![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 1-24 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.](https://www.researchgate.net/profile/Stuart-Warden/publication/8074304/figure/fig2/AS:667652208996355@1536192099129/Effect-of-timing-of-low-intensity-pulsed-ultrasound-introduction-on-femoral-fracture_Q320.jpg)
![Exogen 2000 or Sonic Accelerated Fracture Healing System (courtesy of Smith and Nephew, Inc. [orthopaedic division]).](https://www.researchgate.net/profile/Stuart-Warden/publication/8074304/figure/fig1/AS:281031694405641@1444014585953/Exogen-2000-or-Sonic-Accelerated-Fracture-Healing-System-courtesy-of-Smith-and-Nephew_Q320.jpg)
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Sports Med 2003; 33 (2): 95-107
L
EADING
A
RTICLE
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. Warden
1,2,3
1 Centre for Sports Medicine Research and Education, School of Physiotherapy, The University
of Melbourne, Parkville, Victoria, Australia
2 Department of Orthopaedic Surgery, Indiana University School of Medicine, Indianapolis,
Indiana, USA
3 Physiotherapy Department, Centre for Sports Sciences and Sports Medicine, Australian
Institute of Sport, Bruce, Australian Capital Territory, Australia
Ultrasound therapy is a widely available and frequently used electrophysical
Abstract
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. Consequent-
ly, 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 demonstrat-
ing 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/cm
2
) 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 These units were used on a daily basis by 84% of
available and frequently used electrophysical agents therapists and in a quarter of patient consultations.
in sports medicine. A recent survey of ultrasound Given this large-scale application, ultrasound pro-
use by sports physiotherapists in Australia found all vides an economic contribution to the practice of
therapists to have access to an ultrasound unit.
[1]
sports medicine. This was estimated at 6.3% of the
96 Warden
total income derived by Australian sports physi- tive will discuss the effect of ultrasound on bone
fractures, the dosages introduced and the postulated
otherapists from standard consultations.
[1]
mechanisms of action. It will conclude by discuss-
To validate such a large role for ultrasound in
ing the relevance of these latest findings to sports
sports medicine it is important that interventions
medicine and how this evidence of a beneficial
using this modality be evidence-based.
clinical effect may be implemented to intervene in
Evidence-based medicine is the current ideal of the
sporting injuries to bone and other tissues. The aim
healthcare profession and involves the integration of
of the paper is to highlight this latest direction in
individual clinical expertise with the best available
ultrasound therapy and stimulate new lines of re-
external clinical evidence.
[2]
The latter is considered
search into the efficacy of ultrasound in sports
to be provided by randomised, controlled trials
medicine. In time this may lead to accelerated recov-
(RCTs).
[3,4]
In terms of ultrasound therapy, RCT
ery from injury and subsequent earlier return to
evidence regarding its effectiveness is currently
activity.
lacking. Systematic reviews and meta-analyses of
ultrasound effects have repeatedly concluded that
1. Beneficial Effect of Ultrasound on
there is insufficient evidence to support the current
Bone Fractures
clinical application of ultrasound.
[5-8]
A prominent
reason for this lack of evidence is the limited num-
Over the past decade ultrasound has developed
ber of well-designed RCTs into ultrasound effects.
into an established intervention for bone fractures.
A recent systematic review found that, of the 35
For a complete review, refer to Rubin et al.
[11]
and
English language RCTs investigating the clinical
Warden et al.
[12,13]
In brief, during fresh fracture
effects of ultrasound published between 1975 and
repair ultrasound has been shown to substantially
1999, only ten met minimal methodological stan-
accelerate the rate of repair. In animals, this was
dards.
[7]
Of these ten, only two demonstrated a bene-
primarily illustrated by the enhancement of mechan-
ficial ultrasound effect.
[9,10]
ical strength return following fracture.
[14-18]
Investi-
Due to the lack of evidence for a beneficial effect,
gating the time course of mechanical strength return,
the role of ultrasound therapy in clinical practice is
Pilla et al.
[17]
found rabbit fibular osteotomies treat-
currently in question. This does not mean that ultra-
ed with active-ultrasound to achieve the mechanical
sound should be discarded as a therapeutic modality.
strength of intact bone 17 days post-fracture. In
Eighty-seven percent of clinicians consider ultra-
contralateral inactive-ultrasound treated fractures,
sound to have a place in modern day sports medicine
mechanical strength was regained between 23 and
despite the lack of evidence.
