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WoundhealingWikipedia,thefreeencyclopedia
Woundhealingistheprocessbywhichskinorotherbodytissuerepairsitselfaftertrauma.In
undamagedskin,theepidermis(surfacelayer)anddermis(deeperlayer)formaprotectivebarrier
againsttheexternalenvironment.Whenthebarrierisbroken,anorchestratedcascadeofbiochemical
eventsissetintomotiontorepairthedamage.[1][2]Thisprocessisdividedintopredictablephases:blood
clotting(hemostasis),inflammation,tissuegrowth(proliferation)andtissueremodeling(maturation).
Bloodclottingmaybeconsideredtobepartoftheinflammationstageinsteadofaseparatestage.[3]
Hemostasis(bloodclotting):Withinthefirstfewminutesofinjury,plateletsinthebloodbegintostick
totheinjuredsite.Thisactivatestheplatelets,causingafewthingstohappen.Theychangeintoan
amorphousshape,moresuitableforclotting,andtheyreleasechemicalsignalstopromoteclotting.
Thisresultsintheactivationoffibrin,whichformsameshandactsas"glue"tobindplateletstoeach
other.Thismakesaclotthatservestoplugthebreakinthebloodvessel,slowing/preventingfurther
bleeding.[4][5]
Inflammation:Duringthisphase,damagedanddeadcellsareclearedout,alongwithbacteriaand
otherpathogensordebris.Thishappensthroughtheprocessofphagocytosis,wherewhiteblood
cells"eat"debrisbyengulfingit.Plateletderivedgrowthfactorsarereleasedintothewoundthat
causethemigrationanddivisionofcellsduringtheproliferativephase.
Proliferation(growthofnewtissue):Inthisphase,angiogenesis,collagendeposition,granulation
tissueformation,epithelialization,andwoundcontractionoccur.[6]Inangiogenesis,vascular
endothelialcellsformnewbloodvessels.[7]Infibroplasiaandgranulationtissueformation,fibroblasts
growandformanew,provisionalextracellularmatrix(ECM)byexcretingcollagenandfibronectin.[6]
Concurrently,reepithelializationoftheepidermisoccurs,inwhichepithelialcellsproliferateand
'crawl'atopthewoundbed,providingcoverforthenewtissue.[8]Inwoundcontraction,myofibroblasts
decreasethesizeofthewoundbygrippingthewoundedgesandcontractingusingamechanismthat
resemblesthatinsmoothmusclecells.Whenthecells'rolesareclosetocomplete,unneededcells
undergoapoptosis.[6]
Maturation(remodeling):Duringmaturationandremodeling,collagenisrealignedalongtensionlines,
andcellsthatarenolongerneededareremovedbyprogrammedcelldeath,orapoptosis.
Thewoundhealingprocessisnotonlycomplexbutalsofragile,anditissusceptibletointerruptionor
failureleadingtotheformationofnonhealingchronicwounds.Factorsthatcontributetononhealing
chronicwoundsarediabetes,venousorarterialdisease,infection,andmetabolicdeficienciesofoldage.
[9]

Woundcareencouragesandspeedswoundhealingviacleaningandprotectionfromreinjuryor
infection.Dependingoneachpatient'sneeds,itcanrangefromthesimplestfirstaidtoentirenursing
specialtiessuchaswound,ostomy,andcontinencenursingandburncentercare.
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Approximatetimesofthedifferentphasesofwoundhealing,[10]withfadedintervalsmarkingsubstantialvariation,
dependingmainlyonwoundsizeandhealingconditions,butimagedoesnotincludemajorimpairmentsthatcause
chronicwounds.

Timingandreepithelialization[edit]
Timingisimportanttowoundhealing.Critically,thetimingofwoundreepithelializationcandecidethe
outcomeofthehealing.[11]Iftheepithelizationoftissueoveradenudedareaisslow,ascarwillform
overmanyweeks,ormonths[12][13]Iftheepithelizationofawoundedareaisfast,thehealingwillresult
inregeneration.[13]

Earlyvscellularphase[edit]
AfluorescencemicrographofcellsinDrosophilalarvaehealingafterapuncturewound.Thearrowpointstocellsthat
havefusedtoformsyncytia,andthearrowheadspointtocellsthatareorientedtofacethewound.[14]

Woundhealingisclassicallydividedintohemostasis,inflammation,proliferation,andremodeling.
Althoughausefulconstruct,thismodelemploysconsiderableoverlappingamongindividualphases.A
complementarymodelhasrecentlybeendescribed[1]wherethemanyelementsofwoundhealingare
moreclearlydelineated.Theimportanceofthisnewmodelbecomesmoreapparentthroughitsutilityin
thefieldsofregenerativemedicineandtissueengineering(seeResearchanddevelopmentsection
below).Inthisconstruct,theprocessofwoundhealingisdividedintotwomajorphases:theearlyphase
andthecellularphase:[1]
Theearlyphase,whichbeginsimmediatelyfollowingskininjury,involvescascadingmolecularand
cellulareventsleadingtohemostasisandformationofanearly,makeshiftextracellularmatrixthat
providesstructuralstagingforcellularattachmentandsubsequentcellularproliferation.
Thecellularphaseinvolvesseveraltypesofcellsworkingtogethertomountaninflammatoryresponse,
synthesizegranulationtissue,andrestoretheepitheliallayer.[1]Subdivisionsofthecellularphaseare:
[1]Macrophagesandinflammatorycomponents(within12days),[2]Epithelialmesenchymal
interaction:reepithelialization(phenotypechangewithinhours,migrationbeginsonday1or2),[3]
Fibroblastsandmyofibroblasts:progressivealignment,collagenproduction,andmatrixcontraction
(betweenday4day14),[4]Endothelialcellsandangiogenesis(beginsonday4),[5]Dermalmatrix:
elementsoffabrication(beginsonday4,lasting2weeks)andalteration/remodeling(beginsafterweek
2,lastingweekstomonthsdependingonwoundsize).[1]

Inflammatoryphase[edit]
Justbeforetheinflammatoryphaseisinitiated,theclottingcascadeoccursinordertoachieve
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hemostasis,orstopbloodlossbywayofafibrinclot.Thereafter,varioussolublefactors(including
chemokinesandcytokines)arereleasedtoattractcellsthatphagocytisedebris,bacteria,anddamaged
tissue,inadditiontoreleasingsignalingmoleculesthatinitiatetheproliferativephaseofwoundhealing.

