Article: (LLLT) for Cosmetic Medicine and Dermatology | Mossum K. Sawhney & Michael R. Hamblin | Harvard Medical


Low level laser (light) therapy (LLLT), phototherapy or photobiomodulation, refers to the

use of light for altering biological activity of certain target(s) of interest. Fundamentally, it

involves the use of light within a specific range of wavelengths (optical window), to

effectively stimulate specific tissue chromophores (with absorption bands in the red and

near-infrared spectral regions), which leads to the induction of desirable effects in the target

tissues. Photon absorption has been demonstrated to be effective in causing cellular

reactions capable of promoting cellular growth, cellular proliferation, and cell migration. The

most widely accepted mode of action of LLLT involves the activation of cellular

mitochondria, where components of the electron transport chain (ETC) or respiratory chain

serve as natural chromophores or "light receptors" for the action of LLLT. Mitochondrial

activation stimulates ATP production, causes the release of nitric oxide, and promotes the

formation of reactive oxygen species (ROS), all of which acting together, result in the

stimulation of redox sensitive transcription factors, and the expression of proteins that are

specific gene products. Hence, LLLT is capable of stimulating processes responsible for

tissue repair, wound healing and prevention of cell death (Hamblin and Demidova, 2006).

Non-thermal, coherent (lasers) or non-coherent light sources consisting of filtered lamps or

light-emitting diodes (LED) are primarily used in the therapeutic applications of LLLT for

reducing pain and inflammation, augmenting tissue repair, regenerating tissues and nerves,

and preventing tissue damage (Chung et al., 2012; Gupta et al., 2012). Over the last few

years, LLLT has been demonstrated to be a promising therapeutic modality for a wide range

of dermatological and cosmetic applications. In this article, we discuss the applications of

LLLT as well as its efficacy for a number of cosmetic and dermatological conditions,

including the treatment of alopecia (hair loss), cellulite, and undesirable fat deposits.

LLLT in Dermatology

LLLT for Skin Rejuvenation. Skin aging is a process that can present itself relatively early

on in life, sometimes even as soon as 20-30 years of age. Common signs and symptoms

associated with skin aging include skin wrinkling, skin dyspigmentation, telangiectasia, and

reduced tissue elasticity. At the histological and molecular level, common noticeable

features include a reduction in collagen content, fragmentation of collagen fibers, elastotic

degeneration of elastic fibers, the appearance of dilated and tortuous dermal vessels,

disorientation and atrophy of the epidermis, and up-regulation of matrix metalloproteinases

(MMPs), especially MMP-1 and MMP-2 (Kligman, 1989; Takema et al., 1994). Skin aging can

be influenced by both time (normal aging), as well as environmental factors, but the single

most influential factor responsible for accelerated skin aging is believed to be ultraviolet

(UV) radiation-induced photodamage (Takema et al., 1994).

A wide range of therapeutic modalities has been developed to address the aesthetically

undesirable effects associated with skin aging. Most therapeutic modalities depend on some

form of controlled epidermal removal and skin wounding to promote collagen biosynthesis,

and dermal matrix remodeling; serving as a preliminary means to address the problems

associated with skin aging. Some commonly used modalities include topical ointments

containing vitamin A derivatives such as retinoic acid, dermabrasion, chemical peels, and

ablative laser resurfacing technologies - most commonly utilizing carbon dioxide (CO2) or

erbium: yttrium-aluminum-garnet (Er:YAG) lasers, or, some combined form of therapy

(Airan and Hruza, 2005; Branham and Thomas, 1996; Paasch and Haedersdal, 2011). These

techniques are limited by restrictions such as intensive post-treatment care, prolonged

downtime, and other complications including long-lasting erythema, pain, infections,

bleeding, oozing, burns, hyper- or hypopigmentation and scarring (Nanni and Alster, 1998;

Sriprachya-Anunt et al., 1997). These limitations have facilitated the development of

technologies such as non-ablative laser resurfacing, which can transcend the restrictions of

conventional modalities, and provide safe and efficacious treatment (Hardaway and Ross,

2002; Sachdev et al., 2011; Weiss et al., 2003). Unlike ablative laser resurfacing, non-

ablative laser resurfacing technologies provide aesthetic improvement of aged skin without

inducing epidermal destruction; requiring little to no downtime, thus, providing a suitable

alternative to traditional therapeutic modalities (Hardaway and Ross, 2002; Weiss et al.,


Additionally, intense pulsed light (IPL) sources (532 nm potassium-titanyl-phosphate (KTP)

lasers), and high-dose (585/595 nm) pulsed dye lasers (PDL) can be used to treat irregular

pigmentation and telangiectasia, while low-dose (589/595 nm) PDLs, neodymium: yttrium-

aluminum-garnet (Nd:YAG) lasers (1064 & 1320 nm), diode lasers (1450 nm), and erbium

glass lasers (1540 nm) mainly address skin wrinkle reduction and skin tightening, via

thermal injury to the dermis (photothermolysis) (Lee et al., 2007a). Treatments combining

KTP lasers (532 nm) with Nd:YAG lasers (1064 nm) have been shown to possess synergistic

effects for photorejuvenation (Lee, 2002). Although, ablative and non-ablative modalities

provide a means for treatment of photodamaged skin, they are not without their limitations.

Ablative laser modalities pose the risk for dyspigmentation, scarring, post-operative

erythema and prolonged downtime, while non-ablative modalities suffer from reduced

efficacy. Fractional photothermolysis (FPT), is a modality that bridges the gap between

ablative and non-ablative modalities, and has been gaining popularity due to its desirable

profile of effects, reduced recovery time, and efficacious results (Goel et al., 2011). FPT

utilizes water as a target tissue chromophore for the laser, and results in the creation of an

array of thermal micro-lesions (Goel et al., 2011). These micro-lesions have an amazingly

rapid rate of healing compared to the lesions induced by using traditional laser resurfacing

modalities, resulting in controlled resurfacing of small areas of the skin, without any

damage to the basement membrane (Goel et al., 2011). Consequently, reduced post-

operative problems and increased patient comfort are observed (Goel et al., 2011).

Low-level light therapy (LLLT) is a novel treatment option available for non-thermal and

non-ablative skin rejuvenation, which has been shown to be effective for improving skin

conditions such as wrinkles and skin laxity (Barolet et al., 2009; Bhat et al., 2005; Dierickx

and Anderson, 2005; Russell et al., 2005; Weiss et al., 2004, 2005). A wide range of

different light sources have been used to deliver light for these treatments, particularly to

the face, and some are shown in Figure 1. LLLT provides increased rates of wound healing,

while also reducing post-operative pain, edema and several types of inflammation, making it

a highly desirable modality (Calderhead et al., 2008; Kim and Calderhead, 2011). Early

studies have reported increases in the production of pro-collagen, collagen, basic fibroblast

growth factor (bFGF), and proliferation of fibroblasts, following low-energy laser irradiation

in different settings (Abergel et al., 1987; Yu et al., 1994). The use of LLLT sources of

wavelengths of 633 nm/830 nm is most common in cases of clinical applications involving

wound healing and skin rejuvenation. LLLT is now also used for the treatment of chronic,

non-healing wounds via the restoration of imbalances in collagenesis/collagenase, which

allows for rapid and enhanced wound healing in general (Kim and Calderhead, 2011).

Figure 1. Examples of LLLT devices used for skin rejuvenation and treatment of acne. (A) Selection of different hand-held devices from various manufacturers. (B) Omnilux Revive, Phototherapeutics London, UK. (C) Dermaclear Blue and Red LED Acne Light Therapy, Britebox, Steubenville, OH (D) Gentlewaves, Virginia Beach, VA.

A study conducted by Lee et al. (2007a) investigated the histological and ultrastructural

alterations that followed a series of light treatments, utilizing light emitting diodes (LEDs)

with parameters of: 830 nm, 55 mW/cm2, 66 J/ cm2 and 633 nm, 105 mW/ cm2, 126 J/

cm2. Alterations in the levels of MMPs and tissue inhibitors of metalloproteinases (TIMPs)

were reported. Increased mRNA levels of interleukin-1 beta (IL-1ß), tumor necrosis factor

alpha (TNF-α), intercellular adhesion molecule 1 (ICAM-1), and connexin 43 (Cx43) were

also reported following LED phototherapy whereas, IL-6 levels were reported to be

decreased. Additionally, a well-marked increase in the amount of collagen was reported in

the post-treatment specimens. In fractional-laser resurfacing, the deliberate development of

microscopic, photothermally-induced wounds is believed to be responsible for the

recruitment of pro-inflammatory cytokines IL-1ß and TNF-α to the site of injury, which

contributes to tissue repair. The generation of such a wound healing cascade, thus,

contributes to new collagen synthesis.

