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Objectives. The purpose of this study was to review past and recent literature findings regarding the
effects of ultrasound therapy on bone healing and its clinical efficacy in medical and dental interven-
tions. Methods. A literature review was conducted on the effects of ultrasound therapy on bone heal-
ing. The studies regarding clinical applications in long bones and maxillofacial bones were evaluated
separately from each other. Results. The effects of therapeutic ultrasound on bone healing have been
studied for half a century. Numerous clinical and experimental studies have addressed this relationship,
and many of them have shown positive correlations. Although several theories have been proposed to
explain the mechanism of action, the exact mechanism has not been fully understood. Conclusions.
Therapeutic ultrasound therapy in clinical settings is a noninvasive application and has no serious com-
plications or side effects. It may be an acceptable treatment of choice in many types of clinical proce-
dures involving maxillofacial bones. Key words: bone healing; bone remodeling; fracture;
low-intensity ultrasound; maxillofacial surgery; orthopedic surgery; therapeutic ultrasound.
B
Abbreviations one is dynamic tissue, which is affected by many
BMU, basic multicellular unit; LIPU, low-intensity pulsed systemic and local factors. Bone healing is associ-
ultrasound
ated with a variety of biochemical, biomechani-
cal, cellular, hormonal, and pathologic events.
Numerous therapeutic methods for bone healing have
been described in the literature. These applications
include systemic and local drug delivery and physical
Received November 24, 2008, from the Department
of Dental Services, Diyarbakır Military Hospital,
treatments such as low-intensity lasers, electromagnetic
Diyarbakır, Turkey (Ö.E.); and Department of Oral fields, extracorporeal shock, mechanical stimulation, and
and Maxillofacial Surgery, Cukurova University, ultrasound therapy.1 The use of ultrasound as a therapeu-
Faculty of Dentistry, Adana, Turkey (E.E.). Revision
requested January 6, 2009. Revised manuscript tic approach in bone healing has a history of more than
accepted for publication February 4, 2009. half a century. In this article, the current understanding of
We thank Yakup Üstün, DDS (School of Dentistry,
Cukurova University), for encouraging us to prepare the molecular mechanisms of ultrasound therapy is dis-
the manuscript. cussed, the findings of the literature are surveyed, and the
Address correspondence to Özgür Erdogan, DDS,
PhD, 100 Yil Mahallesi 85337, Sokak 4-7, 01360
future of the application is evaluated. Maxillofacial bones
Seyhan-Adana, Turkey. may differ from extremity bones by their healing mecha-
E-mail: ozgerdogan@yahoo.com nisms.2 Therefore, research regarding maxillofacial bones
was evaluated separately from that regarding other bones
CME Article includes CME test of the skeleton.
© 2009 by the American Institute of Ultrasound in Medicine • J Ultrasound Med 2009; 28:765–776 • 0278-4297/09/$3.50
jum286_707-838online.qxp:Layout 1 5/15/09 9:27 AM Page 766
erties of the nonosteotomized legs on the 17th Successful reports of LIPU therapy in the man-
day, whereas the osteotomized legs in the control agement of closed, fresh, and old fractures led to
group gained the mechanical properties of the the use of this application in other orthopedic
nonosteotomized legs on the 28th day. surgical protocols that involve bone healing.
The first randomized double-blind controlled Positive effects of LIPU have been shown in the
study regarding the effects of LIPU on fresh tibia management of spinal fusion and distraction
fractures in humans was published by Heckman osteogenesis procedures in rabbits.22–25
et al17 in 1994. In that multicenter study of 67 Currently, commercial therapeutic ultrasound
patients, 33 patients received LIPU treatment, devices, which allow home application by the
and 34 constituted the control group. The patient, are available on the market. The use of
authors reported that LIPU accelerated fracture LIPU devices was initially cleared for marketing
healing at a rate of 38%.17 Three years later, by the US Food and Drug Administration in 1994
Kristiansen et al18 reported accelerated healing for treatment of fresh, closed, and posteriorly
of fresh dorsal radius fractures with LIPU treat- displaced distal radius fractures and fresh,
ment. The average healing time for the fractures closed, and grade 1 open tibial diaphysis frac-
in the experimental group was 61 days, whereas tures in skeletally mature individuals when
the healing time in the control group was 98 these fractures are orthopedically managed by
days. closed reduction and cast immobilization.26 In
Numerous studies have sought to determine 2000, the indications were expanded to include
the optimal ultrasound therapy regimen for treatment of established nonunions, excluding
stimulating fracture healing. For that purpose, the skull and vertebrae.
