Emerging Cosmetic and Medical Applications of LED Technology Dr Caerwyn Ash

Emerging Cosmetic and Medical Applications of LED Technology Dr Caerwyn Ash

Abstract The rapid development of high brightness light emitting diodes (LED) makes feasible the use of LED, among other light sources (such as laser, intense pulse light and other incoherent light systems) currently used for cosmetic and medical treatment. Recent research into the comparison dosimetry of LED compared with laser and IPL devices are to be discussed and the relationship of wavelength and treatment modality explained. This is a general review on current and emerging LED applications in cosmetic and medical treatments such as wound healing, Neonatal jaundice, Acne, Inflammation, rejuvenating aged skin, skin cancer PDT, circadian rhythm disorders, and human diagnostics. In-vitro and in-vivo (animal and human) studies utilized a variety of LED wavelengths, power intensity, and energy density parameters to begin to identify conditions for each biological tissue that are optimal for biostimulation. LED is safe, non-thermal, non-toxic and non-invasive, and to date, without side effects have been reported in published literature. LED light sources for medical application are much more economical than using laser sources, highly durable and thus are less-expensive in the long term. Their compact and light design and the resulting lower weight make the use of LED systems simpler than current laser systems. While many of the wavelength segments are not yet available in traditional and semiconductor laser, wavelengths generated from LEDs have covered partial ultraviolet, near infrared, and almost all the visible bands. This work predicts LED technology will become a leading technology in medicine and aesthetic therapy. In such a growing and unsaturated market, the enviable succession of professional salon based light technology is transitioning into consumer markets, bringing with it many emerging launch opportunities. A brief discussion will provide technical information on these devices.

Keywords: LED, Skin, medicine, bioluminescence, photochemistry, PDT Cancer, Cytochrome C Oxidase, Light-Tissue Interaction.

Contact Details: Caerwyn Ash Research Scientist E: caerwynash@yahoo.co.uk M: 07790 160659

An experienced technologist with over 8 years experience of photonic based technologies. A key research scientist at CILT (CyDen Institute of Light Therapy), who was responsible for the development of skin tone meter and optical safety of products sold through Boots (UK) and Proctor & Gamble. He has a PhD in medical physics and deep understanding of the key aspects of all elements of light tissue interaction. Application and understanding of his findings are respected worldwide, and such research is being heavily relied upon in the development and production of consumer products. Such innovative clinical applications of light based products are far-reaching and ever increasing to include the treatment of hair removal, acne, skin rejuvenation, cellulite reduction, and wound healing. Caerwyn is a regular contributor to influential journal publications and maintains a high collaborative relationship with academia. Caerwyn pursues active research into cellular effects of LED, Intense Pulsed Light (IPL) and laser technology for a variety of cosmetic and medical conditions.

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Emerging Cosmetic and Medical Applications of LED Technology Dr Caerwyn Ash

1.0 Introduction The biomedical applications of Low Level Light Therapy (LLLT), so far, reach from accelerated wound healing processes (1) to nerve tissue recovery (2), including strategies to counteract the severe biological imbalances experienced by astronauts in microgravity (e.g. muscle and bone atrophy). The primary importance of intensity thresholds has been verified in-vitro and in-vivo in different biosystems as fibroblasts, keratinocytes, osteoblasts, neurons, retinal receptor cells, heart cells, sperm, and, recently, in cultured nanobacteria. Phototherapy, from the Greek words meaning treatment with light, has been a valid phototherapy modality since at least the days of the ancient Egyptians, when the sun was used in that the Ancient Greeks later termed heliotherapy. Natural light is a double edge sword when it comes to our health. The ultraviolet (UV) rays present in sunlight can also damage DNA in exposed skin, which can lead to skin cancer. They can also damage eyes leading to cataracts. On the other hand, sunlight also has enormous therapeutic benefits, having long been used for example to treat psoriasis and other skin disorders. Phototherapy is, in its broadest sense, the use of light for any kind of surgical or nonsurgical treatment, but it is the non-thermal and nontraumatic therapeutic application of light which is now accepted as the working definition of phototherapy. A medical application of solar therapy was later rediscovered by Niels Ryberg Finsen, 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 vulgaris. Since then phototherapy involving the use of an artificial irradiation source has expanded our knowledge and understanding of human biology. Research into light therapy stems back to the 19th century, the Italian scientist Fubini demonstrated that red light had a specific effect on mitochondria, increasing their metabolic rate. A new lease of life was given to light therapy by the successful development of the first ruby laser in 1960, followed in the next 4 years by the argon, Nd:YAG and CO2 lasers. The introduction of light-emitting diode (LED) devices has reduced many of the concerns formerly associated with lasers, such as expense, safety concerns, and the need for trained personnel to operate them. In the past few years, LED based systems have been successfully applied in an increasingly large number of fields, and three major wavelengths have emerged with a good photobiological basis and proven clinical utility, blue around 415 nm, red 633 nm and near infrared 830 nm. Each has its own specific cellular target or targets and biological action spectrum and reaction, but it has become even clearer that no single wavelength can accomplish everything and combination LED therapy has proved necessary for greatest efficacy. LEDs have become the new favourite in the field of medical treatment and phototherapy. Today, LEDs not only thrive in the field of low intensity photo rejuvenation; but are also used for the treatments of rhinitis, arthritis, jaundice, joint/tissue inflammation, skin abnormality, and for the relief of stress, seasonal affective disorder, as well as biological clock disorders. LED photomodulation is the
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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 Aeronautics 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 investigated the use of LED therapy in wound healing and obtained positive results. This new generation of LEDs was some orders of magnitude more powerful than its predecessors, capable of delivering a much less divergent beam of quasi monochromatic light, only a few nanometres either side of the rated wavelength, yet still comparatively inexpensive. The selectivity of LEDs allows the development of phototherapy treatments using wavelengths with positive effects. The use of LED phototherapy is now applied to many thousands of people worldwide each day for various medical conditions. As a consequence of brighter LEDs of specific wavelengths treatment modalities that werent possible previously are now possible due to technological advancement in LED. Non-invasive therapies for skin disease and skin rejuvenation are being used increasingly at a high rate, especially in Western countries, where relatively high disposable incomes are combined with the desire for an ideal appearance fostered by societal pressures. This article will examine and attempt to justify the use of LED s from photo biological principles, looking at the benefits of LED s a phototherapeutic source, the importance of wavelength, the targets for LED phototherapy including cellular action spectra, a discussion on appropriate intensity, and finally a brief overview illustrating the range of current practical applications in the clinical field.

2.0 Mechanism of Action In the same way that plants use chlorophyll to convert sunlight into plant tissue, LED s 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 chromophore or photo acceptor. Light, at appropriate doses and wavelengths, is absorbed by chromophores such as porphyrins, flavins, and other light absorbing entities within the mitochondria and cell membranes of cells. A growing body of evidence suggests that photomodulation mechanism is ascribed to the activation of mitochondrial respiratory chain components resulting in the initiation of a cascade of cellular reactions. It has been postulated that photo acceptors 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 spectrum and the second peak in the NIR range.

