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Review Article
Shedding Light on a New Treatment for
Diabetic Wound Healing: A Review on Phototherapy
Nicolette N. Houreld
Laser Research Center, Faculty of Health Sciences, University of Johannesburg, P.O. Box 17011, Doornfontein 2028, South Africa
Correspondence should be addressed to Nicolette N. Houreld; nhoureld@uj.ac.za
Received August ; Accepted October ; Published January
Academic Editors: A. Schreiber and S. Ulisse
Copyright © Nicolette N. Houreld. is is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Impaired wound healing is a common complication associated with diabetes with complex pathophysiological underlying
mechanisms and oen necessitates amputation. With the advancement in laser technology, irradiation of these wounds with low-
intensity laser irradiation (LILI) or phototherapy, has shown a vast improvement in wound healing. At the correct laser parameters,
LILI has shown to increase migration, viability, and proliferation of diabetic cells in vitro; there is a stimulatory eect on the
mitochondria with a resulting increase in adenosine triphosphate (ATP). In addition, LILI also has an anti-inammatory and
protective eect on these cells. In light of the ever present threat of diabetic foot ulcers, infection, and amputation, new improved
therapies and the fortication of wound healing research deserves better prioritization. In this review we look at the complications
associated with diabetic wound healing and the eect of laser irradiation both in vitro and in vivo in diabetic wound healing.
1. Introduction
1.1. Diabetes and Wound Healing. Diabetes Mellitus (DM) is a
chronic metabolic disorder due to an absence of, insuciency
in, or resistance to insulin. Complications arise as a result
of elevated glucose levels and protein glycation and include
cardiovascular disease, retinopathy, nephropathy, angiopa-
thy,andneuropathy.Patientsaremorelikelytohavefoot
problemsduetobloodvesselandnervedamageandoen
suer from sensory loss. Small sores can develop on the feet
and oen go unnoticed. ese later develop into deeper ulcers
which become slow to heal, and further complications such
as infection arise which oen necessitate amputation due to
thespreadofinfectiontotheunderlyingtissueandbone.It
is estimated that –% of patients will develop foot ulcers
[,], of which % of these will require hospitalization to
treat these ulcers []. Around –% of these patients will
require lower limb amputation [] and around % of all non
traumatic amputations are as a result of DM []. To further
highlight the seriousness of diabetes associated lower-limb
amputations, the -year mortality rate following amputation
stands at –% [].
To control the development of lower-limb ulcers, patients
are required to check their feet daily, wear the correct
footwear, and regularly visit their health care provider. It
isestimatedthatmorethanmillionpeopleworldwide
suer from DM, and in , . million people died as a
result of DM []. DM and its associated complications impact
heavily on the patient, their family, health care departments,
and countries. e treatment of chronic wounds is becoming
more of a burden due to the increase in health care costs, an
aging population, and an increase in the incidence of diabetes
[].
Despite the huge amount of research into the underlying
pathogenesis of impaired diabetic wound healing, there is still
no clear answer and it appears to be a net result of micro-
and macrovascular disease [] and inadequate angiogenesis
(Figure ). Neuropathy and sensory loss have also been
recognized as a major cause of prolonged healing in diabetic
patients. In addition, advanced glycation end products also
contribute to the pathogenesis [], and hyperglycemia adds
to the oxidative stress.
ere is a decrease in wound strength, reduced angio-
genesis, and poor wound contraction [,]. In DM, there is
a disruption in clot formation and the inammatory phase
is dysregulated [,], oen with a prolonged and excessive
inammatory response. Hypoxia is associated with diabetic
wounds and further amplies the inammatory response [].
Hindawi Publishing Corporation
e Scientific World Journal
Volume 2014, Article ID 398412, 13 pages
http://dx.doi.org/10.1155/2014/398412
e Scientic World Journal
Impaired
diabetic
wound
healing
Neuropathy Ischemia Hypoxia
macrovascular disease Sensory loss
Hyperglycemia
Oxidative
stress
↑Inflammation ↓Circulation ↓Immunity
↓Angiogenesis
↑Infection
↓Fibroblast
migration
Advanced glycation
end products
Disruption in
extracellular
matrix
Micro- &
F : Some of the underlying pathogenesis of impaired diabetic wound healing.
Formation of the extracellular matrix (ECM) is a crucial
step in wound healing and provides structural integrity to
tissue. In diabetic wound healing, there is a malformation
of the ECM due to the disruption in ECM-growth factor
interactions and impaired migration and proliferation of
broblasts []. Collagen is an important component of
the ECM and is synthesized and maintained by a balance
between matrix synthesis and degradation. In DM, there is an
imbalance between matrix degrading enzymes, matrix met-
alloproteases (MMPs), their inhibitors, and tissue inhibitor
metalloproteinases (TIMPs). e loss of collagen which is
associated with diabetes can be due to decreased levels of its
synthesis, enhanced metabolism, or a combination of both
[]. Nonhealing diabetic foot wounds display elevated MMP
activity, with a - to -fold increase in MMP- and MMP-
[,]. Dysregulated cellular functions also play a part,
such as defective T cell immunity, leukocyte chemotaxis,
phagocytosis, and bactericidal capacity [].
Infection of diabetic ulcers remains a real problem. It
can become life threatening and is one of the most common
causes of lower-limb amputation and appropriate treatment
is essential [].WoundsarecommonlyinfectedwithPseu-
domonas aeruginosa and Staphylococcus []. Infection can
spread from one ulcer to another as the foot has several
intercommunicating compartments, and combined with sen-
sory loss patients can continue walking on these infected
ulcers further facilitating their spread []. Ischemia com-
plicates matters further by reducing defense mechanisms.
Administration of antibiotics has its own complications
especially with the emergence of antibiotic resistant bacteria,
poor arterial supply which aects antibiotic delivery, correct
duration of treatment, and toxicity and allergy to patients.
1.2. Treatment of Diabetic Wounds. Management of the dia-
betic foot is multidisciplinary and can become problematic.
Treatment is both local (treating of the diabetic foot) and
systemic (glycemic control). Treatment of the diabetic foot
is extensive and can encompass mechanical and surgical
debridement, management of the wound base, antibiotic
therapy to treat infection, revascularization, prophylactic foot
surgery, mechanical o-loading, accommodative orthotics,
andanalterationoffootwear[,]. Hyperbaric oxygen
therapy (HBOT), which entails delivering % oxygen at
pressures above one atmosphere, increases the amount of
oxygen dissolved in the blood and has been used to treat a
variety of wounds [,]. HBOT has been used as an adjunc-
tive treatment for diabetic foot ulcers; however its evidence
of eciency is limited []. Kaya and colleagues []treated
patients with diabetic foot ulcers with HBOT. Sixty-three
percent of patients responded to treatment, while % showed
no improvement and % underwent amputations. Com-
plications associated with HBOT are not common but can
include claustrophobia, ear, sinus, or lung damage, temporary
worsening of short sightedness, and oxygen poisoning [].
A number of clinical applications have been found for
lasers in a variety of medical specialities and have been used
indentistry,dermatology,osteology,physiotherapy,acupunc-
ture, surgery, photodynamic cancer therapy, and chiropractic
and veterinary science. Lasers have also been used in the
treatment of chronic wounds, including diabetic ulcers.
2. Phototherapy
Phototherapy, also known as photobiomodulation, low-level
laser therapy (LLLT), involves the application of light (oen
e Scientic World Journal
laser light of a specic wavelength or a light emitting diode,
LED) to stimulate cellular processes.
e eects of phototherapy are chemical and not thermal.