Clottingcascade[edit]
Mainarticle:Coagulation
Whentissueisfirstwounded,bloodcomesincontactwithcollagen,triggeringbloodplateletstobegin
secretinginflammatoryfactors.[15]Plateletsalsoexpressstickyglycoproteinsontheircellmembranes
thatallowthemtoaggregate,formingamass.[6]
Fibrinandfibronectincrosslinktogetherandformaplugthattrapsproteinsandparticlesandprevents
furtherbloodloss.[16]Thisfibrinfibronectinplugisalsothemainstructuralsupportforthewounduntil
collagenisdeposited.[6]Migratorycellsusethisplugasamatrixtocrawlacross,andplateletsadhereto
itandsecretefactors.[6]Theclotiseventuallylysedandreplacedwithgranulationtissueandthenlater
withcollagen.
Platelets,thecellspresentinthehighestnumbersshortlyafterawoundoccurs,releaseanumberof
mediatorsintotheblood,includingcytokinesandgrowthfactors.[15]Growthfactorsstimulatecellsto
speedtheirrateofdivision.Plateletsalsoreleaseotherproinflammatoryfactorslikeserotonin,
bradykinin,prostaglandins,prostacyclins,thromboxane,andhistamine,[3]whichserveanumberof
purposes,includingtoincreasecellproliferationandmigrationtotheareaandtocausebloodvesselsto
becomedilatedandporous.Inmanyways,extravasatedplateletsintraumaperformasimilarfunctionto
tissuemacrophagesandmastcellsexposedtomicrobialmolecularsignaturesininfectiontheybecome
activated,andsecretemolecularmediatorsthatinitiatetheinflammatoryprocess.Vasoactiveamines,
eicosanoids,cytokines.

Vasoconstrictionandvasodilation[edit]
Immediatelyafterabloodvesselisbreached,rupturedcellmembranesreleaseinflammatoryfactorslike
thromboxanesandprostaglandinsthatcausethevesseltospasmtopreventbloodlossandtocollect
inflammatorycellsandfactorsinthearea.[3]Thisvasoconstrictionlastsfivetotenminutesandis
followedbyvasodilation,awideningofbloodvessels,whichpeaksatabout20minutespostwounding.[3]
Vasodilationistheendresultoffactorsreleasedbyplateletsandothercells.Themainfactorinvolvedin
causingvasodilationishistamine.[3][15]Histaminealsocausesbloodvesselstobecomeporous,allowing
thetissuetobecomeedematousbecauseproteinsfromthebloodstreamleakintotheextravascular
space,whichincreasesitsosmolarloadanddrawswaterintothearea.[3]Increasedporosityofblood
vesselsalsofacilitatestheentryofinflammatorycellslikeleukocytesintothewoundsitefromthe
bloodstream.[17][18]

Polymorphonuclearneutrophils[edit]
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Withinanhourofwounding,polymorphonuclearneutrophils(PMNs)arriveatthewoundsiteand
becomethepredominantcellsinthewoundforthefirsttwodaysaftertheinjuryoccurs,withespecially
highnumbersonthesecondday.[19]Theyareattractedtothesitebyfibronectin,growthfactors,and
substancessuchaskinins.Neutrophilsphagocytisedebrisandkillbacteriabyreleasingfreeradicalsin
whatiscalleda'respiratoryburst.[20][21]Theyalsocleansethewoundbysecretingproteasesthatbreak
downdamagedtissue.Functionalneutrophilsatthewoundsiteonlyhavelifespansofaround2days,
sotheyusuallyundergoapoptosisoncetheyhavecompletedtheirtasksandareengulfedanddegraded
bymacrophages.[22]
OtherleukocytestoentertheareaincludehelperTcells,whichsecretecytokinestocausemoreTcells
todivideandtoincreaseinflammationandenhancevasodilationandvesselpermeability.[17][23]Tcells
alsoincreasetheactivityofmacrophages.[17]

Macrophages[edit]
Oneofthemacrophage'srolesistophagocytizeotherexpendedphagocytes,[24]bacteriaanddamaged
tissue,[19]andtheyalsodebridedamagedtissuebyreleasingproteases.[25]
Macrophagesfunctioninregeneration[26][27]andareessentialforwoundhealing.[19]Theyarestimulated
bythelowoxygencontentoftheirsurroundingstoproducefactorsthatinduceandspeed
angiogenesis[20]andtheyalsostimulatecellsthatreepithelializethewound,creategranulationtissue,
andlaydownanewextracellularmatrix.[28][29]Bysecretingthesefactors,macrophagescontributeto
pushingthewoundhealingprocessintothenextphase.TheyreplacePMNsasthepredominantcellsin
thewoundbytwodaysafterinjury.[24]
Thespleencontainshalfthebody'smonocytesinreservereadytobedeployedtoinjuredtissue.[30][31]
Attractedtothewoundsitebygrowthfactorsreleasedbyplateletsandothercells,monocytesfromthe
bloodstreamentertheareathroughbloodvesselwalls.[32]Numbersofmonocytesinthewoundpeak
onetooneandahalfdaysaftertheinjuryoccurs.[23]Oncetheyareinthewoundsite,monocytes
matureintomacrophages.Macrophagesalsosecreteanumberoffactorssuchasgrowthfactorsand
othercytokines,especiallyduringthethirdandfourthpostwoundingdays.Thesefactorsattractcells
involvedintheproliferationstageofhealingtothearea.[15]
Inwoundhealingthatresultinincompleterepair,scarcontractionoccurs,bringingvaryinggradationsof
structuralimperfections,deformitiesandproblemswithflexibility.[33]Macrophagesmayrestrainthe
contractionphase.[27]Scientistshavereportedthatremovingthemacrophagesfromasalamander
resultedinfailureofatypicalregenerationresponse(limbregeneration),insteadbringingonarepair
(scarring)response.[34][35]

