Light-Emitting Diodes (LEDs) in Dermatology

Abstract

Light-emitting diode photobiomodulation is the newest category of nonthermal light therapies to find its way to the dermatologic armamentarium. In this article, we briefly review the literature on the development of this technology, its evolution within esthetic and medical dermatology, and provide practical and technical considerations for use in various conditions. This article also focuses on the specific cell-signaling pathways involved and how the mechanisms at play can be put to use to treat a variety of cutaneous problems as a stand-alone application and/or complementary treatment modality or as one of the best photodynamic therapy light source.

Full text

Light-Emitting Diodes (LEDs) in Dermatology
Daniel Barolet, MD*
,†
Light-emitting diode photobiomodulation is the newest category of nonthermal light ther-
apies to find its way to the dermatologic armamentarium. In this article, we briefly review
the literature on the development of this technology, its evolution within esthetic and
medical dermatology, and provide practical and technical considerations for use in various
conditions. This article also focuses on the specific cell-signaling pathways involved and
how the mechanisms at play can be put to use to treat a variety of cutaneous problems as
a stand-alone application and/or complementary treatment modality or as one of the best
photodynamic therapy light source.
Semin Cutan Med Surg 27:227-238 © 2008 Elsevier Inc. All rights reserved.
Light therapy is one of the oldest therapeutic modalities used
to treat various health conditions. Sunlight benefits in treat-
ing skin diseases have been exploited for more than thou-
sands of years in ancient Egypt, India, and China. Solar ther-
apy was later rediscovered by Niels Ryberg Finsen (Fig. 1,
Fig. 2), a Danish physician and scientist who won in 1903 the
Nobel Prize in Physiology or Medicine in recognition of his
contribution to the treatment of diseases, notably lupus vul-
garis. Phototherapy involving the use of an artificial irradia-
tion source was born.1
It was only many years later that light therapeutic benefits
were uncovered again using other segments of the electro-
magnetic spectrum (EMS) with visible and near-infrared
wavelengths. In the late 1960s, Endre Mester, a Hungarian
physician, began a series of experiments on the carcinogenic
potential of lasers by using a low-powered ruby laser (694
nm) on mice. To his surprise, the laser did not cause cancer
but improved hair growth that was shaved off the animal’s
back for the purpose of the experiment. This was the first
demonstration of “photobiostimulation” with low-level laser
therapy (LLLT), thereby opening a new avenue for medical
science. This casual observation prompted him to conduct
other studies provided support for the efficacy of red light on
wound healing. Since then, medical treatment with coherent-
light sources (lasers) and noncoherent light (light-emitting
diodes, LEDs) has expanded. The use of LLLT and LEDs is
now applied to many thousands of people worldwide each
day for various medical conditions.
LED photobiomodulation is the newest category of non-
thermal light therapies to find its way to the dermatologic
armamentarium and will be the focus of this review. Initial
work in this area was mainly developed by National Aero-
nautics and Space Administration (NASA). NASA research
came about as a result of the effects noted when light of a
specific wavelength was shown to accelerate plant growth.
Because of the deficient level of wound healing experienced
by astronauts in zero-gravity space conditions and Navy Seals
in submarines under high atmospheric pressure, NASA in-
vestigated the use of LED therapy in wound healing and
obtained positive results. This research has continued and
innovative and powerful LEDs are now used for a variety of
conditions ranging from cosmetic indications to skin cancer
treatment (as a photodynamic therapy light source).
LED Technology
LEDs are complex semiconductors that convert electrical
current into incoherent narrow spectrum light. LEDs have
been around since the 1960s but have mostly been relegated
to showing the time on an alarm clock or the battery level of
a video camera. They have not until recently been used as
sources of illumination because, for a long time, they could
not produce white light— only red, green, and yellow. Nichia
Chemical of Japan changed that in 1993 when it started pro-
ducing blue LEDs which, combined with red and green, pro-
duce white light, opening up a whole new field for the tech-
nology. The industry has been quick to exploit it. LEDs are
based on semiconductor technology, just like computer pro-
cessors, and are increasing in brightness, energy efficiency,
and longevity at a pace reminiscent of the evolution of com-
puter processors. Emitted light are now available at wave-
lengths ranging from ultraviolet (UV) to visible to near infra-
red (NIR) bandwidth (247 to 1300 nm).
*RoseLab Skin Optics Research Laboratory, Montreal, Canada.
†Professor of Dermatology, McGill University School of Medicine, Montreal,
Canada.