Energy which is delivered to cells produces insignicant and
minimal temperature changes, typically in the range of .–
.∘C[]. Cellular responses are the result of changes in
photoacceptor molecules, or chromophores. Photoacceptors
take part in cellular metabolism and are not connected to a
light response, such as chlorophyll which is a photoreceptor
[]. Once the photon energy is absorbed, the photoacceptor
assumes an electronically excited state [], which in turn
stimulates cellular metabolism [,]byactivatingor
deactivating enzymes which alter other macromolecules such
asDNAandRNA[,]. e energy which is absorbed
bythephotoacceptorcanbetransferredtoothermolecules
causing chemical reactions in the surrounding tissue; this
then gives rise to observable eects at a biological level [,
]. Photon energy is absorbed by the chromophores and
there is an increase in adenosine triphosphate (ATP) [,]
and cell membrane permeability, which leads to activation
of secondary messengers which in turn activate a cascade
of intracellular signals []. ere is also an increase in
mitochondrial membrane potential and proton gradient [].
e exact mechanisms of action following laser irradi-
ation are not well understood, and a number of theories
exist, the most studied and best understood being that of
cytochrome-c oxidase (cyt 𝑎/𝑎3),theterminalenzymeinthe
eukaryotic mitochondrial respiratory chain (complex IV).
Cytochrome c oxidase facilitates the transfer of electrons to
molecular oxygen. e end product of this complex is the pro-
duction of ATP. Cytochrome c oxidase has two heme moieties
(heme 𝑎and heme 𝑎3) and two redox-active copper sites (CuA
and CuB), and these are the possible absorbing chromophores
for visible red and near infrared (NIR) light [,,]. When
photon energy is absorbed by cytochrome c oxidase, there is
achangeinthemitochondrialredoxstateand/orpumping
of protons across the inner mitochondrial membrane []
and an increase in ATP synthesis. ere is also an increase
in intracellular calcium ([Ca2+]i) which stimulates DNA and
RNA synthesis [].IthasbeenspeculatedbyKaru[]
that photoirradiation may intensify the transfer of electrons
within cytochrome c oxidase by making more electrons
available. An increase in the transfer of electrons and protons
accelerates oxidative metabolism which ultimately leads to
increased ATP []. Photoirradiation causes the reduction
or oxidation of cytochrome c oxidase and is dependent
on the initial redox status of the enzyme at the time of
irradiation []. Silveira and colleagues [,]showed
that LILI produced an increase in mitochondrial complexes
I, II, III, and IV, as well as succinate dehydrogenase. Hu
and colleagues [] also found an increase in cytochrome
c oxidase activity and concluded there was a cascade of
reactions which altered cellular homeostasis. Houreld et
al., [] showed that irradiation of isolated mitochondria
resulted in an increase in cytochrome c oxidase (complex
IV) activity. ere is also an increase in the concentration
of active mitochondria in irradiated cells. Both eects lead
to an increase in ATP. e eect of laser irradiation on
the mitochondria at a transcriptional level was also investi-
gated, and there is evidence that that there is an upregulation
of genes involved in complexes I, IV, and V [](Figure ).
Asecondpossibilityisthelocalizedtransientheating
of the photoacceptor which may cause structural changes
and trigger mechanisms such as activation or inhibition of
enzymes []. Another theory is the release of nitric oxide
(NO) from reduced cytochrome c oxidase which reverses the
signalling consequences of excessive NO binding [,,],
as NO in very low concentrations inhibits cytochrome c
oxidase by competing with oxygen [,].
2.1. In Vitro Eects of Photoirradiation. A number of studies,
on various cell types, have shown positive eects of photoir-
radiation. Studies have been conducted on stem cells [–],
keratinocytes [,], mast cells [,], broblasts [–],
smooth muscle cells [], osteoblasts [,], and schwann
cells []tonamebutafew.
Impaired diabetic wound healing has been associated
with impaired cellular function, and there is a decrease
in cellular migration, proliferation, NO synthesis, growth
factors, and collagen synthesis. ere is also an increase in
proteinases that degrade the extracellular matrix and collagen
(MMPs) and cells appear to be stuck in the inammatory
phase of wound healing. e increase in oxidative stress also
leads to increased cell death. Laser irradiation in vitro has
shown that these cells respond in a favourable fashion, even
irradiation of diabetic cells (Tab l e ). ere is an increase
in cellular migration [,], proliferation [,,–],
viability [,], collagen production [,,–], ATP
[], mitochondria concentration [], cytochrome c oxidase
activity [], NO [], growth factors [,,,], and
gene regulation []. ere is also a decrease in MMPs [],
apoptosis [,,] and proinammatory cytokines [].
Irradiation of hypoxic cells has also shown favourable
eects, with an increase in ATP and cyclic adenosine
monophosphate (cAMP) [], proliferation [,], viability
[], transforming growth factor-𝛽(TGF-𝛽) [], intra-
cellular Ca2+ [] and mitochondrial membrane potential
[], and a decrease in apoptosis and the pro-inammatory
cytokine tumour necrosis factor alpha (TNF-𝛼)[]. Irra-
diation of hypoxic/ischemic cells resulted in reduced ROS,
which results in increased angiogenesis []. Laser irradiation
restores homeostasis of injured and stressed cells, resulting in
improved repair and wound healing.
Not all studies have shown positive eects. Pereira et al.
[]andMarquesetal.[] showed that laser irradiation of
broblast cells had no eect on the synthesis of procollagen.
In fact there were ultrastructural changes to the endoplasmic
reticulum which may have resulted in a disruption in protein
synthesis []. Damante et al. [] demonstrated that irra-
diation at nm had no eect on basic broblast growth
factor (bFGF). Interestingly, irradiation of the same cells
at nm signicantly increased bFGF. Hakki and Bozkurt
[] irradiated human gingival broblasts by dierent laser
parameters and found no increase in proliferation at each of
the parameters used. However, they did nd an increase in
e Scientic World Journal
R
O
S
R
O
S
R
O
SR
O
S
cAMP
cAMP
cAMP
cAMP
Gene
transcription
Transcription
factors
ATP
ATPATP
ATP
ATP
NO
NO
NO
NO
NO
Mitochondria
Nucleus
Visible red
Laser light
↑Proliferation
↑Migration
↑Growth factors
↑ECM deposition
↓Inflammation
↓Apoptosis
iCa2+
iCa2+
iCa2+
iCa2+
F : Laser light is absorbed by chromophores in the cell, mitochondria in the case of visible red light. is leads to an increase in
adenosine triphosphate (ATP), reactive oxygen species (ROS), nitric oxide (NO), and intracellular calcium (iCa2+). ere is an activation of
transcription factors which get translocated to the nucleus and activate gene transcription. is leads to increased cell survival and wound
healing.
the transcription of various growth factors, namely, insulin-
like growth factor (IGF), vascular endothelial growth factor
(VEGF), and transforming growth factor-beta (TGF-𝛽). Irra-
diation of hypertrophic scar-derived broblasts and normal
dermal broblasts at a wavelength of nm and a uence
of . and J/cm2had an inhibitory eect []. Pereira and
colleagues [] found no benet when they irradiated human
dentalpulpstemcellsatnmusingvariousuencies(.,
., , and J/cm2). Schwartz-Filho and colleagues []
showed that irradiation at a wavelength of nm with a
density of , , or J/cm2had no eect on osteogenic cell
growth or viability.
ese adverse eects and dierence can be explained
by dierences in laser parameters. e eects of laser irra-
diation are highly dependent on the laser parameters such
as wavelength, power density, and uence. Cells respond to
LILI in a dose- and wavelength-dependent manner, and the
number of exposures as well as the time between exposures
plays an important role [,–]. Higher uencies have
a negative eect on cells, while too low uences have no
eect. e inuence of wavelength was demonstrated by
Gupta et al., [] who demonstrated that irradiation at
andnmhadapositiveeectonwoundhealing,while
awavelengthofandnmhadnoeect.iscan
be explained by the absorption spectrum of chromophores
which absorb light at dierent wavelengths.
