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

  • shri vaishnav vidyapeeth vishwavidyalaya

Abstract and Figures

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.
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The Nuts and Bolts of Low-level Laser (Light) Therapy
Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, MA, USA;
Department of Dermatology,
Harvard Medical School, Boston, MA, USA;
Aesthetic and Plastic Center of Guangxi Medical University, Nanning, People’s
Republic of China;
Thor Photomedicine Ltd, 18A East Street, Chesham HP5 1HQ, UK; and
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.
AbstractSoon 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.
KeywordsLow level laser therapy, Photobiomodulation,
Mitochondria, Tissue optics, Wound healing, Hair regrowth,
Laser acupuncture.
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.
He also demonstrated that the HeNe laser could
stimulate wound healing in mice.
Mester soon
applied his findings to human patients, using lasers to
treat patients with nonhealing skin ulcers.
has now developed into a therapeutic procedure that is
used in three main ways: to reduce inflammation,
edema, and chronic joint disorders
; to promote
healing of wounds, deeper tissues, and nerves
to treat neurological disorders and pain.
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:
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.
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.
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.
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
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
) relative
to the peak irradiance. About 85% of the power of the
laser beam is present within the 1/e
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
), and
integrated optical components may be used to shape its
radiation pattern.
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
where h
is the angle between the light and the surface
normal in the air, h
is the angle between the ray and
the surface normal in the tissue, n
is the index of
refraction of air, n
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
) characterizes the absorption. The
inverse, l
, 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
). The
inverse parameter, 1/l
(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
), is defined as:
The sum of l
and l
is called the total attenuation
coefficient l
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.
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:
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
,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).
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
to increase adenosine tri-
phosphate (ATP) production,
modulation of reactive
oxygen species (ROS), and the induction of transcrip-
tion factors.
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.
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.
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,
which results in the release of the pro-inflammatory
cytokine TNF-a from the cells.
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.
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.
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,
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
This procedure indicates that complex
IV, also known as cytochrome coxidase (CCO), is the
crucial chromophore in the cellular response to
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.
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.
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.
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.
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.
A new explanation has been re-
cently proposed for how light increases NO bioavail-
CCO can act as a nitrite reductase enzyme (a
one electron reduction of nitrite gives NO) particularly
when the oxygen partial pressure is low.
Ball et al.
showed 590 ±14 nm LED light stimulated CCO/NO
synthesis at physiological nitrite concentrations at hy-
poxia condition.
The following reaction may take
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
and the production of
cytokines and growth factors, which have all been
shown to be stimulated by low-level light.
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.
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.
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,
the mid-IR region
including carbon dioxide laser (10.6 lm)
and also
include broad band IR sources in the 10–50 lm
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.
It is at present not clear
at which wavelength CCO absorption ceases and water
absorption commences to be important.
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
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
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.
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’’
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
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.
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
which has subsequently been discussed multiple
times in LLLT research.
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
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
treat skin ulcers.
LLLT is believed to affect all
three phases of wound healing
: 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-
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.
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-
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.
In contrast, other studies noted an increase in prolif-
eration of human fibroblasts exposed to 904 nm GaAs
rat myofibroblasts exposed to 670 nm GaAs
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
Often called Power Density (technically incorrect) and
is calculated as Power (W)/Area (cm
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
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 90rotated
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
The Nuts and Bolts of Low-level Laser (Light) Therapy
sers (670, 692, 780, and 786 nm).
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.
Bisht et al. found a
similar increase in granulation tissue and collagen
expression in rats using the same treatment as Kana.
However, Anneroth et al. failed to observe any bene-
ficial effects after laser treatment in a comparable rat
In human studies, Schindl et al. reported that
application of a HeNe laser was beneficial in promot-
ing wound healing in 3 patients,
whereas Lundeberg
et al. found no statistically significant difference
between leg ulcer patients treated with an HeNe laser
and those treated with a placebo.
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
and is thought to result from various
factors, including decreased collagen production and
impaired functionality of fibroblasts, leukocytes, and
endothelial cells.
It has therefore been hypothe-
sized that LLLT could have beneficial effects in stim-
ulating wound healing in diabetic patients.