Yang et al19 created bilateral closed femoral frac-
tures in rats. The animals in the experimental Bone Healing and Interaction of
group received an ultrasound signal consisting Ultrasound With Bone Tissue
of a 200-microsecond sine wave burst of 0.5
MHz repeating at 1 kHz with an average tempo- Bone formation may occur through transforma-
ral and spatial intensity of 50 or 100 mW/cm2 to tion from cartilage tissue (endochondral ossifi-
1 fracture in each limb. The fractures treated at cation), calcification surrounding the organic
50 mW/cm2 had significantly higher torsional matrix (intramembranous ossification), or for-
stiffness and maximum torque when compared mation of new bone on existing bone (apposi-
with the nontreated side. However, the differ- tional ossification).27 The 3 types of ossification
ences in these biomechanical parameters did occur throughout the formation of new bones,
not show any statistical significance in fractures the regeneration process of the skeleton after an
treated at 100 mW/cm2. Tsai et al20 showed injury or surgery, and the formation of bone
greater mineral apposition rates in rabbit fibulas tumors.28
2 and 3 weeks after fractures that had been treat- Bone or fracture healing may be defined as the
ed with 1.5-MHz compared with 3-MHz ultra- repair of injured bone. It has 3 distinct but over-
sound, both using an intensity of 500 mW/cm2. lapping stages. These are the early inflamma-
To determine the best timing of LIPU therapy in tory stage, the repair stage, and the late
a closed femoral fracture model, Azuma et al21 remodeling stage.29 In the inflammatory stage,
applied LIPU stimulation to experimental frac- hematoma develops, and inflammatory cells
ture sides at 4 different times from the 1st day and fibroblasts infiltrate the injured area.
through the 24th day. They showed that LIPU Granulation tissue forms; ingrowth of vascular
treatment resulted in accelerated fracture heal- tissue occurs; and mesenchymal cells migrate in
ing in each group regardless of the treatment this stage. In the repair stage, fibroblasts serve as
timing. Thus, there were no differences in radio- stroma for vascular ingrowth. They are responsi-
logic, histologic, or biomechanical parameters ble for synthesis of the collagen matrix and
among the 4 groups. The results of that study angiogenesis. The collagen matrix ossifies, and
imply that LIPU treatment accelerates all phases callus tissue consequently develops. Bone heal-
of fracture healing rather than any specific stage. ing is completed during the remodeling stage.30
Woven bone is differentiated from lamellar metalloproteinase 1.33 It is known that this
bone, and the bone gains its original strength enzyme is very sensitive to small variations in
after completion of this stage. Remodeling of temperature. The thermal and nonthermal
bone is regulated by a combination of resorption effects of ultrasound are not separable, and it
and bone formation. The primary cells involved is assumed that nonthermal effects of ultra-
are osteoblasts and osteoclasts. There is a close sound are usually accompanied by some heat
anatomic and functional relationship between increase. The observed nonthermal effects of
resorptive and formative cells at remodeling ultrasound are stable cavitation, microstream-
sites. These cells act within a temporary anatom- ing, acoustic streaming, and direct effects to
ic structure called the basic multicellular unit cell membranes.
(BMU).27 A mature BMU consists of a leading Stable cavitation defines the presence of gas
front of osteoclasts followed by osteoblasts, bubbles in fluids due to ultrasound energy.32
blood supplies, and the associated connective These bubbles may be in different shapes and
tissues. In the remodeling process, the entire sizes depending on the type of ultrasound sig-
BMU moves forward, and osteoclasts resorb nal and may lead to local movement in the
bone and die by apoptosis. The resorbed bone is fluid. This movement in the fluid is called
replaced by newly formed bone. microstreaming. ter Haar et al34 showed that
Despite the complex characteristics of bone ultrasound signals at a frequency of 1.5 MHz
healing and multiple effects of ultrasound on and an intensity of 150 mW/cm2 generated
biological tissues, much is known today about bubbles bigger than 10 mm in body fluids of
the mechanism of action of ultrasound therapy. guinea pigs. Acoustic streaming is defined as
Several theories have been proposed to explain eddying of fluid near a vibrating structure such
the mechanisms and effects. A combination of as a stable cavitation gas bubble,35 resulting in
physical, piezoelectric, and biological effects of localized high-velocity streams of fluid created