2.2. In Vivo Eects of Photoirradiation. Alimitednumberof
clinical studies have been done on diabetic wound healing
(Table ). A reason for the small number of randomized trials
may be due to ethical issues associated with doing human
clinical trials []. A number of studies using phototherapy
in animal models have been done (Table ).
Al-Watban [] irradiated Sprague-Dawley rats (𝑛=
893) to dierent wavelengths (, , , , , nm,
and – nm LED cluster) and uencies (, , ,
and J/cm2). He showed that phototherapy at a wave-
length of nm accelerated healing and was the best
for alleviating diabetic wounds and burn healing. It was
suggested that phototherapy with nm should be given
three times a week at a uence of . J/cm2per dose
for the treatment of diabetic burn wounds or . J/cm2
e Scientic World Journal
T : Summary of in vitro and in vivo studies done on various cell types and animal models, respectively, using low level laser irradiation (LILI).
Species/cell type Study design Outcomes Author reference
In vitro studies
Diabetic wounded human
skin broblasts
Cells were irradiated at nm with J/cmand incubated for
or h. Control cells received no laser irradiation.
Irradiation resulted in increased cellular migration, viability,
proliferation, and collagen production. Ayu k et al. []
Diabetic wounded and
hypoxic human skin
broblast cells (WS)
Cells were irradiated at nm with J/cmand incubated for or
h. Control cells received no laser irradiation.
Irradiated diabetic wounded cells showed increased cellular
migration, viability, and proliferation and a decrease in apoptosis
(caspase /) and proinammatory cytokine interleukin (IL)-𝛽.
NuclearfactorkappaB(NF-𝜅B) also translocated into the nucleus.
Irradiated hypoxic cells regained their normal morphology and
showed an increase in cellular viability, proliferation, and IL- and
decreased apoptosis (caspase /) and proinammatory cytokine
tumor necrosis factor (TNF)-𝛼.NF-𝜅Balsotranslocatedintothe
nucleus.
Sekhejane et al. []
Human skin broblasts
(HSFs)
Cells were cultured in physiologic glucose (. mM/L) or high
glucose concentration (. and mM/L) and irradiated at
. nm with ., , and J/cmon consecutive days.
Densities of . and J/cmhad stimulatory eects on the viability
and proliferation rate of HSFs cultured in physiologic glucose.
Densities of ., , and J/cmhad stimulatory eects on the
proliferation rate of HSFs cultured in high glucose concentrations.
Esmaeelinejad et al.
[]
Diabetic wounded skin
broblast cells (WS)
Cells were irradiated at .nm with or J/cm.Controlcells
received no laser irradiation.
Cells irradiated at J/cmshowed increased cellular migration and
proliferation, while cells irradiated at J/cmshowed decreased
cellular migration and proliferation.
Houreld and
Abrahamse []
NIH T broblast cells
For proliferation studies, cells were grown in .% foetal bovine
serum (FBS) and irradiated at nm. Cells received two
applications ( h interval) of J/cme ach ( J/cmtotal); J/cm
and then J/cm( J/cmtotal); J/cmand then J/cm( J/cm
total). Control cells received no laser irradiation. Cells were
incubated for , , , and days. For procollagen studies, cells were
grown in .% FBS and irradiated at nm, J/cmand
incubated for days.
CellsirradiatedwithandJ/cm
showed increased cellular
proliferation. No signicant increase in procollagen was seen in
any of the irradiated cells.
Pereira et al. []
Murine broblast T
cells and primary human
keloid broblast cell
cultures
Cells were irradiated at nm for consecutive days (, , and
h) with or J. For the MTT assay (proliferation), a power
density of . W/cmwas use d, while . W/cmwas used for
viability assays (Trypan blue).
A dose of J stimulated proliferation, while J inhibited
proliferation of human keloid broblast cells. Laser irradiation is
aected by the physiological state of the cells; high-metabolic rate
and short-cell-cycle T cells were not responsive to LILI. A dose
of J reduced cell death but did not stimulate cell cycle. A dose of
J had negative eects on the cells, as it increased cell death and
inhibited cell proliferation.
Frigo et al. []
HIG- rabbit synovial
broblasts
Cells were synchronized at G by serum starvation (.% FBS for
h) and irradiated at nm with ., ., or . J/cmand
cultured for another h. Control cells received no laser
irradiation.
Cellular proliferation was signicantly stimulated at . and
. J/cm, while no eect was observed at . J/cm. e proportion
of cells at S phase in the laser irradiation group (. J/cm)was
signicantly higher; thus LILI enhances cell cycle progression and
as it promotes synovial broblast proliferation.
Taniguchi et al. []
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T : Cont i n u e d .
Species/cell type Study design Outcomes Author reference
Porcine primar y
aortic smooth muscle cells
(SMCs)
Cells were irradiated at nm with or J/cm.Cellswere
incubated for dierent time periods depending on the assay.
LILI stimulated porcine aortic SMC proliferation, increased
collagen synthesis, modulated activity and expression of matrix
metalloproteinase (MMP)-, gene expression of MMP-, and tissue
inhibitor of metalloproteinases (TIMP)-, and inhibited gene
expression of proinammatory cytokine IL-𝛽.
Gavish et al. []
Primary human gingival
broblasts (GF)
Cells were irradiated at nm with dierent settings used in
dentistry:power:W,pulseinterval:ms,pulselength:ms,
s/cm, J/cm(infected pocket setting); power: . W, pulse
interval: ms, pulse length: ms, s/cm, J/cm(Perio
pocket setting); power: . W in continuous wave, s/cm,
J/cm(biostimulation setting).
No signicant dierence in proliferation was observed in the
dierent laser applications when compared to the control group.
Signicantly increased insulin-like growth factor (IGF) and
vascular endothelial growth factor (VEGF) mRNA was observed in
all irradiated groups. A signicant increase in collagen type I
mRNA expression was noted in only the biostimulation setting.
Hakki and Bozkurt
[]
Human foreskin broblast
HS cells
Cells were grown in % FBS for h and then irradiated with a
light emitting diode (LED) array (nm) with or J. Cells were
incubated for or days. Control cells received no laser irradiation.
A dose of J induced a signicant increase in viability. Irradiation
increased the mRNA expression level of type I collagen and also
aected basic broblast growth factor (bFGF) secretion levels.
Huang et al. []
Human dermal broblasts
LED array populated with and nm LEDs. e ratios of
visible to infrared (IR) light were decreased (in the case of visible)
and increased (in the case of IR) in series of % increments from
no IR to fully IR. Cells were incubated for h.
Photomodulation with a /nm LED array in dierent ratios
has an eect on gene expression proles and is eective for altering
gene expression, collagen synthesis, and reduction of MMP-
expression.
McDaniel et al. []
Human gingival
broblasts, FMM cells
Cells were irradiated at nm with J/cmand incubated for
days. Control cells received no laser irradiation.
Irradiation produced no dierence in the amount of procollagen
between groups, and the amount of type I collagen as well as the
total protein content was signicantly smaller in control cultures.
ere were also ultrastructural changes in cytoplasmic organelles,
especially the mitochondria and rough endoplasmic reticulum.
Marques et al. []
Diabetic and ischemic
skin broblast cells (WS)
Whole cells or isolated mitochondria were irradiated at nm
with or J/cm. Control cells received no laser irradiation.
