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.
`
`*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
`
`1085-5629/08/$-see front matter © 2008 Elsevier Inc. All rights reserved.
`doi:10.1016/j.sder.2008.08.003
`
`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).
`
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`228
`
`D. Barolet
`
`Figure 1 Niels Ryberg Finsen (1860-1904). Courtesy of the Clen-
`dening History of Medicine Library, University of Kansas Medical
`Center.
`
`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-
`
`Figure 3 LED technology. The red arrows indicate the flow of heat.
`Courtesy of Stocker Yale, Inc.
`
`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 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 4 A t-pack LED.
`
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`LEDs in dermatology
`
`229
`
`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.6 Cells 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 c oxidase 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.
`
`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 c oxidase 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.2 Mitochondria
`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.3 These
`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-
`
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`230
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`D. Barolet
`
`Figure 6 Optical penetration depth.
`
`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 c oxidase 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 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.
`
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`LEDs in dermatology
`
`231
`
`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.
`
`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-
`
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`232
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`D. Barolet
`
`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 CO2 ablative 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.
`
`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,
`
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`LEDs in dermatology
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`233
`
`3 weeks
`48-72
`24-48
`
`CW or pulsed
`Sequential pulsing
`Sequential pulsing or
`CW
`Sequential pulsing or
`CW
`CW
`24
`Pre-PDT (q 3 weeks) CW
`
`24-48
`
`24-48
`48
`
`Sequential pulsing
`Sequential pulsing or
`CW
`
`Table 1 LED Parameters for Various Clinical Applications Used in our Practice
`
`No. of Treatments
`3-12
`
`Irradiance
`(mW/cm2)
`50 (minimal)
`
`Fluence
`(J/cm2)
`4
`
`Treatment Time
`(min;sec)
`2:40
`
`Interval
`Treatment Time
`(hours)
`24-72
`
`Mode
`(Pulsed/CW)
`Sequential pulsing**
`
`3-12
`
`50 (minimal)
`
`4
`
`2:40
`
`48-72
`
`Sequential pulsing
`
`Applications
`Wound healing
`
`Inflammation/erythema/edema
`(diffuse type rosacea,
`post- procedure erythema
`(eg, IPL, CO2)
`PDT
`Photorejuvenation
`Sunburn prevention*†
`
`PIH prevention*†
`
`Wavelength
`(nm)
`660 & 850
`combination
`630-660
`
`405-630
`630-660
`660-970
`
`870-970
`
`Scar prevention*
`Photopreparation
`
`Photoregulation
`UV-free phototherapy
`
`805-970
`870-970
`
`660-850
`405-850
`
`3ⴙ
`12
`ad 7
`
`ad 8
`
`50-100
`50-100
`50
`
`>50
`4
`4
`
`13-45
`2:40-16
`2:40-15
`
`50-80
`
`45-96
`
`15-20
`
`Multiple
`3 (before every PDT
`Treatment)
`Long-term
`Depends on inflammatory
`disease
`*Sunburn, PIH, and scar-prevention methods ⴝ Photoprophylaxis.
`**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.
`
`50-80
`>80
`
`8-50
`30-50
`
`45-72
`72-100
`
`4-7,5
`27-135
`
`15
`15
`
`5-16
`15-45
`
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`234
`
`D. Barolet
`
`Figure 11 Pictures of a 47-year-old caucasian patient before CO2 laser resurfacing, and 1 week and 3 weeks post
`procedure after 4 LED treatments given 48 hours apart.
`
`ogy. MMP inhibition through LED treatments may reduce
`lupus-induced damage in inflamed tissues.
`
`hypertrophic scarring, respectively. These LED-preventative
`modalities will be discussed hereafter.
`
`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 CO2 laser treatment or
`a surgery, one may prevent undesirable consequences such
`as sunburn, postinflammatory hyperpigmentation (PIH), or
`
`Figure 12 Picture of a female patient before and after complementary
`LED treatments for diffuse-type rosacea.
`
`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
`System
`(nm)
`Name
`590
`GentleWaves
`630
`Omnilux Revive
`660
`LumiPhase-R
`
`Manufacturer
`Light Bioscience
`Phototherapeutics
`OpusMed
`
`Petitioner Apple Inc. – Ex. 1036, p. 234
`
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`LEDs in dermatology
`
`235
`
`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.
`
`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-
`
`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).
`
`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 t