Lowlevel laser (light) therapy (lllt) for treatment of hair loss

Lasers in Surgery and Medicine 9999:1 (2013) Low-Level Laser (Light) Therapy (LLLT) for Treatment ofHair Loss Pinar Avci, MD,1,2,3 Gaurav K. Gupta, MD, PhD,1,2 Jason Clark, MD,1,2 Norbert Wikonkal, MD, PhD,3and Michael R. Hamblin, 1Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, Massachusetts 021142Department of Dermatology, Harvard Medical School, Boston, Massachusetts 021153Department of Dermatology, Venereology and Dermato-Oncology, Semmelweis University School of Medicine, Budapest1085, Hungary4Harvard-MIT Division of Health Sciences and Technology, Cambridge, Massachusetts 02139 Objective: Alopecia is a common disorder affecting more wound healing, nerve regeneration, joint pain relief, stroke than half of the population worldwide. Androgenetic recovery, and the prevention and treatment of mucosi- alopecia, the most common type, affects 50% of males tis [2–8]. Home-use LLLT devices that emit low power over the age of 40 and 75% of females over 65. Only two coherent monochromatic red light have been developed for drugs have been approved so far (minoxidil and finaste- various skin conditions, including hair growth [9]. In this ride) and hair transplant is the other treatment alterna- review, we will focus on the use of LLLT as a potential tive. This review surveys the evidence for low-level laser treatment for several types of hair loss.
therapy (LLLT) applied to the scalp as a treatment for hairloss and discusses possible mechanisms of actions.
HAIR AND TYPES OF HAIR LOSS Methods and Materials: Searches of PubMed and Google Hair is one of the fastest growing tissues of the human Scholar were carried out using keywords alopecia, hair body and the hair follicle, which is a unique characteristic loss, LLLT, photobiomodulation.
of mammals, represents a stem cell-rich, prototypic Results: Studies have shown that LLLT stimulated hair neuroectodermal–mesodermal interaction system [10].
growth in mice subjected to chemotherapy-induced alope- Hair follicles undergo repetitive regenerative cycles and cia and also in alopecia areata. Controlled clinical trials each of these cycles consists of three stages: anagen (rapid demonstrated that LLLT stimulated hair growth in both growth, active stage), catagen (apoptosis-driven regres- men and women. Among various mechanisms, the main sion, physiological involution stage), and telogen (resting mechanism is hypothesized to be stimulation of epidermal stage) (Fig. 1) [10]. Bulge stem cells are found in the region stem cells in the hair follicle bulge and shifting the follicles of the outer root sheath located just below the sebaceous into anagen phase.
gland, coinciding with the point of anchorage of the Conclusion: LLLT for hair growth in both men and arrector pili muscle [11]. During the telogen to anagen women appears to be both safe and effective. The optimum transition, there is a tightly controlled activation of these wavelength, coherence and dosimetric parameters remain epithelial bulge stem cells and within the same period, to be determined. Lasers Surg. Med. 9999:1–8, 2013. ß secondary hair germ cells give rise to transient amplifying 2013 Wiley Periodicals, Inc.
(TA) progeny cells [12]. Throughout the entire anagen Key words: alopecia; androgenetic alopecia; hair loss;LLLT; low level laser (light) Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Michael R. Hamblin is on the scientificadvisory board and holds stock in Transdermal Cap Inc. He has It has long been known that red or near-infrared laser been on the scientific advisory board and has received sponsoredresearch funding from Lexington Int. He has been an expert light promotes tissue repair and regeneration and low- witness for Advanced Hair Studio Australia. Other authors intensity light called low-level laser therapy (LLLT) reported no conflict of interest.
stimulates cellular activity [1]. After the discovery of Contract grant sponsor: US NIH; Contract grant number: lasers in the 1960s, there has been tremendous interest in Correspondence to: Michael R. Hamblin, PhD, Department of using these laser devices to treat various medical Dermatology, Harvard Medical School, BAR 414 Wellman, conditions. The most commonly used devices have wave- Center for Photomedicine, Massachusetts General Hospital, 40Blossom Street, Boston, MA 02114.
lengths in the range 500–1,100 nm (the so-called optical window of tissue) and they deliver fluences of 1–10 J/cm2 Accepted 30 July 2013 Published online in Wiley Online Library with a power density of 3–90 mW/cm2. LLLT has shown beneficial effects for a variety of medical conditions such as DOI 10.1002/lsm.22170 ß 2013 Wiley Periodicals, Inc.
