Ultrasound in Med. & Biol., Vol. 32, No. 12, pp. 1905–1911, 2006
Copyright © 2006 World Federation for Ultrasound in Medicine & Biology
Printed in the USA. All rights reserved
0301-5629/06/$–see front matter
doi:10.1016/j.ultrasmedbio.2006.06.028
● Original Contribution
LOW-INTENSITY PULSED ULTRASOUND ACCELERATES
OSTEOGENESIS AT BONE-TENDON HEALING JUNCTION
LING QIN,* HONGBIN LU,* PIKKWAN FOK,* WINGHOI CHEUNG,* YONGPING ZHENG,†
KWONGMAN LEE,‡ and KWOKSUI LEUNG*
*Musculo-Skeletal Research Laboratory, Department of Orthopaedics and Traumatology, The Chinese University of
Hong Kong, Shatin; †Jockey Club Rehabilitation Engineering Centre, The Hong Kong Polytechnic University, Hung
Ham; and ‡Lee Hysan Clinical Research Laboratories, The Chinese University of Hong Kong, Shatin,
N.T. Hong Kong
(Received 25 January 2006, revised 31 May 2006, in final form 15 June 2006)
Abstract—This study was designed to evaluate low-intensity pulsed ultrasound (LIPUS) in acceleration of
mineralization and remodeling of the new bone formed at the healing interface of bone-tendon junction.
Thirty-two mature New Zealand white rabbits underwent partial patellectomy and direct repair of the patellar
tendon and proximal patella. Animals were then divided into LIPUS treatment group (20 min/d, 5 times/wk) and
placebo control group and were euthanized at week 8 and 16 postoperatively (n ⴝ 8, for each group and time
point). The main outcome measures included new bone size and its bone mineral density (BMD). Results showed
that the size of new bone was found to be 2.6 and 3.0 times significantly greater in the LIPUS group compared
with that of the control group at weeks 8 and 16, respectively. In addition, the LIPUS group showed significantly
higher BMD at week 8 than controls, but not at week 16. In conclusion, this was the first experimental study to
show that LIPUS was able to enhance osteogenesis at the healing bone-tendon junction, especially before the
postoperative week 8. Findings of this study formed a scientific basis for future clinical trials and establishment
of indication of LIPUS for enhancing bone-tendon junction repair. (E-mail: Lingqin@cuhk.edu.hk) © 2006
World Federation for Ultrasound in Medicine & Biology.
Key Words: Low-intensity pulsed ultrasound, Bone-tendon junction repair, Bone remodeling, Bone mineral
density, Histology.
ized partial patellectomy on patients with displaced patellar fracture and found a significant postoperative increase in length of the remaining patella evaluated using
lateral radiographs. The exact factors involved in this
process were not clear, but the process appeared to be
quantitatively different from the phenomenon of calcification or ossification within the extensor mechanism
after total patellectomy (Burton and Thomas 1972;
Wilkinson 1977). Our previous experimental study in
rabbits revealed that postoperative enlargement of the
remaining patella after partial patellectomy reported by
Saltzman et al. (1990) corresponded to the trabecular
bone outgrowth from the remaining patella radiologically and histologically (Qin et al. 1999a). The size of the
remaining patella after partial patellectomy was found to
be associated with an increased patellofemoral contact
area and a diminished patellofemoral contact pressure
(Marder et al. 1993), which may have the potential
advantage in minimizing development of postoperative
osteoarthritis (Buckwalter et al. 1994; Feller and Bartlett
INTRODUCTION
Vehicular trauma and sports injury are common causes
of injuries around the knee joint (Bennell and Brukner
1997; Hou et al. 2002; Kaye and Jick 2004). The patella
is an important functional component of the knee extensor mechanism. Therefore, the treatment options selected
for repair of the patella-patellar tendon complex may
influence the functional outcome of the knee joint
(Kaufer 1971; Scheinberg and Bucholz 1994; Sutton et
al. 1976).
In comminuted and displaced fractures of the patella, the clinical treatment can be fracture repair or
partial patellectomy (Hung et al. 1993; Saltzman et al.
1990; Scheinber and Bucholz 1994; Sutton et al. 1976).