Address reprint requests to Daniel Barolet, MD, RoseLab Skin Optics Labo-
ratory, 3333 Graham Blvd., Suite 206, Montreal, Quebec, H3R 3L5,
Canada. E-mail: daniel.barolet@mcgill.ca
2271085-5629/08/$-see front matter © 2008 Elsevier Inc. All rights reserved.
doi:10.1016/j.sder.2008.08.003

LED arrays are built using diverse methods each hinging
on the manner in which the chips themselves are packaged
by the LED semiconductor manufacturer. Examples of pack-
aged, lensed LEDs are t-pack LED and surface mount LEDs
(Figs 3-5). These packages can be affixed to a heat-sinking
substrate by using either a “through hole” mounting or sur-
face mounting. Through hole mounted devices are often re-
ferred to as t-pack LEDs. Importantly, it is also possible to
procure wafers of bare, unpackaged chips, also called “dice.”
By using automated pick-and-place equipment, some manu-
facturers take such individual chips and affix them to printed
circuit boards, creating so-called “chip-on-board” LED ar-
rays. LED array is thus assembled on a printed circuit board.
The pins or pads or actual surfaces of the LED chips are
attached to conductive tracks on the PCB (printed circuit
board). Assemblies built from t-pack LEDs are often unsatis-
factory in that they do not always provide sufficiently uni-
form lighting, are not well heat-sinked, and they are bulky
due to the size (several millimeters) of each t-pack device.
Nonetheless, for certain applications, t-packs prove to be the
most appropriate, cost-effective solution. However, when t-
packs cannot provide the required performance, however,
chip-on-board emerges as the answer.
A significant difference between lasers and LEDs is the way
the light energy is delivered [optical power output (OPD)].
The peak power output of LEDs is measured in milliwatts,
whereas that of lasers is measured in watts. LEDs provide a
much gentler delivery of the same wavelengths of light com-
pared to lasers and at a substantially lower energy output.
LEDs do not deliver enough power to damage tissues and do
not have the same risk of accidental eye damage that lasers
do. Visible/NIR-LED light therapy has been deemed a non-
significant risk by the Food and Drug Administration and has
been approved for use in humans. Other advantages over
lasers include the possibility to combine wavelengths with an
array of various sizes. LED disperses over a greater surface
area than lasers and can be used where large areas are tar-
geted, resulting in a faster treatment time.
Mechanism of Action
In the same way that plants use chlorophyll to convert sunlight
into plant tissue, LEDs can trigger natural intracellular photo-
biochemical reactions. To have any effect on a living biological
system, LED-emitted photons must be absorbed by a molecular
Figure 1 Niels Ryberg Finsen (1860-1904). Courtesy of the Clen-
dening History of Medicine Library, University of Kansas Medical
Center.
Figure 2 Finsen’s phototherapy. Due to expense of carbon arc light-
ing, single lamp directed light through four water-cooled focusing
lenses, allowing several patients to be treated simultaneously. Each
patient had nurse attendant to focus light to single small region for
up to 1 hour. (Reprinted from Bie V: Finsen’s phototherapy. BMJ
1899;2:825)
Figure 3 LED technology. The red arrows indicate the flow of heat.
Courtesy of Stocker Yale, Inc.
Figure 4 A t-pack LED.
228
D. Barolet

chromophore or photoacceptor. Light, at appropriate doses and
wavelengths, is absorbed by chromophores such as porphyrins,
flavins, and other light-absorbing entities within the mitochon-
dria and cell membranes of cells.
A growing body of evidence suggests that photobiomodu-
lation mechanism is ascribed to the activation of mitochon-
drial respiratory chain components resulting in the initiation
of a cascade of cellular reactions. It has been postulated that
photoacceptors in the red to NIR region are the terminal
enzyme of the respiratory chain cytochrome coxidase with 2
copper elements. The first absorption peak is in the red spec-
trum and the second peak in the NIR range. Seventy-five
years ago, Otto Warburg, a German biochemist, was given a
Nobel prize for his ingenious work unmasking the enzyme
responsible for the critical steps of cell respiration, especially
cytochrome oxidase governing the last reaction in this pro-
cess. Two chemical quirks are exploited: carbon monoxide
(CO) that can block respiration by binding to cytochrome
oxidase in place of oxygen, and a flash of light that can dis-
place it, allowing oxygen to bind again.
Nowadays, it has been reported that cells often use CO
and, to an even greater extent, nitric oxide (NO) binding to
cytochrome oxidase to hinder cell respiration.2Mitochondria
harbor an enzyme that synthesizes NO. So why would cells
go out of their way to produce NO right next to the respira-
tory enzymes? Evolution crafted cytochrome oxidase to bind
not only to oxygen but also to NO. One effect of slowing
respiration in some locations is to divert oxygen elsewhere in
cells and tissues, preventing oxygen sinking to dangerously
low levels. Fireflies use a similar strategy to flash light (see
section “Pulsing and Continuous Modes”). Respiration is
about generating energy but also about generating feedback
that allows a cell to monitor and respond to its environment.