Fig. 1. Stages of hair cycle. Anagen stage is the growth stage which may last 2–6 years. In cagatenstage, club hair transitions upwards towards the skin pore and the dermal papilla begins to separatefrom the follicle. This phase usually lasts from 1 to 2 weeks. In telogen stage, the dermal papilla fullyseparates from the follicle and it takes about 5–6 weeks. Lastly, the dermal papilla moves upward tomeet hair follicle once again and the hair matrix begins to form new hair, which represents thereturn to anagen stage.
phase, there is a robust proliferation of the TA cells within involved in hair loss are not clearly known, some of the the epithelial matrix of the hair follicle. Consequently, proposed genes responsible for hair growth are desmoglein, proliferating trichocytes terminally differentiate to form activin, epidermal growth factor (EGF), fibroblast growth the bulk of the hair filament which is the final product of factor (FGF), lymphoid-enhancer factor-1 (LEF-1), and the hair cycle. The dermal papilla of the hair follicle is sonic hedgehog [15]. As of today, the most common methods believed to be the key regulatory element in progenitor cell used for treating AGA are topical minoxidil, finasteride activation, hair matrix cell proliferation and terminal (males only), and surgical hair transplantation [14].
differentiation of trichocytes [13].
Unfortunately, current therapies are not efficacious for Androgenetic alopecia (AGA) is the most common form of all patients with AGA. Medical therapies require indefinite hair loss in men affecting almost 50% of the male use and are limited by patient adherence; surgical options population [14]. AGA refers to hair loss in genetically (hair transplants) are limited by cost, each patient's supply susceptible individuals caused by effects of androgens such of donor hair, and possible scarring in donor sites [18]. Due as testosterone and its derivative dihydrotestosterone to a need for more efficacious therapies, LLLT has emerged (DHT). Testosterone is a lipophilic compound that diffuses as a new therapeutic approach to treat AGA. The Hairmax across the cell membrane. Testosterone is converted by the Lasercomb1 was approved by the US Food and Drug cytoplasmic enzyme 5-a reductase to DHT, which is its Administration (FDA) and received 510 K clearance as a more active form. There are two types of 5-a reductase; safe therapy for the treatment of male AGA in 2007 and Type 1 is found in keratinocytes, fibroblasts, sweat glands, female AGA in 2011 [19]. There has been a recent and sebocytes, and Type 2 is found in skin and the inner review [20] on the use of lasers and light therapies for root sheath of hair follicles [15]. DHT binds the nuclear alopecia that covered 308 nm excimer laser, fractional androgen receptor which regulates gene expression [15].
photothermolysis, and UV phototherapy, but did not cover Disruption of epithelial progenitor cell activation and TA LLLT mediated by red laser which is the main subject of the cell proliferation due to abnormal androgen signaling forms present review.