ultrasound plays a role in the interaction of by ultrasound signals in a liquid. These mecha-
ultrasound with bone healing. nisms cause movement and transfer of intra-
cellular and extracellular ions. An increase
Physical Effects in intercellular ion transfer leads to changes in
membrane permeability, thus resulting in alter-
Ultrasound waves generate vibrations in all tis- ations of the electrophysiologic properties of the
sue components, including intracellular and cells. It has been shown that ultrasound applica-
extracellular fluids and cell membranes, when tion increases ion conductibility up to 22% and
penetrating into tissues. They cause movements decreases the need for adenosine triphosphate
or displacements of particles when transmitted consumption by sodium-potassium channels.36
in tissues.31,32 Because of these motions, ultra-
sound treatment produces a micromassage Piezoelectric Effect
effect in tissues, which produces mechanical
stimulation. An increase in electrical potential occurs when
Acoustic vibrations have thermal and non- pressure is applied on bone tissue. This effect is
thermal effects in biological tissues. The energy called the piezoelectric effect.37 The piezoelec-
attenuated by tissues leads to a thermal tric effect induces bone resorption and bone
increase. Ultrasound signals at high intensities healing. Bone as dynamic living tissue remodels
create considerable heat increases. However, the itself according to environmental forces. This
therapeutic ultrasound used for bone healing remodeling action theory was explained by
uses low intensities, as low as 20 to 50 mW/cm2. Wolff’s law38 in the 19th century. Ultrasound
Vibrations at these intensities generate a heat application generates the piezoelectric effect in
increase of less than 1°C, which is negligible in bone, thus increasing the electrical potential
terms of thermal damage. However, it has been within the tissue. It is suggested that an increase
suggested that this small increase in tempera- in the electrical potential induces bone remod-
ture may affect some enzymes such as matrix eling, thereby assisting fracture healing.39
and nonunions may be complicated because of of fractures is complicated in these patients for
systemic and local conditions such as osteo- that reason. Although it was shown that ultra-
porosis and radiotherapy. Ultrasound treatment sound treatment stimulated bone growth in tan-
has been found beneficial in the treatment of talum implants in dogs, no clinical use has been
delayed unions and nonunions. Mayr et al51 used reported.55
the application in 951 patients with delayed
unions and 366 patients with nonunions. They Ultrasound Therapy and Maxillofacial
reported successful healing in more than 86% of Bones
the patients in both groups. Nolte et al52 applied
the treatment to 29 patients with nonunions Most studies regarding the effects of ultrasound
after conventional therapies. The fractures therapy on bone healing have been conducted
were located in the tibia, femur, radius/ulna, on long bones; the number of studies involving
scaphoid, humerus, metatarsal, and clavicle. maxillofacial surgery has been limited, and the
Complete healing was shown in 86% of patients results have been controversial. A report by
in an average of 22 weeks. The efficacy of LIPU Cavaliere56 may be considered the first report of
treatment on open fractures has not been the clinical application of ultrasound for
proved by randomized clinical trials so far. enhancing maxillofacial bone healing. He
Evidence of acceleration of bone healing in applied ultrasound at relatively high intensities
delayed unions and nonunions is weaker com- (1–2 W/cm2) to 4 patients with mandibular frac-
pared with treatment for fresh closed fractures of tures and reported increased calluses and
long bones because of the designs of the pub- decreased pain with the use of ultrasound thera-
lished studies. However, this patient group con- py. The first in vivo study in this area was pub-
stitutes the major group needing ultrasound lished by Fedotov et al57 in 1986. They used
therapy. ultrasound treatment at 0.2 to 0.6 W/cm2 in rab-
Another clinical procedure in which ultra- bit mandibular fractures and reported a stimu-
sound therapy has been used is distraction lated reparative process at the fracture site.
osteogenesis. There are few clinical studies Another clinical report regarding ultrasound
showing positive effects of LIPU on distraction therapy in maxillofacial bones was published by
calluses. In a study by Tsumaki et al,53 21 patients Harris58 in 1992. The author applied ultrasound
with osteoarthritis underwent bilateral tibial at 3 MHz and 1 W/cm2 for 40 days for the treat-
hemicallotasis. One limb of every patient ment of osteoradionecrosis of the mandible.