Irradiation of mitochondria with J/cmresulted in increased
adenosine triphosphate (ATP) production, a higher accumulation
of activated mitochondria in diabetic cells, an increase in complex
IV activity, and a decrease in complex III activity. ere was an
increase in complex IV activity in mitochondria and a higher
accumulation of activated mitochondria in diabetic cells irradiated
with J/cm. Irradiated ischemic cells showed no signicant
dierences compared to their nonirradiated control.
Houreld et al. []
Diabetic wounded skin
broblast cells (WS)
Cells were irradiated at nm with J/cm. Control cells received
no laser irradiation.Cells were incubated for min, , , or h.
Irradiation resulted in increased cellular proliferation ( and
h), nitric oxide ( min), and reactive oxygen species ( min)
and decreased apoptosis ( h), TNF-𝛼( and h), and IL-𝛽
( h).
Houreld et al. []
Primary human gingival
broblasts (hGF)
Cells irradiated at nm with J/cmand incubated for h. Two
study groups, namely, cells which were irradiated once (single-dose
group)andcellswhichwereirradiatedtwicewithhinterval
(double dose). Control cells received no laser irradiation.
Cells in the single-dose group showed a signicant increase in
proliferation and growth factors bFGF and IGF-, with no change
in IGF-binding protein (IGFBP). Cells in the double dose group
showed a signicant increase in proliferation and growth factors
bFGF, IGF-, and IGFBP.
Saygun et al. []
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T : Cont i n u e d .
Species/cell type Study design Outcomes Author reference
Human gingival broblast
cell line (FGH)
Cells were grown in % FBS for h and then irradiated in media
containing % FBS. Cells irradiated twice at or nm with
or J/cmwith h between irradiations.
ere was no signicant dierence in the expression of
keratinocyte growth factor (KGF), while bFGF was signicantly
increased in cells irradiated at nm (no dierence at nm).
Damante et al. []
Wounded, diabetic
wounded, and ischemic
skin broblast cells (WS)
Cells were irradiated at nm with J/cm. Control cells received
no laser irradiation. Cells were incubated for min.
Irradiation upregulated the expression of mitochondrial genes
COXB (complex IV), COXC (complex IV), and PPA (complex
V) in diabetic wounded cells and ATPB (complex V) and
ATPG (complex V) in ischemic cells. COXC (complex IV),
ATPF (complex V), NDUFA (complex I), and NDUFS
(complex I) were upregulated in wounded cells.
Masha et al. []
Isolated mouse embryonic
broblasts
Cells irradiated at nm with ., ., ., , or J/cm.
Control cells received no laser irradiation.
A dose of ., , and J/cmproduced an increase in reactive
oxygenspecies(ROS).NoincreaseinATPwasseenwith
. J/cm, a small increase was s een at . J/cmand a large
increase was seen with uencies of ., , and J/cm.Adoseof
. J/cmincreased NF-𝜅B h aer irradiation. Activation of
NF-𝜅B is mediated via ROS generation.
Chen et al. []
In vivo studies
Rat, Sprague-Dawley,
diabetic (streptozotocin
induced), and nondiabetic
Full-thickness wound (. ±mm
)oraburn(±. mm)
was made on each rat. Rats were irradiated with various
wavelengths (, , , , and , nm) and polychromatic
LED clusters (–, –, –, –, and
–nm)withadoseof,,,orJ/cm
three times per
week.
e best eects on wound and burn healing were exhibited with a
laser with a wavelength of nm. Based on the results,
phototherapy at nm, . J/cm, times/week is recommended
for diabetic burn wounds, and phototherapy at nm, . J/cm,
times/week for diabetic wounds is recommended for human
clinical trials.
Al-Watban []
Mice, diabetic
(BKS.Cg-m+/+Lepr db/J),
male and female
A full-thickness circular wound was made on the le ank in each
mouse using a sterile mm diameter skin punch, and the wound
extended down to the fascial layer over the abdominal
musculature. Wounds were irradiated at nm, with , ., ., or
. J/day. Mice were euthanized on day .
Irradiation of splintered wounds at nm with . J/day
(.–. J/cm/day) for days was shown to cause the maximal
stimulation of healing on day . Wounds healed mainly by
reepithelization and granulation tissue formation.
Chung et al. []
Rats, Wistar, diabetic
(streptozotocin induced),
and male
A×cmcutaneousapwasraisedonthedorsumofeach
animal. A plastic sheet was introduced between the ap and the
bed to impair blood supply, and the ap was then sutured. Rats
were treated transcutaneously every other day with or nm,
on contact points at the wound margin (.J/cm/point; total of
J/cm). Rats were euthanized on day .
e results suggest that the best responses of the aps were
observed on irradiated subjects, in particular those treated with
nm. ere was increased angiogenesis, reduced tissue necrosis
and inammation, and increased broblastic proliferation.
Santos et al. []
Rats, Wistar, diabetic
(streptozotocin induced),
and male
Rats were divided into groups:
control (untreated, nondiabetic); laser (laser treated, nondiabetic);
diabetic (diabetic rats, nonlaser treated); and diabetic + laser
(diabetic rats laser treated). Scars were irradiated once at nm
with J/cm, and rats were euthanized h aer irradiation.
In untreated diabetic rats there was increased MMP- and MMP-
expression compared to untreated nondiabetic rats. Irradiation of
diabetic rats signicantly reduced MMP- and MMP- expression
compared to untreated diabetic rats, and there was also increased
production of collagen.
Aparecida et al. []
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T : Cont i n u e d .
Species/cell type Study design Outcomes Author reference
Rats, Wistar, diabetic
(streptozotocin induced),
male
Full-thickness wounds were made in the hard palates using a mm
biopsy punch. Rats were divided into groups: control group
(nonirradiated) and experimental group (irradiated). Wounds
were irradiated at nm with J/cmaer surgery and on days
, , and aer surgery. Rats were euthanized on days , , and .
Irradiation resulted in decreased numbers of inammatory cells
and increased mitotic activity of broblasts, collagen synthesis, and
vascularization. Oxidative status was also signicantly decreased
on day .
Decreased inammatory cells, and oxidative stress and increased
collagen and vascularization Firat et al. []
Rat, Sprague-Dawley,
normal or diabetic
(streptozotocin induced),
male
Le and right maxillary rst molars were extracted, and extraction
sockets on the le were not irradiated, while the right ones were
irradiated at nm with . J/cm. Rats were euthanized , , ,
or days aer extraction.
Irradiation promoted new bone formation. In normal rats,
osteoblasts and osteoid tissue were observed at day , which was
earlier than in the control group, and new bone reached the top of
the extraction socket at day . In diabetic irradiated rats, less
inltration of inammatory cells and blood clots were observed at
day , and more new bone formed at days and than in the
nonirradiated diabetic group. Laser irradiation stimulated the
dierentiation of osteoblasts and increased the expression of
collagen type I and osteocalcin mRNA.
Park and Kang []
Rats, Wistar, diabetic
(streptozotocin induced)
male
Rats were divided into groups: control (normoglycemic, no
injury), diabetic (no injury), sham (Normoglycemic, sham
irradiated), diabetic sham, nondiabetic cryoinjured submitted to
LLLT, diabetic cryoinjured submitted to LLLT, and diabetic
cryoinjured nontreated. Cryoinjury was carried out on the le
posterior leg: the muscle fascia was carefully removed, and the
tibialis anterior muscle was surgically exposed and cryoinjured for
s with a cooled (in liquid nitrogen) round mm metal probe.
Aer the frozen muscle had thawed, the procedure was repeated
on the same area for another s. Surgical wounds were closed
with sutures and rats were allowed recovering. Two hours aer
injury, the muscle was irradiated at nm with J/cmto points
within the area (energy per point was . J, totalizing . J per
treatment). Irradiations were performed daily (h interval). Rats
that were euthanized on day received treatments, while rats
euthanized on day received treatments.