the essential pathophysiological component of this condi- There are several other forms of hair loss such as tion which in turn leads to continuous miniaturization of alopecia areata (AA), telogen effluvium (TE), and chemo- sensitive terminal hair follicles, and their conversion to therapy-induced alopecia. AA is an autoimmune inflam- vellus hair follicles [16,17]. Although the exact genes matory condition, which presents with non-scarring LLLT FOR HAIR REGROWTH alopecia and is characterized on histology by intra- or peri- LLLT for Hair Regrowth, Proposed Mechanisms follicular lymphocytic infiltrates composed of CD4þ and As previously mentioned, in 2007 and 2011, LLLT CD8þ T-cells [19]. There are severe variants of AA: mediated by a laser comb was approved by the FDA as a alopecia totalis, a total loss of scalp hair and alopecia safe treatment for male and female pattern hair loss universalis, total loss of scalp and body hair [21]. The most respectively [19]. Laser phototherapy is assumed to common treatment modality is intralesional corticosteroid stimulate anagen re-entry in telogen hair follicles, prolong injections; however, other treatments include topical and duration of anagen phase, increase rates of proliferation in systemic corticosteroids, minoxidil, anthralin, contact active anagen hair follicles and to prevent premature sensitizers, psoralen plus ultraviolet A, cyclosporine, catagen development [19,30]. The exact mechanism of tacrolimus, and biologics such as alefacept, efalizumab, action of LLLT in hair growth is not known; however, etanercept, infliximab, and adalimumab [15]. TE is several mechanisms have been proposed. Evidence sug- abnormal hair cycling causing excessive loss of telogen gests that LLLT acts on the mitochondria and may alter hair [15]. Some common causes include acute severe cell metabolism through photodissociation of inhibitory illness, surgery, iron deficient anemia, thyroid disease, nitric oxide (NO) from cytochrome c oxidase (CCO) [31] malnutrition, chronic illness, and medications such as oral (Unit IV in the respiratory chain of mitochondria), causing contraceptives, lithium, and cimetidine. Chemotherapy increased ATP production, modulation of reactive oxygen works by destroying rapidly dividing cancer cells, however, species, and induction of transcription factors such as at the same time, other rapidly dividing cells of the body nuclear factor kappa B, and hypoxia-inducible factor-1 such as hair follicles are also destroyed, and this unwanted [32]. These transcription factors in return cause protein effect leads to chemotherapy-induced alopecia starting 1–3 synthesis that triggers further effects down-stream, such weeks and peaking at 1–2 months of treatment [22].
as increased cell proliferation and migration, alteration inthe levels of cytokines, growth factors and inflammatory LLLT for Prevention and Reversal of Hair Loss mediators, and increased tissue oxygenation [32]. More- In the late 1960s, Endre Mester, a Hungarian physician, over, NO is known to be a potent vasodilator via its effect on began a series of experiments on the carcinogenic potential cyclic guanine monophosphate production and it can be of lasers by using a low-power ruby laser (694 nm) on mice.
speculated that LLLT may cause photodissociation of NO Mice were shaved as a part of the experimental protocol. To not only from CCO but also from intracellular stores such Mester's surprise, the laser did not cause cancer but as nitrosylated forms of both hemoglobin and myoglobin instead improved hair growth around the shaved region on leading to vasodilation and increased blood flow which was the animal's back [23]. This was the first demonstration of reported in several studies [32–34]. Yamazaki and co- "photobiostimulation" with LLLT, and it opened a new workers observed an upregulation of hepatocyte growth path in the field of medicine [24].
factor (HGF) and HGF activator expression following Recently, attention has been drawn towards an uncom- irradiation of the backs of Sprague Dawley rats with linear mon but striking adverse effect of lasers being used for hair polarized infrared laser [35].
removal. It has been noticed in some cases that, increase in Some authors have drawn comparisons between the hair density, color or coarseness or a combination of these mechanism of action of LLLT and the mechanism of occurs at or around sites treated for hair removal [19,25– minoxidil. Even though the mechanism by which minoxidil 27]. The name given for this phenomenon is "Paradoxical promotes hair growth is not fully understood, it is known Hypertrichosis" and the incidence varies from 0.6% to 10% that minoxidil contains an N-oxide group which may be [19]. A group of researchers also observed transformation able to release NO, which is an important cellular of small vellus hairs into larger terminal hairs upon low signaling molecule involved in many physiological and fluence diode laser treatment and named this phenomenon pathological processes [36] and is also a vasodilator [37].
