Maturitas
journalhomepage: www.elsevier.com/locate/maturitas
Therapeuticapplicationsofpolarizedlight:Tissuehealingand immunomodulatoryeffects
JackFeehana,b,SorayaPatriciaBurrowsa,LeonardoCorneliusa,AlyseMalietzisCooka, KathleenMikkelsenc,VassoApostolopoulos c,⁎,1,MajaHusarica,c,d,⁎,1,DimitriosKiatosa,c,⁎,1
a OsteopathyGroup,CollegeofHealthandBiomedicine,VictoriaUniversity,VIC,Australia
b AustralianInstituteforMusculoskeletalScience(AIMSS),UniversityofMelbourneandWesternHealth,St.Albans,VIC,Australia
c InstituteforHealthandSport,VictoriaUniversity,VIC,Australia
d FirstYearCollege,CollegeofHealthandBiomedicine,VictoriaUniversity,VIC,Australia
ARTICLEINFO
Keywords: Polarizedlighttherapy(PLT) Polarizedlight Photodynamictherapy(PDT) Phototherapies Low-levellasertherapy(LLLT) Woundhealing
ABSTRACT
Asthepopulationgrowsandages,non-pharmaceuticaloptionsforthetreatmentandmanagementofwounds, diseaseandinjuryarerequiredtoensureadequatecare.Polarizedlighttherapy(PLT)utilizesvisible-spectrum polarizedlightforanumberofclinicalapplications.Theadvantageofpolarizedlightisthatitisabletopenetratetheskintoadepthofupto5cm,reachingdeepertissuesinvolvedinwoundhealing.PLThasbeenshown toacceleratethehealingprocessforulcers,surgicalwoundsanddermalburnsaswellasasmallnumberof musculoskeletalinjuries.AsresearchintothehistologicalandphysiologicaleffectsofPLTislargelyabsent, studiesrelatedtootherlighttherapymodalities,largelylow-levellasertherapy,maypavethewaytoidentify putativemechanismsbywhichPLTmightexertitseffects.Changestocellsignallingandsecretionofsubstances requiredforwoundhealinghavebeenidentifiedinresponsetophototherapies.Thereviewedliteraturesuggests thatPLTmaybeefficaciousinsomewoundandinjuryhealingcontexts,thoughagapintheliteratureexists regardingitsmechanismsofaction.FuturestudiesshouldfullyexplainthetherapeuticeffectsofPLTandthe physiologicalmechanismsunderpinningthem.
1.Introduction
Healingisacomplexprocesscomprisingawidevarietyofcelltypes, secretedfactorsandotherphysiologicalparameters.Inanormal, healthypatient,thehumanbodyiscapableofhealingcompletelyfrom awiderangeofwoundsandinjuries.Howeverwhenthesystemis compromizedbyexternalfactorssuchasageing,chronicdiseaseor malnourishment,thehealingresponsecanbedelayed,orincomplete, placingthepatientatrisk[1].Despitethiscommonproblem,thereare alimitednumberofinterventionsavailable,mostofwhicharesupportiveinnature.Thetherapeuticuseoflightcanbetracedbackto ancientEgypt.ThesungodRawasworshippedastheirhighestdeity, andtheEgyptianswouldbaskinthesuntoincreasetheirenergylevels [2].TheancientGreeks,whoweremedicallyadvancedfortheirtime, alsousedsunlighttohelptreatillness[3],andinmoderntimes,seasonalaffectivedisorderistreatedwithbrightartificiallights[4].
AccordingtotheInternationalCommissiononIllumination,lightis “anyradiationcapableofcausingavisualsensationdirectly” [5].Its
physicalpropertiesaredescribedbyitswavelength(i.e.thedistance betweenthetwonearestpeaksinthewave),withvisiblelightspanning from390to700nminhumans.Specificwavelengthscorrelatewiththe visualphenomenonofcolorwhenprocessedbythebrain.Lightwavelengthsbelowthisareknownasultraviolet(UV)light,andaboveas infrared(IR),bothofwhicharenotdetectablebythehumanretina.In itstypicalsettinglightisincoherentorunpolarized,withindividual wavestravellinginallplanesanddirections.Polarizationisachievedby passingincoherentlightthroughspeciallydesigned filters,whichallow wavestravellinginthedesiredplanetopassandblockingthoseoutside thedesiredparameter(Fig.1).Polarizedlightcanbeofasinglewavelengthorpolychromatic,aslongasallwavestravelinthesame plane.