Emerging Cosmetic and Medical Applications of LED Technology Dr Caerwyn Ash

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 process. 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 displace it, allowing oxygen to bind again. The mechanisms of low level laser therapy (LLLT) are complex, but essentially rely upon the absorption of particular visible red and near infrared wave lengths in photoreceptors within sub-cellular components, particularly the electron transport (respiratory) chain within the membranes of mitochondria [3, 4]. The absorption of light by the respiratory chain components causes a short-term activation of the respiratory chain, and oxidation of the NADH pool. This stimulation of oxidative phosphorylation leads to changes in the redox status of both the mitochondria and the cytoplasm of the cell. The electron transport chain is able to provide increased levels of promotive force to the cell, through increased supply of Adenosine triphosphate (ATP), as well as an increase in the electrical potential of the mitochondria membrane, alkalization of the cytoplasm, and activation of nucleic acid synthesis [5]. Because ATP is the "energy currency" for a cell, LLLT has a potent action that results in stimulation of the normal functions of the cell. The primary means for photomodulated upregulation of cell activity by LED is the activation of energy switching mechanisms in mitochondria, the energy source for cellular activity. Cytochrome molecules are believed to be responsible for the light absorption in mitochondria. Cytochromes are synthesized from protoporphyrin IX and absorb wavelengths of light from 562 nm to 600 nm. It is believed that LED light absorption causes conformational changes in antenna molecules within the mitochondrial membrane. Proton translocation initiates a pump, which ultimately leads to energy for conversion of ADP to ATP. This essentially recharges the cell battery and provides more energy for cellular activity. 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. Mitochondria harbour an enzyme that synthesizes NO. So why would cells go out of their way to produce NO right next to the respiratory 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. 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 considered signals. The activity of many proteins, or transcription factors, depends, at least in part, on free radicals (6). These include many proteins such as those involved in the p53 cell signalling pathway. Further, to bring free radical leak under control, there is a cross-talk, known as retrograde response, between the mitochondria and genes in the nucleus for which we are
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just beginning to explore the mechanism at play. If we can better modulate this signalling, we might be able to influence the life or death of cells in many pathologies as it is more and more demonstrated in its anti-aging 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 cytochrome C oxidase. 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 oxygen species), reduction and prevention of apoptosis, stimulation of angiogenesis, increase of blood flow, and induction of transcription factors are observed. These signal transduction pathways lead to increased cell proliferation and migration (particularly by fibroblasts), modulation in levels of cytokines (eg, interleukins, tumour necrosis factor), growth factors and inflammatory mediators, and increases in anti-apoptotic proteins (7). The photo dissociation theory incriminating NO as one of the main players suggests that during an inflammatory process, for example, cytochrome C oxidase is clogged up by NO. LED therapy would photo dissociate NO or bump it to the extracellular matrix for oxygen to bind back again to cytochrome C oxidase and resume respiratory chain activity. Understanding the mechanisms of cutaneous LED induced specific cell signalling pathway modulation will assist in the future design of novel devices with tailored parameters even for the treatment of degenerative pathologies of the skin.

Figure 1: the ATP Cycle and the influence of light on the respiratory chain Since wavelength is the most important factor in any type of photo-therapy, the specification of the device must consider which wavelengths are most effective of producing the desired effects within living tissues. The effect of visible red light on the local vasculature is also well recognized. The red light will bring more oxygen and nutrients into the area, further helping to reduce inflammation and enhance the wound repair process. Corazza et al [7] have compared the blood vessels proliferation effects of laser and LEDs

Emerging Cosmetic and Medical Applications of LED Technology Dr Caerwyn Ash

illumination on wounds induced in rats. The results have shown that the proliferations of blood vessels in all irradiated groups are superior in comparison to those of the control group, which indicates that both LED and laser based therapy have demonstrated expressive results in angiogenesis. Light at a wavelength of 830 nm (near infrared) is absorbed in the cellular membrane rather than in cellular organelles, which remain the target when using light in the visible spectrum. Irradiation at 830 nm leads to accelerated fibroblast-myofibroblast transformation and mast-cell degranulation. In addition, chemotaxis and phagocytic activity of leucocytes and macrophages is enhanced through cellular stimulation by this wavelength [8, 9].

Figure 2: Absorption characteristics of human skin (Melanin, Oxyhaemoglobin, Porphyrin and Water)

3.0 Optimal LED Parameters 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 effective LED clinical response are discussed hereafter. Light is predominately measured in wavelength and is expressed in units of nanometres (nm). Different wavelengths have different chromophore absorption characteristics can have various effects on tissue. In general the longer the wavelength, the deeper photons penetrate into tissue. 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). 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.

3.1 Wavelength The first law of photobiology, states that only energy which is absorbed in a target can produce a photochemical or photo physical reaction. However, any such reaction is not an automatic consequence of energy absorption. It may be simply converted into heat, or re-emitted at a different wavelength (fluorescence). The prime arbitrator of this no absorption, no reaction is not the output power on the incident photons, but their wavelength, and this comprises two important considerations: wavelength specificity of the target, or the target chromophore; and the depth of the target. Based on these two considerations, the wavelength must not only be appropriate for the chosen chromophore, but it must also penetrate deeply enough to reach enough of the target chromophores with a high enough photon density to induce the desired reaction (11). Penetration of light into living tissue is, however, extremely important in phototherapy, and very frequently displays characteristics which are often in discord with results produced by mathematical models. The different wavebands, visible light and invisible infrared light, have different primary mechanisms. Absorption of visible light photons at appropriate levels induces a photochemical reaction, and a primary photochemical cascade occurs within the cell, usually instigated by the mitochondria, the adenosine triphosphate producing power houses of the cell. Infrared photons, on the other hand, are primarily involved in photo physical reactions which occur in the cell membrane, changing the rotational and vibrational characteristics of the membrane molecules. Through subsequent activation of the various membrane-located transport mechanisms, such as the Na++/Ca++ and Na++/K++ pumps and changes in the cell permeability, changes occur in the chemical and osmotic balance in the cytosol, finally resulting in the induction of a secondary chemical cascade which gives more or less the same endpoint as the visible light photons, namely cellular activation or proliferation. Wavelength is thus probably the single most important consideration in phototherapy, because without absorption, there can be no reaction.

