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List of Contributors xiii Series Preface xvii Preface xix 1 Chronic Wound Healing: Molecular and Biochemical Basis 1 Sophia Tate and Keith Harding 1.1 Introduction 1 1.2 Acute Wound Healing 1 1.3 Categories of Chronic Wound 3 1.3.1 Pressure Ulcers 3 1.3.2 Venous Stasis Ulcers 4 1.3.3 Ischaemic Ulcers 4 1.3.4 Diabetic Foot Ulcers 4 1.4 How a Chronic Wound Develops: Intrinsic Components 4 1.4.1 Cell Phenotype 5 1.4.2 Immune Cells and Inflammatory Mediators 6 1.4.3 Reactive Oxygen Species 8 1.4.4 Growth Factors 8 1.4.5 The Role of Matrix Metalloproteinases 12 1.5 How a Chronic Wound Develops: Extrinsic Factors 13 1.5.1 Infection 13 1.5.2 Nutrition 13 1.5.3 Tobacco Smoking 14 1.5.4 Hypoxia and Ischaemia-Reperfusion Injury 15 1.6 Concluding Remarks 15 References 16 2 Clinical Perspectives for Treating Chronic Wounds 21 Barun Majumder, Kirstie Lane, Diane Beck, Sandeep Singh and Duniya Majumder 2.1 Background 21 2.2 Aetiology of Diabetic Foot Ulcers 22 2.3 Standard of Care for Treatment of Diabetic Foot Ulcers 22 2.4 Commonly Used Wound Dressings for Diabetic Foot Ulcers and Their Mechanism of Action 22 2.5 Absorbent and Superabsorbent Dressings 23 2.6 Alginates 23 2.7 Films 23 2.8 Foams 24 2.9 Honeys 24 2.10 Hydrogels 25 2.11 The Role of a Split Thickness Skin Graft in Diabetic Foot Ulcers 25 2.12 Negative Pressure Wound Therapy 25 2.13 Larval Therapy 27 2.14 Clinical Case Studies from Multidisciplinary Diabetic Foot Clinic 27 2.14.1 Neuropathic Wound 27 2.14.2 Ischaemic Wound 29 2.14.3 Neuro-Ischaemic Wound 31 2.14.4 Osteomyelitis 33 2.14.5 Charcot’s Foot 35 2.14.6 Necrotising Fasciitis in a Patient with Diabetes 36 2.15 Summary 39 Acknowledgements 39 References 39 3 Prediction, Prevention, Assessment, and Management of Skin Tears in the Aging Population 43 Kimberly LeBlanc and Karen Campbell 3.1 Introduction 43 3.2 Skin Tear Prevalence and Incidence 44 3.3 Predicting Skin Tears 45 3.4 Prevention 47 3.5 ISTAP Risk Reduction Program 49 3.5.1 General Health 49 3.5.2 Mobility 50 3.5.3 Skin 51 3.6 Assessment 52 3.7 Management 54 3.8 Treatment 54 3.9 Conclusion 55 References 55 4 Importance of Debriding and Wound Cleansing Agents in Wound Healing 59 Gwendolyn Cazander, Bianca K. den Ottelander, Sandra Kamga, Martijn C.H.A. Doomen, Tim H.C. Damen and Anne Marie E. van Well 4.1 What is Debridement? 59 4.2 The History of Debridement 59 4.3 Why Undertake Debridement? 60 4.4 Debridement Techniques and Wound Cleansing Agents 62 4.4.1 Mechanical Debridement 62 4.4.2 Biological Debridement 72 4.4.3 Enzymatic Debridement 74 4.4.4 Autolytic Debridement 77 4.4.5 Wound Cleansing 79 4.4.6 Other Debridement Therapies 80 4.5 What is the Future of Debridement? 81 References 82 5 Treatment of Mixed Infections in Wounds 91 Asif Ahmed and Joshua Boateng 5.1 Introduction 91 5.1.1 Wound Healing Process 92 5.1.2 Types of Chronic Wounds 92 5.2 Prevalence of Mixed Infections 94 5.2.1 Bacterial-Fungal Interactions 95 5.2.2 Bacterial-Bacterial Interactions 98 5.2.3 Host Responses to Mixed Infections and Drug Resistance 99 5.3 Management of Mixed Infected Wounds 100 5.3.1 Clinical and Microbiological Diagnosis 101 5.3.2 Debridement and Cleansing 101 5.3.3 Antimicrobial Therapies 102 5.3.4 Hyperbaric Oxygen Therapy 104 5.3.5 Phage Therapy 104 5.4 Summary and Future Perspectives 104 References 105 6 Treatment of Biofilms in Infected Wounds 115 Philip Debrah, Awo Afi Kwapong and Mansa Fredua-Agyeman 6.1 Introduction 115 6.2 Why and How Biofilms Form 116 6.3 Wound Biofilms 118 6.3.1 Wound Healing 119 6.4 Biofilms and Wounds 119 6.4.1 Simulation of Biofilms in Wounds 120 6.5 Treatment