[1]
This suggests that
28 days post-injury. This represented an accelera-
further methodologically-sound RCTs are required
tion in the rate of biomechanical healing by 30–38%
to establish the efficacy of ultrasound. It also sug-
with the use of ultrasound.
gests that we may need to look in new directions to
In humans, the most convincing evidence for the
explore the potential benefits of ultrasound given the
use of ultrasound during fresh fracture repair has
inability of 80% of previous well-designed RCTs to
been provided by three well-designed RCTs. The
elicit a beneficial effect.
methodologies of these studies are detailed in table
A potential new direction for ultrasound in sports
I. In tibial diaphyseal fractures, Heckman et al.
[19]
medicine has been stimulated by recent research
found active-ultrasound to reduce the time taken for
showing that ultrasound can have clinically signifi-
fractures to be classified as both radiographically
cant beneficial effects on injured tissue, and in par-
and clinically healed by an average of 58 days
ticular on fractured bone. These benefits were gen-
(figure 1). When compared with inactive-ultrasound
erated using low-intensity (<0.1 W/cm
2
) pulsed ul-
treated fractures, the acceleration in repair repre-
trasound (LIPUS), a dose alternative to that
sented a 38% reduction in healing time. Kristiansen
traditionally used in sports medicine. This perspec-
et al.
[20]
found active-ultrasound reduced radi-
Adis Data Information BV 2003. All rights reserved. Sports Med 2003; 33 (2)
A New Direction for Ultrasound in Sports Medicine 97
Table I. Methodological details of studies investigating the effect of ultrasound on fresh fracture repair in humans
Reference Study design Fracture characteristics Intervention and Outcome measures Study endpoint
group numbers
Heckman et al.
[19]
Randomised, Closed or grade I open tibial Active: cast Anteroposterior and 3 of 4 cortices
double-blind, shaft fracture. Treatable by immobilisation + lateral radiographs at bridged on
placebo-controlled, closed reduction and cast active-ultrasound 4, 6, 8, 10, 12, 14, 20, radiographical
prospective, immobilisation. Mean maximum (n = 33). Placebo: 33 and 52 weeks. examination.
multicentre fracture gap = 0.4cm. Mean cast immobilisation Clinical assessment at Fracture stable
length of fracture = 4cm. + inactive- 6 and 10 weeks, and and not painful to
Exclusions: long fractures, large ultrasound (n = 34) at time of cast removal manual stress on
displacements, fractures of the (as indicated by clinical
metaphysis, most comminuted radiographs) examination
fractures
Kristiansen et Randomised, Closed, dorsally angulated, Active: cast Posteroanterior and 4 of 4 cortices
al.
[20]
double-blind, metaphyseal fracture of the immobilisation + lateral radiographs at bridged on
placebo-controlled, distal radius (within 4cm of tip) active-ultrasound each follow-up visit. radiographical
prospective, [Colles’ fracture]. Treatable by (n = 30). Placebo: Clinical assessment at examination.
multicentre one closed reduction and below-cast immobilisation each follow-up visit. Fracture stable
elbow cast. Intra-articular + inactive- Follow-up at 1, 2, 3, 4, and not painful to
involvement of radiocarpal or ultrasound (n = 31) 5, 6, 8, 12 and 16 manual stress on
radio-ulnar joint and weeks clinical
concomitant ulnar styloid examination
process fractures acceptable.
Exclusions: Chauffeur, Barton,
Smith fractures
Mayr et al.
[21]
Randomised, Stable, non-dislocated fracture Active: cast Sagittal computer First time 70% or
controlled, through waist of scaphoid (AO immobilisation + tomography. Clinical more cortical
prospective, single- classification B1 and B2). active-ultrasound healing time. Follow-up bridging observed
centre Exclusions: unstable fractures, (n = 15). Control: at 28 days after on computed
bone pathology, greater than 10 cast immobilisation diagnosis and every 14 tomography
days post-fracture alone (n = 14) days thereafter examination. Time
from start of
treatment to
removal of cast
(clinical healing
time)
ographical and clinical healing times in fractures of 1.01–11.81).
[22]
This converts into a mean difference
the distal radius by an average of 37 days when in healing time of 64 days between the active- and
compared with inactive-ultrasound treated fractures. inactive-ultrasound treated groups;
[22]
a difference
This also represented a reduction of 38% in healing which not only has benefits in terms of reductions in
time. Most recently, Mayr et al.
[21]
demonstrated patient morbidity, but also economic benefits.