"terminalization" of vellus hair follicles [28,29]. Until Furthermore, minoxidil is an ATP sensitive Kþ channel today, different mechanisms have been proposed to explain opener which in turn cause hyperpolarization of cell paradoxical hypertrichosis. In one study, this was attrib- membranes [38]. Since ATP sensitive Kþ channels in uted to presence of polycystic ovarian syndrome in 5 out of mitochondria and increased levels of NO [39–41] may have 49 females undergoing IPL laser treatment for facial some role to play in effects of LLLT in brain and heart [41– hirsutism [27]. Another group of researchers suggested 43], given what is known about the role of K-ATP channels that although the heat produced by the laser is less than and NO in hair regrowth mediated by minoxidil, a the temperature necessary for thermolysis of the hair mechanistic overlap can be identified. Weiss and co- follicle, this heat may be sufficient to induce follicular stem workers, by using RT-PCR and microarray analysis, cell proliferation and differentiation by increasing the level demonstrated that depending on the treatment param- of heat shock proteins (HSPs) such as HSP27, which plays eters, LLLT modulates 5-a reductase expression, which a role in regulation of cell growth and differentiation [19].
converts testosterone into DHT, alters vascular endotheli- Sub-therapeutic injury caused by the laser could also al growth factor gene expression as wells as matrix result in the release of certain factors which could metalloproteinase (MMP-2) which have significant roles potentially induce follicular angiogenesis and affect the in hair follicle growth, and in turn the group reported cell cycling [29].
stimulation of hair growth on human dermal papillae cells [44–47]. Notably, similar changes have also been reported that laser irradiation prolongs the anagen phase [50,51].
with topical minoxidil use [47]. Furthermore, LLLT has Furthermore, in testosterone-treated and He–Ne (1 J/cm2) been demonstrated to modulate inflammatory processes irradiated skin, hair follicles were seen to originate from and immunological responses, which may also have an the middle of the dermis, and these follicles represent early effect in hair regrowth [32,48]. A study conducted by anagen phase [49]. Based on this observation, it may be Wikramanayake et al. [19] on C3H/HeJ mouse model of AA proposed that the majority of catagen and telogen follicles supported this assumption wherein the mice treated with re-enter into anagen phase as a result of low-level laser laser comb, increased number of hair follicles with majority irradiation at 1 J/cm2.
in anagen phase were noted with decreased inflammatory The incidence of alopecia related to cancer treatments infiltrates. Considering that inflammatory infiltrates are such as chemotherapy is close to 65% and it has severe highly disruptive to hair follicle biology and multiple negative psychological effects [22]. LLLT has been sug- cytokines such as IFN-g, IL-1a and b, TNF-a, MHC and gested as a treatment modality to promote hair regrowth Fas-antigen and macrophage migration inhibitory factor for chemotherapy-induced alopecia. In a rat model, differ- are all involved in the cyclic hair growth and have been ent regimens of chemotherapy were given to each rat in shown to play a role in the pathogenesis of AA, modulatory conjunction with an LLLT device which had the laser unit effects of LLLT on inflammation might have a significant and switch from the HairMax LaserComb1, but without role in treatment of AA [19].
the comb or handle [52]. Hair regrowth occurred 5 daysearlier in all laser treated rats when compared to control LLLT for Hair Regrowth in Animal Models and sham-treated rats. Histology results demonstrated Wikramanayake et al. [19] demonstrated the hair large anagen hair bulbs penetrating deeper into the growth effects of LLLT on C3H/HeJ mouse model of AA, subcutaneous adipose tissue in LLLT-treated skin. Fur- using HairMax Laser Comb1 (emits nine beams and thermore, it did not compromise the efficacy of chemother- attached combs help to part the hairs and improve delivery apy by causing localized protection of the cancer cells [52].
of laser light to scalp), 655 nm for 20 seconds daily threetimes per week for a total of 6 weeks [19]. At the end of the LLLT for Hair Growth in Clinical Trials treatment, hair regrowth was observed in all the laser In order to test the effect of linear polarized infrared treated mice but no difference was observed in the sham- irradiation in treatment of AA, a study was conducted treated group (control group undergoing similar treatment with 15 patients (6 men, 9 women) using Super LizerTM, a procedures without administration of the key therapeutic medical instrument emitting polarized pulsed linear light element, such as application of light that has no with a high output (1.8 W) of infrared radiation (600– therapeutic effect) [19]. On histology, while an increased 1,600 nm) that is capable of penetrating into deep number of anagen hair follicles was observed in laser- subcutaneous tissue [53]. The scalp was irradiated for treated mice, sham-treated mice demonstrated telogen 3 minutes either once every week or once every other week follicles with absent hair shafts [19].
