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ImagingTechnologiesandTransdermal DeliveryinSkinDisorders

ImagingTechnologiesandTransdermal DeliveryinSkinDisorders

Editedby ChenjieXu

XiaomengWang

ManojitPramanik

Editors

Dr.ChenjieXu

NanyangTechnologicalUniversity SchoolofChemicalandBiomedical Engineering

62NanyangDrive 637459Singapore Singapore

Dr.XiaomengWang NanyangTechnologicalUniversity LeeKongChianSchoolofMedicine 59NanyangDrive 636921Singapore

Singapore

Dr.ManojitPramanik NanyangTechnologicalUniversity SchoolofChemicalandBiomedical Engineering

62NanyangDrive 637459Singapore Singapore

Allbookspublishedby Wiley-VCH arecarefullyproduced.Nevertheless, authors,editors,andpublisherdonot warranttheinformationcontainedin thesebooks,includingthisbook,to befreeoferrors.Readersareadvised tokeepinmindthatstatements,data, illustrations,proceduraldetailsorother itemsmayinadvertentlybeinaccurate.

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©2020Wiley-VCHVerlagGmbH& Co.KGaA,Boschstr.12,69469 Weinheim,Germany

Allrightsreserved(includingthoseof translationintootherlanguages).No partofthisbookmaybereproducedin anyform–byphotoprinting, microfilm,oranyothermeans–nor transmittedortranslatedintoa machinelanguagewithoutwritten permissionfromthepublishers. Registerednames,trademarks,etc.used inthisbook,evenwhennotspecifically markedassuch,arenottobe consideredunprotectedbylaw.

PrintISBN: 978-3-527-34460-4

ePDFISBN: 978-3-527-81466-4

ePubISBN: 978-3-527-81464-0

oBookISBN: 978-3-527-81463-3

Typesetting SPiGlobal,Chennai,India PrintingandBinding

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10987654321

Contents

Foreword xvii

1SkinStructureandBiology 1

Wei-MengWoo

1.1Introduction 1

1.2SkinStructure 2

1.2.1OverviewofSkinTissueOrganization 2

1.2.1.1ThickSkinandThinSkin 2

1.2.2Epidermis 3

1.2.2.1StratumBasale 5

1.2.2.2StratumSpinosum 5

1.2.2.3StratumGranulosum 6

1.2.2.4StratumLucidum 6

1.2.2.5StratumCorneum 6

1.2.3Dermis 6

1.2.4Hypodermis 7

1.2.5SkinAppendages 8

1.3SkinBiology 9

1.3.1Homeostasis:EpidermalSelf-renewal 9

1.3.2FormationofaWaterBarrier 10

1.3.3GettingAcrosstheWaterBarrier 11 References 12

2WoundHealingandItsImaging 15

JiahShinChin,LeighMadden,SingYianChew,AnthonyR.J.Phillips andDavidL.Becker

2.1HemostasisandEssentialInflammation 15

2.2Re-epithelialization 18

2.3GranulationTissueFormation 19

2.4ScarTissueFormation 20

2.5ImagingofWoundHealing 21

2.6MacroscopicDigitalImagingforWoundSize 22

2.7HyperspectralandMultispectralImaging 22

2.8Near-InfraredSpectroscopy 23

2.9RamanImaging 23

2.10ConfocalMicroscopy 24

2.11MultiphotonImagingandSecondHarmonics 24 References 27

3CommonSkinDiseases:ChronicInflammatoryand AutoimmuneDisorders 35

NavinKumarVerma,MauriceAdrianusMoniquevanSteensel, PraseethaPrasannan,ZhiShengPoh,AlanD.IrvineandHazelH.Oon

3.1Introduction 35

3.2Psoriasis 36

3.2.1DefinitionandPrevalence 36

3.2.2ClinicalFeatures,Pathogenesis,andPathophysiology 37

3.2.3Diagnosis 39

3.2.4Therapy 40

3.3AtopicDermatitis(AD) 40

3.3.1DefinitionandPrevalence 40

3.3.2ClinicalFeatures,Pathogenesis,andPathophysiology 41

3.3.3Diagnosis 42

3.3.4Therapy 43

3.4Scleroderma 43

3.4.1DefinitionandPrevalence 43

3.4.2ClinicalFeatures,Pathogenesis,andPathophysiology 44

3.4.3Diagnosis 44

3.4.4Therapy 45

3.5Dermatomyositis(DM) 45

3.5.1DefinitionandPrevalence 45

3.5.2ClinicalFeatures,Pathogenesis,andPathophysiology 46

3.5.3Diagnosis 46

3.5.4Therapy 47

3.6CutaneousLupusErythematosus(CLE) 47

3.6.1DefinitionandPrevalence 47

3.6.2ClinicalFeatures,Pathogenesis,andPathophysiology 47

3.6.3Diagnosis 48

3.6.4Treatment 49

3.7GeneralizedVitiligo(GV) 49

3.7.1DefinitionandPrevalence 49

3.7.2ClinicalFeatures,Pathogenesis,andPathophysiology 49

3.7.3Diagnosis 50

3.7.4Treatment 51

3.8ConcludingRemarks 51 Acknowledgments 51 References 52

4CommonSkinDiseases:AutoimmuneBlisteringDisorders 61 NavinKumarVerma,ShermaineWanYuLow,HazelH.Oon,DermotKelleher andMauriceAdrianusMoniquevanSteensel

