The Nuts and Bolts of Low-level Laser (Light) Therapy

Abstract

Soon after the discovery of lasers in the 1960s it was realized that laser therapy had the potential to improve wound healing and reduce pain, inflammation and swelling. In recent years the field sometimes known as photobiomodulation has broadened to include light-emitting diodes and other light sources, and the range of wavelengths used now includes many in the red and near infrared. The term "low level laser therapy" or LLLT has become widely recognized and implies the existence of the biphasic dose response or the Arndt-Schulz curve. This review will cover the mechanisms of action of LLLT at a cellular and at a tissular level and will summarize the various light sources and principles of dosimetry that are employed in clinical practice. The range of diseases, injuries, and conditions that can be benefited by LLLT will be summarized with an emphasis on those that have reported randomized controlled clinical trials. Serious life-threatening diseases such as stroke, heart attack, spinal cord injury, and traumatic brain injury may soon be amenable to LLLT therapy.

Full text

The Nuts and Bolts of Low-level Laser (Light) Therapy
HOON CHUNG,
1,2
TIANHONG DAI,
1,2
SULBHA K. SHARMA,
1
YING-YING HUANG,
1,2,3
JAMES D. CARROLL,
4
and MICHAEL R. HAMBLIN
1,2,5
1
Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, MA, USA;
2
Department of Dermatology,
Harvard Medical School, Boston, MA, USA;
3
Aesthetic and Plastic Center of Guangxi Medical University, Nanning, People’s
Republic of China;
4
Thor Photomedicine Ltd, 18A East Street, Chesham HP5 1HQ, UK; and
5
Harvard-MIT Division of Health
Sciences and Technology, Cambridge, MA, USA
(Received 26 July 2011; accepted 20 October 2011)
Associate Editor Daniel Elson oversaw the review of this article.
Abstract—Soon after the discovery of lasers in the 1960s it
was realized that laser therapy had the potential to improve
wound healing and reduce pain, inflammation and swelling.
In recent years the field sometimes known as photobiomod-
ulation has broadened to include light-emitting diodes and
other light sources, and the range of wavelengths used now
includes many in the red and near infrared. The term ‘‘low
level laser therapy’’ or LLLT has become widely recognized
and implies the existence of the biphasic dose response or the
Arndt-Schulz curve. This review will cover the mechanisms
of action of LLLT at a cellular and at a tissular level and will
summarize the various light sources and principles of
dosimetry that are employed in clinical practice. The range
of diseases, injuries, and conditions that can be benefited by
LLLT will be summarized with an emphasis on those that
have reported randomized controlled clinical trials. Serious
life-threatening diseases such as stroke, heart attack, spinal
cord injury, and traumatic brain injury may soon be
amenable to LLLT therapy.
Keywords—Low level laser therapy, Photobiomodulation,
Mitochondria, Tissue optics, Wound healing, Hair regrowth,
Laser acupuncture.
INTRODUCTION AND HISTORY
Low level laser therapy (LLLT), also known as
photobiomodulation, came into being in its modern
form soon after the invention of the ruby laser in 1960,
and the helium–neon (HeNe) laser in 1961. In 1967,
Endre Mester, working at Semmelweis University in
Budapest, Hungary, noticed that applying laser light to
the backs of shaven mice could induce the shaved hair
to grow back more quickly than in unshaved mice.
72
He also demonstrated that the HeNe laser could
stimulate wound healing in mice.
70
Mester soon
applied his findings to human patients, using lasers to
treat patients with nonhealing skin ulcers.
69,71
LLLT
has now developed into a therapeutic procedure that is
used in three main ways: to reduce inflammation,
edema, and chronic joint disorders
9,18,40
; to promote
healing of wounds, deeper tissues, and nerves
24,87
;and
to treat neurological disorders and pain.
17
LLLT involves exposing cells or tissue to low levels
of red and near infrared (NIR) light, and is referred to
as ‘‘low level’’ because of its use of light at energy
densities that are low compared to other forms of laser
therapy that are used for ablation, cutting, and ther-
mally coagulating tissue. LLLT is also known as ‘‘cold
laser’’ therapy as the power densities used are lower
than those needed to produce heating of tissue. It was
originally believed that LLLT or photobiomodulation
required the use of coherent laser light, but more re-
cently, light emitting diodes (LEDs) have been pro-
posed as a cheaper alternative. A great deal of debate
remains over whether the two light sources differ in
their clinical effects.
Although LLLT is now used to treat a wide variety
of ailments, it remains controversial as a therapy for
two principle reasons: first, its underlying biochemical
mechanisms remain poorly understood, so its use is
largely empirical. Second, a large number of parame-
ters such as the wavelength, fluence, power density,
pulse structure, and timing of the applied light must be
chosen for each treatment. A less than optimal choice
of parameters can result in reduced effectiveness of the
treatment, or even a negative therapeutic outcome. As
a result, many of the published results on LLLT in-
clude negative results simply because of an inappro-
priate choice of light source and dosage. This choice is
Address correspondence to Michael R. Hamblin, Wellman Cen-
ter for Photomedicine, Massachusetts General Hospital, Boston,
MA, USA. Electronic mail: hamblin@helix.mgh.harvard.edu
Annals of Biomedical Engineering (2011)
DOI: 10.1007/s10439-011-0454-7
2011 Biomedical Engineering Society

particularly important as there is an optimal dose of
light for any particular application, and doses higher
or lower than this optimal value may have no thera-
peutic effect. In fact, LLLT is characterized by a bi-
phasic dose response: lower doses of light are often
more beneficial than high doses.
38,85,105,108
LASER–TISSUE INTERACTIONS
Light and Laser
Light is part of the spectrum of electromagnetic
radiation (ER), which ranges from radio waves to
gamma rays. ER has a dual nature as both particles
and waves. As a wave which is crystallized in Max-
well’s Equations, light has amplitude, which is the
brightness of the light, wavelength, which determines
the color of the light, and an angle at which it is
vibrating, called polarization. The wavelength (k)of
light is defined as the length of a full oscillation of the
wave, such as shown in Fig. 1a. In terms of the modern
quantum theory, ER consists of particles called pho-
tons, which are packets (‘‘quanta’’) of energy which
move at the speed of light. In this particle view of light,
the brightness of the light is the number of photons,
the color of the light is the energy contained in each
photon, and four numbers (X,Y,Zand T) are the
polarization, where X,Y,Zare the directions and Tis
the time.
A laser is a device that emits light through a process
of optical amplification based on the stimulated emis-
sion of photons. The term ‘‘laser’’ originated as an
acronym for light amplification by stimulated emission
of radiation.
65
The emitted laser light is notable for its
high degree of spatial and temporal coherence.
Spatial coherence typically is expressed through the
output being a narrow beam which is diffraction-lim-
ited, often a so-called ‘‘pencil beam.’’ Laser can be
launched into a beam of very low divergence to con-
centrate their power at a large distance. Temporal (or
longitudinal) coherence implies a polarized wave at a
single frequency whose phase is correlated over a rel-
atively large distance (the coherence length) along the
beam. Lasers are employed in applications where light
of the required spatial or temporal coherence could not
be produced using simpler technologies.
Quite often, the laser beam is described as though it
had a uniform irradiance (the power of the laser di-
vided by the spot size). Most often, the laser beam
assumes a Gaussian shape (that of a normal distribu-
tion), as shown in Fig. 1b.
118
There is a peak irradi-
ance, and the irradiance decreases with distance from
the center of the beam. This may be important in sit-
uations in which there are large variations in power. As
power is increased, the irradiance in the tail of the
Gaussian profile increases, and the distance of the
critical threshold from the center of the beam becomes
larger. For this type of profile, the spot size is often
FIGURE 1. Basic physics of LLLT. (a) Light as an electromagnetic wave. (b) Gaussian laser beam profile. (c) Snellius’ law of
reflection. (d) Optical window because of minimized absorption and scattering of light by the most important tissue chromophores
in the near-infrared spectral region.
CHUNG et al.

referred to as the 1/e
2
radius, or diameter, of the beam;
at this radial distance from the center of the beam,
irradiation is lower by a factor of 0.135 (1/e
2
) relative
to the peak irradiance. About 85% of the power of the
laser beam is present within the 1/e
2
diameter.
Light Emitting Diodes (LED)
A light-emitting diode (LED) is a semiconductor
light source. Introduced as a practical electronic com-
ponent in 1962 early LEDs emitted low-intensity red
light, but modern versions are available across the
visible, ultraviolet and infrared wavelengths, with very
high brightness. When a light-emitting diode is for-
ward biased (switched on), electrons are able to
recombine with electron holes within the device,
releasing energy in the form of photons. This effect is
called electroluminescence and the color of the light
(corresponding to the energy of the photon) is deter-
mined by the energy gap of the semiconductor. An
LED is often small in area (less than 1 mm
2
), and
integrated optical components may be used to shape its
radiation pattern.
78
Optical Properties of Tissue
When the light strikes the biological tissue, part of it
is absorbed, part is reflected or scattered, and part is
further transmitted.
Some of the light is reflected, this phenomenon is
produced by a change in the air and tissue refractive
index. The reflection obeys the law of Snellius
(Fig. 1c), which states:
sin h1
sin h2¼n2
n1
where h
1
is the angle between the light and the surface
normal in the air, h
2
is the angle between the ray and
the surface normal in the tissue, n
1
is the index of
refraction of air, n
2
is the index of refraction of tissue.
Most of the light is absorbed by the tissue. The
energy states of molecules are quantized; therefore,
absorption of a photon takes place only when its en-
ergy corresponds to the energy difference between such
quantized states. The phenomenon of absorption is
responsible for the desired effects on the tissue. The
coefficient l
a
(cm
21
) characterizes the absorption. The
inverse, l
a
, defines the penetration depth (mean free
path) into the absorbing medium.
The scattering behavior of biological tissue is also
important because it determines the volume distribu-
tion of light intensity in the tissue. This is the primary
step for tissue interaction, which is followed by
absorption. Scattering of a photon is accompanied by
a change in the propagation direction without loss of
energy.The scattering, similar to absorption, is ex-
pressed by the scattering coefficient l
s
(cm
21
). The
inverse parameter, 1/l
s
(cm), is the mean free path
length until a next scattering event occurs.
Scattering is not isotropic. Forward scattering is
predominant in biological tissue. This characteristic is
described by the anisotropy factor g.gcan have abso-
lute values from 0 to 1, from isotropic scattering
(g=0) to forward scattering (g=1). In tissue, gcan
vary from 0.8 to 0.99. Taking into account the gvalue, a
reduced scattering coefficient, l0
s(cm
21
), is defined as:
l0
s¼ls1gðÞ
The sum of l
s
and l
a
is called the total attenuation
coefficient l
t
(cm
21
):
lt¼lsþla
Light Distribution in Laser-irradiated Tissue
Most of the recent advances in describing the
transfer of light energy in tissue are based upon
transport theory.
13
According to transport theory, the
radiance L(r,s) of light at position rtraveling in the
direction of unit vector sis decreased by absorption
and scattering but it is increased by light that is scat-
tered from s¢direction into direction s. Radiance is a
radiometric measure that describes the amount of light
that passes through or is emitted from a particular
area, and falls within a given solid angle in a specified
direction. Then, the transport equation which de-
scribes the light interaction is:
srLr;sðÞ¼laþls
ðÞLr;sðÞþlsZ
4p
ps;s0
ðÞLr;s0
ðÞdx0
where dx¢is the differential solid angle in the direction
s¢, and p(s,s¢) is the phase function.
Calculations of light distribution based on the
transport equation require l
s
,l
a
,andp. To solve
transport equation exactly is often difficult; therefore,
several approximations have been made regarding the
representation of the radiance and phase function. The
approximate solutions of light distribution in tissue are
dependent upon the type of light irradiation (diffuse or
collimated) and the optical boundary conditions
(matched or unmatched indexes of refraction).
16
CELLULAR AND TISSULAR
MECHANISMS OF LLLT
The precise biochemical mechanism underlying
the therapeutic effects of LLLT are not yet well-
established. From observation, it appears that LLLT
The Nuts and Bolts of Low-level Laser (Light) Therapy

