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Therapeutic Dressings
and Wound Healing Applications
ADVANCES IN PHARMACEUTICAL TECHNOLOGY
A Wiley Book Series
Series Editors:
Dennis Douroumis, University of Greenwich, UK
Alfred Fahr, Friedrich–Schiller University of Jena, Germany
Jürgen Siepmann, University of Lille, France
Martin Snowden, University of Greenwich, UK
Vladimir Torchilin, Northeastern University, USA
Titles in the Series

Hot-Melt Extrusion: Pharmaceutical Applications
Edited by Dionysios Douroumis
Drug Delivery Strategies for Poorly Water-Soluble Drugs
Edited by Dionysios Douroumis and Alfred Fahr
Computational Pharmaceutics: Application of Molecular Modeling in Drug Delivery
Edited by Defang Ouyang and Sean C. Smith
Pulmonary Drug Delivery: Advances and Challenges
Edited by Ali Nokhodchi and Gary P. Martin
Novel Delivery Systems for Transdermal and Intradermal Drug Delivery
Edited by Ryan Donnelly and Raj Singh
Drug Delivery Systems for Tuberculosis Prevention and Treatment
Edited by Anthony J. Hickey
Continuous Manufacturing of Pharmaceuticals
Edited by Peter Kleinebudde, Johannes Khinast, and Jukka Rantanen
Pharmaceutical Quality by Design
Edited by Walkiria S Schlindwein and Mark Gibson
In Vitro Drug Release Testing of Special Dosage Forms
Edited by Nikoletta Fotaki and Sandra Klein
Forthcoming Titles:
Characterization of Micro- and Nanosystems
Edited by Leena Peltonen
Process Analytics for Pharmaceuticals
Edited by Jukka Rantanen, Clare Strachan, and Thomas De Beer
Mucosal Drug Delivery
Edited by Rene Holm
Basic Biopharmaceutics
Edited by Hannah Batchelor
Therapeutic Dressings
and Wound Healing
Applications
Edited by
JOSHUA BOATENG
School of Science, University of Greenwich Medway,
Chatham Maritime, UK
This edition first published 2020
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Library of Congress Cataloging-in-Publication Data applied for
Hardback ISBN: 9781119433262
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Set in 10/12pt, TimesLTStd by SPi Global, Chennai, India
10 9 8 7 6 5 4 3 2 1
Contents
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
vi Contents
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
Contents vii
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
viii Contents
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
7.2 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
8.1.1 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
References 177
9 Hydrogel Dressings 185

Galiya S. Irmukhametova, Grigoriy A. Mun and Vitaliy V. Khutoryanskiy
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
Contents ix
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
10.2 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
x Contents
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

Lucília P. da Silva, Mariana T. Cerqueira and Alexandra P. Marques
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
14.2 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
Contents xi
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
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
xii Contents
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
17.2 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
List of Contributors
Asif Ahmed, School of Science, Faculty of Engineering and Science, University of

Greenwich Medway, Chatham Maritime, UK
Diane Beck, Ashford and St Peter’s Hospitals NHS Foundation Trust, Chertsey, UK
Annalisa Bianchera, Interdepartmental Centre Biopharmanet-TEC, University of Parma,

Italy
Joshua Boateng, School of Science, Faculty of Engineering and Science, University of

Greenwich Medway, Chatham Maritime, UK
Maria Cristina Bonferoni, Department of Drug Sciences, University of Pavia, Italy
Karen Campbell, Western University, London, ON, Canada
Carla Caramella, Department of Drug Sciences, University of Pavia, Italy
Ovidio Catanzano, Department of Life Sciences, University of Trieste, Italy
Gwendolyn Cazander, Wound Expertise Center (WEC), Ikazia, Rotterdam,

The Netherlands
Mariana T. Cerqueira, 3B’s Research Group, I3Bs – Research Institute on Biomaterials,

Biodegradables and Biomimetics, University of Minho, Headquarters of the European Insti-
tute of Excellence on Tissue Engineering and Regenerative Medicine, Barco, Guimarães;
and ICVS/3B’s–PT Government Associate Laboratory, Braga/Guimarães, Portugal
xiv List of Contributors
Michael Clark, Birmingham City University, Birmingham; and Welsh Wound Innovation
Centre, Ynysmaerdy, UK
Tim H.C. Damen, Wound Expertise Center (WEC), Ikazia, Rotterdam, The Netherlands
Lucília P. da Silva, 3B’s Research Group, I3Bs – Research Institute on Biomaterials,

Biodegradables and Biomimetics, University of Minho, Headquarters of the European Insti-
tute of Excellence on Tissue Engineering and Regenerative Medicine, Barco, Guimarães;
and ICVS/3B’s–PT Government Associate Laboratory, Braga/Guimarães, Portugal
Philip Debrah, Department of Pharmaceutics and Microbiology, School of Pharmacy, Uni-

versity of Ghana, Accra, Ghana
Bianca K. den Ottelander, Wound Expertise Center (WEC), Ikazia, Rotterdam,

The Netherlands
Martijn C.H.A. Doomen, Wound Expertise Center (WEC), Ikazia, Rotterdam,

The Netherlands
Dennis Douroumis, School of Science, Faculty of Engineering and Science, University of

Greenwich, Chatham Maritime, UK
Lisa Elviri, Food and Drug Department, University of Parma, Italy
Franca Ferrari, Department of Drug Sciences, University of Pavia, Italy
Mansa Fredua-Agyeman, Department of Pharmaceutics and Microbiology, School of

Pharmacy, University of Ghana, Accra, Ghana
Marcos Garcia-Fuentes, Center for Research in Molecular Medicine and Chronic

Diseases (CIMUS), Universidad de Santiago de Compostela, Spain
Atabak Ghanizadeh Tabriz, School of Science, Faculty of Engineering and Science,