Thereexistarangeofphototherapeuticmodalities,exploitingdifferentpartsofthevisiblespectrum(Fig.2).Themajormodalitiesare: UV-AandUV-Btherapies,lowlevellasertherapy(LLLT),lightemitting diode(LED)therapyandIRtherapies.UVtherapiesareoftenusedto reducetheseverityofsomechronicskinconditionssuchaspsoriasis
⁎ Correspondingauthorsat:InstituteforHealthandSport,VictoriaUniversity,VIC,Australia.
E-mailaddresses: Vasso.Apostolopoulos@vu.edu.au (V.Apostolopoulos), Maja.Husaric@vu.edu.au (M.Husaric), Jim.Kiatos@vu.edu.au (D.Kiatos).
1 Theseauthorscontributedequally.
https://doi.org/10.1016/j.maturitas.2018.07.009
Received8June2018;Receivedinrevisedform7July2018;Accepted18July2018
0378-5122/©2018PublishedbyElsevierB.V.
[6],andthereissomeevidencetosupportitsuseinatopicdermatitis [7].UV-Atherapiestypicallyutilizelightinthe320–400nmrange,and aregenerallyconsideredsafeforuse,thoughduetothehighenergyof lightinthisrange,burnscanoccur[8].NarrowbandUV-Btherapy utilizeslightinthe290–320nmrange.Thoughcorrectapplicationis generallyconsideredsafe,UV-Bradiationisstronglyassociatedwith developmentofawiderangeofskincancersandsoit’susemustbe tightlycontrolled[9].Followingitsinventioninthe1960s,laserlight hasbeensuccessfullyusedtherapeuticallywithmuchoftherelevant researchfocusedonlowlevellasertherapyforitslowriskofburnsand otheradverseeffects.LLLTisusedinarangeofconditions,suchas musculoskeletalinjuries,painreliefandwoundhealing[10],andhas thestrongestevidencetoinformitsusecomparedtootherformsof phototherapy.IRtherapiesutilizeeither “near” or “far” wavelengthsin theIRlightspectrum(700nm–1050nm),andtraditionallyhasbeen usedtowarmprematureinfantsinhospitalduetoitslowenergylevels. TheselowenergylevelsmakeIRlightverysafe,howeverithasquestionablecapacityforpenetration,limitingitsusetodermatological application.LEDtherapiesareanewerentity,whichutilizelightofa singlespecificwavelength,typicallycharacterizedbycolor.Themost commonmodalitiesareblueandredLEDtherapies,howeveryellow andgreendevicesarealsoavailable.Asthereislittleevidencesurroundingitsclinicaluse,thesedevicesarelargelylimitedtocosmetic applications,forconditionssuchasacnevulgaris.ThelowmanufacturingcostofLEDsystemshaspromptedanumberofcommercial entitiestobeginthedevelopmentandsaleofthesedevicesdespite lackingevidencesupportingtheiruse.
Lighttherapyusingbroad,visiblespectrumpolarizedlight(PLT) hasalsogainedinpopularityoverthepast30years.Personalized ‘at home’ devicesexistformanyofthesetherapies,allowingpatientstouse laserorPLTdevicestoself-administertheirowntreatment.Thesedevicesaremarketedasaidsforthetreatmentofvariousskinconditions suchaspsoriasis,atopicdermatitis,acnevulgarisandvitiligo.Despite theseassertionsbydevicemanufacturers,thereisadearthofevidence supportingtheefficacyofPLTinmanyofthesescenarios.
Over3decadesago,itwasproposedthatwhenthecellmembrane phospholipidbilayerisexposedtoalaserorpolarizedlight,therandom distributionofpolar-headedphospholipidsisreplacedbyamore structuredconfiguration,possiblyredistributingthebiologicallyactive proteinsandenablingmoreefficientfunction[11].Additionally,ithas beensuggestedthatPLTcouldalsoimprovecellularprocessessuchas activeandpassivetransport,recognitionofantibodiesandhormones, releaseandreceptionofneurotransmittersorenergytransmissionand conversion[12,13],allofwhichmaycontributetoimprovingthe healingprocess.Morerecently,itwasproposedthatdifferentwavelengthscausedifferentratesofcellularapoptosis,howeverthephysiologicalmechanismsarestillunclear[14].
