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Tissue penetration depths of various wavelengths. (Figure courtesy of Wellman Center for Photomedicine.) 

Tissue penetration depths of various wavelengths. (Figure courtesy of Wellman Center for Photomedicine.) 

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Low-level laser (light) therapy (LLLT) is a fast-growing technology used to treat a multitude of conditions that require stimulation of healing, relief of pain and inflammation, and restoration of function. Although skin is naturally exposed to light more than any other organ, it still responds well to red and near-infrared wavelengths. The photons...

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... and thermally coagulating tissue. Recently, medical treatment with LLLT at various intensities has been found to stimulate or inhibit an assortment of cellular processes. 4 The mechanism associated with the cellular photobiostimulation by LLLT is not yet fully understood. From obser- vation, it appears that LLLT has a wide range of effects at the molecular, cellular, and tissue levels. The basic biological mechanism behind the effects of LLLT is thought to be through absorption of red and NIR light by mitochondrial chromophores, in particular cytochrome c oxidase (CCO), which is contained in the respiratory chain located within the mitochondria, 5-7 and perhaps also by photoacceptors in the plasma membrane of cells. Consequently, a cascade of events occur in the mitochondria, leading to biostimulation of various processes ( Fig. 1). 8 Absorption spectra obtained for CCO in different oxidation states were recorded and found to be very similar to the action spectra for biological responses to the light. 5 It is hypothesized that this absorption of light energy may cause photodissociation of inhibitory nitric oxide from CCO, 9 leading to enhancement of enzyme activity, 10 electron transport, 11 mitochondrial respiration, and adenosine triphosphate production (Fig. 1). 12-14 In turn, LLLT alters the cellular redox state, which induces the activation of numerous intracellular signaling pathways, and alters the af- finity of transcription factors concerned with cell proliferation, survival, tissue repair, and regeneration (Fig. 1). 2,5,6,15,16 Although LLLT is now used to treat a wide variety of ail- ments, it remains somewhat controversial as a therapy for 2 principal reasons. First, there are uncertainties about the fun- damental molecular and cellular mechanisms responsible for transducing signals from the photons incident on the cells to the biological effects that take place in the irradiated tissue. Second, there are significant variations in terms of dosimetry parameters: wavelength, irradiance or power density, pulse structure, coherence, polarization, energy, fluence, irradiation time, contact versus noncontact application, and repeti- tion regimen. Lower dosimetric parameters can result in reduced effectiveness of the treatment, and higher ones can lead to tissue damage. 1 This illustrates the concept of the biphasic dose response that has been reported to operate in LLLT. 1,17,18 Many of the published studies on LLLT include negative results. It is possibly because of an inappropriate choice of light source and dosage. It may also be due to inappropriate preparation of the patient’s skin before application of LLLT, such as lack of removal of makeup and oily debris, which can interfere with the penetration of the light source, and failure to account for skin pigmentation. 19 Inap- propriate maintenance of the LLLT equipment can reduce its performance and interfere with clinical results as well. It is important to consider that there is an optimal dose of light for any particular application. Laser radiation or noncoherent light has a wavelength– and radiant exposure– dependent capability to alter cellular behavior in the absence of significant heating. 20 Phototherapy uses light with wavelengths between 390 and 1100 nm and can be continuous wave or pulsed. In normal circum- stances, it uses relatively low fluences (0.04-50 J/cm 2 ) and power densities ( Ͻ 100 mW/cm 2 ). 21 Wavelengths in the range of 390-600 nm are used to treat superficial tissue, and longer wavelengths in the range of 600-1100 nm, which penetrate further, are used to treat deeper-seated tissues (Fig. 2). 4 Wavelengths in the range of 700-750 nm have been found to have limited biochemical activity and are therefore not often used. 1 Various light sources used in LLLT include inert gas lasers and semiconductor laser diodes such as helium neon (HeNe; 633 nm), ruby (694 nm), argon (488 and 514 nm), krypton (521, 530, 568, 647 nm), gallium arsenide (GaAs; Ͼ 760 nm, with a common example of 904 nm), and gallium aluminum arsenide (GaAlAs; 612-870 nm). 