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Emerging Cosmetic and Medical Applications of LED Technology Dr Caerwyn Ash

Table 1: Effect of different wavelengths on biostimulation (12)

Table 1: Literature based summary of the phototherapeutic wavelength specific efficacy in raising the action potentials of specific cells low and high oxygen tension which can act as highways for the wound healing cells into the target area, particularly those associated with the inflammatory stage of wound healing. In the case of visible red light the main target is the respiratory chain of the mitochondrion in the fibroblast, and specifically cytochrome C oxidase. In the process, in which copper ions play an important role, it translocate protons, helping to establish a chemiosmotic potential that the ATP synthase then uses to synthesize ATP. One of the major peaks in the absorption spectrum of cytochrome C oxidase is in the visible yellow, but bearing in mind the poor penetration of yellow light in living human tissue. It is not possible for yellow light to reach deeply enough into the reticular dermis to affect the activity of fibroblasts in that zone so the yellow waveband is not ideal for any phototherapeutic application involving fibroblasts. Another major peak in the cytochrome C oxidase absorption spectrum is around 633 nm, and that wavelength does offer much deeper penetration, and thus potentially greater applications in phototherapy involving fibroblast activity, such as wound healing and even skin rejuvenation. 3.2 Fluence and Irradiance Wavelength as already argued will determine both the target, and the depths at which the desired targets can be reached, but the photon intensity will help to ensure that treatment is successfully achieved with the selected wavelength or sequential wavelengths to get the desired clinical result. The Arndt-Schulz law states that there is only a narrow window of opportunity where you can actually activate a cellular response using precise sets of parameters, i.e. the fluence or

Table 1 shows in the left hand column a selection of investigated wavelengths, in increasing length from the top, and along the top of the table can be found the most important cellular targets. These cells can be sub grouped into 4 types. The first three subgroups are concerned with the wound healing process. Subgroup 1 consists of mast cells, neutrophils and macrophages, which are associated with the inflammatory stage of wound healing; subgroup 2 consists of fibroblasts, associated with the proliferative stage; and subgroup 3 are the transformational cells associated with the remodelling stage. In subgroup 4 can be found epidermal keratinocytes, which, when photo activated, are an extremely important source of cytokines and other chemokines which can descend into the dermis and are involved in either proinflammatory or anti-inflammatory reactions. From the various wavelengths reported, two are notable for their effect on raising the action potential of target cells, but they do so in different ways. Visible red at 633 nm has been reported to have profound effects on fibroblasts, inducing fibroplasia with increased numbers of highly active mitochondria. Near IR 830 nm, on the other hand, has some apparent effects on fibroblasts, but profound effects on all three of the inflammatory stage cells. Both visible red and near IR wavelengths photo modulate the mechanisms of epidermal keratinocytes, producing an increased amount of interleukins such as IL1, 2, and 6 and also tumour necrosis factor alpha (TNF). Both IR and visible red light are well associated with increased local blood flow post irradiation. This is important when considering that this not only increases the flow of nutrients and oxygen into the treated area, but also provides a gradient between areas of
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Emerging Cosmetic and Medical Applications of LED Technology Dr Caerwyn Ash

dose. The challenge remains to find the appropriate combinations of LED treatment time and irradiance to achieve optimal target tissue effects. Fluence or dose is, indicated in Joules per cm2. In practice, if light intensity (irradiance) is lower than the physiological threshold value for a given target, it does not produce photo stimulatory effects even when irradiation time is extended. It should be cautioned, however, that an excessive dose of radiation can be detrimental. Thus, at proper doses of light there can be a stimulation of growth, but at high doses an excessive amount of singlet oxygen may be produced, and its chemical action can be detrimental to cells. This is another reason for determining an action spectrum. Figure 4: Laboratory collaboration for wound healing.

Fig 3: The biphasic dose response in of a positive response with sufficient illumination for a measurable reaction, however excessive dose can be detrimental. A narrow margin occurs for effective treatment

4.1 Wound Healing The need to care for a population with chronic wounds is a growing challenge that requires innovative approaches. Laser light have been widely acclaimed to speed wound healing of ischemic, hypoxic, and infected wounds (13). Lasers provide low energy stimulation of tissues that results in increased cellular activity during wound healing (14, 15). LED photo modulation has an effect on human skin that is non-thermal and most likely mediated by mitochondrial cytochrome light absorption. This leads to increased cellular metabolic activity by targeted cells, such as increased collagen synthesis by fibroblasts. The second phase of wound healing involves proliferation, with the formation of granulation tissue as a result of new blood vessel growth. This angiogenesis combined with the deposition of new connective tissue requires successful degradation of the wound matrix by macrophages. Tissue repair and healing of injured skin are complex processes that involve a dynamic series of events including coagulation, inflammation, granulation tissue formation, wound contraction and tissue remodelling (16). Photomodulation with light in the red to the near infrared range (630-1000 nm) has been shown to accelerate wound healing, improve recovery from ischemic injury, and attenuate degeneration in the injured optic nerve. Low fluence of photo irradiation at the cellular level can generate significant biological effects including cellular proliferation and the release of growth factors from cells. Erdle et al (17) have evaluated the wound healing effect of 670 nm LED light on incisions and burn injuries in hairless mice and suggested that red light exposure may be helpful in postoperative wound repair. Their results show that while not so effective for burn injuries, 670 nm LED red light sources do accelerate healing in skin of hairless mice with incisions. Desmet et al (18) have also studied the use of near infrared light treatment in various in vitro and in vivo models to determine the effect of near infrared LED light treatment on physiologic and pathologic processes. Their research found that the light treatment stimulates the photo acceptor cytochrome oxidase, which results in increased energy metabolism and production,

4.0 Clinical Literature In our laboratory we perform many dose response experiments to firstly understand the mechanism of action and to understand the limits of the dose response. The magnitude of the bio stimulation effect depends on the physiological condition of the cells and tissues at the moment of irradiation. 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 pro-collagen production, energizing the cell to its own maximal biological potential. This may explain the variability in results in different studies.

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Emerging Cosmetic and Medical Applications of LED Technology Dr Caerwyn Ash

Trelles and Allone (19) have studied 10 subjects regarding the effects of a LED phototherapy system on enhancing wound healing following the combination of eyelid surgery and laser ablative resurfacing. After the surgery, one-half of each subjects face was treated with the red LED therapy (20 min, 96 J/cm2, 633 nm), the other half of each subjects face being the non-irradiated control. Erythema, edema, bruising, and days to healing were independently evaluated from the clinical photography. The 633 nm LED therapy treated side is superior to the non-irradiated control by a factor of two to three in all instances. 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 increase significantly cell growth in a diversity of cell lines, including murine fibroblasts, rat osteoblasts, rat skeletal muscle cells, and normal human epithelial cells. 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 (20, 21). Accelerated healing and greater amounts of epithelialization for wound closure of skin grafts have been demonstrated in human studies (22, 23). The literature also shows that LED therapy is known to positively support and speeds up healing of chronic leg ulcers: diabetic, venous, arterial pressure. 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 (MMP-1) production accelerates wound remodelling. Mast cells, neutrophils, and macrophages are the first cells to respond to a wound, and that these cells respond best to 830 nm light. In contrast, fibroblasts, which are involved later, respond better to 633nm light. The suggestion has been made that it might be better to irradiate first with 830nm light, followed by 633nm light, and then again with 833 nm light to activate the myofibroblasts.