Inmorerecentyears,theuseofPLThasbeenproposedinthe treatmentofvariousconditionsandisreportedtoacceleratethehealing process.PLTutilizesbroadspectrum,polarizedlight,typicallywithin the visible,andinfra-redranges(400nm – 3400nm).Thepolarization reducestheamountofenergyemittedbythelight,makingitsaferto use,whilststillallowingittopenetrateintodeepertissues.PLThas beenassociatedwithimprovedoutcomesin in-vivo modelsaswellasin
theclinicaltreatmentofdeepdermalburns,pressureanddiabeticulcers.Expectedtissuehealingtimesaresignificantlydecreasedincomparisontostandardwoundcareprotocols.Surgicalinterventionsare avoidedandbothcliniciansandpatientsfrequentlyexpresstheirdisbeliefinthepositiveoutcomes[12,15,16].Despitethispositiveevidence,qualitativemeasuresarescarce,relyinginsteadonexpertopinion,subjectiveoutcomemeasuresandlackingrobustcontrolled measures.
VerylittledocumentedresearchhasbeencarriedoutonpolychromaticspectrumPLTunderexperimentalconditions.Mostpublished studiesinvolvelasertreatmentssuchasPDT,ortheuseofsinglewavelengthphototherapy.Itisnotclearwhatchangesoccuratthemolecular,cellularandphysiologicallevelswhenPLTisusedtotreatskin lesionsandwounds.Herewepresentthelimitedresearchthatexists regardingPLTwithanemphasisondermalwoundhealingandmusculoskeletalinjuries.ThisreviewfocusesonpossiblePLTeffectsoccurringatthecellularlevel.Inaddition,wedescribehowotherformsof lighttherapyhavebeenshowntoaffectcellsatthecellularlevel,to identifypossiblelinksbetweenthemandPLT.
2.Methodology
SearcheswereconductedusingPUBMED,CINAHL(Cumulative IndextoNursingandAlliedHealthLiterature),TheCochraneLibrary, andMEDLINEusingthefollowingsearchterms:lighttherapy,phototherapy,polarization,biostimulation,polarizedlight,polychromatic non-coherentlight.Inadditionthefollowingsearchtermswereincludedinthecontextoflighttherapy – woundhealing,skinwound, biostimulation,ulcer,diabeticulcer,pressureulcer,burnsandmusculoskeletalinjuries.EnglishandAmericanEnglishspellingsofpolarized anditderivativeswereincluded.Studiesfromallyearswereincluded. Referencelistsofreviewedarticleswerealsoassessedforotherrelevant articles.Inclusioncriteriawerepeerreviewedpapersandtherapeutic useofpolychromaticpolarizedlight.StudiesthatusedUVspectrum lightfortreatmentandnon-Englisharticleswhichwerenotabletobe translatedwereexcluded.Titleandabstractanalysiswasperformedto identifyappropriatestudies,andfulltextsofincludedstudieswere assessed.Intotal17studieswerefoundonpolarizedlight,coveringa rangeoftopicsincluding:ulcers,burns,woundsandmusculoskeletal injuries.
3.Non-healingwounds
OnestudyinvestigatedtheeffectsofbroadspectrumPLTtopatients withwoundswhichwereresistanttonormaltreatmentmethods.PLTof 400nm–3000nmwasappliedto30patients,withnon-healingwounds includingdiabeticfootulcers,atherosclerosisobliterans,varicositiesor postthrombicsyndromes,decubitusulcerandosteomyelitis.Following PLTexposureresultedindecreasedwoundsecretionsandincreased epithelializationandwoundclosure.Inaddition,thisledtoanincreasedimmunecellinfiltrationandsecretionofcytokinesandchemokineswhichwasproportionaltotherateofhealing[12].However, muchofthisresearchwasnotappropriatelyblinded,controlled,randomized,orstatisticallyanalysedweakeningitsconclusion.Nevertheless,thestudydemonstratedacompellingcaseforthepossibilitiesof PLTapplicationfordelayedwoundhealing.