19 A wide range of LED semiconductors are available at lower wavelengths, the medium of which contains the elements indium, phosphide, and nitride. One question that has not yet been conclusively answered is whether there is any advantage to using coherent laser light over noncoherent LED light. 22 Although some medical practitioners treat deep tissue lesions using focused lasers in “points,” in dermatology, the use of LEDs is becoming increasingly common owing to the relatively large areas of tissue that require irradiation. Skin starts showing its first signs of aging in the late 20s to early 30s, and it usually presents with wrinkles, dyspigmen- tation, telangiectasia, and loss of elasticity. Common histologic and molecular-level features are reduction in the amount of collagen, fragmentation of collagen fibers, elastotic degeneration of elastic fibers, upregulation of matrix metallo- proteinases (MMPs), especially MMP-1 and MMP-2, dilated and tortuous dermal vessels, and atrophy and disorientation of the epidermis. 23,24 Both chronological and environmental influences are responsible for the aging process of skin; however, photodamage seems to be one of the most important causes of these changes. Several modalities have been developed to reverse the dermal and epidermal signs of photo- and chronological aging. The main concept of most of these modalities is removing the epidermis and inducing a controlled form of skin wounding to promote collagen biosynthesis and dermal matrix remodeling. The most commonly used interventions as of today are retinoic acid (a vitamin A derivative) therapy, dermabrasion, chemical peels, and ablative laser resurfacing with carbon dioxide (CO 2 ) or erbium:yttrium-aluminum-garnet (Er:YAG) lasers or a combination of these wavelengths. 25-27 However, these procedures require intensive posttreatment care and prolonged downtime, and may lead to complications such as long-lasting erythema, pain, infection, bleeding, oozing, burns, hyper- or hypopigmentation, and scarring. 28,29 These limitations created a need for the development of alternative rejuvenation procedures that were safer and more effective, had fewer side effects, and required minimum postoperative care and downtime, which in turn led to the emergence of nonablative rejuvenation technologies. 30-32 Nonablative skin rejuvenation aims to improve photoaged and aging skin without destroying the epidermis. 31,32 Irregular pigmentation and telangiectasia can be treated with intense pulsed light sources, 532-nm potassium-titanyl-phosphate lasers, and high-dose 585/595-nm pulsed dye lasers. 33 Wrinkle reduction and skin tightening through thermal injury to the dermis (photothermolysis) can be achieved by other intense pulsed light sources (ie, low-dose 589/595-nm pulsed dye lasers, 1064- and 1320-nm neodymium:yttrium-aluminum-garnet lasers [Nd: YAG], 1450-nm diode lasers, and 1540-nm er- bium fiber lasers). 33 LED, which is a novel light source for nonthermal nonablative skin rejuvenation, has been shown to be effective for improving wrinkles and skin laxity. 34-40 It is not a new phe- nomenon because the first reports of LLLT effects on increased collagen go back to 1987. Studies by Abergel et al and Yu et al reported an increase in production of procollagen, collagen, and basic fibroblast growth factors (bFGF), as well as proliferation of fibroblasts after exposure to low-energy laser irradiation in in vitro and in vivo animal models (Fig. 3). 41,42 Furthermore, LLLT was already known to increase microcirculation and vascular perfusion in the skin, alter platelet-derived growth factor (PDGF) and transforming growth factor (TGF- ␤ 1) expressions, and inhibit apoptosis (Fig. 3). 1,43,44 Lee et al investigated the histologic and ultrastructural changes after a combination of 830-nm, 55-mW/ cm 2 , 66-J/cm 2 and 633-nm, 105-mW/cm 2 , and 126-J/cm 2 LED phototherapy and observed alteration in the status of MMPs and their tissue inhibitors (TIMPs). 33 Furthermore, mRNA levels of interleukin (IL)-1 ␤ , tumor necrosis factor- ␣ (TNF- ␣ ), intercellular adhesion molecule 1 (ICAM-1), and connexin 43 were increased after LED phototherapy, whereas IL-6 levels were decreased (Fig. 3). 33 Finally, an increase in the amount of collagen was demonstrated in the posttreatment specimens. 33 Proinflammatory cytokines IL-1 ␤ and TNF- ␣ are thought to be recruited to heal the intentionally formed photothermally mediated wounds associated with laser treatments, and this cascade of wound ...