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
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.
LLLT has also been shown to relieve pain
because of cervical dentinal hypersensitivity,
or from
periodontal pain during orthodontic tooth move-
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
Energy density J/cm
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
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.
TABLE 3. Pre-clinical studies on animals with low level light therapy for different conditions.
Disease Parameters
Subject Effect References
Myocardial infarction 804 nm; 38 mW; 4.5 ±0.1 mW/cm
0.27 J/cm
; CW, 1.5 93.5 mm
Rats Reduced the loss of myocardial tissue 2
Myocardial infarction 635 nm, 5 mW, 6 mW/cm
; 0.8 J–1 J/cm
CW; 0.8 cm
; 150 s
Rats The expression of multiple cytokines was regulated
in the acute phase after LLLI
Myocardial infarction 804 nm; 400 mW 8 mW/cm
; 0.96 J/cm
CW; 2 cm
; 120 s
Rats and
VEGF and iNOS expression markedly upregulated;
angiogenesis and cardioprotection enhanced
Stroke 808-nm; .5 mW/cm
; 0.9 J/cm
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
Stroke 808-nm; 7.5 mW/cm
; 0.9 J/cm
; 3.6 J/cm
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
TBI 808 ±10 nm; 70 mW; 2230 mW/cm
268 J/cm
at the scalp; 10 mW/cm
1.2 J/cm
at cortical surface; CW; 2 mm
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
TBI 808-nm; 200 mW; 10 and 20 mW/cm
1.2–2.4 J/cm
at cortical surface;
4 h post-trauma
Mice LLLT given 4 h following TBI provides a significant
long-term functional neurological benefit
TBI 660 nm or 780 nm, 40 mW; 3 J/cm
or 5 J/cm
; CW; 0.042 cm
(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
Spinal cord injury 830 nm; 100 mW; 30 mW/cm
; 250 J/cm
CW, 0.028 cm
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
Spinal cord injury 810 nm; 1589 J/cm
; 0.3 cm
, 2997 s;
daily for 14 days
Rats Promotes axonal regeneration and functional recovery
in acute SCI
Arthritis 632.8 nm; 5 mW; 8 J/cm
, 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
Arthritis 632.8-nm; 3.1 mW/cm
CW, 1 cm diameter;
15 min; 3 times a week for 8 weeks
Rats He–Ne laser treatment enhanced the biosynthesis
of arthritic cartilage
Arthritis 810-nm; 5 or 50 mW/cm
; 3 or 30 J/cm
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
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
; 1, 2, 10 and 50 J/cm
CW; 3-cm diameter
Mice 635-nm light had a maximum positive effect at 2 J/cm
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
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.
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
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
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.)
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.
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,
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
This hypothesis is supported by the fact that
the benefits of LLLT following a stroke may take 2–
TABLE 3. continued.
Disease Parameters
Subject Effect References
Familial amyotropic lateral
sclerosis (FALS)
810 nm; 140-mW; 12 J/cm
; CW; 1.4 cm
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
The light sources were all lasers unless LED is specifically mentioned.
The laser parameters are given in the following order: wavelength (nm); power (mW), power density (mW/cm
); energy (J); energy density (J/cm
); mode (CW) or pulsed (Hz); spot size
); 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
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
Stroke (NEST-1) 808-nm; 700 mW/cm
on shaved
scalp with cooling; 1 J/cm
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
808-nm; 700 mW/cm
on shaved scalp
with cooling; 1 J/cm
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
Chronic TBI 9 9635 and 52 9870-nm LED cluster;
12-15 mW per diode; 500 mW;
22.2 mW/cm
; 13.3 J/cm
at scalp
(estimated 0.4 J/cm
to cortex);
2.1¢¢ diameter
2 patients Transcranial LED may improve cognition
in chronic TBI patients even years after injury
Major depression
and anxiety
810-nm, 250 mW/cm
; 60 J/cm
on scalp; 2.1 J/cm
at cortical
surface; CW; 4 cm
; 240 s at
each of 2 sites on forehead
10 patients Significant improvement in Hamilton
depression and anxiety scales at 2 weeks
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
Oral mucositis 830 nm; 15 mW; 12 J/cm
; CW; 0.2 cm
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
Oral mucositis 660-nm; 10-mW; 2.5 J/cm
; 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
The Nuts and Bolts of Low-level Laser (Light) Therapy
TABLE 4. continued.