4.Dermalburns
Dermalburns,whichareknowntohavesignificantlyreducedpotentialforhealing,havebeenstudiedasatargetforPLT.Inonestudy, 22patientswithburnsweretreatedwithpolarizedlightwhichsubjectivelyacceleratedthehealingrateandrequiredlessfrequenttreatments[16].Whilstpromising,thestudyoutcomewasbasedonsubjectiveexpertopinion,andlackedacontrolorshamtreatmentgroupby whichtomakecomparisons,decreasingtheapplicabilityofthestudy.
Inratburnmodelshowever,PLThasbeenshowntohaveapositive effectonwoundhealing.Infact,seconddegreeburnscreatedonthe backsofratswereanalysedandscoredweeklyfor3weeks,comparing theirmacroscopicandhistopathologicalproperties.Macroscopically, woundclosurewasimprovedinthePLTgroup,aswellashistopathologicallysignificantimprovementinvascularizationandepithelialization.ThisdataaddstothetheorythatPLTaccelerateshealingbyaffectingboththeimmediateandlaterstagesofthehealingprocess[17]. Inanotherstudy,theeffectsof400nm–2000 nmPLTonthehealing effectsofthirddegreeburnsinratswithorwithoutdiabeteswas evaluated.Diabetesisknowntocausesignificantdiminishmentofa patientshealingcapacity.Hence,theeffectsofPLTover3weeks,was assessedinregardstoinflammation,re-epithelialization,neovascularization, fibroblastproliferationandcollagen fibredeposition.PLTwas showntoincreasecollagendeposition,enhancetheinflammatoryresponseandimprovevascularizationofwounds.Notably,itwasshown that10.2J/cm2 tobethemosteffectivedose,withincreaseddoses causingeffect[18].
5.Artificialwounds
Somestudieshaveusedartificialorsurgicalwoundstodetermine theeffectsofPLTonhealing.Onesuchstudyusedacohortof20patientsundergoingskingraftsasamodeltoexaminethis.Thedonor areasforskingraftswereconsidered ‘standardwounds’.Aseachpatient wastohavegraftstakenfromskinonboththighs,theybecametheir owncontrol.Thewoundsweretendedanddressedviastandardhospitalprocedures,butonethighwasirradiatedwithPLTwhichshowed vastimprovementinhealing[19].Thecreationofstandardwounds, althoughcontrolled,alsointroducespossiblesourcesoferror.Forexample,controlledsurgicalproceduresareunlikelytogeneralizewellto therealisticsettingofpathologicalwounding.However,thisstudydoes provideagoodbaselineforfuturestudiesofrealwoundsbylimitingthe numberofconfoundingvariablesthatcanbeencounteredinmore realisticsettings,suchasinfection,woundlocationanddebris.The modelofusingthepatientastheirowncontrolhaslikewisebenefits andrisks.Itensuresevenbaselinevariablesbetweenexperimentaland controlsubjects,meaningspecificparticipantfactorsthatmayinfluence healing(e.g.individualpathology),areaccountedforbutdoesnot accountforasystemicmodeofeffectsuchasimmunomodulation, whichwouldhaveeffectsonbilateralwounds.Animalmodelscango somewaytoremedyingthis,asvariablescanbemoretightlycontrolled betweenexperimentalanimals.InWistarratstheeffectsofLLLTand PLTonwoundhealingwasevaluated;eachratreceivedasingle,dorsal, surgicalcut,followedby20J/cm2 and40J/cm2 of685nmLLLTand 400nm–2000nm,andcomparedagainstuntreatedcontrolgroup.It wasnotedthat20J/cm2 ofPLTorLLLTcausedimprovementsincollagendepositionandorganization,andPLTadditionallyincreasedthe numberofmyofibroblastspresent[20].Asimilarstudyused 480nm–3400nmPLTonfullthicknessskinwoundsandnotedstatisticallysignificantimprovementsinepithelializationandsuggesteda qualitative(butnon-significant)improvementinwoundhealing[21]. Inaddition,differentlightparameterswereassessed,suchas,polarized, linearlypolarized,rightcircularlypolarizedandleftcircularlypolarized,toa20mmdiameterwound.Thewoundsshowedsignificant decreaseinsizeafterexposuretorightcircularlyandlinearlypolarized light,andtype1procollagenmRNAexpressionwasupregulatedinthe rightcircularlypolarizedlightgroup[22].Further,rightcircularlyand linearlypolarizedlightgroupsshowedincreasedproliferationof fibroblasts.Thisstudyprovidesimportantinformationregardingthe physiologicaleffectscausedbyrightcircularlypolarizedtreatmentand thatanopticalactivematerialpossessingacirculardichroicspectrum facilitatedabiochemicalreaction[22].Thisstudyhadastrongmethodology,withappropriatecontrolsandquantitativemeasuresgiving morereliableevidenceinfavourofPLT(Table1).
