Medical Engineering and Physics 91 (2021) 28–38

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Medical Engineering and Physics

journal homepage: www.elsevier.com/locate/medengphy

Review of physical stimulation techniques for assisting distraction

osteogenesis in maxillofacial reconstruction applications
Shahrokh Hatefi a,∗, Javad Alizargar b, Francis Le Roux c, Katayoun Hatefi d, Milad Etemadi
Sh e, Hajierah Davids f, Nan-Chen Hsieh g, Farouk Smith h, Khaled Abou-El-Hossein i
a
Precision Engineering Laboratory, Nelson Mandela University, Port Elizabeth, South Africa
b
Research Center for Healthcare Industry Innovation, National Taipei University of Nursing and Health Sciences, Taipei 112, Taiwan
c
Department of Mechatronics Engineering, Nelson Mandela University, Port Elizabeth, South Africa
d
Department of Electrical and Computer Engineering, Isfahan University of Technology, Isfahan, Iran
e
Department of Oral and Maxillofacial Surgery, Dental Implants Research Center, Dental Research Institute, School of Dentistry, Isfahan University of
Medical Sciences, Isfahan, Iran
f
Department of Physiology, Nelson Mandela University, Port Elizabeth, South Africa
g
Department of Information Management, National Taipei University of Nursing and Health Sciences, Taipei 112, Taiwan
h
Department of Mechatronics Engineering, Nelson Mandela University, Port Elizabeth, South Africa
i
Precision Engineering Laboratory, Nelson Mandela University, Port Elizabeth, South Africa

a r t i c l e i n f o a b s t r a c t

Article history: Distraction Osteogenesis (DO) is an emerging limb lengthening method for the reconstruction of the hard
Received 18 May 2020 tissue and the surrounding soft tissue, in different human body zones. DO plays an important role in
Revised 17 February 2021
treating bone defects in Maxillofacial Reconstruction Applications (MRA) due to reduced side effects and
Accepted 24 March 2021
better formed bone tissue compared to conventional reconstruction methods i.e. autologous bone graft,
and alloplast implantation. Recently, varying techniques have been evaluated to enhance the characteris-
Keywords: tics of the newly formed tissues and process parameters. Promising results have been shown in assisting
Distraction osteogenesis DO treatments while benefiting bone formation mechanisms by using physical stimulation techniques,
Physical stimulation techniques including photonic, electromagnetic, electrical, and mechanical stimulation technique. Using assisted DO
Bone healing
techniques has provided superior results in the outcome of the DO procedure compared to a standard
Maxillofacial reconstruction
DO procedure. However, DO methods, as well as assisting technologies applied during the DO procedure,
Medical devices
are still emerging. Studies and experiments on developed solutions related to this field have been limited
to animal and clinical trials. In this review paper, recent advances in physical stimulation techniques and
their effects on the outcome of the DO treatment in MRA are surveyed. By studying the effects of us-
ing assisting techniques during the DO treatment, enabling an ideal assisted DO technique in MRA can be
possible. Although mentioned techniques have shown constructive effects during the DO procedure, there
is still a need for more research and investigation to be done to fully understand the effects of assisting
techniques and advanced technologies for use in an ultimate DO procedure in MRA.
© 2021 IPEM. Published by Elsevier Ltd. All rights reserved.

1. Introduction sequently, in 1992, MacCarthy reported the first clinical case of a

Distraction Osteogenesis (DO) is a novel bone lengthening tech-
nique for the reconstruction of skeletal defects/deformities in hu-
man limbs, by using a gradual supply of tensile stress on the de-
fected bone. In 1989, Illizarov developed the DO technique. Sub-
∗
Corresponding author.
E-mail addresses: s219322546@mandela.ac.za (S. Hatefi), 8javad@ntunhs.edu.tw
(J. Alizargar), s214032507@mandela.ac.za (F. Le Roux), katayoun.hatefi@ec.iut.ac.ir
(K. Hatefi), etemadi@dnt.mui.ac.ir (M. Etemadi Sh), hajierah.davids@mandela.ac.za
(H. Davids), president@ntunhs.edu.tw (N.-C. Hsieh), farouk.smith@mandela.ac.za (F.
Smith), khaled.abou-el-hossein@mandela.ac.za (K. Abou-El-Hossein).
DO procedure on mandible [1–4]. DO is known as a technique for
the reconstruction of bone tissue without the need of bone graft.
Here, the bone tissue is generated along with the surrounding soft
tissue. In the past two decades, different studies have been con-
ducted in order to evaluate and improve the effects of applying DO
techniques as well as the quality of the newly formed bone tissue
[5–9].
In Maxillofacial Reconstruction Applications (MRA), the DO
technique has received increased attention due to the superior out-
come of the reconstruction process compared to conventional bone
reconstruction techniques, including autologous bone graft and al-

