The Nuts and Bolts of Low-level Laser (Light) Therapy · includes many in the red and near...

The Nuts and Bolts of Low-level Laser (Light) Therapy

HOON CHUNG,1,2 TIANHONG DAI,1,2 SULBHA K. SHARMA,1 YING-YING HUANG,1,2,3 JAMES D. CARROLL,4

and MICHAEL R. HAMBLIN1,2,5

1Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, MA, USA; 2Department of Dermatology,Harvard Medical School, Boston, MA, USA; 3Aesthetic and Plastic Center of Guangxi Medical University, Nanning, People’sRepublic of China; 4Thor Photomedicine Ltd, 18A East Street, Chesham HP5 1HQ, UK; and 5Harvard-MIT Division of Health

Sciences and Technology, Cambridge, MA, USA

(Received 26 July 2011; accepted 20 October 2011; published online 2 November 2011)

Associate Editor Daniel Elson oversaw the review of this article.

Abstract—Soon after the discovery of lasers in the 1960s itwas realized that laser therapy had the potential to improvewound healing and reduce pain, inflammation and swelling.In recent years the field sometimes known as photobiomod-ulation has broadened to include light-emitting diodes andother light sources, and the range of wavelengths used nowincludes many in the red and near infrared. The term ‘‘lowlevel laser therapy’’ or LLLT has become widely recognizedand implies the existence of the biphasic dose response or theArndt-Schulz curve. This review will cover the mechanismsof action of LLLT at a cellular and at a tissular level and willsummarize the various light sources and principles ofdosimetry that are employed in clinical practice. The rangeof diseases, injuries, and conditions that can be benefited byLLLT will be summarized with an emphasis on those thathave reported randomized controlled clinical trials. Seriouslife-threatening diseases such as stroke, heart attack, spinalcord injury, and traumatic brain injury may soon beamenable to LLLT therapy.

Keywords—Low level laser therapy, Photobiomodulation,

Mitochondria, Tissue optics, Wound healing, Hair regrowth,

Laser acupuncture.

INTRODUCTION AND HISTORY

Low level laser therapy (LLLT), also known asphotobiomodulation, came into being in its modernform soon after the invention of the ruby laser in 1960,and the helium–neon (HeNe) laser in 1961. In 1967,Endre Mester, working at Semmelweis University inBudapest, Hungary, noticed that applying laser light tothe backs of shaven mice could induce the shaved hairto grow back more quickly than in unshaved mice.72

He also demonstrated that the HeNe laser couldstimulate wound healing in mice.70 Mester soonapplied his findings to human patients, using lasers totreat patients with nonhealing skin ulcers.69,71 LLLThas now developed into a therapeutic procedure that isused in three main ways: to reduce inflammation,edema, and chronic joint disorders9,18,40; to promotehealing of wounds, deeper tissues, and nerves24,87; andto treat neurological disorders and pain.17

LLLT involves exposing cells or tissue to low levelsof red and near infrared (NIR) light, and is referred toas ‘‘low level’’ because of its use of light at energydensities that are low compared to other forms of lasertherapy that are used for ablation, cutting, and ther-mally coagulating tissue. LLLT is also known as ‘‘coldlaser’’ therapy as the power densities used are lowerthan those needed to produce heating of tissue. It wasoriginally believed that LLLT or photobiomodulationrequired the use of coherent laser light, but more re-cently, light emitting diodes (LEDs) have been pro-posed as a cheaper alternative. A great deal of debateremains over whether the two light sources differ intheir clinical effects.

Although LLLT is now used to treat a wide varietyof ailments, it remains controversial as a therapy fortwo principle reasons: first, its underlying biochemicalmechanisms remain poorly understood, so its use islargely empirical. Second, a large number of parame-ters such as the wavelength, fluence, power density,pulse structure, and timing of the applied light must bechosen for each treatment. A less than optimal choiceof parameters can result in reduced effectiveness of thetreatment, or even a negative therapeutic outcome. Asa result, many of the published results on LLLT in-clude negative results simply because of an inappro-priate choice of light source and dosage. This choice is

Address correspondence to Michael R. Hamblin, Wellman Cen-

ter for Photomedicine, Massachusetts General Hospital, Boston,

MA, USA. Electronic mail: [email protected]

Annals of Biomedical Engineering, Vol. 40, No. 2, February 2012 (� 2011) pp. 516–533

DOI: 10.1007/s10439-011-0454-7

0090-6964/12/0200-0516/0 � 2011 Biomedical Engineering Society

516

particularly important as there is an optimal dose oflight for any particular application, and doses higheror lower than this optimal value may have no thera-peutic effect. In fact, LLLT is characterized by a bi-phasic dose response: lower doses of light are oftenmore beneficial than high doses.38,85,105,108

LASER–TISSUE INTERACTIONS

Light and Laser

Light is part of the spectrum of electromagneticradiation (ER), which ranges from radio waves togamma rays. ER has a dual nature as both particlesand waves. As a wave which is crystallized in Max-well’s Equations, light has amplitude, which is thebrightness of the light, wavelength, which determinesthe color of the light, and an angle at which it isvibrating, called polarization. The wavelength (k) oflight is defined as the length of a full oscillation of thewave, such as shown in Fig. 1a. In terms of the modernquantum theory, ER consists of particles called pho-tons, which are packets (‘‘quanta’’) of energy whichmove at the speed of light. In this particle view of light,the brightness of the light is the number of photons,the color of the light is the energy contained in eachphoton, and four numbers (X, Y, Z and T) are thepolarization, where X, Y, Z are the directions and T isthe time.

A laser is a device that emits light through a processof optical amplification based on the stimulated emis-sion of photons. The term ‘‘laser’’ originated as anacronym for light amplification by stimulated emissionof radiation.65 The emitted laser light is notable for itshigh degree of spatial and temporal coherence.

Spatial coherence typically is expressed through theoutput being a narrow beam which is diffraction-lim-ited, often a so-called ‘‘pencil beam.’’ Laser can belaunched into a beam of very low divergence to con-centrate their power at a large distance. Temporal (orlongitudinal) coherence implies a polarized wave at asingle frequency whose phase is correlated over a rel-atively large distance (the coherence length) along thebeam. Lasers are employed in applications where lightof the required spatial or temporal coherence could notbe produced using simpler technologies.

Quite often, the laser beam is described as though ithad a uniform irradiance (the power of the laser di-vided by the spot size). Most often, the laser beamassumes a Gaussian shape (that of a normal distribu-tion), as shown in Fig. 1b.118 There is a peak irradi-ance, and the irradiance decreases with distance fromthe center of the beam. This may be important in sit-uations in which there are large variations in power. Aspower is increased, the irradiance in the tail of theGaussian profile increases, and the distance of thecritical threshold from the center of the beam becomeslarger. For this type of profile, the spot size is often

FIGURE 1. Basic physics of LLLT. (a) Light as an electromagnetic wave. (b) Gaussian laser beam profile. (c) Snellius’ law ofreflection. (d) Optical window because of minimized absorption and scattering of light by the most important tissue chromophoresin the near-infrared spectral region.