Clinically, Saltzman et al. (1990) performed a standardAddress corresponding to: Qin Ling, PhD, Department of Orthopaedics & Traumatology, The Chinese University of Hong Kong,
Shatin, N.T., Hong Kong. Tel: (⫹85) 226-32-3071; Fax: (⫹85) 22632-4618; E-mail: Lingqin@cuhk.edu.hk
1905
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Ultrasound in Medicine and Biology
1993; Leung et al. 1999). Therefore, how to promote
bone formation and mineralization at the healing interface and to achieve greater enlargement of the remaining
patella after partial patellectomy would be of clinical
importance. One of the possible approaches is to use
biophysical intervention, such as low intensity pulsed
ultrasound (LIPUS) (Einhorn 1995; Klassen and Trousdale 1997; Leung et al. 2004b).
LIPUS is a noninvasive form of mechanical energy
transmitted transcutaneously as high-frequency acoustical pressure waves in biologic tissues, which provides a
direct mechanical stimulation on osteoblast proliferation,
endochondral ossification and mineralization reported in
many in vitro and in vivo studies (Einhorn 1995; Klassen
and Trousdale 1997; Leung et al. 2004a; Nelson et al.
2003). LIPUS is recommended for a daily application of
about 20 to 30 min for acceleration of fracture healing,
treatment of delayed or nonunion and bone lengthening
(Einhorn 1995; Klassen and Trousdale 1997; Leung et al.
2004b).
As a better bone-tendon repair with healing over
time was associated with the progressive ingrowth of
collagen fibers, mineralization and maturation of the
healing tissue at the bone-tendon reattachment experimentally (Arnoczky et al. 1988; Leung et al. 2002; Qin et
al. 1999a; Rodeo et al. 1993), we hypothesized that the
LIPUS was not only able to accelerate the growth of new
bone and increase its mineralization. This study was
designed to employ our established partial patellectomy
model in rabbits (Leung et al. 1999, 2002; Qin et al.
1999a) to confirm the above hypothesis by using quantitative radiographic imaging technique, multilayer peripheral quantitative computed tomography (pQCT) and
histology.
MATERIALS AND METHODS
Animals and surgery
Thirty-two 18-week-old skeletally mature female
New Zealand white rabbits (3.5 ⫾ 0.3 kg) were used
for partial patellectomy according to previously established experimental protocol (Feller and Bartlett 1993;
Leung et al. 1999; Qin et al. 1999a). Briefly, under
general anesthesia with sodium pentobarbital (0.8 mL/
kg–1, intravenously) (Sigma Chemical Co., St. Louis,
MO, USA) and aseptic technique, one of the knees
was shaved and approached through an anterolateral
skin incision. A caliper was used to measure the length
of the patella and then transverse osteotomy was performed between the proximal 2/3 and the distal 1/3 of
the patella, using an oscillating hand saw (Synthes,
Mathys AG, Bettlach, Switzerland). After excising the
distal patella, two 0.8 mm diameter drill holes were
made vertically along the patella. The patellar tendon
Volume 32, Number 12, 2006
Fig. 1. Rabbit under treatment with low intensity pulsed ultrasound: the ultrasound probe is placed against the anterior
surface of the healing junction of the operated knee via an
“open window” of the immobilization cast.
was then directly sutured to the proximal 2/3 of the
patella via the two drilled holes with 3/0 nonabsorbable suture (Ethicon Ltd., Edinburgh, UK) and protected with figure-of-eight tension band wire of 0.4
mm in diameter drawn around the superior pole of the
patella and the tibia tuberosity to protect the repair.
After suturing the skin, the knee was immobilized with
a long leg cast at 120° knee flexion, i.e., at a resting
position of the knee joint in rabbits (Feller and Bartlett
1993; Leung et al. 1999; Qin et al. 1999a). The immobilization lasted for three weeks and then the immobilization cast was removed for free cage activity.
All animal surgery was performed by a single surgeon
for avoiding surgical variations. Pain relief drug
(Temgesic, Reckitt & Colman Pharmaceuticals, Hull,
UK) was given subcutaneously at a dose of 0.01 mg/kg
for 3 days after the surgery. The rabbits were individually kept in metal cages in a central animal house and
supplied with standard rabbit food and water ad lib.
Animal ethical approval was obtained before experiment.