University of Greenwich, Chatham Maritime, UK
Keith Harding, Division of Population Medicine, Cardiff University School of Medicine,

Cardiff, UK
Galiya S. Irmukhametova, Faculty of Chemistry and Chemical Technology, al-Farabi

Kazakh National University, Almaty, Kazakhstan
Sandra Kamga, Wound Expertise Center (WEC), Ikazia, Rotterdam, The Netherlands
Vitaliy V. Khutoryanskiy, School of Pharmacy, University of Reading, UK

List of Contributors xv
Awo Afi Kwapong, Department of Pharmaceutics and Microbiology, School of Pharmacy,

University of Ghana, Accra, Ghana
Kirstie Lane, West Byfleet Health Centre, West Byfleet, UK
Kimberly LeBlanc, Wound Ostomy Continence Institute/Association of Nurses Special-

ized in Wound Ostomy Continence, Ottawa, ON, Canada
Barun Majumder, Ashford and St Peter’s Hospitals NHS Foundation Trust, Chertsey, UK
Duniya Majumder, Lanarkshire, Glasgow, UK
Alexandra P. Marques, The Discoveries Centre for Regenerative and Precision Medicine,
Headquarters at University of Minho, Barco, Guimarães, Portugal
Emi Maruhashi, University of Lisbon, Lisbon, Portugal
Grigoriy A. Mun, Faculty of Chemistry and Chemical Technology, al-Farabi Kazakh

National University, Almaty, Kazakhstan
Shiow-Fern Ng, Centre for Drug Delivery Research, Faculty of Pharmacy, Universiti
Kebangsaan Malaysia, Kuala Lumpur, Malaysia
Silvia Rossi, Department of Drug Sciences, University of Pavia, Italy
Giuseppina Sandri, Department of Drug Sciences, University of Pavia, Italy
Sandeep Singh, Ashford and St Peter’s Hospitals NHS Foundation Trust, Chertsey, UK
Sophia Tate, University Hospital of Wales, Cardiff and Vale University Health Board,
Cardiff, UK
Anne Marie E. van Well, Wound Expertise Center (WEC), Ikazia, Rotterdam,
The Netherlands
Series Preface
The series Advances in Pharmaceutical Technology covers the principles, methods and
technologies that the pharmaceutical industry uses to turn a candidate molecule or new
chemical entity into a final drug form and hence a new medicine. The series will explore
means of optimizing the therapeutic performance of a drug molecule by designing and
manufacturing the best and most innovative of new formulations. The processes associated
with the testing of new drugs, the key steps involved in the clinical trials process and the
most recent approaches utilized in the manufacture of new medicinal products will all be
reported. The focus of the series will very much be on new and emerging technologies and
the latest methods used in the drug development process.
The topics covered by the series include the following:
Formulation: The manufacture of tablets in all forms (caplets, dispersible, fast-melting)
will be described, as will capsules, suppositories, solutions, suspensions and emulsions,
aerosols and sprays, injections, powders, ointments and creams, sustained release and
the latest transdermal products. The developments in engineering associated with fluid,
powder and solids handling, solubility enhancement, colloidal systems including the sta-
bility of emulsions and suspensions will also be reported within the series. The influence
of formulation design on the bioavailability of a drug will be discussed and the impor-
tance of formulation with respect to the development of an optimal final new medicinal
product will be clearly illustrated.
Drug Delivery: The use of various excipients and their role in drug delivery will be
reviewed. Among the topics to be reported and discussed will be a critical appraisal
of the current range of modified-release dosage forms currently in use and also those
under development.
The design and mechanism(s) of controlled release systems including macromolecular
drug delivery, microparticulate controlled drug delivery, the delivery of biopharmaceu-
ticals, delivery vehicles created for gastrointestinal tract targeted delivery, transdermal
xviii Series Preface
delivery and systems designed specifically for drug delivery to the lung will all be
reviewed and critically appraised. Further site-specific systems used for the delivery
of drugs across the blood–brain barrier including dendrimers, hydrogels and new
innovative biomaterials will be reported.
Manufacturing: The key elements of the manufacturing steps involved in the production
of new medicines will be explored in this series. The importance of crystallization; batch
and continuous processing, seeding; and mixing including a description of the key engi-
neering principles relevant to the manufacture of new medicines will all be reviewed
and reported. The fundamental processes of quality control including good laboratory
practice, good manufacturing practice, Quality by Design, the Deming Cycle, regulatory
requirements and the design of appropriate robust statistical sampling procedures for the
control of raw materials will all be an integral part of this book series.
An evaluation of the current analytical methods used to determine drug stability, the
quantitative identification of impurities, contaminants and adulterants in pharmaceutical
materials will be described, as will the production of therapeutic bio-macromolecules, bac-
teria, viruses, yeasts, molds, prions and toxins through chemical synthesis and emerging
synthetic/molecular biology techniques. The importance of packaging including the com-
patibility of materials in contact with drug products and their barrier properties will also be
explored.
Advances in Pharmaceutical Technology is intended as a comprehensive one-stop shop
for those interested in the development and manufacture of new medicines. The series will
appeal to those working in the pharmaceutical and related industries, both large and small,
and will also be valuable to those who are studying and learning about the drug development
process and the translation of those drugs into new life-saving and life-enriching medicines.
Dennis Douroumis
Alfred Fahr
Jürgen Siepmann
Martin Snowden
Vladimir Torchilin
Preface
Wounds and their effective healing constitute a common and current global medical concern
with several challenges, including the increasing incidence of obesity and type 2 diabetes,
an ageing population that has increased the incidence of chronic (difficult to heal) wounds,
and the requirement for more effective but also cost-effective dressings. Wounds can be
chronic or acute and can result from burns, amputation, surgical procedures, or underlying
medical conditions. Innovative dressings that take an active part in wound healing in a more
rapid manner and at reasonable cost are currently an unmet public health need. Although
there are several dressings on the market, not all of them take an active part in wound
healing; instead, they depend on the body’s natural physiological tissue processes, which
are normally compromised in patients with underlying medical conditions and in those who
are highly traumatized, such as combat personnel and mass casualties.
Therefore, interest has shifted in academic research laboratories, industry, and general
clinical practice towards more advanced therapeutic dressings that are biologically
active and usually involve multi-disciplinary approaches spanning molecular biology,
biomaterial/polymer science, biochemistry, formulation science, and biopharmaceutics.
These include medicated dressings, biomaterial-based biological dressings (biological and
naturally derived), tissue-engineered scaffolds, as well as nanotechnology.
This book systematically covers various aspects of the above advanced wound healing
therapies and is divided into three main themes. The book comprises 17 chapters written by
various authors who are widely recognized in their fields of expertise. The first six chapters
focus on the physiological and molecular basis of wounds and their healing, including the
various types of chronic wounds as well as some of the complicating and risk factors, such as
infections and dead tissues, and how to manage these from a clinical perspective. Chapters
7–9 focus on advanced moist modern dressings such as wafers and hydrogels as well as
on nanotechnology-based silver dressings. Finally, Chapters 10–17 address more advanced
and novel approaches to wound healing, including gene therapy-based dressings, tissue
engineering, delivery of growth factors, electrospun dressings, biomaterial-based dressings,
xx Preface
and the use of three-dimensional (3D) printed scaffolds embedded with cells and other
active entities that take part in tissue regeneration.
Most importantly, I would like to personally thank all of the authors for their willing-
ness to contribute to this book in the first place, and for preparing their chapters with due
diligence and a sense of purpose to meet the agreed deadlines.
Joshua Boateng
1
Chronic Wound Healing: Molecular
and Biochemical Basis
Sophia Tate1 and Keith Harding2