The Nuts and Bolts of Low-level Laser (Light) Therapy 517

referred to as the 1/e2 radius, or diameter, of the beam;at this radial distance from the center of the beam,irradiation is lower by a factor of 0.135 (1/e2) relativeto the peak irradiance. About 85% of the power of thelaser beam is present within the 1/e2 diameter.

Light Emitting Diodes (LED)

A light-emitting diode (LED) is a semiconductorlight source. Introduced as a practical electronic com-ponent in 1962 early LEDs emitted low-intensity redlight, but modern versions are available across thevisible, ultraviolet and infrared wavelengths, with veryhigh brightness. When a light-emitting diode is for-ward biased (switched on), electrons are able torecombine with electron holes within the device,releasing energy in the form of photons. This effect iscalled electroluminescence and the color of the light(corresponding to the energy of the photon) is deter-mined by the energy gap of the semiconductor. AnLED is often small in area (less than 1 mm2), andintegrated optical components may be used to shape itsradiation pattern.78

Optical Properties of Tissue

When the light strikes the biological tissue, part of itis absorbed, part is reflected or scattered, and part isfurther transmitted.

Some of the light is reflected, this phenomenon isproduced by a change in the air and tissue refractiveindex. The reflection obeys the law of Snellius(Fig. 1c), which states:

sin h1sin h2

¼ n2n1

where h1 is the angle between the light and the surfacenormal in the air, h2 is the angle between the ray andthe surface normal in the tissue, n1 is the index ofrefraction of air, n2 is the index of refraction of tissue.

Most of the light is absorbed by the tissue. Theenergy states of molecules are quantized; therefore,absorption of a photon takes place only when its en-ergy corresponds to the energy difference between suchquantized states. The phenomenon of absorption isresponsible for the desired effects on the tissue. Thecoefficient la (cm

21) characterizes the absorption. Theinverse, la, defines the penetration depth (mean freepath) into the absorbing medium.

The scattering behavior of biological tissue is alsoimportant because it determines the volume distribu-tion of light intensity in the tissue. This is the primarystep for tissue interaction, which is followed byabsorption. Scattering of a photon is accompanied bya change in the propagation direction without loss of

energy. The scattering, similar to absorption, is ex-pressed by the scattering coefficient ls (cm21). Theinverse parameter, 1/ls (cm), is the mean free pathlength until a next scattering event occurs.

Scattering is not isotropic. Forward scattering ispredominant in biological tissue. This characteristic isdescribed by the anisotropy factor g.g can have abso-lute values from 0 to 1, from isotropic scattering(g = 0) to forward scattering (g = 1). In tissue, g canvary from 0.8 to 0.99. Taking into account the g value, areduced scattering coefficient, l0s (cm

21), is defined as:

l0s ¼ ls 1� gð Þ

The sum of ls and la is called the total attenuationcoefficient lt (cm

21):

lt ¼ ls þ la

Light Distribution in Laser-irradiated Tissue

Most of the recent advances in describing thetransfer of light energy in tissue are based upontransport theory.13 According to transport theory, theradiance L(r, s) of light at position r traveling in thedirection of unit vector s is decreased by absorptionand scattering but it is increased by light that is scat-tered from s¢ direction into direction s. Radiance is aradiometric measure that describes the amount of lightthat passes through or is emitted from a particulararea, and falls within a given solid angle in a specifieddirection. Then, the transport equation which de-scribes the light interaction is:

s �rL r; sð Þ ¼� laþlsð ÞL r; sð Þþls

Z

4p

p s; s0ð ÞL r; s0ð Þdx0

where dx¢ is the differential solid angle in the directions¢, and p(s, s¢) is the phase function.

Calculations of light distribution based on thetransport equation require ls, la, and p. To solvetransport equation exactly is often difficult; therefore,several approximations have been made regarding therepresentation of the radiance and phase function. Theapproximate solutions of light distribution in tissue aredependent upon the type of light irradiation (diffuse orcollimated) and the optical boundary conditions(matched or unmatched indexes of refraction).16

CELLULAR AND TISSULAR

MECHANISMS OF LLLT

The precise biochemical mechanism underlyingthe therapeutic effects of LLLT are not yet well-established. From observation, it appears that LLLT

CHUNG et al.518

has a wide range of effects at the molecular, cellular,and tissular levels. In addition, its specific modes ofaction may vary among different applications. Withinthe cell, there is strong evidence to suggest that LLLTacts on the mitochondria27 to increase adenosine tri-phosphate (ATP) production,43 modulation of reactiveoxygen species (ROS), and the induction of transcrip-tion factors.15 Several transcription factors are regu-lated by changes in cellular redox state. Among themredox factor-1 (Ref-1) dependent activator protein-1(AP-1) (a heterodimer of c-Fos and c-Jun), nuclearfactor kappa B (NF-jB), p53, activating transcriptionfactor/cAMP-response element–binding protein (ATF/CREB), hypoxia-inducible factor (HIF)-1, and HIF-like factor.15 These transcription factors then causeprotein synthesis that triggers further effects down-stream, such as increased cell proliferation andmigration, modulation in the levels of cytokines,growth factors and inflammatory mediators, andincreased tissue oxygenation.45 Figure 2 shows theproposed cellular and molecular mechanisms of LLLT.

Immune cells, in particular, appear to be stronglyaffected by LLLT. Mast cells, which play a crucial rolein the movement of leukocytes, are of considerableimportance in inflammation. Specific wavelengths oflight are able to trigger mast cell degranulation,22

which results in the release of the pro-inflammatorycytokine TNF-a from the cells.115 This leads toincreased infiltration of the tissues by leukocytes.LLLT also enhances the proliferation, maturation, andmotility of fibroblasts, and increases the production ofbasic fibroblast growth factor.31,67 Lymphocytesbecome activated and proliferate more rapidly, andepithelial cells become more motile, allowing woundsites to close more quickly. The ability of macrophagesto act as phagocytes is also enhanced under theapplication of LLLT.

At the most basic level, LLLT acts by inducing aphotochemical reaction in the cell, a process referred toas biostimulation or photobiomodulation. When aphoton of light is absorbed by a chromophore in thetreated cells, an electron in the chromophore canbecome excited and jump from a low-energy orbit to ahigher-energy orbit.42,108 This stored energy can thenbe used by the system to perform various cellular tasks.There are several pieces of evidence that point to achromophore within mitochondria being the initialtarget of LLLT. Radiation of tissue with light causesan increase in mitochondrial products such as ATP,NADH, protein, and RNA,83 as well as a reciprocalaugmentation in oxygen consumption, and variousin vitro experiments have confirmed that cellular res-piration is upregulated when mitochondria are exposedto an HeNe laser or other forms of illumination.