Disease Parameters
Subject Effect References
Carpal tunnel
syndrome (CTS)
830-nm; 60 mW; 9.7 J/cm
; 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
Carpal tunnel
syndrome (CTS)
632.8-nm; 9–11 J/cm
; 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
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
; 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
Lateral epicondylitis (LE) 904-nm; 25 mW, 0.275 J/point; 2.4 J/cm
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
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
; 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
Arthritis 830 nm, 50 mW; 10 W/cm
; 6 J/point;
48 J/cm
; CW, 0.5-mm
; 2 times/week
for 4 weeks
27 patients Reduces pain in knee osteoarthritis and
improves microcirculation
Arthritis 904-nm; 10 mW; 3 J/point; 3 J/cm
200 nsec; 2500 Hz; 1 cm
; 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
Leg ulcers 685 nm; 50 mW; 50 mW/cm
; 10 J/cm
CW; 1 cm
; 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
Leg ulcers 685-nm; 200 mW; 4 J/cm
44 patients No statistically significant differences
in reduction of wound size
The light sources were all lasers unless LED is specifically mentioned.
The laser parameters are given in the following order: wavelength (nm); power (mW), power density (mW/cm
); energy (J); energy density (J/cm
); mode (CW) or pulsed (Hz); spot size
); 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.
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).
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,
Trimmer et al. found that motor function was signifi-
cantly improved in human patients treated with LLLT
in an early stage of FALS.
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
(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.
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’’
; platelets are thought to
be rendered less likely to aggregate thus lessening the
likelihood of clot formation,
and the immune system
(dendritic cells, macrophages and lymphocytes) may be
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
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-
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
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).
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.
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).
James D. Carroll is the owner of THOR Photo-
medicine, a company which sells LLLT devices.
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CHUNG et al.
... In recent years, PBM has been recognized as an emerging therapy for treating agerelated degenerative and mitochondrial-related diseases [56][57][58]. The main mechanism may be the promotion of cytochrome c oxidase (COX) activity and ATP content. ...
... The main mechanism may be the promotion of cytochrome c oxidase (COX) activity and ATP content. PBM can also promote the release of nitric oxide (NO) from intracellular storage areas (e.g., heme-containing proteins) to enhance its bioavailability, triggering the activation of subsequent protective signaling pathways [57]. Although the light used in PBM previously had to be coherent and polarized, e.g., the light produced by He-Ne lasers, these properties are no longer considered essential. ...
... As a limitation of this study, we only preliminarily discussed the protective effects of the 1900 K LEDs on RPE cells and zebrafish; further in vivo experiments and related specific mechanisms are lacking. In recent years, PBM has been recognized as an emerging therapy for treating agerelated degenerative and mitochondrial-related diseases [56][57][58]. The main mechanism may be the promotion of cytochrome c oxidase (COX) activity and ATP content. ...
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Low-color-temperature light-emitting diodes (LEDs) (called 1900 K LEDs for short) have the potential to become a healthy light source due to their blue-free property. Our previous research demonstrated that these LEDs posed no harm to retinal cells and even protected the ocular surface. Treatment targeting the retinal pigment epithelium (RPE) is a promising direction for age-related macular degeneration (AMD). Nevertheless, no study has evaluated the protective effects of these LEDs on RPE. Therefore, we used the ARPE-19 cell line and zebrafish to explore the protective effects of 1900 K LEDs. Our results showed that the 1900 K LEDs could increase the cell vitality of ARPE-19 cells at different irradiances, with the most pronounced effect at 10 W/m2. Moreover, the protective effect increased with time. Pretreatment with 1900 K LEDs could protect the RPE from death after hydrogen peroxide (H2O2) damage by reducing reactive oxygen species (ROS) generation and mitochondrial damage caused by H2O2. In addition, we preliminarily demonstrated that irradiation with 1900 K LEDs in zebrafish did not cause retinal damage. To sum up, we provide evidence for the protective effects of 1900 K LEDs on the RPE, laying the foundation for future light therapy using these LEDs.