When respiration is blocked, chemical signals in the form of
free radicals or reactive oxygen species are generated. Free
radicals had a bad reputation, but now they can be consid-
ered signals. The activity of many proteins, or transcription
factors, depends, at least in part, on free radicals.3These
include many proteins such as those involved in the p53
cell-signaling pathway. Further, to bring free radical leak
under control, there is a cross-talk, known as retrograde re-
sponse, between the mitochondria and genes in the nucleus
for which we are just beginning to explore the mechanism at
play.4,5 If we can better modulate this signaling, we might be
able to influence the life or death of cells in many pathologies
as it is more and more demonstrated in its antiaging effects on
collagen metabolism.
A recent discovery has revealed that NO eliminates the
LLLT-induced increase in the number of cells attached to the
glass matrix, supposedly by way of binding NO to cyto-
chrome c oxidase.6Cells use NO to regulate respiratory chain
processes, resulting in a change in cell metabolism. In turn, in
LED-exposed cells like fibroblasts increased ATP production,
modulation of reactive oxygen species (such as singlet oxy-
gen species), reduction and prevention of apoptosis, stimu-
lation of angiogenesis, increase of blood flow, and induction
of transcription factors are observed. These signal transduc-
tion pathways lead to increased cell proliferation and migra-
tion (particularly by fibroblasts), modulation in levels of cy-
tokines (eg, interleukins, tumor necrosis factor-
␣
), growth
factors and inflammatory mediators, and increases in anti-
apoptotic proteins.7
The photodissociation theory incriminating NO as one of
the main players suggests that during an inflammatory pro-
cess, for example, cytochrome coxidase is clogged up by NO.
LED therapy would photodissociate NO or bump it to the
extracellular matrix for oxygen to bind back again to cyto-
chrome c oxidase and resume respiratory chain activity. Un-
derstanding the mechanisms of cutaneous LED-induced spe-
cific cell-signaling pathway modulation will assist in the
future design of novel devices with tailored parameters even
for the treatment of degenerative pathologies of the skin.
Optimal LED Parameters
In LED, the question is no longer whether it has biological
effects but rather what the optimal light parameters are for
different uses. Biological effects depend on the parameters of
the irradiation such as wavelength, dose (fluence), intensity
(power density or irradiance), irradiation time (treatment
time), continuous wave or pulsed mode, and for the latter,
pulsing patterns. In addition, clinically, such factors as the
frequency, intervals between treatments and total number of
treatments are to be considered. The prerequisites for effec-
tive LED clinical response are discussed hereafter.
Well-Absorbed Deeply
Penetrating Wavelength
Light is measured in wavelengths and is expressed in units of
nanometers (nm). Different wavelengths have different chro-
mophores and can have various effects on tissue (Fig. 6).
Wavelengths are often referred to using their associated color
and include blue (400-470 nm), green (470-550 nm), red
(630-700 nm) and NIR (700-1200) lights. In general, the
longer the wavelength, the deeper the penetration into tis-
sues.8-10 Depending on the type of tissue, the penetration
depth is less than 1 mm at 400 nm, 0.5 to 2 mm at 514 nm,
1 to 6 mm at 630 nm, and maximal at 700 to 900 nm.10
Figure 5 Linear chip-on-board LEDs.
LEDs in dermatology
229

The various cell and tissue types in the body have their
own unique light absorption characteristics, each absorbing
light at specific wavelengths. For best effects, the wavelength
used should allow for optimal penetration of light in the
targeted cells or tissue. Red light can be used successfully for
deeper localized target (eg, sebaceous glands), and blue light
may be useful for the treatment of skin conditions located
within the epidermis in photodynamic therapy (PDT) (eg,
actinic keratoses). To reach as many fibroblasts as possible,
which is often the aim of LED therapy, a deeply penetrating
wavelength is desirable. At 660 nm, for instance, light can
achieve such a goal reaching a depth of 2.3 mm in the dermis,
therefore covering fibroblasts up to the reticular dermis. The
wavelength used should also be within the absorption spec-
trum of the chromophore or photoacceptor molecule and
will often determine for which applications LEDs will be
used. Because cytochrome coxidase is the most likely chro-
mophore in LLLT, 2 absorption peaks are considered in the
red (⬃660 nm) and NIR (⬃850 nm) spectra.6
Two major wavelength boundaries exist for LED appli-
cations: at wavelengths ⬍600 nm, blood hemoglobin (Hb)
Figure 6 Optical penetration depth.