The relevant chromophore can be identified bymatching the action spectra for the biological responseto light in the NIR range to the absorption spectra ofthe four membrane-bound complexes identified inmitochondria.42 This procedure indicates that complexIV, also known as cytochrome c oxidase (CCO), is thecrucial chromophore in the cellular response toLLLT.44 CCO is a large transmembrane proteincomplex, consisting of two copper centers and twoheme–iron centers, which is a component of therespiratory electron transport chain.10 The electrontransport chain passes high-energy electrons fromelectron carriers through a series of transmembranecomplexes (including CCO) to the final electronacceptor, generating a proton gradient that is used toproduce ATP. Thus, the application of light directlyinfluences ATP production by affecting one of thetransmembrane complexes in the chain: in particular,LLLT results in increased ATP production and elec-tron transport.47,84

FIGURE 2. Cellular mechanisms of LLLT. Schematic diagram showing the absorption of red or near infrared (NIR) light by specificcellular chromophores or photoacceptors localized in the mitochondrial. During this process in mitochondria respiration chainATP production will increase, and reactive oxygen species (ROS) are generated; nitric oxide is released or generated. Thesecytosolic responses may in turn induce transcriptional changes via activation of transcription factors (e.g., NF-jB and AP1).


The precise manner in which light affects CCO isnot yet known. The observation that NO is releasedfrom cells during LLLT has led to speculation thatCCO and NO release are linked by two possiblepathways (Fig. 3). It is possible that LLLT may causephotodissociation of NO from CCO.46,52 Cellular res-piration is downregulated by the production of NO bymitochondrial NO synthase (mtNOS, a NOS isoformspecific to mitochondria), that binds to CCO andinhibits it. The NO displaces oxygen from CCO,inhibiting cellular respiration and thus decreasing theproduction of ATP.5 By dissociating NO from CCO,LLLT prevents this process from taking place and re-sults in increased ATP production. An alternative orparallel mechanism to explain the biological activity ofred or NIR light to release NO from cells or tissue isthe following.61,127 A new explanation has been re-cently proposed for how light increases NO bioavail-ability.88 CCO can act as a nitrite reductase enzyme (aone electron reduction of nitrite gives NO) particularlywhen the oxygen partial pressure is low.6 Ball et al.showed 590 ± 14 nm LED light stimulated CCO/NOsynthesis at physiological nitrite concentrations at hy-poxia condition.6 The following reaction may takeplace:

NO�2 + 2Hþ + e� CCOð Þ ! NO + H2O

The influence of LLLT on the electron transportchain extends far beyond simply increasing the levels ofATP produced by a cell. Oxygen acts as the finalelectron acceptor in the electron transport chain and is,in the process, converted to water. Part of the oxygenthat is metabolized produces reactive oxygen species(ROS) as a natural by-product. ROS are chemicallyactive molecules that play an important role in cellsignaling, regulation of cell cycle progression, enzymeactivation, and nucleic acid and protein synthesis.Because LLLT promotes the metabolism of oxygen, italso acts to increase ROS production. In turn, ROS

activates transcription factors, which leads to theupregulation of various stimulatory and protectivegenes. These genes are most likely related to cellularproliferation,76 migration,32 and the production ofcytokines and growth factors, which have all beenshown to be stimulated by low-level light.125,128

The processes described above are almost certainlyonly part of the story needed to explain all the effectsof LLLT. Among its many effects, LLLT has beenshown to cause vasodilation by triggering the relaxa-tion of smooth muscle associated with endothelium,which is highly relevant to the treatment of jointinflammation. This vasodilation increases the avail-ability of oxygen to treated cells, and also allows forgreater traffic of immune cells into tissue. These twoeffects contribute to accelerated healing. NO is a po-tent vasodilator via its effect on cyclic guanine mono-phosphate production, and it has been hypothesizedthat LLLT may cause photodissociation of NO, notonly from CCO, but from intracellular stores such asnitrosylated forms of both hemoglobin and myoglobin,leading to vasodilation.61

LIGHT SOURCES AND DOSIMETRY

Currently, one of the biggest sources of debate inthe choice of light sources for LLLT is the choicebetween lasers and LEDs. LEDs have become wide-spread in LLLT devices. Most initial work in LLLTused the HeNe laser, which emits light of wavelength632.8-nm, while nowadays semi-conductor diode laserssuch as gallium arsenide (GaAs) lasers have increasedin popularity. It was originally believed that thecoherence of laser light was crucial to achieve thetherapeutic effects of LLLT, but recently this notionhas been challenged by the use of LEDs, which emitnon-coherent light over a wider range of wavelengthsthan lasers. It has yet to be determined whether there isa real difference between laser and LED, and if it in-deed exists, whether the difference results from thecoherence or the monochromaticity of laser light, asopposed to the non-coherence and wider bandwidth ofLED light.

A future development in LLLT devices will be theuse of organic light emitting diodes (OLEDs). Theseare LEDs in which the emissive electroluminescentlayer is a film of organic compounds which emit lightin response to an electric current.122 They operate in asimilar manner to traditional semiconductor materialwhereby electrons and the holes recombine forming anexciton. The decay of this excited state results in arelaxation of the energy levels of the electron, accom-panied by emission of radiation whose frequency is inthe visible region.

FIGURE 3. Two possible sources of nitric oxide (NO) releasefrom cytochrome c oxidase (CCO). Path1 shows CCO can actas a nitrite reductase enzyme: Path 2 shows possible photo-dissociation of NO from CCO.

CHUNG et al.520

The wavelengths of light used for LLLT fall into an‘‘optical window’’ at red and NIR wavelengths(600–1070 nm) (Fig. 1d). Effective tissue penetration ismaximized in this range, as the principal tissue chro-mophores (hemoglobin and melanin) have highabsorption bands at wavelengths shorter than 600 nm.Wavelengths in the range 600–700 nm are used to treatsuperficial tissue, and longer wavelengths in the range780–950 nm, which penetrate further, are used to treatdeeper-seated tissues. Wavelengths in the range700–770 nm have been found to have limited bio-chemical activity and are therefore not used. There arealso reports of the effectiveness of wavelengths outsidethe range of absorption of NIR light by CCO. Thesewavelengths are in the near IR,36 the mid-IR regionincluding carbon dioxide laser (10.6 lm)126 and alsoinclude broad band IR sources in the 10–50 lmrange.39 The chromophore in these situations is almostcertainly water, possible present in biological mem-branes in some nanostructured form, that is differentfrom bulk water allowing biological effects withoutgross heating of the tissue.94,95 It is at present not clearat which wavelength CCO absorption ceases and waterabsorption commences to be important.

Dosimetry

The power of light used typically lies in the range1–1000 mW, and varies widely depending on the par-ticular application. There is evidence to suggest thatthe effectiveness of the treatment varies greatly on boththe energy and power density used: there appears to beupper and lower thresholds for both parametersbetween which LLLT is effective. Outside thesethresholds, the light is either too weak to have anyeffect, or so strong that its harmful effects outweigh itsbenefits.

Response to LLLT changes with wavelength, irra-diance, time, pulses and maybe even coherence andpolarization, the treatment should cover an adequatearea of the pathology, and then there is a matter ofhow long to irradiate for.