https://doi.org/10.1016/j.medengphy.2021.03.008
1350-4533/© 2021 IPEM. Published by Elsevier Ltd. All rights reserved.
S. Hatefi, J. Alizargar, F. Le Roux et al.
Fig. 1. The place of DO treatment and assisting techniques during DO in MRA.
loplast implantation [9–13]. By using the DO technique in MRA, a
treatment with high quality formed tissue in a short treatment pe-
riod with improved postoperative stability and predictable healing
can be achieved. In addition, DO could reduce the side effects of
the conventional reconstruction methods on the patient including
blood loss, scar formation, and pain. The DO method could be used
for treating various defects in the maxillofacial area including post-
traumatic injuries, congenital malformations, post-tumor-resection,
and acquired bone loss. In the cranio-maxillofacial skeleton, the
most common sites for DO are midface, cranial vault, maxilla, and
mandible [8, 9, 14–16].
The DO technique starts with osteotomy of the bone, and fix-
ing the distractor to the bone segments. After a latency phase, be-
tween 3 and 10 days, the activation phase is started while gradu-
ally moving the bone segment towards a new position and filling
the generated gap with newly formed bone tissue. After the activa-
tion period, there is a consolidation phase, in which the distractor
is left in the distraction zone while the formed tissue consolidates.
Finally, the distractor is removed through a surgical procedure [8,
12].
The application of manual DO methods, based on the princi-
ples of the Ilizarov method [1], is well established. The success of
this treatment method, as well as the high-quality newly formed
tissue in DO of the facial skeleton, have been demonstrated [9].
However, there are still limitations and complications in the appli-
cation of the DO technique in human MRA [17–19]. Different ef-
forts have been undertaken to shorten the treatment time and re-
duce complications and related physical/psychological side effects
[20]. There are different approaches that can enhance the DO pro-
cedure and improve the outcome of the treatment. Various tech-
niques have been developed and used to positively impact the DO
treatment from different perspectives.
The results of performed studies have shown that distraction
rhythm and rate, distraction accuracy, and distraction force are ma-
jor factors which influence the condition of the DO procedure and
the quality of the newly formed tissue [21]. For example, by in-
creasing the distraction accuracy and improving the smoothness
29
Medical Engineering and Physics 91 (2021) 28–38
of the applied distraction force during the activation phase, higher
distraction rates could be applied, which would result in a shorter
treatment period and higher quality of the newly formed tissue.
Recent studies [2, 4, 9, 10, 22] have revealed that by using au-
tomatic devices and applying a continuous distraction force, the
condition of DO in MRA as well as the outcome of the recon-
struction procedure could be enhanced. Automatic distractors are
emerging medical devices used for enabling a continuous, accurate,
and smooth bone distraction, while improving the working factors
during the DO procedure. Recently developed automatic continu-
ous distractors have shown promising results, and could success-
fully cover standard working parameters of the DO procedure in
clinical and animal trials [9]. However, there are limitations asso-
ciated with the developed distractors. Further research needs to be
conducted to develop an ideal solution to be used in human MRA
[9, 12, 23].
Alternatively, different techniques could be used during the
DO treatment to benefit the bone formation mechanisms and ac-
celerate bone healing. Fig. 1 illustrates the position of the DO
method and assisting techniques in MRA. Recently, different tech-
niques have been developed and used to benefit the bone forma-
tion/healing, while positively affecting physical and/or biological
characteristics of the generated bone tissue [24–29].
Chemical stimulation techniques, including mesenchymal cell
implementation, growth factors, and drug delivery techniques,
could chemically increase the activity of the bone cells and en-
hance bone formation mechanisms [29–31]. Bone Marrow-Derived
Mesenchymal Stromal Cell (BMMSC) has the potential to evolve
into active osteoblastic cells [32]. Growth factors could affect the
bone formation; recombinant human Bone Morphogenic Proteins
(BMPs) are important inductive proteins used in bone reconstruc-
tion treatments [33]. The osteoinductive growth factors are an-
other category of factors which promote bio-activity of the cells
[31]. The above-mentioned growth factors could also be used in
nano-biotechnologies and injectable delivery systems developing
customizable, localized, and release-controlled delivery materials
[34, 35].
S. Hatefi, J. Alizargar, F. Le Roux et al.
Fig. 2. The application of LLLT during mandibular DO in a dog model [20].
Physical stimulation techniques are another category of tech-
niques that could accelerate and benefit bone healing, by affect-
ing the bone formation mechanisms during the treatment [29]. The
aim of this review paper is to examine the available literature and
study advanced technologies developed and used for assisting DO
procedures in MRA. In the following sections, physical stimulation
techniques are categorized and reviewed. Subsequently, the effects
of the applying these techniques on the outcome of DO procedure
are evaluated and discussed.
2. Physical stimulation techniques for assisting DO in MRA
The application of using advanced techniques during DO treat-
ment has recently emerged. Research has been conducted in or-
der to develop and use physical stimulation techniques during DO,
while investigating their effects on bone formation mechanisms as
well as the quality of newly formed bone tissue. There are differ-
ent mechanisms that could potentially influence the DO treatment.
These mechanisms have made use of different types of energy re-
sources [29, 36].
Applying these techniques during the bone reconstruction pro-
cess using DO techniques could enhance the activity of bone cells
and promote bone formation by osteogenesis-inducing abilities.
Cell activities including migration, differentiation, proliferation, and
apoptosis are important bone healing mechanisms, in which stim-
ulation techniques could induce/accelerate these mechanisms [29].
In general, physical stimulation techniques for assisting bone heal-
ing mechanisms could be classified into four groups: photonic,
electromagnetic, electrical, and mechanical stimulation techniques.
In the following subsections, developed technologies and their
mechanisms for use during the DO treatment are introduced and
discussed.
2.1. Photonic stimulation techniques
Photonic stimulation techniques could positively affect bone
healing by producing a biochemical effect in cells that strengthens
the mitochondria. By increasing the function of the mitochondria
using photonic stimulation, a cell could synthesize more adeno-
sine triphosphate. With more energy, cells could function more ef-
ficiently, rejuvenate themselves, and repair damage [37–40].
Low-Level Laser Therapy (LLLT) is a novel photobiostimulation
technique that could enhance bone formation mechanisms and
accelerate metabolic activities during bone healing [41–43]. LLLT
could also decrease pain and bone swelling during the reconstruc-
tion procedure. The beneficial impacts of LLLT on bone forma-
tion have been revealed in different MRA, including DO, autoge-
nous bone graft, bovine bone graft, peri-implant tissue healing,
and wound healing [44–52]. The application of LLLT during DO in
30
Medical Engineering and Physics 91 (2021) 28–38
MRA, as well as the effect of applying different treatment condi-
tions on bone healing, has been under investigation in different
animal studies and clinical trials [28].
During the development of LLLT solutions for assisting DO treat-
ments, laser sources with different specifications and wavelengths
have been used. The low-power Ga-Al-As laser has shown a posi-
tive impact on bone healing whilst assisting the DO technique. In
an experimental study performed on a sheep model [53], the effect
of applying LLLT during the activation and consolidation phases of
the mandibular DO procedure was investigated. In the test groups,
a Ga-Al-As laser was used to emit onto the distraction region at
four pre-established points on the mandible. Results showed that
applying LLLT during the treatment could improve bone mineral-
ization in the newly formed tissue, with improved effects when
LLLT is applied during the consolidation phase. In another study
performed on a rabbit model [39], applying low-power Ga-Al-As
during the activation phase of the DO treatment showed improved
quality of newly formed tissue, whilst having a shorter consolida-
tion period. In addition, the results of other experimental studies
conducted on these animal models [24, 54] have shown that ap-
plying low-power Ga-Al-As laser during the consolidation period
could increase the hardness and the values of elasticity modulus
in newly formed tissue, while accelerating bone healing.
The low-power Ga-As laser also has a positive impact on bone
formation mechanisms when assisting DO. In an animal study per-
formed on a dog model [20], animals underwent mandibular DO
treatment, while low-power Ga-As laser was applied onto the dis-
traction area during the consolidation period. Fig. 2 presents the
installed DO device and the application of LLLT during the treat-
ment. The histological and bone histomorphometry results ob-
tained from this study revealed that LLLT could positively affect
bone formation quality and quantity, neoangiogenesis, and colla-
gen synthesis. Additionally, applying LLLT has more influence on
bone healing during the early stages of the consolidation period
compared to other activation time frames.
Furthermore, the results of performed clinical trials on humans
have shown the positive impact of LLLT during DO [28]. In a recent
study, a low-power Ga-As laser was applied during the consolida-
tion phase of the DO procedure for the treatment of mandibular
defects. The radiographic density on digital panoramic radiographs
was used to assess the newly formed tissue. Results showed signif-
icant improvements on bone formation quality and quantity, with
decreased relapse and morbidity in the photonic-stimulated sam-
ples [28].
LLLT could enhance vascularity, osteoblast activity, organiza-
tion of collagen fibers, formation of bone callus, production of the
bone matrix, and osteogenesis [20, 24, 39]. The biostimulatory ef-
fect of laser light could enhance the production/release of growth
factors and stimulate neoangiogenesis. LLLT could stimulate the
transformation of the mesenchymal stem cells into osteoprogeni-
S. Hatefi, J. Alizargar, F. Le Roux et al.
Table 1
Effects of photonic stimulation techniques on DO in MRA (TG: test group, CG: control group).
Ref. Year Model Method and details (performed on TG)
[53] 2007 Animal LLLT, Ga-Al-As laser at four
(sheep) pre-established points, with treatment
doses of 4 J/cm2 , and total delivered
energy of 16 J/session
[39] 2007 Animal LLLT, Ga-Al-As laser at six
(rabbit) pre-established points, with treatment
doses of 6 J/cm2 , and total delivered
energy of 36 J/session
[54] 2012 Animal LLLT, Ga-Al-As laser in a continuous
(sheep) emission mode, with total delivered
energy of 120 J/cm2
[28] 2015 Human LLLT, Ga-As laser at four
pre-established points, laser 905 nm,
dose 5 J/cm2 per spot, and total
delivered energy 20 J/session
[24] 2016 Animal LLLT, Ga-Al-As laser, 830 nm, emission
(rabbit) at 4 points, dose 5 J/cm2 per spot, and
total delivered energy 200 J/session
[20] 2018 Animal LLLT, Ga-As laser, 970 nm,
(dog) extracorporeal treatment, power
=2 W, spot size 320 nm, and total
delivered energy 840 J/session
tor cells, then into osteoblasts. LLLT can also stimulate osteoblast
differentiation and proliferation. LLLT could modulate the inflam-
matory and angiogenic genes expression and immunoexpression of
cyclooxygenase-2 (COX-2), as well as vascular endothelial growth
factor (VEGF). Applying a 830 nm laser light could increase the
expression of osteocalcin, BMP-2, BMP-9, COX-2, and runt-related
transcription factor 2 (RUNX2); applying 635 nm and 809 nm laser
lights could enhance the expression of osteocalcin, collagen type
I, and related transcription factor-2; while applying Ga-Al-As and
Nd:YAG lasers could promote the expression of VEFG. LLLT could
improve bone healing factors up to 10% and shorten the consolida-
tion phase [20, 41, 54–69].
Table 1 presents the studies using photonic stimulation tech-
niques for assisting DO in MRA, and their effects on bone healing
and the outcome of the reconstruction procedure.
2.2. Electromagnetic stimulation techniques
Applying a Magnetic Field (MF) around the reconstruction area,
could enhance bone healing by increasing metabolism and cell pro-
liferation. This technique could be applied during different recon-
struction procedures, including bone graft integration, fractures,
post-fracture non-union, and osteotomy sites. The results of ex-
perimental studies revealed that MF could benefit bone formation
mechanisms including collagen formation, proliferation and differ-
entiation of the cells, and vascularization [70–75]. In addition, re-
sults of experimental studies performed on human bone marrow
mesenchymal stem cells showed that applying a continuous/pulsed
MF could enhance the osteogenic differentiation of the cells and
affect bone healing/growth factors, including vascular endothelial
growth factor, BMP-2, collagen I, alkaline phosphatase, and osteo-
calcin [76–79].
The presence of a magnetic field around the distraction zone
could stimulate osteogenesis by producing a hall effect, where
Medical Engineering and Physics 91 (2021) 28–38
Activation period/duration Results/conclusions (TG compared to
non-stimulated CG)
Five times daily during the activation - Improved bone mineralization
phase - Generating unwanted cartilaginous tissues
Five times daily during the consolidation - Improved bone mineralization
phase - No unwanted cartilaginous tissues
One time daily during the activation - Shorter consolidation phase and shorter
phase formation of a complete inferior border
- Less intervening fibrovascular intermediate
zone in the regenerated bone tissue, advanced
trabeculation and ossification, less intervening
fibrovascular intermediate zone in formed
tissue
Continuous emission during the - Increased hardness and values of elasticity
consolidation phase modulus
- Improved bone healing
During a 24-days consolidation phase, - Higher mean bone density value
continuous contact mode, 12 sessions, - Increased quality and quantity of newly
2 min each session formed bone tissue
- Shorter consolidation
- Decreased morbidity and relapse
During the activation and consolidation - Greater newly formed bone tissue and
phases, 10 times, each time 10 s, every collagen fibers
48 h - Increased number of osteoblasts in the cell
division procedure and AgNOR per osteoblast
During a two-week consolidation phase, - Increased rate of osteoblasts proliferation
continuous emission for two minutes, five and differentiation, increased neoangiogenesis
times daily - Faster intramembranous ossification
During a four-week consolidation phase, - Higher mean bone trabecular size, bone
continuous emission for two minutes, five trabecular total area, and the bony area
times daily fraction of the regenerate
During an eight-week consolidation - LLLT during early stages of bone formation
phase, continuous emission for two has better effects
minutes, five times daily
the moving charged ions between the osteocyte membrane and
bone matrix will experience a Lorenz force in the presence of a
MF, and form a generated hall voltage. This technique could pro-
mote the cell membrane permanently, in which ions will pass
through the membranes of the cells and enhance the conductiv-
ity, while the higher current produces sequential bioeffects for en-
hancing bone formation. Applying a MF during DO could also in-
crease the calcium concentration in the newly formed bone tissue;
this will affect the activity of the intercellular enzymes, as well as
metabolism and activity of the bone cells. Another effect of ap-
plying a MF is the activation of the cyclic adenosine monophos-
phate system; inducing physiological functions and growth of the
bone cells [76–78]. In addition, MF can improve osteogenic activ-
ity of the osteoblast, and reduce the bone reabsorption capacity
[79]. However, only a limited number of studies have been con-
ducted to evaluate the application of this technique during DO in
MRA [24].
In an experimental study performed on a rabbit model [24], the
effect of applying MF during mandibular DO was evaluated. Fig. 3
presents the installed magnets in this experiment. In this study, a
5∗ 2∗ 2.5 mm ring-shaped gold-coated neodymium magnet was at-
tached to each side of the corticotomy on the rabbit’s mandible;
for forming a MF with a magnetic field intensity of 100 G. Re-
sults of this experiment showed that the presence of MF during
the DO could have constructive/destructive effects on the bone
formation. The results obtained from this study are presented in
Table 2.
In another study performed on a rat model [80], DO was used
to reconstruct a tibia bone defect. During the treatment, a pulsed
MF device was used to apply high slew rate electromagnetic sig-
nals around the distraction zone. The results of this study showed
that this technique could promote osteogenesis and angiogenesis,
which would result in a shorter consolidation period and improved
quality of newly formed bone tissue.
31
S. Hatefi, J. Alizargar, F. Le Roux et al. Medical Engineering and Physics 91 (2021) 28–38