[23]
scaphoid fractures treated with active-ultrasound
In addition to its beneficial effects on fresh frac-
healed 19 days earlier than inactive-ultrasound treat-
tures, ultrasound has also been shown to facilitate
ed fractures, an acceleration of 30%.
healing in fractures displaying delayed- and non-
union.
[24-27]
In a fracture non-union model in ro-
Combining the outcomes of these clinical trials,
dents, Takikawa et al.
[27]
found 6 weeks of active-
ultrasound is observed to accelerate the rate of fresh
ultrasound to stimulate union in 50% of fractures.
tibial, radial and scaphoid fracture repair by
This compared with a 0% union rate in contralateral
30–38%. This correlates well with the aforemen-
fractures treated with inactive-ultrasound. With
tioned acceleration in the rate of biomechanical
lengthier intervention, it is possible that ultrasound
healing observed in animals. Pooling the results of
may have stimulated union in more than 50% of
the 158 fractures investigated, a weighted average
fractures. Clinically, ultrasound has been found to
effect size can be calculated at 6.41 (95% CI =
Adis Data Information BV 2003. All rights reserved. Sports Med 2003; 33 (2)
98 Warden
stimulate union in 91% of fractures displaying
delayed-union (n = 951; average fracture interval =
151 days) and 86% of fractures displaying non-
union (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 perspec-
tive 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 bone’s high ab-
Days to clinical and radiological healing (mean ± SD)
0
240
200
160
120
80
40
Active-ultrasound treated
Inactive-ultrasound treated
*
Tibial diaphysis
*
Distal radius
*
Scaphoid
Fig. 1. Effect of ultrasound on fresh tibial diaphyseal,
[19]
distal radi-
us
[20]
and scaphoid
[21]
fracture repair in humans. * Indicates p <
0.01.
sorption coefficient, high relative acoustic impe-
dance and ability to propagate shear waves, ultra-
clinical practice. Clinically, ultrasound is introduced
sound has selective interfacial effects at the bone
at an intensity commonly in the range of 0.5–2 W/
surface.
[28]
When superclinical dosages are used
cm
2
.
[1]
In comparison, in investigations into the
these effects can generate considerable tissue dam-
therapeutic effect of ultrasound on bone a spatial-
age, including premature closure, slipping and dis-
average temporal-average intensity (I
SATA
) of be-
placement of epiphyseal growth plates, bone sclero-
low 0.1 W/cm
2
has predominantly been used, with
sis, diaphyseal fractures and fibrosis, and delayed
the most common I
SATA
introduced being 0.03 W/
healing during fracture repair.
[29,30]
This explains
cm
2
.
[13]
The I
SATA
refers to the average ultrasound
why bone is directly treated with ultrasound by less
power output over the area of the ultrasound beam
than 7% of therapists in clinical practice.
[1]
(spatial-average) and the average of this intensity
Given the benefits of ultrasound observed during
over a complete pulse cycle (ultrasound ‘on’ and
fracture repair, yet inherent risk of tissue damage, it
‘off’ period; temporal-average). The low I
SATA
in-
is reasonable to question how it is possible to safely
troduced during fracture repair is coupled with a
introduce ultrasound to bone. This has been
pulsing regimen of 1:4 (duty factor = 0.20). Using
achieved by substantially changing the ultrasound
dose introduced from that traditionally introduced in 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 Healed/treated Healing rate (%) Average healing time (mean Average fracture age
no. of days ± SD) (days)
Clavicle 8/10 80 181 ± 39 435
Humerus 33/48 69 174 ± 20 596
Radius/radius-ulna 21/22 95 117 ± 16 690
Scaphoid 24/24 100 123 ± 12 513
Femur 57/66 86 157 ± 10 813
Tibia/tibia-fibula 105/120 88 166 ± 11 734
Metatarsal 14/18 78 117 ± 17 634
Foot 18/20 90 138 ± 18 871
Other 34/38 89 131 ± 13 551
Total 314/366 86 152 ± 5 755
Adis Data Information BV 2003. All rights reserved. Sports Med 2003; 33 (2)
A New Direction for Ultrasound in Sports Medicine 99
interface has been shown both theoretically
[31]
and duced for 5 minutes per intervention
[1]
and, presum-
ably, no more than 3 times per week. Likewise, in
experimentally
[17,32]
to be insignificant (<1.0°C).
the methodologically-sound RCTs that failed to es-
Similarly, the risk for tissue damaging inertial cavi-
tablish a beneficial effect, ultrasound was intro-
tation is negligible.
[31]
duced infrequently for treatment periods of less than
In addition to a different intensity from that being
10 minutes.