received a 20-minute ultrasound treatment daily He found positive progress in 10 of 21 patients.58
for 4 weeks. The authors showed increased cal- In vitro studies conducted on mandibular
lus bone mineral density in the LIPU-treated osteoblast and fibroblast cultures showed that
limbs. Another study by El-Mowafi and Mohsen54 ultrasound signals increased proliferation of
showed accelerated healing of tibial distraction cells, synthesis of cytokines such as interleukins
calluses in LIPU-treated patients. Clinical and fibroblast growth factor, and synthesis of
studies mainly favor LIPU treatment for dis- nitric oxide and prostaglandins, which are
traction osteogenesis procedures. However, important mediators in angiogenesis and bone
the numbers of studies and patients have been healing.42,59
limited, and more clinical studies are needed Beginning in 2002, two different study groups
in this area. published several in vivo and human studies
Spinal arthrodesis is another orthopedic pro- regarding the effects of ultrasound on maxillofa-
cedure in which LIPU treatment may be advan- cial bones. With application of LIPU, El-Bialy et
tageous. Although several animal studies al60–64 showed enhanced bone formation at the
showed positive effects of LIPU treatment on callus tissue of mandibular distraction osteogen-
spinal arthrodesis procedures, no clinical study esis in rabbits, better repair of orthodontically
has been reported to date. Because of an altered induced root resorption in humans, enhanced
bone turnover rate, implant osseointegration is mandibular incisor growth and eruption in rab-
impaired in osteoporotic patients. Management bits, enhanced mandibular growth in rabbits,
and enhanced mandibular growth in growing They reported accelerated new bone formation
baboons when ultrasound treatment was com- on the LIPU-treated sides. There were no differ-
bined with functional appliances. However, ences between the groups for root resorption
another series by Schortinghuis et al65–67 showed and gingival recession. Immunochemical analy-
contrary results. They showed no effect of LIPU sis showed expression of heat shock protein
treatment on mandibular bone defects either 70–positive cells in the LIPU-treated wounds.
covered with a polytetrafluoroethylene mem- El-Bialy et al73 investigated the effects of pulsed
brane, covered with a collagen membrane, or and continuous ultrasound therapy on distrac-
left uncovered in rats. Similarly, 2 clinical articles tion osteogenesis in rabbit mandibles. They used
published by Schortinghuis et al68,69 reported no 36 rabbits divided into 3 groups. One group
notable contribution of LIPU treatment to received pulsed ultrasound therapy at 30
mandibular vertical osteogenesis procedures. mW/cm2, whereas the second group received
As with the management of fractures of the continuous ultrasound at the same intensity. The
long bones, the treatment of maxillofacial frac- third group received sham treatment. The data
tures may be problematic for both the patient showed increased callus healing compared with
and the surgeon. Most maxillofacial fractures other groups for the continuous mode in the first
require intermaxillary fixation, and a long fixa- 2 weeks and the pulsed mode in the third and
tion duration causes many problems such as fourth weeks.
feeding impairment, temporomandibular joint It is mainly accepted that ultrasound treatment
problems, and dental/periodontal problems. enhances endochondral bone formation.21,25
Shortening the intermaxillary fixation time may The fact that maxillofacial bones have intra-
be a main indication for LIPU applications in membranous ossification makes the use of ultra-
the maxillofacial area. One animal study con- sound therapy questionable in this particular
ducted on rabbits showed increased fracture region. The close relationship to important
healing in a mandibular fracture model.70 anatomic structures such as the brain, parotid
However, more studies are needed to determine gland, and eyes, in which the effects of ultra-
the optimal dosing and treatment modality sound are not known, is another drawback for
before using this procedure in clinical settings. use in maxillofacial bones. Another drawback is
Some other recent studies showed positive the thicker soft tissue layer compared with tibial,
effects of ultrasound therapy associated with ulnar, and scaphoid bone regions. This makes
oral surgery. Kerr et al71 evaluated the effects of penetration of ultrasound signals weaker, thus
ultrasound therapy in socket preservation after reducing the effectiveness of the treatment.
tooth extraction, which has a critical role in den- However, an increased interest in the therapeutic
tal implant placement. They prepared acrylic use of ultrasound for oral and maxillofacial sur-
stents for each patient and applied ultrasound gical protocols is apparent in the literature. More
via the stents to one side after tooth extraction in studies lie ahead to be conducted, and the effec-
a split-mouth manner. The intensity of the ultra- tiveness of ultrasound therapy in this area should
sound output was 30 mW/cm2. The pulse status be clearer in the coming years. A list of previous
of the ultrasound transmission, however, was animal and clinical studies involving the max-
not specified in the article. Although the absolute illofacial bones is given in Table 1.