until vellus hair regrowth in at least 50% of the affected Shukla et al. [49] investigated the effect of helium–neon area was observed. Additionally, carpronium chloride 5% (He–Ne) laser (632 nm, at doses of 1 and 5 J/cm2 at 24-hour was applied topically twice daily to all the lesions in intervals for 5 days) on the hair follicle growth cycle of combination with oral antihistamines, cepharanthin and testosterone-treated and un-treated Swiss albino mice glycyrrhizin (extracts of Chinese medicine herbs) [53]. As skin. Testosterone treatment led to the inhibition of hair a result of this study, in 47% of the patients' hair growth growth which was characterized by a significant increase occurred 1.6 months earlier in irradiated areas than in in catagen follicles [49].The results showed that exposure non-irradiated areas [53]. However, 1 year after irradia- of testosterone treated mice to the He–Ne laser at a dose of tion, all the lesions disappeared; hair density, length and 1 J/cm2 led to significant increase in the number of hair diameter of hair shafts were the same both in irradiated follicles in anagen phase when compared to the other and non-irradiated lesions; suggesting that LLLT only groups. However, the 5 J/cm2 treated group showed a accelerates the process of hair regrowth in AA patients. It significant decrease in the number of anagen hair and an is worth mentioning that the method for assessment of increase in telogen hair follicles. This is consistent with the hair regrowth, density and thickness was not clearly biphasic effect of LLLT wherein low irradiation doses may stated, which was one of the main limitations of this cause biostimulation and high irradiation doses may cause inhibition [32,49]. Since hair growth promoting effect of Using 655 nm red light and 780 nm infrared light once He–Ne laser (1 J/cm2) was much higher for the testoster- a day for 10 minutes, 24 male AGA patients were treated one-treated mice than the non-testosterone treated mice, it and evaluated by a group of investigators [54]. Evalua- can be suggested that cells growing at slower rate or under tion has been performed via global photography and stress conditions respond better to the stimulatory effects phototrichogram [54]. Following 14 weeks of treatment, of LLLT. Another notable observation in this study is that increase in hair density on both the vertex (145.1/cm2 vs.
in He–Ne laser (1 J/cm2) irradiated skin, some of the 137.3/cm2 pre-treatment, P < 0.005) and occiput (163.3/ anagen follicles appeared from deeper layers of the skin cm2 vs. 153.3/cm2, P < 0.005) as well as anogen/telogen and possessed a different orientation which both represent ratio (vertex: 84.7 vs. 79.7 pre-treatment and occiput: the late anagen stage in the hair cycle that in turn suggests 91.9 vs. 89.6 pre-treatment) was observed, and 83% of LLLT FOR HAIR REGROWTH the patients reported to be satisfied with the treatment patients. Each patient was given a HairMax LaserComb1 655 nm, to use at home for 6 months for 5–10 minutes every Satino et al. [55] tested the efficacy of LLLT on hair other day [55]. Tensile strength was measured by VIP growth and tensile strength on 28 male and 7 female AGA HairOSCope (Belson Imports, Hialeah, FL) through TABLE 1. Summary of the Studies That Investigated the Efficacy of LLLT for Hair Growth Device type, parameters and treatment regimen 655 nm, 20 seconds daily, 3 times/week, for 6 weeks Shukla et al., 2010 Swiss albino mice Testosterone treated 632 nm, 1 and 5 J/cm2 at (increase in catagen 24-hour intervals follicles) vs. non-treated Laser unit and switch HairMaxLaserComb1, but without the comb or Super LizerTM emitting polarized pulsed linear light, 600–1,600 nm, 1.8 W. 3 minutes/week or every other week.
Additional supplements and medications have been given. Treated until vellus hair regrowth in at least 50% of the affected area was observed.