[7]
introduced clinically, the mode by which ultrasound
Given the beneficial effect of ultrasound ob-
is introduced during fracture repair varies from
served when used for longer durations and intro-
traditional ultrasound therapy theory and applica-
duced more frequently, it is possible that ultrasound
tion. Therapists are traditionally instructed to use a
introduction has traditionally been too short and too
dynamic (moving) treatment head when introducing
infrequent to permit a suitable cellular response and
ultrasound. This is in an attempt to evenly distribute
subsequent tissue effect. Supporting this theory, the
areas of high local acoustic pressure (‘hot-spots’)
two methodologically-sound RCTs demonstrating
resulting from uneven vibration of the piezoelectric
beneficial ultrasound effects at conventional thera-
crystal (transducer) and wave interference within
peutic intensities introduced ultrasound frequently
the near field of the ultrasound beam.
[28]
In compari-
(5 times per week) for lengthy treatment durations
son, LIPUS during fracture repair is introduced us-
(15 minutes).
[9,10]
Similarly, the theory is supported
ing a stationary treatment head over the fracture site.
by a recent study investigating the effect of LIPUS
This is possible without a risk of tissue damage due
on cartilage repair in rabbits.
[33]
By increasing the
to the combination of the low I
SATA
being intro-
duration of daily ultrasound intervention (up to a
duced and the low beam non-uniformity ratio (BNR)
maximum of 40 minutes) increasing advantages in
of the ultrasound treatment heads being used. The
terms of histologic signs of repair were found.
BNR refers to the ratio between the spatial-peak and
spatial-average intensities within the ultrasound
3. Mechanism for Beneficial Ultrasound
beam. During fracture repair the ultrasound treat-
Effect During Fracture Repair
ment heads being used have a BNR of less than 4.
As the I
SATA
being used during fracture repair is
Ultrasound at low intensities can be safely ap-
most commonly 0.03 W/cm
2
, this means that the
plied to bone using a stationary treatment head with
spatial-peak intensity within the ultrasound beam is
no known risk of tissue damage. However, consider-
less than 0.12 W/cm
2
, a value low enough to not
ing that the intensity being introduced during frac-
pose any tissue damage risk.
ture repair is within the traditional diagnostic ultra-
The low I
SATA
introduced during fracture repair
sound range, a range previously considered to have
coupled with the low BNR of the ultrasound treat-
minimal biological effect and no therapeutic value,
ment heads being used enables ultrasound to be
it is valid to consider how LIPUS induces its thera-
introduced to bone with no known risk of tissue
peutic effect. Unfortunately, this is currently not
damage. However, these dosage features are unable
known. The predominant reason for this is the fact
to fully explain why LIPUS has such a beneficial that it is not known how ultrasound signals are
transduced in vivo to produce a cellular response.
effect in bone repair studies, in comparison to the
This results from a dearth of a priori mechanistic
frequent lack of an ultrasound effect found in studies
hypotheses in reporting ultrasound biological ef-
using conventional therapeutic intensities. Two ad-
fects.
[34]
ditional features of the dose introduced that poten-
tially contribute to the beneficial effect of LIPUS
Despite the lack of supportive evidence establish-
during fracture repair are the duration and frequency
ing underlying biophysical effects, the beneficial
of ultrasound introduction. During fracture repair
effect of LIPUS observed in fracture repair studies
ultrasound is introduced daily for 20 minutes. In
may have resulted from three main mechanisms.
comparison, in clinical practice ultrasound is intro-
The first relates to ultrasound being a form of
Adis Data Information BV 2003. All rights reserved. Sports Med 2003; 33 (2)
100 Warden
mechanical stimulation. Ultrasound can be de- cial effect of LIPUS during fracture repair remains
unclear.
scribed as longitudinal mechanical waves. A
mechanical wave is one in which energy is transmit-
The third and final mechanism by which LIPUS
ted by the movement of particles within the medium
may have its beneficial effect during fracture repair
through which the wave is travelling. Given the
is through the generation of localised heat at the
inherent mechanosensitivity of bone, it has been
fracture site. Ultrasound energy generates alternat-
suggested that the micro-mechanical loading exert-
ing waves of compression and rarefaction in the
ed by ultrasound is potentially the mechanism for
propagating medium resulting in increased molecu-
the beneficial effect of LIPUS during fracture re-
lar motion. This leads to increased molecular vibra-
pair.
[11,33,35,36]
This is possible with recent research
tion and collisions, and subsequent heat genera-
showing bone to be responsive to very low magni-
tion.