1
University Hospital of Wales, Cardiff and Vale University Health Board, Cardiff, UK
2
Division of Population Medicine, Cardiff University School of Medicine, Cardiff, UK
1.1 Introduction
A wound can be defined as a break in the epithelial integrity of the tissue, or a disruption
of normal anatomical structure and function [1]. Usually a wound progresses through
several sequential, though overlapping, stages of cellular and biochemical activity to
achieve healing. A chronic wound may be defined as one that is failing to progress
through the wound healing process in an anticipated time frame [2]. A wound that does
not show significant improvement within 4 weeks, or heal completely in 8 weeks, may be
considered a chronic wound [3]. There are four stages described in normal wound healing:
haemostasis, inflammation, proliferation, and remodelling. The healing of a chronic
wound may be arrested in any of these stages, but most commonly during inflammation or
proliferation [4]. This chapter will briefly describe normal wound healing, consider some
subtypes of chronic wound, and then examine the different molecular and biochemical
processes that occur.
1.2 Acute Wound Healing

The process of acute wound healing is well described and widely reported in the literature,
and is summarised in Figure 1.1.
Therapeutic Dressings and Wound Healing Applications, First Edition. Edited by Joshua Boateng.
© 2020 John Wiley & Sons Ltd. Published 2020 by John Wiley & Sons Ltd.
2 Therapeutic Dressings and Wound Healing Applications
TIME
INJURY
Haemostasis
Vasoconstriction
Platelet activation
Coagulation cascade
PDGF, TGF-β, IL-1, TNF-α
Inflammation
Vasodilation, increased vascular permeability
Neutrophils
Macrophages
PDGF, TGF-β, IL-1,TNF-α
Proliferation
Fibroblasts
Collagen deposition
Keratinocytes
Re-epithelialisation
Endothelial cells
Angiogenesis
VEGF, FGF, PDGF, EGF, TGF-α, IGF
Remodelling
Collagen replacement and cross-linking
Myofibroblasts
Wound contraction
TGF-α, MMPs
HEALED
WOUND
Figure 1.1 A summary of acute wound healing. EGF, epidermal growth factor; FGF, ﬁbroblast
growth factor; IGF, insulin-like growth factor; IL-1, interleukin 1; MMP, matrix metallopro-
teinase; PDGF, platelet-derived growth factor; TGF, transforming growth factor; TNF-𝛼, tumour
necrosis factor 𝛼; VEGF, vascular endothelial growth factor.
The first step, haemostasis, is characterised by vasoconstriction and coagulation; it takes

place soon after injury and is complete within hours. The tissue in the wound is exposed to
blood because of disruption of the blood vessels and lymphatics during injury. Platelets are
activated when they come into contact with collagen and initiate the coagulation cascade,
resulting in the deposition of a haemostatic ‘plug’ [5]. A number of cytokines are released
Chronic Wound Healing: Molecular and Biochemical Basis 3
by the degranulation of activated platelets. Of particular importance are platelet-derived

growth factor (PDGF) and transforming growth factor-beta (TGF-β). PDGF is a chemoat-
tractant of neutrophils, macrophages, smooth muscle cells, and fibroblasts [1]. TGF-β is
also involved in the chemotaxis of macrophages, fibroblasts, and smooth muscle cells, and
has a role in activating these cells to express other cytokines and enzymes which are crucial
to enable the wound healing to progress [1].
After the initial vasoconstriction during haemostasis, there is vasodilation and increased
vascular permeability as the stage of inflammation begins. This is regulated by mast cell
degranulation, which releases histamine and other vasoactive mediators [1]. Debris, dead
cells, and bacteria are cleared from the tissue by neutrophils, and later by macrophages.
Inflammation is usually complete after 48–72 h, but may last as long as 5–7 days [6].
The next stage is proliferation, which continues for weeks. The hallmark of the prolif-
erative phase is the migration of fibroblasts into the wound, where they are activated to
produce collagen III, fibrin, fibronectin, and hyaluronic acid in the new extracellular matrix
[7]. Granulation tissue is deposited to fill the defect. Keratinocytes, stimulated by epider-
mal growth factor (EGF) and transforming growth factor-alpha (TGF-α), migrate to the
wound edges, and eventually close the defect [1]. Angiogenesis is important to support
the increased metabolic activity in the wound. A number of growth factors stimulate the
neovascularisation, including vascular endothelial growth factor (VEGF). Epidermal cells,
fibroblasts, macrophages, and vascular endothelial cells produce these factors in response
to conditions in the wound environment, such as low pH and reduced oxygen tension [1].
The final stage, remodelling, begins after about a week and may last for years. This
phase is characterised by the removal of type III collagen from the extracellular matrix
and the deposition of mature type I collagen [8]. Collagenase enzymes from fibroblasts,
neutrophils, and macrophages are important in this stage [1]. Wound contraction is mediated
by differentiated fibroblasts (myofibroblasts) in response to TGF-α, and the presence of
matrix proteins such as extra-domain-A fibronectin and tenascin C [9]. Once remodelling
has occurred, there is apoptosis of fibroblasts, leaving relatively acellular scar tissue [9].
1.3 Categories of Chronic Wound