of Biofilms in Wounds 126 6.5.1 Biofilm Eradication 126 6.5.2 Current Treatment Protocols 128 6.6 Clinical Examples 128 6.7 Summary 128 References 130 7 Freeze-Dried Wafers for Wound Healing 137 Shiow-Fern Ng 7.1 Introduction 137 7.2 Wafer as a Modern Wound Dressing 138 7.3 Freeze-Drying Process 139 7.4 Wafer Preparation 140 7.5 Wafer Assessments 141 7.5.1 Morphology 142 7.5.2 Swelling Index 144 7.5.3 Mechanical Properties 145 7.5.4 In Vitro Drug Release 145 7.5.5 Cell Viability 146 7.6 Wafer Biopolymers 146 7.6.1 Alginate 147 7.6.2 Chitosan 148 7.6.3 Carboxymethylcellulose 149 7.7 Conclusion 150 References 150 8 Silver and Silver Nanoparticle-Based Antimicrobial Dressings 157 Joshua Boateng and Ovidio Catanzano 8.1 Introduction 157 8.1.1 Brief History of Silver as an Antibiotic 159 8.1.2 Mechanism of Action 160 8.1.3 Bacterial Resistance to Silver 164 8.2 Silver Dressings in Wound Healing 167 8.2.1 Silver-Based Antimicrobial Dressings 169 8.2.2 Silver Nanoparticle-Based Antimicrobial Dressings 170 8.3 Cost-Effectiveness of Silver Dressings 175 8.4 Concluding Remarks 176 References 177 9 Hydrogel Dressings 185 Galiya S. Irmukhametova, Grigoriy A. Mun and Vitaliy V. Khutoryanskiy 9.1 Introduction 185 9.1.1 Classification by Origin of Materials Used to Prepare Hydrogels 186 9.1.2 Classification by Composition and Structure of Hydrogels 186 9.1.3 Classification by the Type of Cross-Linking 187 9.1.4 Classification Based on the Shape and Dimensions of Hydrogels 187 9.1.5 Classification Based on the Charge of Macromolecules Forming Hydrogels 187 9.1.6 Classification Based on Functional Properties of the Hydrogels 187 9.2 Mechanism of Hydrogel Swelling 187 9.2.1 Swelling of Temperature-Sensitive Hydrogels and Their Application in Wound Healing 189 9.2.2 Swelling of Light-Sensitive Hydrogels 190 9.2.3 Swelling of Electro-Sensitive Hydrogels 191 9.3 Application of Hydrogels as Wound Dressings 191 9.4 Industrial Methods for the Synthesis of Hydrogels for Wound Dressings 193 9.4.1 Polymerization Methods 193 9.4.2 Cross-Linking of Polymers 195 9.5 Antimicrobial Hydrogels with Special Additives 198 9.6 Conclusion 200 Acknowledgments 201 References 201 10 Gene Therapy for the Treatment of Chronic Wounds 209 Marcos Garcia-Fuentes 10.1 Introduction 209 10.2 Pharmacodynamics of Gene Therapy in Chronic Wounds 210 10.2.1 Signalling Supplementation 210 10.2.2 Pathway Inhibition 211 10.3 Administration Routes and Methods 212 10.3.1 Systemic Delivery 212 10.3.2 Topical Delivery 212 10.3.3 Intralesional Delivery 213 10.4 Gene Delivery Systems 213 10.4.1 Physical Methods 214 10.4.2 Viral Vectors 215 10.4.3 Chemical Delivery Systems 217 10.4.4 Gene-Activated Matrices 220 10.5 Clinical Evaluation 221 10.6 Conclusion 226 Acknowledgements 226 References 227 11 Honey in Wound Healing 235 Emi Maruhashi 11.1 The History of Honey 235 11.2 Composition 236 11.3 Honey Research 236 11.4 Medical Grade Honey 237 11.5 Modes of Action 238 11.6 Applications and Specific Wound Types 242 11.7 Practical Considerations 246 11.8 Novel Concepts and Conclusions 247 References 248 12 Regeneration Using Tissue Engineered Skin Strategies 255 Lucilia P. da Silva, Mariana T. Cerqueira and Alexandra P. Marques 12.1 Introduction 255 12.2 Skin Physiology and Wounding 256 12.3 Skin Tissue Engineering 258 12.4 Evolving Skin Tissue Engineering Strategies 259 12.4.1 Balancing the Inflammatory Phase 261 12.4.2 Enhancement of Re-Epithelialization 263 12.4.3 Target of Dermal Matrix Synthesis and Remodeling 269 12.4.4 Re-Establishment of the Vascular Network 270 12.4.5 Innervation Shaping 280 12.4.6 Appendages and Pigmentation 281 12.5 Conclusion 282 References 