Fig. 3. MF-assisted DO treatment on rabbit’s mandible. A Mechanical distractor is fixed to the sides of the fracture. B Small-size magnets installed next to the distractor [24].

Table 2
Effects of electromagnetic stimulation techniques on DO in MRA (TG: test group, CG: control group).

Ref. Year Model Method and details Activation Results/Conclusions

(performed on TG) period/Duration (TG compared to non-stimulated CG)
[24] 2016 Animal (rabbit) Intra-oral static magnetic field, using From osteotomy to - Decreased bone formation
5∗ 2∗ 2.5 mm ring-shaped gold-coated the end of - Greater amount of collagen fibers and
neodymium magnet attached to the treatment osteoblasts
mandible, with a magnetic field intensity - Greater blood vessel formation and
of 100 G degree of collagen fiber formation

2.3. Electrical stimulation techniques trical pulses in each session could increase the positive influence of
ESWT on bone formation mechanisms, including quality and quan-
Studies have shown that applying electrical signals to the bone tity of newly formed tissue and new vessel values in both test
cells during bone healing has a positive impact on the outcome groups.
of the bone reconstruction procedures. Extracorporeal Shock Wave Furthermore, the influence of ESWT on the pre-surgical phase
Therapy (ESWT) is an electrical stimulation technique that has of the DO procedure, before and immediately after the osteotomy,
been used for the promotion of bone healing. Experimental stud- have been investigated on a rabbit model [94]. Improvements on
ies on mesenchymal stem cells and animal models showed that the volume of the connective tissue and newly formed bone tissue
electrical waves could benefit different formation mechanisms in- were observed. However, no significant improvements in the Bone
cluding osteogenesis, mineralization, proliferation, and neovascu- Mineral Density (BMD), bone mineral content, and neovasculariza-
larization of the bone cells [81–83]. ESWT could also up-regulate tion were observed.
the mRNA expression of some growth factors, including transform- Table 3 presents the performed studies using electrical stimula-
ing growth factor (TGF)-β and BMP families, as well as fibroblast tion techniques for assisting DO in MRA, and their effects on bone
growth factor (FGF)-2, alkaline phosphates, and osteocalcin (BGP) healing and the outcome of the reconstruction procedure
[84, 85].
ESWT could stimulate bone healing by increasing the level of
2.4. Mechanical stimulation techniques
Ca2+ in the newly formed bone tissue. Electrical waves could fa-
cilitate the movement of the calcium salt to the cathode site and
Mechanical stimulation is a technique in which the energy
increase the rate of extracellular calcium ion influx to cells. It can
packet affects bone formation mechanisms by using mechanical
also increase the blood circulation in the healing zone, and en-
means, such as vibration of the bone cells. There are a few tech-
hance the ossification by affecting bio-chemical changes around
niques which have been developed and used to cause vibration
the healing zone [29, 86–90]. In a DO treatment, applying electrical
during bone healing, including continuous and intermittent ultra-
waves with different working parameters and treatment methods
sound waves, tensile stress, and piezoelectric [95].
during the osteotomy, latency, activation, and consolidation phases
Low-Intensity Pulsed Ultra-Sound (LIPUS) is a well-known tech-
is possible [29, 91].
nique applied to assist with bone healing in fresh fractures and
The application of direct current electrical waves during
non-unions. In LIPUS, by applying a piezoelectric crystal within a
mandibular DO has been studied on a rabbit model [26]. Fig. 4
transducer on the target tissue, acoustic energy is generated at a
illustrates the condition of this experiment; a direct-current elec-
high frequency. LIPUS could induce blood flow, angiogenesis, and
trical stimulator device was installed on the rabbit’s mandible and
signal transduction within the cell including biochemical pathways.
two screws were used as electrodes. Low-current electrical waves
This technique could promote protein synthesis, calcium uptake,
were applied to the distraction zone after osteotomy. Histological
and osteogenic gene expression with minimal thermal effects [96–
results showed that applying low levels of electrical waves with di-
102]. It can also increase endochondral ossification, stability of the
rect currents could promote bone formation and shorten the treat-
healing fracture, level of alkaline phosphate and osteogenic differ-
ment period.
entiation [95, 103, 104].
In other studies conducted on rat and rabbit models [92, 93],
The application of mechanical stimulation techniques during DO
the effects of applying ESWT during the DO procedure, as well
has recently been under investigation. The results of studies con-
as the influence of electrical signal parameters on the outcome of
ducted on animal models show that LIPUS could accelerate bone
the treatment, have been investigated. The results obtained from
healing and promote bone density during DO [96]. It can also re-
these experiments revealed that 14 kV pulsed ESWT had an im-
duce overall treatment time and increase the BMD of the callus in
proved effect on bone formation during consolidation phase com-
the distraction gap [105–110].
pared to 21 kV pulsed ESWT. In addition, upon applying a 14 kV
The application of different ultrasound modes during mandibu-
pulsed ESWT during the treatment, increasing the number of elec-
lar DO in different animal models have been investigated. The re-