Although chronic wounds may seem varied in their presentation and characteristics, often
the underlying aetiological processes are similar. Some common chronic wound categories
are considered here. Ultimately, the final common pathway is an open wound that has
been colonised with bacteria, initiating a damaging inflammatory response that impedes
healing [10].
1.3.1 Pressure Ulcers

Pressure ulcers are an example of chronic ischaemia–reperfusion injury. Repeated tissue
trauma occurs in insensate areas when the pressure in the tissue exceeds capillary perfusion
pressure [10]. This results in skin breakdown, which is followed by bacterial colonisation,
often compounded by the location of such ulcers near to the perineum. There is failure
of the processes of angiogenesis, extracellular matrix deposition, and wound contraction,
resulting in the development and persistence of a chronic ulcer [11]. These steps in wound
healing are usually driven by growth factors, and the destruction or reduced synthesis of
these proteins in pressure ulcers has been investigated. In a study using an enzyme-linked
immunosorbent assay technique to quantify the levels of growth factors in wound fluid from
pressure ulcers, Cooper et al. [12] found that PDGF, fibroblast growth factor (FGF), EGF,
and TGF-β levels were variable, and decreased compared with the levels of growth factors
in acute wounds.
1.3.2 Venous Stasis Ulcers

Venous stasis ulcers occur when damaged or defective leg vein valves result in venous
hypertension and oedema. Eventually the venous pressure exceeds the capillary perfusion
pressure of the skin, and the tissue becomes ischaemic. The increase in intraluminal pressure
affects the permeability of the vessel walls, and the veins leak fibrin and other plasma com-
ponents into the perivascular space [9]. Accumulation of fibrin impairs healing by impairing
collagen synthesis, and by forming peri-capillary fibrin cuffs that impede normal vessel
function [9]. Often a venous ulcer is precipitated by minor trauma, for example a scratch
or insect bite. The skin breakdown is accelerated by the hypoxic conditions, and secondary
bacterial colonisation. This increases the tissue injury and inflammation at the wound site,
and impairs epithelialisation [11].
1.3.3 Ischaemic Ulcers

Atherosclerosis and/or embolism in leg arteries leads to narrowing of the lumens of the
vessels and ischaemia of distal tissue. Minor trauma may then result in an ulcer. Healing is
slow because of the low oxygen concentration in the tissue, and the resultant open wound
is colonised by bacteria. This increases inflammation in the wound, and the tissue defect
persists. The effects of hypoxia are described in more detail in Section 1.5.4.
1.3.4 Diabetic Foot Ulcers

Diabetic foot ulcers are another category of wounds which are commonly chronic in their
course. The diabetic foot may be subject to repeated trauma as a result of sensory loss.
There may also be a degree of ischaemia because of microvascular arteriopathy. Once the
skin barrier is breached, low-grade bacterial colonisation is common. Tissue fragments and
bacterial products perpetuate the inflammatory response. The effects of hyperglycaemia are
described in more detail in Section 1.5.2.
1.4 How a Chronic Wound Develops: Intrinsic Components

There are several hallmarks of chronic wounds when compared with normal acute wounds
[9]. In a normal wound bed, there will be a high concentration of growth factors, with
healthy cell populations in an organised extracellular matrix. By comparison, chronic
wound beds tend to have low concentrations of growth factors and a disorganised extracel-
lular matrix. This is because of excessive proteolysis driven by a persistent inflammatory
state, often a response to a bacterial biofilm or low-grade infection. Impaired angiogenesis
Hyperproliferative but
non-advancing
epithelium
High bacterial
load in the wound
Senescent
Activated neutrophils fibroblasts
MMPs ROS Pro-inflammatory

Growth factors macrophages
Impaired
neovascularisation
Increased vascular
permeability – extravasation
of monocytes, neutrophils,
and plasma
Figure 1.2 The local environment in the chronic wound. MMP, matrix metalloproteinase;
ROS, reactive oxygen species.
and neovascularisation mean that cells in the wound environment are starved of oxygen and
nutrients. The result is impaired fibroblast and epithelial cell proliferation and migration,
and delayed healing. Figure 1.2 summarises these components.
1.4.1 Cell Phenotype