Figure 7 Main tissue constituents absorbing in the 600 –1000 nm spec-
tral range. Adapted with permission from Taroni P, Pifferi A, Torricelli
A, et al: In vivo absorption and scattering spectroscopy of biological
tissues. Photochem Photobio Sci 2:124-129, 2003. Figure 8 Schematic representation of Arndt-Schulz curve.
230
D. Barolet

is a major obstacle to photon absorption because blood
vessels are not compressed during treatment. Futhermore,
at wavelengths ⬎1000 nm, water is also absorbing many
photons, reducing their availability for specific chro-
mophores located, for instance, in dermal fibroblasts. Be-
tween these 2 boundaries, there is a valley of LED possible
applications (see Fig. 7).
Fluence and Irradiance
The Arndt-Schulz law states that there is only a narrow win-
dow of opportunity where you can actually activate a cellular
response using precise sets of parameters, i.e. the fluence or
dose (see Fig. 8). The challenge remains to find the appropri-
ate combinations of LED treatment time and irradiance to
achieve optimal target tissue effects. Fluence or dose is, indi-
cated in joules per cm2(J/cm2). The law of reciprocity states
that the dose is equal to the intensity ⫻time. Therefore, the
same exposure should result from reducing duration and
increasing light intensity, and vice versa. Reciprocity is as-
sumed and routinely used in LED and LLLT experiments.
However, the scientific evidence supporting reciprocity in
LED therapy is unclear.11
Dose reciprocity effects were examined in a wound healing
model and showed that varying irradiance and exposure time
to achieve a constant specified energy density affects LED
therapy outcomes.12 In practice, if light intensity (irradiance)
is lower than the physiological threshold value for a given
target, it does not produce photostimulatory effects even
when irradiation time is extended. Moreover, photoinhibi-
tory effects may occur at higher fluences.
In Fig. 9, different light delivery patterns are shown. Inter-
estingly, they are all of the same fluence but over time, the
energy of photons does not reach the biological targets in the
same way. This may alter the LED biological response signif-
icantly. The importance of pulsing will be discussed in the
next section.
Certainly a minimal exposure time per treatment is neces-
sary—in the order of several minutes rather than only a few
seconds—to allow activation of the cell machinery; other-
wise, tissue response is evanescent and no clinical outcome is
expected. The ideal treatment time has to be tailored accord-
ing to the skin condition or degree of inflammation present at
the time of treatment.
Pulsing and Continuous Modes
Both pulsed wave and continuous wave (CW) modes are
available in LED devices, which add to the medical applica-
bility. The influence of CW versus pulsing mode, as well as
precise pulsing parameters (eg, duration, interval, pulse per
train, pulse train interval), on cellular response has not been
fully studied. To date, comparative studies have shown con-
flicting results.13 In our own experience, sequentially pulsed
optical energy (proprietary pulsing mode with repeated se-
quences of short pulse trains followed by longer intervals)
has been shown to stimulate more collagen production than
CW mode.14
Under certain conditions, ultra-short pulses can travel
deeper into tissues than CW radiation.15,16 This is because the
first part of a powerful pulse may contain enough photons to
take all chromophore molecules in the upper tissue layer to
excited states, thus literally opening a road for itself into
tissue. Moreover, too long a pulse may produce cellular ex-
haustion whereas too short a pulse may deliver insufficient
energy for a biologic effect to occur. Targeted molecules and
cells may-on a smaller scale than selective photothermolysis-
have their own thermal relaxation times.14
The NO photodissociation theory could also be part of the
answer, especially the need for pulsing characteristics during
LED therapy. Interestingly, fireflies use such pulsing phe-
nomenon. There, oxygen reacts with the luciferyl intermedi-
ate to produce a flash of light. The glory is that the flash
switches itself off. Light dissociates NO from cytochrome
oxidase, allowing oxygen to bind again. Then, the mitochon-
dria consume oxygen once more, allowing the luciferyl inter-
mediate to build up until another wave of NO arrives.17
Precise Positioning of Treatment Head
Very precise positioning or working distance is mandatory to
ensure optimal beam delivery intensity covering the treat-
ment area so as to achieve maximum physiological effects.
Accurate positioning ensures that the proper amount of pho-
tons is delivered to the treated skin to avoid hot or cold spots
in the treatment field. This is especially important in photo-
biology as a required amount of energy must be delivered to
the target to trigger the expected cell response. If insufficient
photons reach the target, no cell response will result. Some
LED devices even provide optical positioning systems to al-
low reproducible treatment distance within precise limits
(⫾3 mm).
Timing of Treatments Outcomes
There are some indications that cellular responses after light
irradiation are time dependent. A recent study suggests that
responses such as ATP viability can be observed directly (1
hour) after the irradiation, whereas other responses such as
cell proliferation require at least 24 hours before the true
Figure 9 Different light delivery patterns with similar fluence.