dimension of bone volume was not affected by
the ultrasound therapy, some increase in buccal Complications and Side Effects
height was found at the bone crest level and 3
mm apical to the crest level. Ikai et al72 studied Ultrasound treatment for bone healing gener-
periodontal wound healing and bone repair after ates low-intensity energy, which is comparable
LIPU treatment. They created bone defects to diagnostic ultrasound doses. Pulsed signals
intraorally at the root level of premolar teeth in 4 and low energy minimize the thermal effects of
beagles bilaterally. They applied LIPU to one side ultrasound on biological tissues. No serious
and evaluated the bone healing using histologic complications have been reported regarding the
analysis and immunohistochemical studies. clinical use of therapeutic ultrasound. Reported
adverse effects due to ultrasound treatment been shown that ultrasound signals do not inter-
include muscle spasms on the treatment side, fere with metal objects, and its use in sites with
mild erythema, and mild swelling.47 It also has implanted metal biomaterial is safe.55 One disad-
Table 1. Clinical and Animal Studies Concerning the Effects of Ultrasound Therapy on Maxillofacial Bones
Animal/Clinical Ultrasound Frequency,
Study Indication (No. of Subjects) Intensity, Treatment Time Conclusions
56 2
Cavaliere, 1957 Mandibular fracture Clinical (4) 0.7–1 MHz, 1–2 W/cm , pulsed, Increased callus tissue, less
10–15 d pain
Fedotov et al,57 Mandibular fracture Rabbits (36) 0.2–0.6 W/cm2, 5 min daily for 8 d Stimulated reparative
1986 process at fracture site
Harris,58 1992 Osteoradionecrosis of mandible Clinical (21) 3 MHz, 1 W/cm2, pulsed, 40 d Effective treatment in
48% of patients
El-Bialy et al,60 Mandibular distraction Rabbits (21) 1.5 MHz, 30 mW/cm2, pulsed, 4 wk Enhanced bone formation
2002 osteogenesis at the distraction site
El-Bialy et al,61 Effects on mandibular incisor Rabbits (15) 1.5 MHz, 30 mW/cm2, pulsed, 4 wk Enhanced mandibular
2003 teeth eruption incisor growth and
eruption
El-Bialy et al,62 Mandibular growth modifi- Rabbits (8) 1.5 MHz, 30 mW/cm2, pulsed, 4 wk Enhanced mandibular
2003 cation growth
El-Bialy et al,63 Effects on orthodontic root Clinical (12) 1.5 MHz, 30 mW/cm2, pulsed, 4 wk Decrease in root
2004 resorption resorption
Schortinghuis et al,65 Healing of mandibular defects Rats (72) 1.5 MHz, 30 mW/cm2, pulsed, 2 or No notable benefit of
2004 4 wk ultrasound treatment
Schortinghuis et al,66 Healing of mandibular defects Rats (72) 1.5 MHz, 30 mW/cm2, pulsed, 2 or No notable benefit of
2004 covered with polytetrafluoro- 4 wk ultrasound treatment
ethylene membrane
Schortinghuis et al,67 Healing of mandibular defects Rats (64) 1.5 MHz, 30 mW/cm2, pulsed, 2 or No notable benefit of
2005 covered with collagen 4 wk ultrasound treatment
membrane
Schortinghuis et al,68 Vertical distraction osteogenesis Clinical (8) 1.5 MHz, 30 mW/cm2, pulsed, No stimulation of bone
2005 of the mandible total 13 h ultrasound exposure formation at the distrac-
tion gap
El-Bialy et al,64 2006 Mandibular growth modification Baboons (14) 1.5 MHz, 30 mW/cm2, pulsed, 4 mo Enhanced mandibular
growth in growing
baboons when ultra-
sound treatment was
combined with function-
al appliances
Erdogan et al,70 2006 Mandibular fracture Rabbits (30) 1.5 MHz, 30 mW/cm2 , pulsed, 3 wk Stimulated reparative
process at fracture site
Schortinghuis et al,69 Vertical mandibular distraction Clinical (9) 1.5 MHz, 30 mW/cm2, pulsed, 46 ± No evidence of accelerat-
2008 osteogenesis 8.1 d ed callus healing by
ultrasound treatment
compared with control
group
Kerr et al,71 2008 Bone preservation at extraction Clinical (12) 30 mW/cm2 (frequency and pulse No notable effect on over-
socket status not specified), 10 sessions all bone volume; however,
over 4 wk increased buccal height
at the bony crest as well
as apical to the crest
Ikai et al,72 2008 Ossification around bony defect Beagles (4) 1.5 MHz, 30 mW/cm2, pulsed, 4 wk Accelerated periodontal
created at the mesial root of wound healing and bone
premolar tooth repair, increase in level of
expression of heat shock
protein 70
El-Bialy et al,73 2008 Mandibular distraction Rabbits (36) 1.5 MHz, 30 mW/cm2, pulsed or Increased callus healing by
osteogenesis continuous, 1–4 wk continuous mode in the
first 2 wk and by pulsed
mode in 3rd and 4th wk
the molecular effects of ultrasound treatment on 18. Kristiansen TK, Ryaby JP, McCabe J, Frey JJ, Roe LR.
Accelerated healing of distal radial fractures with the use of
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