The cells in chronic wounds have an altered phenotype, with fewer growth factor receptors
and less mitogenic potential [9]. They do not therefore respond to the wound environment
in the same way as cells observed in a healthy acute wound. Some specific observations in
different cell types are briefly described below.
1.4.1.1 Fibroblasts
In a healthy wound, fibroblasts respond to chemical signals in the form of growth factors,
such as PDGF, insulin-like growth factor (IGF), and FGF, to migrate towards the site of
injury, divide, and synthesise key extracellular matrix proteins such as collagen III, fib-
rin, fibronectin, and hyaluronic acid [7]. Fibroblasts from many chronic wound types have
a reduced response to growth factors. Studies of fibroblasts from chronic diabetic [13],
chronic non-diabetic [13], and chronic venous ulcers [14] have demonstrated lower rates
of cell division in response to PDGF, IGF, and FGF, which usually promote proliferation,
while cell motility is also reduced at the same time. These findings are thought to be due
to reduced growth factor receptor density [9]. As well as having reduced activity, fibrob-
lasts from chronic wounds show signs of premature senescence. In a study where fibroblast
cultures were generated from punch biopsies taken from venous leg ulcers, and compared
with those from uninjured skin in the contralateral limb, the cells from the wound showed
a reduction in growth potential and altered gene expression. This observation was indepen-
dent of the age of the patient [15].
1.4.1.2 Keratinocytes
In healthy skin, basal keratinocytes at the dermal–epidermal junction undergo cell division
periodically, and then these daughter cells differentiate to form the supra-basal epider-
mal layers. Keratinocytes express keratin proteins, with the pattern of keratin filament
subtypes indicating the degree of differentiation of the keratinocyte [16]. In response to
injury, keratinocytes in the adjacent skin, as well as those in the supra-basal layer, start to
express keratins 6 and 16, demonstrating a more activated phenotype, which then reverts
to normal when the wound has been closed [16]. In addition, cells at the leading edge of
the wound deposit an extracellular matrix protein (laminin-332), which mediates the ker-
atinocyte migration and anchors cells to the basement membrane [9, 16]. Keratinocytes in
chronic wounds, such as diabetic and venous ulcers, are not able to complete these key
steps in re-epithelialisation. Whilst they have an activated phenotype and are highly pro-
liferative, they are not well differentiated [16, 17]. They have impaired ability to migrate,
which is thought to be because of decreased production of laminin-332 [9]. They also have
decreased expression of the growth factors VEGF and TGF-α, although they show increased
expression of PDGF when compared with keratinocytes in healthy wounds [9]. Overall,
this imbalance in gene expression results in the disorganised hyperkeratosis observed at the
non-advancing edges of chronic wounds.
1.4.2 Immune Cells and Inflammatory Mediators

1.4.2.1 Neutrophils
The chemoattractants released by platelet degranulation during haemostasis mean that
neutrophils are recruited to the wound early and are required for the control of pathogens
at the site of injury. Once activated, the neutrophils adhere to the endothelium of the
blood vessels at the wound site, and move into the wound by transmigration through
an intracellular junction and then through the extracellular matrix. In order to do this,
and also to phagocytose bacteria and damaged extracellular matrix, neutrophils have
numerous enzymes contained in cytoplasmic granules and secretory vesicles [18]. These
include proteases, such as elastase and cathepsin B, D, and G, and antimicrobials, such as
myeloperoxidase and lysozyme [18].
Neutrophils also release a number of cytokines, including interleukin (IL)-1, IL-6, and
TNF-α, antimicrobial substances, for example reactive oxygen species (ROS), and growth
factors [19]. They are important in the recruitment of other immune cells, such as mono-
cytes, and also in promoting proliferation of keratinocytes, fibroblasts, and endothelial cells.
However, whilst neutrophil activity is essential, it must be carefully regulated and
uncontrolled activity is detrimental. Excessive numbers of neutrophils have been observed
in non-healing wounds and this results in a pro-inflammatory environment. Overproduction
of ROS causes damage to the extracellular matrix, increases matrix metalloproteinase
(MMP) activation, and leads to early cell senescence [19]. Levels of MMPs and other
neutrophil-produced proteases such as neutrophil elastase are increased in chronic wound
fluid compared with acute wound fluid [20]. Increased protease activity breaks down
growth factors in the wound environment, reducing their effects. Adhesion molecules such
as fibronectin are also broken down, impairing the cell adhesion that is needed for wound
closure [21].
1.4.2.2 Macrophages
Monocytes arrive in the wound 5–6 h after injury, and differentiate into macrophages. In
addition to monocytes recruited from the circulation by chemokines, there is a popula-
tion of resident tissue macrophages that proliferate in response to injury. Macrophages
are important in all stages of wound healing, and their actions and phenotype change as
wound healing progresses [22]. In the inflammatory stage, activated macrophages clear
damaged tissue and control pathogens through phagocytosis and antigen presentation to T
cells. They secrete a number of pro-inflammatory cytokines and growth factors IL-1, FGF,
VEGF, and PDGF [19]. These pro-inflammatory ‘M1’ macrophages undergo apoptosis a
few days after injury. However, a second population of ‘M2’ macrophages survive to the
proliferative phase [19]. Their phenotype changes, and they have a role in the stimulation
of keratinocytes, fibroblasts, and endothelial cells to re-epithelialise the defect, deposit new
extracellular matrix, and carry out neovascularisation [22]. During this phase, macrophages
are important in the production of TGF-β and VEGF, the effects of which are discussed in
more detail in Section 1.4.4.
In chronic wounds, macrophage numbers are increased [23]; however, the cells present
are thought to be dysfunctional. The switch from the pro-inflammatory ‘M1’ phenotype to
the anti-inflammatory ‘M2’ phenotype is impaired [19]. Studies in diabetic mouse models
have shown that if macrophages do not undergo phenotypic conversion there is a reduction
in key growth factors (TGF-β, VEGF, IGF-1), and therefore failure to move into the prolifer-
ative phase of wound healing [24]. Additionally, the macrophages in these chronic wounds
have a reduced phagocytic capacity, and the resulting build-up of debris and pathogenic
material perpetuates the pro-inflammatory state in the wound [25].
1.4.2.3 Tumour Necrosis Factor Alpha

