibroblast growth factor; COX-2 = cyclo-oxygenase-2; IGF-I = insulin-like growth factor-I; IL-1 = interleukin-1; NO = nitric oxide; p38 MAPK = p38 mitogen-activated protein kinase; PDGF = platelet-derived growth factor; PGE2 = prostaglandin E2; PI3K = phosphoinositide 3-kinase; TGF = transforming growth factor-; TNF = tumour necrosis factor-; VEGF = vascular endothelial growth factor.

has beneficial effects on multiple processes during fracture repair, and that it may stimulate a phase shift in reparative phases whereby they commence and complete at an earlier stage during the repair process. 4. Potential Implications for Sports Medicine The evidence of a beneficial effect of LIPUS during fracture repair is of high clinical relevance to the practice of sports medicine. A major goal in sports medicine is to return athletes to function following injury. Consequently, any modality that has potential in accelerating tissue repair and subsequently facilitating return to sport has obvious clinical implications.
4.1 Potential Implications with Regard to the Intervention of Bone

and fractures of the waist of the scaphoid. Although only investigated with regard to its effects on these fractures, the benefits of LIPUS are believed to carry over to fractures of similar severity and similarsized fracture gaps (<0.5cm) within other regions. In light of this, LIPUS has been applied clinically to fractures of the humerus, femur, ulna, fibula and metatarsals.[24] RCT evidence on these fractures is not yet available. The application of LIPUS also need not be restricted to fractures that have been treated with closed reduction and cast immobilisation. Animal studies suggest that ultrasound can also positively influence fractures that have been managed with internal or external fixation,[18,57,58] although evidence in humans is currently inconclusive.[59,60] Sato et al.[60] demonstrated a beneficial effect of LIPUS with distraction osteogenesis in a single-case study. However, Emani et al.[59] was unable to elicit a beneficial effect in an RCT of the effect of LIPUS on tibial fractures managed with an intramedullary rod. The absence of a beneficial effect in the latter study may be attributed to reaming of the fractures, which is known to have osteoblastic effects and may have masked the beneficial effect of LIPUS.[22]
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Given the proven benefit of LIPUS on both fresh fractures and fractures displaying healing defects, the intervention of bone injuries is currently the primary potential clinical application of LIPUS in sports medicine. In terms of fresh fractures, LIPUS has been shown to have benefits on closed and grade I open tibial diaphyseal and distal radius fractures,
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Maximal torsional torque [N l mm] (mean SD)

240

Active-ultrasound treated Inactive-ultrasound treated

200

* * * *

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delayed- and non-union, LIPUS has been found to stimulate union in 98% and 94% of cases, respectively.[25] These findings suggest that LIPUS may have beneficial effects on stress fracture repair. However, before it can become an established intervention these preliminary findings need to be validated with RCT evidence.
4.2 Potential Implications with Regard to the Intervention of Other Tissues

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0 Throughout Days 18 Days 914 Days 1524 Treatment group

Fig. 2. Effect of timing of low-intensity pulsed ultrasound introduction on femoral fracture repair in rodents. The throughout group received unilateral active-ultrasound and contralateral inactive-ultrasound on days 124 post-fracture. The other treatment groups received ultrasound on the days post-fracture corresponding to their group name. All treatment groups were assessed 25 days following fracture. Irrespective of the timing of ultrasound introduction, fractures treated with active-ultrasound demonstrated significantly greater maximal torsional torque than contralateral inactiveultrasound treated fractures (reprinted from Azuma et al.,[14] with permission from the American Society for Bone and Mineral Research). * Indicates p < 0.01.