32
S. Hatefi, J. Alizargar, F. Le Roux et al. Medical Engineering and Physics 91 (2021) 28–38

Fig. 4. Applying low-current electrical waves during DO on rabbit’s mandible [26].

Table 3
Effects of electrical stimulation techniques on DO in MRA (TG: test group, CG: control group).

Ref. Year Subject Method and details Activation Results/Conclusions

(performed on TG) period/Duration (TG compared to non-stimulated CG)
[26] 2000 Animal(rabbit) Direct current electrical signals, From distraction - Promoted bone formation and %BMD in the early
3 V voltage and 10 μA current phase, periods of 10-, retention period
20-, 30- and 60-days
continuous activation
[92] 2010 Animal TG1: Pulsed ESWT, 500 impulses Two weeks - Enhanced biomechanical strength of the formed bone
(rat) at 14 kV with 1 Hz, and postoperatively tissue, osteoblastic cell recruitment, new bone formation,
0.18 mJ/mm2 total energy flux BMD, and vascularization in both test group
density - Up-regulation of neovascularization, cell proliferation,
TG2: Pulsed ESWT, 500 impulses and osteogenic growth factor expression in both test
at 21 kV with 1 Hz, and groups
0.49 mJ/mm2 total energy flux - 14 kV is optimal dosage of ESWT compared to 21 kV to
density be used during DO
[93] 2017 Animal TG1: pulsed ESWT, On the first and fourth - Enhanced BMD, new bone formation, new fibrous
(rabbit) 2∗ 500 impulses at 14 kV, and day of consolidation tissue, and new vessel formation in both groups
0.19 mJ/mm2 total energy flux phase - Highest volume of the new vessel, lowest volume of
density connective tissue, and extended consolidation phase in
TG2: pulsed ESWT, TG1
2∗ 1000 impulses at 14 kV, and - Highest %BMD and newly formed bone tissue and
0.19 mJ/mm2 total energy flux accelerated consolidation phase
density
[94] 2019 Animal TG1: Unfocused ESWT, 500 On days 5th, 12th and - High value of connective tissue and new bone tissue in
(rabbit) impulses with 5 Hz, and 19th after osteotomy both groups
0.19 mJ/mm2 total energy flux - No significant difference in BMD and neovascularization
density between TG1 and TG2
TG2: Unfocused ESWT, 500 On days 7th,14th and - Applying ESWT before and after osteotomy has no
impulses with 5 Hz, and 21st before osteotomy significant effect on DO
0.19 mJ/mm2 total energy flux and days 5th, 12th and
density 19th after osteotomy

sults showed that both continuous and pulsed ultrasound methods
could stimulate bone healing and increase the BMD of the newly
formed tissue. Pulsed ultrasound showed better results at an early
stage of consolidation phase, and continuous ultrasound showed
better results during the last two weeks of the process. In addi-
tion, LIPUS showed an improved impact on bone healing when it
was directly applied to the distraction zone [97, 111–113]. However,
clinical trials on humans reported incompatible results compared
to animal studies [114, 115]. Fig. 5 presents the application of LIPUS
during these studies, where the patients received self-treatment LI-
PUS therapy during mandibular DO. Examination results showed
that the ultrasound therapy during DO in the human mandible did
not stimulate bone healing.
Table 4 presents the performed studies using mechanical stimu-
lation techniques for assisting DO in MRA and their effects on bone
healing and the outcome of the reconstruction procedure.
3. Physical stimulation techniques during DO in MRA:
evaluation of the effects
Physical stimulation techniques have different origins and en-
ergy resources. These techniques could assist the DO procedure by
affecting different bone formation mechanisms. The major differ-
ence between applying different types of techniques is the origin,
amount of energy, and impact level of the energy packages that are
delivered to the distraction zone. Therefore, during the DO treat-
ment, suitable techniques and characteristics should be used [57,
116].
3.1. Comparison of the effects
In a few studies, the effects of applying different physical stim-
ulation techniques on the outcome of DO treatment have been
compared [24, 117]. In the study by Freddo et al. [24], the effects of
applying MF and LLLT during mandibular DO were evaluated and
compared. Fig. 6 illustrates the bone healing results after applying
LLLT and MF techniques. This study showed a statistically signifi-
cant difference in the quantity of the formed bone tissue in the MF
group compared to the LLLT group (p=0.006). In addition, the sum
of cells with three or more argyrophilic nucleolar organizer re-
gions (AgNORs) was significantly different between the mentioned
groups (p=0.038). Table 5 presents the statistical analyses on the
obtained results. It has been revealed that LLLT could accelerate
bone healing at a faster rate than MF and control groups. LLLT has

33
S. Hatefi, J. Alizargar, F. Le Roux et al. Medical Engineering and Physics 91 (2021) 28–38

Fig. 5. LIPUS therapy during DO in human mandible (a) LIPUS device (b) Radiographic image [115].

Table 4
Effects of mechanical stimulation techniques on DO in MRA (TG: test group, CG: control group).

Ref. Year Subject Method and details Activation period/Duration Results/Conclusions

(performed on TG) (TG compared to non-stimulated CG)
[112] 2002 Animal TG1: pulsed ultrasound, with During the activation and - Enhanced bone formation and bone density
(rabbit) 200 ms pulses of 1.5 MHz at a consolidation phases, 20 min daily - High level of significance when assessed by the increase in
1.1 kHz pulsing frequency, and new bone photodensity, mechanical stiffness, vibratory,
output power of 30 mW/cm2 , coherence, and qualitative histological
applied to both sides of the
mandible
TG2: pulsed ultrasound, with During the activation and
200 ms pulses of 1.5 MHz at a consolidation phases, 20 min daily
1.1 kHz pulsing frequency, and
output power of 30 mW/cm2 ,
applied to one side of the
mandible
[115] 2005 Human Low intensity pulsed During the consolidation phase, LIPUS signals do not stimulate bone formation in the severely
ultrasound 20 min daily resorbed vertical distracted mandible
[114] 2008 Human Low intensity pulsed During the activation and LIPUS signals do not stimulate bone formation in the severely
ultrasound consolidation phases, 20 min daily resorbed vertical distracted mandible
[97] 2008 Animal TG1: Continuous ultrasound, During the consolidation phase, - Better formed bone tissue and higher BMD in both test
(rabbit) with frequency of 1.5 MHz 20 min daily groups
and output power of - Highest bone formation in the 3rd and 4th weeks in TG1
30 mW/cm2 - Highest bone formation in 1st and 2nd weeks in TG2
TG2: Pulsed ultrasound, with During the consolidation phase, - Earlier stage of bone healing is more enhanced with
200 μs pulses of 1.5 MHz at a 20 min daily continuous ultrasound
1.12 KHz pulsing frequency, - Late stage of bone healing is more enhanced with pulsed
with duty cycle of 22:4% ultrasound
[113] 2009 Animal(dog) Low intensity pulsed During the activation period, - Thicker and numerous trabeculae
ultrasound, with 200 μs pulses 10 min, twice daily - Increased BMD
of 1.5 MHz at a 1 KHz pulsing - Accelerated bone formation
frequency, and output power - No effect on the volume of new bone
of 40 mW/cm2
[111] 2011 Animal(rabbit) Low intensity pulsed During the activation and - Higher radiopacity, microhardness, and newly formed bone
ultrasound, with frequency of consolidation phases, 20 min daily tissue at 2nd week
1.5 MHz and output power of - No statistical difference between TG and CG at 4th week
30 mW/cm2 - Accelerated bone formation during the early stage of DO

Table 5
The average percentages of the bone regeneration factors obtained after assisted-DO treatment [24].