TNF-α is secreted by many cell types in the wound environment, including keratinocytes,
fibroblasts, vascular endothelial cells, and inflammatory cells (neutrophils and macro-
phages). TNF-α stimulates its own release, as well as the production of IL-1, and upregu-
lates the production of MMPs whilst downregulating the production of tissue inhibitors of
MMPs (TIMPs) by macrophages, keratinocytes, and fibroblasts. In low concentrations for
a short period, this is beneficial, as wound healing is enhanced by the removal of damaged
tissue and the stimulation of inflammatory cells and resulting growth factor production
[10]. However, prolonged and increased TNF-α secretion delays wound healing as the
overall result of sustained TNF-α signalling is the degradation of the extracellular matrix,
as well as a number of growth factors and their receptors [10].
Whilst the release of TNF-α is part of the normal cytokine response to injury, the usual
pattern in an acute wound is that the increase in TNF-α is limited and transient. In chronic
wounds, the pro-inflammatory cytokine cascade is prolonged and amplified because of the
persistence of noxious stimuli [10]. Studies of wound fluid from chronic wounds have found
markedly elevated levels of TNF-α compared with healthy surgical wounds [26].
1.4.2.4 Interleukin 1
In the skin IL-1 is manufactured and stored in keratinocytes, ready for release when injury
occurs. It is therefore present from the very beginning of the haemostasis and inflammatory
stages of wound healing. Levels are further increased by the release of IL-1 from other
inflammatory cells, such as macrophages, once they are activated at the site of injury. IL-1
is a chemokine for neutrophils, which are required in injury to remove pathogens. Chronic
wounds have increased levels of IL-1 [26] and, in many cases, this is at least partly in
response to the presence of bacteria. These wounds also have elevated levels of proteolytic
enzymes, such as collagenases, gelatinases, and stromelysins, whose production is induced
by IL-1 and TNF-α [26].
1.4.3 Reactive Oxygen Species

ROS are released from endothelial cells in response to TNF, PDGF, and thrombin, from
fibroblasts in response to IL-1, and also from neutrophils and macrophages [27]. They are
essential in oxidative bacterial killing, and enhance the chemotaxis of neutrophils; they are,
therefore, important in the prevention of wound infection. ROS production by nicotinamide
adenine dinucleotide phosphate hydrogen (NADPH)-linked oxygenase is highly oxygen
dependent [27]. However, like most processes in the inflammatory stage of wound healing,
regulation is critical, as very high concentrations of ROS are damaging. Antioxidants such
as nitric oxide are produced, and reductases are activated to prevent oxidative damage.
Again, these processes are dependent on oxygen [27]. The chronic wound environment is
often hypoxic, either as a result of systemic or regional disease, for example atherosclerosis
or venous hypertension, or as a result of local factors such as infection, or a combination of
both. There is often a repetitive cycle of ischaemia and reperfusion, such as when a leg with
a poor arterial blood supply is elevated and then dependent. In such circumstances, there is
a net build-up of ROS and an increase in inflammation and tissue damage [27].
1.4.4 Growth Factors

1.4.4.1 The Platelet-Derived Growth Factor Family
PDGF is made up of a family of homo- or heterodimeric growth factors, which bind
to three different transmembrane tyrosine kinase receptors [28]. PDGF is released by
platelet degranulation during the haemostasis stage of wound healing, and is found in
high concentrations in wound fluid early after injury [29]. It has a chemotactic effect on
neutrophils, monocytes, fibroblasts, and smooth muscle cells [30]. In addition, PDGF
stimulates fibroblasts to proliferate and synthesise extracellular matrix components [28]. It
promotes angiogenesis in hypoxic conditions, and in vivo experiments have demonstrated
that PDGF increases pericyte and smooth muscle cell recruitment to the new capillaries,
increasing structural integrity [30].
PDGF levels are decreased in chronic wounds [11]. It is thought that this is due to
increased MMP and neutrophil elastase activity in chronic wounds, as PDGF degradation
can be reversed if these enzymes are inhibited [30].
There has been interest in PDGF as a potential treatment in non-healing wounds, and
it is the only growth factor approved by the United States Food and Drug Administration
available for clinical use. The results of pre-clinical experiments were promising, but there
has been only limited success in translational clinical trials. A systematic review in 2013
found a small benefit over standard care in achieving complete wound closure; however, the
authors commented that the quality of the clinical trials reviewed meant that the strength of
the evidence was low [31].
1.4.4.2 The Epidermal Growth Factor Family

This family includes a number of members which are important in wound healing: EGF,
heparin-binding EGF (HB-EGF), and TGF-α [30].
EGF is secreted by platelets, macrophages, and fibroblasts. It is a potent chemotactic
for a number of cell types, including keratinocytes. HB-EGF and TGF-α are produced by
keratinocytes and macrophages [32]. These growth factors all activate the EGF receptor
(EGFR), a tyrosine kinase transmembrane protein found throughout the dermis although
most prominent in the basal layer [30, 33]. HB-EGF and TGF-α have been found in high
concentrations in wound fluid. Schultz et al. [33] found that the fluid collected from the
drains of mastectomy wounds stimulated fibroblasts in vitro. It was rich in peptide growth
factors, including TGF-α, IGF-I, and TGF-β. In comparison, fluid collected from chronic
wounds had low levels of growth factors, and did not stimulate fibroblasts in vitro. This inhi-
bition of mitogenesis was reversible when acute wound fluid was added [33]. Other groups
have also found that fluid from chronic wounds not only inhibits fibroblast proliferation but
also decreases cell viability in vitro [34].
EGFR expression is upregulated in the proliferative phase of acute wound healing,
but subsequently declines [28]. Re-epithelialisation is significantly impaired in EGFR
knock-out mice compared with similar injuries in wild-type mice [35]. Alterations in the
expression of EGFR in chronic wounds has been demonstrated. Brem et al. [36] used
histology, gene expression profiling, and in vitro migration assays to analyse skin biopsies
from the edge of non-healing venous ulcers. They used healthy skin adjacent to the wound
edge from the same patients as a comparison, as well as ‘normal skin’ biopsies as a control.
They noted that wound edge biopsies had a ‘distinct pathogenic morphology’, with a
hyperproliferative epidermis, dermal fibrosis, and increased pro-collagen synthesis. When
cultured in vitro, fibroblasts from these biopsies demonstrated impaired migration. The
gene expression profile of the wound fibroblasts was reproducibly altered, and immuno-
histochemistry demonstrated reduced EGFR expression. The EGFR that was present was
predominantly cytoplasmic. In fibroblasts from adjacent skin there was increased EGFR
expression, and the receptor was present at the cell surface as well as in the cytoplasm. In
the control samples, EGFR was only expressed at the cell membrane and expression was
reduced compared with the adjacent skin samples.
These studies suggest that the EGF family and its receptor play an important role
in wound healing by driving the expansion of the keratinocyte population in the
wound, promoting both proliferation of existing cells and migration of cells from the
surrounding healthy skin. However this process must be correctly regulated for successful
re-epithelialisation.
1.4.4.3 The Fibroblast Growth Factor Family