Dosimetry is best described in two parts,

1. Irradiation parameters (‘‘the medicine’’) seeTable 1

2. Time/energy/fluence delivered (‘‘the dose’’) seeTable 2

Dosimetry in LLLT is highly complicated. The largeof number of interrelated parameters (see Table 1) hasmeant that there has not yet been a comprehensivestudy reported that examined the effect of varying allthe individual parameters one by one, and it must bepointed out that it is unlikely there will ever be such astudy carried out. This considerable level of complexity

has meant that the choice of parameters has oftendepended on the experimenter’s or the practitioner’spersonal preference or experience rather than on aconsensus statement by an authoritative body. Never-theless, the World Association of Laser Therapy(WALT) has attempted to provide dosage guidelines(http://www.walt.nu/dosage-recommendations.html).

Biphasic Dose Response

It is well established that if the light applied is not ofsufficient irradiance or the irradiation time is too shortthen there is no response. If the irradiance is too highor irradiation time is too long then the response maybe inhibited.11,33,53 Somewhere in between is the opti-mal combination of irradiance and time for stimula-tion. This dose response often likened to the biphasicresponse known as ‘‘Arndt-Schulz Law’’68,105,116 whichdates back to 1887 when Hugo Schulz published apaper showing that various poisons at low doses have astimulatory effect on yeast metabolism when given inlow doses116 then later with Rudolph Arndt theydeveloped their principle claiming that a weak stimulislightly accelerates activity, stronger stimuli raise itfurther, but a peak is reached and that a strongerstimulus will suppress activity.63 A more credible termbetter known in other areas of science and medicine isHueppe’s Rule. In 1896 Ferdinand Hueppe built onHugo Schulz’s initial findings by showing low dosestimulation/high dose inhibition of bacteria by toxicagents. This is better known today by the term ‘‘hor-mesis’’ first coined in 1941 and first referenced in1943,63 which has subsequently been discussed multipletimes in LLLT research.34,38

A graphical depiction of how the response to LLLTvaries as a function of the combination of irradiance(medicine) and time (dose) is shown in Fig. 4, as a 3Dmodel to represent the possible biphasic responses tothe various combinations of irradiance and time orfluence.

SURVEY OF CONDITIONS TREATED WITH

LLLT

LLLT is used for three main purposes: to promotewound healing, tissue repair, and the prevention oftissue death; to relieve inflammation and edema be-cause of injuries or chronic diseases; and as ananalgesic and a treatment for other neurologicalproblems. These applications appear in a wide range ofclinical settings, ranging from dentistry, to dermatol-ogy, to rheumatology and physiotherapy. Table 3summarizes some of the published studies in animalmodels of diseases and conditions treated with LLLT.


http://www.walt.nu/dosage-recommendations.html

Table 4 summarizes some of the published clinicaltrials of LLLT.

Wound healing was one of the first applications ofLLLT, when HeNe lasers were used by Mester et al. totreat skin ulcers.69–71 LLLT is believed to affect allthree phases of wound healing111: the inflammatoryphase, in which immune cells migrate to the wound,the proliferative phase, which results in increasedproduction of fibroblasts and macrophages, and theremodeling phase, in which collagen deposition occursat the wound site and the extra-cellular matrix is re-built.

LLLT is believed to promote wound healing byinducing the local release of cytokines, chemokines, andother biological response modifiers that reduce the timerequired for wound closure, and increase the meanbreaking strength of the wound.8,32,73 Proponents

of LLLT speculate that this result is achieved byincreasing the production and activity of fibroblastsand macrophages, improving the mobility of leuko-cytes, promoting collagen formation, and inducing neo-vascularization.31,60,67,80,90,104

However, there is a lack of convincing clinicalstudies that either prove or disprove the efficacy ofLLLT in wound healing. The results that are currentlyavailable are conflicting and do not lead to any clearconclusions. For example, Abergel et al. found that the632.8 nm HeNe laser did not have any effect on thecellular proliferation of fibroblasts, while the 904 nmGaAs laser actually lowered fibroblasts proliferation.1

In contrast, other studies noted an increase in prolif-eration of human fibroblasts exposed to 904 nm GaAslasers,85 rat myofibroblasts exposed to 670 nm GaAslasers,67 and gingival fibroblasts exposed to diode la-

TABLE 1. Irradiation parameters (the medicine).

Irradiation parameter Unit of measurement

Wavelength nm Light is packets of electromagnetic energy that also have

a wave-like property. Wavelength is measure in

nanometers (nm) and is visible in the 400–700 nm range.

Wavelength determines which chromophores will absorb

the light. LLLT devices are typically in the range

600–1000 nm as there are many peaks for

cytochrome c oxidase in that range and clinical trials

have been successful with them. There is some contention

as wavelengths above 900 nm are probably more absorbed by

water than CCO and excitation seems less likely

so it introduces the possibility that maybe IR absorption

by water in the phospholipid bilayers causes

molecular vibration and rotation) sufficient to perturb

ion channels alter cellular function

Irradiance W/cm2 Often called Power Density (technically incorrect) and

is calculated as Power (W)/Area (cm2) = Irradiance

Pulse structure Peak power (W)

Pulse freq (Hz)

Pulse width (s)

Duty cycle (%)

If the beam is pulsed then the Power reported should

be the Average Power and calculated as follows:

Peak Power (W) 9 pulse width (s) 9 pulse

frequency (Hz) = Average Power (W). Pulses can be

significantly more effective than CW30 however,

the optimal frequencies and pulse duration

(or pulse intervals) remain to be determined

Coherence Coherence length depends

on spectral bandwidth

Coherent light produces laser speckle, which has

been postulated to play a role in the

photobiomodulation interaction with cells

and sub-cellular organelles. The dimensions

of speckle patterns coincide with the dimensions

of organelles such as mitochondria.

No definitive trials have been published to-date to

confirm or refute this claim

Polarization Linear polarized or

zcircular polarized

Polarized light may have different effects than otherwise

identical non-polarized light (or even 90� rotated

polarized light). However, it is known that polarized light is

rapidly scrambled in highly scattering media such as tissue

(probably in the first few hundred lm). However, for the

birefringent protein structures such as collagen the transmission

of plane polarized light will depend on orientation. Several

authors have demonstrated effects on wound healing

and burns with polarized light19,86,91

CHUNG et al.522

sers (670, 692, 780, and 786 nm).3 In vivo studies inboth animal and human models show similar discrep-ancies. A study by Kana et al. claimed that treatmentof open wounds in rats with HeNe and argon lasersresulted in faster wound closure.41 Bisht et al. found asimilar increase in granulation tissue and collagenexpression in rats using the same treatment as Kana.7

However, Anneroth et al. failed to observe any bene-ficial effects after laser treatment in a comparable ratmodel.4 In human studies, Schindl et al. reported thatapplication of a HeNe laser was beneficial in promot-ing wound healing in 3 patients,99 whereas Lundeberget al. found no statistically significant differencebetween leg ulcer patients treated with an HeNe laserand those treated with a placebo.62