LLLT may also, induce wound healing through the non-thermal and non-traumatic induction

of a subclinical 'quasi-wound', without inflicting thermal injury, and thus, avoiding the

complications seen with other therapeutic laser modalities. Additionally, since TIMPs are

known to inhibit the activities of MMPs, increased collagen synthesis via the induction of

TIMPs, may also contribute to the effects associated with LLLT. Collectively, the findings

suggest that, an increased production of IL-1ß and TNF-α may be responsible for the

stimulation of MMP activity (as an early response to light treatment), which may contribute

to the removal of photodamaged collagen fragments, and facilitate new collagen

biosynthesis. Furthermore, as a result of therapy, increased concentrations of TIMPs may be

observed, which would protect newly synthesized collagen against proteolytic degradation

by MMPs. Additionally, the heightened expression of Cx43 may be responsible for enhanced

cell-to-cell communication between dermal components (especially, fibroblasts), resulting in

greater synchrony between cellular responses, following photobiostimulation (Lee et al.,


A clinical study by Weiss et al. demonstrated the benefits of LLLT over traditional thermal-

based rejuvenation modalities. A group of 300 patients was administered LLLT (590 nm,

0.10 J/cm2) alone, and another group of 600 patients received LLLT in association with a

thermal-based photorejuvenation procedure. Of the patients who received solely light

treatment, 90% reported an observable softening of skin textures, as well as a reduction in

skin coarseness, and fine lines (Weiss et al., 2005b). It was observed that, patients who

received some form of LLLT (n = 152) reported a noticeable reduction in post-treatment

erythema, and an overall impression of increased efficacy, when compared to the patients

that received treatment via a thermal photorejuvenation laser or light source lacking any

form of LLLT photomodulation (Kucuk et al., 2010; Weiss et al., 2005b).

The reduction in post-treatment erythema can most likely be attributed to the anti-

inflammatory effects of LLLT (Barolet et al., 2009). Using various pulse sequence

parameters, a multicenter clinical trial was conducted, wherein 90 patients received 8 LLLT

treatments over 4 weeks (Geronemus et al., 2003; McDaniel et al., 2003; Weiss et al.,

2004, 2005a). The study displayed good overall results, with more than 90% of patients

improving by at least one Fitzpatrick photoaging category, and 65% of the patients

displaying global improvements in facial texture, fine lines, background erythema and

pigmentation with results peaking at 4 to 6 months, following the 8 treatments. A noticeable

increase in papillary dermal collagen and a reduction in MMP-1 were generally observed. A

study conducted by Barolet et al. also supported the aforementioned results. The study

used a 3-D model of tissue-engineered Human Reconstructed Skin (HRS) to investigate the

potential of LLLT (660 nm, 50 mW/cm2, 4 J/cm2) for collagen and MMP-1 modulation. The

results showed an up-regulation of collagen and down-regulation of MMP-1 in vitro. A split-

face, single-blinded clinical study was then carried out to assess the results of this

treatment on skin texture, and the appearance of individuals with aged/photoaged skin.

Profilometric quantification demonstrated that, more than 90% of individuals had a

reduction in rhytid depth and surface roughness, and 87% of individuals reported a

reduction in the Fitzpatrick wrinkling severity score, following 12 LLLT treatments (Barolet

et al., 2009).

LLLT for Acne. Acne vulgaris is a relatively common skin disorder, with a reported

prevalence of up to 90% among adolescents. Some studies have reported a comedone

prevalence nearing 100% for both male and female sexes during adolescence (Stathakis et

al., 1997). Although typical acne is neither a serious nor a contagious condition, it can

greatly impact the emotional and social aspects of an individual’s life. The pathogenesis of

acne is not completely understood, but the current consensus is that it involves four major

events: follicular hyperconification, increased sebum production, colonization

ofPropionibacterium acnes (P. acnes), and inflammation (Lee et al., 2007b). P. acnes plays

a major role in the development of acne by acting on triglycerides and releasing cytokines,

which results in inflammatory reactions, and alters infundibular keratinization (Lee et al.,

2007b). Current therapeutic options for acne vulgaris include topical antibiotics (e.g.,

clindamycin and erythromycin), topical retinoids (e.g., tretinoin and adapalene), benzoyl

peroxide, alpha hydroxy acids (AHA), salicylic acid, and azelaic acid. In severe cases,

administration of antibiotics (e.g., tetracycline, doxycycline), oral retinoids, and certain

hormonal treatments is recommended (Aziz-Jalali et al., 2012). Most medications work by

counteracting microcomedone formation, sebum production, P. acnes, and inflammation

(Aziz-Jalali et al., 2012). Despite the many treatment options currently available, several

patients still show an inadequate response to the treatment, while others suffer from actual

adverse effects.

Phototherapy offers an alternative mode of treatment for acne vulgaris with a suitable

profile of side-effects (Rotunda et al., 2004). Sunlight exposure has often been reported to

have a significant impact on the treatment of acne, with a high efficacy of up to 70%. More

recently, techniques utilizing broad-spectrum visible light (LLLT) are currently being

employed for the treatment of acne (Cunliffe and Goulden, 2000). One mechanism of action

of phototherapy is via the excitation of porphyrins generated by P. acnes as part of its

normal metabolism. These porphyrins act as endogenous photosensitizers, absorbing light

(specifically blue light, and to a lesser extent, red light) and stimulating photochemical

reactions that generate reactive free radicals and singlet oxygen species, which are toxic

for P. acnes (Figure 2) (Lee et al., 2007b; Ross, 2005). Red light has been demonstrated to

have a greater penetration depth when compared to that of blue light (Aziz-Jalali et al.,

2012). Infrared (IR) light has been proposed to destroy sebaceous glands, and thus, reduce

acne lesions (Lloyd and Mirkov, 2002). Red light is believed to stimulate cytokine release

from various cells including macrophages, and reduce inflammation (Rotunda et al., 2004;

Sadick, 2008).

Figure 2. Illustration of acne treatment with red and blue light. The sebaceous gland is colonized by bacteria, which can be killed by blue light due to the endogenous porphyrins they produce, acting as photosensitizers and forming reactive oxygen species. Red light can reduce inflammation and stimulate healing with minimal scarring.

Several studies have demonstrated the efficacy of red to near infrared light (NIR) (spectral

range 630 nm to 1000 nm, and non-thermal power less than 200 mW) for the treatment of

acne vulgaris. Red light maybe used alone or in combination with other modalities (in

particular, blue light) (Cunliffe and Goulden, 2000; Goldberg and Russell, 2006; Lee et al.,

2007b; Posten et al., 2005; Sadick, 2008). One study demonstrated a significant reduction

in active acne lesions after 12 sessions of treatment, using 630 nm red spectrum LLLT with

a fluence of 12 J/cm2, twice a week for 12 sessions in conjunction with 2% topical

clindamycin (Aziz-Jalali et al., 2012). However, the study showed no significant effects when

an 890 nm laser was used (Aziz-Jalali et al., 2012). Other studies have reported that, the

use of blue light and red light in combination, results in synergistic effects for the treatment

of acne (Goldberg and Russell, 2006; Lee et al., 2007b; Papageorgiou et al., 2000; Sadick,

2008). It was proposed that, the enhanced effects of mixed light were due to synergy

between the anti-bacterial and anti-inflammatory effects of blue light and red light

respectively (Lee et al., 2007b; Papageorgiou et al., 2000) (Figure 2). In several studies,

improvements in inflammatory lesions were reported to be greater than the improvements

in comedones (Lee et al., 2007b; Papageorgiou et al., 2000).

Additionally, fractional laser therapy can be used to treat post-acne scars with the best

results obtained for the treatment of macular, superficial and medium-depth scars. Deep

scars and ice-pick scars show only marginal improvement with the use of fractional laser

treatment, although, severe scarring can be treated in combination with other modalities

such as chemical peels, surgical dermabrasion, derma-roller, and trichloroacetic acid

chemical peel (CROSS) techniques. Additionally, fractional laser treatment provides a

suitable means for the treatment of scars in individuals with darker skin tones, and has also

shown remarkable pore improvement (Goel et al., 2011). As with any therapeutic modality,

proper counseling and evaluation should be conducted to minimize the probability of

adverse effects.

LLLT for Photoprotection. It is broadly accepted that UV radiation (spectral range < 400

nm) is responsible for most (if not all) of the photodamage inflicted on the skin, from

chronic sunlight exposure. Proposed mechanisms of action for UV radiation include the

induction of free radical formation, formation of DNA cross-links, inhibition of DNA repair,

inhibition and suppression of the immune system, and collagen degradation (Sinha and

Hader, 2002). Presently available treatments depend on reducing UV exposure of the skin

by either, avoiding sun exposure, or using sunscreens. The former option poses practical

difficulties, especially, for individuals engaged in outdoor activities, while the

photoprotective efficacy of topical sunscreens leave a lot to be desired. The limitations of

using topical sunscreens include reduced efficacy after water exposure or perspiration,

spectral limitations, possible nanoparticle (present in most sunscreens) toxicity (Kimura et

al., 2012), compliance and user allergies.

Recent studies suggest that, LLLT (specifically red or NIR radiation) may provide effective

protection against UV-induced photodamage. This is believed to be due to the fact that,

earlier on during the day (morning time) red/NIR wavelengths of the solar spectrum

predominate, and prepare the skin for the potentially harmful UV radiation that

predominates later on in the day (noon/afternoon) (Barolet & Boucher, 2008).