... 31 Primarily, the biological mechanisms of t-PBM are due to the NIR and red-light absorption by the cytochrome c oxidase (CCO) essential mitochondrial enzyme, with a consequent increase in CCO activity, nitric oxide release, and adenosine triphosphate (ATP) production. 32,33 Secondarily, cerebral blood flow and brain energy metabolism are enhanced. 23 Given its unique mechanism of action, t-PBM has the potential to benefit depressed patients; the main focus of this review is to revisit such t-PBM effects in individuals with MDD who do not respond to other more traditional treatment approaches. ...
... There are different types of lasers exist and have been used in orthodontic treatment. Due to the nature of stable temperature, low-level laser therapy (LLLT) is identified as a 'cold laser' and does not intensify the temperature in tissues unlike other types of lasers that were utilized in thermal coagulation or cutting of the tissues [9]. Furthermore, cellular assimilation of the laser light by the target tissues mitochondria initiates implying cascades [10] and promoting vascularization, epithelization, and collagen synthesis [11]. ...
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This study aimed to assess the outcomes of low-level laser therapy (LLLT) with the conventional bracket (CB) and self-ligating (SL) bracket systems on root resorption (RR) during orthodontic treatment. A total of 32 patients were included in this randomized clinical trial. All the patients were randomly divided into four individual groups (SLL: self-ligating laser, CBL: conventional bracket laser, SLNL: self-ligating non-laser, CBNL: conventional bracket non-laser). RR was measured from the cone-beam computed tomography (CBCT) radiographs which were taken at two stages of the orthodontic treatment: pre-treatment (T1) and after leveling and alignment stage (T2). Wilcoxon rank test for the comparison was conducted to compare the RR at T1 and T2 stages within each group and showed a significant difference (p < 0.05) for various variables. Mann Whitney test compared the RR in laser and non-laser groups irrespective of the bracket systems and exhibited no significant differences except the left lateral incisor. Moreover, CB and SL groups showed no significant difference in RR among any tooth. Kruskal Wallis test was performed to compare the RR among all groups which presented no significant differences. LLLT and bracket systems have no consequences on RR until the leveling and alignment stage of orthodontic treatment.
... Photobiomodulation (PBM), also known as low-level light therapy (LLLT), has been proposed to be a noninvasive method that intervenes in a wide range of biological processes including the enhancement of energy production, gene expression, the prevention of cell death, and so on [1]. Its underlying mechanism is the non-thermal photon interaction of incident light with atoms or molecules in the cells and tissues [2]. PBM therapy is a form of treatment involving irradiating selected light on the target area of the human body in order to obtain beneficial effects, such as pain attenuation, wound healing, neurological disorder improvement, etc. ...
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Transcranial photobiomodulation (tPBM) is an innovative intervention for a wide range of neurological and psychological conditions. tPBM therapy can enhance the metabolic capacity of neurons and bring about a variety of beneficial changes. This study mainly investigated the photobiological effects of pulsed red and near-infrared (NIR) light on neuron-like neuroblastoma SH-SY5Y cells by in vitro experiments. We covered the irradiation parameters, including wavelength (660, 850 nm), power density (5, 10, 20, 50, 100 mW/cm2), frequency (40, 100, 1000 Hz), and duty cycle (10%, 50%, 90%), finding that pulsed light generated a distinct effect compared with continuous-wave light on the cellular responses. Cell viability, mitochondrial membrane potential (MMP), adenosine triphosphate (ATP), and reactive oxygen species (ROS) showed significant increase after irradiation of the adequate fluence amount (4.8–9.6 J/cm2), and the enhancement was more notable under 40 Hz pulsed lighting. Under pulsed lighting with an average power density of 10 mW/cm2, cells that received irradiation of higher peak power density up to 100 mW/cm2 with a 10% duty cycle showed slightly higher metabolic responses. In addition, it was found that under same total fluence, short-term irradiation with high power density was more effective than long-term irradiation with low power density, which indicated the existence of a threshold to achieve effectiveness.