LIPUS treatment
The surgical rabbits were randomly divided into
LIPUS treatment group and placebo control group. For
the LIPUS treatment, animals were sedated with ketamine (0.25 mL/kg, intramuscularly) (Qin et al. 1997)
and LIPUS (SAFHS, Smith and Nephew, Inc., Memphis,
TN, USA) was delivered by a 2.5 cm diameter ultrasound transducer placed against the anterior surface of
the operated knee via coupling gel through a cast window (Fig. 1). The ultrasound signal composes a 200 ␮s
burst of 1.5-MHz, 1-kHz repetition rate and 30.0 ⫾ 5.0
Ultrasound enhances bone-tendon junction repair ● L. QIN et al.
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Fig. 2. The anterior-posterior digital x-ray films of patella. (a) Intact patella; (b) Proximal patella taken immediately after
partial patellectomy without any new bone formation; (c) An ultrasound treated sample taken 16 weeks after operation
with new bone formation at the healing interface of the bone-tendon reattachment; and (d) sketch of the Fig. 2c: new
bone, i.e., the region within the dotted frame, where its size is measured.
mW/cm2 spatial and temporal average incident intensity
(Einhorn 1995; Leung et al. 2004b). The LIPUS treatment started 3 d after operation, 20 min/d, up to postoperative weeks 8 and 16, when the rabbits were euthanized
for evaluation. The sample size was n ⫽ 8 for each group
at each time point. For descriptive histology on new bone
formation, one rabbit of week 8 and week 16 of both
LIPUS and control group was injected (i.m.) with sequential fluorescence labeling with calcein green (10
mg/kg) and xylenol orange (30 mg/kg) (SIGMA, Chemicals Co., St. Louis, MO, USA) in a time sequence of
four weeks and two weeks before euthanizing the animals (Parfitt 1983).
Sampling and evaluations
Animals were euthanized with an overdose of sodium pentobarbital as scheduled above. Patella-patellar
tendon complex of the operated knee was harvested for
evaluation of the size, bone mineral density (BMD) and
maturation of the new bone formed at the bone-tendon
junction healing interface.
Radiographic measurement. Anterior-posterior highresolution x-ray films of the patella-patellar tendon complex
were taken using x-ray machine (Faxitron X-ray Corp,
Wheeling, IL, USA) with an exposure time of 6 s and tube
voltage 60 kVp and an x-ray source– object distance of 40
cm. After digitizing the x-ray films into an image analysis
system (Metamorph, Universal Imaging Corp., Downington, PA, USA), new bone size, i.e., the enlarged bony part
from the proximal remaining patella, was quantified using
our previous measurement protocol by a single examiner
(Fig. 2) (Qin et al. 1999a).
BMD measurements. A multilayer high-resolution
peripheral computed tomography scanner (pQCT) (Densiscan 2000, Scanco, Bassersdorf, Switzerland) with a
spatial resolution of 0.3 mm and a CT-slice thickness of
1 mm (Qin et al. 2003; Siu et al. 2004) was used to
measure volumetric BMD of the new bone where it was
defined for measuring its size on x-ray films.
Descriptive histology. After pQCT BMD measurement, two patella-patellar tendon complexes from
each group, i.e., one with and another without florescence labeling, were prepared for undecalcified and
decalcified histology using our established protocols
(Qin et al. 1999a, 1999b). Briefly: (1) Decalcified
histology. Specimens were first fixed in 10% neutral
buffered formalin for three weeks and then decalcified
in 25% formic acid for three weeks. Specimens were
processed using a Histo-center (Histokinette 2000,
Reichert-Jung GmbH, Nussloch, Germany). After embedding in paraffin using an Embedding-center, histologic sections from the midsagittal plane of each specimen were cut at 5 ␮m using 1130/Biocut microtome
(Reichert-June GmbH, Nussloch, Germany) and
stained with hematoxylin and eosin (H&E). Maturity
of the new bone in terms of level of its collagen
alignment was observed under the polarized light. (2)
Undecalcified histology. The patella-patellar tendon
complex was embedded in methyl methacrylate without decalcification. Midsagittal sections in a thickness
of 10 ␮m were cut using saw heavy duty microtome
(Polycut & Ultramiller system, Reichert-Jung GmbH,
Nussloch, Germany). Sequentially labeled calcein
green, xylenol and orange fluorescence in the new
bone were observed under a fluorescence microscopic
system (Leica Q500MC, Leica Cambridge Ltd., Cambridge, UK) to reveal dynamic bone remodeling.