Table1
EffectsofLowlevellasertherapy(LLLT)oncellsurfacemarkers,chemokines,cytokines.
Celltype/Model
MaturedendriticCells[34]
MaturedendriticCells[35]
RatModel[36]
Aorticsmoothmusclecells(in-vitro)[37] IL-1beta
Mice[41] MCP-1
Arthritisinducedrats[40] CCL2 CCL4
Humanmonocytes[39] CCL2 CXCL10 TNF-alpha
6.Ulcers
Ulcers,regardlessoftheircause,oftenhavepoorcapacityfor healing,andseveralstudieshavedeterminedwhetherPLTcanplaya roleinreversingthis.Inastudycomprising55patientswithpaired controlandexperimentalulcers,demonstratedsignificantimprovement inhealingwith50%ofthewoundscompletelyresolvedwithinone week[15].Likewise,pressureulcerswerealsosignificantlyimprovedin 40patientsinarandomizedsingle-blindedcontroltrialwhichused woundsurfaceareaandthepressureulcerscaleasoutcomemeasures [23].However,thecontrolandexperimentalgroupswerepoorly matchedatbaselineandwoundscoringwasinconsistent.Despitethe promisingoutcomes,thedifferencesatbaselinemayhaveskewedthe resultstowardsfavourablehealingwithPLT.Inaddition,in25patients withvenouslegulcersweresignificantlyreduced(woundsurfacearea andnumberofulcers)followingphototherapyonceadayforfour weeks[24].PLThasalsobeenshowntobeeffectiveinulcerprevention inanacutecaresetting.Infact,10minofPLT/dayinadditionto standardulcerpreventionprotocolsresultedinlesssacralandheelulcersofgradeIIandaboveoverthetwomonthsin23patientscompared tocontrols.ThissuggeststhatPLTcouldbeaneffectiveadjunctto normalulcerpreventiontechniquesinbedriddenpatients.Thisevidence,whilstpreliminary,indicatesthatPLThaspotentialasanoninvasivenon-pharmacologicalinterventioninulcercontrolandprevention,howeverrobust,controlledtrialsarerequiredtofullyexpand these findings.
7.Musculoskeletalinjuries
AnotherareainwhichPLThasbeenappliedclinicallyisthetreatmentofmusculoskeletalinjuries.Threestudieshaveassessedtheuseof PLTintendinousinjuriesofthelateralelbow,generally findingpositive results.Tendinopathiesareknowntobedifficultinjurieswhichoften havelimitedimprovementstostandardtherapies.Onestudycompared theeffectsofsupervisedexerciserehabilitation,Cyriaxphysiotherapy (astructured,unsupervisedrehabilitationregimen)andPLTtopatients reportedpainandpain-freegripstrengthinthesepatients.Itwasnoted thatsupervisedphysiotherapytobethesuperiorintervention,however, PLTdidshowsignificantimprovementsinallparameters[25].PLThas alsobeencomparedtoLLLTinthetreatmentofthesepatients.Fifty patientsweredividedintotwogroupsandreceivedfourweeksofeither LLLTorPLTinconjunctionwithastandardexerciseprogram, finding nosignificantdifferencesamongstthetwoinpainandfunctionalimprovement,thoughbothgroupsshowedimprovementfrombaseline [26].Inasimilarvein,PLThasbeenshowntobeeffectiveintreating lateralelbowepicondylalgia,decreasingpatientpainandincreasing functionandpain-freegripstrength[27].Whilethesestudiesprovide
positiveevidencefortheplaceofPLTintreatingtheseconditions,all threesufferfromthelackofanuntreated,orstandardpracticecontrol andlackofblindingofpatientsandpractitioners.Thisweakenstheir conclusionsasitisunclearwhethertheeffectsdemonstratedweredue tothePLTintervention,oranotherfactorsuchaspatienthealing, placeboorchance.Nonetheless,theyprovideaninterestingoutlookof PLT’sefficacyinthetreatmentofthesestubborninjuries.Anotherstudy investigatedtheeffectofPLTonacuteanklesprains,acommon,painful injury encounteredinphysicaltherapy.Theyenrolled50participants anddividedthemevenlyintocontrolandexperimentalgroups.Both groupsreceivedstandardcryotherapyandtheexperimentalgroupadditional5treatmentsofPLT(10min.daily,for5days),andpatient reportedpainscores,oedemaandanklerangeofmotion(ROM)were assessedafter5days.PLTwasfoundtocausestatisticallysignificant improvementacrossallparameterswhencomparedtocontrol,providingstrongevidenceofitspotentialfortreatment.Thisstudyhad robustmethodology,thoughwasonlysingleblinded,leavingitunable toaccountforplaceboeffectoftreatment,orthepsychologicaleffects