... It has been hypothesized that NIR laser light can reduce pain, decrease inflammation and stimulate tissue healing, which is favorable in the treatment of various musculoskeletal diseases [1][2][3][4][5]. NIR light is used in laser therapy because the NIR wavelengths coincide with the so-called therapeutic window, in which light absorption in biological tissue is comparably low and the penetration depth therefore accordingly large [6]. However, there are also differences in the penetration depth within this therapeutic window that depend on the exact absorption and scattering spectra of the tissue [7]. ...
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The choice of parameters for laser beams used in the treatment of musculoskeletal diseases is of great importance. First, to reach high penetration depths into biological tissue and, secondly, to achieve the required effects on a molecular level. The penetration depth depends on the wavelength since there are multiple light-absorbing and scattering molecules in tissue with different absorption spectra. The present study is the first comparing the penetration depth of 1064 nm laser light with light of a smaller wavelength (905 nm) using high-fidelity laser measurement technology. Penetration depths in two types of tissue (porcine skin and bovine muscle) were investigated. The transmittance of 1064 nm light through both tissue types was consistently higher than of 905 nm light. The largest differences (up to 5.9%) were seen in the upper 10 mm of tissue, while the difference vanished with increasing tissue thickness. The higher penetration was most likely due to a combination of lower absorption in hemoglobin and less scattering at larger wavelengths, and not due to absorption in melanin. Overall, differences in penetration depth were comparably small and high peak power and short pulse lengths of laser light seem to be more important to efficiently treat deep musculoskeletal diseases.
... PBMT is a safe, non-invasive low energy light (red and near infrared) therapy that is absorbed by endogenous chromophores to induce cellular changes [25,42,95]. Localised PBMT demonstrates positive results across a multitude of acute and chronic pain conditions [14,21,24,28,33,34,43,49,54,59,61,81,103,105,138]. ...
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Effective treatment for fibromyalgia (FM) is lacking and further treatment options are needed. Photobiomodulation therapy (PBMT) represents one potential treatment option. Whilst favourable findings have been reported using localised PBMT, no investigations have established the value of whole-body PBMT for the complete set of symptom domains in FM. A single-arm feasibility study was conducted in accordance to CONSORT guidelines. A non-probability sampling method was used to access individuals with FM. The primary outcome measure was identified as the Revised Fibromyalgia Impact Questionnaire (FIQR). Forty-nine participants were screened and 21 trial participants entered the trial. Nineteen participants completed the intervention (18 whole-body PBMT sessions over approximately six weeks). Descriptive statistics and qualitative analysis was undertaken to represent feasibility outcomes. Acceptability of the trial device and processes were established. Outcome measures towards efficacy data were guided by core and peripheral OMERACT domains, utilising a combination of participant-reported and performance-based outcome measures. Positive changes were observed for FM-specific quality of life, pain, tenderness, stiffness, fatigue, sleep disturbance, anxiety, depression and cognitive impairment. Patient global assessment revealed improvements at 6 weeks, with continued effect at 24 weeks. FM-specific quality of life at 24 weeks remained improved compared with baseline scores. Data for the embedded qualitative component of the trial were captured by participant-reported experience measures and audio-recorded semi-structured interviews. Findings provide evidence to support a full-scale trial and shows promise regarding potential efficacy of this novel non-invasive treatment in an FM population.
... The light used for PBM or LLLT is red to near-infrared (NIR) light with wavelength 600 to 1070 nm (Chung et al., 2012), while NIR light is often used in tPBM because of better skull penetration (Jagdeo et al., 2012). Particularly, NIR with wavelength 808 nm (810 nm) had promising scalp and skull penetration , and thus, the wavelength 808 nm was widely used for human studies, in vivo and in vitro studies of neurological diseases. ...