has a wide range of effects at the molecular, cellular,
and tissular levels. In addition, its specific modes of
action may vary among different applications. Within
the cell, there is strong evidence to suggest that LLLT
acts on the mitochondria
27
to increase adenosine tri-
phosphate (ATP) production,
43
modulation of reactive
oxygen species (ROS), and the induction of transcrip-
tion factors.
15
Several transcription factors are regu-
lated by changes in cellular redox state. Among them
redox factor-1 (Ref-1) dependent activator protein-1
(AP-1) (a heterodimer of c-Fos and c-Jun), nuclear
factor kappa B (NF-jB), p53, activating transcription
factor/cAMP-response element–binding protein (ATF/
CREB), hypoxia-inducible factor (HIF)-1, and HIF-
like factor.
15
These transcription factors then cause
protein synthesis that triggers further effects down-
stream, such as increased cell proliferation and
migration, modulation in the levels of cytokines,
growth factors and inflammatory mediators, and
increased tissue oxygenation.
45
Figure 2shows the
proposed cellular and molecular mechanisms of LLLT.
Immune cells, in particular, appear to be strongly
affected by LLLT. Mast cells, which play a crucial role
in the movement of leukocytes, are of considerable
importance in inflammation. Specific wavelengths of
light are able to trigger mast cell degranulation,
22
which results in the release of the pro-inflammatory
cytokine TNF-a from the cells.
115
This leads to
increased infiltration of the tissues by leukocytes.
LLLT also enhances the proliferation, maturation, and
motility of fibroblasts, and increases the production of
basic fibroblast growth factor.
31,67
Lymphocytes
become activated and proliferate more rapidly, and
epithelial cells become more motile, allowing wound
sites to close more quickly. The ability of macrophages
to act as phagocytes is also enhanced under the
application of LLLT.
At the most basic level, LLLT acts by inducing a
photochemical reaction in the cell, a process referred to
as biostimulation or photobiomodulation. When a
photon of light is absorbed by a chromophore in the
treated cells, an electron in the chromophore can
become excited and jump from a low-energy orbit to a
higher-energy orbit.
42,108
This stored energy can then
be used by the system to perform various cellular tasks.
There are several pieces of evidence that point to a
chromophore within mitochondria being the initial
target of LLLT. Radiation of tissue with light causes
an increase in mitochondrial products such as ATP,
NADH, protein, and RNA,
83
as well as a reciprocal
augmentation in oxygen consumption, and various
in vitro experiments have confirmed that cellular res-
piration is upregulated when mitochondria are exposed
to an HeNe laser or other forms of illumination.
The relevant chromophore can be identified by
matching the action spectra for the biological response
to light in the NIR range to the absorption spectra of
the four membrane-bound complexes identified in
mitochondria.
42
This procedure indicates that complex
IV, also known as cytochrome coxidase (CCO), is the
crucial chromophore in the cellular response to
LLLT.
44
CCO is a large transmembrane protein
complex, consisting of two copper centers and two
heme–iron centers, which is a component of the
respiratory electron transport chain.
10
The electron
transport chain passes high-energy electrons from
electron carriers through a series of transmembrane
complexes (including CCO) to the final electron
acceptor, generating a proton gradient that is used to
produce ATP. Thus, the application of light directly
influences ATP production by affecting one of the
transmembrane complexes in the chain: in particular,
LLLT results in increased ATP production and elec-
tron transport.
47,84
FIGURE 2. Cellular mechanisms of LLLT. Schematic diagram showing the absorption of red or near infrared (NIR) light by specific
cellular chromophores or photoacceptors localized in the mitochondrial. During this process in mitochondria respiration chain
ATP production will increase, and reactive oxygen species (ROS) are generated; nitric oxide is released or generated. These
cytosolic responses may in turn induce transcriptional changes via activation of transcription factors (e.g., NF-jB and AP1).
CHUNG et al.

The precise manner in which light affects CCO is
not yet known. The observation that NO is released
from cells during LLLT has led to speculation that
CCO and NO release are linked by two possible
pathways (Fig. 3). It is possible that LLLT may cause
photodissociation of NO from CCO.
46,52
Cellular res-
piration is downregulated by the production of NO by
mitochondrial NO synthase (mtNOS, a NOS isoform
specific to mitochondria), that binds to CCO and
inhibits it. The NO displaces oxygen from CCO,
inhibiting cellular respiration and thus decreasing the
production of ATP.
5
By dissociating NO from CCO,
LLLT prevents this process from taking place and re-
sults in increased ATP production. An alternative or
parallel mechanism to explain the biological activity of
red or NIR light to release NO from cells or tissue is
the following.
61,127
A new explanation has been re-
cently proposed for how light increases NO bioavail-
ability.
88
CCO can act as a nitrite reductase enzyme (a
one electron reduction of nitrite gives NO) particularly
when the oxygen partial pressure is low.
6
Ball et al.
showed 590 ±14 nm LED light stimulated CCO/NO
synthesis at physiological nitrite concentrations at hy-
poxia condition.
6
The following reaction may take
place:
NO
2+2H
þ+e
CCOðÞ!NO + H2O
The influence of LLLT on the electron transport
chain extends far beyond simply increasing the levels of
ATP produced by a cell. Oxygen acts as the final
electron acceptor in the electron transport chain and is,
in the process, converted to water. Part of the oxygen
that is metabolized produces reactive oxygen species
(ROS) as a natural by-product. ROS are chemically
active molecules that play an important role in cell
signaling, regulation of cell cycle progression, enzyme
activation, and nucleic acid and protein synthesis.
Because LLLT promotes the metabolism of oxygen, it
also acts to increase ROS production. In turn, ROS
activates transcription factors, which leads to the
upregulation of various stimulatory and protective
genes. These genes are most likely related to cellular
proliferation,
76
migration,
32
and the production of
cytokines and growth factors, which have all been
shown to be stimulated by low-level light.
125,128
The processes described above are almost certainly
only part of the story needed to explain all the effects
of LLLT. Among its many effects, LLLT has been
shown to cause vasodilation by triggering the relaxa-
tion of smooth muscle associated with endothelium,
which is highly relevant to the treatment of joint
inflammation. This vasodilation increases the avail-
ability of oxygen to treated cells, and also allows for
greater traffic of immune cells into tissue. These two
effects contribute to accelerated healing. NO is a po-
tent vasodilator via its effect on cyclic guanine mono-
phosphate production, and it has been hypothesized
that LLLT may cause photodissociation of NO, not
only from CCO, but from intracellular stores such as
nitrosylated forms of both hemoglobin and myoglobin,
leading to vasodilation.
61
LIGHT SOURCES AND DOSIMETRY
Currently, one of the biggest sources of debate in
the choice of light sources for LLLT is the choice
between lasers and LEDs. LEDs have become wide-
spread in LLLT devices. Most initial work in LLLT
used the HeNe laser, which emits light of wavelength
632.8-nm, while nowadays semi-conductor diode lasers
such as gallium arsenide (GaAs) lasers have increased
in popularity. It was originally believed that the
coherence of laser light was crucial to achieve the
therapeutic effects of LLLT, but recently this notion
has been challenged by the use of LEDs, which emit
non-coherent light over a wider range of wavelengths
than lasers. It has yet to be determined whether there is
a real difference between laser and LED, and if it in-
deed exists, whether the difference results from the
coherence or the monochromaticity of laser light, as
opposed to the non-coherence and wider bandwidth of
LED light.
A future development in LLLT devices will be the
use of organic light emitting diodes (OLEDs). These
are LEDs in which the emissive electroluminescent
layer is a film of organic compounds which emit light
in response to an electric current.
122
They operate in a
similar manner to traditional semiconductor material
whereby electrons and the holes recombine forming an
exciton. The decay of this excited state results in a
relaxation of the energy levels of the electron, accom-
panied by emission of radiation whose frequency is in
the visible region.
FIGURE 3. Two possible sources of nitric oxide (NO) release
from cytochrome coxidase (CCO). Path1 shows CCO can act
as a nitrite reductase enzyme: Path 2 shows possible photo-
dissociation of NO from CCO.
The Nuts and Bolts of Low-level Laser (Light) Therapy