LEDs in dermatology
231

effect can be observed.18 It is thus important to establish time-
dependent responses to adequately assess photomodulatory
effects. Fibroblasts in culture show physiological cyclical
patterns of procollagen type I up-regulation and metallo-
proteinase-1 (MMP-1) down-regulation that can be empha-
sized by LED treatments every 48 hours.19
State of Cells and Tissues
The magnitude of the biostimulation effect depends on the
physiological condition of the cells and tissues at the moment
of irradiation.20 Compromised cells and tissues respond
more readily than healthy cells or tissues to energy transfers
that occur between LED-emitted photons and the receptive
chromophores. For instance, light would only stimulate cell
proliferation if the cells are growing poorly at the time of the
irradiation. Cell conditions are to be considered because light
exposures would restore and stimulate procollagen produc-
tion, energizing the cell to its own maximal biological poten-
tial. This may explain the variability in results in different
studies.
Effects of LED
LED therapy is known for its healing and antiinflammatory
properties and is mostly used in clinical practice as a supple-
ment to other treatments such as nonablative thermal tech-
nologies. Different LED applications can now be subdivided
according to the wavelength or combination of wavelengths
used (see Fig. 10). LED therapy can be used as a standalone
procedure for many indications, as described herein. A sum-
mary of recommended LED parameters for various clinical
applications are presented in Table 1.
When reviewing the literature, one needs to keep in mind
that results from different studies may be difficult to compare
because the potential effects of variation of treatment param-
eters (eg, wavelength, fluence, power density, pulse/contin-
uous mode and treatment timing) may vary from one study to
the next. Moreover, there is the possibility that the photobi-
omodulatory effects are dissimilar across different cell lines,
species and patient types. We will now discuss current LED
applications.
Wound Healing
Early work involving LED mainly focused on the wound
healing properties on skin lesions. Visible/NIR-LED light
treatments at various wavelengths have been shown to in-
crease significantly cell growth in a diversity of cell lines,
including murine fibroblasts, rat osteoblasts, rat skeletal
muscle cells, and normal human epithelial cells.21 Decrease
in wound size and acceleration of wound closure also has
been demonstrated in various in vivo models, including
toads, mice, rats, guinea pigs, and swine.22,23 Accelerated
healing and greater amounts of epithelialization for wound
closure of skin grafts have been demonstrated in human
studies.24,25 The literature also shows that LED therapy is
known to positively support and speed up healing of chronic
leg ulcers: diabetic, venous, arterial, pressure.26
According to our experience, LED treatments are also very
useful after CO2ablative resurfacing in reducing the signs of
the acute healing phase resulting in less swelling, oozing,
crusting, pain, and prolonged erythema thereby accelerating
wound healing (see Fig. 11). It is important to keep in mind
that to optimize healing of necrotic wounded skin, it may be
useful to work closer to the near infrared spectrum as an
increase in metalloproteinases (ie, MMP-1, debridment-like
effect) production accelerates wound remodeling.
Inflammation
Free radicals are known to cause subclinical inflammation.
Inflammation can happen in a number of ways. It can be the
result of the oxidation of enzymes produced by the body’s
defense mechanism in response to exposure to trauma such
as sunlight (photodamage) or chemicals. LED therapy brings
a new treatment alternative for such lesions possibly by coun-
teracting inflammatory mediators.
A series of recent studies have demonstrated the antiin-
flammatory potential of LED. A study conducted in arachi-
donic acid-treated human gingival fibroblast suggests that
635 nm irradiation inhibits PGE 2 synthesis like COX inhib-
itor and thus may be a useful antiinflammatory tool.27 LED
photobiomodulation treatment has also been shown to accel-
erate the resolution of erythema and reduce posttreatment
discomfort in pulsed dye laser (IPL)-treated patients with
photodamage and to prevent radiation-induced dermatitis in
breast cancer patients.28,29 Patients with diffuse type rosacea
(unstable) (see Fig. 12), keratosis pilaris rubra, as well as
postintervention erythema (eg, IPL, CO2)(Fig. 11) can ben-
efit from a quicker recovery with complementary LED ther-
apy. (See also section on wound healing).
Because LED is known to reduce MMPs, it might be useful
in conditions in which MMPs are implicated. One such case
is lupus erythematosus (LE). LE is a heterogeneous autoim-
mune disease associated with aberrant immune responses
including production of autoantibodies and immune com-
plexes and specific MMPs have been implicated in its etiol-
Figure 10 Current and promising LED applications as a function of
wavelengths.