Diabetic animals that received LLLT exhibited morphological
aspects of skeletal muscle healing similar to those found in the
normoglycemic animals having received LLLT, with the
organization of immature bers in the collagen meshwork. e
diabetic sham irradiated group exhibited brosis. us, LLLT can
help avoid brosis and reduce muscle atrophy
Franc¸a et al. []
Double-blind, randomized,
placebo-controlled study.
Twenty patients with
chronic lower extremity
venous ulcers
Inclusion criteria included the following: ulcer in the lower
extremity, () ulcers larger than . cm, () ulcer duration >wk,
() presence of classical signs of venous insuciency such as
edema, varicosities, lipodermatosclerosis, eczema, and
elephantiasis nostra, () and () controlled systemic arterial
hypertension (diastolic arterial pressure < mm Hg). Each group
of ulcers was treated x/week. Ulcers were covered with % silver
sulfadiazine (SDZ) cream, dressed, and then bandaged. Group
received placebo phototherapy; group were irradiated at and
nm (LEDs) s per point until the entire ulcer surface was
treated with the probe; and the control group received standard
care without phototherapy. Ulcers were treated for a maximum of
days.
Laser therapy increased wound healing. At all time points, light
treated ulcers healed faster than the control group treated with
SDZ cream dressing alone, as well as the placebo treatment group.
Caetano et al. []
e Scientic World Journal
T : Cont i n u e d .
Species/cell type Study design Outcomes Author reference
Double-blind, randomized
placebo-controlled,
experimental design,
patients with chronic
diabetic leg ulcers
Inclusion criteria: () diagnosis of type II diabetes independent of
glycemic control with neuropathic or mixed (venous and arterial)
ulcers, () ulcer located on the lower extremity, () ulcer present
for a minimum of weeks during which it has been either stable or
worsening, () willingness to participate in the study and
commitment to the follow-up protocol, and () signed written
consent. Ulcers were cleaned with .% physiological saline and
dried before phototherapy was applied twice per week for a
maximum of days. Ulcers were dressed with % silver
sulfadiazine cream covered with gauze and bandaged. Ulcers in the
irradiated group were treated with and nm probes (LEDs)
s per point until the entire ulcer surface was treated.
Laser irradiation using a combination of and nm
promoted tissue granulation and rapid healing of diabetic ulcers
that failed to respond to other forms of treatment.
Minatel et al. []
Double-blind, randomized
controlled clinical trial,
patients with chronic
diabetic ulcers
Patients having a diabetic foot ulcer for a minimum of weeks
with ulcer stages I and II who were capable of giving informed
consent, understanding instructions, and cooperating with study
protocol were enrolled. Patients were divided into laser treated and
conventional therapy or conventional therapy alone (placebo
group). Ulcers were treated x/week for two successive weeks and
then every other day up to complete healing. Ulcers were treated
with a nm laser at a dose of J/cm. Patients in the placebo
treatment group received sham irradiation.
Laser irradiation increased wound healing. Four weeks aer
beginning treatment, the size of ulcers was signicantly decreased
and by weeks a greater number of patients in the irradiated
group showed complete healing than in the placebo group, and the
mean time of healing was lower.
Kaviani et al. []
e Scientic World Journal
for diabetic wounds. Chung et al. [] treated full-thickness
circular wounds ( mm) in diabetic mice (type diabetes)
with a nm laser to various uencies (– J/cm2)for
seven consecutive days. Wounds were splintered to minimize
contraction; the main process of healing would thus be
epithelization and granulation. On day mice were eutha-
nized and the wound excised. At a uence between . and
J/cm2, splinted irradiated wounds responded better and
healed quicker than nonirradiated splintered wounds. Santos
et al. [] irradiated cutaneous aps with poor circulation
in diabetic Wistar rats either with or nm (.J/cm2
per point). It was shown that angiogenesis was increased in
irradiated rats compared to control, non-irradiated rats, more
so when a wavelength of nm was used.
Irradiation of diabetic male Wistar rats reduced the
expression of MMP and accelerated collagen production [].
Firat and colleagues []irradiatedfullthicknesswounds
in diabetic male Wistar rats with a nm diode laser
( J/cm2). Histopathological analysis revealed that there
was a decrease in inammatory cells and an increase in
collagen and vascularization. Blood tests showed that there
was a decrease in oxidative stress. LILI has been found to
promote healing in both so and hard tissue. Irradiation at
nm has been shown to stimulate wound healing and
the formation of new bone []. Peplow and colleagues
[] demonstrated that the eect of irradiation is due to
cellular and biochemical changes in the wound environment,
rather than a hypoglycemic eect. One of the long-term
complications of diabetes includes musculoskeletal abnor-
malities, and it is a source of disability in these patients. Laser
irradiation ( nm, J/cm2) of cryoinjured diabetic male
Wistar rats showed improved muscle repair, with enhanced
reorganization of the myobers and the perimysium and
reduced brosis [].
Caetano et al. []conductedarandomizedplacebo-
controlled double-blind study on patients with a total
of chronic venous ulcers. Patients were divided into
three groups: in group one (placebo), ulcers were cleaned
with saline and treated with % silver sulfadiazine (SDZ)
cream and patients received a placebo phototherapy; in
group two ulcers were treated similarly and patients received
phototherapy (combined nm and nm at a uence of
J/cm
2); and in group three (controls) ulcers were treated
similarly and received no phototherapy. Patients that received
phototherapy responded to the laser treatment, and ulcers
healed signicantly faster than the control and placebo group,
particularly larger ulcers. Minatel et al. []showedthatcom-
bined irradiation with and nm promoted granulation
and healing of diabetic ulcers that failed to respond to other
forms of treatment. Kaviani et al. []performedarandom-
ized study on diabetic patients with foot ulcers that would
not respond to other treatments. Patients were divided into
two groups: group one received conventional treatment and
placebo irradiation, while group two received conventional
treatment and phototherapy ( nm, J/cm2). e size of
theulcersinthephototherapytreatedgroupwassignicantly
smaller and the average time of healing was weeks as
opposedtoweeksasobservedintheplacebogroup.
Infectionindiabeticwoundsisamajorproblem,and
eradication with antibiotics proves dicult due to decreased
blood ow. Laser irradiation has also been shown to inhibit
bacteria. Enwemeka et al. [] showed a dose-dependent
decrease in the number of methicillin-resistant Staphylo-
coccus aureus (MRSA) treated in vitro at a wavelength of
nm (blue light). Irradiation at a wavelength of nm was
suggested by Ankri and colleagues []intreatinginfected
wounds to clear the infection, followed by irradiation at
nmtospeedupthehealingprocess.isisanimportant
breakthrough as combined irradiation with visible red and
blue light can potentially be used to treat infected diabetic
ulcers.
3. Conclusion
DM is the leading cause for lower limb amputations. Current
treatments are challenging, lengthy, costly, and associated
with failure to heal and relapse. e patient’s quality of life
is aected, and a burden is placed on both patients and
caregivers. ere is a need to develop additional therapies
to treat diabetic ulcers. Due to its stimulatory eect and
no reported sideeects, laser therapy has been used to treat
chronic wounds, including diabetic ulcers. Phototherapy
has been shown to be benecial in treating diabetic ulcers
which are unresponsive to conventional treatments. is has
ledtoanimprovementinthequalityofpatient’slives.By
studying the eects of LILI in vitro, the underlying mech-
anisms are being identied. e number of clinical studies
in DM is limited, and there is methodological heterogeneity
which explains the varied results seen. Better designed, well-
controlled, randomized, and double-blind studies are needed
for this type of therapy to become accepted and used as
an adjuvant therapy for the treatment of diabetic ulcers.