[28]
Although this heating effect when using
tude (5 microstrain), high frequency (30Hz)
LIPUS is small, some enzymes are exquisitely sen-
mechanical loading.
[37]
However, the frequency of
sitive to small variations in temperature.
[45]
Thus, it
is possible that the small degree of heating associat-
loading associated with ultrasound is a number of
ed with LIPUS may contribute to its beneficial ef-
magnitudes higher and its loading magnitude lower
fect during fracture repair. However, this mecha-
than that introduced in traditional mechanical load-
nism lacks support from a recent study by Chang et
ing studies. In addition, mechanical loading associ-
al.
[15]
They found that ultrasound therapy augmented
ated with LIPUS has been found to be unable to
fracture repair but an equivalent level of
induce adaptation in intact bone.
[38,39]
Although this
hyperthermia generated with microwave therapy did
latter finding may have been influenced by the in-
not. Consequently, as with the previous two mecha-
ability of ultrasound to effectively penetrate the
nisms, this potential mechanism for the beneficial
outer bone cortex due to its acoustic properties, the
effect of LIPUS during fracture repair is not estab-
theory that LIPUS generates mechanically-induced
lished.
bone adaptation during fracture repair remains un-
resolved.
Despite the underlying biophysical mechanism/s
of action of ultrasound during fracture repair not
The second possible mechanism for the observed
being known, a number of studies
[42,44,46-55]
have
beneficial effect of LIPUS in the treatment of bone
investigated potential cellular processes influenced
fractures is the generation of ultrasound unique phe-
by LIPUS. In vitro, LIPUS has been shown to direct-
nomena. In addition to being described as mechani-
ly influence a number of cells associated with the
cal waves, ultrasound can equivalently be described
repair process (table III). These changes suggest that
as alternating pressure waves. These may generate
ultrasound may have direct effects on the reparative
unique phenomena, such as stable cavitation and
processes of angiogenesis, chondrogenesis and oste-
microstreaming within the propagating tissues.
[40]
ogenesis. Although the potentiation of cavitation
Although the occurrence and significance of these
and microstreaming in vitro necessitates caution
phenomena in vivo has been disputed,
[41]
their thera-
when extrapolating in vitro findings to the in vivo
peutic potential may be in the generation of shear
environment,
[46]
these in vitro results suggest that
forces on cellular membranes. These forces may
multiple cells involved in fracture repair are poten-
influence the cellular cytoskeleton to directly alter
tially responsive to LIPUS. This is supported by in
gene expression.
[42]
Alternatively, they may influ-
vivo investigation. Principally, Azuma et al.
[14]
ence transmembrane cellular channels resulting in
showed LIPUS to influence multiple cellular reac-
the altered transport of ions across the membrane
tions during fresh fracture repair. This was evident
and a subsequent cellular response.
[42-44]
However,
by the advancement of healing irrespective of the
as with the theory that ultrasound is a mechanical
phase of repair during which ultrasound was intro-
duced (figure 2). Overall, it appears that ultrasound
stimulus, this proposed mechanism for the benefi-
Adis Data Information BV 2003. All rights reserved. Sports Med 2003; 33 (2)
A New Direction for Ultrasound in Sports Medicine 101
Table III. In vitro effects of low-intensity pulsed ultrasound
Cell type Reference Findings
Fibroblasts 47 ↑ Collagen synthesis
Endothelial 48 ↑ PDGF with co-introducton of vitamin D
3
Chondrocytes 49 ↑ Aggrecan mRNA and proteoglycan synthesis
42 ↑ Intracellular calcium and proteoglycan synthesis
Osteoblasts 44 ↑ Calcium incorporation
50 ↓ Adenylate cyclase and TGFβ production, ↓ response to parathyroid hormone
47 ↑ Collagen and non-collagenous protein synthesis, IL-1β, bFGF and VEGF production
51 ↑ PGE
2
production and regulation of COX-2 mRNA
52 ↑ cfos, IGF-I, osteocalcin and bone sialoprotein mRNA expression
46 ↑ cfos, COX-2, alkaline phosphatase and osteocalcin mRNA expression
53 ↑ Osteoblast proliferation, alkaline phosphatase, PGE
2
and TNFα
54 ↑ cfos, COX-2, IGF-I and osteocalcin, stimulation of p38 MAPK and upstream effector, PI3K
55 ↑ NO and PGE
2
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-1β = interleukin-1β; NO = nitric
oxide; p38 MAPK = p38 mitogen-activated protein kinase; PDGF = platelet-derived growth factor; PGE
2
= prostaglandin E
2
; PI3K =
phosphoinositide 3-kinase; TGFβ = transforming growth factor-β; TNFα = tumour necrosis factor-α; VEGF = vascular endothelial growth
factor.