4.1Introduction 61

4.2Pemphigus 62

4.2.1DefinitionandPrevalence 62

4.2.2ClinicalFeatures,Pathogenesis,andPathophysiology 62

4.2.2.1PemphigusVulgaris(PV) 63

4.2.2.2PemphigusFoliaceous(PF) 64

4.2.2.3ParaneoplasticPemphigus(PNP) 64

4.2.2.4IgAPemphigus 66

4.2.2.5PemphigusErythematosus(PE) 66

4.2.2.6Drug-InducedPemphigus 66

4.2.3Diagnosis 67

4.2.4Treatment 67

4.3Pemphigoid 68

4.3.1DefinitionandPrevalence 68

4.3.2ClinicalFeatures,Pathogenesis,andPathophysiology 68

4.3.2.1BullousPemphigoid(BP) 68

4.3.2.2MucousMembranePemphigoid(MMP) 69

4.3.2.3PemphigoidGestationis(PG) 69

4.3.3Diagnosis 70

4.3.4Treatment 70

4.4DermatitisHerpetiformis(DH) 70

4.4.1DefinitionandPrevalence 70

4.4.2ClinicalFeatures,Pathogenesis,andPathophysiology 71

4.4.3Diagnosis 71

4.4.4Treatment 71

4.5EpidermolysisBullosaAcquisita(EBA) 72

4.5.1DefinitionandPrevalence 72

4.5.2ClinicalFeatures,Pathogenesis,andPathophysiology 72

4.5.3Diagnosis 73

4.5.4Treatment 73

4.6ConcludingRemarksandFutureDirections 73 Acknowledgments 74 References 74

5CommonSkinDiseases:SkinCancer 83 TuyenT.L.Nguyen,EricTaraporeandScottX.Atwood

5.1Introduction 83

5.2BasalCellCarcinoma 83

5.2.1RiskFactors 84

5.2.2Classification 85

5.2.3CellofOrigin 85

5.2.4SignalingPathways 86

5.2.5CommonTreatments 87

5.3SquamousCellCarcinoma 88

5.3.1RiskFactors 89

5.3.2Classification 89

5.3.3CellofOrigin 90

5.3.4SignalingPathways 90

5.3.5CommonTreatments 91

5.4Melanoma 92

5.4.1RiskFactors 92

5.4.2Classification 93

5.4.3CellofOrigin 94

5.4.4SignalingPathways 94

5.4.5CommonTreatments 94

5.5ConcludingRemarks 95 References 96

6PreclinicalModelsforDrugScreeningandTarget Validation 105

IvoJ.H.M.deVos,JuliaVerbistandMauriceA.M.vanSteensel

6.1Introduction 105

6.2 ExVivo ModelsofHumanSkin 105

6.2.1Introduction 105

6.2.2 ExVivo ModelsofSkinBarrierFunctionandDermalAbsorption 107

6.2.3 ExVivo ModelsofCutaneousWoundHealing 107

6.2.4 ExVivo HairFollicleCulture 108

6.3 InVitro ModelsofHumanSkin 108

6.3.1Introduction 108

6.3.2Two-DimensionalCellCultureModels 109

6.3.3Three-DimensionalReconstructedHumanSkinModels 109

6.3.3.1ReconstitutedHumanEpidermisModels 110

6.3.3.2ReconstitutedHumanDermisModels 111

6.3.3.3ReconstitutedSkinEquivalentModels 111

6.3.3.4Organoids 112

6.4 InVivo AnimalModels 112

6.4.1 Caenorhabditiselegans112

6.4.1.1Introduction 112

6.4.1.2AnatomyandPhysiologyoftheRoundwormEpidermis 112

6.4.1.3TheUseof Caenorhabditiselegans toStudyCutaneousWound Healing 113

6.4.2 Drosophilamelanogaster113

6.4.2.1Introduction 113

6.4.2.2AnatomyandPhysiologyoftheFruitFlyEpidermis 114

6.4.2.3StudyingCutaneousWoundHealingUsingFruitFlies 114

6.4.2.4InsightsinCutaneousInnateImmunityfrom Drosophila melanogaster115

6.4.2.5FruitFlyModelsofBullousDermatoses 115

6.4.2.6FruitFlyModelsofSkinCancer 115

6.4.3 Daniorerio116

6.4.3.1Introduction 116

6.4.3.2AnatomyandPhysiologyofZebrafishSkin 116

6.4.3.3ZebrafishModelstoStudyPigmentationandMelanoma 117

6.4.3.4StudyingCutaneousWoundHealingUsing Daniorerio117

6.4.3.5ZebrafishasPlatformforDrugDevelopment 117

6.4.3.6ZebrafishModelsofGenodermatoses 118

6.4.4 Musmusculus118

6.4.4.1Introduction 118

6.4.4.2AnatomyandPhysiologyofMurineSkin 119

6.4.4.3MurineModelsforStudyingCutaneousWoundHealing 120

6.4.4.4MurineModelsofPsoriasis 120

6.4.4.5MouseModelsofAutoimmuneBullousDermatoses 120

6.4.4.6StudyingMelanomaUsingMouseModels 121

6.4.4.7MouseandRatModelsofAlopeciaAreata 121

6.4.4.8InsightsinAcnePathogenesisandComedolysisfromMouse Models 122

6.4.5 Caviaporcellus122

6.4.5.1Introduction 122

6.4.5.2AnatomyandPhysiologyofGuineaPigSkin 123

6.4.5.3StudyingDermatophytosesUsingGuineaPigs 123

6.4.5.4GuineaPigModelsofEpidermalPermeabilityTopicalIrritant Testing 123

6.4.5.5StudyingBurnWoundsUsingGuineaPigs 123

6.4.5.6GuineaPigModelsforPigmentationStudies 124

6.4.6 Oryctolaguscuniculus124

6.4.6.1Introduction 124

6.4.6.2AnatomyandPhysiologyofLeporineSkin 124

6.4.6.3RabbitModelsofAcneVenenataandContact Dermatitis 125

6.4.6.4RabbitModelsofCutaneousWoundHealingand Scarring 125

6.4.6.5RabbitModelsforGenodermatoses 126

6.4.7 Canislupusfamiliaris126

6.4.7.1Introduction 126

6.4.7.2AnatomyandPhysiologyofDogSkin 126

6.4.7.3DogModelsofAtopicDermatitis 126

6.4.7.4DogModelsofAutoimmuneDisorders 127

6.4.7.5StudyingFollicularHyperkeratosisandKeratolysisinDogs 127

6.4.7.6DogModelsofMucosalMelanoma 127

6.4.7.7BullousDermatosesinDogs 128

6.4.8 Susscrofadomesticus128

6.4.8.1Introduction 128

6.4.8.2AnatomyandPhysiologyofPigSkin 128

6.4.8.3PorcineModelsofCutaneousWoundHealing 129

6.4.8.4PigModelsofCutaneousPermeability 129 References 129

7SkinTissueEngineeringwithNanostructuredMaterials 147 ZahraDavoudiandQunWang

7.1Introduction 147

7.2NanostructuredMaterialsforSkinTissueEngineering 148

7.2.1NaturalBiomaterialsforSkinTissueEngineering 148

7.2.1.1Collagen,CS,andBlendofTwo 148

7.2.1.2FibronectinandHyaluronicAcid(HA) 149

7.2.2SyntheticPolymersforSkinTissueEngineering 152

7.2.2.1PLA,PGA,andPolyurethaneHomopolymers 152

7.2.2.2PLGACopolymersandBlenders 153

7.2.3BlendofNaturalandSyntheticMaterials 153

7.3FabricationTechniques 154

7.3.1Self-AssemblyandPhaseSeparation 154

7.3.2Electrospinning 156

7.4ClinicalApplicationofTissueEngineeredSkin 157

7.4.1SkinGrafts 157

7.4.2StemCellApplicationinSkinTissueEngineering 159

7.5Summary 162 References 163

8TopicalandTransdermalDeliverywithChemicalEnhancers andNanoparticles 169

ChandrashekharVoshavar,PraveenKumarVemulaandSrujanMarepally

8.1Introduction 169

8.2AnatomyofSkin/SkinStructure 170

8.3SkinPermeationRoutes 171

8.4ChemicalEnhancers(CEs)orSkinPenetrationEnhancers 172

8.4.1CharacteristicsofanIdealChemicalEnhancer 173

8.4.2ClassificationofChemicalEnhancers 173

8.4.2.1Water 173

8.4.2.2Alcohols,FattyAlcohols,andGlycols 175

8.4.2.3Amides/AzonesandDerivatives 175

8.4.2.4Esters 176

8.4.2.5SulfoxidesandSimilarChemicals 177

8.4.2.6Ureas 177

8.4.2.7FattyAcids 178

8.4.2.8EssentialOils(EOs),Terpenes,andTerpenoids 179

8.4.2.9Surfactants 180

8.4.2.10PyrrolidonesandDerivatives 181

8.4.2.11Phospholipids 182

8.4.2.12Cyclodextrins 182

8.5TransdermalDeliveryUsingNanoparticles 182

8.5.1LipidBasedNanoparticles 184

8.5.2PolymerBasedNanoparticles 185

8.5.2.1NanoparticlesBasedonBiodegradableSyntheticPolymers 186

8.5.2.2NanoparticlesBasedonBiodegradableSyntheticPolymers 187

8.5.2.3CationicHybridPolymericNanoparticlesforNucleicAcid Delivery 188

8.5.2.4MechanismofPolymericNanoparticlesSkinPermeation 189

8.6PeptidesforSkinPermeation 189

8.7Peptide–NucleicAcidNanoconjugates 190

8.8SphericalNucleicAcids 191

8.9Conclusion 191

References 192

9Needle-FreeJetInjectorsforDermalandTransdermalDelivery ofActives 201

MicheleSchlich,RositaPrimavera,FrancescoLai,ChiaraSinico andPaoloDecuzzi

9.1Introduction 201

9.2ComponentsandFunctioningPrinciple 203

9.3ModulatingtheDepthofActiveDelivery 203

9.4ClinicalandPreclinicalUseofNeedle-FreeJetInjectorsforSystemic DrugDelivery 206