In a study conducted by Menezes et al. (1998), it was reported that LLLT, utilizing non-

coherent near infrared radiation (700-2,000 nm), was able to generate a strong cellular

defense against solar UV cytotoxicity in the absence of rising skin temperature, and it was

believed to be a long-lasting (at least 24 hours) and cumulative phenomenon. A study

conducted by Frank et al.(2004) proposed that, NIR irradiation prepares cells to resist UVB-

induced damage by influencing the intrinsic (mitochondrial) apoptotic pathway. NIR

irradiation of human fibroblasts, before subsequent UV exposure, was reported to inhibit

UVB-nduced activation of caspase-9 and caspase-3, induce the partial release of cytochrome

c and Smac/Diablo, decrease pro-apoptotic proteins (i.e., Bax), and increase anti-apoptotic

proteins (i.e., Bcl-2 or Bcl-xL). The results suggested that UVB-induced apoptosis was

inhibited by NIR, which was most likely induced by modulating the Bcl-2/Bax balance,

suggesting that p53, a sensor of gene integrity involved in cell apoptosis and repair

mechanisms, had an influential role in the process of NIR induced photoprotection against

UVB radiation. Another study looked at the role of p53 in the cell-signaling pathway for the

prevention of UVB-induced toxicity (Frank et al., 2004). The response to NIR irradiation was

shown to be p53 dependent, which further suggests that NIR irradiation prepares cells to

resist and/or repair UV-B-induced DNA damage. Additionally, the induction of defense

mechanisms (via NIR) was supported by Applegate et al., who reported that the protective

protein, ferritin, normally involved in skin repair (scavenger of ferrous iron [Fe2+],

otherwise available for oxidative reactions) was induced by NIR radiation (Applegate et al.,


It has also been reported that an increase in dermal fibroblast procollagen secretion reduces

MMP or collagenase production following non-thermal, non-coherent, deep-red visible (close

to NIR) light exposures (660 nm, sequential pulsing mode). These results correlated with

significant clinical improvement of rhytids observed in an in vivostudy (Barolet et al., 2009).

In a previous pilot study, the effect of LLLT on UV-induced erythema was measured in a

group of healthy subjects, using a minimal erythema dose (MED) method (adapted from

that used for sunscreen sun protection factor (SPF) determination). The results showed that

LLLT had a significant effect in reducing UVB-induced erythema (Barolet & Boucher, 2008).

Additionally, the effects of non-thermal, non-coherent 660 nm low-level light pulsed

treatments for enhancing skin resistance to UV radiation have been studied in healthy (fair

skinned) individuals, as well as polymorphous light eruption (PLE) patients. The results

show that a decrease in UVB-induced erythema is observed with the administration of LLLT

prior to UVB exposure. A noticeable reduction in UVB-induced erythema reaction was

observed for 85% of healthy subjects, as well as in patients with PLE. Accompanying the

reduced UVB erythema, a supplemental SPF-15 like effect was observed along with a

reduced post-inflammatory hyperpigmentation response. Yu et al. (2003) showed that LLLT,

using a HeNe laser (632.8 nm), stimulated an increase in gene expression of nerve growth

factor (NGF) in vitro, a major paracrine maintenance factor responsible for melanocyte

survival in skin, as well as its release from cultured keratinocytes. NGF has been shown to

stimulate the up-regulation of Bcl-2 in cells, and thus, induce photoprotection of

melanocytes against UV-induced apoptosis (Zhai et al., 1996). Hence, the effects of LLLT on

NGF may contribute to the photoprotective abilities of LLLT.

LLLT for Herpes Virus. Herpes simplex virus (HSV) infections are some of the most

common types of infections in the present age, and are a bane to patients due to the life-

long persistence of the virus within the host’s body. Two strains of this virus most

commonly infect humans: HSV-1 and HSV-2. HSV-1 is primarily responsible for infections of

the mouth, throat, face, eye(s), and central nervous system, while HSV-2 primarily causes

anogenital infections, however, each may cause infections in any of the mentioned systems.

Following the initial infection and resolution of lesions, the virus traverses across nerve

endings of the affected nerve, and establishes a state of latency in the sensory ganglia of

the nerve (usually the trigeminal nerve) (de Paula Eduardo et al., 2011). Several cues can

trigger reactivation and migration of the virus to the skin and mucosa (via the sensory

nerves), leading to reactivation of the virus, especially, on the basal epithelium of the lips

and perioral areas. These cues may be physical or emotional, and include fever, exposure to

UV light, and immune suppression (de Paula Eduardo et al., 2011). Manifestations of viral

infection can vary from cold sores in immunocompetent individuals to severe complications

in immunocompromised patients. Up to 60% of all patients (both immunocompetent and

immunocompromised) experience a prodromal period after which, outbreaks develop

through the stages of erythema, papule, vesicle, ulcer and crust, until finally, healing is

achieved. This prodromal period is accompanied by pain, burning, itching, or tingling, at the

site of future blister formation, causing great discomfort to the patients. Immune responses

to viral infection encompass action of macrophages, Langerhans cells, natural killer cells,

lymphocyte-mediated delayed-type hypersensitivity and cytotoxicity (Whitley et al., 1998).

Although a variety of anti-viral drugs (e.g., acyclovir and valacyclovir) are available for

managing outbreaks, they can only operate within a narrow time window to accomplish any

patient benefit at all, and even then only limited effects are observed with regard to the

healing time of the viral lesions (de Paula Eduardo et al., 2011). Additionally, drug resistant

strains of the herpes virus pose an ever-increasing risk of severe, unmanageable infections,

especially for immunocompromised patients (Whitley et al., 1998). Thus, new treatment

modalities that can reduce the frequency of recurrent episodes, as well as address the issue

of undesirable effects of current treatment modalities are desirable.

LLLT serves as a suitable alternative to current therapeutic modalities, providing accelerated

healing, reduced symptoms, and managing the recurrence of outbreaks (Bello-Silva et al.,

2010; de Paula Eduardo et al., 2011; Munoz Sanchez et al., 2012). One study reported that,

when LLLT was administered to a group of 50 patients suffering from recurrent perioral HSV

infections, during an outbreak-free period (wavelength: 690 nm, intensity: 80 mW/cm2, and

dosage: 48 J/cm2), a reduction in the frequency of recurrence of herpes labialis episodes

was observed (Schindl & Neumann, 1999). In another study with similar irradiation

parameters (intensity: 50 mW/cm2, fluence: 4.5 J/cm2, wavelength: 647 nm), it was

reported that intervals of remission were prolonged from 30 days to 73 days in patients with

recurrent HSV infections (Landthaler et al., 1983). Intriguingly, the treatment proved more

effective in patients suffering from herpes labialis than in those with genital infections. LLLT

treatment, however, did not affect established HSV latency in a murine model (Perrin et al.,


The mechanism of action of LLLT in inducing anti-viral effects is not known, however it can

be hypothesized that LLLT acts in an indirect manner, influencing cellular and humoral

components of the immune system, as opposed to through a mechanism involving direct

viral inactivation (Korner et al., 1989). In one particular instance, a study conducted by

Inoue et al. investigating suppressed tuberculin reactions in guinea pigs, suggested that the

application of LLLT through the use of a low power laser (fluence of 3.6 J/cm2) was

responsible for a systemic inhibitory effect on delayed hypersensitivity (Inoue et al.,

1989b). Activation and proliferation of lymphocytes (Inoue et al., 1989a; Manteifel et al.,

1997; Schindl et al., 1997; Yu et al., 1997) and macrophages (Bolton et al., 1990) as well

as the synthesis and expression of cytokines (Funk et al., 1992; Yu et al., 1996)

accompanying exposure to low intensities of red and NIR light have been reported on

several occasions. Whether or not these findings are actually influential against HSV

infection remains to be seen.

LLLT for Vitiligo. Vitiligo is an acquired pigmentary disorder characterized by

depigmentation of the skin and hair. The underlying mechanism of how functional

melanocytes are lost from the affected skin is still under investigation, however, up-to-date

findings suggest that melanocytes, melanoblasts, keratinocytes and fibroblasts may be

involved in the repigmentation process of vitiligo (Kitamura et al., 2004; Lan et al., 2009;

Lan et al., 2006; Lee, 2012; Yu et al., 2003, 2012). Thus, stimulation of such cells may

offer a possible mode of treatment, but due to the obscure pathogenesis of the condition,

treatment outcomes have generally been unsatisfactory. Topical corticosteroids,

phototherapy and photochemotherapy are some current therapeutic modalities that have

shown varying degrees of repigmentation in vitiligo patients (Lan et al., 2006). In 1982, a

group of investigators looked into the effect of LLLT on the defective biosynthesis of

catecholamines (involved in melanin biosynthesis) and discovered that it was able to

influence conditions such as vitiligo and scleroderma (Mandel and Dunaeva, 1982; Mandel

et al., 1997). Later on, one of the investigators from the same group reported that,

following 6-8 months of low-energy HeNe laser (632.8 nm, 25 mW/cm2) therapy there was

a noticeable degree of repigmentation in 64% of the patients belonging to a group of 18

individuals, while in another 34% of the patients follicular repigmentation was observed

(Mandel et al., 1997). Thus, LLLT has been suggested as a suitable modality for the

treatment of vitiligo (Lan et al., 2006, 2009; Yu et al., 2003).