The FGF family is a group of structurally related polypeptides which act at tyrosine kinase
transmembrane protein receptors. The four FGF receptors bind the different FGFs with
variable affinity. FGFs are generally mitogenic, stimulating a broad range of cell types,
including fibroblasts and keratinocytes to proliferate, but also to migrate or differentiate in
some cases. [28].
FGFs have been found in wound fluid early after injury [12, 29]. Studies have also
demonstrated increased expression of FGFs during wound healing, and that reduction in
the expression of FGFs increases the likelihood of wound healing disorder [37]. An in vivo
study of diabetic mice, which demonstrate impaired wound healing, found that FGFs were
expressed at lower levels and for less time than in wild-type mice with similar injuries [37].
FGFs have been investigated as a potential treatment for chronic wounds, with studies
carried out in patients with pressure ulcers [38] and diabetic foot ulcers [39]. However,
the results of clinical trials have not supported the introduction of FGF supplements into
clinical practice.
1.4.4.4 The Vascular Endothelial Growth Factor Family

The VEGF family includes six subtypes that bind to three transmembrane tyrosine kinase
receptors. VEGF-A and its receptors VEGF receptors 1 and 2 (VEGFR-1 and VEGFR-2)
have been the most extensively studied in greater detail and found to be important in angio-
genesis and vasculogenesis [28]. VEGF is produced in response to hypoxia, and also in
response to several other growth factors, including TGF-β, FGF, and PDGF [38]. Animal
studies in rats and guinea pigs have shown that VEGF expression is significantly elevated
in keratinocytes at the edge of an acute wound, and remains high in the keratinocytes that
move to close the defect [40]. Platelets, macrophages, and keratinocytes also secrete VEGF
during wound healing [38].
When activated, the VEGF receptors trigger multiple events: vascular permeability is
increased, enabling extravasation of neutrophils and monocytes, MMP-1 and MMP-2 are
induced, activating plasminogen and breaking down the basement membrane, and endothe-
lial migration is stimulated [38, 40]. All of these processes are essential for angiogenesis.
VEGF acts on smooth muscle cells, increasing the production of MMPs and stimulating
migration and proliferation [41]. The same receptor pathway is present in monocytes, stim-
ulating migration and activating the cells to produce tissue factors [41]. Other effects include
fibroblast proliferation and keratinocyte motility [38]. VEGF, along with nitric oxide and
MMP-9, is thought to be important in endothelial cell progenitor migration from the bone
marrow [9]. These progenitor cells are essential for wound healing, although the exact
mechanisms of recruitment and homing to the wound site are not yet clear [9].
Angiogenesis is impaired in chronic wounds [42] and it is therefore not surprising
that VEGF expression and processing have also been found to be altered in chronic
wounds. Soluble VEGFR-1 (sVEGFR-1) is an endogenous inhibitor of VEGF. A high

level of sVEGFR-1 in a wound is a poor prognostic sign [43]. It is thought that sVEGFR-1
acts as a decoy receptor, mopping up the VEGF in the wound and preventing it from
activating its target pathways. Expression of sVEGFR-1 is increased in chronic wounds
[42]. Furthermore, a study of biopsies from chronic venous ulcers found that, although
VEGF and VEGFR expression was elevated compared with normal uninjured tissue,
it was not as high as in psoriatic lesions, which were used as a positive control [44].
Recombinant VEGF was then incubated with fluid from the chronic wounds, and fluid
from acute wounds. Western blotting demonstrated that in chronic wound fluid the VEGF
was broken down, whereas in acute wound fluid it remained stable [44]. It is suggested
that this increased proteolytic activity in a chronic wound is the reason why, despite the
increased expression of VEGF, its beneficial effects are not observed [42]. It is also likely
to be the reason that treatment with exogenous VEGF does not improve wound healing.
1.4.4.5 The Transforming Growth Factor Family

Whilst there are over 30 members of this growth factor family, only a few of them have
been implicated in wound healing: TGF-β1, -β2, and -β3 are synthesised by macrophages,
platelets, keratinocytes, and fibroblasts, and activins βA and βB are expressed by fibroblasts,
endothelial cells, and keratinocytes [38]. TGF-β1 is generated by platelets in an active form,
but all the other members of the family are produced as precursors, in an inactive form
[38, 45]. They are sequestered bound to proteins linked to extracellular matrix components,
and therefore require enzymatic activation by proteases [45].
TGF-β1, -β2, and -β3 are important in wound healing for the recruitment and migration
of inflammatory cells, fibroblasts, and keratinocytes. More specifically, TGF-β1 and -β2
induce differentiation of fibroblasts to myofibroblasts, thus increasing extracellular matrix
deposition and prompting wound contraction and scar formation [30]. However, the con-
centration of TGF-β1 affects its action on cells, with low levels promoting endothelial
proliferation and migration and high levels increasing extracellular matrix deposition by
stimulating collagen deposition and inhibiting MMPs through the increased expression of
TIMPs [22, 45].
Levels of the TGFs are decreased in chronic wounds, and as with other growth factors
this is likely to be a result of excessive protease activity in the wound bed. In addition, the
action of TGFs is impaired in chronic wounds by a decrease in receptor expression on target
cells [30].
1.4.4.6 Insulin-Like Growth Factor