Group Newly formed bone area (H&E) Picrosirius collagen fibers AgNORs > 3 Average AgNORs per Cell
Control 55.06% 49.64% 29.33% 2.00
DO + MF 38.76% 60.37% 26.16% 2.06
DO + LLLT 64.74% 55.35% 32.23% 2.28

shown a positive impact on bone cell organelles in the maturation
phase, while promoting cell division and increasing the collagen
secreted by osteoblasts. In the MF group, limited bone tissue was
formed, and the presence of 100-Gausee MF did not influence os-
teoblast activity. However, in the MF group, a greater number of
blood vessels were formed, and a substantial amount of collagen
fibers and osteoblasts within the area of trabecular bone and in
the interstitial tissue were observed.
In another experimental study [117], the effects of applying LLLT
and LIPUS on the BMD of the newly formed tissue during DO were
evaluated and compared. This study showed increased BMD when
both methods were assisting the DO process. In the LIPUS group,
the mean BMD values increased from the baseline value for the
first 30 days, and continued to increase from day 30 to day 60. The
LLLT group indicated a decrease in the mean BMD values within
the first 30 days, but showed a significant increase from day 30 to
day 60. Both treatments groups showed significantly higher mean
BMD values than the control group throughout the process, except
at day 60 where LLLT showed the highest mean BMD value and
the LIPUS group showed only a slightly higher value than the con-