A certain type of vitiligo (called segmental-type) is linked to sympathetic nerve dysfunction

in affected areas of the skin, and has proved to be resistant to several conventional forms of

treatment (Yu et al., 2003). Studies show that, LLLT improves nerve injury (Anders et al.,

1993; Khullar et al., 1996; Rochkind et al., 1989), and also generates responses to promote

repigmentation (Mandel, 1984; Yu, 2000). Thus, the data suggests that LLLT may serve as

a potential therapeutic modality for this treatment resistant form of vitiligo, i.e., segmental-

type vitiligo. Upon local administration of a low-powered HeNe laser (3 J/cm2, 1.0 mW,

632.8 nm), it was observed that 60% of the patients showed noticeable perilesional and

perifollicular repigmentation with successive treatments. In the same study, upon irradiation

of keratinocytes and fibroblasts with a HeNe laser (0.5-1.5 J/cm2), significant increases in

the amount of NGF released from keratinocytes were observed. Significant increases in

bFGF release from keratinocytes and fibroblasts have also been reported (Lan et al., 2006).

NGF and bFGF are known to stimulate the migration of melanocytes, and may contribute to

the repigmentation of process of vitiligo (Peacocke et al., 1988; Wu et al., 2006; Yu et al.,

2012). Furthermore, the medium that had been irradiated with the HeNe laser (along with

the keratinocytes) led to the stimulation of deoxythymidine uptake and proliferation of

cultured melanocytes. Finally, enhanced melanocyte migration was observed, which is

thought to have arisen either from the direct action of the HeNe laser or indirectly due to

some effect induced by the laser-irradiated medium.

Another study showed that LLLT could lead to enhanced expression of α2β1 integrins, and

stimulate melanocyte proliferation (Lan et al., 2009). Also, LLLT demonstrated the ability to

induce melanocyte growth through up-regulated expression of phosphorylated cyclic-AMP

response element binding protein (CREB), an important melanocyte growth regulator (Lan

et al., 2009). Components of the ECM also operate as regulators of factors such as

morphology, migration, tyrosinase activity and proliferation of pigment cells, and thus, are

important to the pigmentation process (Hedley et al., 1997; Ma et al., 2006; Morelli et al.,

1993). Type IV collagen is an ECM component present in the basement membranes of

tissues and is known to have intricate associations with melanocytes in the epidermis, such

as promoting melanocyte mobility (Lan et al., 2006). LLLT has been shown to greatly

promote melanocyte attachment to type IV collagen, and thus, modulate the physiological

functioning of melanocytes (Lan et al., 2009). Fibronectin, among other ECM elements has

been shown to have significant effects on differentiation, and the migration of cultured

melanoblasts and melanocytes (Ideta et al., 2002; Takano et al., 2002). An in vivo study

conducted by Gibson et al. (1983) demonstrated that the physical distribution of fibronectin

was closely associated with the migration path undertaken by melanoblasts during the

repigmentation process of vitiligo (Gibson et al., 1983). A significant decrease in fibronectin

binding was displayed by immature melanoblast cell lines (NCCmelb4), while a more

differentiated melanoblast cell line (NCCmelan5) showed an increase in attachment to

fibronectin by about 20% following LLLT (1 J/cm2, 10 mW HeNe laser) (Lan et al., 2006).

Lastly, the expression of integrin α5β1 on NCCmelb4 cells was observed to be enhanced,

which is responsible for regulation of locomotion of pigmented cells (Lan et al., 2006).

LLLT for Reduction of Pigmented Lesions. Several studies, especially for vitiligo, show

that LLLT exhibits stimulatory effects on pigmentation. Despite these studies, which are

supportive of the pigmentation promoting abilities of LLLT, one study showed that, the

effects of blue light (415 + 5 nm, irradiance 40 mW/cm2, 48 J/cm2) and red light (633 + 6

nm, 80 mW/cm2, 96 J/cm2) in combination, yielded results where an overall decrease in

melanin was observed (Lee et al., 2007b). Melanin levels increased by 6.7 arbitrary units in

individuals after blue light irradiation, without a statistical significance (P-value > 0.1),

whereas, they decreased by 15.5 arbitrary units, with a statistical significance (P-value <

0.005), following red light irradiation. These findings may be associated with the ability of

the laser to brighten the skin tone of the irradiated area, which was reported by 14 out of

24 subjects after the treatment period. Up to now however, no other studies have shown

similar results. Considering the differences in parameters used for vitiligo and acne

treatments, different effects of LLLT on the same tissue could be attributed to the biphasic

dose response of LLLT (Huang et al., 2009).

LLLT for Treatment of Hypertrophic Scars and Keloids.Hypertrophic scars and keloids

are benign fibrotic skin lesions that usually arise following surgery, trauma or acne, and are

difficult to remove. Fibroblastic proliferation and excess collagen deposition are the main

characteristics of these lesions (Uitto and Kouba, 2000), and, imbalances between rates of

collagen biosynthesis and degradation, superimposed on the individual’s genetic

predisposition have been implicated in the pathogenesis of keloids and hypertrophic scars. A

broad range of surgical (e.g., cryotherapy and excision), non-surgical (e.g., pharmacological

administration, mechanical pressure and silicone gel dressings), and laser-based therapies

(CO2, pulsed dye, fractional ablative and non-ablative lasers) have been tested with variable

success, however, the optimal method of treating these lesions remains undefined (Bouzari

et al., 2007; Louw, 2007; Wolfram et al., 2009). Recently, it has been suggested that poor

regulation of the transforming growth factor beta-I (TGF-βI) expression and interleukin 6

(IL-6) signaling pathways has a significant role in this process, and thus, the inhibition of

the IL-6 pathway and/or TGF-βI expression could serve as a potential therapeutic target

(Bouzari et al., 2007; Ghazizadeh et al., 2007; Liu et al., 2004; Uitto, 2007; Wolfram et al.,

2009). Reports indicating the effects of LLLT on the reduction of IL-6 mRNA levels (Lee et

al., 2007a), modulation of platelet-derived growth factor (PDGF), TGF-β, interleukins such

as IL-13, IL- 15, and MMPs, all of which are associated with abnormal wound repair (Barolet

and Boucher, 2010; Hamblin and Demidova, 2006), have led to the proposal of LLLT as an

alternative to the currently available therapeutic options.

A new promising treatment modality seems to be the utilization of pulsed dye lasers (PDL)

of wavelength 585 nm, and is believed to act through the induction of capillary destruction

and alteration of local collagen formation (Gauglitz, 2013). Moreover, PDL appears to

stimulate the up-regulation of MMPs, which also helps to improve keloids and hypertrophic

scars (Gauglitz, 2013). Recommended protocols call for non-overlapping pulse doses of

fluences between 6.0 to 7.5 J/cm2 for 7 mm spots, and 4.5 to 5.5 J/cm2 for 10 mm spot;

however, results definitively indicating the efficacy of PDL for clinical use are lacking

(Gauglitz, 2013). PDL treatments can present with mild side-effects, generally purpura;

however, in certain instances reactivation of the keloids has been observed (Gauglitz,

2013). Also in some cases, prolonged hyperpigmentation is observed, particularly, in the

case of individuals possessing darker pigmented skin, but can be managed using low


It is worth mentioning that the 1064 nm Nd:YAG laser has been suggested as a means for

improving hypertrophic scars and keloids as the Nd:YAG laser has a greater penetration

depth than PDL, and would allow for treatment of thicker scars, but may be limited by

decreased efficacy associated with increased penetration depth (Gauglitz, 2013). The use of

LLLT as a prophylactic means in order to avoid and impair the formation of hypertrophic

scars or keloids has been investigated by Barolet and Boucher (2010). They examined three

different cases, wherein a single scar was treated by the patient at home on a daily basis

with NIR-LED (805 nm at 30 mW/cm2, 27 J/cm2), following scar revision by surgery or

CO2 laser ablation on bilateral areas (Barolet & Boucher, 2010). The first patient had pre-

auricular, linear, bilateral keloids, and a post-face lift procedure, and surgical scar

revision/excision had been conducted. The second patient had post-acne, bilateral

hypertrophic scars on the chest, and CO2 laser resurfacing had been performed. For the

third patient, CO2 laser resurfacing had also been used for post-excision, bilateral

hypertrophic scars on the back (Barolet & Boucher, 2010). Collectively, in these studies, it

was observed that, the NIR-LED treated scars showed significant improvement over the

control scars in all measures of efficacy. Additionally, no adverse effects associated with

treatment were reported (Barolet & Boucher, 2010).

LLLT for Healing Burns. In a clinical study by Weiss et al. (2005b) 10 patients were

treated with LLLT (590 nm, 0.10 J/cm2), for acute sunburn, once or twice a day for 3 days,

where only half of the affected area was treated. A reduction in redness, swelling, burning

and peeling was reported by the patients post-treatment. In one of the individuals who

received treatment twice a day for 3 days, immunofluorescence staining showed that the

LLLT treated area exhibited a reduction in MMP-1. Furthermore, the light treated area also

exhibited a decrease in MMP-1 gene activity, both 4 and 24 hours post-UV injury, as shown

by reverse transcription-polymerase chain reaction (RT-PCR). Four days after UV exposure,

changes in inflammation and the dermal matrix were also reported to be associated with

LLLT treatment (Weiss et al., 2005b).