Statistical methods
Except for the descriptive histology, all the above
experimental data were analyzed statistically using
two-way ANOVA to evaluate the effect of healing
time and LIPUS intervention on new bone size and its
bone mineral density. If any significant effect was
found, post hoc Bonferroni multiple range tests were
used for statistical differences. The significant level
was set at p ⱕ 0.05. All statistical analyses were
performed with a SPSS 10.0 software program (SPSS
Inc., Chicago, IL, USA).
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Ultrasound in Medicine and Biology
Volume 32, Number 12, 2006
Fig. 3. Comparison of new bone size measured on anteriorposterior radiographs, which is formed at the healing interface
of the remaining patella after partial patellectomy. The ultrasound-treated group at both postoperative weeks 8 and 16 show
significantly higher new bone size as compared with controls
(**p ⬍ 0.01). No difference in new bone size is found between
postoperative weeks 8 and 16 in both groups. Sample size: n ⫽
8 for each group.
Fig. 4. Volumetric bone mineral density (BMD) of the new
bone formed after partial patellectomy at bone-tendon healing
interface compared between ultrasound treatment group and
control group: significant higher volumetric BMD found in
ultrasound group as compared with control group at postoperative week 8 (p ⬍ 0.01) and compared between postoperative
week 8 and 16 of the ultrasound treatment groups (p ⫽ 0.05).
Sample size: n ⫽ 8 for each group.
RESULTS
between LIPUS treated sample and control sample at
each time point. As compared with that of the control
specimen, the week-16 LIPUS-treated sample reveals
more advanced remodeling from woven bone to la-
New bone size measured on radiographs
There is a significant postoperative enlargement or
outgrowth of the new bone from the remaining proximal
patella after partial patellectomy in both LIPUS group
and control group (refer to Fig. 2). When the size of
radiographic new bone from the remaining patella is
compared between both groups, significant more new
bone is formed in LIPUS group as compared with nontreated controls both at week 8 (4.2 ⫾ 0.8 mm2 vs. 1.6 ⫾
0.7 mm2) and at week 16 (4.6 ⫾ 0.8 mm2 vs. 1.5 ⫾ 0.5
mm2) (p ⬍ 0.01). However, no difference in new bone
size is shown compared between week 8 and week 16 for
each group (Fig. 3).
BMD measured by pQCT
LIPUS treatment group shows significantly higher
volumetric BMD in the new bone at week 8 compared
with that of the control group (0.97 ⫾ 0.20 g/cm3 vs. 0.81
⫾ 0.13 g/cm3, p ⬍ 0.05), but not for week 16 (LIPUS:
0.74 ⫾ 0.26 g/cm3 vs. control: 0.87 ⫾ 0.23 g/cm3, p ⬎
0.05). The volumetric BMD of week 16 LIPUS group is,
however, found to be lower than that of the week 8
LIPUS group (p ⬍ 0.05) (Fig. 4).
Descriptive histology
H&E sections observed under both bright light
(Fig. 5a-d) and polarized microscopy (Fig. 6a-d) show
that the radiographic new bone formation from the
remaining patella after partial patellectomy (Fig. 2) is
trabecular bone, less remodeled at week 8 specimens
compared with week-16 samples and also compared
Fig. 5. Sagittal H&E stained sections of patellae after partial
patellectomy. (a) and (b) Week 8 control and ultrasound treated
sample, respectively; (c) and (d) week 16 control and ultrasound
treated sample, respectively. All samples show new bone (trabecular bone) formation from the remaining patella after partial patellectomy region within the dotted circular frame. Compared with
that of the control specimens (a, c), the ultrasound-treated weeks 8
and 16 samples (b, d) suggest more advanced remodeling from
woven bone to lamellar bone and in terms of formation of more
marrow cavity. Consistent findings are also observed for the same
sections under the polarized microscope in Fig. 6a-d-d. Objective
magnification: 1.6⫻ for all.
Ultrasound enhances bone-tendon junction repair ● L. QIN et al.
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DISCUSSION
This was the first experimental study to explore that
LIPUS was able to enhance osteogenesis in terms of size
of the new bone and acceleration of its mineralization at
the healing interface between the patellar tendon and the
remaining proximal patella after partial patellectomy.