ofregularcontactwithhealthcarepersonnel[28].Likewise,inpatients withidiopathiccarpaltunnelsyndrome,apainfulconditioninthehand PLT3times/weekfor6minover4weeks,showedimprovementsin nocturnalpainandparaesthesiabutdidnotreportanystatisticalanalysisoreffectsizesanddidnotuseacontrolgroup,limitingtheinformationthatcanbegainedfromthestudy[29].Overall,thereis evidencethatsuggeststhatPLTcanimprovepatientsymptomsand functionintendinousandligamentousinjuries,howevermethodologicalissueswithmostofthestudiesinthearealimittheapplicabilityof thisresearch,andmorecarefullycontrolledtrialsarerequiredtofully confirmPLTsefficacy,aswellastocreatedoseresponsecurvesand protocols.Additionally,therearenoreportsonthephysiologicalmechanismfortheeffectsofPLTintheseinjuries,and invitro studiesare requiredtoexpandonthistoenableitstranslationintoclinicalpractice.
8.Limitations
Whilethereisagrowingbodyofevidencedemonstratingthe healingpotentialofPLT,thebodyofliteratureremainssmall,and generallyoflowquality.Mostoftheidentifiedstudieshadsmallsample sizesandgenerallylackedrobustmethodologies,includingblinding andcontrolpopulations.Additionally,manyofthestudiesrelied heavilyonqualitativeoutcomesandhadmixedresultsregardingstatisticallysignificantchanges.TherewasalsovariancewithintheprotocolsofPLTapplication.Ingeneral,theapplicationofPLTwassimilar: treatmentwasappliedforshorttimeframes(1–3weeks),withsome shorttermfollowup.However,anumberofdifferingprotocolswere usedregardingtheamount,timeandfrequencyofapplication,making acomparisonofresultsdifficult.Additionally,nolong-termfollowup
studieshavebeenreported,leavinginformationastothelong-term effectsofPLTscarce.Despitethese flaws,theoverallconsensuswasthat PLTprovidedsmalltomodestimprovements,particularlyattheearly timepoints[12,15–17,19]onwoundswithagreaterpreservationof tissuestructuralintegrity[23,30].However,therearestillmany questionsremainingthatneedtobeansweredformorewidespreaduse ofPLTtoberecommended.Firstly,thesafetyofPLTisyettobefully evaluated.ThereisacasestudyreportingthedevelopmentofametastasizedmyxoidmelanomainapatientusingPLT[31]however,the applicationofthisislimitedduetomethodologicalissues.Someforms oflight,mostnotablyUV,havebeenassociatedwithanincreasedrisk ofmalignancy[32],andassuchitisimportanttoevaluatethese,and anyother,patientrisks.Itisimportanttonotehowever,thatUV therapyhasbeenfoundtobeasafeintervention[33],andbasedonthe lowerenergylevelsinvolvedinPLT,thisislikelytoholdtrue.However, ifPLTistobecomeamorewidelyusedinterventionfullriskevaluation mustbeperformed.ThereisalsolittleevidenceregardingthemechanismsbywhichPLTmayexertitseffect.Thereissomeindication thatPLThaseffectsonbothlocalconnectivetissuecells[12,22],and hascapacitytoinfluencetheimmunesystem[12],thoughlittleinformationexistsregardingspecific,biologicalchangesdrivingthis.One studyidentifiedachangeintheexpressionofprocollagenmRNA[22], providingarationaleforfurtherstudiestodeterminechangesatthe molecularandcellularlevel(Fig.3).Whilethereisacompleteabsence ofevidencesupportingabiochemicalorphysicalmechanismforthe effectsofPLToncellfunction.However,somesuggestedmechanisms havebeentheorizedabout,theseareyettobesubstantiated(Fig.4). Thesemechanismsincludechangestothepolarizationorstructureof thephospholipidmembrane,increasedATPproductionviamitochondrialstimulationoractivationofphotosensitivereceptorsineitherthe cellornuclearmembranes,withresultingchangestocellphysiologyor geneexpression.Finally,furthercontrolled,robuststudiesarerequired todemonstratePLTseffectiveness,aswellastoestablishbestpractice dosageprotocolsanddoseresponsecurves.Overall,theliteratureseems toindicateagenerallypositiveeffect,howeversignificantmethodologicalissuesmakedefinitivestatementsofefficacyimpossible.Itdoes howeverprovideadirectionforfutureresearch,asitholdsthepotential toprovideasafe,cheapandeffectiveadjuncttothestandardcareofa
numberofconditions.