283 13 Local Delivery of Growth Factors Using Wound Dressings 291 Ovidio Catanzano and Joshua Boateng 13.1 Wound Dressings as Delivery Platforms for Growth Factors 291 13.2 Growth Factors Involved in the Wound Healing Process 292 13.3 Local Delivery of Growth Factors Using Wound Dressings 296 13.4 Integration of Platelet-Rich Plasma in Wound Dressings 299 13.5 Enhancing Local Growth Factor Expression Using Gene Therapy 300 13.6 Wound Delivery of Growth Factors from Living Systems 302 13.7 Regulatory Considerations 305 13.8 Conclusions and Future Perspectives 306 References 307 14 Electrospinning Technologies in Wound Dressing Applications 315 Giuseppina Sandri, Silvia Rossi, Maria Cristina Bonferoni, Carla Caramella and Franca Ferrari 14.1 Introduction 315 14.2 Basic Concept and Electrospinning Set-Up 316 14.3 Parameters Affecting the Electrospinning Process 318 14.4 Process Parameters 319 14.4.1 Electric Field Strength 319 14.4.2 Flow Rate 319 14.4.3 Needle-to-Collector Distance 320 14.4.4 Collector and Needle Types 320 14.5 Solution Parameters 321 14.5.1 Molecular Weight and Polymer Concentration 321 14.5.2 Surface Tension 322 14.5.3 Conductivity/Surface Charge Density 322 14.5.4 Environmental Parameters 322 14.6 Biomedical Applications of Nanofibrous Membranes 323 14.6.1 Wound Dressings and Wound Healing 323 14.6.2 Electrospun Dressings 325 14.7 Chemicophysical and Biopharmaceutical Characterizations 325 14.8 Dressing/Scaffold Parameters Affecting Cell Functions 327 14.9 Materials for Fabricating Nanofibers 328 14.9.1 Biopolymers 328 14.10 Concluding Remarks 333 References 333 15 The Place of Biomaterials in Wound Healing 337 Annalisa Bianchera, Ovidio Catanzano, Joshua Boateng and Lisa Elviri 15.1 Introduction to Biomaterials for Wound Healing 337 15.1.1 Definition of Biomaterials 337 15.1.2 Functional Requirements of Wound Repair Biomaterials 338 15.1.3 Classification of Biomaterials Commonly Used in Wound Healing 338 15.2 Synthetic Biomaterials for Wound Healing 339 15.2.1 Polyurethanes and their Derivatives 340 15.2.2 Poly l-Lactic Acid 340 15.2.3 Poly(Ethylene Glycol) 341 15.2.4 Polycaprolactone 341 15.2.5 Poly(Glycolic Acid) and Poly(Lactic-co-Glycolic Acid) 342 15.3 Natural Biomaterials for Wound Healing 343 15.3.1 Polysaccharide-Based Biomaterials 343 15.3.2 Protein-Based Biomaterials 348 15.4 Application of Biomaterials in Wound Healing 350 15.4.1 Traditional and Impregnated Dressings 350 15.4.2 Hydrogels 352 15.4.3 Film Dressings 353 15.4.4 Foam Dressings 354 15.4.5 Nanofiber-Based Dressings 355 15.4.6 Three-Dimensional Printed Dressings 356 15.5 New Trends in Biomaterials for Wound Healing 357 15.5.1 Extracellular Matrix-Derived Biomaterials 357 15.5.2 Tissue Engineered Skin Substitutes 357 15.6 Conclusions and Future Perspectives 358 References 359 16 Wound Dressings and Pressure Ulcers 367 Michael Clark 16.1 Overview 367 16.2 Introduction to Pressure Ulcers 367 16.3 The Impact of Pressure Ulcers 369 16.4 Managing Pressure Ulcers 370 16.5 Wound Dressings in Pressure Ulcer Treatment 371 16.6 Pressure Ulcer Prevention and Wound Dressings 377 16.6.1 Pressure Ulcers at the Nose 378 16.6.2 Pressure Ulcers at the Heel 378 16.6.3 Pressure Ulcers at the Sacrum 378 16.7 Conclusions 380 References 380 17 3D Printed Scaffolds for Wound Healing and Tissue Regeneration 385 Atabak Ghanizadeh Tabriz, Dennis Douroumis and Joshua Boateng 17.1 Introduction 385 17.2 3D Printing 386 17.3 Laser-Based Bioprinting 387 17.4 Jet-Based Printing 389 17.5 Extrusion-Based Printing 391 17.6 Hybrid Printing 393 17.7 Conclusions 395 References 395 Index 399

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