4.2 Inflammation The phases of wound healing and the cells involved must be understood in order to appreciate the important role of inflammation in these processes. In the inflammatory phase, leukocytes peak, monocytes transform into phagocytes and mast cells peak and degranulate. This response initiates the migration of more macrophage cells and fibroblasts to the target stimulated by chemotactic signals from pre-existing fibroblasts, leukocytes and macrophages. At the start of the proliferation phase macrophages gradually decrease and the number of fibroblasts peak then start to drop off. At the end of the proliferation phase two transitional events occur: the differentiation of active fibroblasts into myofibroblasts and the differentiation of active fibroblasts into dormant fibrocytes. The role of the myofibroblasts is to position themselves on collagen fibres and exert a longitudinal force on them, tightening and aligning them. Red light at 633 nm has been shown to make mast cells preferentially degranulate. Mast cells are present in the dermis, located near blood vessels. The stimulation given by their fast-acting proallergenic granules is seen by the surrounding tissue as inflammation, so the wound healing process is triggered without any thermal damage. The inflammatory response from 633 nm is a controlled short lived phase, which transcends through to the proliferation phase, together with the creation of neovascularization and the increase of local blood and lymphatic vessel flow. Lymphatic drainage is important in transporting leukocytes and lymphocytes into the target area and maintaining homeostasis of the treated skin. An increased blood supply raises the oxygen tension in the target area, creating cellular gradients and ensuring that the connection between the papillary dermis and the basement membrane of the dermal epidermal junction and the basement membrane is supported. Fibroblasts are essential in achieving the desired effect in the dermis during the second and third phases following the inflammatory reaction caused by mediated mast cell degranulation. The fibroblast is multifunctional, not only synthesizing collagen and elastin, but also regulating the homeostasis of the ground substance and maintaining collagen fibres. 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 bodys defence 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 counteracting inflammatory mediators. A series of recent studies have demonstrated the anti-inflammatory potential of LED. A study conducted in arachidonic acid treated human gingival fibroblast suggests that 635 nm irradiation inhibits PGE 2 synthesis like COX inhibitor and thus may be a useful anti-inflammatory tool.

Figure 5: 15 years old wound on a diabetic male (aged 46), previously had 8 skin grafts over 15 years. Image shows 12% closure after 7 weeks as the keratinocytes migrate from the edges of the wound.

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4.3 Acne vulgaris Acne vulgaris is an exceedingly common chronic disease of the sebaceous gland and follicle, affecting approximately 40 million U.S. adolescents and 25 million adults (24) and accounts for over 30% of annual dermatology visits. It is the current consensus that acne is a multifactor disease which involves four primary events; follicular hypercornification, increased sebum secretion, colonization by the gram positive bacterium, Propionibacterium acnes (P. acnes), and inflammation (25). The rise in antibiotic resistance threatens to reduce the future usefulness of the current mainstay of therapy. Acne often improves after exposure to sunlight or artificially produced solar radiation. P. acnes produces porphyrins (26) which absorb light energy at the near ultraviolet (UV) and blue light spectrum. Irradiation of P. acnes colonies with blue visible light leads to photoexcitation of bacterial porphyrins, singlet oxygen production and eventually bacterial destruction (27). In-vivo it has been shown that acne may be treated successfully with blue visible light phototherapy Papageorgiou et al (28) have evaluated the effectiveness of blue light (peak at 415 nm) and a mixed blue and red light (peaks at 415 and 660 nm) in acne treatments. Their study randomly assigned 107 patients with mild to moderate acne in four treatment groups to be treated with blue light, mixed blue and red light, cool white light, and 5% benzoyl peroxide cream, respectively. Subjects in the phototherapy groups received irradiation 15 min daily from portable light sources. After 12 weeks of active treatment, the combined blue/red light group achieved a mean improvement of 76% in inflammatory lesions, significantly superior to that in all other groups. The final mean improvement by using blue red light is 58%, still better than that in the other groups. The author has just reported a significant study using 414 nm LEDs in combination with a proprietary cream for clearing acne vulgaris. In a study of 39 adults with mild-tomoderate facial inflammatory acne were recruited. Subjects were randomly assigned to blue light therapy (n=31) or control (n=8). Subjects were well matched at baseline in terms of age, sex and duration of acne. Severity of cyclic breakouts, improvement in skin appearance, clarity, radiance, tone, texture, smoothness and subject satisfaction was recorded at 1, 2, 3, 4, 6, 8, 12 weeks. Inflammatory lesion counts reduced by 64% in treatment group and 4% in controls. The reduction was most observed in the first 3 weeks after start of treatment. Treatment is pain and side effect-free. Home-use blue light therapy improves inflammatory facial acne three weeks after first treatment with no serious adverse effects. The blue light device offers a valuable alternative to antibiotics and potentially irritating topical treatments. The onset of the effect was observable at week 3, and maximal between weeks 8 and 12. Blue light phototherapy using a narrowband LED light source appears to be a safe and effective additional therapy for mild to moderate acne (29).

4.4 Skin Rejuvenation Over time, skin gradually displays the effects of aging. The collagen in the skin begins to break down and results in fine lines and then deeper grooves on the skin surface. Factors like sun, gravity, and hormones can speed up the aging process. The treatment of aging skin has always been a very popular topic. Lubart et al (30) propose a photo rejuvenation mechanism based on light-induced reactive oxygen species (ROS) formation. They irradiate collagen in-vitro with a broadband of visible light (400800 nm, 2472 J/cm2) and have found that the irradiated collagen results in the formation of hydroxyl radicals. These researchers suggest that visible light at the energy doses used for skin rejuvenation (20 30 J/cm2) produces high amounts of ROS, which destroy old collagen fibres, encouraging the formation of new ones. While at inner depths of the skin, where the light intensity is much weaker, low amounts of ROS are formed, which are well known to stimulate fibroblast production. Trelles (31) have suggested that LED therapy represents a potential approach in anti-aging prevention. He has proposed to apply prevention to subjects in their very early 20 s before the appearance of fine lines. The prevention can be achieved via irradiating low level photo energy with specific wavelengths that, based on the photo biological findings, can stimulate both epidermal and dermal cells. He has also reported that the LEDs from the NASA Space Medicine Program can enhance action potentials of the skin cells and increases in local blood and lymphatic flow in a non-invasive, a thermal manner. His conclusion is that LED-based systems can be less-expensive but clinically useful light source against photo aging.

Figure 6: Possible mechanism of actions for LLLTs effects on skin rejuvenation. LLLT aids skin rejuvenation through increasing collagen production and decreasing collagen degradation. Increase in collagen production occurs by LLLTs increasing effects on PDGF and fibroblast production, which happens through decreasing apoptosis and increasing vascular perfusion and bFGF and TGF- expressions. Decrease in IL-6 and increase in TIMPs, which in turn reduce MMPs, aid in reduction of collagen degradation. (Figure courtesy of Wellman Center for Photomedicine.)

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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 reduction in MMP. A significant increase in collagen production after LED treatment has been shown in various experiments, including fibroblasts cultures, third-degree burn animal models, and human blister fluids, and skin biopsies.