9.4.1Vaccines 206

9.4.2Insulin 208

9.4.3GrowthHormone 210

9.4.4Triptans 211

9.4.5Others 211

9.5ClinicalandPreclinicalUseofNeedle-FreeJetInjectorsforLocalDrug Delivery 212

9.5.1LocalAnesthetics 212

9.5.2Others 213

9.6FuturePerspectives:JetInjectionforNano-/Microparticles 215 References 216

10MicroneedlesforTransdermalDrugDelivery 223

EmanM.MigdadiandRyanF.Donnelly

10.1Introduction 223

10.2Microneedles 223

10.2.1MNDeliveryStrategies 225

10.2.1.1SolidMNs 225

10.2.1.2CoatedMNs 226

10.2.1.3HollowMNs 227

10.2.1.4DissolvingMNs 228

10.2.1.5Hydrogel-FormingMNs 230

10.2.2MNFabricationMethods 232

10.2.3MNsandVaccineDelivery 235

10.2.4MNsforPatientDrugMonitoring 237

10.2.5MNSkinInsertionandRecoveryProcess 239

10.2.6PainPerceptionandSkinAdverseReactionsofMNApplication 242

10.2.7MNProducts 243

10.2.8CombinationofMNswithOtherTechniques 245

10.2.9MN-AssistedMicroparticleandNanoparticlePermeation 245

10.3MicroneedlesinManagementofSkinDisorders 247

10.4FutureConsiderationsforMNTechnology 249

10.5Conclusion 250 References 251

11Ultrasound-EnhancedTransdermalDrugDelivery 271

JamesJingKwanandSunaliBhatnagar

11.1Introduction 271

11.2PrinciplesinUltrasound 271

11.2.1AcousticWaves 271

11.2.2UltrasoundTransducersandInstrumentation 272

11.2.3PropagationofUltrasound 274

11.2.4UltrasoundPhenomena 274

11.2.4.1MechanicalEffects 274

11.2.4.2ThermalEffects 275

11.2.4.3AcousticCavitation 275

11.2.5MechanismsofAction 276

11.3StateoftheArtinUltrasound-EnhancedTransdermalDrug Delivery 277

11.3.1ModesofDelivery 277

11.3.1.1UltrasoundPretreatment 277

11.3.1.2Co-applicationofUltrasoundandDrug 278

11.3.2DrugDosageMedium 279

11.3.3Ultrasound-AssistedDrugDelivery:DrugFormulationsandSafety Concerns 280

11.3.3.1DrugFormulations 280

11.3.3.2SafetyConcerns 282

11.3.4ApplicationsofUltrasound-EnhancedTransdermalDelivery 283

11.3.4.1ImmunizationUsingUltrasound 283

11.4Conclusions 284 References 284

12IontophoresisEnhancedTransdermalDrugDelivery 291

XiayuNing,RazinaZ.SeeniandChenjieXu

12.1Introduction 291

12.1.1Hyperhidrosis 292

12.1.2DeliveryofAnestheticsforPainManagement 292

12.1.3DiagnosisofCysticFibrosis 292

12.1.4GlucoseMonitoring 293

12.1.5GrowingInterest 293

12.2EnhancingTransdermalDrugDeliveryUsingIontophoresis Alone 294

12.2.1IontophoreticTransdermalDeliveryofSmallMolecules 297

12.2.2IontophoreticTransdermalDeliveryofMacromolecules 297

12.3EnhancingTransdermalDrugDeliveryUsingCombinationof IontophoresisandOtherApproaches 300

12.3.1IontophoresiswithChemicalEnhancers 300

12.3.2IontophoresiswithMicroneedles 302

12.3.3IontophoresisandNanoparticles 303

12.4SummaryandOutlook 304 References 304

13UltrasoundImaginginDermatology 309

JihunKim,SangyeonYounandJaeYounHwang

13.1Introduction 309

13.2ThePhysicsofUltrasound 309

13.3UltrasonicTransducers 313

13.3.1PiezoelectricMaterials 314

13.3.1.1PZTCeramics 316

13.3.1.2PiezoelectricSingleCrystals 316

13.3.1.3Relaxor-BasedSingleCrystals 316

13.3.2MatchingLayer 317

13.3.3BackingLayer 317

13.3.4Single-ElementUltrasoundTransducers 318

13.3.5ArrayUltrasoundTransducers 318

13.4UltrasoundImagingSystemsforSkinDiagnosis 320

13.4.1UltrasoundImagingwithSingle-ElementUltrasound Transducers 321

13.4.1.1ScanningMethodsforUltrasoundImagingBasedonSingle-Element UltrasoundTransducers 322

13.4.1.2High-FrequencyUltrasoundImagingoftheSkinUsingAdvanced Techniques 323

13.4.2UltrasoundImagingwithArrayUltrasoundTransducers 326

13.5ApplicationsofUltrasoundImaginginDermatology 330

13.5.1UltrasoundImagingofSkinCancer 330

13.5.2UltrasoundImagingofInflammatoryandInfectiousSkin Diseases 332

13.5.3UltrasoundImagingforOtherSkinApplications 334

13.6Conclusions 334 Acknowledgments 335 References 335

14QuantitativeMagneticResonanceImagingoftheSkin: InVitro andInVivo Applications 341

BernardQuerleux,GenevièveGuillot,Jean-ChristopheGinéfri, MariePoirier-QuinotandLucDarrasse