The wavelengths of light used for LLLT fall into an
‘‘optical window’’ at red and NIR wavelengths
(600–1070 nm) (Fig. 1d). Effective tissue penetration is
maximized in this range, as the principal tissue chro-
mophores (hemoglobin and melanin) have high
absorption bands at wavelengths shorter than 600 nm.
Wavelengths in the range 600–700 nm are used to treat
superficial tissue, and longer wavelengths in the range
780–950 nm, which penetrate further, are used to treat
deeper-seated tissues. Wavelengths in the range
700–770 nm have been found to have limited bio-
chemical activity and are therefore not used. There are
also reports of the effectiveness of wavelengths outside
the range of absorption of NIR light by CCO. These
wavelengths are in the near IR,
36
the mid-IR region
including carbon dioxide laser (10.6 lm)
126
and also
include broad band IR sources in the 10–50 lm
range.
39
The chromophore in these situations is almost
certainly water, possible present in biological mem-
branes in some nanostructured form, that is different
from bulk water allowing biological effects without
gross heating of the tissue.
94,95
It is at present not clear
at which wavelength CCO absorption ceases and water
absorption commences to be important.
Dosimetry
The power of light used typically lies in the range
1–1000 mW, and varies widely depending on the par-
ticular application. There is evidence to suggest that
the effectiveness of the treatment varies greatly on both
the energy and power density used: there appears to be
upper and lower thresholds for both parameters
between which LLLT is effective. Outside these
thresholds, the light is either too weak to have any
effect, or so strong that its harmful effects outweigh its
benefits.
Response to LLLT changes with wavelength, irra-
diance, time, pulses and maybe even coherence and
polarization, the treatment should cover an adequate
area of the pathology, and then there is a matter of
how long to irradiate for.
Dosimetry is best described in two parts,
1. Irradiation parameters (‘‘the medicine’’) see
Table 1
2. Time/energy/fluence delivered (‘‘the dose’’) see
Table 2
Dosimetry in LLLT is highly complicated. The large
of number of interrelated parameters (see Table 1) has
meant that there has not yet been a comprehensive
study reported that examined the effect of varying all
the individual parameters one by one, and it must be
pointed out that it is unlikely there will ever be such a
study carried out. This considerable level of complexity
has meant that the choice of parameters has often
depended on the experimenter’s or the practitioner’s
personal preference or experience rather than on a
consensus statement by an authoritative body. Never-
theless, the World Association of Laser Therapy
(WALT) has attempted to provide dosage guidelines
(http://www.walt.nu/dosage-recommendations.html).
Biphasic Dose Response
It is well established that if the light applied is not of
sufficient irradiance or the irradiation time is too short
then there is no response. If the irradiance is too high
or irradiation time is too long then the response may
be inhibited.
11,33,53
Somewhere in between is the opti-
mal combination of irradiance and time for stimula-
tion. This dose response often likened to the biphasic
response known as ‘‘Arndt-Schulz Law’’
68,105,116
which
dates back to 1887 when Hugo Schulz published a
paper showing that various poisons at low doses have a
stimulatory effect on yeast metabolism when given in
low doses
116
then later with Rudolph Arndt they
developed their principle claiming that a weak stimuli
slightly accelerates activity, stronger stimuli raise it
further, but a peak is reached and that a stronger
stimulus will suppress activity.
63
A more credible term
better known in other areas of science and medicine is
Hueppe’s Rule. In 1896 Ferdinand Hueppe built on
Hugo Schulz’s initial findings by showing low dose
stimulation/high dose inhibition of bacteria by toxic
agents. This is better known today by the term ‘‘hor-
mesis’’ first coined in 1941 and first referenced in
1943,
63
which has subsequently been discussed multiple
times in LLLT research.
34,38
A graphical depiction of how the response to LLLT
varies as a function of the combination of irradiance
(medicine) and time (dose) is shown in Fig. 4,asa3D
model to represent the possible biphasic responses to
the various combinations of irradiance and time or
fluence.
SURVEY OF CONDITIONS TREATED WITH
LLLT
LLLT is used for three main purposes: to promote
wound healing, tissue repair, and the prevention of
tissue death; to relieve inflammation and edema be-
cause of injuries or chronic diseases; and as an
analgesic and a treatment for other neurological
problems. These applications appear in a wide range of
clinical settings, ranging from dentistry, to dermatol-
ogy, to rheumatology and physiotherapy. Table 3
summarizes some of the published studies in animal
models of diseases and conditions treated with LLLT.
CHUNG et al.

Table 4summarizes some of the published clinical
trials of LLLT.
Wound healing was one of the first applications of
LLLT, when HeNe lasers were used by Mester et al.to
treat skin ulcers.
69–71
LLLT is believed to affect all
three phases of wound healing
111
: the inflammatory
phase, in which immune cells migrate to the wound,
the proliferative phase, which results in increased
production of fibroblasts and macrophages, and the
remodeling phase, in which collagen deposition occurs
at the wound site and the extra-cellular matrix is re-
built.
LLLT is believed to promote wound healing by
inducing the local release of cytokines, chemokines, and
other biological response modifiers that reduce the time
required for wound closure, and increase the mean
breaking strength of the wound.
8,32,73
Proponents
of LLLT speculate that this result is achieved by
increasing the production and activity of fibroblasts
and macrophages, improving the mobility of leuko-
cytes, promoting collagen formation, and inducing neo-
vascularization.
31,60,67,80,90,104
However, there is a lack of convincing clinical
studies that either prove or disprove the efficacy of
LLLT in wound healing. The results that are currently
available are conflicting and do not lead to any clear
conclusions. For example, Abergel et al. found that the
632.8 nm HeNe laser did not have any effect on the
cellular proliferation of fibroblasts, while the 904 nm
GaAs laser actually lowered fibroblasts proliferation.
1
In contrast, other studies noted an increase in prolif-
eration of human fibroblasts exposed to 904 nm GaAs
lasers,
85
rat myofibroblasts exposed to 670 nm GaAs
lasers,
67
and gingival fibroblasts exposed to diode la-
TABLE 1. Irradiation parameters (the medicine).
Irradiation parameter Unit of measurement
Wavelength nm Light is packets of electromagnetic energy that also have
a wave-like property. Wavelength is measure in
nanometers (nm) and is visible in the 400–700 nm range.
Wavelength determines which chromophores will absorb
the light. LLLT devices are typically in the range
600–1000 nm as there are many peaks for
cytochrome coxidase in that range and clinical trials
have been successful with them. There is some contention
as wavelengths above 900 nm are probably more absorbed by
water than CCO and excitation seems less likely
so it introduces the possibility that maybe IR absorption
by water in the phospholipid bilayers causes
molecular vibration and rotation) sufficient to perturb
ion channels alter cellular function
Irradiance W/cm
2
Often called Power Density (technically incorrect) and
is calculated as Power (W)/Area (cm
2
)=Irradiance
Pulse structure Peak power (W)
Pulse freq (Hz)
Pulse width (s)
Duty cycle (%)
If the beam is pulsed then the Power reported should
be the Average Power and calculated as follows:
Peak Power (W) 9pulse width (s) 9pulse
frequency (Hz) =Average Power (W). Pulses can be
significantly more effective than CW
30
however,
the optimal frequencies and pulse duration
(or pulse intervals) remain to be determined
Coherence Coherence length depends
on spectral bandwidth
Coherent light produces laser speckle, which has
been postulated to play a role in the
photobiomodulation interaction with cells
and sub-cellular organelles. The dimensions
of speckle patterns coincide with the dimensions
of organelles such as mitochondria.
No definitive trials have been published to-date to
confirm or refute this claim
Polarization Linear polarized or
zcircular polarized
Polarized light may have different effects than otherwise
identical non-polarized light (or even 90rotated
polarized light). However, it is known that polarized light is
rapidly scrambled in highly scattering media such as tissue
(probably in the first few hundred lm). However, for the
birefringent protein structures such as collagen the transmission
of plane polarized light will depend on orientation. Several
authors have demonstrated effects on wound healing
and burns with polarized light
19,86,91
The Nuts and Bolts of Low-level Laser (Light) Therapy

sers (670, 692, 780, and 786 nm).
3
In vivo studies in
both animal and human models show similar discrep-
ancies. A study by Kana et al. claimed that treatment
of open wounds in rats with HeNe and argon lasers
resulted in faster wound closure.
41
Bisht et al. found a
similar increase in granulation tissue and collagen
expression in rats using the same treatment as Kana.
7
However, Anneroth et al. failed to observe any bene-
ficial effects after laser treatment in a comparable rat
model.
4
In human studies, Schindl et al. reported that
application of a HeNe laser was beneficial in promot-
ing wound healing in 3 patients,
99
whereas Lundeberg
et al. found no statistically significant difference
between leg ulcer patients treated with an HeNe laser
and those treated with a placebo.
62
The scarcity of well-designed clinical trials makes it
difficult to assess the impact of LLLT on wound heal-
ing. Our task is further complicated by the difficulty in
comparing studies, because of the large number of
factors involved. In addition to the multiple parameters
that must be adjusted to apply LLLT, such as the
wavelength and power of the light, the effectiveness of
the treatment also depends on many factors such as the
location and nature of the wound, and the physiologic
state of the patient. For example, impaired wound
healing is one of the major chronic complications of
diabetes,
25,89
and is thought to result from various
factors, including decreased collagen production and
impaired functionality of fibroblasts, leukocytes, and
endothelial cells.
25,106
It has therefore been hypothe-
sized that LLLT could have beneficial effects in stim-
ulating wound healing in diabetic patients.
98,100,124
Thus, in order to obtain a convincing verdict on the
impact of LLLT on wound healing, we will require
several large, randomized, placebo controlled, and
double blind trials that compare the effects of LLLT on
wounds that are as similar as possible. A greater
understanding of the cellular and biochemical mecha-
nisms of LLLT would also be useful in assessing these
studies, as it would enable us to pinpoint exactly what
criteria to use in determining the effectiveness of the
therapy.
There appears to be more firm evidence to support
the success of LLLT in alleviating pain and treating
chronic joint disorders, than in healing wounds. A
review of 16 randomized clinical trials including a total
of 820 patients found that LLLT reduces acute neck
pain immediately after treatment, and up to 22 weeks
after completion of treatment in patients with chronic
neck pain.
17
LLLT has also been shown to relieve pain
because of cervical dentinal hypersensitivity,
93
or from
periodontal pain during orthodontic tooth move-
ment.
114
A study of 88 randomized controlled trials
indicated that LLLT can significantly reduce pain and
TABLE 2. Irradiation time/energy/fluence (‘‘dose’’).
Energy (Joules) J Calculated as: Power (W) 9time (s) =Energy (Joules)
This mixes medicine and dose into a single expression
and ignores irradiance. Using Joules as an expression
of dose is potentially unreliable as it assumes assumes
a reciprocity relationship between irradiance and time
37,38
Energy density J/cm
2
Common expression of LLLT ‘‘dose’’ is Energy Density.
This expression of dose again mixes medicine and
dose into a single expression and is potentially
unreliable as described above
Irradiation time Seconds Given the possible lack of reciprocity between irradiance
and time
37,38
it is our view that the safest way to
record and prescribe LLLT is to define the irradiation
parameters (‘‘the medicine’’) see Table 1, and then
define the irradiation time (as the ‘‘dose’’).
Treatment interval Hours, days
or weeks
The effects of different treatment intervals is underexplored
at this time though there is sufficient evidence to suggest
that this is an important parameter. With the exception
of some early treatment of acute injuries LLLT generally
requires at least two treatments a week for several
weeks to achieve clinical significance
FIGURE 4. Biphasic dose response in LLLT. Three dimen-
sional plot illustrating effects of varying irradiation time
equivalent to fluence or irradiance on the biological response
resulting in stimulation or inhibition.
CHUNG et al.