Burns associated with laser treatments themselves are also an issue for patients, as these

burns cause great discomfort to the patients. Studies support that LLLT facilitates faster

healing. In one study, a group of patients (n = 9) that had received second-degree burns as

a result of non-ablative laser therapy, were administered LLLT daily for a week. According to

patient and clinician reports, healing of the burns was observed to be substantially faster

(50% faster) in patients who received LLLT treatment, over those who did not (Weiss et al.,

2005b). In another study, by Weiss et al. (2005b), intentional injury was afflicted on the

forearm of a patient, and a CO2 laser and a computerized pattern generator were used to

induce two identical burns on the patient’s forearm; one on each side of the forearm. Both

sites of injury were given daily dressing changes using a non-stick dressing and Polysporin®

ointment, and one of the sites was also treated with LLLT. The injury site that was

administered LLLT, displayed accelerated tissue reepithelialization, in comparison to the

untreated site.

In a study conducted by Schlager et al. (2000), the efficacy of a low-powered laser (670

nm, 250 mW, 2 J/cm2) was studied using a rat model (n = 30 rats). The rats received burns

on their left and right flanks, and one of the burn sites received light treatment, whereas,

the other site was left untreated. Macroscopic and histological evaluations of the wounded

tissue were conducted, but they failed to show any accelerated wound healing in the light

treated areas in comparison to the control wounds.

A study conducted by Ezzati et al. (2009) also tested the efficacy of LLLT for healing burns.

The study used a mouse model, where a sample size of 74 mice was used, and each mouse

received two, third-degree burns; one proximal (control) and one distal (experimental). The

mice were divided into 4 different groups. The mice in the first group received sham-LLLT

on the distal burn with the laser powered-off, and were used as the placebo group. Mice of

the second and third groups were administered a 3000 Hz-pulsed IR diode laser at the distal

burn with fluences of 2.3 J/cm2 and 11.7 J/cm2, respectively. The fourth and final group was

treated with 0.2 % nitrofurazone alone. Assessment of the LLLT treated groups, showed a

substantial reduction in the incidence of pathogenic infections by microbes such

as Staphylococcus epidermidis,Lactobacillus, and Corynebacterium diphtheriae when

compared to the baseline. Additionally, the LLLT treated groups showed enhanced tissue

healing over the baseline, and nitrofurazone treatment groups. Enhanced healing was

reported for the laser with a fluence of 2.3 J/cm2, but it was mostly during the early stages

of healing. The most substantial increases in tissue repair were reported for the group that

was treated with a fluence of 11.7 J/cm2. Studies suggest that LLLT is able to effectively

stimulate tissue repair, by modulating cellular interactions that are responsible for repair.

LLLT can induce the release of growth factors by stimulation of macrophages and mast cells.

Fibroblast, endothelial cell, and keratinocyte proliferation, which are maintained during

adverse situations, can also be stimulated by means of LLLT (Ezzati et al., 2009).

Burn scars are problematic to treat as they progressively worsen with hypertrophy and

contracture, thus, with limited treatment options, LLLT may be a potential mode of

treatment. In a study consisting of 19 patients with burn scars, the patients were treated

with a low-powered light source (400 mW, 670 nm, 4 J/cm2), twice a week over a period of

8 weeks. Post-treatment, the scars were reported to be softer and more pliable.

Additionally, relief from pain and pruritus, and, occasional improvements in scar patterns

(within mesh grafts) were also reported. These effects were sometimes limited, and thus,

complete scar disappearances could not be expected. Moreover, it is important to note that,

following treatment, better results were obtained in the cases where the burn scars were

not more than 12 months of age (Gaida et al., 2004).

LLLT for Psoriasis. Psoriasis is a chronic and recurrent inflammatory skin condition that

affects about 1 to 3% of the population (Gelfand et al., 2005; Stern et al., 2004). Its

etiology is not entirely known, however, psoriasis is known to result from the interactions of

systemic, genetic, immunological, and environmental factors (Zhang, 2012). Psoriasis

patients present with well-demarcated plaques, formed as a result of keratinocyte

hyperproliferation, mediated by T-lymphocytes that attack the skin (Griffiths and Barker,


The regions of the body that are most commonly affected in psoriasis include the knees,

elbows, scalp, nails and lower back (sacrum), however, the body in its entirety may be

affected. The severity of the condition is measured by assessing the total body area

involved in the disease (plaque severity). The different variants of psoriasis include, chronic

plaque psoriasis (psoriasis vulgaris) (Griffiths and Barker, 2007), flexural psoriasis (inverse

psoriasis) (Laws and Young, 2010; van de Kerkhof et al., 2007), guttate psoriasis

(Krishnamurthy et al., 2010), erythrodermic psoriasis (Laws and Young, 2010), palmar-

plantar psoriasis, facial psoriasis, and scalp psoriasis, and, almost all the variants result in

great morbidity and diminished quality of life for the patient (Finlay et al., 1990). Some of

the therapeutic modalities, implemented for the treatment of psoriasis, include topical agent

use, systemic drug administration, photodynamic therapy (PDT), UV phototherapy, and

laser therapy. Psoralen combined with UVA and UVB phototherapy provided a revolutionary

means for the treatment of psoriasis, when it was initially introduced. However, some later

studies suggested that, repeated and excess exposure to UVB radiation put individuals at an

increased risk for developing skin cancer. Thus, Psoralen + UVA (PUVA) was introduced as a

therapeutic modality, with a reduced risk of developing cancer, but its use was still

restricted as it did not completely eliminate the risk of cancer. Studies investigating the use

of LLLT for treatment, with CO2ablative laser (Bekassy and Astedt, 1985), helium-neon

lasers (Colver et al., 1984), and red light photodynamic therapy can be dated to the 1980s

(Berns et al., 1984).

Laser treatment provides a variety of advantages over conventional treatment modalities; it

allows for selective treatment of a lesion without affecting the surrounding skin, with limited

or no systemic effects. It can also be used in combination with other therapeutic modalities,

allowing for more effective treatment of resistant lesions. Several studies were conducted

using a selective excimer laser of 308 nm wavelength (Asawanonda et al., 2000; Gattu et

al., 2009; Trehan and Taylor, 2002). Laser therapy displayed results analogous to those

observed in UVB treatment. The laser treatment was effective in that it prevented epidermal

cell replication while also suppressing the localized immune responses and thereby reducing

the characteristic inflammation observed in psoriasis (Railan and Alster, 2008). However,

uncertainty exists regarding the carcinogenic ability of long-term excimer laser exposure.

Thus, pulse dye laser (PDL) possessing a wavelength of 585 nm was suggested as an

alternative. PDL lasers are commonly used for the treatment of vascular disorders, and

thus, have proven to be a legitimate treatment modality for psoriasis due to, the association

of increased vascularity with psoriasis (De Leeuw et al., 2009; Ilknur et al., 2006).

Furthermore, a recent study which investigated the efficacy of combination 830 nm (NIR)

and 630 nm (visible red light) LLLT, for the treatment of recalcitrant psoriasis, has

facilitated the consideration of LLLT for the treatment of plaques associated with psoriasis.

In the study, patients that presented with psoriasis resistant to conventional treatment were

administered sequential treatments with 830 nm and 630 nm wavelengths for two, 20-

minute sessions, spaced 48 hours apart for a total of 4 or 5 weeks. The results from the

study did not display any adverse effects; rather, the results demonstrated resolution of

psoriasis (Ablon, 2010). Although the study was promising, it was limited by its small

sample size; however, the results of the study provided motivation for future investigations

to look at the applications of LLLT as a therapeutic modality.

LLLT for Treatment of Hair Loss

Hair and Types of Hair Loss. Hair is amongst the fastest growing tissues of the body,

undergoing repetitive and regenerative cyclical changes, with each cycle consisting of

telogen (resting), anagen (active) and catagen (physiological involution) stages (Paus and

Foitzik, 2004) (Figure 3). During the transition from telogen to anagen, there is stringent

regulation of the activation of epithelial bulge stem cells, while transit amplifying (TA)

progeny cells arise from the secondary hair germ cells (Tiede et al., 2007). Along the period

of the anagen phase, the TA cells display resilient proliferation within the epithelial matrix of

the hair follicle. As a result, the end product of the hair cycle (i.e., the bulk of the hair

filament) is formed through terminal differentiation of the proliferating trichocytes. The

prime regulatory element of progenitor cell activation, hair matrix cell proliferation, and

terminal differentiation of trichocytes is believed to be the dermal papilla of the hair follicle

(Plikus et al., 2006). The anagen stage represents the growth stage of the hair cycle, and

may last 2 to 6 years. The catagen stage, which generally lasts 1 to 2 weeks, is when

transitioning of club hair is observed; as it progresses towards the skin pore, and the

dermal papilla begins to separate from the hair follicle. The telogen stage which lasts from 5

to 6 weeks, exhibits a complete dermal papillary separation from the hair follicle. Lastly, the

cycle progresses again towards the anagen stage as the dermal papilla joins up with the

hair follicle and the hair matrix starts synthesizing new hair.

Figure 3. This figure depicts the stages of cycling in the hair follicle. Shown are the transitions between anagen to catagen stage, catagen to telogen stage and eventually the return back to anagen stage following senescence of the hair at the end of telogen stage.