The scarcity of well-designed clinical trials makes itdifficult to assess the impact of LLLT on wound heal-ing. Our task is further complicated by the difficulty incomparing studies, because of the large number of

factors involved. In addition to the multiple parametersthat must be adjusted to apply LLLT, such as thewavelength and power of the light, the effectiveness ofthe treatment also depends on many factors such as thelocation and nature of the wound, and the physiologicstate of the patient. For example, impaired woundhealing is one of the major chronic complications ofdiabetes,25,89 and is thought to result from variousfactors, including decreased collagen production andimpaired functionality of fibroblasts, leukocytes, andendothelial cells.25,106 It has therefore been hypothe-sized that LLLT could have beneficial effects in stim-ulating wound healing in diabetic patients.98,100,124

Thus, in order to obtain a convincing verdict on theimpact of LLLT on wound healing, we will requireseveral large, randomized, placebo controlled, anddouble blind trials that compare the effects of LLLT onwounds that are as similar as possible. A greaterunderstanding of the cellular and biochemical mecha-nisms of LLLT would also be useful in assessing thesestudies, as it would enable us to pinpoint exactly whatcriteria to use in determining the effectiveness of thetherapy.

There appears to be more firm evidence to supportthe success of LLLT in alleviating pain and treatingchronic joint disorders, than in healing wounds. Areview of 16 randomized clinical trials including a totalof 820 patients found that LLLT reduces acute neckpain immediately after treatment, and up to 22 weeksafter completion of treatment in patients with chronicneck pain.17 LLLT has also been shown to relieve painbecause of cervical dentinal hypersensitivity,93 or fromperiodontal pain during orthodontic tooth move-ment.114 A study of 88 randomized controlled trialsindicated that LLLT can significantly reduce pain and

TABLE 2. Irradiation time/energy/fluence (‘‘dose’’).

Energy (Joules) J Calculated as: Power (W) 9 time (s) = Energy (Joules)

This mixes medicine and dose into a single expression

and ignores irradiance. Using Joules as an expression

of dose is potentially unreliable as it assumes assumes

a reciprocity relationship between irradiance and time37,38

Energy density J/cm2 Common expression of LLLT ‘‘dose’’ is Energy Density.

This expression of dose again mixes medicine and

dose into a single expression and is potentially

unreliable as described above

Irradiation time Seconds Given the possible lack of reciprocity between irradiance

and time37,38 it is our view that the safest way to

record and prescribe LLLT is to define the irradiation

parameters (‘‘the medicine’’) see Table 1, and then

define the irradiation time (as the ‘‘dose’’).

Treatment interval Hours, days

or weeks

The effects of different treatment intervals is underexplored

at this time though there is sufficient evidence to suggest

that this is an important parameter. With the exception

of some early treatment of acute injuries LLLT generally

requires at least two treatments a week for several

weeks to achieve clinical significance

FIGURE 4. Biphasic dose response in LLLT. Three dimen-sional plot illustrating effects of varying irradiation timeequivalent to fluence or irradiance on the biological responseresulting in stimulation or inhibition.


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ct

Eff

ect

Refe

rences

Myocard

ialin

farc

tion

804

nm

;38

mW

;4.5

±0.1

mW

/cm

2;

0.2

7J/c

m2;

CW

,1.5

93.5

mm

Rats

Reduced

the

loss

of

myocard

ialtissue

2

Myocard

ialin

farc

tion

635

nm

,5

mW

,6

mW

/cm

2;

0.8

J–1

J/c

m2;

CW

;0.8

cm

2;

150

s

Rats

The

expre

ssio

nof

multip

lecyto

kines

was

regula

ted

inth

eacute

phase

aft

er

LLLI

123

Myocard

ialin

farc

tion

804

nm

;400

mW

8m

W/c

m2;

0.9

6J/c

m2;

CW

;2

cm

2;

120

s

Rats

and

dogs

VE

GF

and

iNO

Sexpre

ssio

nm

ark

edly

upre

gula

ted;

angio

genesis

and

card

iopro

tection

enhanced

113

Str

oke

808-n

m;

.5m

W/c

m2;

0.9

J/c

m2

at

cort

ical

surf

ace;

CW

;300

lspuls

eat

1kH

z;

2.2

ms

at

100

Hz

Rabbits

The

results

show

ed

that

laser

adm

inis

tere

d6

hfo

llow

ing

em

bolic

str

okes

inra

bbits

inP

mode

can

result

in

sig

nifi

cant

clin

icalim

pro

vem

ent

and

should

be

consid

ere

d

for

clin

icaldevelo

pm

ent

54

Str

oke

808-n

m;

7.5

mW

/cm

2;

0.9

J/c

m2;

3.6

J/c

m2

at

cort

icalsurf

ace;

CW

and

70

Hz,

4-m

mdia

mete

r

Rats

LLLT

issued

24

haft

er

acute

str

oke

may

pro

vid

ea

sig

nifi

cant

funct

ionalbenefit

with

an

underlyin

gm

ech

anis

mpossib

ly

bein

gin

ductio

nof

neuro

genesis

81

TB

I808

±10

nm

;70

mW

;2230

mW

/cm

2;

268

J/c

m2

at

the

scalp

;10

mW

/cm

2;

1.2

J/c

m2

at

cort

icalsurf

ace;

CW

;2

mm

2

Rats

Sin

gle

and

multip

leapplic

ations

of

transcr

ania

lla

ser

thera

py

with

808-n

mC

Wla

ser

light

appears

tobe

safe

in

Spra

gue–D

aw

ley

rats

1year

aft

er

treatm

ent

64

TB

I808-n

m;

200

mW

;10

and

20

mW

/cm

2;

1.2

–2.4

J/c

m2

at

cort

icalsurf

ace

;

4h

post-

traum

a

Mic

eLLLT

giv

en

4h

follo

win

gT

BI

pro

vid

es

asig

nifi

cant

long-t

erm

funct

ionalneuro

logic

albenefit

82

TB

I660

nm

or

780

nm

,40

mW

;3

J/c

m2

or

5J/c

m2;

CW

;0.0

42

cm

2(3

sand

5s)

irra

dia

ted

twic

e(3

hin

terv

al)

Rats

LLLT

aff

ecte

dT

NF

-alp

ha,

IL-1

beta

,and

IL-6

levels

in

the

bra

inand

incircula

tion

inth

efirs

t24

hfo

llow

ing

cry

ogenic

bra

inin

jury

77

Spin

alcord

inju

ry830

nm

;100

mW

;30

mW

/cm

2;

250

J/c

m2;

CW

,0.0

28

cm

2R

ats

LLLT

initia

ted

apositiv

ebone-t

issu

ere

sponse,

mayb

e

thro

ugh

stim

ula

tion

of

oste

obla

sts

.H

ow

ever,

the

evoked

tissue

response

did

not

aff

ect

bio

mechanic

alor

densi

tom

etr

icm

odifi

cations

66

Spin

alcord

inju

ry810

nm

;1589

J/c

m2;