34
S. Hatefi, J. Alizargar, F. Le Roux et al.
Fig. 6. A: The formed bone tissue in the laser-assisted group. B: Arrangement of collagen fibers in the MF-assisted group. C: Osteoblast containing 3 AgNORs in an animal
from the LLLT group. AgNOR, argyrophilic nucleolar organizer region [24].
trol group. Results showed that LIPUS had a positive effect on the
DO procedure by stimulating healing and ossification when applied
during the early stages, which demonstrated the importance of the
timeframe of the process, to ensure that the LIPUS treatment is ap-
plied at the correct time.
3.2. Combination of stimulation techniques
By applying more than one stimulation technique during MRA,
the DO procedure is subject to the combined effects of the differ-
ent energy types and mechanisms. Therefore, by applying a com-
bined stimulation method during the treatment, various bone heal-
ing mechanisms can be positively influenced. The combined solu-
tions can accelerate the bone regeneration and optimize the out-
come of the bone healing procedure more than using a single as-
sisting solution. In addition, physical stimulation techniques could
positively influence the effect of chemical stimulation techniques,
including BMP.
Limited studies have been conducted to evaluate and compare
the effects of applying combined stimulation methods during bone
healing in MRA. The results of experimental studies revealed that
MF and ESWT are physical stimulation techniques which could im-
prove the effects of chemical stimulation techniques on bone heal-
ing. By using such combined techniques, different healing factors
including BMD, bone volume, trabecular thickness, trabecular num-
ber, and trabecular separation, could be further improved [118–
120]. Additionally, the effects of applying LLLT and LIPUS tech-
niques, alone and in combination, during bone healing, have been
evaluated [121]. The results showed that in the early stage of bone
healing, LLLT and LIPUS had similar effects on bone healing, while
accelerating osteogenesis and bone healing. However, the com-
35
Medical Engineering and Physics 91 (2021) 28–38
bined technique showed no additional positive effect during bone
healing.
The application of physical and chemical stimulation techniques
in the development of combined methods for assisting DO in MRA
is not fully understood. Further research needs to be conducted
for evaluating the effectiveness of various combined solutions for
stimulating bone healing during DO in MRA.
4. Conclusions
Physical stimulation techniques are emerging solutions for pro-
moting bone formation mechanisms, as well as accelerating bone
healing during DO in MRA. The results of experimental studies and
clinical trials have shown optimized conditions of DO treatment
and improved quality of newly formed tissue when these tech-
niques are assisting the bone reconstruction process. With regard
to recent contributions to the application of physical stimulation
techniques during DO in MRA, the following conclusions can be
drawn:
• Photonic stimulation techniques, including LLLT, are effective
solutions for promoting bone healing during the DO treatment.
The application of LLLT is painless and easy, without the need
of sedation or anesthesia. The application of LLLT during DO
could enhance bone formation mechanisms and the production
of growth factors, which would result in an accelerated consol-
idation period, as well as a harder, longer, and thicker formed
bone tissue.
• Electromagnetic stimulation techniques, including pulsed and
static MF, are effective solutions for promoting bone healing by
improving osteogenesis and bone cell activities. Electromagnetic
field is a constant, safe, and non-invasive technique, void of side
effects and infections during the treatment.
S. Hatefi, J. Alizargar, F. Le Roux et al.
• Electrical stimulation techniques, including ESWT, have shown
positive impacts on bone formation mechanisms by stimulating
bone growth, as well as inducing osteogenic differentiation of
mesenchymal stem cells. Applying a suitable dose of ESWT dur-
ing the early stages of the consolidation period could promote
bone formation mechanisms.
• Mechanical stimulation techniques, including ultrasound, ten-
sile stress, and piezoelectric, have shown positive results on
bone healing. LIPUS is a safe and non-invasive technique that
could be used during the DO treatment for promoting bone
generation mechanisms and accelerating bone healing. The ap-
plication of LIPUS during DO has less complications compared
to other techniques.
• Results of experimental studies show that applying stimulation
techniques during the consolidation phase has improved effects
compared to the application of stimulation techniques during
the latency and activation periods.
• Applying more than one stimulation technique during the DO
treatment can benefit the bone regeneration and healing mech-
anisms more than applying a single solution, while affecting
the treatment from different perspectives. In addition, physical
stimulation techniques can positively impact the application of
chemical stimulation techniques when they are applied during
the treatment simultaneously. Applying hybrid methods, based
on suitable combinations of stimulation techniques, could fur-
ther improve the quality of reconstructed tissue and accelerate
bone healing.
The application of physical stimulation techniques for assisting
DO in MRA is at initial levels of development. Various limitations
still exist in the developed techniques. Further research needs to
be conducted to completely understand the effects of these tech-
niques and to develop an ultimate solution based on the combi-
nation of suitable stimulation techniques, to be used during DO
in human MRA. Discovering the optimized working parameters,
improving the biocompatibility of intra-oral components, and de-
termination of standard activation protocols are important factors
that need to be further investigated. In MRA, an ideal DO solu-
tion would be the application of an automatic continuous distrac-
tion osteogenesis method, while a suitable combination of stimu-
lation techniques is applied to impact the bone formation during
the treatment.
Funding
No funding was received for this study.
Availability of data and materials
The research data related to this review paper are included
within the article. Readers may contact the corresponding author
for further details. All figures are reproduced with permission.
Ethical approval
Not applicable.
Declaration of Competing Interest
The authors declare that they have no competing interests.
Acknowledgments
Not applicable.
36
Medical Engineering and Physics 91 (2021) 28–38
References
[1] Ilizarov GA. The principles of the Ilizarov method. Bull Hosp Jt Dis Orthop
Inst 1987;48(1):1–11.
[2] Aykan A, et al. Mandibular distraction osteogenesis with newly designed elec-
tromechanical distractor. J Craniofac Surg 2014;25(4):1519–23.
[3] Codivilla A. The classic: on the means of lengthening, in the lower limbs, the
muscles and tissues which are shortened through deformity. Clin Orthop Re-
lat Res 2008;466(12):2903–9.
[4] Peacock ZS, et al. Automated continuous distraction osteogenesis may al-
low faster distraction rates: a preliminary study. J Oral Maxillofac Surg
2013;71(6):1073–84.
[5] Guastaldi, F.P.S., et al., Maxillofacial reconstruction: from autogenous bone
grafts to bone tissue engineering, in Advances in dental implantology using
nanomaterials and allied technology applications, R.S. Chaughule and R. Dasha-
putra, Editors. 2021, Springer International Publishing: Cham. p. 353-364.
[6] Mofid MM, et al. Craniofacial distraction osteogenesis: a review of 3278 cases.
Plast Reconstruct Surg 2001;108(5):1103–14 discussion 1115-7.
[7] Molina F. Mandibular distraction osteogenesis: a clinical experience of the
last 17 years. J Craniofac Surg 2009;20(8):1794–800.
[8] Singh M, et al. Biological basis of distraction osteogenesis–a review. J Oral
Maxillofac Surg Med Pathol 2016;28(1):1–7.
[9] Hatefi S, et al. Review of automatic continuous distraction osteogene-
sis devices for mandibular reconstruction applications. BioMed Eng OnLine
2020;19(1):1–21.
[10] Peacock ZS, et al. Bilateral continuous automated distraction osteogenesis:
proof of principle. J Craniofac Surg 2015;26(8):2320–4.
[11] Peacock ZS, et al. Skeletal and soft tissue response to automated,
continuous, curvilinear distraction osteogenesis. J Oral Maxillofac Surg
2014;72(9):1773–87.
[12] Goldwaser BR, et al. Automated continuous mandibular distraction osteogen-
esis: review of the literature. J Oral Maxillofac Surg 2012;70(2):407–16.
[13] Park J-T, et al. A piezoelectric motor-based microactuator-generated distractor
for continuous jaw bone distraction. J Craniofac Surg 2011;22(4):1486–8.
[14] Resnick CM, Padwa BL. Use of distraction osteogenesis in orthognathic
surgery. Semin Orthod 2019;25(3):205–17.
[15] Swennen G, Dempf R, Schliephake H. Cranio-facial distraction osteogenesis:
a review of the literature. Part II: experimental studies. Int J Oral Maxillofac
Surg 2002;31(2):123–35.
[16] Dasukil S, et al. Unpredicted bilateral device breakage during active phase of
mandibular distraction: a case report and literature review. J Stomatol Oral
Maxillofac Surg 2020 In Press. doi:10.1016/j.jormas.2020.08.011.