Declineofinflammatoryphase[edit]
Asinflammationdiesdown,fewerinflammatoryfactorsaresecreted,existingonesarebrokendown,
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andnumbersofneutrophilsandmacrophagesarereducedatthewoundsite.[19]Thesechanges
indicatethattheinflammatoryphaseisendingandtheproliferativephaseisunderway.[19]Invitro
evidence,obtainedusingthedermalequivalentmodel,suggeststhatthepresenceofmacrophages
actuallydelayswoundcontractionandthusthedisappearanceofmacrophagesfromthewoundmaybe
essentialforsubsequentphasestooccur.[27]
Becauseinflammationplaysrolesinfightinginfection,clearingdebrisandinducingtheproliferation
phase,itisanecessarypartofhealing.However,inflammationcanleadtotissuedamageifitlaststoo
long.[6]Thusthereductionofinflammationisfrequentlyagoalintherapeuticsettings.Inflammationlasts
aslongasthereisdebrisinthewound.Thus,iftheindividual'simmunesystemiscompromisedandis
unabletoclearthedebrisfromthewoundand/orifexcessivedetritus,devitalizedtissue,ormicrobial
biofilmispresentinthewound,thesefactorsmaycauseaprolongedinflammatoryphaseandprevent
thewoundfromproperlycommencingtheproliferationphaseofhealing.Thiscanleadtoachronic
wound.

Proliferativephase[edit]
Abouttwoorthreedaysafterthewoundoccurs,fibroblastsbegintoenterthewoundsite,markingthe
onsetoftheproliferativephaseevenbeforetheinflammatoryphasehasended.[36]Asintheother
phasesofwoundhealing,stepsintheproliferativephasedonotoccurinaseriesbutratherpartially
overlapintime.
Alsocalledneovascularization,theprocessofangiogenesisoccursconcurrentlywithfibroblast
proliferationwhenendothelialcellsmigratetotheareaofthewound.[37]Becausetheactivityof
fibroblastsandepithelialcellsrequiresoxygenandnutrients,angiogenesisisimperativeforotherstages
inwoundhealing,likeepidermalandfibroblastmigration.Thetissueinwhichangiogenesishasoccurred
typicallylooksred(iserythematous)duetothepresenceofcapillaries.[37]
Angiogenesisoccursinoverlappingphasesinresponsetoinflammation:
1.Latentperiod:Duringthehaemostaticandinflammatoryphaseofthewoundhealingprocess,
vasodilationandpermeabilisationallowleukocyteextravasationandphagocyticdebridementand
decontaminationofthewoundarea.Tissueswellingaidslaterangiogenesisbyexpandingandloosening
theexistingcollagenousextracellularmatrix.
2.Endothelialactivation:Asthewoundmacrophagesswitchesfrominflammatorytohealingmode,it
beginstosecreteendothelialchemotacticandgrowthfactorstoattractadjacentendothelialcells.
Activatedendothelialcellsrespondbyretractingandreducingcelljunctions,looseningthemselvesfrom
theirembeddedendothelium.Characteristicallytheactivatedendothelialcellsshowenlargednucleoli.
3.Degradationofendothelialbasementmembrane:Thewoundmacrophages,mastcellsandthe
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endothelialcellsthemselvessecreteproteasestobreakdownexistingvascularbasallamina.
4.Vascularsprouting:Withthebreakdownofendothelialbasementmembrane,detachedendothelial
cellsfrompreexistingcapillariesandpostcapillaryvenuescandivideandmigratechemotactically
towardsthewound,layingdownnewvesselsintheprocess.Vascularsproutingcanbeaidedby
ambienthypoxiaandacidosisinthewoundenvironment,ashypoxiastimulatestheendothelial
transcriptionfactor,hypoxiainduciblefactor(HIF)totransactivateangiogenicgenessuchasVEGFand
GLUT1.Sproutedvesselscanselforganiseintoluminalmorphologies,andfusionofblindchannelsgive
risetonewcapillarynetworks.
5.Vascularmaturation:theendotheliumofvesselsmaturebylayingdownnewendothelialextracellular
matrix,followedbybasallaminaformation.Lastlythevesselestablishesapericytelayer.
Stemcellsofendothelialcells,originatingfrompartsofuninjuredbloodvessels,developpseudopodia
andpushthroughtheECMintothewoundsitetoestablishnewbloodvessels.[20]
Endothelialcellsareattractedtothewoundareabyfibronectinfoundonthefibrinscaband
chemotacticallybyangiogenicfactorsreleasedbyothercells,[38]e.g.frommacrophagesandplatelets
wheninalowoxygenenvironment.Endothelialgrowthandproliferationisalsodirectlystimulatedby
hypoxia,andpresenceoflacticacidinthewound.[36]Forexample,hypoxiastimulatestheendothelial
transcriptionfactor,hypoxiainduciblefactor(HIF)totransactivateasetofproliferativegenesincluding
vascularendothelialgrowthfactor(VEGF)andglucosetransporter1(GLUT1).
Tomigrate,endothelialcellsneedcollagenasesandplasminogenactivatortodegradetheclotandpart
oftheECM.[3][19]ZincdependentmetalloproteinasesdigestbasementmembraneandECMtoallowcell
migration,proliferationandangiogenesis.[39]
Whenmacrophagesandothergrowthfactorproducingcellsarenolongerinahypoxic,lacticacidfilled
environment,theystopproducingangiogenicfactors.[20]Thus,whentissueisadequatelyperfused,
migrationandproliferationofendothelialcellsisreduced.Eventuallybloodvesselsthatarenolonger
neededdiebyapoptosis.[38]