has beneficial effects on multiple processes during and fractures of the waist of the scaphoid. Although
fracture repair, and that it may stimulate a phase
only investigated with regard to its effects on these
shift in reparative phases whereby they commence
fractures, the benefits of LIPUS are believed to carry
and complete at an earlier stage during the repair
over to fractures of similar severity and similar-
process.
sized fracture gaps (<0.5cm) within other regions. In
light of this, LIPUS has been applied clinically to
4. Potential Implications for
fractures of the humerus, femur, ulna, fibula and
Sports Medicine
metatarsals.
[24]
RCT evidence on these fractures is
The evidence of a beneficial effect of LIPUS
not yet available.
during fracture repair is of high clinical relevance to
The application of LIPUS also need not be re-
the practice of sports medicine. A major goal in
stricted to fractures that have been treated with
sports medicine is to return athletes to function
closed reduction and cast immobilisation. Animal
following injury. Consequently, any modality that
studies suggest that ultrasound can also positively
has potential in accelerating tissue repair and subse-
influence fractures that have been managed with
quently facilitating return to sport has obvious
internal or external fixation,
[18,57,58]
although evi-
clinical implications.
dence in humans is currently inconclusive.
[59,60]
Sato
4.1 Potential Implications with Regard to the
et al.
[60]
demonstrated a beneficial effect of LIPUS
Intervention of Bone
with distraction osteogenesis in a single-case study.
However, Emani et al.
[59]
was unable to elicit a
Given the proven benefit of LIPUS on both fresh
beneficial effect in an RCT of the effect of LIPUS
fractures and fractures displaying healing defects,
on tibial fractures managed with an intramedullary
the intervention of bone injuries is currently the
rod. The absence of a beneficial effect in the latter
primary potential clinical application of LIPUS in
study may be attributed to reaming of the fractures,
sports medicine. In terms of fresh fractures, LIPUS
which is known to have osteoblastic effects and may
has been shown to have benefits on closed and grade
have masked the beneficial effect of LIPUS.
[22]
I open tibial diaphyseal and distal radius fractures,
Adis Data Information BV 2003. All rights reserved. Sports Med 2003; 33 (2)
102 Warden
delayed- and non-union, LIPUS has been found to
stimulate union in 98% and 94% of cases, re-
spectively.
[25]
These findings suggest that LIPUS
may have beneficial effects on stress fracture repair.
However, before it can become an established inter-
vention these preliminary findings need to be vali-
dated with RCT evidence.
4.2 Potential Implications with Regard to the
Intervention of Other Tissues
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
Maximal torsional torque [N mm] (mean ± SD)
0
240
200
160
120
80
40
Active-ultrasound treated
Inactive-ultrasound treated
*
Throughout
*
Days 1–8
*
Days 9–14
*
Days 15–24
Treatment group
Fig. 2. Effect of timing of low-intensity pulsed ultrasound introduc-
tion on femoral fracture repair in rodents. The ‘throughout’ group
received unilateral active-ultrasound and contralateral inactive-ul-
trasound on days 1–24 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 introduc-
tion, fractures treated with active-ultrasound demonstrated signifi-
cantly greater maximal torsional torque than contralateral inactive-
ultrasound treated fractures (reprinted from Azuma et al.,
[14]
with
permission from the American Society for Bone and Mineral Re-
search
)
. * Indicates
p
< 0.01.
healing when compared 2 weeks post-fracture with
contralateral inactive-ultrasound treated fractures.
The effect of LIPUS on traditional bone fractures
Meanwhile, Rawool et al.
[32]
using power Doppler
is clinically relevant. However, of greater interest to
assessment demonstrated canine ulna osteotomies (n
sports medicine is its potential benefit in the inter-
= 3) treated over a 10-day period with LIPUS
vention of stress fractures. Considering stress frac-
showed an increased degree of blood flow when
tures are believed to heal in comparable stages to
compared with osteotomies in control dogs (n = 3).
traditional bone fractures and that they consist of
This increase was first noticeable within the inflam-
small undisplaced fractures similar to those inter-
matory phase of repair (2–3 days post-fracture) and
vened in previous RCTs of the effect of LIPUS on
lasted up to 2 weeks. Most significantly and recent-
fracture repair, it is possible that LIPUS will have
ly, Azuma et al.