232
D. Barolet

Table 1 LED Parameters for Various Clinical Applications Used in our Practice
Applications
Wavelength
(nm) No. of Treatments
Irradiance
(mW/cm2)
Fluence
(J/cm2)
Treatment Time
(min;sec)
Interval
Treatment Time
(hours)
Mode
(Pulsed/CW)
Wound healing 660 & 850
combination
3-12 50 (minimal) 4 2:40 24-72 Sequential pulsing**
Inflammation/erythema/edema
(diffuse type rosacea,
post- procedure erythema
(eg, IPL, CO2)
630-660 3-12 50 (minimal) 4 2:40 48-72 Sequential pulsing
PDT 405-630 3ⴙ50-100 >50 13-45 3 weeks CW or pulsed
Photorejuvenation 630-660 12 50-100 4 2:40-16 48-72 Sequential pulsing
Sunburn prevention*† 660-970 ad 7 50 4 2:40-15 24-48 Sequential pulsing or
CW
PIH prevention*† 870-970 ad 8 50-80 45-96 15-20 24-48 Sequential pulsing or
CW
Scar prevention* 805-970 Multiple 50-80 45-72 15 24 CW
Photopreparation 870-970 3 (before every PDT
Treatment)
>80 72-100 15 Pre-PDT (q 3 weeks) CW
Photoregulation 660-850 Long-term 8-50 4-7,5 5-16 24-48 Sequential pulsing
UV-free phototherapy 405-850 Depends on inflammatory
disease
30-50 27-135 15-45 48 Sequential pulsing or
CW
*Sunburn, PIH, and scar-prevention methods ⴝPhotoprophylaxis.
**Sequential pulsing mode with proprietary pulsed characteristics (50% duty cycle).
†LED treatments should be preferably performed in the week before UV insult or skin trauma to better prevent sunburn or PIH, respectively.
LEDs in dermatology
233

ogy. MMP inhibition through LED treatments may reduce
lupus-induced damage in inflamed tissues.
Photorejuvenation
In aged photo-damaged human skin, collagen synthesis is
reduced with a concomitant elevation of matrix MMP expres-
sion.30 Hence, a possible strategy for treating and preventing
the clinical manifestations of skin aging is the restoration of
the collagen deficiency by the induction of new collagen syn-
thesis and reduction of MMP.
Using a variety of LED light sources in the visible to NIR
regions of the spectrum, in vitro studies have revealed that
LED can trigger skin collagen synthesis with concurrent re-
duction in MMP. A significant increase in collagen produc-
tion after LED treatment has been shown in various experi-
ments, including fibroblasts cultures, third-degree burn
animal models, and human blister fluids, and skin biop-
sies.14,31-34 In clinical studies, the increase in collagen pro-
duction with concurrent MMP-1 reduction has been seen in
association with improved appearance of photodamaged
skin. Table 2 shows currently available LED sources for skin
rejuvenation.
Photoprophylaxis or Photoprevention
Photoprophylaxis is a novel approach that we were the first to
introduce—to the best of our knowledge—in the use of LEDs
for the prevention of cutaneous manifestations after a trauma.
If LED therapy is administered several times prior to a UV
insult, a mechanical trauma such as a CO2laser treatment or
a surgery, one may prevent undesirable consequences such
as sunburn, postinflammatory hyperpigmentation (PIH), or
hypertrophic scarring, respectively. These LED-preventative
modalities will be discussed hereafter.
Sunburn Prevention
Beyond the repair of previous UV insults to the skin, visible to
NIR light might offer protection against upcoming photo-
damage. It has been suggested that protective mechanisms
against skin UV-induced damage may be activated by IR ex-
posure in a number of in vitro studies using primary-culture
human fibroblasts.35,36 Therefore, LED treatment could stim-
ulate skin resistance to UV damage.
Results from our own laboratory testing suggest that LED
660 nm treatment before UV exposure provides significant
protection against UV-B induced erythema.37 The induction
of cellular resistance to UV insults may possibly be explained
by the induction of a state a natural resistance to the skin
(possibly via the p53 cell signaling pathways) without the
drawbacks and limitations of traditional sunscreens.38 These
results represent an encouraging step toward expanding the
potential applications of LED therapy and could be useful in
the treatment of patients with anomalous reactions to sun-
light such as polymorphous light eruption or lupus.