14.1Introduction 341

14.2ClinicalMagneticResonanceImagingoftheSkin 342

14.2.1HardwareChallengesforSkinImaging 342

14.2.1.1Introduction:ChallengesforHigh-ResolutionMRImaging 342

14.2.1.2OptimizedRFCoilDesignforSkinImaging 345

14.2.2StateoftheArtofClinicalMRApplicationsofHealthyandDiseased Skin 348

14.2.3MRImagingoftheSkinontheFace 349

14.2.4WaterStatesinSkinbyQuantitativeMRImaging 350

14.3QuantitativeMRImagingoftheSkinInVitro 351

14.3.1OpportunitieswithPreclinicalMRSystems 351

14.3.2StateoftheArtofInVitroMRApplications 352

14.3.3QuantificationofWaterStatesinReconstructedSkin 354

14.3.3.1Introduction 354

14.3.3.2BasicsofMT 354

14.3.3.3MRProtocolonReconstructedSkinSamples 355

14.3.3.4WaterStatesinReconstructedSkinSamples 356

14.4ConclusionandPerspectives 359 References 360

15High-ResolutionOpticalCoherenceTomography(OCT)forSkin Imaging 371

XiaojunYu,XianghongWang,LuluWang,RazinaZ.SeeniandLinboLiu

15.1Introduction 371

15.2HR-OCTSystemsforSkinImaging 373

15.2.1TD-OCTSystems 373

15.2.1.1ConventionalTD-OCT 373

15.2.1.2High-Definition(HD)-OCT 374

15.2.2FD-OCTSystems 375

15.2.2.1Full-Field(FF)-OCT 375

15.2.2.2Micro-OCT(μOCT) 376

15.2.3PS-OCT 381

15.3SkinImagingwithHR-OCT 382

15.3.1NormalSkinImagingApplications 382

15.3.2SkinImaginginClinicalPractice 387

15.3.3SkinImagingforLaboratoryResearch 388

15.3.3.1Characterizationof InSitu MicroneedleReal-TimeSwellingin Skin 388

15.3.3.2OCT-BasedForensicSubsurfaceFingerprintDetection 392

15.4Discussions 398

15.5Conclusion 400 Acknowledgments 400 References 400

16PhotoacousticImagingofSkin 411

EmelinaVienneau,TriVuandJunjieYao

16.1Introduction 411

16.2PhotoacousticImagingTechnology 412

16.3ApplicationstoSkinImaging 414

16.3.1SkinCancers 414

16.3.1.1MelanomaDetectionandDiagnosis 414

16.3.1.2CirculatingTumorCellDetection 416

16.3.1.3DetectionofNon-MelanomaSkinCancers 417

16.3.2TumorEnvironmentAnalysis 418

16.3.2.1Angiogenesis 418

16.3.2.2OxygenSaturation 420

16.3.2.3BloodFlowandMetabolicRateofOxygen(MRO2 ) 421

16.3.3DetectionofNoncancerousSkinDiseases 422

16.3.3.1PortWineStain 422

16.3.3.2Psoriasis 422

16.3.3.3OtherPigmentedLesions 422

16.3.4BurnInjuryAssessmentandMonitoringofHealing 423

16.3.5MonitoringGlucoseLevels 425

16.3.6OtherMolecularApplicationsinSkinImaging 426

16.4Outlook 428 References 429

17LaserSpeckleTechniquesforFlowMonitoringinSkin 443 RenzheBi,MaliniOlivoandKijoonLee

17.1Introduction 443

17.2LaserSpeckleContrastImaging 444

17.2.1WorkingPrincipleofLaserSpeckleContrastImaging 444

17.2.2ApplicationsofLSCI 446

17.3DiffuseSpeckleContrastAnalysis 448

17.3.1TheoryofDiffuseSpeckleContrastAnalysis 449

17.3.2DeepTissueBloodFlowandCold-InducedVasodilation 451

17.4DiffuseSpeckleTomography 456

17.4.1DepthSensitivityofFlowMeasurement 456

17.4.2TomographicFlowImaging 458

17.5TheFutureofDiffuseSpeckleAnalysisandImaging 459

References 460

Index 465

Foreword

SkinisnotonlythelargestorganinthehumanbodybutalsoIbelieveoneofthe mostimportant.Itistheoutermostlayerofthehumanbodyandhasacomplex structurethatiscriticaltofulfillingitsdiversefunctions.Itprotectsthebody fromphysicalandenvironmentalassaults;providessensation,heatregulation, waterresistance,andvitaminDsynthesis,andplusisthefirstlineofdefense againstpathogens.Incertaincircumstances,skinabnormalitiesanddamageput patient’slifeatrisk.

Thehealthandconditionofhumanskincanbeevaluatedwithavarietyof imagingtechniques,includingmagneticresonanceimaging,opticalmethods, andultrasoundimaging.Veryrecently,scientistssucceededindeveloping in vivo imagingtechnologythatcansimultaneouslygeneratedual-wavelength photoacousticimagesandultrasoundimages.Theseadvancesnotonlyallow ustounderstandthebiologybehinddiseasesbutalsoprovidetoolsforearly diagnosis.Theamountofdatacollectedbyinnovativeimagingmodalities nowadaysisunprecedentedandgrowing.Addingtothisistheemergenceof mobilephonetechnologiesthatareempoweringpatientswithunprecedented accesstohigh-resolutionimagingandtheworld’slargestdatabase,theWorld WideWeb.Thisisaformidableadvance,placingthepromiseofimproved healthcareintothehandsofeveryindividual.

Onekeyroleofskinistoformabarrierpreventingtheentryofexternalorganismsandchemicals.Thus,todeliverdrugsandtherapies,forexample,pharmaceuticals,vaccines,andmoisturizers,novelstrategiesandtechniquesareneeded todeliversuchreagentsintotheskinandsubsequentlyintothecirculation.Considerableinvestmentinresearchactivityisdrivingcontinuousgrowthinthefield oftransdermaldrugdelivery,withanimpressivearrayofactiveandpassive-based technologiesthatpromisetochangedermatologyandskinhealthintothefuture. Manyofthesetechnologiesrepresentaparadigmshiftindermatology.

Withtheemergenceofnewandinnovativetechnologies,thisbookisvery timely.Itfirstoutlinesthestructuralcharacteristicsofskinandskinappendages, whichisfollowedbydiscussionsofthekeypathwaysinvolvedinskingrowth anddevelopment.Clinicalpresentations,pathophysiologicalmechanisms,and currentclinicalpracticesusedtotreatdiseasesaffectingtheskinarethen introduced,includingabnormalwoundhealing,autoimmuneskindisorders, autoimmuneblisteringdiseases,andskincancers.Further,commonpreclinical modelsusedforstudyingthemechanismsofdiverseskindiseases,validation

Foreword

ofnoveltherapeutictargets,andscreeningofnewdrugstotreatthesediseases arecovered.Thelatestimagingtechnologiesthatallowustoexamineand understandchangesintheskin invivo arealsointroducedandcoveredin detail.Technologiesincludinghigh-resolutionultrasoundimaging,quantitative magneticresonanceimaging,high-resolutionopticalcoherencetomography, andemerginghybridimagingmodalitiessuchasphotoacousticimagingare described.Thebookconcludeswithchaptersintroducingemergingdrugdelivery technologiesandpotentialfutureinnovativedevelopments.Emergingdevelopmentsthatrepurposetraditionalchemicalenhancerswithmodernnanoparticles aredescribed,alongwithreimaginedtransdermaldeliverytechnologiesfeaturingneedle-freejetinjectors,microneedles,ultrasound,andiontophoresis, helpingthereadertograspemergingdevelopmentsintransdermaldelivery.

Athemethatpervadesthisbookisthecriticalrolethatinterdisciplinaryscience occupiestoachievetherequisitelevelofunderstandingofskinconditionsand theirmanagementthatisessentialtocreatingtechnologiesthatwork.Successis mostoftenfoundwiththeintegrationofconceptsandtechniquesfromcellbiology,chemistry,physics,optics,materialscience,nanoscience,clinicalsciences, andcriticallythepatient.Thisbookwillthereforemotivateandenthusestudents andresearchersfrommanydisciplinarybackgrounds.