Phototherapy can be an important tool in speeding up the
healing process as well as alleviating pain and inammation.
ere is also a need to inform clinicians and other health care
providers of the benecial eects of phototherapy.
Conflict of Interests
e material in this research paper neither has been published
nor is being considered elsewhere for publication.
References
[] S. P. Pendsey, “Understanding diabetic foot,” Inter national
JournalofDiabetesinDevelopingCountries,vol.,no.,pp.
–, .
[]N.Singh,D.G.Armstrong,andB.A.Lipsky,“Preventing
foot ulcers in patients with diabetes,” Journal of the American
Medical Association,vol.,no.,pp.–,.
[]A.L.Carrington,C.A.Abbott,J.Grithsetal.,“Afootcare
program for diabetic unilateral lower-limb amputees,” Diabetes
Care,vol.,no.,pp.–,.
[]A.Schindl,M.Schindl,H.Sch
¨
on,R.Knobler,L.Havelec,
and L. Schindl, “Low-intensity laser irradiation improves skin
circulation in patients with diabetic microangiopathy,” Diabetes
Care, vol. , no. , pp. –, .
e Scientic World Journal
[] G. E. Reiber, “Epidemiology of foot ulcers and amputations in
the diabetic foot,” in e Diabetic Foot,J.H.BowkerandM.A.
Pfeifer,Eds.,pp.–,Mosby,St.Louis,Mo,USA,.
[] World Health Organisation, “Diabetes, Fact sheet ,” ,
http://www.who.int/mediacentre/factsheets/fs/en/.
[] C.K.Sen,G.M.Gordillo,S.Royetal.,“Humanskinwounds:a
major and snowballing threat to public health and the economy:
perspective article,” Wound Repair and Regeneration,vol.,no.
, pp. –, .
[] M.Peppa,P.Stavroulakis,andS.A.Raptis,“Advancedglycoxi-
dation products and impaired diabetic wound healing,” Wo u nd
Repair and Regeneration,vol.,no.,pp.–,.
[] K.N.Francis-Goforth,A.H.Harken,andJ.D.Saba,“Normal-
ization of diabetic wound healing,” Surgery,vol.,no.,pp.
–, .
[] J. Chen, M. Kasper, T. Heck et al., “Tissue factor as a link
between wounding and tissue repair,” Diabetes,vol.,no.,
pp.–,.
[] S. Guo and L. A. DiPietro, “Critical review in oral biology &
medicine: factors aecting wound healing,” Journal of Dental
Research,vol.,no.,pp.–,.
[] D.O’Reilly,R.Linden,L.Fedorkoetal.,“Aprospective,double-
blind, randomized, controlled clinical trial comparing stan-
dard wound care with adjunctive hyperbaric oxygen therapy
(HBOT) to standard wound care only for the treatment of
chronic, non-healing ulcers of the lower limb in patients with
diabetes mellitus: a study protocol,” Tri als,vol.,article,
.
[] N. J. Trengove, M. C. Stacey, S. Macauley et al., “Analysis of the
acute and chronic wound environments: the role of proteases
and their inhibitors,” Wound Repair and Regeneration,vol.,no.
, pp. –, .
[] J. L. Richard, A. Sotto, and J. P. Lavigne, “New insights in
diabetic foot infection,” Wound J o ur nal of Dia b e t es,vol.,no.
, pp. –, .
[]A.M.Eskes,D.T.Ubbink,M.J.Lubbers,C.Lucas,andH.
Vermeulen, “Hyperbaric oxygen therapy: solution for dicult
to heal acute wounds? Systematic review,” Wor l d Jour n a l o f
Surgery, vol. , no. , pp. –, .
[] A. Kaya, F. Aydin, T. Altay, L. Karapinar, H. Ozturk, and C.
Karakuzu, “Can major amputation rates be decreased in dia-
betic foot ulcers with hyperbaric oxygen therapy?” Inter national
Orthopaedics,vol.,no.,pp.–,.
[] A. J. Nemeth, “Las ers and wound healing,” Dermatologic Clinics,
vol. , no. , pp. –, .
[] T. Karu, “Primary and secondary mechanisms of action of
visible to near-IR radiation on cells,” JournalofPhotochemistry
and Photobiology B,vol.,no.,pp.–,.
[] J. Tuner and L. Hode, Laser erapy. Clinical Practice and
Scientic Background,PrimaBooks,Gr
¨
angesberg, Sweden,
.
[] A. L. Barbosa Pinheiro, S. Carneiro Nascimento, A. L. De Barros
Vieira et al., “Eects of low-level laser therapy on malignant
cells: in vitro study,” Journal of Clinical Laser Medicine and
Surgery,vol.,no.,pp.–,.
[] M. Mati´
c, B. Lazeti´
c, M. Poljacki, V. Duran, and M. Ivkov-Simi´
c,
“Low level laser irradiation and its eect on repair processes in
the skin,” Medicinski Pregled,vol.,no.-,pp.–,.
[] S. Takac and S. Stojanovi´
c, “Diagnostic and biostimulating
lasers,” Medicinski Pregled,vol.,no.-,pp.–,.
[] T. I. Karu, “Primary and secondary mechanisms of the action of
monochromatic visible and near infrared radiation on cells,” in
e Science of Low-Power Laser erapy,T.I.Karu,Ed.,pp.–
, Gordon and Breach Science, Amsterdam, e Netherlands,
.
[] R. Lubart, H. Friedmann, I. Peled, and N. Grossman, “Light
eect on broblast proliferaton,” Laser erapy,vol.,no.,pp.
–, .
[] P.C.L.Silveira,L.A.D.Silva,D.B.Fraga,T.P.Freitas,E.L.
Streck, and R. Pinho, “Evaluation of mitochondrial respiratory
chain activity in muscle healing by low-level laser therapy,”
Journal of Photochemistry and Photobiology B,vol.,no.,pp.
–, .
[] D. H. Evans and H. Abrahamse, “A review of laboratory-based
methods to investigate second messengers in low-level laser
therapy (LLLT),” Medical Laser Application,vol.,no.,pp.
–, .
[] T. I. Karu, “Multiple roles of cytochrome c oxidase in mam-
malian cells under action of red and IR-A radiation,” IUBMB
Life,vol.,no.,pp.–,.
[] T.I.Karu,L.V.Pyatibrat,S.F.Kolyakov,andN.I.Afanasyeva,
“Absorptionmeasurementsofcellmonolayersrelevantto
mechanisms of laser phototherapy: reduction or oxidation
of cytochrome c oxidase under laser radiation at .nm,”
Photomedicine and Laser Surgery,vol.,no.,pp.–,
.
[]P.C.L.Silveira,E.L.Streck,andR.A.Pinho,“Evaluation
of mitochondrial respiratory chain activity in wound healing
by low-level laser therapy,” Journal of Photochemistry and
Photobiology B, vol. , no. , pp. –, .
[] W.-P. Hu, J.-J. Wang, C.-L. Yu, C.-C. E. Lan, G.-S. Chen, and H.-
S. Yu, “Helium-neon laser irradiation stimulates cell prolifera-
tion through photostimulator y eects in mitochondr ia,” Journal
of Investigative Dermatology,vol.,no.,pp.–,.
[] N. N. Houreld, R. T. Masha, and H. Abrahamse, “Low-intensity
laser irradiation at nm stimulates cytochrome c oxidase in
stressed broblast cells,” Lasers in Surgery and Medicine,vol.,
pp.–,.