The effect of LIPUS on traditional bone fractures is clinically relevant. However, of greater interest to sports medicine is its potential benefit in the intervention of stress fractures. Considering stress fractures are believed to heal in comparable stages to traditional bone fractures and that they consist of small undisplaced fractures similar to those intervened in previous RCTs of the effect of LIPUS on fracture repair, it is possible that LIPUS will have beneficial effects on stress fractures. This has support from preliminary case reports.[25,61,62] In seven posterior-medial cortex stress fractures of the tibia, introduction of LIPUS enabled continuation of activity and return to competition within 4 weeks.[61] In one tarsal navicular stress fracture, LIPUS reportedly stimulated bony union and allowed return to competition within 5 weeks.[61] LIPUS had no effect on the one anterior tibial cortex stress fracture treated,[61] although this may have been influenced by the continuation of activity resulting in disruption of any healing attempts. In stress fractures displaying
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The potential of LIPUS in sports medicine may extend beyond its established effects on injured bone. Studies in animals have shown that tissues other than bone are sensitive to ultrasound.[63-65] Using LIPUS it is possible that clinically significant beneficial effects may be generated in a variety of tissues. This is predicted from the beneficial effect of LIPUS on the inflammatory phase of fracture repair. Applying LIPUS during the inflammatory and early reparative phases of fibula fracture repair in rodents, Dyson and Brookes[66] reported 79% of fractures to demonstrate more advanced signs of healing when compared 2 weeks post-fracture with contralateral inactive-ultrasound treated fractures. Meanwhile, Rawool et al.[32] using power Doppler assessment demonstrated canine ulna osteotomies (n = 3) treated over a 10-day period with LIPUS showed an increased degree of blood flow when compared with osteotomies in control dogs (n = 3). This increase was first noticeable within the inflammatory phase of repair (23 days post-fracture) and lasted up to 2 weeks. Most significantly and recently, Azuma et al.[14] showed that LIPUS applied during days 18 post-femoral fracture in rodents resulted in increased mechanical strength return when fractures were assessed 25 days post-fracture (figure 2). This latter finding demonstrates that changes induced with LIPUS during the early stages of repair can augment later repair processes. Given that the inflammatory phase of bone repair is similar to that which occurs in alternative tissues, and involves similar cells and cellular processes, it is valid to hypothesise that LIPUS will also have significant beneficial effects on alternative tissues displaying an acute inflammatory reaction. This theory
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Fig. 3. Effect of low-intensity pulsed ultrasound on surgically-induced full-thickness osteochondral defects of the femoral patellar groove in rabbits. Gross appearance at 4 weeks post-operation of: (a) active-ultrasound treated and (b) contralateral inactive-ultrasound treated defects. With active-ultrasound the repair cartilage had developed a smooth homogenous appearance and the defect margins were difficult to discern from the host cartilage. In contrast, with inactive-ultrasound the defect was not yet covered with cartilage, and the repair tissue was disorganised and easily differentiated from the host cartilage. Photomicrographs at 4 weeks post-operation of: (c) active-ultrasound treated and (d) contralateral inactive-ultrasound treated defects. Arrows indicate the defect margins. With active-ultrasound, the subchondral bone layer was nearly restored to its normal height, and the repair cartilage had a hyaline-like appearance and was bonded to the host cartilage. In comparison, in the inactive-ultrasound treated side, only a thin layer of subchondral bone had been regenerated, marrow was present in the defect, and the repair layer overlying the early subchondral bone was made up of undifferentiated cells and coarse horizontally oriented fibrous tissue (reprinted from Cook et al.,[33] with permission from Lippincott Williams & Wilkins).

has preliminary experimental support. Cook et al.[33] found LIPUS to improve the gross and histological appearance of surgically-induced, full-thickness osteochondral defects of the patellar groove in rabbits (figure 3). Fitting with the theory of a beneficial effect on acute repair processes, most benefits with LIPUS were observed within the initial 4 weeks of repair rather than latter weeks. Similarly, during the repair of acute medial collateral ligament injuries in rodents, Takakura et al.[67] showed LIPUS to have beneficial effects on the early stages of repair. At 12 days post-injury, ligaments treated with LIPUS had greater strength and mean collagen fibril diameter than contralateral inactive-ultrasound treated ligaments (figure 4). These differences were not ob Adis Data Information BV 2003. All rights reserved.

served at 21 days post-injury, however, at this stage both the active- and inactive-ultrasound treated sides exhibited the strength of normal, uninjured ligaments. It is possible that the side treated with LIPUS reached this normal level at an earlier stage. In light of the hypothesis that LIPUS potentially has a beneficial effect on tissues displaying an acute inflammatory reaction, it is currently being used on acute tissue injuries to elite athletes at the Australian Institute of Sport (AIS). Given the site-specific nature of the ultrasound beam, localised injuries are primarily being treated. For injuries larger in area than the effective radiating area (ERA) of the ultrasound treatment head, multiple treatments are being
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35 Ultimate tensile load [N] (mean SD) 50 25 20 15 10 5 0 12

Active-ultrasound treated Inactive-ultrasound treated

21 Days following injury

Fig. 4. Effect of daily low-intensity pulsed ultrasound on medial collateral ligament repair in rodents. Twelve days following surgically-induced ligament injury active-ultrasound treated ligaments demonstrated significantly greater ultimate tensile strength than contralateral inactive-ultrasound treated ligaments. No difference was observed at 21 days post-injury with both sides exhibiting the strength of normal, uninjured ligaments (reprinted from Takakura et al.,[67] with permission). * Indicates p < 0.05.

performed or multiple treatment heads are being used simultaneously. Injuries being treated include those to ligament, tendon, muscle and cartilage tissue. Although there is currently no RCT evidence for a beneficial effect of LIPUS on injuries to these tissues, clinical outcomes have been promising. 5. Ultrasound Therapy Units and Their Limitations Before researchers contemplate investigating LIPUS in clinical trials, a significant practical factor that should be considered is the ultrasound units they intend to use. Specialised ultrasound units have been developed for the intervention of fractured bone. Termed the Exogen 20001 or Sonic Accelerated Fracture Healing System (figure 5), these units produce ultrasound at a single dose with a duty factor of 0.20 and ISATA of 0.03 W/cm2. They have US FDA approval to be used on specific fresh fractures of the tibial diaphysis and distal radius as well as non-united fractures at numerous sites. As the majority of research regarding the effectiveness
1