4.5 Sunburn prevention LLLT for Photo protection Results from our own laboratory testing suggest that LED 660 nm treatment before UV exposure provides significant protection against UV-B induced erythema. 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 signalling pathways) without the drawbacks and limitations of traditional sunscreens. It is widely accepted that the UV range (400 nm) exposure is responsible for almost all damaging photo induced effects on human skin (32, 33, 34). Some proposed mechanisms for UV induced skin damage are collagen breakdown, formation of free radicals, inhibition of DNA repair, and inhibition of the immune system. Existing solutions to prevent UV induced damaging effects are based on minimizing the amount of UV irradiation that reaches the skin, which is achieved by either avoidance of sun exposure or use of sunscreens. However, sometimes sun avoidance might be hard to implement, especially for the people involved in outdoor occupations or leisure activities. In contrast, the photo protective efficacy of topical sunscreens has limitations as well, which include decreased efficacy after water exposure or perspiration, spectral limitations, possible toxic effects of nanoparticles that are contained by most sunscreens (35), user allergies, and compliance. It has recently been suggested that infrared (IR) exposure might have protective effects against UV induced skin damage mainly by triggering protective/repair responses to UV irradiation. In the natural environment, visible and IR solar wavelengths predominate in the morning, and UVB and UVA are maximal around noon, which suggests that mammals already possess a natural mechanism that, in reaction to morning IR radiation, prepares the skin for upcoming potentially damaging UV radiation at noon (36). However, opposing views also exist, such as Krutmann and Schroeders study demonstrating IR induced disturbance of the electron flow of the mitochondrial electron transport chain, which leads to inadequate energy production in dermal fibroblasts (37) Schroeder et als report is another example stating that IR alters the collagen equilibrium of the dermal extracellular matrix (ECM) by leading to an increased expression of the collagen degrading enzyme MMP-1, and by decreasing the de novo synthesis of the collagen itself (38). As previously mentioned, the same light source may have opposite effects on the same tissue, depending on the parameters used, and these conflicting views are probably due to the biphasic effects of light. Menezes et al demonstrated that non-coherent NIR (7002000 nm) generated a strong cellular defence against solar UV cytotoxicity in the absence of rising skin temperature, and it was assumed to be a long lasting (at least 24 h) and cumulative phenomenon (39). Following this study, Frank et al proposed that IR irradiation prepares cells to resist UVB
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UVB induced damage by affecting the mitochondrial apoptotic pathway (40). IR pre-irradiation of human fibroblasts was shown to inhibit UVB activation of caspase9 and -3, partially release cytochrome C and Smac/DIABLO, decrease proapoptotic proteins (ie, Bax), and increase anti apoptotic proteins (ie, Bcl-2 or Bcl-xL). The results suggested that IR inhibited UVB induced apoptosis by modulating the Bcl-2/Bax balance, pointing to a role of p53, a sensor of gene integrity involved in cell apoptosis and repair mechanisms. In a further study, Frank et al studied more specifically the role of the p53 cell signalling pathway in the prevention of UVB toxicity. The response to IR irradiation was shown to be p53 dependent, which further suggests that IR irradiation prepares cells to resist and/or to repair further UVB-induced DNA damage. Finally, the IR induction of defence mechanisms was supported by Applegate et al, who reported that the protective protein, ferritin, normally involved in skin repair (scavenger of Fe2 otherwise available for oxidative reactions) was induced by IR radiation (41). In an in vitro study, it was reported that an increase in dermal fibroblast procollagen secretion reduces MMP or collagenase production after non thermal non coherent deep red visible LED exposures (660 nm, sequential pulsing mode). These results correlated with significant clinical improvement of rhytids in-vivo. In a subsequent in-vivo pilot study, effect of this wavelength in 3 healthy subjects using a minimal erythema dose method adapted from sunscreen sun protection factor (SPF) determination has been investigated. The results showed that LED therapy was effective, achieving a significant response in the reduction of the erythema induced by UVB. Following this pilot study, a further investigation has been performed to find out in-vivo aspects of this phenomenon. Effects of non-thermal non coherent 660 nm LED pulsed treatments in providing enhanced skin resistance before upcoming UV damage were investigated in a group of subjects with normal fair skin and patients presenting with polymorphous light eruption. Results suggested that LED based therapy before UV exposure provided significant dose related protection against UVB induced erythema. A significant reduction in UVB induced erythema reaction was observed in at least one occasion in 85% of subjects as well as in the patients suffering from polymorphous light eruption. Furthermore, an SPF 15 like effect and a reduction in post inflammatory hyperpigmentation were observed. An in vitro study by Yu et al revealed that HeNe laser irradiation stimulated an increase in nerve growth factor (NGF) release from cultured keratinocytes and its gene expression (42). NGF is a major paracrine maintenance factor for melanocyte survival in skin (43). It was shown that NGF can protect melanocytes from UV induced apoptosis by upregulating Bcl-2 levels in the cells (44). Therefore, an increase in NGF production induced by HeNe laser treatment may provide another explanation for the photo protective effects of LLLT.

Emerging Cosmetic and Medical Applications of LED Technology Dr Caerwyn Ash

4.6 Scar Prevention Hypertrophic scars and keloids can form after surgery, trauma, or acne and are characterized by fibroblastic proliferation and excess collagen deposition. An imbalance between rates of collagen biosynthesis and degradation superimposed on the individuals genetic predisposition have been implicated in the pathogenesis of these scar types. It has recently been proposed that interleukin (IL)-6 signalling pathways play a central role in this process and thus, that IL-6 pathway inhibition could be a promising therapeutic target for scar prevention. As LED therapy has been shown to decrease IL-6 mRNA levels, it may potentially be preventing aberrant healing.

4.9 Neonatal Jaundice UV phototherapy has been used for decades in the management of common skin diseases (46). However, there are side effects associated with UV deleterious effects as well as several contraindications, including the long-term management 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 interleukins (47, 48). 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.

4.7 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. Red light (630 nm) has been used for many years in combination with a sensitizer (levulinic acid) for photodynamic therapy (PDT). When exposed to light of the proper wavelength, the sensitizer produces an activated oxygen species, singlet oxygen, which oxidizes the plasma membrane of targeted cells. Due to a lower metabolic rate, there is less sensitizer in the adjacent normal tissue, hence a lesser reaction. One of the absorption peaks of the metabolic product of levulinic acid, protoporphyrin absorbs strongly at 630 nm. Nowadays, the importance of treatment parameters of this light source is unfortunately greatly underestimated. High-end LED devices meet this challenge and can be used as the light source of choice for PDT. Figure x: tradition UV phototherapy for neonatal jaundice 4.8 Rheumatoid arthritis McDonald has conducted a study in which she instructed 60 female rheumatoid arthritis patients to place their hands into a box to be exposed in blue light for up to 15 min (45). Most subjects have experienced a pain relief after the exposure. McDonald has concluded that the pain relief is due to the blue light and the length of time exposed. The longer the exposure is, the greater the chance of pain relief. While the light source used in this 1982 study is not specified, there is no reason to rule out that blue light LED will have similar treatment effect. Hart and Malak have patented a therapeutic light source for the treatment of arthritis or joint inflammation. The device includes a set of 350 to 1000 nm LEDs and fibre optic connections for treating and reducing inflammation and edema both internal and external, to joints, muscles, nerves, and skin tissues of the subject. The device can be worn in contact with the skin and surrounding the areas of inflammation, edema, neural, and muscular damage over short and long periods of time. Our solution of flexible LEDs incorporated into fabric to provide comfortable treatment to infant, without any UV eye risk to the infant. The blanket or baby grow suit may also have continuous bilirubin measurement and will turn off the UV phototherapy when normal bilirubin levels are sustained. This is an attractive solution as the infant wont have to endure painful blood tests, and better monitoring of infant than relying on nurses. Without the need of the sick baby being in an incubator the infant can be wrapped in the blanket and greater direct bonding and interaction between mother and baby.