[] R. T. Masha, N. N. Houreld, and H. Abrahamse, “Low-Intensity
Laser Irradiation at nm Stimulates Transcription of Genes
Involved in the Electron Transport Chain,” Photomedicine and
Laser Surgery,vol.,no.,pp.–,.
[] T. I. Karu, L. V. Pyatibrat, and N. I. Afanasyeva, “Cellular eects
of low power laser therapy can be mediated by nitric oxide,”
Lasers in Surgery and Medicine,vol.,no.,pp.–,.
[]M.G.Mason,P.Nicholls,M.T.Wilson,andC.E.Cooper,
“Nitric oxide inhibition of respiration involves both competitive
(heme) and noncompetitive (copper) binding to cytochrome c
oxidase,” Proceedings of the National Academy of Sciences of the
United States of America,vol.,no.,pp.–,.
[] J.-Y. Wu, C.-H. Chen, C.-Z. Wang, M.-L. Ho, M.-L. Yeh,
and Y. -H. Wang, “Low-power laser irradiation suppresses
inammatory response of human adipose-derived stem cells by
modulation intracellular cyclic AMP level and NF-𝜅Bactivity,”
PLoS ONE,vol.,no.,ArticleIDe,.
[]K.Choi,B.J.Kang,H.Kimetal.,“Low-levellasertherapy
promotes the osteogenic potential of adipose-derived mes-
enchymal stem cells seeded on an acellular dermal matrix,”
Journal of Biomedical Materials Research Part B,vol.,no.,
pp.–,.
[] M. Giannelli, F. Chellini, C. Sassoli et al., “Photoactivation
of bone marrow mesenchymal stromal cells with diode laser:
e Scientic World Journal
eects and mechanisms of action,” Journal of Cellular Physiol-
ogy,vol.,no.,pp.–,.
[] J. A. de Villiers, N. N. Houreld, and H. Abrahamse, “Inuence
of low intensity laser irradiation on isolated human adipose
derived stem cells over hours and their dierentiation
potential into smooth muscle cells using retinoic acid,” Stem Cell
Reviews and Reports,vol.,no.,pp.–,.
[] F.G.Basso,C.F.Oliveira,C.Kurachi,J.Hebling,andC.A.
D. S. Costa, “Biostimulatory eect of low-level laser therapy on
keratinocytes in vitro,” Lasers in Medical Science,vol.,no.,
pp. –, .
[] L.Gavish,Y.Asher,Y.Becker,andY.Kleinman,“Lowlevellaser
irradiation stimulates mitochondrial membrane potential and
disperses subnuclear promyelocytic leukemia protein,” Lasers in
Surgery and Medicine,vol.,no.,pp.–,.
[] F. F. Fathabadie, M. Bayat, A. Amini, M. Bayat, and F. Rezaie,
“Eects of pulsed infra-red low level-laser irradiation on mast
cells number and degranulation in open skin wound healing
of healthy and streptozotocin-induced diabetic rats,” Journal of
Cosmetic and Laser erapy,vol.,no.,pp.–,.
[] A. Khoshvaghti, M. Zibamanzarmofrad, and M. Bayat, “Eect
of low-level treatment withan -Hz pulsed infrared diode laser
on mast-cell numbers and degranulation in a rat model of third-
degree burn,” Photomedicine and Laser Surgery,vol.,no.,pp.
–, .
[] F. G. Basso, T. N. Pansani, A. P. Turrioni, V. S. Bagnato, J.
Hebling, and C. A. de Souza Costa, “In vitro wound healing
improvement by low-level laser therapy application in cultured
gingival broblasts,” International Journal of Dentistry,vol.,
ArticleID,pages,.
[] M. Esmaeelinejad, M. Bayat, H. Darbandi, M. Bayat, and N.
Mosaa, “e eects of low-level laser irradiation on cellular
viability and proliferation of human skin broblasts cultured in
high glucose mediums ,” Lasers in Medical Science.Inpress.
[]S.M.Ayuk,N.N.Houreld,andH.Abrahamse,“Collagen
production in diabetic wounded broblasts in response to low-
intensity laser irradiation at nm,” Diabetes Technology &
erapeutics, vol. , no. , pp. –, .
[] P. R. Sekhejane, N. N. Houreld, and H. Abrahamse, “Irradiation
at nm positively aects diabetic wounded and hypoxic cells
in vitro,” Photomedicine and Laser Surgery,vol.,no.,pp.–
, .
[] N. Houreld and H. Abrahamse, “In vitro exposure of wounded
diabetic broblast cells to a helium-neon laser at and J/cm2
,” Photomedicine and Laser Surgery,vol.,no.,pp.–,
.
[] I. L. Zungu, D. Hawkins Evans, N. Houreld, and H. Abrahamse,
“Biological responses of injured human skin broblasts toass ess
the ecacy of in vitro models for cell stress studies,” Alliance
Journal of Business Research,vol.,no.,pp.–,.
[] L. Gavish, L. Perez, and S. D. Gertz, “Low-level laser irradiation
modulates matrix metalloproteinase activity and gene expres-
sioninporcineaorticsmoothmusclecells,”Lasers in Surgery
and Medicine, vol. , no. , pp. –, .
[] S. Hamajima, K. Hiratsuka, M. Kiyama-Kishikawa et al., “Eect
of low-level laser irradiation on osteoglycin gene expression in
osteoblasts,” Lasers in Medical Science,vol.,no.,pp.–,
.
[] S.-J. Pyo, W.-W. Song, I.-R. Kim et al., “Low-level laser therapy
induces the expressions of BMP-, osteocalcin, and TGF-𝛽in
hypoxic-cultured human osteoblasts,” Lasers in Medical Science,
vol. , no. , pp. –, .
[] S. O. Yazdani, A. F. Golestaneh, A. Shaee, M. Hazi, H.-A. G.
Omrani, and M. Soleimani, “Eects of low level laser therapy
on proliferation and neurotrophic factor gene expression of
human schwann cells in vitro,” Journal of Photochemistry and
Photobiology B,vol.,no.,pp.–,.
[] N. Houreld and H. Abrahamse, “Irradiation with a . nm
helium-neon laser with J/cm2stimulates proliferation and
expression of interleukin- in diabetic wounded broblast
cells,” Diabetes Technology and erapeutics,vol.,no.,pp.
–, .
[] A. N. Pereira, C. De Paula Eduardo, E. Matson, and M. M.
Marques, “Eect of low-power laser irradiation on cell growth
and procollagen synthesis of cultured broblasts,” Lasers in
Surgery and Medicine, vol. , no. , pp. –, .
[] L. Frigo, G. M. F´
avero, H. J. Campos Lima et al., “Low-
level laser irradiation (InGaAIP- nm) increases broblast
cell proliferation and reduces cell death in a dose-dependent
manner,” Photomedicine and Laser Surgery,vol.,no.,pp.
S–S, .
[] D. Taniguchi, P. Dai, T. Hojo, Y. Yamaoka, T. Kubo, and T.
Takamatsu, “Low-energy laser irradiation promotes synovial
broblast proliferation by modulating p subcellular localiza-
tion,” Lasers in Surgery and Medicine,vol.,no.,pp.–,
.
[] S. S. Hakki and S. B. Bozkurt, “Eects of dierent setting of
diode laser on the mRNA expression of growth factors and
type I collagen of human gingival broblasts,” Lasers in Medical
Science,vol.,no.,pp.–,.
[] P.-J. Huang, Y.-C. Huang, M.-F. Su, T.-Y. Yang, J.-R. Huang, and
C.-P. Jiang, “In vitro observations on the inuence of copper
peptide aids for the LED photoirradiation of broblast collagen
synthesis,” Photomedicine and Laser Surgery,vol.,no.,pp.