Personally,Iappreciatethegreateffortthatthethreeeditors,ChenjieXu, XiaomengWang,andManojitPramanik,havemadetobringthisexcellentbook tocompletion.Ianticipatethatthisbookwillcatalyzenewconversationsacross theaislesofbiologyandengineeringwithinindustry,academia,andclinical settings.

ZeeUpton 1,2

1. InstituteofMedicalBiology,AgencyforScience,TechnologyandResearch (A*STAR),Singapore

2. SkinResearchInstituteofSingapore(SRIS),Singapore

SkinStructureandBiology

Wei-MengWoo

NanyangTechnologicalUniversity,LeeKongChianSchoolofMedicine,ClinicalSciencesBuilding,11Mandalay Road,Singapore,308232,Singapore

1.1Introduction

Theintegumentsystemofananimalservesasaboundarytoprotecttheinterior organsfromexternalassaults,preventsthelossofheatandwater,andmaintains osmoticpressure.Thesimplestformofintegumentisexemplifiedbythe diploblastic(twogermlayers:ectodermandendoderm)bodyplanofcnidarians, suchashydra,whosesingle-celllayeredectoderm(integument)supportsand protectsitsendoderm(guts:internalorgan).Invertebrates,theintegument includeskinandspecializedstructuresderivedfromtheskin.Theseskin-derived specializedstructuresrangefromscalesinreptiles,feathersinbirds,tofurs/hairs inmammals.Hairs,nails,claws,sweatglands,andteethareskinderivativesand arealsopartoftheintegumentofvertebrates[1,2].Analogoustothediploblastic animals,inthesetriploblastic(threegermlayers)animals,theirectoderm (epidermis)andmesoderm(dermis)protecttheirendoderms(internalorgans). Inhuman,skinconstitutes15–20%ofthebodymass,assuch,itisthelargest organofthehumanbody.Astheoutermostlayer,thehumanskinactsasaninterfacebetweenourbodyandtheenvironment;itprotectstheunderlyingtissues andinternalorgansandalsorespondstoexternalstimuli,avoidingdangersand injuries.

Asaphysicalbarrier,skinprovidesthefirstlineofdefenseagainstenvironmentalhazards.SkinprotectsourbodyfromUVdamage,chemicaland mechanicalassaults,injuries,andinvasionofmicroorganisms.Fromtheinterior, skinprotectsourbodyfromwaterloss,preventingdehydration,whichcouldbe life-threatening.Furthermore,skincontributestobodytemperatureregulation, whichisachievedbysweatingandinsulation.Throughsweatingandawater barrierfunction,theskinhelpsmaintainthebalanceofwaterandelectrolytes. Theskinisalsoasensoryorgan;withitstouch,thermal,andpainsensors,it informsthebrainofchangesintheimmediateenvironment.Inadditionto aphysicalbarrier,theskin’sprotectionagainstmicrobesalsocomefromthe itsimmuneresponseandproductionofpathogenfightingpeptides[3].Ona differentnote,perhapspartofaprotectionfunction(forthebone),vitaminDis synthesizedintheskin.

ImagingTechnologiesandTransdermalDeliveryinSkinDisorders, FirstEdition. EditedbyChenjieXu,XiaomengWangandManojitPramanik. ©2020Wiley-VCHVerlagGmbH&Co.KGaA.Published2020byWiley-VCHVerlagGmbH&Co.KGaA.

Inthischapter,thestructureandorganizationofthehumanskinandits cellularcompositionandfunctions,withadditionalfocusontheformationof thestratifiedepidermisandofawaterbarrier,willbeintroduced.

1.2SkinStructure

1.2.1OverviewofSkinTissueOrganization

Theskinorganconsistsofthreetissuelayers:fromthesurfacetotheinterior aretheepidermis,dermis,andhypodermis.Theorganizationofthesethree tissuelayersisalsoreflectedintheirnames:the“epi-”dermissitsontopofthe dermis,andthe“hypo-”dermissitsbelowthedermis.Historically,andstilla well-recognizeddefinition,theepidermisanddermisformthecutaneoustissue (Latin- cutis:theskin).Underthisdefinition,theskiniscomposedofonly epidermisanddermis,whereasthehypodermisisthesubcutaneoustissue, whichisnotpartoftheskin.Thecutaneoustissuerestsonthehypodermis, whichconnectsandanchorsthecutaneoustissuetotheunderlyingfascia[4,5]. Inmammals,theepidermisisaformofstratifiedsquamousepithelium,which meansitislayered(stratified)andscale-like(squamous).Thisisincontrastto thesimpleepitheliumthatissinglelayer,whichcanbefoundasliningofinternal organssuchaslungsandlivers.Theepidermisconsistsmostlyofepithelialcells thatarecommonlyknownaskeratinocytes,whichareprotein-richepithelial cellswithabundantkeratinsandkeratohyalin.Keratinocytesintheoutermost epidermallayerareflattenandenucleated,formingascale-likeorcornified patternthatiswaterimpermeable,therebycontributingthemostprominent functionfortheskin:waterbarrier.Thedermisisaconnectivetissuewith fibroblastcellsinterspersedinacollagen–elastin-basedextracellularmatrix. Bloodvessels,lymphaticvessels[6],nerveendings[7],andappendagesincluding hairfollicles,sebaceousglands,andsweatglandsresideinthedermis.The hypodermisiscomposedofadiposetissue,whichservesasenergystorageand insulationforthebodyandservesasacushionfortheskin.Itisalsotheorigin ofsomebloodvesselsthatextendtothedermis.

Theepidermisanddermisarephysicallyseparatedbyabasementmembrane. Bycontrast,dermisandhypodermisarenotphysicallyseparated.Thebasement membraneconsistsofextracellularmatrixcomponentsthattheepidermis attachesto;thiskindofattachmentmechanicallysupportstheepidermis. Theepidermal–dermaljunctionundulateswithfinger-likeprojectionsofthe dermisintotheepidermis,formingadermalpatterntermedthedermalpapilla. Fingerprintsaretheresultsoftheridgesthatformedbydermalpapillaeunder ourfingertips.Inadditiontoprovidingmechanicalsupportfortheepidermis, dermisalsosupportstheepidermiswithnutrientsviaitsbloodvesselsinthe dermalpapillae.

1.2.1.1ThickSkinandThinSkin

Thehumanskincanbecategorizedasthickskinandthinskin,basedonskin compositions,epidermalthickness,andepitheliallayers,althoughthemostearliestnotabledifferenceistheepidermalthickness.Thickskinisfoundinareas

Figure1.1 (a)Thickskinand(b)thinskin(hairyskin).Thickskinsarefoundinthepalms,soles, andatthesurfaceoffingertipsandtoes.Thinskinscovermostpartofthebody,andthey containhairfolliclesthusalsoknownashairyskins.Whilethickskinhasthickerepidermis, theirdermisisthinner,andtheylackhairfollicles,sebaceousglandsandarrectorpilimuscle.In thickskin,therearemoresensoryreceptorssuchasMeissner’sandPaciniancorpuscles.APM: arrectorpilimuscle,SG:sebaceousgland.Red:arteriole,blue:venules,green:nervefibers, Meissner’scorpuscle(nearepidermis).

whereabrasionoccursfrequently,includingthepalms,soles,fingers,andtoes. Thinskincoversalargeproportionofthebody,mostofthethinskinhavehairs, sothinskinisalsoknownashairyskin.Bycontrast,thickskinishairless–they donothavehairfolliclesnordotheyhavesebaceousglands.However,thickskin hasmoresweatglandsandsensoryreceptorsthanthinskin.