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Emerging Cosmetic and Medical Applications of LED Technology Dr Caerwyn Ash

4.10 Psoriasis Typically UVA is used to treat Psoriasis, Atopic Dermatitis and Uricaria pigmentosa. Although a visible LED and laser diode have been used to treat acne and facial rejuvenation, to our knowledge there are no reports of UV LED based phototherapy with adequate reporting of results. Most hospitals use large arrays of florescent tubes to treat the whole body. These are highly inefficient typically consuming 3.5-5KW electricity, costly and difficult to maintain, requiring several meters of floor space. Irradiation of health tissue is difficult to avoid when using large area irradiation. Medical workers are also exposed to UV irradiation while operating the system. Considerable heat generated is uncomfortable during treatment while standing. LEDs provide a significant reduction in running costs, Improved Lifetime and no toxic compounds and only treat body areas affected. Treatment performed at work, home, or at night.

4.12 Hypertrophic Scars and Keloids Hypertrophic scars and keloids are benign skin tumours that usually form after surgery, trauma, or acne and are difficult to eradicate. Fibroblastic proliferation and excess collagen deposits are the 2 main characteristics, and imbalance between rates of collagen biosynthesis and degradation superimposed on the individuals genetic predisposition has been implicated in their pathogenesis. It has recently been proposed that poor regulation of IL-6 signalling pathways and TGF expression have a significant role in this process, and thus inhibition of the IL-6 pathway and/or TGF expression could be a potential therapeutic target. Based on the reports demonstrating the role of LLLT in decreasing IL6 mRNA levels and modulation of PDGF, TGF, ILs such as IL-13 and IL-15, and MMPs, which are also associated with abnormal wound healing, it was proposed to be an alternative therapy to existing treatment options. The use of LLLT as a prophylactic method to alter the wound healing process to avoid or attenuate the formation of hypertrophic scars or keloids has been investigated by Barolet and Boucher in 3 case studies, where after scar revision by surgery or CO2 laser ablation on bilateral areas, a single scar was treated daily by the patient at home with 805 nm NIRLED at 30 mW/cm2 and 27 J/cm2.

4.13 Diagnostics The biggest use of the multi wavelength monochromatic properties of LED is for tissue diagnostics. LEDs have been used for decades for quantifying blood oxygenation in-vivo by absorption of oxygenated and deoxygenated haemoglobin on both side of the isobastic point. Skin tone is a continuous shade from Albino to dark AfroCaribbean, the author published work on the optimum wavelength and the results on 220 subjects to quantify skin tone into 6 categories (58, 59). The same technology previously described can also be used to quantify bilirubin in-vivo. Its been shown that fresh fibroblasts in which are key in the process of wound healing fluoresce under certain near UV wavelengths, this may be used to optimise treatment for wound care and skin rejuvenation as illuminating fresh fibroblasts may be detrimental in their transformation stages optimising the best time for treatment. A long-term ambition from many global companies to produce an in-vivo blood glucose meter for diabetic for monitoring of their blood glucose levels. Patients with type 1 diabetes test their blood glucose by pricking their fingertip and self-injecting insulin, an alternative to this technique particularly for paediatric cases is an ideal goal.

Figure X: 4.11 Herpes simplex virus (HSV) HSV is chronic and lasts ones entire life. The exposure of the host to several kinds of physical or emotional stresses such as fever, exposure to UV light, and immune suppression causes virus reactivation and migration through sensory nerves to skin and mucosa, localizing particularly on the basal epithelium of the lips and the perioral area (49). Although several antiviral drugs such as acyclovir and valacyclovir are used to control recurrent herpes outbreaks, only limited reduction in the lesions healing time has been observed. Although mechanism of action is still not clear, an indirect effect of LLLT on cellular and hormonal components of the immune system involved in antiviral responses rather than a direct virus-inactivating effect was proposed (50). Activation and proliferation of lymphocytes (51, 52, 53, 54) and macrophages (55), as well as the synthesis and expression of cytokines (56, 57) after low intensities of red and NIR light, have been reported by several investigators.

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Emerging Cosmetic and Medical Applications of LED Technology Dr Caerwyn Ash

5.0 Discussion LEDs are based on semiconductor technology, just like computer processors, and are increasing in brightness, energy efficiency, and longevity at a pace reminiscent of the evolution of computer processors. Basic science is elucidating some of the mechanisms at tissue, cellular and subcellular levels, proving what clinicians and therapists have already found in patients. The combination of one LED wavelength with another, used sequentially, has appeared as the best and most effective approach. LED therapy may be used as a standalone light therapy, but has very interesting effects when used in an adjunctive manner to improve and speed up the already good results achieved with other light sources, or conventional surgery. There is no doubt that LED phototherapy, when used based on the solid photobiological precepts of appropriate wavelength, target and photon intensity, is a safe, flexible, effective and comparatively inexpensive modality, very welcome in this era of ever-spiralling costs for both practitioners and patients. Besides being used for the treatments of rhinitis, arthritis, jaundice, etc. LEDs are used for the relief of stress, seasonal affective disorder, and biological clock disorders; not to mention that LEDs are thriving in the field of low intensity photo rejuvenation. The LED based PDT has even been expanded to cancer treatments. LEDs allow the adjustment of light intensity. They have the ability to produce high light levels with low radiant heat output and maintain useful light output for years. LED based systems can provide a homogenous light dose in optimal intensity. It is inevitable that one day a body suit for astronauts and submariners can provide visible and UV for vitamin D synthesis in situations of light is limited or restricted. This paper does not cover UV bacteria decontamination or teeth whitening, which are currently large markets both domestically in the UK and globally.