Postinflammatory
Hyperpigmentation Prevention
PIH is a frequently encountered problem and represents the
sequelae of various cutaneous disorders as well as therapeutic
interventions especially on Asian and dark complexion pa-
tients. A preventative and complementary approach to ther-
mal laser induced PIH using LED therapy is possible. Accord-
ing to unpublished work performed in our laboratory, the
use of LED 660 nm therapy can prevent or treat PIH. On the
basis of photographic analysis and melanin content measure-
ments, most patients can achieve substantial reduction or
absence of PIH lesions in the LED-treated areas (versus con-
Table 2 LED Sources Used for Noninvasive Skin Rejuvenation
Wavelength
(nm)
System
Name Manufacturer
590 GentleWaves Light Bioscience
630 Omnilux Revive Phototherapeutics
660 LumiPhase-R OpusMed
Figure 11 Pictures of a 47-year-old caucasian patient before CO2laser resurfacing, and 1 week and 3 weeks post
procedure after 4 LED treatments given 48 hours apart.
Figure 12 Picture of a female patient before and after complementary
LED treatments for diffuse-type rosacea.
234
D. Barolet

trol). In our hands, from 1 to 8 treatments delivered during a
1- to 2-week period prior to trauma will provide significantly
less pigmentary response at the site of the trauma, especially
if the area has been irradiated by UV posttrauma (by a sun
simulator; Fig. 13). This could have tremendous implications
since more than half of the planet (Asians and dark-complex-
ioned people) is prone to such a postinflammatory pigmen-
tary response.
Scar Prevention
Hypertrophic scars and keloids can form after surgery,
trauma, or acne and are characterized by fibroblastic prolif-
eration and excess collagen deposition.39 An imbalance be-
tween rates of collagen biosynthesis and degradation super-
imposed on the individual’s genetic predisposition have been
implicated in the pathologenesis of these scar types. It has
recently been proposed that interleukin (IL)-6 signaling
pathways play a central role in this process and thus, that IL-6
pathway inhibition could be a promising therapeutic target
for scar prevention.40,41 As LED therapy has been shown to
decrease IL-6 mRNA levels,42 it may potentially be prevent-
ing aberrant healing. A recent study conducted by our re-
search group revealed significant improvements on the
treated versus the control side in appearance and outline of
scars (Fig. 14).43
Photopreparation
Photopreparation is another new concept that we have been
working on that characterizes a way to enhance the delivery,
through a substantially uniform penetration, of a given com-
pound in the skin resulting in more active conversion of such
topical agents (ie, ALA to PpIX) in targeted tissues. Radiant IR
photopreparation increases skin temperature, which may
lead to an increase in pore size (diameter) for enhanced pen-
etration of a given topical in the pilosebaceous unit.
The efficacy of aminolevulinic acid photodynamic therapy
(ALA-PDT), for instance, is dependent on ALA absorption
and remains one of the main challenges of PDT. We have
recently showed that increasing the skin temperature for 15
minutes with radiant IR (CW LEDs emitting @
␭
970 nm,
irradiance 50 mW/cm2, total fluence 45 J/cm2) before ALA-
PDT in the treatment of a cystic acne patient significantly
Figure 14 Patient after facelift preauricular scar revision (upper) and
12-month follow-up (lower). Left: LED-treated side X30 days post-
surgery; Right: control (no LED).
Figure 15 Nineteen year-old male patient before and 4-weeks after
PDT for control right hemiface (upper panel) and LED-pretreated
left hemiface with no residual inflammatory lesion on his cheek
pretreated (lower panel).
Figure 13 UV photography of skin taken 30 days after (SS) UV irra-
diation on areas pretreated for 7 days or 30 days with LED and
control. The 7-day LED treatment before UV insult appears to be the
best regimen to prevent PIH.
LEDs in dermatology
235

decreased the number of cystic lesions in comparison with
the non IR-heated side (Fig. 15).44
Photoregulation
Photoregulation involves an exciting new 2-level (impor-
tance of dermal–epidermal communication via cytokines)
approach that we have evaluated with success to enhance the
biological effects of a given topical. The main goal of this
application would be to synergistically optimize any bioac-
tive compound trajectory/route to ultimately up-regulate
specific gene expression with simultaneous down-regulation
of undesired ones via cell signaling pathways. In the esthetics
industry, we believe such a method—even though still in its
infancy—will become applicable in such applications as
home-use skin rejuvenation and the treatment of inflamma-
tory acne, hyperpigmentation disorders, oily skin, hyperhi-
drosis, eczema, etc.
UV-Free Phototherapy
UV radiation phototherapy has been used for decades in the
management of common skin diseases.45 However, there are
side effects associated with UV deleterious effects as well as
several contra-indications, including the long-term manage-
ment of children and young adults and patients receiving
topical or systemic immunosuppressive drugs. The primary
effectors of UV phototherapy in the treatment of various skin
conditions bear similarities with some of those associated
with blue LEDs and IR phototherapy with LEDs, including
singlet oxygen production and modulation of interleu-
kins.46,47 This provides a unique opportunity to explore the
use of LED in skin conditions where UV therapy is used
without the downside of inherent side effects. This approach
has been termed UV-free therapy.