Fibroplasiaandgranulationtissueformation[edit]
Simultaneouslywithangiogenesis,fibroblastsbeginaccumulatinginthewoundsite.Fibroblastsbegin
enteringthewoundsitetwotofivedaysafterwoundingastheinflammatoryphaseisending,andtheir
numberspeakatonetotwoweekspostwounding.[19]Bytheendofthefirstweek,fibroblastsarethe
maincellsinthewound.[3]Fibroplasiaendstwotofourweeksafterwounding.
Asamodelthemechanismoffibroplasiamaybeconceptualisedasananalogousprocessto
angiogenesis(seeabove)onlythecelltypeinvolvedisfibroblastsratherthanendothelialcells.Initially
thereisalatentphasewherethewoundundergoesplasmaexudation,inflammatorydecontamination
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anddebridement.Oedemaincreasesthewoundhistologicaccessibilityforlaterfibroplasticmigration.
Second,asinflammationnearscompletion,macrophageandmastcellsreleasefibroblastgrowthand
chemotacticfactorstoactivatefibroblastsfromadjacenttissue.Fibroblastsatthisstageloosen
themselvesfromsurroundingcellsandECM.Phagocytesfurtherreleaseproteasesthatbreakdownthe
ECMofneighbouringtissue,freeingtheactivatedfibroblaststoproliferateandmigratetowardsthe
wound.Thedifferencebetweenvascularsproutingandfibroblastproliferationisthattheformeris
enhancedbyhypoxia,whilstthelatterisinhibitedbyhypoxia.Thedepositedfibroblasticconnective
tissuematuresbysecretingECMintotheextracellularspace,forminggranulationtissue(seebelow).
LastlycollagenisdepositedintotheECM.
Inthefirsttwoorthreedaysafterinjury,fibroblastsmainlymigrateandproliferate,whilelater,theyare
themaincellsthatlaydownthecollagenmatrixinthewoundsite.[3]Originsofthesefibroblastsare
thoughttobefromtheadjacentuninjuredcutaneoustissue(althoughnewevidencesuggeststhatsome
arederivedfrombloodborne,circulatingadultstemcells/precursors).[40]Initiallyfibroblastsutilizethe
fibrincrosslinkingfibers(wellformedbytheendoftheinflammatoryphase)tomigrateacrossthe
wound,subsequentlyadheringtofibronectin.[38]Fibroblaststhendepositgroundsubstanceintothe
woundbed,andlatercollagen,whichtheycanadheretoformigration.[15]
Granulationtissuefunctionsasrudimentarytissue,andbeginstoappearinthewoundalreadyduring
theinflammatoryphase,twotofivedayspostwounding,andcontinuesgrowinguntilthewoundbedis
covered.Granulationtissueconsistsofnewbloodvessels,fibroblasts,inflammatorycells,endothelial
cells,myofibroblasts,andthecomponentsofanew,provisionalextracellularmatrix(ECM).The
provisionalECMisdifferentincompositionfromtheECMinnormaltissueanditscomponentsoriginate
fromfibroblasts.[28]Suchcomponentsincludefibronectin,collagen,glycosaminoglycans,elastin,
glycoproteinsandproteoglycans.[38]Itsmaincomponentsarefibronectinandhyaluronan,whichcreatea
veryhydratedmatrixandfacilitatecellmigration.[32]LaterthisprovisionalmatrixisreplacedwithanECM
thatmorecloselyresemblesthatfoundinnoninjuredtissue.
Growthfactors(PDGF,TGF)andfibronectinencourageproliferation,migrationtothewoundbed,and
productionofECMmoleculesbyfibroblasts.Fibroblastsalsosecretegrowthfactorsthatattractepithelial
cellstothewoundsite.Hypoxiaalsocontributestofibroblastproliferationandexcretionofgrowth
factors,thoughtoolittleoxygenwillinhibittheirgrowthanddepositionofECMcomponents,andcanlead
toexcessive,fibroticscarring.
Oneoffibroblasts'mostimportantdutiesistheproductionofcollagen.[37]
Collagendepositionisimportantbecauseitincreasesthestrengthofthewoundbeforeitislaiddown,
theonlythingholdingthewoundclosedisthefibrinfibronectinclot,whichdoesnotprovidemuch
resistancetotraumaticinjury.[20]Also,cellsinvolvedininflammation,angiogenesis,andconnective
tissueconstructionattachto,growanddifferentiateonthecollagenmatrixlaiddownbyfibroblasts.[41]

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TypeIIIcollagenandfibronectinaregenerallybeginningtobeproducedinappreciableamountsat
somewherebetweenapproximately10hours[42]and3days,[38]dependingmainlyonwoundsize.Their
depositionpeaksatonetothreeweeks.[28]Theyarethepredominatingtensilesubstancesuntilthelater
phaseofmaturation,inwhichtheyarereplacedbythestrongertypeIcollagen.
Evenasfibroblastsareproducingnewcollagen,collagenasesandotherfactorsdegradeit.Shortlyafter
wounding,synthesisexceedsdegradationsocollagenlevelsinthewoundrise,butlaterproductionand
degradationbecomeequalsothereisnonetcollagengain.[20]Thishomeostasissignalstheonsetofthe
latermaturationphase.Granulationgraduallyceasesandfibroblastsdecreaseinnumberinthewound
oncetheirworkisdone.[43]Attheendofthegranulationphase,fibroblastsbegintocommitapoptosis,
convertinggranulationtissuefromanenvironmentrichincellstoonethatconsistsmainlyofcollagen.[3]