–, .
[] D. H. McDaniel, R. A. Weiss, R. G. Geronemus, C. Mazur, S.
Wilson, and M. A. Weiss, “Varying ratios of wavelengths in
dual wavelength LED photomodulation alters gene expression
proles in human skin broblasts,” Lasers in Surgery and
Medicine,vol.,no.,pp.–,.
[] N. N. Houreld, P. R. Sekhejane, and H. Abrahamse, “Irradiation
at nm stimulates nitric oxide production and inhibits pro-
inammatory cytokines in diabetic wounded broblast cells,”
Lasers in Surgery and Medicine,vol.,no.,pp.–,.
[] I. Saygun, S. Karacay, M. Serdar, A. U. Ural, M. Sencimen,
and B. Kurtis, “Eects of laser irradiation on the release of
basic broblast growth factor (bFGF), insulin like growth
factor- (IGF-), and receptor of IGF- (IGFBP) from gingival
broblasts,” Lasers in Medical Science,vol.,no.,pp.–,
.
[] C. A. Damante, G. De Micheli, S. P. H. Miyagi, I. S. Feist, and
M. M. Marques, “Eect of laser phototherapy on the release of
broblast growth factors by human gingival broblasts,” Lasers
in Medical Science,vol.,no.,pp.–,.
[] A. C.-H. Chen, P. R. Arany, Y.-Y. Huang et al., “Low-Level
laser therapy activates NF-kB via generation of reactive oxygen
species in mouse embryonic broblasts,” PLoS ONE,vol.,no.
, Article ID e, .
[] I. L. Zungu, D. Hawkins Evans, and H. Abrahamse, “Mitochon-
drial responses of normal and injured human skin broblasts
following low level laser irradiation—an in vitro study,” Photo-
chemistry and Photobiology,vol.,no.,pp.–,.
[] W. B. Lim, J. S. Kim, Y. J. Ko et al., “Eects of nm light-
emitting diode irradiation on angiogenesis in CoCl2-exposed
e Scientic World Journal
HUVECs,” Lasers in Surgery and Medicine,vol.,no.,pp.
–, .
[] M. M. Marques, A. N. Pereira, N. A. Fujihara, F. N. Nogueira,
andC.P.Eduardo,“Eectoflow-powerlaserirradiation
on protein synthesis and ultrastructure of human gingival
broblasts,” Lasers in Surgery and Medicine,vol.,no.,pp.
–, .
[] C. Webb and M. Dyson, “e eect of nm low level laser
energy on human broblast cell numbers: a possible role in
hypertrophic wound healing,” Journal of Photochemistry and
Photobiology B,vol.,no.,pp.–,.
[] L. O. Pereira, J. P. F. Longo, and R. B. Azevedo, “Laser irradiation
did not increase the proliferation or the dierentiation of stem
cells from normal and inamed dental pulp,” Archives of Oral
Biology,vol.,no.,pp.–,.
[] H. O. Schwartz-Filho, A. C. Reimer, C. Marcantonio, E. Mar-
cantonioJr.,andR.A.C.Marcantonio,“Eectsoflow-levellaser
therapy ( nm) at dierent doses in osteogenic cell cultures,”
Lasers in Medical Science,vol.,no.,pp.–,.
[] N. N. Houreld and H. Abrahamse, “Eectiveness of helium-
neon laser irradiation on viability and cytotoxicity of diabetic-
wounded broblast cells,” Photomedicine and Laser Surgery,vol.
, no. , pp. –, .
[] D. Hawkins and H. Abrahamse, “Eect of multiple exposures
of low-level laser therapy on the cellular responses of wounded
human skin broblasts,” Photomedicine and Laser Surgery,vol.
, no. , pp. –, .
[] D. H. Hawkins and H. Abrahamse, “e role of laser uence in
cell viability, proliferation, and membrane integrity of wounded
human skin broblasts following Helium-Neon laser irradia-
tion,” Lasers in Surgery and Medicine,vol.,no.,pp.–,
.
[] A. Gupta, T. Dai, and M. R. Hamblin, “Eect of red and near-
infrared wavelengths on low-level laser (light) therapy-induced
healing in partial-thickness dermal abrasion in mice ,” Lasers in
Medical Science.Inpress.
[] F. A. H. Al-Watban, “Laser therapy converts diabetic wound
healingtonormalhealing,”Photomedicine and Laser Surgery,
vol. , no. , pp. –, .
[]T.-Y.Chung,P.V.Peplow,andG.D.Baxter,“Laserphoto-
biostimulation of wound healing: dening a dose response
for splinted wounds in diabetic mice,” Lasers in Surgery and
Medicine,vol.,no.,pp.–,.
[] N. R. S. Santos, J. N. Dos Santos, J. A. Dos Reis et al., “Inuence
of the use of laser phototherapy (𝜆 or nm) on the
survivalofcutaneousapsondiabeticrats,”Photomedicine and
Laser Surgery, vol. , no. , pp. –, .
[] A. Aparecida Da Silva, E. C. Leal-Junior, A. C. Alves et al.,
“Wound-healing eects of low-level laser therapy in diabetic
rats involve the modulation of MMP- and MMP- and the
reduction of collagen types I and III,” Journal of Cosmetic and
Laser erapy,vol.,no.,pp.–,.
[] E. T. Firat, A. Da˘
g, A. G˝
unay et al., “e eects of low-level laser
therapy on palatal mucoperiosteal wound healing and oxidative
stress status in experimental diabetic rats,” Photomedicine and
Laser Surgery, vol. , no. , pp. –, .
[] J. J. Park and K. L. Kang, “Eect of -nm GaAIAs diode laser
irradiation on healing of extraction sockets in streptozotocin-
induced diabetic rats, a pilot study,” Lasers in Medical Science,
vol. , pp. –, .
[] C. M. Franc¸a,C.deLouraSantana,C.B.Takahashietal.,“Eect
of laser therapy on skeletal muscle repair process in diabetic
rats,” Lasers in Medical Science,vol.,no.,pp.–,.
[] K. S. Caetano, M. A. C. Frade, D. G. Minatel, L. ´
A. Santana, and
C. S. Enwemeka, “Phototherapy improves healing of chronic
venous ulcers,” Photomedicine and Laser Surgery,vol.,no.,
pp. –, .
[] D. G. Minatel, M. A. C. Frade, S. C. Franc¸a, and C. S. Enwemeka,
“Phototherapy promotes healing of chronic diabetic leg ulcers
that failed to respond to other therapies,” Lasers in Surgery and
Medicine,vol.,no.,pp.–,.
[] A. Kaviani, G. E. Djavid, L. Ataie-Fashtami et al., “A random-
ized clinical trial on the eect of low-level laser therapy on
chronic diabetic foot wound healing: a preliminary report,”
Photomedicine and Laser Surgery,vol.,no.,pp.–,.
[] P. V. Peplow, T.-Y. Chung, and G. D. Baxter, “Laser photo-
stimulation ( nm) of wound healing in diabetic mice is not
brought about by ameliorating diabetes,” Lasers in Surgery and
Medicine,vol.,no.,pp.–,.
[]C.S.Enwemeka,D.Williams,S.K.Enwemeka,S.Hollosi,
and D. Yens, “Blue -nm light kills Methicillin-Resistant
Staphylococcus aureus (MRSA) in vitro,” Photomedicine and
Laser Surgery, vol. , no. , pp. –, .
[] R. Ankri, R. Lubart, and H. Taitelbaum, “Estimation of the
optimal wavelengths for laser-induced wound healing,” Lasers
in Surgery and Medicine,vol.,no.,pp.–,.
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