9.Immunomodulation:alow-levellaserperspective
Astheimmunesystemismostactiveintheacutestagesofwound healing,andPLThasbeenshowntobemosteffectiveatthistime,itis inferred thatPLTmayexhibitimmunomodulatoryeffects.ThesequestionsmaybeansweredbyselectivelyexaminingtheeffectsofPLTon immunecells.ThelackofPLTresearchmakesthesequestionsdifficult toanswer,however,researchpublishedusingLLLT,inwhichasingle wavelengthisusedmaypavethewaytopossiblemechanismsofaction forPLT.
Phototherapies,particularlyLLLT,havebeendemonstratedtohave immunomodulatoryeffectsonmammaliancells.Chenetal.,examined theeffectsofan810nmlaseronmurinebone-marrowderiveddendritic cells(DCs), in-vitro.ImmatureDCswerematuredwitheitherlipopolysaccharideorCpGoligodeoxynucleotide,andexposedtolaserlight therapy,resultinginthedownregulationofMHCclassIIandupregulationofCD86cellsurfacemarkers.ImmatureDCsexposedtothesame LLLThadnochange.TheauthorsconcludedthatLLLThasananti-inflammatoryeffectonactivatedDCs,andsuggesteditwaspossibly mediatedbycAMPandreducedNF-κBsignalling[34].Inanother study,maturesplenicDCs,whichhadbeentreatedwithaphotosensitizer,weretreatedwitha690nmlaseratadoseof5J/cm2,and showeddownregulationofcellsurfacemarkers(MHCclassI,MHCclass II,CD80andCD86)andaresultingsuppressionofTcellactivation [35].Inrats,2groupsreceivedwoundsbyscalpel(groupsAandC) whilsttheother2groupshadtheirwoundsinducedbylaser(groupsB andD).Twoofthefourgroups(AandB)weresubjectto2boutsoflow levellaserirradiation24hapartfollowingtheirwounds(wavelength 870nm,totalirradiationtime120sand9.6Jcm2).Whencomparing GroupA(scalpelinducedwoundwithLLLT)withgroupC(laserinducedwoundwithnoLLLT)itwasclearthattherewasamarkeddecreaseintheexpressionofIL-1β forgroupA.Additionally,therewere slight,non-significantdecreasesinmRNAlevelsofIL-1β inGroupB (laser-inducedwoundswithLLLT)whencomparedtoGroupD(laser inducedwoundswithnoLLLT)[36].GeneexpressionofIL-1β inGroup B(laserinducedwoundandLLLT)wasslightlylowerthanthatofGroup
Summaryofthepossiblephysiologicalmechanismsofpolarizedlighttherapy.
C(scalpelinducedwoundandnoLLLT)butnotsignificantlydifferent. Likewise,inporcineaorticsmoothmusclecells,IL-1β geneexpression wasalsoreducedwithinthe firsthalfhourfollowingLLLTtreatment (780nmwith1–2J/cm2)[37].Moreover,theeffectsoflight-emitting diodetherapy(LEDT)showedthatLEDTinducedpro-inflammatory cytokines(TNF-α andIL-1β)inanacutetimeframebutswitchedto anti-inflammatory(IL-10)post5daysLEDTexposure[38].