i-
TABLE 3. Pre-clinical studies on animals with low level light therapy for different conditions.
Disease Parameters
ab
Subject Effect References
Myocardial infarction 804 nm; 38 mW; 4.5 ±0.1 mW/cm
2
;
0.27 J/cm
2
; CW, 1.5 93.5 mm
Rats Reduced the loss of myocardial tissue 2
Myocardial infarction 635 nm, 5 mW, 6 mW/cm
2
; 0.8 J–1 J/cm
2
;
CW; 0.8 cm
2
; 150 s
Rats The expression of multiple cytokines was regulated
in the acute phase after LLLI
123
Myocardial infarction 804 nm; 400 mW 8 mW/cm
2
; 0.96 J/cm
2
;
CW; 2 cm
2
; 120 s
Rats and
dogs
VEGF and iNOS expression markedly upregulated;
angiogenesis and cardioprotection enhanced
113
Stroke 808-nm; .5 mW/cm
2
; 0.9 J/cm
2
at cortical
surface; CW; 300 ls
pulse at 1 kHz; 2.2 ms at 100 Hz
Rabbits The results showed that laser administered 6 h following
embolic strokes in rabbits in P mode can result in
significant clinical improvement and should be considered
for clinical development
54
Stroke 808-nm; 7.5 mW/cm
2
; 0.9 J/cm
2
; 3.6 J/cm
2
at cortical surface; CW and 70 Hz,
4-mm diameter
Rats LLLT issued 24 h after acute stroke may provide a significant
functional benefit with an underlying mechanism possibly
being induction of neurogenesis
81
TBI 808 ±10 nm; 70 mW; 2230 mW/cm
2
;
268 J/cm
2
at the scalp; 10 mW/cm
2
;
1.2 J/cm
2
at cortical surface; CW; 2 mm
2
Rats Single and multiple applications of transcranial laser therapy
with 808-nm CW laser light appears to be safe in
Sprague–Dawley rats 1 year after treatment
64
TBI 808-nm; 200 mW; 10 and 20 mW/cm
2
;
1.2–2.4 J/cm
2
at cortical surface;
4 h post-trauma
Mice LLLT given 4 h following TBI provides a significant
long-term functional neurological benefit
82
TBI 660 nm or 780 nm, 40 mW; 3 J/cm
2
or 5 J/cm
2
; CW; 0.042 cm
2
(3 s and 5 s)
irradiated twice (3 h interval)
Rats LLLT affected TNF-alpha, IL-1beta, and IL-6 levels in
the brain and in circulation in the first 24 h following
cryogenic brain injury
77
Spinal cord injury 830 nm; 100 mW; 30 mW/cm
2
; 250 J/cm
2
;
CW, 0.028 cm
2
Rats LLLT initiated a positive bone-tissue response, maybe
through stimulation of osteoblasts. However, the evoked
tissue response did not affect biomechanical or
densitometric modifications
66
Spinal cord injury 810 nm; 1589 J/cm
2
; 0.3 cm
2
, 2997 s;
daily for 14 days
Rats Promotes axonal regeneration and functional recovery
in acute SCI
120
Arthritis 632.8 nm; 5 mW; 8 J/cm
2
, CW; 2-mm
diameter; 50 s; daily for 5 days
Rats Laser reduced the intensity of the inflammatory process
in the arthritis model induced by hydroxyapatite and
calcium pyrophosphate crystals
92
Arthritis 632.8-nm; 3.1 mW/cm
2
CW, 1 cm diameter;
15 min; 3 times a week for 8 weeks
Rats He–Ne laser treatment enhanced the biosynthesis
of arthritic cartilage
59
Arthritis 810-nm; 5 or 50 mW/cm
2
; 3 or 30 J/cm
2
;
CW; 4.5-cm diameter; 1, 10 or 100 min;
daily for 5 days
Rats Highly effective in treating inflammatory arthritis.
Illumination time may be an important parameter
11
Wound healing 632.8-nm laser; 635, 670, 720 or 810-nm
(±15-nm filtered lamp); 0.59, 0.79, and
0.86 mW/cm
2
; 1, 2, 10 and 50 J/cm
2
;
CW; 3-cm diameter
Mice 635-nm light had a maximum positive effect at 2 J/cm
2
.
820 nm was found to be the best wavelength. No difference
between non-coherent 635 ±15-nm light from a lamp and
coherent 633-nm light from a He/Ne laser. LLLT increased
the number of a-smooth muscle actin (SMA)-positive cells
at the wound edge
20
The Nuts and Bolts of Low-level Laser (Light) Therapy

mprove health in chronic joint disorders such as
osteoarthritis, patellofemoral pain syndrome, and
mechanical spine disorders.
9
However, the authors of
the study urge caution in interpreting the results be-
cause of the wide range of patients, treatments, and
trial designs involved.
LLLT for Serious Diseases
LLLT is also being considered as a viable treatment
for serious neurological conditions such as traumatic
brain injury (TBI), stroke, spinal cord injury, and
degenerative central nervous system disease.
Although traumatic brain injury is a severe health
concern, the search for better therapies in recent years
has not been successful. This has led to interest in more
radical alternatives to existing procedures, such as
LLLT. LLLT is hypothesized to be beneficial in the
treatment of TBI. In addition to its effects in increasing
mitochondrial activity and activating transcription
factors, LLLT could benefit TBI patients by inhibiting
apoptosis, stimulating angiogenesis, and increasing
neurogenesis.
29
Experiments carried out with two
mouse models indicated that LLLT could reduce the
brain damaged area at 3 days after treatment, and
treatment with a 665 nm and 810 nm laser could lead
to a statistically significant difference in the Neuro-
logical Severity Score (NSS) of mice that had been
injured by a weight being dropped onto the exposed
skull.
121
Transcranial LLLT has also been shown to have a
noticeable effect on acute human stroke patients, with
significantly greater improvement being seen in
patients 5 days after LLLT treatment compared to
sham treatment (p<0.05, National Institutes of
Health Stroke Severity Scale.)
51
This difference per-
sisted up to 90 days after the stroke, with 70% of
patients treated with LLLT having a successful out-
come compared to 51% of control patients. The
improvement in functional outcome because of
applying transcranial LLLT after a stroke has been
confirmed by studies in rat and rabbit models.
54,81
Further experiments have tried to pinpoint the
mechanism underlying these results. As expected,
increased mitochondrial activity has been found in
brain cells irradiated with LLLT,
54
indicating that the
increased respiration and ATP production that usually
follow laser therapy are at least partly responsible for
the improvement shown in stroke patients. However,
there is still the possibility that LLLT has other effects
specific to the brain. Several groups have suggested
that the improvements in patient outcomes are because
of the promotion of neurogenesis, and migration of
neurons.
81
This hypothesis is supported by the fact that
the benefits of LLLT following a stroke may take 2–
TABLE 3. continued.
Disease Parameters
ab
Subject Effect References
Familial amyotropic lateral
sclerosis (FALS)
810 nm; 140-mW; 12 J/cm
2
; CW; 1.4 cm
2
Mice Rotarod test showed significant improvement in
the light group in the early stage of the disease.
Immunohistochemical expression of the astrocyte marker,
glial fibrilary acidic protein, was significantly reduced in
the cervical and lumbar enlargements of the spinal
cord as a result of LLLT
75
a
The light sources were all lasers unless LED is specifically mentioned.
b
The laser parameters are given in the following order: wavelength (nm); power (mW), power density (mW/cm
2
); energy (J); energy density (J/cm
2
); mode (CW) or pulsed (Hz); spot size
(cm
2
); illumination time (sec); treatment repetition. In many cases, the parameters are partially unavailable.
CHUNG et al.

TABLE 4. Clinical studies on patients with low level light therapy for different conditions.
Disease Parameters
ab
Subject Effect References
Myocardial infarction 632.8-nm, 5 mW; CW; 15 min;
6 days a week for 4 weeks
on chest skin
39 patients An improvement of functional capacity
and less frequent angina symptoms
during exercise tests
131
Stroke (NEST-1) 808-nm; 700 mW/cm
2
on shaved
scalp with cooling; 1 J/cm
2
at
cortical surface; 20 predetermined
locations 2 min each
120 patients The NEST-1 study indicated that
infrared laser therapy has shown
initial safety and effectiveness for
the treatment of ischemic stroke
in humans when initiated within
24 h of stroke onset
51
Stroke
(NEST-2)
808-nm; 700 mW/cm
2
on shaved scalp
with cooling; 1 J/cm
2
at cortical
surface; 20 predetermined
locations 2 min each
660 patients TLT within 24 h from stroke onset demonstrated
safety but did not meet formal statistical
significance for efficacy. However,
all predefined analyses showed a favorable
trend, consistent with the previous clinical
trial (NEST-1). Both studies indicate that
mortality and adverse event rates were not
adversely affected by TLT. A definitive trial with
refined baseline National Institutes of Health
Stroke Scale exclusion criteria is planned
130
Chronic TBI 9 9635 and 52 9870-nm LED cluster;
12-15 mW per diode; 500 mW;
22.2 mW/cm
2
; 13.3 J/cm
2
at scalp
(estimated 0.4 J/cm
2
to cortex);
2.1¢¢ diameter
2 patients Transcranial LED may improve cognition
in chronic TBI patients even years after injury
79
Major depression
and anxiety
810-nm, 250 mW/cm
2
; 60 J/cm
2
on scalp; 2.1 J/cm
2
at cortical
surface; CW; 4 cm
2
; 240 s at
each of 2 sites on forehead
10 patients Significant improvement in Hamilton
depression and anxiety scales at 2 weeks
96
Oral mucositis 830 nm; 150 mW; repeated every 48 h 16 patients Immediate pain relief and improved wound
healing resolved functional impairment
that was obtained in all cases
12
Oral mucositis 830 nm; 15 mW; 12 J/cm
2
; CW; 0.2 cm
2
;
daily for 5 days commencing at start
of radio/chemotherapy
12 patients The prophylactic use of the treatment proposed
in this study seemed to reduce the incidence
of severe oral mucositis lesions. LLLT was
effective in delaying the appearance
of severe oral mucosistis
58
Oral mucositis 660-nm; 10-mW; 2.5 J/cm
2
,CW;
4mm
2
; daily for 5 days
75 patients LLLT therapy was not effective in reducing severe
oral mucositis, although a marginal benefit could
not be excluded. It reduced radiation therapy
interruptions in these head-and-neck cancer
patients, which might translate into
improved CRT efficacy
26
The Nuts and Bolts of Low-level Laser (Light) Therapy