0.3

cm

2,

2997

s;

daily

for

14

days

Rats

Pro

mote

saxonalre

genera

tion

and

funct

ionalre

covery

inacute

SC

I

120

Art

hritis

632.8

nm

;5

mW

;8

J/c

m2,

CW

;2-m

m

dia

mete

r;50

s;

daily

for

5days

Rats

Laser

reduced

the

inte

nsity

of

the

inflam

mato

rypro

cess

inth

eart

hritis

modelin

duced

by

hydro

xyapatite

and

calc

ium

pyro

phosphate

cry

sta

ls

92

Art

hritis

632.8

-nm

;3.1

mW

/cm

2C

W,

1cm

dia

mete

r;

15

min

;3

tim

es

aw

eek

for

8w

eeks

Rats

He–N

ela

ser

treatm

ent

enhanced

the

bio

synth

esis

of

art

hritic

cart

ilage

59

Art

hritis

810-n

m;

5or

50

mW

/cm

2;

3or

30

J/c

m2;

CW

;4.5

-cm

dia

mete

r;1,

10

or

100

min

;

daily

for

5days

Rats

Hig

hly

effective

intr

eating

inflam

mato

ryart

hritis.

Illu

min

ation

tim

em

ay

be

an

import

ant

para

mete

r

11

Wound

healin

g632.8

-nm

laser;

635,

670,

720

or

810-n

m

(±15-n

mfiltere

dla

mp);

0.5

9,

0.7

9,

and

0.8

6m

W/c

m2;

1,

2,

10

and

50

J/c

m2;

CW

;3-c

mdia

mete

r

Mic

e635-n

mlig

ht

had

am

axim

um

positiv

eeff

ect

at

2J/c

m2.

820

nm

was

found

tobe

the

best

wavele

ngth

.N

odiffe

rence

betw

een

non-c

ohere

nt

635

±15-n

mlig

ht

from

ala

mp

and

cohere

nt

633-n

mlig

ht

from

aH

e/N

ela

ser.

LLLT

incre

ased

the

num

ber

ofa-

sm

ooth

musc

leactin

(SM

A)-

positiv

ecells

at

the

wound

edge

20

CHUNG et al.524

improve health in chronic joint disorders such asosteoarthritis, patellofemoral pain syndrome, andmechanical spine disorders.9 However, the authors ofthe study urge caution in interpreting the results be-cause of the wide range of patients, treatments, andtrial designs involved.

LLLT for Serious Diseases

LLLT is also being considered as a viable treatmentfor serious neurological conditions such as traumaticbrain injury (TBI), stroke, spinal cord injury, anddegenerative central nervous system disease.

Although traumatic brain injury is a severe healthconcern, the search for better therapies in recent yearshas not been successful. This has led to interest in moreradical alternatives to existing procedures, such asLLLT. LLLT is hypothesized to be beneficial in thetreatment of TBI. In addition to its effects in increasingmitochondrial activity and activating transcriptionfactors, LLLT could benefit TBI patients by inhibitingapoptosis, stimulating angiogenesis, and increasingneurogenesis.29 Experiments carried out with twomouse models indicated that LLLT could reduce thebrain damaged area at 3 days after treatment, andtreatment with a 665 nm and 810 nm laser could leadto a statistically significant difference in the Neuro-logical Severity Score (NSS) of mice that had beeninjured by a weight being dropped onto the exposedskull.121

Transcranial LLLT has also been shown to have anoticeable effect on acute human stroke patients, withsignificantly greater improvement being seen inpatients 5 days after LLLT treatment compared tosham treatment (p< 0.05, National Institutes ofHealth Stroke Severity Scale.)51 This difference per-sisted up to 90 days after the stroke, with 70% ofpatients treated with LLLT having a successful out-come compared to 51% of control patients. Theimprovement in functional outcome because ofapplying transcranial LLLT after a stroke has beenconfirmed by studies in rat and rabbit models.54,81

Further experiments have tried to pinpoint themechanism underlying these results. As expected,increased mitochondrial activity has been found inbrain cells irradiated with LLLT,54 indicating that theincreased respiration and ATP production that usuallyfollow laser therapy are at least partly responsible forthe improvement shown in stroke patients. However,there is still the possibility that LLLT has other effectsspecific to the brain. Several groups have suggestedthat the improvements in patient outcomes are becauseof the promotion of neurogenesis, and migration ofneurons.81 This hypothesis is supported by the fact thatthe benefits of LLLT following a stroke may take 2–

TA

BL

E3.

co

nti

nu

ed

.

Dis

ease

Para

mete

rsab

Subje

ct

Eff

ect

Refe

rences

Fam

ilialam

yotr

opic

late

ral

scle

rosis

(FA

LS

)

810

nm

;140-m

W;

12

J/c

m2;

CW

;1.4

cm

2M

ice

Rota

rod

test

show

ed

sig

nifi

cant

impro

vem

ent

in

the

light

gro

up

inth

eearly

sta

ge

of

the

dis

ease

.

Imm

unohis

tochem

icalexpre

ssio

nof

the

astr

ocy

tem

ark

er,

glia

lfibrila

ryacid

icpro

tein

,w

as

sig

nifi

cantly

reduced

in

the

cerv

icaland

lum

bar

enla

rgem

ents

of

the

spin

al

cord

as

are

sult

of

LLLT

75

aT

he

light

sourc

es

were

all

lasers

unle

ss

LE

Dis

specifi

cally

mentioned.

bT

he

laser

para

mete

rsare

giv

en

inth

efo

llow

ing

ord

er:

wavele

ngth

(nm

);pow

er

(mW

),pow

er

densi

ty(m

W/c

m2);

energ

y(J

);energ

ydensity

(J/c

m2);

mode

(CW

)or

puls

ed

(Hz)

;spot

siz

e

(cm

2);

illum

ination

tim

e(s

ec);

treatm

ent

repetit

ion.

Inm

any

cases,

the

para

mete

rsare

part

ially

unava

ilable

.


TA

BL

E4.

Clin

ical

stu

die

so

np

ati

en

tsw

ith

low

level

lig

ht

thera

py

for

dif

fere

nt

co

nd

itio

ns.

Dis

ease

Para

mete

rsab

Subje

ct

Eff

ect

Refe

rence

s

Myocard

ialin

farc

tion

632.8

-nm

,5

mW

;C

W;

15

min

;

6days

aw

eek

for

4w

eeks

on

chest

skin

39

patients

An

impro

vem

ent

of

funct

ionalcapacity

and

less

frequent

angin

asym

pto

ms

during

exerc

ise

tests

131

Str

oke

(NE

ST

-1)

808-n

m;

700

mW

/cm

2on

shaved

scalp

with

coolin

g;

1J/c

m2

at

cort

icalsurf

ace;

20

pre

dete

rmin

ed

locations

2m

ineach

120

patients

The

NE

ST

-1stu

dy

indic

ate

dth

at

infr

are

dla

ser

thera

py

has

show

n

initia

lsafe

tyand

effectiveness

for

the

treatm

ent

of

ischem

icstr

oke

inhum

ans

when

initia

ted

within

24

hof

str

oke

onset

51

Str

oke

(NE

ST

-2)

808-n

m;

700

mW

/cm

2on

shaved

scalp

with

coolin

g;

1J/c

m2

at

cort

ical

surf

ace;

20

pre

dete

rmin

ed

locations

2m

ineach

660

patients

TLT

within

24

hfr

om

str

oke

onset

dem

onstr

ate

d

safe

tybut

did

not

meet

form

alsta

tistical

sig

nifi

cance

for

effi

cacy.