Astheirnamesimply,thickskinisthickerthanthinskin(Figure1.1).Thethicknessofthinskinisaround1–2mm,whereasthickskincanreachathicknessof 6mm.Thisisprominentattheepidermislevelwherethethickskinepidermisis considerablythickerthanthinskinepidermis.Theindividualepitheliallayersof thethickskinarethickerthanthoselayersinthethinskin,especiallytheoutermostlayer,thestratumcorneum,whichcanbecomeremarkablythick.Another distinctfeatureofthickskinisthattheyhavefiveepitheliallayerswithadistinct stratumlucidumbelowthestratumcorneum,whileinthinskintherearefour epitheliallayers(Figure1.1andSection1.2.2).Underneaththeepidermis,dermalpapillaeinthickskinaremoreregularanddeeperthanthoseinthinskin, althoughdermisofthickskinisrelativelythinner.

Thethicknessofhumanskinvariesatdifferentbodylocations[8–12].The thicknessofhumanepidermisrangesfrom0.05to1mm,whereasthedermisis about1–2mmthick.Thethinnestskinisfoundontheeyelids:theepidermisof eyelidsis0.04mm,thedermisofeyelidsis0.3mm.Incontrast,theepidermisof thepalmsandsolesis1.6mm,whereasthedermisonthebackreaches3mm.

1.2.2Epidermis

Asmentionedintheoverview(Section1.2.1andsubsection1.2.1.1),thehuman epidermisisastratifiedsquamousepitheliumandiscategorizedasthinandthick

Ecccrine sweat gland
Hair follicle SG APM
Pacinian corpuscle

Stratum corneum

Stratum lucidum

Stratum granulosum

Stratum spinosum

Stratum basale

Basement membrane

Figure1.2 Schematicdiagramoffiveepitheliallayersintheepidermisofthickskin.The stratumlucidumisabsentinthinskin.Theepidermisisconnectedtothedermisviathe basementmembrane.

skins.Theepidermisinthinskinsconsistsoffourlayersofepithelialcells,while inthickskinstherearefivelayersofepithelialcells(Figure1.2).Inthinskin,from thebottomtothetop,orfromdeeptosuperficial,theepidermallayersarethe stratumbasale(basalcelllayer),stratumspinosum(spinouslayerorsuprabasal layer),stratumgranulosum(granularcelllayer),andstratumcorneum(cornified layer).Inthickskin,anadditionallayer,thestratumlucidum,ispresentbetween stratagranulosumandcorneum.ThesefivelayersarefurtherintroducedinSubsections1.2.2.1–1.2.2.5.

Thestratifiedepidermisconsistspredominantlyofepithelialcellsknownas keratinocytes,whichexpressasubstantialamountofkeratinproteinsthatform keratinfilamentsandkeratohyalin.Attheepidermallayerlevel,keratinocytes ofeachepidermallayerarecharacterizedbytheexpressionofaspecificpair ofkeratinproteins,usuallyabasicandanacidickeratinprotein.Forexample, keratinocytesofthestratumbasaleproducekeratin5(K5,belongstobasic keratins)andK14(acidickeratins)proteins,whereaskeratinocytesinstratum spinosumproduceK1(basickeratins)andK10(acidickeratins).Thespecific pairofkeratinproteinsformsobligateheterodimersandconstitutesthefundamentalsubunitofthekeratinintermediatefilament.Thekeratinintermediate filamentsstretchacrossthecytoplasmofthekeratinocytes,givingtheepidermis itstensilestrength,shape,andresiliencetomechanicalinsult.

Whereaskeratinocytesmakeupover90%oftheepidermis,thereareasmall percentageofnon-epithelialcellsresideintheepidermis.Thesecellsinclude melanocytes,Langerhanscells,andMerkelcells.Whilethekeratinocyteisresponsibleforthemechanicalandwaterbarrierfunctionoftheepidermis, melanocytes,Langerhanscells,andMerkelcellsareresponsibleforskinpigmentation,immuneprotection,andsensory(touch)functions,respectively.

1.2.2.1StratumBasale

Thestratumbasale(basallayer)ismadeupofasinglelayerofbasalepidermalcells.Thesecellsarealsoknownasbasalcellsorbasalkeratinocytes. Basalkeratinocytesarecuboidalinshapewithrelativelybignucleus.Withina basalkeratinocyte,K5/K14intermediatefilamentsrunperpendiculartotheskin surface,andtheyattachtothehemidesmosomesonthebasalsurfaceofthecell, therebyanchoringbasalkeratinocytestothebasementmembrane.Epidermal stemcellsinterspersedinthislayer;duringnormalhomeostasis,thesearethe residentepidermalstemcellsthatgenerateallthekeratinocytesintheepidermis.

Inadditiontokeratinocytes,twotypesofnon-epithelialcells,melanocytes andMerkelcells,immigrateandresideinthestratumbasale.Melanocytes originatefromtheneuralcrest,andtheyproducemelaninthatcontributeto skinpigmentation.Inthestratumbasale,melanocytesconstituteabout3%of thecellpopulation.Althoughtheyresideinthestratumbasale,melanocytesare notconnectedwithbasalkeratinocytes.Instead,theirlongdendritesextendto thestratumspinosum,makingconnectionswithkeratinocytesinthestratum spinosum.Inmelanocytes,melaninaregeneratedandpackedinmelanosomes, whicharethentransportedviaextendeddendritesfromthemelanocytecellbody tothekeratinocytesinthestratumspinosum.Thesemelanosomessurround thenucleusofthekeratinocytes,shieldingthemformUVrays.Sunexposure andgeneticsdeterminestheamountofmelaninproduced,buteveryonehas aboutthesamenumbersofmelanocytes.Ofnote,thereisanothergroupof melanocytesthatimmigratetoandresideinthehairfollicles.Thehairfollicle residentmelanocytescontributetohairpigmentationbutnottoskin/epidermal pigmentation.Merkelcellsarethoughttofunctionastouchreceptors.Inline withitsfunction,Merkelcellsaremoreabundantatthefingertips.However,the originofMerkelcellsisnotclear.

1.2.2.2StratumSpinosum

Thestratumspinosum(spinouslayer)acquiresitsnamefromitsspinyappearanceinstainedspecimens,itisalsoknownasthesuprabasallayer.Stratum spinosumconsistsofeighttotensublayersofpolygonal-shapedkeratinocytes. Thespinyappearanceofthestratumspinosumcomesfromprotrusionstructures generatedbydesmosomesthatinterconnecttheirkeratinocytes.Suprabasal/ spinouskeratinocytescanbedifferentiatedfromthebasalkeratinocyteby thespecificexpressionofK1andK10intermediatefilamentproteins.The K1/K10dimersformintermediatefilamentsthatextendradially,spanningthe cytoplasmandinsertingintothedesmosomesatthecellperiphery.Thespinous keratinocytesproducewater-repellingglycolipids.Overall,thespinouslayer contributestoskinstrengthandflexibility.