Fig. 6. Same sagittal decalcified sections of patellae after partial
patellectomy from Fig. 5a-d, observed under polarized microscope. (a) and (b) Week 8 control and ultrasound-treated sample, respectively; (c) and (d) week 16 control and ultrasoundtreated sample, respectively. All samples show new bone (trabecular bone) formation from the remaining patella after partial
patellectomy region within the dotted circular frame in (a, b)
and the close-up of the selected region (i-IV) within their
corresponding frames. The ultrasound-treated weeks 8 and 16
samples (ii&IV) suggest more advanced remodeling from woven bone to lamellar bone, characterized with better collagen
alignment within the trabecular bone matrix. Objective
magnification: 1.6⫻ for (a-d); 10⫻ for (i-IV).
mellar bone with better collagen alignment of the
trabecular bone matrix (Fig. 6a-d) and formation of
more marrow cavities (Fig. 5a-d). Fluorescence microscopic observation reveals more xylenol orange
labeling compared with calcein green labeling in the
week 8 LIPUS-treated sample as compared with that
of the control sample (Fig. 7 ai-bii). Such difference
is, however, diminished in the week 16 samples in
both groups (Fig. 7 ciii-div).
Fig. 7. Sagittal undecalcified sections of patellae after partial
patellectomy with sequential florescence labeling. (a) Ultrasound-treated week 8 sample, with the new bone within the
dotted circular frame; (i) close-up of the new bone from (a),
showing more later-injected xylenol orange as compared with
calcein green as compared with week 8 control sample (b); (ii)
close-up of the new bone from (b); (c) ultrasound treated week
16 sample, with the new bone within the dotted circular frame;
(iii) close-up of the new bone from (c), showing dominant
earlier-injected calcein green as compared with xylenol orange;
(d) week 16 control sample, with the new bone within the
dotted circular frame; (IV) close-up the new bone from (d),
showing similar labeling pattern as week 16 ultrasound-treated
sample (c). Objective magnification: 1.6⫻ for (a-d) and
10⫻ for (i-IV).
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Ultrasound in Medicine and Biology
The weeks 8 and 16 after partial patellectomy were
the time points selected for evaluating the new bone
mass, its mineralization and remodeling in the present
experimental study. This was based on the observation
made in our previous studies, that only showed radiographically measurable new bone outgrowth formed at
the healing interface of the remaining proximal patella
after 8 weeks of operation (Leung et al. 2002; Qin et al.
1999a). As hypothesized, the digital radiographs showed
significant postoperative enlargement or outgrowth of
new bone from the remaining proximal patella after
partial patellectomy; however, it was only significant in
the early weeks, i.e., before week 8, as no further measurable effects were found when compared between
week 8 and week 16 samples in both LIPUS and control
groups. The volumetric BMD measurement revealed significantly higher BMD in the new bone at week 8 in
LIPUS group, but such difference also diminished with
healing over time when compared for week 16 samples
between both LIPUS group and control group.
Interestingly, the volumetric BMD of week 16 specimens was found to be even lower than that of the week 8
samples in LIPUS treated groups. This “inconsistent” finding between radiographic measurements and volumetric
BMD may be explained by the nature of volumetric BMD
in mg/cm3 measured by the peripheral quantitative computed tomography (pQCT), which is calculated by bone
mineral content (BMC) over the total volume of the new
bone. This provides information on degree of bone mineralization only at organ level, i.e., the BMD calculated
within its bulk bone volume, with the bone mineralized
phase, marrow spaces, osteon canals, lacunae and canaliculi, without providing the degree of BMD at matrix level
(Genant et al. 1996; Rauch and Schoenau 2001; Siu et al.
2004). In fact, histologic sections demonstrated that the new
bone remodeling of week 16 LIPUS specimen was more
advanced in terms of transformation of the woven bone into
lamellar bone. This was evidenced with better collagen
alignment and more formation of bone marrow cavities.
The latter might have resulted in a higher marrow cavity to
bone matrix ratio and so a lower pQCT BMD. Fluorescence
microscopic observation also supported this assumption
that the earlier injected xylenol organ was more visualized
as compared with the later injected calcein green in the
LIPUS treated samples. Similar characteristics of the new
bone remodeling at the healing interface between patellar
tendon and remaining patella after partial patellectomy was
also observed in our early experimental studies (Leung et al.