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Convulsive status epilepticus (CSE) is the most common neurological emergency in children and adolescents, yet about 30% patients had poor response to antiepileptic drugs (AEDs). Due to the refractory pediatric CSE to AEDs, developing new non-pharmacological treatments for pediatric CSE is urgently needed. It was known that transcranial photobiomodulation (tPBM) could reduce the elevated excitatory neurotransmitters after SE. However, whether tPBM could alleviate seizure behaviors was unknown. Clinically, Depakine (sodium valproate, valproic acid, VPA) is one of the most frequent used AEDs for pediatric CSE. Nevertheless, there is the dose-dependent hepatotoxicity in VPA. Therefore, it would be a good news for patients suffered from pediatric CSE if add-on therapy to VPA could reduce the dose of VPA while maintaining or even increase the anticonvulsive effects so that the hepatotoxicity would be reduced. Considering the mechanic similarities between tPBM and VPA, tPBM is a potential candidate for add-on therapy to VPA. Therefore, in this study of PhD dissertation, I applied near infrared laser with a wavelength 808 nm transcranially, and the tPBM was served as monotherapy, add-on therapy to valproic acid, and preconditioning to evaluate their effects on peripubertal rats with seizures. In this study, Sprague-Dawley rats at postnatal day 30-39 received subcutaneous pentylenetetrazole (PTZ, 90 mg/kg) to induce seizures and status epilepticus (SE). Rat scalp with hair removed received irradiation of near-infrared with wavelength 808 nm。In Part I—tPBM monotherapy experiments, the PTZ was injected right after tPBM. In Part-II —tPBM add-on therapy to VPA, the tPBM was performed 30 min after VPA injection and the PTZ was also injected right after tPBM. There were low-dose (100 mg/kg), medium-dose (200 mg/kg), and high-dose (400 mg/kg) VPA in tPBM add-on therapy experiments. In part III—tPBM preconditioning, tPBM was performed 60 min before PTZ injection. Further mechanisms or phenomena were elucidated in tPBM monotherapy experiments. The evaluation methods include Hematoxylin‐eosin (H&E) staining, immunofluorescence, and terminal deoxynucleotidyl transferase dUTP nick‐end labeling (TUNEL) assay on frozen sections of rat brains. As for tPBM add-on therapy and tPBM preconditioning, only seizure behaviors were analyzed. In Part I, I showed that tPBM is capable of attenuating PTZ-induced seizures by significantly reducing mean seizure scores, incidence of severe status epilepticus (SE), and reduced the incidence of mortality. According to results of H & E staining, tPBM lessened neuronal damage in multiple brain regions involved in epileptogenesis. The TUNEL assay and PV immunofluorescence staining showed that tPBM reduced apoptotic ratio of parvalbumin-positive interneurons (PV-INs) in the hippocampus and preserved perisomatic inhibitory network of PV-INs surrounding principle cells. tPBM also attenuated neuroinflammation, astrogliosis and microgliosis. The phenomenon that therapeutic actions of tPBM through hippocampal cytochrome c oxidase (CCO) was also validated. In Part II, I demonstrated that tPBM added-on to valproic acid had synergistic anticonvulsive effect, but it was restricted to low-dose VPA, yet off-set effects were observed at medium and high-level VPA. In part III, I examined the effects of tPBM preconditioning on PTZ-induced seizures, and found that tPBM had trends of shortening the total duration of severe seizures and prolonged the latency of stage 4-7 seizures which contributes to SE, but without statistical significance. In conclusion, tPBM with wavelength 808 nm had anticonvulsive effects to PTZ-induced seizures. In which, tPBM served as monotherapy attenuates PTZ-induced seizures and SE. Particularly, the effects of tPBM add-on therapy differed from the doses of VPM which tPBM add-on with. Lastly, tPBM preconditioning in the setting of tPBM 1hr before PTZ injection could not alleviate PTZ-induced generalized tonic-clonic seizures. These data suggested that tPBM with wavelength 808 nm had therapeutic effect to pediatric epilepsy.