TABLE 4. continued.
Disease Parameters
ab
Subject Effect References
Carpal tunnel
syndrome (CTS)
830-nm; 60 mW; 9.7 J/cm
2
; 10 Hz,
50% duty cycle, 10-min per day
for 5 days a week
75 patients Alleviate pain and symptoms, improve functional
ability and finger and hand strength
for mild and moderate CTS patients
14
Carpal tunnel
syndrome (CTS)
632.8-nm; 9–11 J/cm
2
; CW;
5 times/week for 3 weeks
80 patients Effective in treating CTS paresthesia and numbness
and improved the subjects’ power of hand-grip
and electrophysiological parameters
102
Carpal tunnel
syndrome (CTS)
830-nm; 50 mW; 1.2 J/point; CW;
1 mm diameter. 2 min/point; 5 points across
the median nerve trace; 5 times per
week for 3 weeks
60 patients LLLT was no more effective than placebo in CTS 110
Lateral epicondylitis (LE) 905 nm; 100 mW; 1 J/cm
2
; 1000 Hz;
2 min; 5 days per week for 3 weeks
49 patients No advantage for the short term; significant
improvement in functional parameters
in the long term
23
Lateral epicondylitis (LE) 904-nm; 25 mW, 0.275 J/point; 2.4 J/cm
2
;
pulse duration 200 nsec; 5000 Hz;
4-mm diameter 11 s/point; 3 times/week
for 3 weeks
39 patients LLLT in addition to exercise is effective in
relieving pain, and in improving the grip
strength and subjective rating of physical
function of patients with lateral epicondylitis
50
Lateral epicondylitis (LE) 830 nm; 120 mW; CW; 5-mm diameter;
632.8 nm, 10 mW, CW; 2-mm diameter;
904 nm, 10 mW; pulsed; 2.5–4 J/point;
12 J/cm
2
; 3–5 times/week for 2–5 weeks
324 patients It was observed that under- and overirradiation can
result in the absence of positive therapy effects
or even opposite, negative (e.g., inhibitory) effects.
The current clinical study provides further evidence
of the efficacy of LLLT in the management
of lateral and medial epicondylitis
103
Arthritis 830 nm, 50 mW; 10 W/cm
2
; 6 J/point;
48 J/cm
2
; CW, 0.5-mm
2
; 2 times/week
for 4 weeks
27 patients Reduces pain in knee osteoarthritis and
improves microcirculation
35
Arthritis 904-nm; 10 mW; 3 J/point; 3 J/cm
2
;
200 nsec; 2500 Hz; 1 cm
2
; 2 points
5 times/week for 2 weeks
90 patients The study demonstrated that applications
of LLLT in regardless of dose and duration
were a safe and effective method in
treatment of knee osteoarthritis
28
Leg ulcers 685 nm; 50 mW; 50 mW/cm
2
; 10 J/cm
2
;
CW; 1 cm
2
; 200 s; 6 times per week,
for 2 weeks then every 2 days
23 patients The study provided evidence that LLLT can
accelerate the healing process of chronic
diabetic foot ulcers, and it can be presumed
that LLLT may shorten the time period
needed to achieve complete healing
48
Leg ulcers 685-nm; 200 mW; 4 J/cm
2
44 patients No statistically significant differences
in reduction of wound size
49
a
The light sources were all lasers unless LED is specifically mentioned.
b
The laser parameters are given in the following order: wavelength (nm); power (mW), power density (mW/cm
2
); energy (J); energy density (J/cm
2
); mode (CW) or pulsed (Hz); spot size
(cm
2
); illumination time (sec); treatment repetition. In many cases, the parameters are partially unavailable.
CHUNG et al.

4 weeks to manifest, reflecting the time necessary for
new neurons to form and gather at the damaged site
in the brain.
21,101
However, the exact processes
underlying the effects of LLLT in a stroke patient are
still poorly understood.
LLLT has also been considered as a candidate for
treating degenerative brain disorders such as familial
amyotropic lateral sclerosis (FALS), Alzheimer’s dis-
ease, and Parkinson’s disease (PD).
75,129
Although
only preliminary studies have been carried out, there
are encouraging indications that merit further investi-
gation. Michalikova et al. found that LLLT could
reverse memory degradation and induce improved
cognitive performance in middle-aged mice,
74
and
Trimmer et al. found that motor function was signifi-
cantly improved in human patients treated with LLLT
in an early stage of FALS.
112
Intravascular Laser Therapy
Intravenous or intravascular blood irradiation
involves the in vivo illumination of the blood by feeding
low level laser light generated by a 1–3 mW low power
laser at a variety of wavelengths through a fiber optic
inserted in a vascular channel, usually a vein in the
forearm (Fig. 5a), under the assumption that any
therapeutic effect will be circulated through the
circulatory system
117
(see Fig. 5b). The feasibility of
intravascular laser irradiation for therapy of cardio-
circulatory diseases was first presented in the American
Heart Journal in 1982.
57
The technique was developed
primarily in Asia (including Russia) and is not exten-
sively used in other parts of the world. It is claimed to
improve blood flow and its transport activities, but has
not been subject to randomized controlled trials and is
subject to skepticism. Although it is at present uncer-
tain what the mechanisms of intravascular laser actu-
ally are, and why it differs from traditional laser
therapy; it has been hypothesized to affect particular
components of the blood. Blood lipids (low density
lipoprotein, high density lipoprotein, and cholesterol)
are said to be ‘‘normalized’’
56
; platelets are thought to
be rendered less likely to aggregate thus lessening the
likelihood of clot formation,
107
and the immune system
(dendritic cells, macrophages and lymphocytes) may be
activated.
109
Laser Acupuncture and Trigger Points
Low power lasers with small focused spots can be
used to stimulate acupuncture points using the same
rules of point selection as in traditional Chinese needle
FIGURE 5. Some examples of LLLT devices and applications. (a and b) Intravascular laser therapy (Institute of Biological Laser
therapy, Gottingen, Germany). (c and d) Laserneedle acupuncture system (Laserneedle GmbH, Glienicke-Nordbahn, Germany). (e
and f) Lasercomb (Lexington Int LLC, Boca Raton, FL) for hair regrowth. (g) Laser cap (Transdermal Cap Inc, Gates Mills, OH) for
hair regrowth.
The Nuts and Bolts of Low-level Laser (Light) Therapy

acupuncture.
119
Laser acupuncture may be used solely
or in combination with needles for any given condition
over a course of treatment. Trigger points are defined
as hyperirritable spots in skeletal muscle that are
associated with palpable nodules in taut bands of
muscle fibers. They may also be found in ligaments,
tendons, and periosteum. Higher doses of LLLT may
be used for the deactivation of trigger points. Direct
irradiation over tendons, joint margins, bursae etc.
may be effective in the treatment of conditions in
which trigger points may play a part. The Laserneedle
system (see Figs. 5c, 5d) can be used to stimulate
multiple acupuncture points or trigger points simulta-
neously.
97
LLLT for Hair Regrowth
One of the most commercially successful applica-
tions of LLLT is the stimulation of hair regrowth in
balding individuals. The photobiomodulation activity
of LLLT can cause more hair follicles to move from
telogen phase into anagen phase. The newly formed
hair is thicker and also more pigmented. The Hairmax
Lasercomb (Fig. 5e) was shown
55
to give a statistically
significant improvement in hair growth in a random-
ized, double-blind, sham device-controlled, multicenter
trial in 110 men with androgenetic alopecia and this led
to FDA clearance for efficacy (FDA 510(k) number
K060305).The teeth of the comb are supposed to im-
prove the penetration of light though the existing hair
to the follicles requiring stimulation (Fig. 5f). Re-
cently, a different LLLT device received FDA clear-
ance in women suffering from androgenetic alopecia
(FDA 510(k) numberK091496). This group of patients
have fewer treatment options than men. In order to
make the application of light to the head more user-
friendly and increase patient compliance, companies
have developed ‘‘laser caps’’ (Fig. 5g).
CONCLUSION AND OUTLOOK
Advances in design and manufacturing of LLLT
devices in the years to come will continue to widen the
acceptability and increase adoption of the therapy
among the medical profession, physical therapists and
the general public. While the body of evidence for
LLLT and its mechanisms is still weighted in favor of
lasers and directly comparative studies are scarce,
ongoing work using non-laser irradiation sources is
encouraging and provides support for growth in the
manufacture and marketing of affordable home-use
LED devices. The almost complete lack of reports of
side effects or adverse events associated with LLLT
gives security for issues of safety that will be required.
We believe that LLLT will steadily progress to be
better accepted by both the medical profession and the
general public at large. The number of published
negative reports will continue to decline as the opti-
mum LLLT parameters become better understood,
and as reviewers and editors of journals become aware
of LLLT as a scientifically based therapy. On the
clinical side, the public’s distrust of big pharmaceutical
companies and their products is also likely to continue
to grow. This may be a powerful force for adoption of
therapies that once were considered as ‘‘alternative and
complementary,’’ but now are becoming more scien-
tifically accepted. LLLT is not the only example of this
type of therapy, but needle acupuncture, transcranial
magnetic stimulation and microcurrent therapy also
fall into this class. The day may not be far off when
most homes will have a light source (most likely a LED
device) to be used for aches, pains, cuts, bruises, joints,
and which can also be applied to the hair and even
transcranially to the brain.
ACKNOWLEDGMENTS
Funding: Research in the Hamblin laboratory is
supported by NIH grant R01AI050875, Center for
Integration of Medicine and Innovative Technology
(DAMD17-02-2-0006), CDMRP Program in TBI
(W81XWH-09-1-0514) and Air Force Office of Scien-
tific Research (FA9950-04-1-0079). Tianhong Dai
was supported by an Airlift Research Foundation
Extremity Trauma Research Grant (grant 109421).
CONFLICTS OF INTEREST
James D. Carroll is the owner of THOR Photo-
medicine, a company which sells LLLT devices.
REFERENCES
1
Abergel, R. P., R. F. Lyons, J. C. Castel, R. M. Dwyer,
and J. Uitto. Biostimulation of wound healing by lasers:
experimental approaches in animal models and in fibro-
blast cultures. J. Dermatol. Surg. Oncol. 13:127–133,
1987.
2
Ad, N., and U. Oron. Impact of low level laser irradiation
on infarct size in the rat following myocardial infarction.
Int. J. Cardiol. 80:109–116, 2001.
3
Almeida-Lopes, L., J. Rigau, and R. A. Zangaro. Com-
parison of the low level laser therapy effects on cultured
human gingival fibroblasts proliferation using different
irradiance and same fluence. Lasers Surg. Med. 29:179–
184, 2001.
4
Anneroth, G., G. Hall, H. Ryden, and L. Zetterqvist. The
effect of low-energy infra-red laser radiation on wound
CHUNG et al.