Inadditiontokeratinocytes,Langerhanscellsarealsofoundinthestratum spinosum.Langerhanscellsaredendriticcellswithflattendendritesthatextend alongahorizontalplaneintheepidermis.Thecellbodyandextendeddendritesof Langerhanscellsgeneratea25%coverageoftheskinsurface.Withsuchcoverage, Langerhanscellsareefficientatrecognizingandcapturingantigensandother foreignsubstancesintheepidermis.

1.2.2.3StratumGranulosum

Asitsnameindicates,stratumgranulosumappearsgrainy.Withthreetofive sublayers,theirkeratinocytesareflatterincellshape,withthickencellmembrane.Keratinizationbeginsinthislayer;thegrainyappearanceisgenerated bykeratinsandkeratohyalin(lamellargranules)inthekeratinocytes.These keratohyalingranulesaremadeupofprofilaggrin,whichisa ∼400–500kDa proteinthatwillbecleavedinto ∼26–48kDafilaggrins(fil ament aggr egating proteins).Thecleavageofprofilaggrinoccursasthekeratinocytesmovefromthe stratumgranulosumtostratumcorneum.Enucleationhappensasgranularcells differentiatetocorneocytes,specializedkeratinocytesofthestratumcorneum (sub-section1.2.2.5).Tightjunctionsareformedinthegranularcells,whichalso contributetoabarrierfunction.

1.2.2.4StratumLucidum

Thislayerisonlypresentintheepidermisofthickskin,mainlyatthepalmsand soles.Microscopically,thestratumlucidumhasasmoothandseeminglytranslucentappearance,henceitsname.Theirkeratinocytesarefurtherflattenedandare deadcells.Thelucidumkeratinocytesaredenselypackedwitheleiden,alipid-rich proteinthatisderivedfromkeratohyalinandcontributetowaterbarrierfunction.

1.2.2.5StratumCorneum

Thestratumcorneum,orthecornifiedlayer,isthemainlayerthatcontributes waterbarrierfunctionfortheskin.Stratumcorneumisabout10–20 μmthick andconsistsof15–20sublayersofflattenkeratinocyteswiththeirnucleiremoved (enucleatedoranucleated).Keratinocytesinthislayerareterminallydifferentiatedandnonviable,andtheyarealsoknownascorneocytes.Corneocytes arefilledwithkeratinfilaments;underneathcorneocytes’plasmamembrane, keratins,filaggrin,loricrin,involucrin,andafewotherproteinsassembleinto acornifiedenvelopof ∼10–15nmthick.Theseproteinsarecross-linkedby transglutaminases.Thiscornifiedenvelopbecomesthestructuretowhichboth intracellularkeratinsandintercellularlipidsattachto.

Whiletheoutermostlayerofstratumcorneumisdesquamated,orsloughedoff, continuously,theproliferationrateofepidermalstemcellsinthestratumbasale matchesthedesquamationratesuchthatawaterbarrierisalwayspresent.

1.2.3Dermis

Dermisprovidessupportandnutrientsfortheepidermis.Thedermisisessentiallyaconnectivetissuewithcellscompriseonly10%ofitscontent,whileacellularcomponentscomprisethemajorityofitscontent.Themajorcelltypeinthe dermisisthefibroblast,spindle-shapedcellsthataremainlyoriginatedfromthe mesodermandexpressedtheintermediatefilamentvimentin.Dermalfibroblasts depositcollagensandelastinstotheirextracellularspace,formingmeshworkof collagenandelastinfibersinagel-likegroundsubstance.Collagenfibersmake up70%ofthedryweightofdermis,whereaselastinfibersmakeuplessthan 1%.Collagenfibersconferhightensilestrength,whereaselastinfibersconfer theabilityofskintoreturntoitsoriginalshapeupondeformationbyexternal forces.Groundsubstanceisalsoproducedbyfibroblasts,anditmakesupabout

0.2%ofthedryweightofdermisbutconstitutesmostofthedermalvolume.The maincompositionofgroundsubstanceisglycosaminoglycans;togetherwithits othercompositionsincludingwater,electrolytesandplasmaproteins,ground substanceplaysimportantroleinsalt-waterbalanceandprovidessupportfor othercomponentsinthedermis.

Withinthedermis,two“layers”ofdermiscanbereadilyobserved:theupper layeristhepapillarydermis,andthelowerlayerthereticulardermis,without distinctboundaries.Theextracellularmatrixmeshworkthateachlayerproduces areinterconnected.Thepapillarylayerisalooseconnectivetissuewithrelatively morefibroblastcells,andtheircollagenfibrilsandelastinfibersarethinnerand looselyorganized.Asdescribedintheoverviewsectionofthischapter,thepapillarydermisextendstothestratumbasaleoftheepidermisformingfinger-like dermalpapillae.Bycontrast,thereticularlayerisadenseconnectivetissue.Relativelyfewerfibroblastcellsarepresentinthereticulardermis,alongwithless groundsubstance.Thereticularpatternofthislayerisduetoatightmeshwork ofcollagenandelastinfibers,withthickcollagenbundlesarrangedmoreorless paralleltotheskin.Elastinfibersinthereticulardermisarecoarseandform irregularlyorganizedarrays.Inadditiontodifferentialorganizationpatternsof collagenandelastinfibers,dermalfibroblastsinthepapillaryandreticulardermis producedistinctsetsofproteinsandresponddifferentlytostimuliandinjuries [13,14].

Whereasfibroblastscomprisethemajorcelltypeinthedermis,anumberof non-fibroblastcellsarepresentinthedermis.Thesenon-fibroblastcellsinclude adipocytes,macrophages,mastcells,andothercirculatingimmunecells.Inadditiontotheseresidentandimmigrantcelltypes,thepapillarydermisissupplied withabundantbloodcapillaries,italsoconsistsnervefibers,touchreceptors knownasMeissnercorpuscles,andlymphaticvessels.Reticulardermisisalso wellvascularized,withsensoryandsympatheticnerveslocatedinthisdermal layer.Thebloodvesselsinthedermisformextensivenetworksorplexusesthat extendtounderneaththestratumbasale(Figure1.1).Thesebloodvesselnetworkssupplytheskinwithnutrients;importantly,forexternalsubstancesapplied topicallyorinjectedintotheskin,suchbloodvesselnetworksprovidetheman accesstothesystemiccirculation.Overall,dermisconferselasticity,pliability,and tensilestrengthtotheskin,anditalsosupportstheskinwithnutrients,water–salt balance,touchandsensoryreception,anddefenseagainstforeignagents.

1.2.4Hypodermis

Thehypodermisconnectstheepidermisanddermistotheunderlyingfascia. Thehypodermisisprimarilyadiposetissueandiswellvascularized;itisthe originofsomebloodvesselsthatextendtothedermis.Similartobloodvessels inthedermis,bloodsupplyinthehypodermisactstosupplytheskinwith nutrientswhilealsoactsastheentrytosystemiccirculation.Mechanosensory receptorsinthehypodermis,knownasPaciniancorpuscle,arelocalizednearthe dermis.PaciniancorpuscleiscomposedofSchwanncellsthatareconcentrically arranged,withacentralafferentnerve(Figure1.1).Overall,thehypodermis isalooseconnectivetissuethatprovidescushioningandbloodsupplyforthe dermisandepidermis.