For instance, the mode of action of UVA phototherapy for
atopic dermatitis was found to involve the induction of apo-
ptosis in skin-infiltrating T-helper cells through a mechanism
that requires the generation of singlet oxygen.48 A recent
study demonstrated that visible light (400-500 nm) can be
successfully used for the treatment of patients with atopic
eczema.49 In our hands, even resistant KPR (keratosis pilaris
rubra) may respond to LED therapy in the visible-NIR spec-
trum (Fig. 16). These promising results introduce a wide
range of new potential application for LED.
Photodynamic Therapy (PDT)
PDT can best be defined as the use of light to activate a
photosensitive medication that is applied to the skin prior to
treatment. The PDT light source has a direct influence on
treatment efficacy. Nowadays, the importance of treatment
parameters of this light source is unfortunately greatly under-
estimated. High-end LED devices meet this challenge and can
be used as the light source of choice for PDT (Table 3). Thus,
PDT can serve as a treatment that complements other skin
rejuvenation therapies or topical agents used to enhance col-
lagen production. The use of a dual wavelength (red and
blue) LED light source enhances PDT results for acne and
other sebaceous disorders.50 Red wavelength (630 nm) can
reach the sebaceous glands and blue (405 nm) light photo-
bleaches any residual protoporphyrin IX (PpIX) in the epi-
dermis, thereby reducing posttreatment photosensitivity
(Fig. 17). The way light photons are delivered seems to hold
part of the answer for more effective PDT. Hence, dose rate is
becoming one of the important criteria as opposed to total
dose (fluence). Also, it is now suggested to avoid peak power
effects on the photosensitizer—so-called thermal effects
—that are usually encountered with light sources (thermal
technologies) such as IPLs and lasers (ie, PDL). PDT frequent
indications, both cosmetic and medical, are described in Ta-
ble 4. LED technology clearly brings several advantages to
Figure 16 A 24-year-old patient with KPR after 2 months of daily
treatments with 660/805 nm home use LED device.
Table 3 Fluorescent and High end LED Systems for PDT
Model
Device Parameters Blu-U LumiPhase-R/B Omnilux Revive
Wavelength (nm) Fluorescent tubes LED LED
417 405/630 (R/B) 633
Power density (mW/cm2) 10 150/60 (R/B) 105
Working distance gauge No Optical Positioning
System on both
R & R/B Models
No
Treatment time (sec) 1000 160-1000 1200-1800
PDT light source Yes Yes Yes
236
D. Barolet

enhance PDT clinical efficacy: progressive photoactivation of
photosenstizers, large uniform beam profile, reduced proce-
dural pain, and multiple wavelengths available.
Other Potential Applications
Rapidly emerging areas in light-based therapy include the
treatment of cellulite and hair loss. Both conditions are very
prevalent for which acceptable treatment options are lacking.
Genetic, hormonal, and vascular factors have been impli-
cated etiologies. Cellulite manifests as herniations of the sub-
cutaneous fat into the dermis. It has been suggested that light
therapy can improve the appearance of cellulite through the
contracture and increase in deep dermal collagen, resulting
in skin tightening and hypothetically providing a stronger
dermo-subcuticular junction barrier to herniation.51 A recent
study demonstrated that cellulite responded positively to an
anticellulite gel combined with red/NIR LED light expo-
sure.52 Light-based treatment (laser and LED) has also been
shown to promote hair regrowth and increased hair tensile
strength.53 These effects are thought to be due to the dilation
of blood vessels and increase in blood supply to hair follicles.
Safety
LED is safe, nonthermal, nontoxic and noninvasive, and to
date, no side effects have been reported in published litera-
ture. Caution must be emphasized especially for epileptic
and photophobic patients especially if LEDs are pulsed.
Conclusion
We are now part of an exciting era in which complex
subcellular reactions can actually be influenced favorably
with the help of sophisticated configured LED ballistic
photons to obtain excellent outcomes in a variety of skin
conditions. Safer than sunlight, this new low level light
therapy allows for the treatment of patients without pain,
downtime or side effects. On the basis of sound photobi-
ology principles, scientific and clinical studies conducted
so far have shown promising results. The future seems
limitless for LED therapy with innovative methods such as
photoprophylaxis, photopreparation, and home use pho-
toregulation although many challenges lie ahead. Future
research should focus on investigating specific cell-signal-
ing pathways involved to better understand the mecha-
nisms at play, search for cellular activation threshold of
targeted chromophores, as well as study its effectiveness in
treating a variety of cutaneous problems as a stand alone
application and/or complementary treatment modality or
as one of the best PDT light source.
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