healing in rats. Br. J. Oral. Maxillofac. Surg. 26:12–17,
1988.
5
Antunes, F., A. Boveris, and E. Cadenas. On the mech-
anism and biology of cytochrome oxidase inhibition by
nitric oxide. Proc. Natl Acad. Sci. USA. 101:16774–16779,
2004.
6
Ball, K. A., P. R. Castello, and R. O. Poyton. Low
intensity light stimulates nitrite-dependent nitric oxide
synthesis but not oxygen consumption by cytochrome c
oxidase: Implications for phototherapy. J. Photochem.
Photobiol. B. 102:182–191, 2011.
7
Bisht, D., S. C. Gupta, and V. Mistra. Effect of low
intensity laser radiation on healing of open skin wounds
in rats. Indian J. Med. Res. 100:43–46, 1994.
8
Bisht, D., R. Mehrortra, P. A. Singh, S. C. Atri, and
A. Kumar. Effect of helium-neon laser on wound healing.
Indian J. Exp. Biol. 37:187–189, 1999.
9
Bjordal, J. M., C. Couppe, R. T. Chow, J. Tuner, and
E. A. Ljunggren. A systematic review of low level laser
therapy with location-specific doses for pain from chronic
joint disorders. Aust. J. Physiother. 49:107–116, 2003.
10
Capaldi, R. A., F. Malatesta, and V. M. Darley-Usmar.
Structure of cytochrome coxidase. Biochim. Biophys. Acta
726:135–148, 1983.
11
Castano, A. P., T. Dai, I. Yaroslavsky, R. Cohen, W. A.
Apruzzese, M. H. Smotrich, and M. R. Hamblin. Low-
level laser therapy for zymosan-induced arthritis in rats:
importance of illumination time. Lasers Surg. Med.
39:543–550, 2007.
12
Cauwels, R. G., and L. C. Martens. Low level laser
therapy in oral mucositis: a pilot study. Eur. Arch Paedi-
atr. Dent. 12:118–123, 2011.
13
Chandrasekhar, S. Radiative transfer. New York: Dover
Publications, 1960.
14
Chang, W. D., J. H. Wu, J. A. Jiang, C. Y. Yeh, and C. T.
Tsai. Carpal tunnel syndrome treated with a diode laser: a
controlled treatment of the transverse carpal ligament.
Photomed. Laser Surg. 26:551–557, 2008.
15
Chen, A. C.-H., P. R. Arany, Y.-Y. Huang, E. M. Tom-
kinson, T. Saleem, F. E. Yull, T. S. Blackwell, and M. R.
Hamblin. Low level laser therapy activates NF-jB via
generation of reactive oxygen species in mouse embryonic
fibroblasts. Proc. SPIE. 7165:71650–71659, 2009.
16
Cheong, W. F., S. A. Prahl, and A. J. Welch. A review of
the optical properties of biological tissues. IEEE J.
Quantum Electron. 26:2166–2185, 1990.
17
Chow, R. T., M. I. Johnson, R. A. Lopes-Martins, and J.
M. Bjordal. Efficacy of low-level laser therapy in the
management of neck pain: a systematic review and meta-
analysis of randomised placebo or active-treatment con-
trolled trials. Lancet 374:1897–1908, 2009.
18
Christie, A., G. Jamtvedt, K. T. Dahm, R. H. Moe,
E. Haavardsholm, and K. B. Hagen. Effectiveness of
nonpharmacological and nonsurgical interventions for
patients with rheumatoid arthritis: an overview of sys-
tematic reviews. Phys. Ther. 87:1697–1715, 2007.
19
da Silva, D. F., B. C. Vidal, D. M. Zezell, T. M. Zorn, S.
C. Nunez, and M. S. Ribeiro. Collagen birefringence in
skin repair in response to red polarized-laser therapy. J.
Biomed. Opt. 11:024002, 2006.
20
Demidova-Rice, T. N., E. V. Salomatina, A. N. Yaro-
slavsky, I. M. Herman, and M. R. Hamblin. Low-level
light stimulates excisional wound healing in mice. Lasers
Surg. Med. 39:706–715, 2007.
21
deTaboada, L., S. Ilic, S. Leichliter-Martha, U. Oron,
A. Oron, J. Streeter, et al. Transcranial application of low-
energy laser irradiation improves neurological deficits in
rats following acute stroke. Lasers Surg. Med. 38:70–73,
2006.
22
el Sayed, S. O., and M. Dyson. Effect of laser pulse rep-
etition rate and pulse duration on mast cell number and
degranulation. Lasers Surg. Med. 19:433–437, 1996.
23
Emanet, S. K., L. I. Altan, and M. Yurtkuran. Investi-
gation of the effect of GaAs laser therapy on lateral epi-
condylitis. Photomed. Laser Surg. 28:397–403, 2010.
24
Gigo-Benato, D., S. Geuna, and S. Rochkind. Photo-
therapy for enhancing peripheral nerve repair: a review of
the literature. Muscle Nerve. 31:694–701, 2005.
25
Goodson, W. H., and T. K. Hunt. Wound healing and the
diabetic patient. Surg. Gynecol. Obstet. 149:600–608, 1979.
26
Gouvea de Lima, A., R. C. Villar, G. de Castro, Jr., R.
Antequera, E. Gil, M. C. Rosalmeida, M. H. Federico,
and I. M. Snitcovsky. Oral mucositis prevention by low-
level laser therapy in head-and-neck cancer patients
undergoing concurrent chemoradiotherapy: a phase III
randomized study. Int. J. Radiat. Oncol. Biol. Phys. 2010.
[Epub ahead of print]. doi:10.1016/j.ijrobp.2010.10.012.
27
Greco, M., G. Guida, E. Perlino, E. Marra, and
E. Quagliariello. Increase in RNA and protein synthesis
by mitochondria irradiated with helium-neon laser. Bio-
chem. Biophys. Res. Commun. 163:1428–1434, 1989.
28
Gur, A., A. Cosut, A. J. Sarac, R. Cevik, K. Nas, and
A. Uyar. Efficacy of different therapy regimes of low-
power laser in painful osteoarthritis of the knee: a double-
blind and randomized-controlled trial. Lasers Surg. Med.
33:330–338, 2003.
29
Hashmi, J. T., Y.-Y. Huang, B. Z. Osmani, S. K. Sharma,
M. A. Naeser, and M. R. Hamblin. Role of low-level laser
therapy in neurorehabilitation. PM & R. 2:S292–S305,
2010.
30
Hashmi, J. T., Y. Y. Huang, S. K. Sharma, D. B. Kurup,
L. De Taboada, J. D. Carroll, and M. R. Hamblin. Effect
of pulsing in low-level light therapy. Lasers Surg. Med.
42:450–466, 2010.
31
Hawkins, D., and H. Abrahamse. Biological effects of
helium-neon laser irradiation on normal and wounded
human skin fibroblasts. Photomed. Laser Surg. 23:251–
259, 2005.
32
Hawkins, D., N. Houreld, and H. Abrahamse. Low level
laser therapy (LLLT) as an effective therapeutic modality
for delayed wound healing. Ann. NY Acad. Sci. 1056:486–
493, 2005.
33
Haxsen, V., D. Schikora, U. Sommer, A. Remppis,
J. Greten, and C. Kasperk. Relevance of laser irradiance
threshold in the induction of alkaline phosphatase in
human osteoblast cultures. Lasers Med. Sci. 23:381–384,
2008.
34
Hayworth, C. R., J. C. Rojas, E. Padilla, G. M. Holmes,
E. C. Sheridan, and F. Gonzalez-Lima. In vivo low-level
light therapy increases cytochrome oxidase in skeletal
muscle. Photochem. Photobiol. 86:673–680, 2010.
35
Hegedus, B., L. Viharos, M. Gervain, and M. Galfi. The
effect of low-level laser in knee osteoarthritis: a double-
blind, randomized, placebo-controlled trial. Photomed.
Laser Surg. 27:577–584, 2009.
36
Hoffmann, G. Principles and working mechanisms of
water-filtered infrared-A (wIRA) in relation to wound
healing. GMS Krankenhhyg Interdiszip. 2:Doc54, 2007.
The Nuts and Bolts of Low-level Laser (Light) Therapy