[14]
showed that LIPUS applied
beneficial effects on stress fractures. This has sup-
during days 1–8 post-femoral fracture in rodents
port from preliminary case reports.
[25,61,62]
In seven
resulted in increased mechanical strength return
posterior-medial cortex stress fractures of the tibia,
when fractures were assessed 25 days post-fracture
introduction of LIPUS enabled continuation of ac-
(figure 2). This latter finding demonstrates that
tivity and return to competition within 4 weeks.
[61]
changes induced with LIPUS during the early stages
In one tarsal navicular stress fracture, LIPUS report-
of repair can augment later repair processes.
edly stimulated bony union and allowed return to
Given that the inflammatory phase of bone repair
competition within 5 weeks.
[61]
LIPUS had no effect
is similar to that which occurs in alternative tissues,
on the one anterior tibial cortex stress fracture treat-
and involves similar cells and cellular processes, it is
ed,
[61]
although this may have been influenced by the
valid to hypothesise that LIPUS will also have sig-
continuation of activity resulting in disruption of
nificant beneficial effects on alternative tissues dis-
any healing attempts. In stress fractures displaying playing an acute inflammatory reaction. This theory
Adis Data Information BV 2003. All rights reserved. Sports Med 2003; 33 (2)
A New Direction for Ultrasound in Sports Medicine 103
a
b
cd
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 subchon-
dral 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
horizontall
y
oriented fibrous tissue
(
re
p
rinted from Cook et al.,
[33]
with
p
ermission from Li
pp
incott Williams & Wilkins
)
.
has preliminary experimental support. Cook et al.
[33]
served at 21 days post-injury, however, at this stage
both the active- and inactive-ultrasound treated
found LIPUS to improve the gross and histological
sides exhibited the strength of normal, uninjured
appearance of surgically-induced, full-thickness os-
ligaments. It is possible that the side treated with
teochondral defects of the patellar groove in rabbits
LIPUS reached this ‘normal’ level at an earlier
(figure 3). Fitting with the theory of a beneficial
stage.
effect on acute repair processes, most benefits with
LIPUS were observed within the initial 4 weeks of
In light of the hypothesis that LIPUS potentially
repair rather than latter weeks. Similarly, during the
has a beneficial effect on tissues displaying an acute
repair of acute medial collateral ligament injuries in
inflammatory reaction, it is currently being used on
rodents, Takakura et al.
[67]
showed LIPUS to have
acute tissue injuries to elite athletes at the Australian
beneficial effects on the early stages of repair. At 12 Institute of Sport (AIS). Given the site-specific na-
days post-injury, ligaments treated with LIPUS had ture of the ultrasound beam, localised injuries are
greater strength and mean collagen fibril diameter primarily being treated. For injuries larger in area
than contralateral inactive-ultrasound treated liga- than the effective radiating area (ERA) of the ultra-
ments (figure 4). These differences were not ob- sound treatment head, multiple treatments are being
Adis Data Information BV 2003. All rights reserved. Sports Med 2003; 33 (2)
104 Warden
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. Al-
though numerous insurance companies cover the
use of the Exogen 2000, this is only for specific
fractures and its use on alternative tissues and condi-
tions 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 physiother-
apists. 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, con-
Ultimate tensile load [N] (mean ± SD)
0
35
50
25
20
15
10
5
Active-ultrasound treated
Inactive-ultrasound treated
*
12 21
Days following injury
Fig. 4. Effect of daily low-intensity pulsed ultrasound on medial
collateral ligament repair in rodents. Twelve days following surgical-
ly-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
p
ermission
)
. * Indicates
p
< 0.05.
ventional therapeutic ultrasound units are currently
being used to generate LIPUS with a I
SATA
of 0.1
performed or multiple treatment heads are being
W/cm
2
(table IV). With a duty factor of 0.20, this
used simultaneously. Injuries being treated include
equates to a metered reading of 0.5 W/cm
2
(in
those to ligament, tendon, muscle and cartilage tis-
ultrasound units that conform to International Elec-
sue. Although there is currently no RCT evidence
trotechnical Commission 60601-2-5
[68]
the metered
for a beneficial effect of LIPUS on injuries to these
dose indicates the spatial-average, temporal-peak
tissues, clinical outcomes have been promising.
intensity). The I
SATA
of 0.1 W/cm
2
being used at the
AIS compares with the 0.03 W/cm
2
produced by the
5. Ultrasound Therapy Units and
Exogen 2000 and the intensities of 0.5–2 W/cm
2
Their Limitations
currently being introduced in clinical sports physio-
therapy. Using conventional therapeutic ultrasound
Before researchers contemplate investigating
units over the past 18 months to generate LIPUS we
LIPUS in clinical trials, a significant practical factor
have not identified any detrimental effects, and ben-
that should be considered is the ultrasound units
efits have been reported in the literature using
they intend to use. Specialised ultrasound units have
LIPUS at this higher intensity than that produced by
been developed for the intervention of fractured
the Exogen 2000.