Epithelialization[edit]
Theformationofgranulationtissueintoanopenwoundallowsthereepithelializationphasetotake
place,asepithelialcellsmigrateacrossthenewtissuetoformabarrierbetweenthewoundandthe
environment.[38]Basalkeratinocytesfromthewoundedgesanddermalappendagessuchashair
follicles,sweatglandsandsebacious(oil)glandsarethemaincellsresponsiblefortheepithelialization
phaseofwoundhealing.[43]Theyadvanceinasheetacrossthewoundsiteandproliferateatitsedges,
ceasingmovementwhentheymeetinthemiddle.Inhealingthatresultsinascar,sweatglands,hair
follicles[44][45]andnervesdonotform.Withthelackofhairfollicles,nervesandsweatglands,thewound,
andtheresultinghealingscar,provideachallengetothebodywithregardstotemperaturecontrol.[45]
Keratinocytesmigratewithoutfirstproliferating.[46]Migrationcanbeginasearlyasafewhoursafter
wounding.However,epithelialcellsrequireviabletissuetomigrateacross,soifthewoundisdeepit
mustfirstbefilledwithgranulationtissue.[47]Thusthetimeofonsetofmigrationisvariableandmay
occuraboutonedayafterwounding.[48]Cellsonthewoundmarginsproliferateonthesecondandthird
daypostwoundinginordertoprovidemorecellsformigration.[28]
Ifthebasementmembraneisnotbreached,epithelialcellsarereplacedwithinthreedaysbydivision
andupwardmigrationofcellsinthestratumbasaleinthesamefashionthatoccursinuninjuredskin.[38]
However,ifthebasementmembraneisruinedatthewoundsite,reepithelizationmustoccurfromthe
woundmarginsandfromskinappendagessuchashairfolliclesandsweatandoilglandsthatenterthe
dermisthatarelinedwithviablekeratinocytes.[28]Ifthewoundisverydeep,skinappendagesmayalso
beruinedandmigrationcanonlyoccurfromwoundedges.[47]
Migrationofkeratinocytesoverthewoundsiteisstimulatedbylackofcontactinhibitionandby
chemicalssuchasnitricoxide.[49]Beforetheybegintomigrate,cellsmustdissolvetheirdesmosomes
andhemidesmosomes,whichnormallyanchorthecellsbyintermediatefilamentsintheircytoskeletonto
othercellsandtotheECM.[23]Transmembranereceptorproteinscalledintegrins,whicharemadeof
glycoproteinsandnormallyanchorthecelltothebasementmembranebyitscytoskeleton,arereleased
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fromthecell'sintermediatefilamentsandrelocatetoactinfilamentstoserveasattachmentstotheECM
forpseudopodiaduringmigration.[23]Thuskeratinocytesdetachfromthebasementmembraneandare
abletoenterthewoundbed.[36]
Beforetheybeginmigrating,keratinocyteschangeshape,becominglongerandflatterandextending
cellularprocesseslikelamellipodiaandwideprocessesthatlooklikeruffles.[32]Actinfilamentsand
pseudopodiaform.[36]Duringmigration,integrinsonthepseudopodattachtotheECM,andtheactin
filamentsintheprojectionpullthecellalong.[23]TheinteractionwithmoleculesintheECMthrough
integrinsfurtherpromotestheformationofactinfilaments,lamellipodia,andfilopodia.[23]
Epithelialcellsclimboveroneanotherinordertomigrate.[43]Thisgrowingsheetofepithelialcellsis
oftencalledtheepithelialtongue.[46]Thefirstcellstoattachtothebasementmembraneformthe
stratumbasale.Thesebasalcellscontinuetomigrateacrossthewoundbed,andepithelialcellsabove
themslidealongaswell.[46]Themorequicklythismigrationoccurs,thelessofascartherewillbe.[50]
Fibrin,collagen,andfibronectinintheECMmayfurthersignalcellstodivideandmigrate.Like
fibroblasts,migratingkeratinocytesusethefibronectincrosslinkedwithfibrinthatwasdepositedin
inflammationasanattachmentsitetocrawlacross.[25][32][43]
Ascabcoveringahealingwound

Askeratinocytesmigrate,theymoveovergranulationtissuebutunderneaththescab(ifonewas
formed),separatingitfromtheunderlyingtissue.[43][48]Epithelialcellshavetheabilitytophagocytize
debrissuchasdeadtissueandbacterialmatterthatwouldotherwiseobstructtheirpath.Becausethey
mustdissolveanyscabthatforms,keratinocytemigrationisbestenhancedbyamoistenvironment,
sinceadryoneleadstoformationofabigger,tougherscab.[25][38][43][51]Tomaketheirwayalongthe
tissue,keratinocytesmustdissolvetheclot,debris,andpartsoftheECMinordertogetthrough.[48][52]
Theysecreteplasminogenactivator,whichactivatesplasminogen,turningitintoplasmintodissolvethe
scab.Cellscanonlymigrateoverlivingtissue,[43]sotheymustexcretecollagenasesandproteaseslike
matrixmetalloproteinases(MMPs)todissolvedamagedpartsoftheECMintheirway,particularlyatthe
frontofthemigratingsheet.[48]Keratinocytesalsodissolvethebasementmembrane,usinginsteadthe
newECMlaiddownbyfibroblaststocrawlacross.[23]
Askeratinocytescontinuemigrating,newepithelialcellsmustbeformedatthewoundedgestoreplace
themandtoprovidemorecellsfortheadvancingsheet.[25]Proliferationbehindmigratingkeratinocytes
normallybeginsafewdaysafterwounding[47]andoccursataratethatis17timeshigherinthisstageof
epithelializationthaninnormaltissues.[25]Untiltheentirewoundareaisresurfaced,theonlyepithelial
cellstoproliferateareatthewoundedges.[46]
Growthfactors,stimulatedbyintegrinsandMMPs,causecellstoproliferateatthewoundedges.
Keratinocytesthemselvesalsoproduceandsecretefactors,includinggrowthfactorsandbasement
membraneproteins,whichaidbothinepithelializationandinotherphasesofhealing.[53]Growthfactors
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arealsoimportantfortheinnateimmunedefenseofskinwoundsbystimulationoftheproductionof
antimicrobialpeptidesandneutrophilchemotacticcytokinesinkeratinocytes.
Keratinocytescontinuemigratingacrossthewoundbeduntilcellsfromeithersidemeetinthemiddle,at
whichpointcontactinhibitioncausesthemtostopmigrating.[32]Whentheyhavefinishedmigrating,the
keratinocytessecretetheproteinsthatformthenewbasementmembrane.[32]Cellsreversethe
morphologicalchangestheyunderwentinordertobeginmigratingtheyreestablishdesmosomesand
hemidesmosomesandbecomeanchoredonceagaintothebasementmembrane.[23]Basalcellsbegin
todivideanddifferentiateinthesamemannerastheydoinnormalskintoreestablishthestratafoundin
reepithelializedskin.[32]