1.2.5SkinAppendages

Themajorskinappendagesarefoundinthedermis.Theseappendagesinclude hairfollicles,sebaceousglands,eccrineglands(sweatglands),andapocrine glands.Hairsofferwarmth;sebaceousglandssecretesebumtolubricatehairs andepidermis;andeccrineglandsexcretesweat(water),thusregulatebody temperatureaswaterevaporationgeneratesacoolingeffectontheskin.These appendagesaregeneratedbyepithelialdowngrowthsthatextendtothedermis. Withopeningstotheouterenvironment,appendagesespeciallyhairfollicles, becomeapassagewayforexternalsubstancetoentertheskin.

Hairfollicle,orhairroot,istheportionofthehairfollicleappendagethat locatesundertheskinsurface,whereashairsaretheskinexposedportionof hairfollicleshafts.Ahairfollicleiscomposedofsevenconcentricallyorganized tubularlayersofdifferentiatedepithelialcells,withagroupofdermalfibroblasts aggregatesatthebaseofthishairfollicleepithelium.Thisdermalcomponentis alsonamedthedermalpapilla(nottobeconfusedwiththefinger-likedermal papillaeofthepapillarydermis).Theoutermosttubularlayerofhairfollicle epitheliumistheouterrootsheath,whichisacontinuouslayerwiththebasal epidermallayer.Interiortotheouterrootsheathistheinnerrootsheath,further insideisthehairshaftproper.Thelowestportionofhairfollicleepitheliumisthe hairbulb,whichconsistsofactivelyproliferatinghairepithelialprogenitors.As hairfolliclematures,hairshaftextendsbeyondtheskinsurfacethroughachannel formedbythedifferentiatedhairfollicleepithelium.Althoughnotasnoticeable asthescalphairs,mostotherpartsofthehumanbodyarecoveredwithhairs, exceptionsbeingthelips,palms,soles,andbackofears.Thesearethevellus hairs,whichareshorter,thinner,andlighter-pigmentedthanthatofscalphairs.

Sebaceousglandislocatedattheupperportionofhairfollicle.;together,the twoarenamedthepilosebaceousunits.Sebaceousglandiscomposedofpolyhedralcellswithsmallnucleiandpalecytoplasmthatfilledwithlipids.Ithaslobule thatopensintothehairfollicleandsecretssebum,formingoilycoatingforthe hairandskin.Inadditiontosebaceousglands,hairfolliclesareassociatedwith bloodvesselsandnerveendings,receivinginputsfromthevesselsandnerves.A muscletissue,thearrectorpilimuscle,attachestothehairfollicleataposition belowthesebaceousgland,connectinghairfolliclesheathtothedermis.Contractionofthearrectorpilimusclemoveshairfollicletoamoreuprightposition, generatinggoosebumpsappearance.

Theeccrinegland,oreccrinesweatgland,isasinglelongtubethatisstraightat theupperregionbuthighlycoiledatthelowerpartinthedeepdermis.Eccrine glandiscomposedofonelayerofcuboidalcellssurroundedbymyoepithelial cells.Saltandwaterareproducedbytheglandbuttheductwillabsorbsalt, thereby,sweatsecretedishypotonic.Eccrineglandhasitsindependentopening totheskinsurface.Sweatevaporationafteritssecretionhelpscoolthebody. Eccrineglandsarebroadlydistributed,exceptafewareaslikelipsandforeskin, whereastheyaremoreabundantinpalms,soles,andaxillae.

Apocrineglandisdistributedintheaxilla,areola,andnipples.Althoughit isreferredtoassweatgland,apocrineglandismoreofascentgland.Apocrineglandisoriginatedfromhairbuds,andithasasingleductthatopensto

1.3SkinBiology 9

theupperhairfollicles.Theiraciniorsecretoryportionisinthesubcutaneous layer(hypodermis)andarelargerthanthoseofeccrineglands.Apocrineglands undergocelldecapitationforsecretingtheirproducts,whichareviscous,milky, andodorless.Thesecretionwillbesmellywhentheyarebrokendownbybacteria andproduceshort-chainedfattyacids,whichgeneratesbodyodor.

1.3SkinBiology

1.3.1Homeostasis:EpidermalSelf-renewal

Acriticalfunctionoftheskinistopreventwaterloss;otherwise,desiccationand deathmayensue.Basedontheorganizationandpropertiesofthestratifiedepidermis,itisgenerallyrecognizedthattheprimaryroleofthestratifiedepidermis istogenerateawaterbarrier[15].Thisismainlyachievedbytheformationand maintenanceofthestratumcorneum.Throughaperiodicalself-renewalofthe epidermis,asoldcorneocytessloughedofffromthestratumcorneum,acontinuouslysuppliednewcorneocytesreplacetheloss,thusmaintainingawater barrier.

Thisepidermalself-renewaloccursduringnormalhomeostasisofthestratified epidermisuponactivationoftheresidentepidermaltissuestemcells,whichare distributedinthestratumbasale[16,17].Onceactivated,theresidentstemcell undergoescelldivisionsuchthattwodaughtercellsaregeneratedinthestratumbasale.Inmostcases,ofthetwodaughtercellsgenerated,oneofthemwill remainasanepidermalstemcellandstaysinthestratumbasale,whereasthe otherdaughtercellwillbedestinedfordifferentiationandwillmoveupwardto thesuprabasallayer.Itisbelievedthatsuchupwardmovementisdrivenbya pushfromthenewlyaddedbasalcell,whichisthedifferentiatingdaughtercell generatedfromstemcelldivision.Similarly,theepidermalcellsinthesuprabasal layerfurtherdifferentiateandmoveupwardtothegranularcelllayer,inwhichthe existinggranularcellsundergomaturationandenucleationastheymoveupward tothestratumcorneum.Ittakesabout14daysforakeratinocytetotransitfrom thestratumbasaletothestratumcorneumandanother14daysforkeratinocytes withinthestratumcorneumtoturnover.Therefore,theturnoverandrenewalof theepidermallayersarewellbalanced.Theseprocessesarepartofthenormal homeostasisoftheskin.Havingsaidthat,ageandinflammatoryconditionscan adverselyaffecttheseprocesses.

Beyondnormalhomeostasis,thestratifiedepidermiswillberegeneratedifitis lostduetoinjuryorwounding[17].Inthiscase,studiesinmouseskinrevealed thatepithelialstemcellsfromthehairfollicleswillalsobeactivatedandparticipateinre-epithelializingthewound[18].There-epithelializationformsthefirst oneortwolayersoftheepidermis,whichpreventsinfectionandfurtherinjury. Nevertheless,thecontributionofmosthairfolliclestemcellsistransient,whereas epidermalstemcellsfromthestratumbasaleofthenearbyuninjuredskinregion areresponsibleforreformingastratifiedepidermisthatcanundergolong-term self-renewal.Thesubsequentepidermalstratificationisnecessarytorebuilda waterbarrierandtoregainotherprotectivefunctionsoftheskin.Itisinteresting

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