Androgenetic alopecia (AGA) is the most common form of hair loss in men, affecting almost

50% of the male population (Otberg et al., 2007). As the name suggests, AGA refers to hair

loss induced in genetically susceptible individuals due to the effects of androgens such as

testosterone. Testosterone is a lipophilic hormone that diffuses across the cell membrane to

carry out its function. It is converted to a more active form called dihydrotestosterone

(DHT), which is responsible for many of the effects observed in AGA. The enzyme

responsible for the conversion of testosterone to DHT is 5α-reductase. Two types of 5α-

reductase enzymes are found in body tissues: Type 1, which is prevalent in keratinocytes,

fibroblasts, sweat glands, and sebocytes, and Type 2, found in skin and the inner root

sheath of hair follicles. DHT acts by binding to its nuclear androgen receptor, which is

responsible for regulating associated gene expression (Ghanaat, 2010).

Abnormal androgen signaling is responsible for the disruption of epithelial progenitor cell

activation and TA cell proliferation, which forms the essential pathophysiological basis for

AGA (Itami and Inui, 2005). The exact genes associated with the process of hair loss are

not entirely known, however, some genes implicated in hair growth are known, and include

genes for desmoglein, activin, epidermal growth factor (EGF), fibroblast growth factor

(FGF), lymphoid-enhancer factor-1 (LEF-1), and sonic hedgehog (Ghanaat, 2010).

Presently, amongst the treatment options available, the most commonly used include

minoxidil, finasteride, or surgical hair transplantation (Otberg et al., 2007). Recently, the

United States Food and Drug Administration (FDA) has approved the use of LLLT as a novel

treatment modality for hair loss (Wikramanayake et al., 2012) (Figure 4).

Figure 4. Examples of LLLT devices for treatment of hair loss. (A) Lasercap 660 nm laser diodes, Transdermal Cap, Inc, Cleveland OH; (B) HairMax LaserComb®, 635 nm laser diodes; Lexington International, Boca Raton, FL; (C) iGrow Helmet, 655 nm laser diodes and LEDs, Apira Science, Inc., Boca Raton, FL.

Several other forms of hair loss also exist such as telogen effluvium (TE), alopecia areata

(AA), and alopecia induced via chemotherapy. AA is an autoimmune inflammatory condition

that presents with non-scarring alopecia, where histologic characterizations display intra- or

peri-follicular lymphocytic infiltrates composed of CD4+ and CD8+ T-cells (Wikramanayake

et al., 2012). AA has two variants, with one being alopecia totalis (complete loss of scalp

hair), and the other being alopecia universalis (total loss of body and scalp hair)

(Wasserman et al., 2007). The most common forms of treatments for alopecia involve intra-

lesional corticosteroids, however, other treatment modalities are also available such as

topical and systemic corticosteroids, e.g., minoxidil (used in moderate cases) and anthralin.

Contact sensitizers are used when more than half of the scalp is affected. PUVA treatment,

cyclosporine, tacrolimus, and biologics such as alefacept, efalizumab, etanercept, infliximab,

and adalimumab are also utilized for the treatment of hair loss (Ghanaat, 2010). TE is a

condition where abnormal hair cycling results in excessive loss of telogen hair (Ghanaat,

2010). Some of the common causes that result in TE include acute severe illness, surgery,

iron deficiency anemia, thyroid disease, malnutrition, chronic illness, and medications (e.g.,

contraceptives, lithium and cimetidine). Chemotherapy functions by acting on fast-growing

cancer cells and destroying them, but it also results in the destruction of fast-growing

somatic cells in the body, such as those of the hair follicles, and thus, results in the

induction of alopecia. It is usually observed within 1 to 3 weeks of initiating therapy, where

the most profound effects are observed (Trueb, 2009).

LLLT for Treatment of Hair Loss. Quite recently, lasers have gathered much attention

due to their remarkable ability to cause selective hair removal, however, in some instances

it has been observed that, lasers can result in undesirable effects on hair growth such as

increased hair density, increased color or coarseness, or a combination of these (Moreno-

Arias et al., 2002a, 2002b; Vlachos and Kontoes, 2002; Wikramanayake et al., 2012). This

phenomenon is known as "Paradoxical Hypertrichosis", and its incidence varies from 0.6%

to 10% (Wikramanayake et al., 2012). It has also been reported that low-powered laser

irradiation of small vellus hairs, can cause them to transform into larger terminal hairs

(terminalization of vellus hair follicles) (Bernstein, 2005; Bouzari and Firooz, 2006). The

idea that lasers are able to induce hair growth is not something new. In the late 1960s,

Endre Mester, a Hungarian scientist, conducted a series of experiments to investigate the

ability of the newly developed lasers to cause cancer in mice, using a low-powered ruby

laser (694 nm). The laser exposure failed to cause cancer on shaved mice, but it enhanced

hair growth (Mester et al., 1968). This fortuitous observation was the first example of

"photobiostimulation" using LLLT, and it opened up a new avenue for the field of medicine

(Barolet and Boucher, 2008).

Different mechanisms have been proposed in an attempt to explain the effects of LLLT. In

one particular study, this ability of lasers (to promote hair growth) was attributed to a side-

effect of polycystic ovarian syndrome (PCOS) present in 5 out of 49 females undergoing IPL

laser treatment for facial hirsutism (Moreno-Arias et al., 2002a). Another study suggested

that, although lasers were responsible for heat generating effects in tissues, the heat

produced was not sufficient enough to induce hair follicle thermolysis, however, it may be

sufficient to stimulate follicular stem cell proliferation and differentiation by increasing levels

of heat shock proteins (HSPs) such as HSP27, which influence the regulation of cell growth

and differentiation (Wikramanayake et al., 2012). Some form of sub-therapeutic injury

could potentially cause the release of certain factors that could induce follicular

angiogenesis, and influence the cycling of cells (Bouzari and Firooz, 2006).

In 2007, the FDA approved LLLT as a possible treatment modality for hair loss

(Wikramanayake et al., 2012). Some of the devices that are used for LLLT in hair regrowth

are shown in Figure 4. It is believed that LLLT can stimulate re-entry of telogen hair follicles

into the anagen stage, bring about greater rates of proliferation in active anagen follicles,

prevent development of premature catagen stage, and extend the duration of the anagen

phase (Leavitt et al., 2009; Wikramanayake et al., 2012). Although the exact underlying

mechanism regarding how LLLT promotes hair growth is not known, several hypotheses

have been proposed. Current data suggests that, the action of LLLT on mitochondria leads

to increased adenosine triphosphate (ATP) production, modulation of reactive oxygen

species (ROS), and stimulation of transcription factors. These transcription factors, in turn,

are responsible for the synthesis of proteins that cause certain down-stream responses

leading to enhanced proliferation and migration of cells, modulation of cytokine levels,

growth factors and mediators of inflammation, and increased tissue oxygenation (Chung et

al., 2012).

In one study, the backs of Sprague Dawley rats were irradiated using a linearly polarized IR

laser, and, an up-regulation of hepatocyte growth factor (HGF) and HGF activator was

observed (Miura et al., 1999). Another study reported increases in temperature of the skin

as well as improved blood flow around areas of the stellate ganglion, following LLLT (Wajima

et al., 1996).

Minoxidil is another therapeutic modality available for the treatment of hair loss, however,

the exact mechanism of action of minoxidil is not completely understood, but it is known

that minoxidil contains nitric oxide (NO), which is an important cellular signaling molecule

and vasodilator (Proctor, 1989) that influences a variety of physiological and pathological

processes (Hou et al., 1999). Furthermore, NO regulates the opening of ATP-dependent

potassium (K+) channels, and thus, is responsible for the hyperpolarization of cell

membranes (Rossi et al., 2012). Also, It has been suggested that ATP sensitive K+ channels

of the mitochondria, and elevated levels of NO might be involved in the mechanism of

action of LLLT (Karu et al., 2005, 2008; Tuby et al., 2006) in areas of the brain and heart

(Ignatov et al., 2005; Karu et al., 2004, 2008). Thus, given the dependency of both

minoxidil and LLLT on the aforementioned factors, there is possibly some mechanistic

overlap between the two modalities.

Other studies have demonstrated that, LLLT is able to modulate 5α-reductase, the enzyme

responsible for the conversion of testosterone to DTH, as well as alter the genetic

expression of vascular endothelial growth factor (VEGF), which plays an influential role in

hair follicle growth, and thus, LLLT is able to stimulate hair growth (Castex-Rizzi et al.,

2002; Weiss et al., 2005; Yano et al., 2001). Furthermore, it has been demonstrated that

LLLT may stimulate hair growth through the modulation of inflammatory processes and

immunological responses (Meneguzzo et al., 2012). A study conducted on C3H/HeJ AA mice

models supported this assumption, where the mice were exposed to a LaserComb®, and it

was observed that, treatment led to an increase in the quantity of hair follicles, where the

majority of the follicles in anagen phase were seen to have decreased inflammatory

infiltrates. Taking into account the disruptive effect that inflammatory infiltrates have on

hair follicles, along with the notion that several cytokines such as interferon gamma (IFN-γ),

IL-1α and β, TNF-α and Fas-antigen, and macrophage migration inhibitory factor, are all

involved in cyclical hair growth as well as the pathogenesis of alopecia areata (AA), LLLT

may be able to play a significant role in the treatment of AA, due to its modulating effects

on inflammation (Wikramanayake et al., 2012).