[15,66]
bone. Termed the Exogen 2000
1
or Sonic Acceler-
ated Fracture Healing System (figure 5), these units Before using conventional therapeutic ultrasound
produce ultrasound at a single dose with a duty units to introduce LIPUS researchers need to consid-
factor of 0.20 and I
SATA
of 0.03 W/cm
2
. They have er the potential ramifications of using these units in a
US FDA approval to be used on specific fresh manner other than that which is approved by US
fractures of the tibial diaphysis and distal radius as FDA market compliance. There are potential risks
well as non-united fractures at numerous sites. As associated with using conventional therapeutic ul-
the majority of research regarding the effectiveness trasound units. Equipment surveys undertaken glob-
1 Use of tradenames is for product identification purposes only and does not imply endorsement.
Adis Data Information BV 2003. All rights reserved. Sports Med 2003; 33 (2)
A New Direction for Ultrasound in Sports Medicine 105
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 treat-
ment 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]
Fig. 5. Exogen 2000 or Sonic Accelerated Fracture Healing Sys-
tem
(
courtes
y
of Smith and Ne
p
hew, Inc.
[
ortho
p
aedic division
])
.
6. Conclusion
ally have repeatedly illustrated that many ultrasound
units being used in clinical practice are unable to
The established beneficial effect of LIPUS dur-
produce an ultrasound dose that matches the me-
ing fracture repair when used frequently (daily) for
tered dose to within set standards.
[69,70]
This output
lengthy durations (20 minutes) signals a potential
variance may not only influence treatment efficacy
new direction in terms of generating beneficial ultra-
but may also be detrimental to surrounding tissues.
sound effects in sports medicine. Although currently
To address this problem, we regularly assess the
developed for the intervention of bone fractures,
accuracy of our dose using a commercially available
LIPUS has the potential to be used on tissues and
ultrasound power meter (UPM-DT-1; Ohmic Instru-
conditions more commonly encountered in sports
ments, Easton, MD, USA). As this power meter
medicine. These include stress fractures and acute
cannot respond to the temporal variation of pulsed-
injuries to ligament, tendon, muscle and cartilage.
wave ultrasound because of the inertia of the target it
Technology is available to generate and introduce
detects the temporal-average power. Division of this
LIPUS to these conditions. However, its use in
power by the ERA of the ultrasound transducer
clinical sports medicine is currently not feasible. It is
provides the I
SATA
.
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 methodologi-
cally-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 Re-
search Council (Australia) CJ Martin Fellowship (Regkey no.
209169). The author provided no information on sources of
Table IV. Ultrasound dosages currently introduced at the Australian
Institute of Sport (AIS), compared with that produced by the Exogen
2000
Dosage parameter AIS Exogen 2000
Frequency 1.0 MHz 1.5 MHz
Pulse period 2ms 0.2ms
Interval period 8ms 0.8ms
Duty factor 0.20 0.20
I
SATA
0.1 W/cm
2
0.03 W/cm
2
I
SPTA
<0.6 W/cm
2
<0.12 W/cm
2
Beam non-uniformity ratio <6 <4
Effective radiating area 5 cm
2
3.88 cm
2
Duration of intervention 20 min 20 min
Frequency of introduction Daily Daily
I
SATA
= spatial-average temporal-average intensity; I
SPTA
= spatial-
peak temporal-average intensity.
Adis Data Information BV 2003. All rights reserved. Sports Med 2003; 33 (2)
106 Warden
20. Kristiansen TK, Ryaby JP, McCabe J, et al. Accelerated healing
funding and has no conflicts of interest directly relevant to the
of distal radius fractures with the use of specific, low-intensity
content of this review.
ultrasound. J Bone Joint Surg 1997; 79A: 961-73
21. Mayr E, Rutzki MM, Rutzki M, et al. Beschleunigt niedrig
intensiver, gepulster Ultraschall die Heilung von Skaphoid-
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Correspondence and offprints: Stuart J. Warden, Centre for
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