[17] Saulačić N, et al. Complications in alveolar distraction osteogenesis: a clinical
investigation. J Oral Maxillofac Surg 2007;65(2):267–74.
[18] Mazzonetto R, et al. A retrospective study of the potential complications dur-
ing alveolar distraction osteogenesis in 55 patients. Int J Oral Maxillofac Surg
2007;36(1):6–10.
[19] Uckan S, Veziroglu F, Dayangac E. Alveolar distraction osteogenesis versus
autogenous onlay bone grafting for alveolar ridge augmentation: technique,
complications, and implant survival rates. Oral Surg Oral Med Oral Pathol Oral
Radiol Endodontol 2008;106(4):511–15.
[20] Taha SK, et al. Effect of laser bio-stimulation on mandibular distraction osteo-
genesis: an experimental study. J Oral Maxillofac Surg 2018;76(11):2411–21.
[21] Farhadieh RD, et al. Effect of distraction rate on biomechanical, mineraliza-
tion, and histologic properties of an ovine mandible model. Plast Reconstruct
Surg 20 0 0;105(3):889–95.
[22] Zheng LW, Wong MC, Cheung LK. Quasi-continuous autodriven system with
multiple rates for distraction osteogenesis. Surg Innov 2011;18(2):156–9.
[23] Hatefi S, et al. Continuous distraction osteogenesis device with MAAC
controller for mandibular reconstruction applications. Biomed Eng Online
2019;18(1):43.
[24] Freddo AL, et al. Influence of a magnetic field and laser therapy on the quality
of mandibular bone during distraction osteogenesis in rabbits. J Oral Maxillo-
fac Surg 2016;74(11) p. 2287. e1-2287. e8.
[25] Shimazaki A, et al. Low-intensity pulsed ultrasound accelerates bone matura-
tion in distraction osteogenesis in rabbits. J Bone Jt Surg 20 0 0;82(7):1077–82
British volume.
[26] Hagiwara T, Bell WH. Effect of electrical stimulation on mandibular distrac-
tion osteogenesis. J Cranio-Maxillofac Surg 20 0 0;28(1):12–19.
[27] Stewart K, et al. A quantitative analysis of the effect of insulin-like growth
factor-1 infusion during mandibular distraction osteogenesis in rabbits. Br J
Plast Surg 1999;52(5):343–50.
[28] Abd-Elaal A, et al. Evaluation of the effect of low-level diode laser therapy ap-
plied during the bone consolidation period following mandibular distraction
osteogenesis in the human. Int J Oral Maxillofac Surg 2015;44(8):989–97.
[29] Shuai C, et al. Physical stimulations and their osteogenesis-inducing mecha-
nisms. Int J Bioprint 2018;4:138–58.
[30] Hu K, Olsen BR. The roles of vascular endothelial growth factor in bone repair
and regeneration. Bone 2016;91:30–8.
[31] Yang F, et al. Bone regeneration using cell-mediated responsive degrad-
able PEG-based scaffolds incorporating with rhBMP-2. Biomaterials
2013;34(5):1514–28.
[32] Kim IS, et al. Bone regeneration by transplantation of human mesenchymal
stromal cells in a rabbit mandibular distraction osteogenesis model. Tissue
Eng Part A 2013;19(1-2):66–78.
S. Hatefi, J. Alizargar, F. Le Roux et al.
[33] Kroczek A, et al. Effects of osteoinduction on bone regeneration in distraction:
results of a pilot study. J Cranio-Maxillofac Surg 2010;38(5):334–44.
[34] Kitoh H, et al. Transplantation of culture expanded bone marrow cells and
platelet rich plasma in distraction osteogenesis of the long bones. Bone
2007;40(2):522–8.
[35] Olate SM, Haidar ZS. NanoBioTechnology-guided distraction osteogenesis and
histiogenesis. J Oral Res 2017;6(6):142–4.
[36] Huang X, et al. Physical stimulations for bone and cartilage regeneration. Re-
gen Eng Transl Med 2018;4(4):216–37.
[37] Karu T. Photobiology of low-power laser effects. Health Phys
1989;56(5):691–704.
[38] Cakarer S, et al. Acceleration of consolidation period by thrombin pep-
tide 508 in tibial distraction osteogenesis in rats. Br J Oral Maxillofac Surg
2010;48(8):633–6.
[39] Miloro M, Miller JJ, Stoner JA. Low-level laser effect on mandibular distraction
osteogenesis. J Oral Maxillofac Surg 2007;65(2):168–76.
[40] Matsumoto H, et al. Pulsed electromagnetic fields promote bone formation
around dental implants inserted into the femur of rabbits. Clin Oral Implants
Res 20 0 0;11(4):354–60.
[41] Hübler R, et al. Effects of low-level laser therapy on bone formed after dis-
traction osteogenesis. Lasers Med Sci 2010;25(2):213–19.
[42] Freddo AL, et al. Effect of low-level laser therapy after implantation
of poly-L-lactic/polyglycolic acid in the femurs of rats. Lasers Med Sci
2009;24(5):721–8.
[43] Jafarpour T, Smith F. Design of multi-wavelength low-level laser therapy
device for assisting bone reconstruction applications. Majlesi J Electr Eng
2020;14(2):117–25.
[44] Gurler G, Gursoy B. Investigation of effects of low level laser therapy in dis-
traction osteogenesis. J Stomatol Oral Maxillofac Surg 2018;119(6):469–76.
[45] Liu X, et al. Effect of lower-level laser therapy on rabbit tibial fracture. Pho-
tomed Laser Surg 2007;25(6):487–94.
[46] Garcia VG, et al. Effect of LLLT on autogenous bone grafts in the repair of crit-
ical size defects in the calvaria of immunosuppressed rats. J Cranio-Maxillofac
Surg 2014;42(7):1196–202.
[47] de Oliveira Gonçalves JB, et al. Effects of low-level laser therapy on auto-
genous bone graft stabilized with a new heterologous fibrin sealant. J Pho-
tochem Photobiol B: Biol 2016;162:663–8.
[48] Bosco AF, et al. Effects of low-level laser therapy on bone healing of criti-
cal-size defects treated with bovine bone graft. J Photochem Photobiol B: Biol
2016;163:303–10.
[49] Aragão-Neto AC, et al. Combined therapy using low level laser and
chitosan-policaju hydrogel for wound healing. Int J Biol Macromol
2017;95:268–72.
[50] Massotti FP, et al. Histomorphometric assessment of the influence of
low-level laser therapy on peri-implant tissue healing in the rabbit mandible.
Photomed Laser Surg 2015;33(3):123–8.
[51] Hatefi K, et al. Design of laser-assisted automatic continuous distraction os-
teogenesis device for oral and maxillofacial reconstruction applications. Ma-
jlesi J Electr Eng 2019;13(4):135–45.
[52] Landucci A, et al. Efficacy of a single dose of low-level laser therapy in reduc-
ing pain, swelling, and trismus following third molar extraction surgery. Int J
Oral Maxillofac Surg 2016;45(3):392–8.
[53] Cerqueira A, et al. Bone tissue microscopic findings related to the use of diode
laser (830etam) in ovine mandible submitted to distraction osteogenesis. Acta
Cir Bras 2007;22(2):92–7.
[54] Freddo A-L, et al. A preliminary study of hardness and modulus of elasticity
in sheep mandibles submitted to distraction osteogenesis and low-level laser
therapy. Med Oral Patol Oral Cir Bucal 2012;17(1):e102.
[55] de Almeida AL, et al. The effect of low-level laser on bone healing in critical
size defects treated with or without autogenous bone graft: an experimental
study in rat calvaria. Clin Oral Implant Res 2014;25(10):1131–6.
[56] Shakouri SK, et al. Effect of low-level laser therapy on the fracture healing
process. Lasers in Med Sci 2010;25(1):73.
[57] Hosseinpour S, et al. Molecular impacts of photobiomodulation on bone re-
generation: a systematic review. Progr Biophys Mol Biol 2019;149:147–59.
[58] Franco RdL, et al. Human osteoblastic cell response to a Ca-and P-enriched
titanium surface obtained by anodization. J Biomed Mater Res Part A: Off
J Soc Biomater Jpn Soc Biomater Aust Soc Biomater Korean Soc Biomater
2009;88(4):841–8.
[59] Bisht D, et al. Effect of low intensity laser radiation on healing of open skin
wounds in rats. Indian J Med Res 1994;100:43–6.
[60] Rosa AL, et al. Human alveolar bone cell proliferation, expression of os-
teoblastic phenotype, and matrix mineralization on porous titanium produced
by powder metallurgy. Clin Oral Implant Res 2009;20(5):472–81.
[61] Qokakoglu S, Aydogan F, Aydm B. Low level laser therapy in orthodon-
tics/Dusuk Doz Lazcrlcrin Ortodonti Alaninda Kullanimi. Meandros Med Den-
tal J 2018;19(2):99–106.
[62] Skondra FG, et al. The effect of low-level laser therapy on bone healing af-
ter rapid maxillary expansion: a systematic review. Photomed Laser Surg
2018;36(2):61–71.
[63] Carroll JD, et al. Developments in low level light therapy (LLLT) for dentistry.
Dental Mater 2014;30(5):465–75.
[64] Khadra M, et al. Enhancement of bone formation in rat calvarial bone defects
using low-level laser therapy. Oral Surg Oral Med Oral Pathol Oral Radiol En-
dodontol 2004;97(6):693–700.
[65] Morrone G, et al. Osteochondral lesion repair of the knee in the rabbit after
37
Medical Engineering and Physics 91 (2021) 28–38
low-power diode Ga-Al-As laser biostimulation: an experimental study. Artif
Cells Blood Substit Biotechnol 20 0 0;28(4):321–36.
[66] Pinheiro ALB, et al. Bone repair following bone grafting hydroxyapatite guided
bone regeneration and infra-red laser photobiomodulation: a histological
study in a rodent model. Lasers Med Sci 2009;24(2):234–40.
[67] Pretel H, Lizarelli RF, Ramalho LT. Effect of low-level laser therapy on bone
repair: histological study in rats. Lasers Surg Med: Off J Am Soc Laser Med
Surg 2007;39(10):788–96.
[68] Tim CR, et al. Effects of low level laser therapy on inflammatory and angio-
genic gene expression during the process of bone healing: a microarray anal-
ysis. J Photochem Photobiol B: Biol 2016;154:8–15.
[69] Kreisner PE, et al. Histological evaluation of the effect of low-level laser on
distraction osteogenesis in rabbit mandibles. Med Oral Patol Oral Cir Bucal
2010;15(4) Valenciap. e616-e618, 2010.
[70] Fredericks DC, et al. Effects of pulsed electromagnetic field stimulation on