Contraction[edit]
Contractionisakeyphaseofwoundhealingwithrepair.Ifcontractioncontinuesfortoolong,itcanlead
todisfigurementandlossoffunction.[33]Thusthereisagreatinterestinunderstandingthebiologyof
woundcontraction,whichcanbemodelledinvitrousingthecollagengelcontractionassayorthedermal
equivalentmodel.[27][54]
Contractioncommencesapproximatelyaweekafterwounding,whenfibroblastshavedifferentiatedinto
myofibroblasts[55]Infullthicknesswounds,contractionpeaksat5to15dayspostwounding.[38]
Contractioncanlastforseveralweeks[47]andcontinuesevenafterthewoundiscompletely
reepithelialized.[3]Alargewoundcanbecome40to80%smalleraftercontraction. [32][43]Woundscan
contractataspeedofupto0.75mmperday,dependingonhowloosethetissueinthewoundedarea
is.[38]Contractionusuallydoesnotoccursymmetricallyrathermostwoundshavean'axisofcontraction'
whichallowsforgreaterorganizationandalignmentofcellswithcollagen.[55]
Atfirst,contractionoccurswithoutmyofibroblastinvolvement.[56]Later,fibroblasts,stimulatedbygrowth
factors,differentiateintomyofibroblasts.Myofibroblasts,whicharesimilartosmoothmusclecells,are
responsibleforcontraction.[56]Myofibroblastscontainthesamekindofactinasthatfoundinsmooth
musclecells.[33]
Myofibroblastsareattractedbyfibronectinandgrowthfactorsandtheymovealongfibronectinlinkedto
fibrinintheprovisionalECMinordertoreachthewoundedges.[25]TheyformconnectionstotheECMat
thewoundedges,andtheyattachtoeachotherandtothewoundedgesbydesmosomes.Also,atan
adhesioncalledthefibronexus,actininthemyofibroblastislinkedacrossthecellmembraneto
moleculesintheextracellularmatrixlikefibronectinandcollagen.[56]Myofibroblastshavemanysuch
adhesions,whichallowthemtopulltheECMwhentheycontract,reducingthewoundsize.[33]Inthispart
ofcontraction,closureoccursmorequicklythaninthefirst,myofibroblastindependentpart.[56]
Astheactininmyofibroblastscontracts,thewoundedgesarepulledtogether.Fibroblastslaydown
collagentoreinforcethewoundasmyofibroblastscontract.[3]Thecontractionstageinproliferationends
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asmyofibroblastsstopcontractingandcommitapoptosis.[33]Thebreakdownoftheprovisionalmatrix
leadstoadecreaseinhyaluronicacidandanincreaseinchondroitinsulfate,whichgraduallytriggers
fibroblaststostopmigratingandproliferating.[19]Theseeventssignaltheonsetofthematurationstage
ofwoundhealing.

Maturationandremodeling[edit]
Whenthelevelsofcollagenproductionanddegradationequalize,thematurationphaseoftissuerepair
issaidtohavebegun.[20]Duringmaturation,typeIIIcollagen,whichisprevalentduringproliferation,is
replacedbytypeIcollagen.[17]Originallydisorganizedcollagenfibersarerearranged,crosslinked,and
alignedalongtensionlines.[32]Theonsetofthematurationphasemayvaryextensively,dependingon
thesizeofthewoundandwhetheritwasinitiallyclosedorleftopen,[28]rangingfromapproximately3
days[42]to3weeks.[57]Thematurationphasecanlastforayearorlonger,similarlydependingonwound
type.[28]
Asthephaseprogresses,thetensilestrengthofthewoundincreases,withthescartissueultimately
becomingasstrongas80%ofthestrengthofnormaltissue.[28]Sinceactivityatthewoundsiteis
reduced,thescarlosesitsredappearanceasbloodvesselsthatarenolongerneededareremovedby
apoptosis.[20]
Thephasesofwoundhealingnormallyprogressinapredictable,timelymanneriftheydonot,healing
mayprogressinappropriatelytoeitherachronicwound[6]suchasavenousulcerorpathological
scarringsuchasakeloidscar.[58][59]

Factorsaffectingwoundhealing[edit]
Manyfactorscontrollingtheefficacy,speed,andmannerofwoundhealingfallundertwotypes:local
andsystemicfactors.[2]

Localfactors[edit]
Moisturekeepingawoundmoistratherthandrymakeswoundhealingmorerapidandwithlesspain
andlessscarring[60]
Mechanicalfactors
Foreignbodies

Researchanddevelopment[edit]
Upuntiladecadeago,theclassicparadigmofwoundhealing,involvingstemcellsrestrictedtoorgan
specificlineages,hadneverbeenseriouslychallenged.Sincethen,thenotionofadultstemcellshaving
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cellularplasticityortheabilitytodifferentiateintononlineagecellshasemergedasanalternative
explanation.[1]Tobemorespecific,hematopoieticprogenitorcells(thatgiverisetomaturecellsinthe
blood)mayhavetheabilitydedifferentiatebackintohematopoieticstemcellsand/ortransdifferentiate
intononlineagecells,suchasfibroblasts.[40]

Stemcellsandcellularplasticity[edit]
Multipotentadultstemcellshavethecapacitytobeselfrenewingandgiverisetodifferentcelltypes.
Stemcellsgiverisetoprogenitorcells,whicharecellsthatarenotselfrenewing,butcangenerate
severaltypesofcells.Theextentofstemcellinvolvementincutaneous(skin)woundhealingiscomplex
andnotfullyunderstood.
Itisthoughtthattheepidermisanddermisarereconstitutedbymitoticallyactivestemcellsthatresideat
theapexofreteridges(basalstemcellsorBSC),thebulgeofhairfollicles(hairfollicularstemcellor
HFSC),andthepapillarydermis(dermalstemcells).[1]Moreover,bonemarrowmayalsocontainstem
cellsthatplayamajorroleincutaneouswoundhealing.[40]
Inrarecircumstances,suchasextensivecutaneousinjury,selfrenewalsubpopulationsinthebone
marrowareinducedtoparticipateinthehealingprocess,wherebytheygiverisetocollagensecreting
cellsthatseemtoplayaroleduringwoundrepair.[1]Thesetwoselfrenewalsubpopulationsare(1)bone
marrowderivedmesenchymalstemcells(MSC)and(2)hematopoieticstemcells(HSC).Bonemarrow
alsoharborsaprogenitorsubpopulation(endothelialprogenitorcellsorEPC)that,inthesametypeof
setting,aremobilizedtoaidinthereconstructionofbloodvessels.[40]Moreover,itthoughtthat,
extensiveinjurytoskinalsopromotestheearlytraffickingofauniquesubclassofleukocytes(circulating
fibrocytes)totheinjuredregion,wheretheyperformvariousfunctionsrelatedtowoundhealing.[1]