LLLT for Treatment of Alopecia Areata. A clinical study was carried out to investigate

the effect of LLLT on the treatment of AA, consisting of a sample size of 15 patients (6 men,

9 women), utilizing a Super LizerTM; a medical instrument operating on polarized linear light

with a high output (1.8 W) of IR radiation (600-1600 nm), possessing sufficient penetration

depth to reach deep subcutaneous tissues. The patients received a 3-minute laser treatment

on the scalp, either once a week or once every 2 weeks, and were administered additional

carpronium chloride 5% twice daily to all lesions. Supplemental oral antihistamines,

cepharanthin and glycyrrhizin (extracts of medicinal Chinese herbs) were prescribed as well.

The results of the study showed that, 47% of the patients experienced hair growth 1.6

months earlier on areas irradiated with a laser when compared to the areas that were not

irradiated (Yamazaki et al., 2003).

In another study, the hair growth stimulating effects of LLLT were studied in a C3H/HeJ

mouse model of AA, where the mice were irradiated using a HairMax LaserComb® (the

comb emits 9 beams of light at 655 nm, while utilizing the attached combs for parting of

hair and allowing for a better delivery of light to the scalp) for 20 seconds daily, three times

a week for a total of 6 weeks (Figure 4). When the treatment was concluded, increased hair

regrowth was observed in the mice that were treated, but the sham treatment group

showed no difference in hair growth. Histological examination of mouse tissues showed that,

there was an increase in the content of anagen follicles in the light treated mice, whereas,

the sham treatment group exhibited more telogen follicles (Wikramanayake et al., 2012).

LLLT for Treatment of Androgenetic Alopecia. The effects of HeNe laser (632.8 nm) on

cyclical hair follicle growth, were studied at doses of 1 and 5 J/cm2 at 24 hour intervals for 5

days, in Swiss albino mice; both with and without the administration of testosterone (Shukla

et al., 2010). The mice that received He-Ne laser treatment at a dosage of 1 J/cm2showed

greater proportions of hair follicles in the anagen phase, when compared to those of the

control group, which received no testosterone or HeNe laser. Furthermore, exposure of the

mice to a dose of 5 J/cm2showed a decrease in the proportion of hair follicles in the anagen

phase when compared to the control group, which could be due to, the biphasic dose

response of LLLT (Chung et al., 2012; Shukla et al., 2010). It was also noted that treatment

with testosterone caused an inhibition of hair growth with respect to the control group,

which was shown by a significant reduction in the proportion of catagen hair follicles.

Despite this finding, mice that were treated with a HeNe laser at 1 J/cm2 and with

testosterone still showed an increase in the percentage of anagen stage follicles, when

compared to testosterone alone. However, when testosterone treated mice were exposed to

a HeNe laser dose of 5 J/cm2; a two-fold increase in the amount of anagen stage hair

follicles was observed. These results showed that, the hair promoting ability of LLLT (HeNe

laser 1 J/cm2) was higher in combination with testosterone, thus, it can be proposed that

cells possessing slow rates of growth or undergoing stressful conditions respond better to

the stimulatory effects of LLLT.

Another noteworthy finding of the study was that, in the skin irradiated by the HeNe laser

(1 J/cm2), some of the anagen follicles possessed a different orientation, and appeared to

arise from a greater depth within the skin (Shukla et al., 2010). Such follicles are

characteristic of the late anagen phase of the hair growth cycle, and the observation

suggests that LLLT may act by prolonging the anagen phase of the hair cycle (Muller-Rover

et al., 2001; Philp et al., 2004). Also, in the HeNe (1 J/cm2) irradiated skin that received

testosterone treatment, it was observed that the hair follicles originated from the middle of

the dermis, and such type of follicles are generally seen during early anagen phase (Shukla

et al., 2010). Thus, when considering the above observations, it can be concluded that LLLT

is able to stimulate the re-entry of telogen and catagen follicles into anagen phase. In

another study, twenty-four male androgenetic alopecia (AGA) patients were evaluated via

global photography and phototrichogram using 655 nm red light and 780 nm IR light, once

a day for a period of 10 minutes. Following 14 weeks of treatment, significant increases in

hair density and anagen were observed; telogen ratios were observed at both the vertex

and occiput, with 83% patients reporting that the treatment resulted in satisfactory results

(Kim et al., 2007).

A study was performed to investigate the efficacy of LLLT on hair growth and tensile

strength involving 28 male and 7 female AGA patients. Each patient was given a 655 nm

HairMax LaserComb® to use at home for a period of 6 months, applying it for five to ten

minutes per day on alternate days. The results showed improvements in hair growth in all

treated areas for both male and female sexes, however, in the case of males the greatest

improvements were observed in the vertex area, whereas, for females the best

improvements were seen in the temporal areas. All treated areas of both sexes showed an

improvement in hair count, but the vertex area showed the greatest improvement in the

male patients (Satino and Markou, 2003). In a double-blinded, sham device-controlled,

multi-center, randomized 26-week trial, the same device was tested on 110 male AGA

patients, where the patients used the device three times a week for fifteen minutes for a

total period of 26 weeks. Noticeable increases in the mean terminal density of hair were

observed in the treatment group, when compared to the sham treatment group. Also,

subjective assessments of the patients over the 26 week period showed significant

improvements in overall hair regrowth, a decreased rate of hair loss, thicker feeling hair,

improved scalp health and hair shine (Leavitt et al., 2009).

LLLT for Treatment of Chemotherapy-Induced Alopecia. About 65% of the patients

that receive chemotherapy for cancer develop alopecia, which can have detrimental effects

on the psychological health of the patient (Trueb, 2009). It has been proposed that LLLT

may serve as a treatment modality to stimulate and promote hair growth in cases of

chemotherapy-induced alopecia. In one study conducted in a rat model, the animals were

administered varying regimens of chemotherapy, in conjunction with LLLT, using a device

that possessed the components (laser unit and switch, lacking comb or handle) of the

HairMax LaserComb® (Wikramanayake et al., 2012). In all rats that were given laser

treatment; hair regrowth occurred at a faster rate, when compared to the sham treatment

group (Wikramanayake et al., 2012). Additionally, LLLT did not hinder the efficacy of the

chemotherapeutic procedures (Wikramanayake et al., 2012).

LLLT for Fat Reduction and Cellulite Treatment

Lipoplasty and Liposuction. Charles Dujarier, a French surgeon, first introduced the

concept of lipoplasty (also known as liposuction) in the 1920s. Dujarier attempted to

perform body sculpting on the knee of one of his patients, a model, but ultimately the

patient developed gangrene, leading to the amputation of her affected limb, thus, the

concept of lipoplasty suffered a major setback (Thorek, 1939). In 1974, Fischer

reintroduced liposuction, using a novel arrangement of oscillating blades within a cannula to

chisel away subcutaneous fat (Fischer, 1990). In 1983, Illouz reported his 5-year

experience with a new liposuction technique that could use relatively large cannulas along

with suction tubing to safely remove fat from several regions of the body (Illouz, 1983).

This technique ushered in the modern era of lipoplasty. Over the following decades, the

concept of tumescent liposuction allowed for better results, and decreased morbidity

associated with liposuction.

LLLT for Fat Reduction and Cellulite Treatment. Neira et al. first demonstrated the use

of LLLT as a new means for liposuction, and successfully utilized it with doses that did not

produce any detectable increases in tissue temperature or cause any noticeable macroscopic

alterations in tissue structure (Neira et al., 2000, 2002). Prior investigations concerned with

the effects of LLLT on wound healing, pain relief and edema prevention helped pave the way

for this therapeutic application (Baxter et al., 1991; King, 1989). The development of LLLT

as a therapeutic modality to augment liposuction, while avoiding macroscopic tissue

alterations, were based on the determination of optimal parameters such as wavelength and

power output for use (Oschmann, 2000). Evidence suggests that wavelengths suitable for

biomodulation range between 630 and 640 nm (Al-Watban and Zang, 1996; Frohlich, 1968,

1970, 1975; Sroka et al., 1997; van Breugel and Bar, 1992). Several intriguing

observations regarding the effects of LLLT on adipocytes were made using a low-level diode

laser (635 nm) with a maximal power of 10 mW, with energy values ranging from 1.2 to 3.6

J/cm2 (Neira et al., 2002). Using scanning electron microscopy (SEM) and transmission

electron microscopy (TEM) it was demonstrated that, adipocyte plasma membranes

exhibited transitory pore formation as a result of the irradiation. It was suggested that this

enabled the release of intracellular lipids from the adipocytes, and thus, supplemented

liposuction as it was expected to reduce the time taken for the procedure, allowing for the

extraction of greater volumes of fat, and reducing the energy expenditure of the surgeon.

Although the findings associated with LLLT gathered much attention and enthusiasm, a

study by Brown et al. (2004) put these findings associated with LLLT into question. They

cultured human preadipocytes after 60 minutes of irradiation using an LLLT source (635 nm

and 1 J/cm2), and did not find any differences in lipid content, when compared to non-

irradiated cells. Furthermore, the histological examination of human lipoaspirates and

lipoaspirates from a porcine model, treated with LLLT for 30 minutes, failed to demonstrate

transitory pores in adipocytes when analyzed using SEM (Brown et al., 2004). Additional

data raised questions regarding the ability of red light (635 nm) to effectively penetrate

below the skin into the sub-dermal tissues (Kolari and Airaksinen, 1993). Since the data

reported by Brown et al. (2004), there have been several reports in the literature that have

supported the efficacy of LLLT in lipolysis (Caruso-Davis et al., 2011; Mulholland et al.,

2011; Nestor et al., 2013). Some of the devices that are used for fat reduction are shown in

Figure 5.