2002; Qin et al. 1999a; Wong et al. 2003). In addition,
LIPUS-induced enhancement of osteogenesis and bone remodeling or microarchitecture were also reported in fracture repair, bone lengthening or distraction osteogenesis in
rat and rabbit models (Eberson et al. 2003; Einhorn 1995;
Machen et al. 2002; Nelson et al. 2003).
Volume 32, Number 12, 2006
Human studies are not available to show the fine
structure of the enlarged bone from the remaining patella
after partial patellectomy. Radiographically, Saltzman et al.
(1990) performed a standardized partial patellectomy and
lateral radiographic follow-up on 11 patients and showed
that the length of the remaining patella gradually increased
by 2.4 to 2.8 cm at a 5-y follow-up. In accordance with our
previous experimental studies (Qin et al. 1999a; Siu et al.
2004), the present radiographic and histologic study also
confirmed that the new bone along the sagittal section of
healing patella after partial patellectomy was in fact the new
bone formation or “outgrowth” of the trabecular bone from
the remaining patellar after partial patellectomy. However,
the present study did not show further effects of LIPUS on
osteogenesis after 8 weeks’ treatment. This may imply the
importance of timing and duration of LIPUS treatment to be
included for design of cost-effective LIPUS intervention.
The potential explanation to be offered for this phenomenon
may be related to the decreased cellularity or decrease in
number of mechanosensors, accompanied with an increase
in bone mineralization with healing over time in the late
phase of fracture healing. Similar results were also reported
for the LIPUS used for enhancement of bone mineralization
and remodeling in the consolidation phase of the distraction
osteogenesis (Eberson et al. 2003; Einhorn 1995; Genant et
al. 1996; Machen et al. 2002; Nelson et al. 2003).
The significance of postoperative enlargement of the
remaining patella may bear special clinical significance.
The partial patellectomy shortens the extensor mechanism
and decreases patellofemoral contact areas and subsequently results in an increased contact pressure of the patellofemoral joint (Marder et al. 1993) and decreased proteoglycans contents in the cartilage matrix. The latter has been
regarded as causative factor in the development of chondromalacia and osteoarthritis (Buckwalter et al. 1994; Donohue et al. 1983; Guilak et al. 1994; Leung et al. 1999).
The theoretical advantage of more enlargement of the remaining patella or new bone formation from the proximal
patella might reverse the above adverse effects of partial
patellectomy (Guilak et al. 1994; Marder et al. 1993). As
patellofemoral symptoms are generally stress-related (Burton and Thomas 1972; Feller and Bartlett 1993; Hung et al.
1993; Matthews et al. 1977; Saltzman et al. 1990; Wilkinson 1977), such enlargement may lead to diminished symptoms and contribute to the improvement of knee function
with healing over time.
The present study did not address the underlying
molecular and cellular mechanism related to the enhanced osteogenesis and remodeling under LIPUS treatment, because all the specimens used in this study were
treated for more than 8 weeks, which might have passed
the critical period of gene expression or cellular response
for evaluations. However, previous in vitro studies
(Doan et al. 1999; Reher et al. 2002; Wang et al. 2004)
Ultrasound enhances bone-tendon junction repair ● L. QIN et al.
and experimental studies using fracture healing and bone
distraction lengthening models (Azuma et al. 2001; Eberson et al. 2003; Einhorn 1995; Machen et al. 2002)
suggested that such osteogenic effects found in this study
may share the common pathways related to inflammatory
reaction, angiogenesis, chondrogenesis and osteogenesis
under the influence of LIPUS.
In conclusion, LIPUS was able to promote bonetendon junction healing in a partial patellectomy rabbit
model by enhancing osteogenesis in terms of mass of
new bone formation, its remodeling and mineralization,
especially in the early healing period before postoperative week 8. Clinical trials are suggested, to establish the
relevant indications for patients.
Acknowledgements—This study was supported by RGC Earmarked
Grant of the Research Grants Council of Hong Kong (ref. CUHK:
4098/01 and 4155/02) and by the Animal Research Ethics Committee
of the Chinese University of Hong Kong. The authors thank Miss Hung
VWY for her assistance in bone mineral measurements and Miss Ho
NM for her assistance in animal surgery and ultrasound treatment.
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