Woundrepairversusregeneration[edit]
Aninjuryisaninterruptionofmorphologyand/orfunctionalityofagiventissue.Afterinjury,structural
tissuehealswithincompleteorcompleteregeneration.[61][62]Ontheotherhand,tissuewithoutan
interruptiontomorphologyalmostalwayscompletelyregenerates.Anexampleofcompleteregeneration
withoutaninterruptionofthemorphologyisnoninjuredtissue,suchasskin.[63]Noninjuredskinhasa
continuedreplacementandregenerationofcellswhichalwaysresultsincompleteregeneration.[63]
Thereisasubtledistinctionbetween'repair'andregeneration.[1][61][62]Repairmeansincomplete
regeneration.[61]Repairorincompleteregeneration,referstothephysiologicadaptationofanorgan
afterinjuryinanefforttoreestablishcontinuitywithoutregardstoexactreplacementoflost/damaged
tissue.[61]Truetissueregenerationorcompleteregeneration,[62]referstothereplacementof
lost/damagedtissuewithanexactcopy,suchthatbothmorphologyandfunctionalityarecompletely
restored.[62]Thoughafterinjurymammalscancompletelyregeneratespontaneously,theyusuallydonot
completelyregenerate.Anexampleofatissueregeneratingcompletelyafteraninterruptionof
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morphologyistheendometriumtheendometriumaftertheprocessofbreakdownviathemenstruation
cyclehealswithcompleteregeneration.[63]
Insomeinstances,afteratissuebreakdown,suchasinskin,aregenerationclosertocomplete
regenerationmaybeinducedbytheuseofbiodegradable(collagenglycoaminoglycan)scaffolds.These
scaffoldsarestructurallyanalogoustoextracellularmatrix(ECM)foundinnormal/uninjureddermis.[64]
Interestingly,fundamentalconditionsrequiredfortissueregenerationoftenopposeconditionsthatfavor
efficientwoundrepair,includinginhibitionof(1)plateletactivation,(2)inflammatoryresponse,and(3)
woundcontraction.[1]Inadditiontoprovidingsupportforfibroblastandendothelialcellattachment,
biodegradablescaffoldsinhibitwoundcontraction,therebyallowingthehealingprocesstoproceed
towardsamoreregenerative/lessscarringpathway.Pharmaceuticalagentshavebeeninvestigated
whichmaybeabletoturnoffmyofibroblastdifferentiation.[65]
Anewwayofthinkingderivedfromthenotionthatheparansulfatesarekeyplayerintissue
homeostasis:theprocessthatmakesthetissuereplacedeadcellsbyidenticalcells.Inwoundareas,
tissuehomeostasisislostastheheparansulfatesaredegradedpreventingthereplacementofdead
cellsbyidenticalcells.Heparansulfateanaloguescannotbedegradedbyallknowheparanasesand
glycanasesandbindtothefreeheparinsulfatebindingspotsontheECM,thereforepreservingthe
normaltissuehomeostasisandpreventingscarring.[66][67][68]
Repairorregenerationwithregardstohypoxiainduciblefactor1alpha(HIF1a).Innormal
circumstancesafterinjuryHIF1aisdegradedbyprolylhydroxylases(PHDs).Scientistsfoundthatthe
simpleupregulationofHIF1aviaPHDinhibitorsregenerateslostordamagedtissueinmammalsthat
havearepairresponseandthecontinueddownregulationofHif1aresultsinhealingwithascarring
responseinmammalswithapreviousregenerativeresponsetothelossoftissue.Theactofregulating
HIF1acaneitherturnoff,orturnonthekeyprocessofmammalianregeneration.[69][70]

Scarlesswoundhealing[edit]
Scarlesswoundhealingisaconceptbasedonthehealingorrepairoftheskin(orothertissue/organs)
afterinjurywiththeaimofhealingwithsubjectivelyandrelativelylessscartissuethannormally
expected.Scarlesshealingissometimesmixedupwiththeconceptofscarfreehealing,whichiswound
healingwhichresultsinabsolutelynoscar(freeofscarring).Howevertheyaredifferentconcepts.
Areversetoscarlesswoundhealingisscarification(woundhealingtoscarmore).Historically,certain
culturesconsiderscarificationattractive,[71]however,thisisgenerallynotthecaseinthemodern
westernsociety,inwhichmanypatientsareturningtoplasticsurgeryclinicswithunrealisticexpectations.
Dependingonscartype,treatmentmaybeinvasive(intralesionalsteroidinjections,surgery)and/or
conservative(compressiontherapy,topicalsiliconegel,brachytherapy,photodynamictherapy).[72]
Clinicaljudgmentisnecessarytosuccessfullybalancethepotentialbenefitsofthevarioustreatments
availableagainstthelikelihoodofapoorresponseandpossiblecomplicationsresultingfromthese
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treatments.Manyofthesetreatmentsmayonlyhaveaplaceboeffect,andtheevidencebaseforthe
useofmanycurrenttreatmentsispoor.[73]
Inthelastfewdecades,comprehensionofthebasicbiologicprocessesinvolvedinwoundrepairand
tissueregenerationhaveexpandedduetoadvancesincellularandmolecularbiology.[74]Currently,the
principalgoalsinwoundmanagementaretoachieverapidwoundclosurewithafunctionaltissuethat
hasminimalaestheticscarring.[75]However,theultimategoalofwoundhealingbiologyistoinducea
moreperfectreconstructionofthewoundarea.Scarlesswoundhealingonlyoccursinmammalianfoetal
tissues[76]andcompleteregenerationislimitedtolowervertebrates,suchassalamanders,and
invertebrates.[77]Inadulthumans,injuredtissuearerepairedbycollagendeposition,collagen
remodellingandeventualscarformation,wherefetalwoundhealingisbelievedtobemoreofa
regenerativeprocesswithminimalornoscarformation.[76]Therefore,foetalwoundhealingcanbeused
toprovideanaccessiblemammalianmodelofanoptimalhealingresponseinadulthumantissues.
Cluesastohowthismightbeachievedcomefromstudiesofwoundhealinginembryos,whererepairis
fastandefficientandresultsinessentiallyperfectregenerationofanylosttissue.
Theetymologyofthetermscarlesswoundhealinghasalonghistory.[78][79][80]Inprinttheantiquated
conceptofscarlesshealingwasbroughtuptheearly20thcenturyandappearedinapaperpublishedin
theLondonLancet.Thisprocessinvolvedcuttinginasurgicalslant,insteadofarightangleitwas
describedinvariousNewspapers.[78][79][80]