Figure 5. Examples of external LLLT devices for use in fat reduction and cellulite treatment. (A) iLipo, 650 nm laser diodes; Chromogenex US Inc. Howell, MI. (B) Zerona Laser Scanner, 635 nm laser diodes, Erchonia, McKinney, TX.

Mechanism of Action of LLLT for Fat Reduction. The fat liberating effects of LLLT on

adipocytes have been attributed to its ability to induce transitioning micropores, which were

visualized with the help of SEM (Figure 6). Furthermore, it was postulated that these pores

stimulated the release of intracellular lipids from the adipocytes. Based on this, it was

suggested that up to 99% of the fat stored within the adipocytes could be released, and

subsequently removed with the help of LLLT (635 nm, 10 mW intensity, 6 minutes

irradiation time) (Neira et al., 2002). However, another study demonstrated that, cultured

adipocytes when treated with LLLT, exhibited a tendency to attain their native cellular

conformation following treatment, which was confirmed using a live-dead assay to assess

the viability of these adipocytes following irradiation (Caruso-Davis et al., 2011). An

increase in ROS following LLLT has been proposed to bring about lipid peroxidation within

the cell membranes of adipocytes, and may be responsible for membrane injury, which

could present itself as transitory pores (Chen et al., 2011; Geiger et al., 1995; Karu, 2008;

Tafur and Mills, 2008). However, when Brown et al. attempted to replicate the Neira group’s

findings (Neira et al., 2002), they failed to see any transitory micropores via SEM (Brown et

al., 2004). No further SEM studies have documented these pores, but findings have been

reported, that indirectly support the transitory micropore formation theory.

Figure 6. Formation of transitory micropores and shrinkage of adipocytes following LLLT. (A). Formation of a transitory pore forming in the bi-lipid membrane of an adipose cell, causing fatty contents of the cell to evacuate (Neira et al., 2002).

(B). Secretion of triglycerides and fatty acids and shrinkage of adipocytes (Neira et al., 2002).

Another proposed mechanism that explains the release of intracellular lipids form adipocytes

suggests that, the activation of the compliment cascade, which is responsible for the

induction of adipocyte apoptosis, results in the subsequent release of intracellular lipid

components (Caruso-Davis et al., 2011). To test the feasibility of this theory, a group of

researchers exposed differentiated human adipocytes to blood plasma, and treated one

group of cells to a laser (experimental), while the control group received no laser

intervention. No differences were noticed regarding the complement system components in

either group, and it was concluded that LLLT did not act through the activation of the

complement cascade (Caruso-Davis et al., 2011).

Other evidence suggests that LLLT is capable of inducing an increase in cAMP levels (Karu et

al., 1985, 1999). cAMP is responsible for the activation of certain protein kinases, which

further activate certain enzymes such as hormone sensitive lipase, which is responsible for

the breakdown of triglycerides into fatty acids and glycerol; both of which can traverse the

adipocyte membrane and reach the bloodstream (Honnor et al., 1985; Nestor et al., 2012).

However, the findings obtained from cell cultures of human adipocytes treated with LLLT

(635-680 nm for 10 min), did not exhibit any increases in glycerol and fatty acid levels,

suggesting that fat liberation from adipocytes in response to LLLT is not due to the lypolytic

breakdown of the adipose tissue. Interestingly enough, as the cellular components were

being examined, the presence of triglycerides in the supernatant of extracted samples

seemed to support the theory of transient micropore formation in adipocytes (Caruso-Davis

et al., 2011). Although these mechanisms have been worked out independently, the

mechanism by which triglycerides could traverse the adipocyte lipid membrane remains


Following the initial results obtained by Neira et al. (2000), a subsequent study was

conducted where adipose tissue samples, extracted from lipectomy samples of patients via

the tumescent method, were treated with a 10 mW diode laser (635 nm, total fluence

values ranging from 1.2 to 3.6 J/cm2) for a period of 0 to 6 minutes (Neira et al., 2002). It

was discovered that, the tumescent method facilitated greater laser penetration and

intensity, and allowed for enhanced fat liquefaction (Neira et al., 2002). A similar model was

used to test the efficacy of LLLT on lipectomy, where 12 female patients undergoing

lipectomy received extraction of both deep and superficial fat, infra-umbilically, using the

tumescent method, followed by LLLT. The results showed the synergistic ability of LLLT to

effectively work with the tumescent technique for effective fat removal. It was observed

that, without laser irradiation the fat tissue remained intact, and the fat cells maintained

their original spherical shape. The supplementary effect of the tumescent method on LLLT is

hypothesized to be due to, the stimulation of epinephrine-induced cAMP production via

adenyl cyclase, and/or, the enhanced penetrative ability and intensity facilitated by the

tumescent solution (Neira et al., 2002).

The efficacy of LLLT in combination with vibration therapy, for reduction in local adiposities

has also been studied. The study consisted of a total number of 33 patients including both

men and women aged 18–64 years, where the patients were divided into groups depending

on whether treatment was to take place in the abdomen, and/or the flanks, thighs or

buttocks. The parameters for the treatment of localized adiposities were as follows: 6 Hz

(Frequency of Oscillating Platform) with LLLT (635 nm) for 10 min, 9 Hz with LLLT (635 nm)

for 2 min, 16 Hz with LLLT (635 nm) for 5 min, and, 7 Hz with LLLT (635 nm) for 2 min.

These parameters varied depending on the area being treated, but none of the treatments

exceeded a total time period of 28 minutes; to maximize patient comfort, and avoid

unnecessary exertion. Several means of analysis were employed to gauge the effect of LLLT

on fat reduction including histological and echographic evaluation. It was found that the

treatment brought about a significant reduction in the median fat by 6.83 cm for the

abdomen and flanks, 3.42 cm for thighs, and, 6.16 cm for buttocks. The greatest results

were seen with the abdominal/flank regions, whereas, the thighs showed the least response

to treatment (Savoia et al., 2013). Thus, studies such as the aforementioned have

attempted to describe the mechanistic functioning of LLLT, but the topic still remains

somewhat controversial.

LLLT for Treatment of Cellulite. Cellulite is a condition observed in about 85% of post-

pubertal women, posing a major cosmetic concern for such women, where affected

individuals display a characteristic "orange peel" dimpling of the skin, most commonly in

areas of the thighs and buttocks. The underlying mechanism regarding the pathophysiology

of cellulite is still under investigation, but it is suspected that the enlargement of adipocytes,

weakening of connective tissue, and decrease in microcirculation are possible triggering

factors, helping to initiate the condition (Gold et al., 2011). Several devices and topical

treatment agents are available for managing the condition, but are limited by their abilities

to generate only temporary effects. Considering the stimulatory effects of LLLT on

circulation, collagen formation, and fat reduction; it may provide an alternative to current

treatment modalities. In a study conducted with 83 subjects possessing mild to moderate

cellulite, administration of a dual-wavelength (650 nm and 915 nm) laser, in combination

with a massage device, was carried out to test the efficacy of LLLT on cellulite. The results

demonstrated an improvement in cellulite appearance, as well as a 71% reduction in the

circumference of patient thighs that were treated; as compared to a 53% reduction in the

circumference of the thighs belonging to the control group (Gold et al., 2011).

Topical phosphotidylcholine-based anticellulite gels have also been used, along with LED

arrays (660 nm and 950 nm), as an experimental modality for the reduction of cellulite

(Sasaki et al., 2007). The results of the study were intriguing as LLLT alone failed to

generate improvement in cellulite, but in combination with the topical anti-cellulite gel, LLLT

was able to bring about remarkable cellulite reduction (Sasaki et al., 2007). Eight, out of

nine, patients were reported to have experienced a reduction in cellulite of the thighs when

LLLT was used in combination with the anti-cellulite gel (Sasaki et al., 2007). Further clinical

examinations, measurements, and ultrasound evaluations showed a noticeable reduction in

hypodermal thickness, and supported the results (Sasaki et al., 2007). However, 18 months

following treatment, it was reported that five of the improved thighs had reverted back to

their original grade of cellulite, and only three remained with their improved status. Such

studies have shown that LLLT can be a promising treatment modality as an alternative to

current treatment modalities, especially, when used in combination with other existing

modalities. Current literature suggests that, LLLT may have a broad range of applications

with a relatively small profile of adverse effects, however, the full extent of its potential

remains unknown.


LLLT has been investigated as a novel therapeutic modality for the treatment and

management of several dermatological conditions. The majority of the applications of LLLT

have been concerned with some form of skin rejuvenation (mostly, the reversal of chronic

photodamage). Several studies have demonstrated the use of LLLT for photorejuvenation,

photoprotection and the treatment of conditions such as acne and vitiligo. More recent data

demonstrates its potential for the treatment of cosmetic conditions such as alopecia,

cellulite and adiposities. Furthermore, LLLT is a modality that provides a patient-friendly

treatment approach, with its noninvasive mode of action, mild side-effects and convenience

of use. LLLT shows promise for future applications, being a novel treatment modality, which

not only works well on its own, but also in association with other therapeutic modalities.

With growing acceptance and continuing research in the field of photomedicine, it can be

concluded that LLLT, among other phototherapeutic modalities, will continue to grow and

emerge as a versatile tool in the field of dermatology.


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Jacob Hulcer