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Using LED array light source for medical devices is much more economical than using IPL or laser sources. LEDs are highly durable and thus are less expensive in the long term. Their compact and light design and the resulting lower weight make the use of LED systems simpler. Solid-state high efficiency LED is safer to use than the traditional gas laser. The energy level of LED is low. When used in medical treatment, LED based systems do not need a high voltage power supply as required in laser based ones. When required, LED based devices are more easily to be made selfcontained. They can be continuously operated with a battery pack for a longer period. For any medical treatment equipment, especially those used in the remote areas where no modern utilities are readily available, this is an attractive feature. While many of the wavelength segments are not yet available in semiconductor laser, wavelengths generated from LEDs have covered partial ultraviolet, near infrared, and almost all the visible bands. LEDs produce less heat than high pressure lamps and thus the hyperthermic effects that can be induced by high-intensity light sources are avoided. As a result, LEDs can be placed in a closer range from the treatment areas than other light sources so there will be less distance to diminish the intensity required. This accounts for more energy saving. Their relatively narrow emission spectrum of LED systems can be optimally tuned so as to correspond to the treatment requirement and thus eliminates wavelengths not needed for the therapy. As a result, the irradiation time required for treatment is much shorter than with incoherent light sources. The studies reviewed in this paper indicate that LED s have opened up new prospects as an effective light source of phototherapy and medical treatment

6.0 Conclusion Phototherapy has definitely arrived in the clinical field for the treatment of inflammatory acne, wound healing, skin rejuvenation, and the treatment of pain. LLLT appears to have a wide range of applications in dermatology, especially in indications where stimulation of healing, reduction of inflammation, reduction of cell death, and skin rejuvenation are required. The introduction of LED array based devices has simplified the application to large areas of skin. It is difficult for lasers to produce the efficient wavelength combination optimal for wound healing. The size of wounds that may be treated by the small beam width of laser is also limited. In contrast, LEDs allow the control of spectral composition and can be arranged in flat arrays of all sizes for the treatment of small or large areas. LEDs offer an effective alternative to conventional light sources also for the following reasons:

These manufacturers may also develop new patent technology to produce new products that can boost the LED industry. All these lead to lower LED costs and more LED varieties. Therefore, LED based applications, along with phototherapy, are setting out for a superior outlook in the years to come as LED becomes more qualified to replace its more energy demanding counterparts. LED is safe, non-thermal, non-toxic and non-invasive, and to date, no side effects have been reported in published literature. Caution must be emphasized especially for epileptic and photophobic patients especially if LEDs are pulsed. On the basis of sound photobiology principles, scientific and clinical studies conducted so far have shown promising results. The application of LEDs has ushered in a new and exciting era in phototherapy, and offers a versatile and inexpensive therapeutic modality either as a standalone therapy or in combination with reactive drug compounds. Phototherapy, whether using low intensity radiation of the proper wavelength from a laser, an LED, or a filtered incandescent lamp, can be beneficial in a number of clinical situations, from pain remission to wound healing.

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Emerging Cosmetic and Medical Applications of LED Technology Dr Caerwyn Ash

Unfortunately, the absence of this type of phototherapy from the mainstream of medicine makes it currently unavailable to many patients who would benefit from it. Phototherapy has been found to accelerate wound healing and reduce pain, possibly by stimulating oxidative phosphorylation in mitochondria and modulating inflammatory responses. By influencing the biological function of a variety of cell types, it is able to exert a range of several beneficial effects upon inflammation and healing. Phototherapy exerts marked effects upon cells in all phases on wound healing, but particularly so during the proliferative phase. There is good evidence that the enhanced cell metabolic functions seen after phototherapy are the result of activation of photoreceptors within the electron transport chain of mitochondria. The effect is specific for wavelength, and cannot be gained efficiently with normal, non-coherent, non-polarized light sources, such as LEDs.

8.0 References
1. Mester, E.; Mester, A. F.; Mester, A. Lasers Surg. Med. 1985, 5, 31. 2. Wollman, Y.; Rochkind, S. Neurol. Res. 1998, 20, 470. 3. Karu TI. Photobiology of low-power laser effects. Hlth Phys 1989:56:691-704. 4. Karu TI. Photobiology of low-power laser therapy. London: Harwood Academic Publishers. 1989. 5. Yu W, Naim JO, Lanzafame RJ. Effects of photostimulation on wound healing in diabetic mice. Lasers Surg Med 1997:20:5663. 6. Barolet D, Light-Emitting Diodes (LEDs) in Dermatology 7. Photobiomodulation on the Angiogenesis of Skin Wounds in Rats Using Different Light Sources 8. Osanai T, Shiroto C, Mikami Y (1990) Measurement of Ga ALA diode laser action on phagocytic activity of human neutrophils as a possible therapeutic dosimetry determinant. Laser Th er 2:123 134 9. Dima VF, Suzuko K, Liu Q (1997) Eff ects of GaALAs diode laser on serum opsonic activity assessed by neutrophil-associated chemiluminescence. Laser Th er 9:153158 10. Ash C, Effect of Wavelength and Beam Width on Penetration in LightTissue Interaction using Computational Methods, Laser Europe 2013, Manchester UK 11. Ash C, Effect of Wavelength and Beam Width on Penetration in LightTissue Interaction using Computational Methods, Laser Europe 2013, Manchester UK 12. Laakso EL, Richardson CR, Cramond T. Factors affecting low level laser therapy. Aust J Physio 1993:39:95-99. 13. Conlan, MJ., Rapley, J.W., and Cobb, C.M. (1996). Biostimulation of wound healing by low-energy laser irradiation. J. Clin. Periodont. 23, 492 496. 14. Beauvoit, B., Kitai, T., and Chance, B. (1994). Correlation between the light scattering and the mitochondrial content of normal tissues and transplantable rodent tumors. Biophys. 67, 25012510. 15. Beauvoit, B., Evans, S.M., Jenkins, T.W., Miller, E.E., and Chance B. (1995). Contribution of the mitochondrial compartment to the optical properties of the rat liver: a theoretical and practical approach. Anal. Biochem. 226, 167174. 16. Karukonda S, Corcoran Flynn T, Boh E, McBurney E, Russo G, Millikan L (2000) The effects of drugs on wound healing: part 1. Int J Dermatol 39:250257 17. BRANDON J. ERDLE, Effects of Continuous-Wave (670-nm) Red Light on Wound Healing Dermatol Surg 2008;34:320325 18. Desmet 19. Trelles and Allone Combined Nonablative Skin Rejuvenation with the 595m and 1450-nm Lasers 20 Manteifel V, Bakeeva L, Karu T. Ultrastructural changes in chondriome of human lymphocytes after irradiation with He-Ne laser: Appearance of giant mitochondria. J Photochem Photobiol B. 1997;38:25- 30. 21. Bolton P, Young S, Dyson M. Macrophage responsiveness to light therapy: A dose response study. Laser Ther. 1990;2:101-106. 22. Funk JO, Kruse A, Kirchner H. Cytokine production after heliumneon laser irradiation in cultures of human peripheral blood mononuclear cells. J Photochem Photobiol B. 1992;16:347-355. 23. Yu HS, Chang KL, Yu CL, et al. Low-energy helium-neon laser irradiation stimulates interleukin-1 alpha and interleukin-8 release from cultured human keratinocytes. J Invest Dermatol. 1996;107:593-596. 24. Leyden JJ. Acne vulgaris is a multifactorial disease. J Am Acad Dermatol 2003;49 (3 Suppl):S199. 25. Charakida A, Seaton ED, Charakida M, et al. Phototherapy in the treatment of acne vulgaris: What is its role? Am J Clin Dermatol 2004;5:211216. 26. Melo TB. Uptake of protoporphyrin and violet light photodestruction of Propionibacterium acnes. Z Naturforch C 1987; 42: 1238. 27. McGinley KJ, Webster GF, Leyden JJ. Facial follicular porphyrin fluorescence. Correlation with age and density of Propionibacterium acnes. Br J Dermatol 1980; 102: 43741. 28. Papageorgiou P, Katasambas A, Chu A. Phototherapy with blue (415 nm) and red (660 nm) light in the treatment of acne vulgaris. Br J Dermatol. 2000;142:973 978. 29. Ash C, Home Use Efficacy and Safety Study for Mild to Moderate Acne using High Intensity 414nm Solid State Diode Arrays, Laser Europe 2013, Manchester UK 30. A Reasonable Mechanism for Visible Light Induced Skin Rejuvenation - Rachel Lubart et al 31. Trelles and Allone Combined Nonablative Skin Rejuvenation with the 595nm and 1450nm Lasers 32. Sinha RP, Hder DP. UV-induced DNA damage and repair: A review. Photochem Photobiol Sci. 2002;1:225-236.