Simulatingwoundhealingfromagrowthperspective[edit]
Considerableefforthasbeendevotedtounderstandingthephysicalrelationshipsgoverningwound
healingandsubsequentscarring,withmathematicalmodelsandsimulationsdevelopedtoelucidate
theserelationships.[81]Thegrowthoftissuearoundthewoundsiteisaresultofthemigrationofcells
andcollagendepositionbythesecells.Thealignmentofcollagendescribesthedegreeofscarring
basketweaveorientationofcollagenischaracteristicofnormalskin,whereasalignedcollagenfibers
leadtosignificantscarring.[82]Ithasbeenshownthatthegrowthoftissueandextentofscarformation
canbecontrolledbymodulatingthestressatawoundsite.[83]
Thegrowthoftissuecanbesimulatedusingtheaforementionedrelationshipsfromabiochemicaland
biomechanicalpointofview.Thebiologicallyactivechemicalsthatplayanimportantroleinwound
healingaremodeledwithFickiandiffusiontogenerateconcentrationprofiles.Thebalanceequationfor
opensystemswhenmodelingwoundhealingincorporatesmassgrowthduetocellmigrationand
proliferation.Herethefollowingequationisused:
Dt0=Div(R)+R0,
whererepresentsmassdensity,Rrepresentsamassflux(fromcellmigration),andR0representsa
masssource(fromcellproliferation,division,orenlargement).[84]
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Primaryintention[edit]
Whenwoundedgesarebroughttogether(sutured/glued)sothattheyareadjacenttoeachother(re
approximated)
Minimizesscarring
Mostsurgicalwoundshealbyprimaryintentionhealing
Woundclosureisperformedwithsutures(stitches),staples,oradhesivetapeorglue.
Examples:wellrepairedlacerations,wellreducedbonefractures,healingafterflapsurgery

Secondaryintention[edit]
Thewoundisallowedtogranulate
Surgeonmaypackthewoundwithagauzeoruseadrainagesystem
Granulationresultsinabroaderscar
Healingprocesscanbeslowduetopresenceofdrainagefrominfection
Woundcaremustbeperformeddailytoencouragewounddebrisremovaltoallowforgranulation
tissueformation
Examples:gingivectomy,gingivoplasty,toothextractionsockets,poorlyreducedfractures,burns,
severelacerations,pressureulcers

Tertiaryintention[edit]
(Delayedprimaryclosureorsecondarysuture):
Thewoundisinitiallycleaned,debridedandobserved,typically4or5daysbeforeclosure.
Thewoundispurposelyleftopen
Examples:healingofwoundsbyuseoftissuegrafts.
Ifthewoundedgesarenotreapproximatedimmediately,delayedprimarywoundhealingtranspires.This
typeofhealingmaybedesiredinthecaseofcontaminatedwounds.Bythefourthday,phagocytosisof
contaminatedtissuesiswellunderway,andtheprocessesofepithelization,collagendeposition,and
maturationareoccurring.Foreignmaterialsarewalledoffbymacrophagesthatmaymetamorphoseinto
epithelioidcells,whichareencircledbymononuclearleukocytes,forminggranulomas.Usuallythe
woundisclosedsurgicallyatthisjuncture,andifthe"cleansing"ofthewoundisincomplete,chronic
inflammationcanensue,resultinginprominentscarring.

Overviewofinvolvedgrowthfactors[edit]
Followingarethemaingrowthfactorsinvolvedinwoundhealing:
Growthfactor

Abbreviation

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Mainorigins
Activated

Effects
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Activated
Epidermalgrowth

macrophages

Keratinocyteandfibroblastmitogen

Salivary

Keratinocytemigration

glands

Granulationtissueformation

EGF
factor

Keratinocytes

Activated
macrophages
Transforming
growthfactor

TGF

T
lymphocytes
Keratinocytes

Hepatocytegrowth
factor

Mesenchymal
HGF

Vascular
endothelialgrowth

VEGF

cells

Hepatocyteandepithelialcell
proliferation
Expressionofantimicrobialpeptides
Expressionofchemotacticcytokines

Epithelialandendothelialcell
proliferation
Hepatocytemotility

Mesenchymal

Vascularpermeability

cells

Endothelialcellproliferation

factor
Granulocyte,macrophage,fibroblast
andsmoothmusclecellchemotaxis

Plateletderived
growthfactor

PDGF

Platelets

Granulocyte,macrophageand

Macrophages

fibroblastactivation

Endothelial

Fibroblast,endothelialcellandsmooth

cells

musclecellproliferation

Smooth

Matrixmetalloproteinase,fibronectin

musclecells

andhyaluronanproduction

Keratinocytes

Angiogenesis
Woundremodeling
Integrinexpressionregulation

Macrophages
Mastcells
T
Fibroblastgrowth
factor1and2

FGF1,2

lymphocytes
Endothelial
cells

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Fibroblasts

Fibroblastchemotaxis
Fibroblastandkeratinocyteproliferation
Keratinocytemigration
Angiogenesis
Woundcontraction
Matrix(collagenfibers)deposition
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Fibroblasts

Transforming
growthfactor

TGF

Platelets

Granulocyte,macrophage,lymphocyte,

fibroblastandsmoothmusclecell

lymphocytes

chemotaxis

Macrophages

TIMPsynthesis

Endothelial

Angiogenesis

cells

Fibroplasia

Keratinocytes

Matrixmetalloproteinaseproduction

Smooth

inhibition

musclecells

Keratinocyteproliferation

Fibroblasts

Keratinocyte
growthfactor

KGF

Keratinocytes

Keratinocytemigration,proliferationand
differentiation

Unlesselsespecifiedinboxes,thenreferenceis:[85]

ComplicationsofWoundHealing[edit]
ThissectionmayrequirecleanuptomeetWikipedia'squalitystandards.(April2012)
Themajorcomplicationsaremany:
1.DeficientScarFormation:Resultinwounddehiscenceorruptureofthewoundduetoinadequate
formationofgranulationtissue.
2.ExuberantGranulation(Proudflesh).
3.DeficientContraction(inskingrafts)orexcessivecontraction(inburns).
4.Others:Dystrophiccalcification,pigmentarychanges,painfulscars,inscisionalherniaetc.

Biologics,skinsubstitutes,biomembranesandscaffolds[edit]
Advancementsintheclinicalunderstandingofwoundsandtheirpathophysiologyhavecommanded
significantbiomedicalinnovationsinthetreatmentofacute,chronic,andothertypesofwounds.Many
biologics,skinsubstitutes,biomembranesandscaffoldshavebeendevelopedtofacilitatewoundhealing
throughvariousmechanisms.Thisincludesproductssuchasmonoterpenes,Epicel,Laserskin,
Transcyte,Dermagraft,AlloDerm/Strattice,Biobrane,Integra,Apligraf,OrCel,GraftJacketand
PermaDerm.Asystematicreviewoftheseproductswithmechanismsandclinicaloutcomesis
summarizedbyVyas,etal.[86]

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