Androgenetic alopecia 655 and 780 nm, once a day for 10 minutes, for 14 Satino et al., 2003 28 male and 7 female Androgenetic alopecia 655 nm, 5–10 minutesevery other day, for 6 Lanzafame et al., Androgenetic alopecia Helmet (TOPHAT655) containing 21, 5 mW lasers and 30 LEDs, 655  5 nm, 67.3 J/cm2 25 minutes every other day, for 16 Androgenetic alopecia Helmet type LLLT device, 650 nm laser with 630 and 660 nm LEDs, 92.15 mW/ cm2, 47.90 J/cm2, 18 minutes/day, for 24 Leavitt et al., 2009 110 male patients Androgenetic alopecia HairMaxLaserComb, 3 times/week for 15 minutes, removal of three typical terminal hairs from a one square centimeter area. Hair count was performed within one LLLT was discovered serendipitously in the 1960s when centimeter square space created within a mold that was mice irradiated with a low fluence red laser grew hair.
prepared around the area of greatest alopecia. A surgical Since that time LLLT has demonstrated promise in hook and magnification has been used while counting the conditions from wound healing to stroke recovery, from number of hair. In terms of hair tensile strength, the treatment of musculoskeletal pain to prevention of results revealed greater improvement in the vertex area mucositis. Animal and human data have slowly accumu- for males and temporal area for females; however, both lated supporting LLLT for hair growth (Table 1). LLLT sexes benefited in all areas significantly [55]. In terms of appears to improve a variety of non-scarring alopecias— hair count, both sexes and all areas had substantial AGA, AA, and chemotherapy-induced alopecia. Based on improvement (for temporal area: 55% in women, 74% in the studies demonstrating LLLT's effects on promoting men, in vertex area: 65% in women, 120% in men) with graft survival, it may be further suggested to have a vertex area in males having the best outcome [55]. The potential to be used during the immediate period of post- HairMax LaserComb1 device was tested by Leavitt et al.
hair transplant surgery to facilitate the healing process in a double-blind, sham device-controlled, multicenter, 26- and enhance viability and earlier growth of the grafts week trial randomized study among 110 male AGA [60,61]. While mechanisms are still emerging, LLLT may patients [30]. Patients used the device three times per increase anagen hairs through release of NO from CCO by week for 15 minutes for a total of 26 weeks [30].
photodissociation and LLLT may reduce inflammation in Significantly greater increase in mean terminal hair AA. However, more studies are needed to optimize density compared to subjects in the sham device group treatment parameters and determine long-term efficacy has been reported [30]. Significant improvements in as well as safety of emerging LLLT technologies. Most overall hair regrowth, slowing of hair loss, thicker feeling studies investigating effects of LLLT on hair growth have hair, better scalp health and hair shine were also used wavelengths that range from 635 to 650 nm, but as of demonstrated in terms of patients' subjective assessment today no study has compared the effect of near-infrared at 26 weeks over baseline [30].
wavelengths such as 810 nm, which have deeper penetrat- Recently, a double-blind randomized controlled trial by ing capacities, to red light. Moreover, further studies are Lanzafame et al. [56] using a helmet containing 21, 5 mW required to compare efficacy of different light sources lasers and 30 LEDs (655  5 nm, 67.3 J/cm2, 25 minutes (continuous vs. pulsed) and methods of light delivery (laser treatment) every other day for 16 weeks reported 35% increase in hair growth among male AGA patients.
Another recent study by Kim et al. [57] designed a 24 weeks randomized, double-blind, sham device-controlled Research in the Hamblin Laboratory is supported by US multicenter trial among both male and female AGA NIH Grant R01AI050875.
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Exertional myopathy post fox attack in an agile wallaby (Macropus agilis). 1.1 Introduction Exertional myopathy or ‘capture myopathy' refers to a non-infectious, metabolic syndrome characterized by damage to skeletal or cardiac muscle following intense physical activity. Skeletal muscle necrosis and acute renal failure are common sequelae (Hartup et al. 1999).