distraction osteogenesis in the rabbit tibial leg lengthening model. J Pediatr
Orthop 2003;23(4):478–83.
[71] Ishisaka R, et al. Effects of a magnetic fields on the various functions of sub-
cellular organelles and cells. Pathophysiology 20 0 0;7(2):149–52.
[72] Aaron RK, Ciombor DM. Therapeutic effects of electromagnetic fields in the
stimulation of connective tissue repair. J Cell Biochem 1993;52(1):42–6.
[73] Grace KL, Revell WJ, Brookes M. The effects of pulsed electromagnetism on
fresh fracture healing: osteochondral repair in the rat femoral groove. Ortho-
pedics 1998;21(3):297–302.
[74] Kesemenli CC, et al. The effects of electromagnetic field on distraction osteo-
genesis. Yonsei Med J 2003;44(3):385–91.
[75] Puricelli E, et al. Histological analysis of the effects of a static magnetic field
on bone healing process in rat femurs. Head Face Med 2006;2(1):43.
[76] Jiang P, et al. Fe3 O4 /BSA particles induce osteogenic differentiation of
mesenchymal stem cells under static magnetic field. Acta Biomater
2016;46:141–50.
[77] Poh PS, et al. Osteogenic effect and cell signaling activation of extremely
low-frequency pulsed electromagnetic fields in adipose-derived mesenchymal
stromal cells. Stem Cells Int 2018;2018.
[78] Lim K-T, et al. Evaluation of the osteogenic potential of stem cells in the pres-
ence of growth hormone under magnetic field stimulation. ACS Biomater Sci
Eng 2020;6(7):4141–54.
[79] Zhang J, et al. The effects of static magnetic fields on bone. Progr Biophys Mol
Biol 2014;114(3):146–52.
[80] Li Y, et al. A novel pulsed electromagnetic field promotes distraction osteo-
genesis via enhancing osteogenesis and angiogenesis in a rat model. J Orthop
Transl 2020;25:87–95.
[81] Wang C-J, Wang F-S, Yang KD. Biological effects of extracorporeal shock-
wave in bone healing: a study in rabbits. Arch Orthop Trauma Surg
2008;128(8):879.
[82] Chen YJ, et al. Recruitment of mesenchymal stem cells and expression of
TGF-β 1 and VEGF in the early stage of shock wave-promoted bone regen-
eration of segmental defect in rats. J Orthop Res 2004;22(3):526–34.
[83] Wang F-S, et al. Temporal and spatial expression of bone morphogenetic pro-
teins in extracorporeal shock wave-promoted healing of segmental defect.
Bone 2003;32(4):387–96.
[84] Hu W-W, et al. Electrical stimulation to promote osteogenesis using conduc-
tive polypyrrole films. Mater Sci Eng: C 2014;37:28–36.
[85] Clark CC, Wang W, Brighton CT. Up-regulation of expression of selected genes
in human bone cells with specific capacitively coupled electric fields. J Orthop
Res 2014;32(7):894–903.
[86] Supronowicz P, et al. Novel current-conducting composite substrates for ex-
posing osteoblasts to alternating current stimulation. J Biomed Mater Res:
Off J Soc Biomater Jpn Soc Biomater Aust Soc Biomater Korean Soc Biomater
2002;59(3):499–506.
[87] Hronik-Tupaj M, et al. Osteoblastic differentiation and stress response of hu-
man mesenchymal stem cells exposed to alternating current electric fields.
Biomed Eng Online 2011;10(1):9.
[88] Xu J, et al. Signal transduction in electrically stimulated articular chondro-
cytes involves translocation of extracellular calcium through voltage-gated
channels. Osteoarthr Cartil 2009;17(3):397–405.
[89] Kim IS, et al. Novel effect of biphasic electric current on in vitro osteogene-
sis and cytokine production in human mesenchymal stromal cells. Tissue Eng
Part A 2009;15(9):2411–22.
[90] Pelissier P, et al. Induced membranes secrete growth factors including vas-
cular and osteoinductive factors and could stimulate bone regeneration. J Or-
thop Res 2004;22(1):73–9.
[91] Wieland D, et al. Investigation of the inverse piezoelectric effect of trabecu-
lar bone on a micrometer length scale using synchrotron radiation. Acta Bio-
mater 2015;25:339–46.
[92] Lai J-P, et al. Extracorporeal shock wave accelerates consolidation in dis-
traction osteogenesis of the rat mandible. J Trauma Acute Care Surg
2010;69(5):1252–8.
[93] Onger M-E, et al. Is it possible to change of the duration of consolidation
period in the distraction osteogenesis with the repetition of extracorporeal
shock waves? Med Oral Patol Oral Cir Bucal 2017;22(2):e251.
[94] Senel E, et al. The assessment of new bone formation induced by unfocused
extracorporeal shock wave therapy applied on pre-surgical phase of distrac-
tion osteogenesis. Eur Oral Res 2019;53(3):125.
[95] Harrison A, et al. Mode & mechanism of low intensity pulsed ultrasound (LI-
PUS) in fracture repair. Ultrasonics 2016;70:45–52.
S. Hatefi, J. Alizargar, F. Le Roux et al.
[96] Ginini JG, et al. Low intensity pulsed ultrasound for accelerating distraction
osteogenesis: a systematic review of experimental animal studies. J Mol Clin
Med 2018;1(2):107–14.
[97] El-Bialy T, et al. Effects of ultrasound modes on mandibular osteodistraction.
J Dental Res 2008;87(10):953–7.
[98] Heckman JD, et al. Acceleration of tibial fracture-healing by non-invasive,
low-intensity pulsed ultrasound. JBJS 1994;76(1):26–34.
[99] Kristiansen TK, et al. Accelerated healing of distal radial fractures with the
use of specific, low-intensity ultrasound. A multicenter, prospective, random-
ized, double-blind, placebo-controlled study. JBJS 1997;79(7):961–73.
[100] Nolte PA, et al. Low-intensity pulsed ultrasound in the treatment of
nonunions. J Trauma Acute Care Surg 2001;51(4):693–703.
[101] Gebauer D, et al. Low-intensity pulsed ultrasound: effects on nonunions. Ul-
trasound Med Biol 2005;31(10):1391–402.
[102] Roussignol X, et al. Indications and results for the ExogenTM ultrasound sys-
tem in the management of non-union: a 59-case pilot study. Orthop Trauma-
tol: Surg Res 2012;98(2):206–13.
[103] Leung K, et al. Low intensity pulsed ultrasound stimulates osteogenic activity
of human periosteal cells. Clin Orthop Relat Res® 2004;418:253–9.
[104] Hasegawa T, et al. Osteogenic activity of human fracture haematoma-derived
progenitor cells is stimulated by low-intensity pulsed ultrasound in vitro. J
Bone Jt Surg 2009;91(2):264–70 British volume.
[105] Raza H, et al. Effect of low-intensity pulsed ultrasound on distraction osteo-
genesis treatment time: a meta-analysis of randomized clinical trials. J Ultra-
sound Med 2016;35(2):349–58.
[106] El-Mowafi H, Mohsen M. The effect of low-intensity pulsed ultra-
sound on callus maturation in tibial distraction osteogenesis. Int Orthop
2005;29(2):121–4.
[107] Tsumaki N, et al. Low-intensity pulsed ultrasound accelerates maturation of
callus in patients treated with opening-wedge high tibial osteotomy by hem-
icallotasis. JBJS 2004;86(11):2399–405.
[108] Dudda M, et al. Low-intensity pulsed ultrasound as a useful adjuvant during
distraction osteogenesis: a prospective, randomized controlled trial. J Trauma
Acute Care Surg 2011;71(5):1376–80.
[109] Salem KH, Schmelz A. Low-intensity pulsed ultrasound shortens the treat-
ment time in tibial distraction osteogenesis. Int Orthop 2014;38(7):1477–82.
38
Medical Engineering and Physics 91 (2021) 28–38
[110] Lou S, et al. Effect of low-intensity pulsed ultrasound on distraction osteoge-
nesis: a systematic review and meta-analysis of randomized controlled trials.
J Orthop Surg Res 2018;13(1):205.
[111] Xie L, et al. A preliminary study of the effect of low intensity pulsed ultra-
sound on new bone formation during mandibular distraction osteogenesis in
rabbits. Int J Oral Maxillofac Surg 2011;40(7):730–6.
[112] El-Bialy TH, et al. The effect of pulsed ultrasound on mandibular distraction.
Ann Biomed Eng 2002;30(10):1251–61.
[113] Ding Y, et al. Effect of low-intensity pulsed ultrasound on bone formation
during mandible distraction osteogenesis in a canine model—a preliminary
study. J Oral Maxillofac Surg 2009;67(11):2431–9.
[114] Schortinghuis J, et al. The effect of ultrasound on osteogenesis in the verti-
cally distracted edentulous mandible. A double-blind trial. Int J Oral Maxillo-
fac Surg 2008;37(11):1014–21.
[115] Schortinghuis J, et al. Ultrasound to stimulate early bone formation in a dis-
traction gap: a double blind randomised clinical pilot trial in the edentulous
mandible. Arch Oral Biol 2005;50(4):411–20.
[116] dos Santos Santinoni C, et al. Influence of low-level laser therapy on the heal-
ing of human bone maxillofacial defects: a systematic review. J Photochem
Photobiol B: Biol 2017;169:83–9.
[117] Kocyigit ID, et al. A comparison of the low-level laser versus low inten-
sity pulsed ultrasound on new bone formed through distraction osteogenesis.
Photomed Laser Surg 2012;30(8):438–43.
[118] Yang HJ, Kim RY, Hwang SJ. Pulsed electromagnetic fields enhance bone
morphogenetic protein-2 dependent-bone regeneration. Tissue Eng Part A
2015;21(19-20):2629–37.
[119] Huang H-M, et al. Effects of roughly focused extracorporeal shock waves ther-
apy on the expressions of bone morphogenetic protein-2 and osteoprotegerin
in osteoporotic fracture in rats. Chin Med J 2016;129(21):2567.
[120] Ahmed OM, et al. Quercetin and low level laser therapy promote wound
healing process in diabetic rats via structural reorganization and modu-
latory effects on inflammation and oxidative stress. Biomed Pharmacother
2018;101:58–73.
[121] Acar AH, et al. Bone regeneration by low-level laser therapy and low-in-
tensity pulsed ultrasound therapy in the rabbit calvarium. Arch Oral Biol
2016;61:60–5.