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... Since the penetration depth of blue light is known to be limited compared to, e.g., red light [44], further research is needed to evaluate if this limited penetration into deeper skin layers also could be an explanation for varying results of in vivo and in vitro studies. On the other hand-if blue light should have no effects or even harmful effects on wound healing-this limited penetration could be useful to treat superficial wound infections where bacteria normally are located in superficial skin layers without causing greater damage to deeper skin layers. ...
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... Studies have shown that lights with wavelength from 600 to 1000 nm may be able to activate mitochondria, increase mitochondrial-derived reactive oxygen species and calcium, promote ATP production and initiate a series of cascade reactions [42,43]. Moreover, lasers with wavelengths ranging from 650 to 950 nm exert the most effective role in tissues with a penetrating depth of 2-3 mm, which is suitable for deep injuries [44,45]. Considering the biological stimulation effects and tissue-penetration ability, we used 808 nm-wavelength near-infrared laser and combined it with BG in the present study to examine their effects on early angiogenesis in vitro and in vivo. ...
... The effect of PBM is dose-dependent, in which both low and high doses might result in inhibition while moderate doses induce cells activity [44]. Therefore, we first investigated the effect of PBM with different fluences on HUVEC proliferation to determine the optimum dose of PBM in vitro. ...
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... In animal models and humans, red-near-infrared PBM has shown benefits for osteoarthritis, pain control [31], management of adverse reactions to chemotherapy [32], and wound healing [33]. The basic mechanisms of red-near-infrared PBM have been postulated to involve mitochondrial cytochrome c oxidase (COX) that is activated by preferentially absorbing red light. ...
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... In addition, evidence has increasingly suggested beneficial effects of LEDs in the treatment of many conditions such as skin inflammatory conditions, aging, and disorders linked to hair growth [1]. However, despite these beneficial effects, the therapeutic potential of LED irradiation remains controversial due to the divergence of protocols used [2,3]. ...
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... A large body of evidence has demonstrated that LLLT could suppress inflammatory reaction through decreasing the expression of inflammatory cytokines [26]. However, our findings indicate laser irradiation significantly increased The expression levels of the osteogenic genes ALP, Runx2, OCN, and BMP2 were measured by real time PCR at day 7 after osteogenic differentiation induced. ...
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... Under appropriate conditions, visible to near-infrared light irradiation exerts woundhealing, anti-inflammatory, anti-edema, and hair growth-promoting effects [1]. This phenomenon is called photobiomodulation (PBM). ...
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Photobiomodulation studies have reported that blue light irradiation induces the production of reactive oxygen species. We investigated the effect of blue laser (405 nm) irradiation on the ATP levels in mouse skin and determined the types of reactive oxygen species and reactive nitrogen species using cultured mouse fibroblasts. Blue laser irradiation caused a decrease in the ATP level in the mouse skin and triggered the generation of superoxide anion and hypochlorous acid, whereas nitric oxide and peroxynitrite were not detected. Moreover, blue laser irradiation resulted in reduced cell viability. It is believed that the decrease in the skin ATP level due to blue light irradiation results from the increased levels of oxidative stress due to the generation of reactive oxygen species. This method of systematically measuring the levels of reactive oxygen species and reactive nitrogen species may be useful for understanding the effects of irradiation conditions.