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Bioactive glasses (BG) has been generally used in bone defects repair for its good osteoinductivity and osteoconductivity. However, the early angiogenesis of BG in the repair of large-sized bone defects may not be sufficient enough to support new bone formation, resulting in the failure of bone repair. Photobiomodulation (PBM) therapy, which is superior on promoting early angiogenesis, may contribute to the angiogenesis of BG and further enhance the repair of bone defects. Therefore, we applied BG and PBM in combination and preliminarily investigated their additive effects on bone regeneration both in vitro and in vivo. The in vitro results revealed that BG combined with PBM remarkably enhanced hBMMSCs’ proliferation, osteogenic-related genes expression and mineralization, which was better than applying BG or PBM respectively. For in vivo studies, the histological staining results showed that BG induced new bone formation in the interior of defects and promoted new bone reconstruction at 6 weeks post-operation. The micro-Computed Tomography results further confirmed that BG combined with PBM accelerated bone formation and maturation, improved the speed and quality of bone regeneration, and promoted bone repair. In conclusion, with the optimum BG and PBM parameters, BG combined with PBM generated additive effects on promoting bone regeneration.
Background: Photobiomodulation (PBM), the therapeutic use of light, is used to treat a myriad of conditions, including the management of acute and chronic wounds. Despite the presence of clinical evidence surrounding PBM, the fundamental mechanisms underpinning its efficacy remain unclear. There are several properties of light that can be altered in the application of PBM, of these, polarization-the filtering of light into specified plane(s)-is an attractive variable to investigate. Aims: To evaluate transcriptomic changes in human dermal fibroblasts in response to polarized PBM. Results: A total of 71 Differentially Expressed Genes (DEGs) are described. All DEGs were found in the polarized PBM group (P-PBM), relative to the control group (PC). Of the 71 DEGs, 10 genes were upregulated and 61 were downregulated. Most DEGs were either mitochondrial or extracellular matrix (ECM)-related. Gene Ontology (GO) analysis was then performed using the DEGs from the P-PBM vs. PC group. Within biological processes there were 95 terms found (p < 0.05); in the molecular function there were 18 terms found (p < 0.05); while in the cellular component there were 32 terms enriched (p < 0.05). A KEGG pathways analysis was performed for the DEGs found in the P-PBM vs. PC group. This revealed 21 significantly enriched pathways (p < 0.05). Finally, there were 24 significantly enriched reactome pathways when comparing the DEGs of the P-PBM vs. PC groups (p < 0.05). Discussion and conclusions: The P-PBM DEGs were almost always down regulated compared to the comparator groups. This may be explained by the P-PBM treatment conditions decreasing the amount of cellular stress, hence causing a decreased mitochondria and ECM protective response. Alternatively, it could point to an alternate mechanism, outside the mitochondria, by which PBM exerts its effects. Additionally, PBM appears to have a more widespread effect on the mitochondria than previously thought, opening up many new avenues of investigation in the process.
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To assess the extent of water flow through channels in the membranes of intact higher plant cells, the effects of HgCl2 on hydraulic conductivity (L P) of wheat (Triticum aestivum L.) root cells were investigated using a pressure probe. The L P of root cells was reduced by 75% in the presence of 100 μm HgCl2. The K⁺-channel blocker tetraethylammonium had no effect on theL P at concentrations that normally block K⁺ channels. HgCl2 rapidly depolarized the membrane potential (V m) of the root cells. The dose-response relationship of inhibition ofL P and depolarization ofV m were not significantly different, with half-maximal inhibition occurring at 4.6 and 7.8 μm, respectively. The inhibition of L P and the depolarization of V m caused by HgCl2 were partially reversed by β-mercaptoethanol. The inhibition of L P by HgCl2 was similar in magnitude to that caused by hypoxia, and the addition of HgCl2 to hypoxia-treated cells did not result in further inhibition. We compared the L P of intact cells with that predicted from a model of cortical cells incorporating water flow across both the plasma membrane and the tonoplast using measured values of water permeability from isolated membranes, and found that HgCl2 has other effects in addition to the direct inhibition of water channels.