of LIPUS has been performed using the Exogen 2000, it would be ideal to use this technology on suitable patients in sports medicine. However, a major drawback is the cost of these units which is in the vicinity of several thousand $US per fracture. This cost is per fracture as the units are returned to the manufacturer following fracture union. That is, the units are leased on a patient-to-patient basis rather than purchased by individual clinics. Although numerous insurance companies cover the use of the Exogen 2000, this is only for specific fractures and its use on alternative tissues and conditions commonly encountered in sports medicine is currently not covered. An alternative to using the Exogen 2000 to generate LIPUS is to use conventional therapeutic ultrasound units as traditionally used by physiotherapists. At the lower intensity settings on these units, it is possible to produce a comparable dose to that produced by the Exogen 2000. At the AIS, conventional therapeutic ultrasound units are currently being used to generate LIPUS with a ISATA of 0.1 W/cm2 (table IV). With a duty factor of 0.20, this equates to a metered reading of 0.5 W/cm2 (in ultrasound units that conform to International Electrotechnical Commission 60601-2-5[68] the metered dose indicates the spatial-average, temporal-peak intensity). The ISATA of 0.1 W/cm2 being used at the AIS compares with the 0.03 W/cm2 produced by the Exogen 2000 and the intensities of 0.52 W/cm2 currently being introduced in clinical sports physiotherapy. Using conventional therapeutic ultrasound units over the past 18 months to generate LIPUS we have not identified any detrimental effects, and benefits have been reported in the literature using LIPUS at this higher intensity than that produced by the Exogen 2000.[15,66] Before using conventional therapeutic ultrasound units to introduce LIPUS researchers need to consider the potential ramifications of using these units in a manner other than that which is approved by US FDA market compliance. There are potential risks associated with using conventional therapeutic ultrasound units. Equipment surveys undertaken glob-

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Fig. 5. Exogen 2000 or Sonic Accelerated Fracture Healing System (courtesy of Smith and Nephew, Inc. [orthopaedic division]).

In addition to considering the performance of their ultrasound units, researchers need to consider the ramifications of using conventional therapeutic ultrasound units with a stationary ultrasound treatment head. Conventional therapeutic ultrasound units possess higher BNR values than the Exogen 2000 resulting in a higher spatial-peak intensity within the ultrasound beam (table IV). This can lead to the generation of tissue hot-spots, particularly if the ultrasound treatment head has a BNR beyond recommended values.[71] To date, we have safely introduced LIPUS using stationary conventional therapeutic ultrasound treatment heads that have BNRs of up to 6.[39] 6. Conclusion The established beneficial effect of LIPUS during fracture repair when used frequently (daily) for lengthy durations (20 minutes) signals a potential new direction in terms of generating beneficial ultrasound effects in sports medicine. Although currently developed for the intervention of bone fractures, LIPUS has the potential to be used on tissues and conditions more commonly encountered in sports medicine. These include stress fractures and acute injuries to ligament, tendon, muscle and cartilage. Technology is available to generate and introduce LIPUS to these conditions. However, its use in clinical sports medicine is currently not feasible. It is possible to use conventional therapeutic ultrasound units to generate and introduce LIPUS. In doing so, the output performance of these units needs to be carefully monitored and researchers need to be aware of the potential ramifications of using these units in a manner other than that which is currently approved. If established to be safe by way of further animal based studies and subsequent methodologically-sound RCTs, the use of LIPUS in sports medicine may gain approval leading to accelerated recovery from injury and earlier return to activity. Acknowledgements
Dr SJ Warden holds a National Health and Medical Research Council (Australia) CJ Martin Fellowship (Regkey no. 209169). The author provided no information on sources of

ally have repeatedly illustrated that many ultrasound units being used in clinical practice are unable to produce an ultrasound dose that matches the metered dose to within set standards.[69,70] This output variance may not only influence treatment efficacy but may also be detrimental to surrounding tissues. To address this problem, we regularly assess the accuracy of our dose using a commercially available ultrasound power meter (UPM-DT-1; Ohmic Instruments, Easton, MD, USA). As this power meter cannot respond to the temporal variation of pulsedwave ultrasound because of the inertia of the target it detects the temporal-average power. Division of this power by the ERA of the ultrasound transducer provides the ISATA.
Table IV. Ultrasound dosages currently introduced at the Australian Institute of Sport (AIS), compared with that produced by the Exogen 2000 Dosage parameter Frequency Pulse period Interval period Duty factor ISATA ISPTA Beam non-uniformity ratio Effective radiating area Duration of intervention AIS 1.0 MHz 2ms 8ms 0.20 0.1 W/cm2 <0.6 W/cm2 <6 5 cm2 20 min Exogen 2000 1.5 MHz 0.2ms 0.8ms 0.20 0.03 W/cm2 <0.12 W/cm2 <4 3.88 cm2 20 min

Frequency of introduction Daily Daily ISATA = spatial-average temporal-average intensity; ISPTA = spatialpeak temporal-average intensity.

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Warden

funding and has no conflicts of interest directly relevant to the content of this review.

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Correspondence and offprints: Stuart J. Warden, Centre for Sports Medicine Research and Education, School of Physiotherapy, The University of Melbourne, Parkville, VIC 3010, Australia. E-mail: s.warden@unimelb.edu.au

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