TheeffectsofasingleboutofLLLT(660nmat1–2J/cm2)tohuman monocytecellline(THP-1)showedthatCCL2mRNAexpressionwas enhanced24h’ postirradiation,althoughexposureat3J/cm2 LLLT suppressedCCL2expressioninTHP-1cells[39].Thisresultsuggests thatatdifferingdoses,LLLTcanbeapotentenhancerorsuppressorof pro-inflammatorycytokinesandchemokinesinhumanmonocytes.This studyalsoshowedthat1J/cm2 LLLTinducedCCL2andCXCL10proteinexpressionwhereashigherdosesof2J/cm2 and3J/cm2 didnot.In ratswithcollagen-inducedarthritis,LLLTupregulatedtheexpressionof CCL2andCCL4inthesynovialtissues,resultingintheenhancementof healing[40].Additionally,inanotherstudyitwasnotedthatinfrared LLLTof780nmat10J/cm2 administeredacrossthreesessionsmarkedlyreducedMCP-1levels,andmayhaveabeneficialeffectonsurgical wounds[41].Althoughitisnotpossibletoautomaticallyextrapolate theresultsofthis invitro experimenttointactlivingorganisms,thedata issuggestivethattheimmunomodulatoryeffectofLLLTonmonocyte polarizationcouldbeapotentialtreatmentforallergicorauto-immune diseasesandatadifferentdosecouldalsobeusedtopromoteinflammationandimmuneresponsetopathogenicstimuli.
10.Conclusionandfutureprospects
Manyofthestudiesincludedinthisreviewsufferedfrom flawed methodology,weakeningtherecommendationsthatcanbemadefrom thisreview.Overallhowever,theevidenceislargelyfavourableofPLT asatherapyinarangeofconditions,withastrongsafetyprofile,and unanimouslybeneficialeffectsreported.However,beforePLTcanbe
confidentlyrecommendedforregularmedicaluse,researchwithrobust methodologiesmustbedoneinbothhealthyandpathologicalsettings tofullyunderstanditseffects.Doseresponsetrailsmustalsobeperformedto findthemosteffectiveprotocolsfortreatmentofthevarious conditionsidentified.Additionally,studieswithlongtermfollowup shouldbeemployedtofullyvalidatethelong-termefficacyandsafety profileofPLT.Asanadjuncttothis, invitro studiesontheeffectsofPLT onthevariouscelltypesinvolvedinthehealingprocessshouldbe performedtoprovideplausibletherapeuticmechanismsandtargets. Overall,PLTisanexcitingtherapywithlargepotentialforutilizationin arangeofconditions,howeveradeeperunderstandingofitsbiological mechanismsandphysiologicaleffectsisessentialforitstranslationinto commonplacemedicaluse.
Contributors
JackFeehancontributedtothedraftingofthearticle,andedited andreviewedthedraft.
SorayaPatriciaBurrowscontributedtothedraftingofthearticle. LeonardoCorneliuscontributedtothedraftingofthearticle.
AlyseMalietzisCookcontributedtothedraftingofthearticle.
KathleenMikkelsencontributedtothedraftingofthearticle,and editedandreviewedthedraft.
VassoApostolopouloscontributedtothedraftingofthearticle,and editedandreviewedthedraft.
MajaHusariccontributedtothedraftingofthearticle,andedited andreviewedthedraft.
DimitriosKiatoscontributedtothedraftingofthearticle,andedited andreviewedthedraft.
Conflictofinterest
Theauthorshavenoconflictofinteresttodeclare.
Funding
Nofundingwasreceivedspecificallyforthepreparationofthisreview.
Ethicalapproval
Noethicswasrequiredforthisreviewarticle.
Provenanceandpeerreview
Thisarticlehasundergonepeerreview.
Acknowledgements
TheauthorswouldliketothanktheImmunologyprograminthe CentreforChronicDiseaseandtheCollegeofHealthandBiomedicine forsupportanddiscussions.VAwouldliketothanktheVictoria UniversityCollegeofHealthandBiomedicinestart-upfundsandthe CentreforChronicDisease,VictoriaUniversityfor financialsupport. KMwassupportedbytheViceChancellorsVictoriaUniversity ScholarshipandJFbytheUniversityofMelbournePostgraduate Scholarship.Finally,theauthorsthankMyfanwyThewlisfortheproductionofthe figures.
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