Predicting the effects of polychromatic light on biological systems is a central goal of environmental photobiology. If the dose-response function for a process is a linear function of the light incident on a system at each wavelength within the spectrum, the effect of a polychromatic spectrum is obtained by integrating the product of the cross section for the reaction at each wavelength and the spectral irradiance at that wavelength over both wavelength and time. This procedure cannot be used, however, if the dose-response functions for an effect are not linear functions of photon dose. Although many photochemical reactions are linear within the biologically relevant range of doses, many biological end points are not. I describe procedures for calculating the effects of polychromatic irradiations on systems that exhibit certain classes of dose-response functions, including power law responses typical of mutation induction and exponential dose-responses typical of cell survival. I also present an approach to predict the effects of polychromatic spectra on systems in which the ultraviolet components form pyrimidine dimers, and the longer-wavelength ultraviolet and visible components remove them by photoreactivation, thus generating complex dose-response functions for these coupled light-driven reactions.
Background: Intravenous laser blood irradiation was accomplished for the first time approximately 25 years ago in the former Soviet Union. Laser light was brought directly into the blood flow through a one-way-catheter. Various in-vitro-tests verified that biological soft laser irradiation of white blood cells caused various positive effects, in particular expression of immunoglobulins, interferons and interleukins. After the introduction of the new method various clinical studies were published, showing additional effects on various metabolic pathways. Objective: In the presented work the mainly Russian publications on the therapy of fat metabolism disorders, chronic liver diseases and diabetes mellitus are reproduced. Methods: The development and certification of a new intravenous laser blood irradiation device in 2005 in the research support program Biophotonik II of the government of Lower Saxony opened for the first time the possibility in Germany to check the new therapy in clinical studies. Results: In our research the results of the Russian studies could be confirmed to a large extent. Nearly all treated patients described general stabilisation, energization and positive effects on chronic liver diseases, Diabetes mellitus, metabolism disorders and other various diseases. Discussion: The biological mechanisms of intravenous laser blood irradiation are until now only partially known or guessed at and further intensive clinical research will be necessary. Conclusion: The new method of intravenous laser blood irradiation and the availability of a certified device are possibly opening new ways in the therapy of systemic metabolic and immunological diseases.
• We performed a study to determine whether laser radiation of low-power density would affect the healing of open skin wounds in rats. The wounds were irradiated daily with a helium-neon laser (wavelength, 632.8 nm) and an argon laser (wavelength, 514.5 nm) at a constant power density of 45 mW/sq cm. The rate of wound closure was followed by photographing the wounds in a standardized way. The collagen hydroxyproline concentration in the scar tissue was determined on the 18th postoperative day. Helium-neon laser radiation had a statistically significant stimulating effect on collagen synthesis in the wound, with a maximum effect at an energy density of 4 joules/sq cm. The rate of wound closure was enhanced significantly between the third and 12th postoperative days. The argon laser exposure produced a significant increase in collagen concentration both in irradiated and nonirradiated contralateral wounds. However, an acceleration of the healing rate was not registered in this case. The wound contraction up to the fourth day of the experiment was inhibited under helium-neon and argon laser exposure to 20 joules/sq cm. The described effects were not specific for the laser light. There may be a wavelength-selective influence of coherent light on the metabolic and proliferation processes in wound healing, with the associated problem of the possible carcinogenic effects of laser radiation.(Arch Surg 1981;116:293-296)
Conference Paper
Conclusions based on systematic reviews of randomized controlled trials are considered to provide the highest level of evidence about the effectiveness of an intervention. This overview summarizes the available evidence from systematic reviews on the effects of nonpharmacological and nonsurgical interventions for rheumatoid arthritis (RA). Systematic reviews of studies of patients with RA (aged > 18 years) published between 2000 and 2007 were identified by comprehensive literature searches. Methodological quality was independently assessed by 2 authors, and the quality of evidence was summarized by explicit methods. Pain, function, and patient global assessment were considered primary outcomes of interest. Twenty-eight systematic reviews were included in this overview. High-quality evidence was found for beneficial effects of joint protection and patient education, moderate-quality evidence was found for beneficial effects of herbal therapy (gamma-linolenic acid) and low-level laser therapy, and low-quality evidence was found for the effectiveness of the other interventions. The quality of evidence for the effectiveness of most nonpharmacological and nonsurgical interventions in RA is moderate to low.