7.0 Future Work Andrei Sommer et al used 670 nm to improve the uptake of chemotherapeutic drugs into human cancer cells in vitro. Light increases cell volume by absorption of IR in membrane, this increase in volume makes the cells breathe in surrounding water. Traditional chemotherapeutic drugs rely on drugs entering cells by diffusing across the bilayer lipid structure of the cell membrane. The drawback to this process is that its relatively slow. This new process is a potentially powerful delivery system for chemotherapy drugs that can pull chemotherapy drugs into a cell faster than they would normally penetrate. Future research should focus on investigating specific cell signalling pathways involved to better understand the mechanisms 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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Emerging Cosmetic and Medical Applications of LED Technology Dr Caerwyn Ash

33. Calles C, Schneider M, Macaluso F, et al. Infrared A radiation influences the skin fibroblast transcriptome: Mechanisms and consequences. J Invest Dermatol. 2010;130:1524-1536. 34. Schroeder P, Calles C, Benesova T, et al. Photoprotection beyond ultraviolet radiationEffective sun protection has to include protection against infrared A radiation-induced skin damage. Skin Pharmacol Physiol. 2010;23:15-17. 35. Kimura E, Kawano Y, Todo H, et al. Measurement of skin permeation/ penetration of nanoparticles for their safety evaluation. Biol Pharm Bull. 2012;35:1476-1486. 36. Barolet D, Boucher A. LED photoprevention: Reduced MED response following multiple LED exposures. Lasers Surg Med. 2008;40:106-112. 37. Krutmann J, Schroeder P. Role of mitochondria in photoaging of human skin: The defective powerhouse model. J Investig Dermatol Symp Proc. 2009;14:44-49. 38. Schroeder P, Calles C, Benesova T, et al. Photoprotection beyond ultraviolet radiationEffective sun protection has to include protection against infrared A radiation-induced skin damage. Skin Pharmacol Physiol. 2010;23:15-17. 39. Menezes S, coulomb B, Lebreton C, et al. Non-coherent near infrared radiation protects normal human dermal fibroblasts from solar ultraviolet toxicity. J Invest Dermatol. 1998;111:629-633. 40. Frank S, Oliver L, Lebreton-De Coster C, et al. Infrared radiation affects the mitochondrial pathway of apoptosis in human fibroblasts. J Invest Dermatol. 2004;123:823-831. 41. Applegate LA, Scaletta C, Panizzon R, et al. Induction of the putative protective protein ferritin by infrared radiation: Implications in skin repair. Int J Mol Med. 2000;5:247-251. 42. Yu HS, Wu CS, Yu CL, et al. Helium-neon laser irradiation stimulates migration and proliferation in melanocytes and induces repigmentation in segmental-type vitiligo. J Invest Dermatol. 2003;120:56-64. 43. Yaar M, Grossman K, Eller M, et al. Evidence for nerve growth factor mediated paracrine effects in human epidermis. J Cell Biol. 1991;115: 821828. 44. Zhai S, Yaar M, Doyle SM, et al. Nerve growth factor rescues pigment cells from ultraviolet-induced apoptosis by upregulating BCL-2 levels. Exp Cell Res. 1996;224:335-343. 45. Effect of visible lightwaves on arthritis pain: A controlled study. McDonald, Sharon F. International Journal of Biosocial Research, Vol 3(2), 1982, 49-54. 46. Krutmann J, Hnigsmann H, Elmets CA, et al: Dermatological Phototherapy and Photodiagnostic Methods. New York, Springer, 2001 47. Morita A, Werfel T, Stege H, et al: Evidence that singlet oxygeninduced human T helper cell apoptosis is the basic mechanism of ultraviolet-A radiation phototherapy. J Exp Med 17:1763-1768, 1997 48. Kramer M, Sachsenmaier C, Herrlich P, et al: UV irradiation-induced interleukin-1 and basic fibroblast growth factor synthesis and release mediate part of the UV response. J Biol Chem 268:6734-6741, 1993 49. de Paula Eduardo C, Bezinelli LM, de Paula Eduardo F, et al. Prevention of recurrent herpes labialis outbreaks through low-intensity laser therapy: A clinical protocol with 3-year follow-up. Lasers Med Sci. 2012;27:1077-1083. 50. Krner R, Bahmer F, Wigand R. The effect of infrared laser rays on herpes simplex virus and the functions of human immunocompetent cells. Hautarzt. 1989;40:350-354. 51. Inoue K, Nishioka J, Hukuda S. Altered lymphocyte proliferation by low dosage laser irradiation. Clin Exp Rheumatol. 1989;7:521-523. 52. Yu W, Chi LH, Naim JO, et al. Improvement of host response to sepsis by photobiomodulation. Lasers Surg Med. 1997;21:262-268. 53. Schindl L, Schindl M, Polo L, et al. Effects of low power laserirradiation on differential blood count and body temperature in endotoxinpreimmunized rabbits. Life Sci. 1997;60:1669-1677. 54. Manteifel V, Bakeeva L, Karu T. Ultrastructural changes in chondriome of human lymphocytes after irradiation with He-Ne laser: Appearance of giant mitochondria. J Photochem Photobiol B. 1997;38:25- 30. 55. Bolton P, Young S, Dyson M. Macrophage responsiveness to light therapy: A dose response study. Laser Ther. 1990;2:101-106. 56. Funk JO, Kruse A, Kirchner H. Cytokine production after helium neon laser irradiation in cultures of human peripheral blood mononuclear cells. J Photochem Photobiol B. 1992;16:347-355. 57. Yu HS, Chang KL, Yu CL, et al. Low-energy helium-neon laser irradiation stimulates interleukin-1 alpha and interleukin-8 release from cultured human keratinocytes. J Invest Dermatol. 1996;107:593-596. 58. Ash C, Town G, Clement M, Bjerring P, Kiernan M, Optimum Choice of Irradiation Wavelength for Skin Colour Determination using Skin Reflectance Measurements. Presented at 31th Annual Conference, American Society for Laser Medicine and Surgery Dallas, Texas, USA. 2011
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59. Ash C, Town G, Bjerring P, Evaluation of a Commercial Fitzpatrick Skin Type Classification Device and the Correlation Between Fitzpatrick Skin Type and Skin Colour, Abstract O.46. Presented at Laser Europe 2010 Congress, La Pineda, Taragonna, Spain, 2010.