37
Huang, Y.-Y., A. C.-H. Chen, J. D. Carroll, et al. Bi-
phasic dose response in low level light therapy. Dose Re-
sponse 7:358–383, 2009.
38
Huang, Y. Y., S. K. Sharma, J. D. Carroll, and M. R.
Hamblin. Biphasic dose response in low level light ther-
apy—an update. Dose Response 2011, in press.
39
Huang, C. Y., R. S. Yang, T. S. Kuo, and K. H. Hsu.
Phantom limb pain treated by far infrared ray. Conf. Proc.
IEEE Eng. Med. Biol. Soc. 2009:1589–1591, 2009.
40
Jamtvedt, G., K. T. Dahm, A. Christie, R. H. Moe, E.
Haavardsholm, I. Holm, and K. B. Hagen. Physical
therapy interventions for patients with osteoarthritis of
the knee: an overview of systematic reviews. Phys. Ther.
88:123–136, 2008.
41
Kana, J. S., G. Hutschenreiter, D. Haina, and W. Wa-
idelich. Effect of low-power density laser radiation on
healing of open skin wounds in rats. Arch. Surg. 116:293–
296, 1981.
42
Karu, T. I. Photobiological fundamentals of low-power
laser therapy. IEEE J. Quantum Electron. 23:1703–1717,
1987.
43
Karu, T. I. Primary and secondary mechanisms of action
of visible to near-IR radiation on cells. J. Photochem.
Photobiol. B. 49:1–17, 1999.
44
Karu, T. I., and N. I. Afanas’eva. Cytochrome coxidase
as the primary photoacceptor upon laser exposure of
cultured cells to visible and near IR-range light. Dokl.
Akad. Nauk. 342:693–695, 1995.
45
Karu, T. I., and S. F. Kolyakov. Exact action spectra for
cellular responses relevant to phototherapy. Photomed.
Laser Surg. 23:355–361, 2005.
46
Karu, T. I., L. V. Pyatibrat, and N. I. Afanasyeva. Cel-
lular effects of low power laser therapy can be mediated
by nitric oxide. Lasers Surg. Med. 36:307–314, 2005.
47
Karu, T. I., L. V. Pyatibrat, and G. S. Kalendo. Irradia-
tion with He-Ne laser increases ATP level in cells culti-
vated in vitro. J. Photochem. Photobiol. B 27:219–223,
1995.
48
Kaviani, A., G. E. Djavid, L. Ataie-Fashtami, M. Fateh,
M. Ghodsi, M. Salami, N. Zand, N. Kashef, and B.
Larijani. A randomized clinical trial on the effect of low-
level laser therapy on chronic diabetic foot wound healing:
a preliminary report. Photomed. Laser Surg. 29:109–114,
2011.
49
Kokol, R., C. Berger, J. Haas, and D. Kopera. Venous leg
ulcers: no improvement of wound healing with 685-nm
low level laser therapy. Randomised, placebo-controlled,
double-blind study. Hautarzt 56:570–575, 2005.
50
Lam, L. K., and G. L. Cheing. Effects of 904-nm low-level
laser therapy in the management of lateral epicondylitis: a
randomized controlled trial. Photomed. Laser Surg. 25:65–
71, 2007.
51
Lampl, Y., J. A. Zivin, M. Fisher, R. Lew, L. Welin, B.
Dahlof, P. Borenstein, B. Andersson, J. Perez, C. Caparo,
S. Ilic, and U. Oron. Infrared laser therapy for ischemic
stroke: a new treatment strategy: results of the Neuro-
Thera Effectiveness and Safety Trial-1 (NEST-1). Stroke
38:1843–1849, 2007.
52
Lane, N. Cell biology: power games. Nature 443:901–903,
2006.
53
Lanzafame, R. J., I. Stadler, A. F. Kurtz, R. Connelly, T.
A. Peter, Sr., P. Brondon, and D. Olson. Reciprocity of
exposure time and irradiance on energy density during
photoradiation on wound healing in a murine pressure
ulcer model. Lasers Surg. Med. 39:534–542, 2007.
54
Lapchak, P. A., K. F. Salgado, C. H. Chao, and J. A.
Zivin. Transcranial near-infrared light therapy improves
motor function following embolic strokes in rabbits: an
extended therapeutic window study using continuous and
pulse frequency delivery modes. Neuroscience 148:907–
914, 2007.
55
Leavitt, M., G. Charles, E. Heyman, and D. Michaels.
HairMax LaserComb laser phototherapy device in the
treatment of male androgenetic alopecia: a randomized,
double-blind, sham device-controlled, multicentre trial.
Clin. Drug Invest. 29:283–292, 2009.
56
Lebed’kov, E. V., P. I. Tolstykh, L. F. Marchenko, T. I.
Turkina, and V. T. Krivikhin. The effect of the laser
irradiation of the blood on its lipid and phospholipid
components in diabetes mellitus. Voen Med. Zh. 319:37–
38, 95, 1998.
57
Lee, G., R. M. Ikeda, R. M. Dwyer, H. Hussein, P.
Dietrich, and D. T. Mason. Feasibility of intravascular
laser irradiation for in vivo visualization and therapy of
cardiocirculatory diseases. Am. Heart J. 103:1076–1077,
1982.
58
Lima, A. G., R. Antequera, M. P. Peres, I. M. Snitcosky,
M. H. Federico, and R. C. Villar. Efficacy of low-level
laser therapy and aluminum hydroxide in patients with
chemotherapy and radiotherapy-induced oral mucositis.
Braz Dent J. 21:186–192, 2010.
59
Lin, Y. S., M. H. Huang, and C. Y. Chai. Effects of he-
lium-neon laser on the mucopolysaccharide induction in
experimental osteoarthritic cartilage. Osteoarthr. Cartil.
14:377–383, 2006.
60
Loevschall, H., and D. Arenholt-Bindeslev. Effect of low
level diode laser irradiation of human oral mucosa fibro-
blasts in vitro. Lasers Surg. Med. 14:347–354, 1994.
61
Lohr, N. L., A. Keszler, P. Pratt, M. Bienengraber, D. C.
Warltier, and N. Hogg. Enhancement of nitric oxide re-
lease from nitrosyl hemoglobin and nitrosyl myoglobin by
red/near infrared radiation: potential role in cardiopro-
tection. J. Mol. Cell. Cardiol. 47:256–263, 2009.
62
Lundeberg, T., and M. Malm. Low-power HeNe laser
treatment of venous leg ulcers. Ann. Plast. Surg. 27:537–
539, 1991.
63
Martius, F. Das Amdt-Schulz Grandgesetz. Munch. Med.
Wschr. 70:1005–1006, 1923.
64
McCarthy, T. J., L. De Taboada, P. K. Hildebrandt, E. L.
Ziemer, S. P. Richieri, and J. Streeter. Long-term safety of
single and multiple infrared transcranial laser treatments
in Sprague-Dawley rats. Photomed. Laser Surg. 28:663–
667, 2010.
65
McGuff, P. E., D. Bushnell, H. S. Soroff, and R. A. De-
terling, Jr. Studies of the surgical applications of laser
(light amplification by stimulated emission of radiation).
Surg. Forum. 14:143–145, 1963.
66
Medalha, C. C., B. O. Amorim, J. M. Ferreira, P. Oli-
veira, R. M. Pereira, C. Tim, A. P. Lirani-Galvao, O. L.
da Silva, and A. C. Renno. Comparison of the effects of
electrical field stimulation and low-level laser therapy on
bone loss in spinal cord-injured rats. Photomed. Laser
Surg. 28:669–674, 2010.
67
Medrado, A. R., L. S. Pugliese, S. R. Reis, and Z. A.
Andrade. Influence of low level laser therapy on wound
healing and its biological action upon myofibroblasts.
Lasers Surg. Med. 32:239–244, 2003.
68
Mester, E., A. F. Mester, and A. Mester. The biomedical
effects of laser application. Lasers Surg. Med. 5:31–39,
1985.
CHUNG et al.

69
Mester, E., S. Nagylucskay, A. Doklen, and S. Tisza.
Laser stimulation of wound healing. Acta Chir. Acad. Sci.
Hung. 17:49–55, 1976.
70
Mester, E., T. Spiry, B. Szende, and J. G. Tota. Effect of
laser rays on wound healing. Am. J. Surg. 122:532–535,
1971.
71
Mester, E., B. Szende, T. Spiry, and A. Scher. Stimulation
of wound healing by laser rays. Acta Chir. Acad. Sci.
Hung. 13:315–324, 1972.
72
Mester, E., B. Szende, and J. G. Tota. Effect of laser on
hair growth of mice. Kiserl Orvostud. 19:628–631, 1967.
73
Meyers, A. D. Lasers and wound healing. Arch. Otolar-
yngol. Head Neck Surg. 116:1128, 1990.
74
Michalikova, S., A. Ennaceur, R. van Rensburg, and P. L.
Chazot. Emotional responses and memory performance
of middle-aged CD1 mice in a 3D maze: effects of low
infrared light. Neurobiol. Learn. Mem. 89:480–488, 2008.
75
Moges, H., O. M. Vasconcelos, W. W. Campbell, R. C.
Borke, J. A. McCoy, L. Kaczmarczyk, J. Feng, and J. J.
Anders. Light therapy and supplementary Riboflavin in
the SOD1 transgenic mouse model of familial amyotro-
phic lateral sclerosis (FALS). Lasers Surg. Med. 41:52–59,
2009.
76
Moore, P., T. D. Ridgway, R. G. Higbee, E. W. Howard,
and M. D. Lucroy. Effect of wavelength on low-intensity
laser irradiation-stimulated cell proliferation in vitro.
Lasers Surg. Med. 36:8–12, 2005.
77
Moreira, M. S., I. T. Velasco, L. S. Ferreira, S. K. Ariga,
D. F. Barbeiro, D. T. Meneguzzo, F. Abatepaulo, and M.
M. Marques. Effect of phototherapy with low intensity
laser on local and systemic immunomodulation following
focal brain damage in rat. J. Photochem. Photobiol. B.
97:145–151, 2009.
78
Moreno, I., and C. C. Sun. Modeling the radiation pattern
of LEDs. Opt. Express 16:1808–1819, 2008.
79
Naeser, M. A., A. Saltmarche, M. H. Krengel, M. R.
Hamblin, and J. A. Knight. Improved cognitive function
after transcranial, light-emitting diode treatments in
chronic, traumatic brain injury: two case reports. Pho-
tomed. Laser Surg. 29:351–358, 2011.
80
Noble, P. B., E. D. Shields, P. D. Blecher, and K. C.
Bentley. Locomotory characteristics of fibroblasts within
a three-dimensional collagen lattice: modulation by a
Helium/Neon soft laser. Lasers Surg. Med. 12:669–674,
1992.
81
Oron, A., U. Oron, J. Chen, A. Eilam, C. Zhang, M.
Sadeh, Y. Lampl, J. Streeter, L. DeTaboada, and M.
Chopp. Low-level laser therapy applied transcranially to
rats after induction of stroke significantly reduces long-
term neurological deficits. Stroke 37:2620–2624, 2006.
82
Oron, A., U. Oron, J. Streeter, L. de Taboada, A. Alex-
androvich, V. Trembovler, and E. Shohami. Low-level
laser therapy applied transcranially to mice following
traumatic brain injury significantly reduces long-term
neurological deficits. J. Neurotrauma. 24:651–656, 2007.
83
Passarella, S., E. Casamassima, S. Molinari, D. Pastore,
E. Quagliariello, I. M. Catalano, and A. Cingolani. In-
crease of proton electrochemical potential and ATP syn-
thesis in rat liver mitochondria irradiated in vitro by
helium-neon laser. FEBS Lett. 175:95–99, 1984.
84
Pastore, D., M. Greco, V. A. Petragallo, and S. Passarella.
Increase in H
+
/e
2
ratio of the cytochrome coxidase
reaction in mitochondria irradiated with helium-neon
laser. Biochem. Mol. Biol. Int. 34:817–826, 1994.
85
Pereira, A. N., P. Eduardo Cde, E. Matson, and M. M.
Marques. Effect of low-power laser irradiation on cell
growth and procollagen synthesis of cultured fibroblasts.
Lasers Surg. Med. 31:263–267, 2002.
86
Pinheiro, A. L., D. H. Pozza, M. G. Oliveira, R. Weiss-
mann, and L. M. Ramalho. Polarized light (400–2000 nm)
and non-ablative laser (685 nm): a description of the
wound healing process using immunohistochemical anal-
ysis. Photomed. Laser Surg. 23:485–492, 2005.
87
Posten, W., D. A. Wrone, J. S. Dover, K. A. Arndt, S.
Silapunt, and M. Alam. Low-level laser therapy for
wound healing: mechanism and efficiency. Dermatol.
Surg. 31:334–340, 2005.
88
Poyton, R. O., and K. A. Ball. Therapeutic photobio-
modulation: nitric oxide and a novel function of mito-
chondrial cytochrome coxidase. Discov. Med. 11:154–159,
2011.
89
Raskin, P., J. F. Marks, H. Burns, M. D. Plumer, and M.
D. L. Siperstein. Capillary basement membrane within
diabetic children. Am. J. Med. 58:365–375, 1975.
90
Reddy, G. K., L. Stehno-Bittel, and C. S. Enwemeka.
Laser photostimulation accelerates wound healing in
diabetic rats. Wound Repair Regen. 9:248–255, 2001.
91
Ribeiro, M. S., D. F. Da Silva, C. E. De Araujo, S. F. De
Oliveira, C. M. Pelegrini, T. M. Zorn, and D. M. Zezell.
Effects of low-intensity polarized visible laser radiation on
skin burns: a light microscopy study. J. Clin. Laser Med.
Surg. 22:59–66, 2004.
92
Rubio, C. R., D. Cremonezzi, M. Moya, F. Soriano, J.
Palma, and V. Campana. Helium-neon laser reduces the
inflammatory process of arthritis. Photomed. Laser Surg.
28:125–129, 2010.
93
Sandford, M. A., and L. J. Walsh. Thermal effects during
desensitisation of teeth with gallium-aluminium-arsenide
lasers. Periodontology 15:25–30, 1994.
94
Santana-Blank, L., and E. Rodriguez-Santana. The
interaction of light with nanoscopic layers of water may
be essential to the future of photobiomodulation. Pho-
tomed. Laser Surg. 28(Suppl 1):S173–S174, 2010.
95
Santana-Blank, L., E. Rodriguez-Santana, and K. San-
tana-Rodriguez. Theoretic, experimental, clinical bases of
the water oscillator hypothesis in near-infrared photo-
biomodulation. Photomed. Laser Surg. 28(Suppl 1):S41–
S52, 2010.
96
Schiffer, F., A. L. Johnston, C. Ravichandran, A. Polcari,
M. H. Teicher, R. H. Webb, and M. R. Hamblin. Psy-
chological benefits 2 and 4 weeks after a single treatment
with near infrared light to the forehead: a pilot study of 10
patients with major depression and anxiety. Behav. Brain
Funct. 5:46, 2009.
97
Schikora, D. Laserneedle acupuncture: a critical review
and recent results. Med. Acupunct. 20:37–42, 2008.
98
Schindl, A., G. Heinze, M. Schindl, H. Pernerstorfer-
Schon, and L. Schindl. Systemic effects of low-intensity
laser irradiation on skin microcirculation in patients with
diabetic microangiopathy. Microvasc. Res. 64:240–246,
2002.
99
Schindl, A., M. Schindl, and H. Pernerstorfer-Schon. Low
intensity laser irradiation in the treatment of recalcitrant
radiation ulcers in patients with breast cancer–long-term
results of 3 cases. Photodermatol. Photoimmunol. Pho-
tomed. 16:34–37, 2000.
100
Schindl, A., M. Schindl, H. Schon, R. Knobler, L. Havelec,
and L. Schindl. Low-intensity laser irradiation improves
The Nuts and Bolts of Low-level Laser (Light) Therapy