How

ever,

all

pre

defined

analy

ses

show

ed

afa

vora

ble

trend,

consis

tent

with

the

pre

vio

us

clin

ical

tria

l(N

ES

T-1

).B

oth

stu

die

sin

dic

ate

that

mort

alit

yand

advers

eevent

rate

sw

ere

not

advers

ely

aff

ecte

dby

TLT

.A

definitiv

etr

ialw

ith

refined

baselin

eN

ationalIn

stitu

tes

of

Health

Str

oke

Sca

leexclu

sio

ncrite

ria

ispla

nned

130

Chro

nic

TB

I9

9635

and

52

9870-n

mLE

Dclu

ste

r;

12-1

5m

Wper

dio

de;

500

mW

;

22.2

mW

/cm

2;

13.3

J/c

m2

at

scalp

(estim

ate

d0.4

J/c

m2

tocort

ex);

2.1

¢¢dia

mete

r

2patients

Tra

nscr

ania

lLE

Dm

ay

impro

ve

cognitio

n

inchro

nic

TB

Ipatients

even

years

aft

er

inju

ry

79

Majo

rdepre

ssio

n

and

anxie

ty

810-n

m,

250

mW

/cm

2;

60

J/c

m2

on

scalp

;2.1

J/c

m2

at

cort

ical

surf

ace;

CW

;4

cm

2;

240

sat

each

of

2sites

on

fore

head

10

patients

Sig

nifi

cant

impro

vem

ent

inH

am

ilton

depre

ssio

nand

anxie

tyscale

sat

2w

eeks

96

Ora

lm

ucositis

830

nm

;150

mW

;re

peate

devery

48

h16

patients

Imm

edia

tepain

relie

fand

impro

ved

wound

healin

gre

solv

ed

functionalim

pairm

ent

that

was

obta

ined

inall

case

s

12

Ora

lm

ucositis

830

nm

;15

mW

;12

J/c

m2;

CW

;0.2

cm

2;

daily

for

5days

com

mencin

gat

sta

rt

of

radio

/chem

oth

era

py

12

patients

The

pro

phyla

ctic

use

of

the

treatm

ent

pro

posed

inth

isstu

dy

seem

ed

tore

duce

the

incid

ence

of

seve

reora

lm

uco

sitis

lesio

ns.

LLLT

was

eff

ectiv

ein

dela

yin

gth

eappeara

nce

of

seve

reora

lm

uco

sis

tis

58

Ora

lm

ucositis

660-n

m;

10-m

W;

2.5

J/c

m2,

CW

;

4m

m2;

daily

for

5days

75

patients

LLLT

thera

py

was

not

eff

ectiv

ein

reducin

gsevere

ora

lm

ucositi

s,

although

am

arg

inalbenefit

could

not

be

excl

uded.

Itre

duced

radia

tion

thera

py

inte

rruptions

inth

ese

head-a

nd-n

eck

cancer

patients

,w

hic

hm

ight

transla

tein

to

impro

ved

CR

Teffi

cacy

26

CHUNG et al.526

TA

BL

E4.

co

nti

nu

ed

.

Dis

ease

Para

mete

rsab

Subje

ct

Eff

ect

Refe

rence

s

Carp

altu

nnel

syndro

me

(CT

S)

830-n

m;

60

mW

;9.7

J/c

m2;

10

Hz,

50%

duty

cycle

,10-m

inper

day

for

5days

aw

eek

75

patients

Alle

via

tepain

and

sym

pto

ms,

impro

vefu

nctional

abili

tyand

finger

and

hand

str

ength

for

mild

and

modera

teC

TS

patients

14

Carp

altu

nnel

syndro

me

(CT

S)

632.8

-nm

;9–11

J/c

m2;

CW

;

5tim

es/w

eek

for

3w

eeks

80

patients

Eff

ectiv

ein

treatin

gC

TS

pare

sth

esia

and

num

bness

and

impro

ved

the

subje

cts

’pow

er

of

hand-g

rip

and

ele

ctr

ophysio

logic

alpara

mete

rs

102

Carp

altu

nnel

syndro

me

(CT

S)

830-n

m;

50

mW

;1.2

J/p

oin

t;C

W;

1m

mdia

mete

r.2

min

/poin

t;5

poin

tsacro

ss

the

media

nnerv

etr

ace;

5tim

es

per

week

for

3w

eeks

60

patients

LLLT

was

no

more

eff

ectiv

eth

an

pla

cebo

inC

TS

110

Late

ralepic

ondylit

is(L

E)

905

nm

;100

mW

;1

J/c

m2;

1000

Hz;

2m

in;

5days

per

week

for

3w

eeks

49

patients

No

advanta

ge

for

the

short

term

;sig

nifi

cant

impro

vem

ent

infu

nctionalpara

mete

rs

inth

elo

ng

term

23

Late

ralepic

ondylit

is(L

E)

904-n

m;

25

mW

,0.2

75

J/p

oin

t;2.4

J/c

m2;

puls

edura

tion

200

nsec;

5000

Hz;

4-m

mdia

mete

r11

s/p

oin

t;3

tim

es/w

eek

for

3w

eeks

39

patients

LLLT

inadditi

on

toexerc

ise

iseff

ective

in

relie

vin

gpain

,and

inim

pro

ving

the

grip

str

ength

and

subje

ctiv

era

ting

of

physic

al

funct

ion

of

patients

with

late

ralepic

ondylit

is

50

Late

ralepic

ondylit

is(L

E)

830

nm

;120

mW

;C

W;

5-m

mdia

mete

r;

632.8

nm

,10

mW

,C

W;

2-m

mdia

mete

r;

904

nm

,10

mW

;puls

ed;

2.5

–4

J/p

oin

t;

12

J/c

m2;

3–5

tim

es/w

eek

for

2–5

weeks

324

patients

Itw

as

observ

ed

that

under-

and

overirr

adia

tion

can

result

inth

eabsence

of

positiv

eth

era

py

eff

ects

or

even

opposite

,negative

(e.g

.,in

hib

itory

)effects

.