skin circulation in patients with diabetic microangiopathy.
Diabetes Care. 21:580–584, 1998.
101
Shen, J., L. Xie, X. O. Mao, Y. Zhou, R. Zhan, D. A.
Greenberg, and K. Jin. Neurogenesis after primary intra-
cerebral hemorrhage in adult human brain. J. Cereb.
Blood Flow Metab. 28:1460–1468, 2008.
102
Shooshtari, S. M., V. Badiee, S. H. Taghizadeh, A. H.
Nematollahi, A. H. Amanollahi, and M. T. Grami. The
effects of low level laser in clinical outcome and neuro-
physiological results of carpal tunnel syndrome. Electro-
myogr. Clin. Neurophysiol. 48:229–231, 2008.
103
Simunovic, Z., T. Trobonjaca, and Z. Trobonjaca.
Treatment of medial and lateral epicondylitis–tennis and
golfer’s elbow—with low level laser therapy: a multicenter
double blind, placebo-controlled clinical study on 324
patients. J. Clin. Laser Med. Surg. 16:145–151, 1998.
104
Skinner, S. M., J. P. Gage, P. A. Wilce, and R. M. Shaw. A
preliminary study of the effects of laser radiation on collagen
metabolism in cell culture. Aust. Dent. J. 41:188–192, 1996.
105
Sommer, A. P., A. L. Pinheiro, A. R. Mester, R. P. Franke,
and H. T. Whelan. Biostimulatory windows in low-intensity
laser activation: lasers, scanners, and NASA’s light-emitting
diode array system. J. Clin. Laser Med. Surg. 19:29–33, 2001.
106
Spanheimer, R. G., G. E. Umpierrez, and V. Stumpf.
Decreased collagen production in diabetic rats. Diabetes
37:371–376, 1988.
107
Stebliukova, I. A., N. B. Khairetdinova, A. M. Belov, and
N. A. Kakitelashvili. Effects of low-energy laser irradia-
tion on platelet aggregation in cerebrovascular disorders.
Sov. Med. (3):77–80, 1989.
108
Sutherland, J. C. Biological effects of polychromatic light.
Photochem. Photobiol. 76:164–170, 2002.
109
Tadakuma, T. Possible application of the laser in
immunobiology. Keio J. Med. 42:180–182, 1993.
110
Tascioglu, F., N. A. Degirmenci, S. Ozkan, and O. Meh-
metoglu. Low-level laser in the treatment of carpal tunnel
syndrome: clinical, electrophysiological, and ultrasono-
graphical evaluation. Rheumatol. Int. 2010. [Epub ahead
of print]. doi:10.1007/s00296-010-1652-6.
111
Thomas, D. W., I. D. O’Neill, K. G. Harding, and J. P.
Shepherd. Cutaneous wound healing: a current perspec-
tive. J. Oral Maxillofac. Surg. 53:442–447, 1995.
112
Trimmer, P. A., K. M. Schwartz, M. K. Borland,
L. DeTaboada, J. Streeter, and U. Oron. Reduced axonal
transport in Parkinson’s disease cybrid neurites is restored
by light therapy. Mol. Neurodegener. 4:26, 2009.
113
Tuby, H., L. Maltz, and U. Oron. Modulations of VEGF
and iNOS in the rat heart by low level laser therapy are
associated with cardioprotection and enhanced angiogen-
esis. Lasers Surg. Med. 38:682–688, 2006.
114
Wahl, G., and S. Bastanier. Soft laser in postoperative
care in dentoalveolar treatment. ZWR 100:512–515, 1991.
115
Walsh, L. J., G. Trinchieri, H. A. Waldorf, D. Whitaker,
and G. F. Murphy. Human dermal mast cells contain and
release tumor necrosis factor-alpha which induces endo-
thelial leukocyte adhesion molecule-1. Proc. Natl Acad.
Sci. USA. 88:4220–4224, 1991.
116
Webb, C., M. Dyson, and W. H. Lewis. Stimulatory effect
of 660 nm low level laser energy on hypertrophic scar--
derived fibroblasts: possible mechanisms for increase in
cell counts. Lasers Surg. Med. 22:294–301, 1998.
117
Weber, M. H., and T. W. Fussga
¨nger-May. Intravenous
laser blood irradiation. German J. Acupunct. Rel. Tech.
50:12–23, 2007.
118
Welch, A. J., J. H. Torres, and W. F. Cheong. Laser
physics and laser-tissue interaction. Tex. Heart Inst. J.
16:141–149, 1989.
119
Whittaker, P. Laser acupuncture: past, present, and fu-
ture. Lasers Med. Sci. 19:69–80, 2004.
120
Wu, X., A. E. Dmitriev, M. J. Cardoso, A. G. Viers-
Costello, R. C. Borke, J. Streeter, and J. J. Anders.
810 nm wavelength light: an effective therapy for tran-
sected or contused rat spinal cord. Lasers Surg. Med.
41:36–41, 2009.
121
Wu, Q., Y. Y. Huang, S. Dhital, S. K. Sharma, A. C.
Chen, M. J. Whalen, and M. R. Hamblin. Low level laser
therapy for traumatic brain injury. Proc. SPIE.
7552:755201–755206, 2010.
122
Xiao, L., Z. Chen, B. Qu, J. Luo, S. Kong, Q. Gong, and
J. Kido. Recent progresses on materials for electrophos-
phorescent organic light-emitting devices. Adv. Mater.
23:926–952, 2011.
123
Yang, Z., Y. Wu, H. Zhang, P. Jin, W. Wang, J. Hou, Y.
Wei, and S. Hu. Low-level laser irradiation alters cardiac
cytokine expression following acute myocardial infarction:
a potential mechanism for laser therapy. Photomed. Laser
Surg. 29:391–398, 2011.
124
Yu, W., J. O. Naim, and J. Lanzafame. Effects of phot-
ostimulation on wound healing in diabetic mice. Lasers
Surg. Med. 20:56–63, 1997.
125
Yu, H. S., C. S. Wu, C. L. Yu, Y. H. Kao, and M. H.
Chiou. Helium-neon laser irradiation stimulates migration
and proliferation in melanocytes and induces repigmen-
tation in segmental-type vitiligo. J. Invest. Dermatol.
120:56–64, 2003.
126
Zand, N., L. Ataie-Fashtami, G. E. Djavid, M. Fateh, M.
R. Alinaghizadeh, S. M. Fatemi, and F. Arbabi-Kalati.
Relieving pain in minor aphthous stomatitis by a single
session of non-thermal carbon dioxide laser irradiation.
Lasers Med. Sci. 24:515–520, 2009.
127
Zhang, R., Y. Mio, P. F. Pratt, N. Lohr, D. C. Warltier,
H. T. Whelan, D. Zhu, E. R. Jacobs, M. Medhora, and M.
Bienengraeber. Near infrared light protects cardiomyo-
cytes from hypoxia and reoxygenation injury by a nitric
oxide dependent mechanism. J. Mol. Cell. Cardiol. 46:4–
14, 2009.
128
Zhang, Y., S. Song, C. C. Fong, C. H. CTsang, Z.
Yang, and M. Yang. cDNA microarray analysis of
gene expression profiles in human fibroblast cells irra-
diated with red light. J. Invest. Dermatol. 120:849–857,
2003.
129
Zhang, L., D. Xing, D. Zhu, and Q. Chen. Low-power
laser irradiation inhibiting Abeta25–35-induced PC12 cell
apoptosis via PKC activation. Cell Physiol. Biochem.
22:215–222, 2008.
130
Zivin, J. A., G. W. Albers, N. Bornstein, T. Chippendale,
B. Dahlof, T. Devlin, M. Fisher, W. Hacke, W. Holt, S.
Ilic, S. Kasner, R. Lew, M. Nash, J. Perez, M. Rymer, P.
Schellinger, D. Schneider, S. Schwab, R. Veltkamp, M.
Walker, and J. Streeter. Effectiveness and safety of
transcranial laser therapy for acute ischemic stroke. Stroke
40:1359–1364, 2009.
131
Zycinski, P., M. Krzeminska-Pakula, C. Peszynski-Drews,
A. Kierus, E. Trzos, T. Rechcinski, L. Figiel, M. Kurpesa,
M. Plewka, L. Chrzanowski, and J. Drozdz. Laser bi-
ostimulation in end-stage multivessel coronary artery dis-
ease–a preliminary observational study. Kardiol. Pol.
65:13–21, 2007; discussion 22–13.
CHUNG et al.