The

curr

ent

clin

icalstu

dy

pro

vid

es

furt

her

evid

ence

of

the

effi

cacy

of

LLLT

inth

em

anagem

ent

of

late

raland

media

lepic

ondylit

is

103

Art

hritis

830

nm

,50

mW

;10

W/c

m2;

6J/p

oin

t;

48

J/c

m2;

CW

,0.5

-mm

2;

2tim

es/w

eek

for

4w

eeks

27

patients

Reduces

pain

inknee

oste

oart

hritis

and

impro

ves

mic

rocircula

tion

35

Art

hritis

904-n

m;

10

mW

;3

J/p

oin

t;3

J/c

m2;

200

nsec;

2500

Hz;

1cm

2;

2poin

ts

5tim

es/w

eek

for

2w

eeks

90

patients

The

stu

dy

dem

onstr

ate

dth

at

applic

ations

of

LLLT

inre

gard

less

of

dose

and

dura

tion

were

asafe

and

effective

meth

od

in

treatm

ent

of

knee

oste

oart

hritis

28

Leg

ulc

ers

685

nm

;50

mW

;50

mW

/cm

2;

10

J/c

m2;

CW

;1

cm

2;

200

s;

6tim

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4 weeks to manifest, reflecting the time necessary fornew neurons to form and gather at the damaged sitein the brain.21,101 However, the exact processesunderlying the effects of LLLT in a stroke patient arestill poorly understood.

LLLT has also been considered as a candidate fortreating degenerative brain disorders such as familialamyotropic lateral sclerosis (FALS), Alzheimer’s dis-ease, and Parkinson’s disease (PD).75,129 Althoughonly preliminary studies have been carried out, thereare encouraging indications that merit further investi-gation. Michalikova et al. found that LLLT couldreverse memory degradation and induce improvedcognitive performance in middle-aged mice,74 andTrimmer et al. found that motor function was signifi-cantly improved in human patients treated with LLLTin an early stage of FALS.112

Intravascular Laser Therapy

Intravenous or intravascular blood irradiationinvolves the in vivo illumination of the blood by feedinglow level laser light generated by a 1–3 mW low powerlaser at a variety of wavelengths through a fiber opticinserted in a vascular channel, usually a vein in theforearm (Fig. 5a), under the assumption that any

therapeutic effect will be circulated through thecirculatory system117 (see Fig. 5b). The feasibility ofintravascular laser irradiation for therapy of cardio-circulatory diseases was first presented in the AmericanHeart Journal in 1982.57 The technique was developedprimarily in Asia (including Russia) and is not exten-sively used in other parts of the world. It is claimed toimprove blood flow and its transport activities, but hasnot been subject to randomized controlled trials and issubject to skepticism. Although it is at present uncer-tain what the mechanisms of intravascular laser actu-ally are, and why it differs from traditional lasertherapy; it has been hypothesized to affect particularcomponents of the blood. Blood lipids (low densitylipoprotein, high density lipoprotein, and cholesterol)are said to be ‘‘normalized’’56; platelets are thought tobe rendered less likely to aggregate thus lessening thelikelihood of clot formation,107 and the immune system(dendritic cells, macrophages and lymphocytes) may beactivated.109

Laser Acupuncture and Trigger Points

Low power lasers with small focused spots can beused to stimulate acupuncture points using the samerules of point selection as in traditional Chinese needle

FIGURE 5. Some examples of LLLT devices and applications. (a and b) Intravascular laser therapy (Institute of Biological Lasertherapy, Gottingen, Germany). (c and d) Laserneedle acupuncture system (Laserneedle GmbH, Glienicke-Nordbahn, Germany). (eand f) Lasercomb (Lexington Int LLC, Boca Raton, FL) for hair regrowth. (g) Laser cap (Transdermal Cap Inc, Gates Mills, OH) forhair regrowth.

CHUNG et al.528

acupuncture.119 Laser acupuncture may be used solelyor in combination with needles for any given conditionover a course of treatment. Trigger points are definedas hyperirritable spots in skeletal muscle that areassociated with palpable nodules in taut bands ofmuscle fibers. They may also be found in ligaments,tendons, and periosteum. Higher doses of LLLT maybe used for the deactivation of trigger points. Directirradiation over tendons, joint margins, bursae etc.may be effective in the treatment of conditions inwhich trigger points may play a part. The Laserneedlesystem (see Figs. 5c, 5d) can be used to stimulatemultiple acupuncture points or trigger points simulta-neously.97

LLLT for Hair Regrowth

One of the most commercially successful applica-tions of LLLT is the stimulation of hair regrowth inbalding individuals. The photobiomodulation activityof LLLT can cause more hair follicles to move fromtelogen phase into anagen phase. The newly formedhair is thicker and also more pigmented. The HairmaxLasercomb (Fig. 5e) was shown55 to give a statisticallysignificant improvement in hair growth in a random-ized, double-blind, sham device-controlled, multicentertrial in 110 men with androgenetic alopecia and this ledto FDA clearance for efficacy (FDA 510(k) numberK060305).The teeth of the comb are supposed to im-prove the penetration of light though the existing hairto the follicles requiring stimulation (Fig. 5f). Re-cently, a different LLLT device received FDA clear-ance in women suffering from androgenetic alopecia(FDA 510(k) numberK091496). This group of patientshave fewer treatment options than men. In order tomake the application of light to the head more user-friendly and increase patient compliance, companieshave developed ‘‘laser caps’’ (Fig. 5g).

CONCLUSION AND OUTLOOK

Advances in design and manufacturing of LLLTdevices in the years to come will continue to widen theacceptability and increase adoption of the therapyamong the medical profession, physical therapists andthe general public. While the body of evidence forLLLT and its mechanisms is still weighted in favor oflasers and directly comparative studies are scarce,ongoing work using non-laser irradiation sources isencouraging and provides support for growth in themanufacture and marketing of affordable home-useLED devices. The almost complete lack of reports ofside effects or adverse events associated with LLLTgives security for issues of safety that will be required.

We believe that LLLT will steadily progress to bebetter accepted by both the medical profession and thegeneral public at large. The number of publishednegative reports will continue to decline as the opti-mum LLLT parameters become better understood,and as reviewers and editors of journals become awareof LLLT as a scientifically based therapy. On theclinical side, the public’s distrust of big pharmaceuticalcompanies and their products is also likely to continueto grow. This may be a powerful force for adoption oftherapies that once were considered as ‘‘alternative andcomplementary,’’ but now are becoming more scien-tifically accepted. LLLT is not the only example of thistype of therapy, but needle acupuncture, transcranialmagnetic stimulation and microcurrent therapy alsofall into this class. The day may not be far off whenmost homes will have a light source (most likely a LEDdevice) to be used for aches, pains, cuts, bruises, joints,and which can also be applied to the hair and eventranscranially to the brain.

ACKNOWLEDGMENTS

Funding: Research in the Hamblin laboratory issupported by NIH grant R01AI050875, Center forIntegration of Medicine and Innovative Technology(DAMD17-02-2-0006), CDMRP Program in TBI(W81XWH-09-1-0514) and Air Force Office of Scien-tific Research (FA9950-04-1-0079). Tianhong Daiwas supported by an Airlift Research FoundationExtremity Trauma Research Grant (grant 109421).

CONFLICTS OF INTEREST

James D. Carroll is the owner of THOR Photo-medicine, a company which sells LLLT devices.

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