There are two types of IGF: IGF-1 and IGF-2. They are released by platelet degranulation,
and also synthesised by fibroblasts. The IGF receptor, a transmembrane tyrosine kinase
receptor, stimulates mitogenesis and increases survival in a number of cell types [28]. It
is thought that IGF is a factor in the aetiology of chronic wounds associated with diabetes
and glucocorticoid treatment because the expression of IGFs and their receptors is abnor-
mal in these conditions [28]. Immunohistochemistry comparing skin from a diabetic foot
ulcer with uninjured diabetic skin and non-diabetic skin found that, whilst the expression
of IGF-2 was comparable in all samples, the expression of IGF-1 was markedly differ-
ent. In non-diabetic skin, IGF-1 was widely expressed throughout the epidermis, whilst
in uninjured diabetic skin it was only found in the stratum granulosum and spinosum, and in
ulcerated diabetic skin it was absent [46]. Fibroblasts from the tissue samples from patients
with diabetes also lacked IGF-1 [46].
1.4.5 The Role of Matrix Metalloproteinases

The MMPs are a group of proteases, a number of which have a role in wound healing.
MMP-1 and MMP-8 are collagenases. Their substrates include collagen I, the predominant
collagen of the skin, and collagen III, the collagen initially laid down to close a wound
defect. MMP-1 is expressed on the first day after injury, but then gradually decreases and
MMP-8 becomes the main collagenase in the healing wound [47]. MMP-2 and MMP-9
are gelatinases, and their substrates include gelatin, type I collagen, and type IV colla-
gen, which are found in the basement membrane. They are expressed by keratinocytes and
enable cell migration [47]. MMP-3 and MMP-10 are stromelysins, and can break down col-
lagens, as well as non-collagenous matrix macromolecules including fibronectin, elastin,
and gelatin [47]. These activities are important for successful wound healing. Breakdown
of the basement membrane is required to allow migration of monocytes and neutrophils
from the vasculature into the tissue. Damaged extracellular matrix must be broken down
and removed. The initial granulation tissue laid down is disorganised and not as strong as
native tissue, and must therefore be remodelled once the epithelial defect has been closed.
In healthy tissue there is minimal expression of MMPs, but if remodelling is required
they can be rapidly upregulated in a number of different cell types, including keratinocytes,
fibroblasts, endothelial cells, monocytes, lymphocytes, and macrophages. They are pro-
duced in response to cytokines and growth factors, including EGF, FGF, VEGF, PDGF,
TNF-α, TGF-β, and some interleukins. MMPs are initially produced in an inactive form
(pro-MMPs), and subsequently activated by serine proteases or other MMPs. Neutrophil
elastase is one such activating enzyme [48].
MMP activity must be tightly controlled in order to enable repair whilst avoiding tissue
damage. In addition to the pathways described above, which promote gene expression and
MMP activation, there are also inhibitors of both the MMPs themselves and the enzymes
which activate the pro-MMPs. TIMPs are proteins produced by cells in the wound, and are
also found in serum. There are three forms of TIMP, all of which have been shown to be
active in wound healing, and specifically in the control of cell migration and extracellular
matrix remodelling [47]. They bind and inhibit activated MMPs.
The normal control of MMP activity is dysfunctional in chronic wounds. However, it is
a complex situation. Increased MMP activity has been proposed as a causative factor in
chronic wounds. Elevated levels of MMP activity have been found in wound fluid from
venous leg ulcers [20, 49], diabetic foot ulcers [20], and pressure ulcers [50], when com-
pared with that from acute wounds. In these studies MMP-2 and MMP-9 were specifically
implicated. However it is also suggested that inadequate MMP activity can be a prob-
lem, with another study suggesting that overexpression of TIMP-1 and -2 and the resultant
decreased levels of active MMP-1 and MMP-2 caused the defective extracellular matrix
reorganisation and failure of healing in chronic leg wounds [51].
1.5 How a Chronic Wound Develops: Extrinsic Factors

There are a number of extrinsic factors that have been shown to predispose a person to
developing a chronic wound. They are summarised in Figure 1.3. They share a common
overall effect, which is that inflammation is promoted in the wound site, and this leads to
impaired function of the wound cells and failure of the normal healing processes.
1.5.1 Infection
The duration of a wound as well as the resulting morbidity and mortality are all increased
by the presence of infection. The persistently high bacterial counts present in colonised
wounds are a key driver of the inflammatory response, and the bacteria, the toxins they
produce, and the inflammatory cells activated by them are all detrimental to the wound
environment. There is an increased concentration of proteases, which break down the extra-
cellular matrix, as well as key growth factors and their receptors in the wound bed [9]. Some
of these are released by bacteria, such as the zinc metalloproteinase, elastase, produced by
Pseudomonas aeruginosa [52]. The release of host MMPs and leukocyte-derived proteases,
such as neutrophil elastase, is also increased. Whilst invasive infection is a problem, often
the bacteria are localised in a biofilm. It is thought that these secreted polymer matrices
enable bacteria to evade host immune defences and enhance production of virulence factors,
significantly delaying wound re-epithelialisation in animal models [53].
1.5.2 Nutrition
1.5.2.1 Hyperglycaemia
Diabetes is known to be a risk factor for chronic wounds. The metabolic syndrome
that is often present in patients with diabetes means that there is a greater likelihood
Nutrition
Hypoxia Inflammation and Smoking

impaired wound
cell function
CHRONIC
WOUND
Repeated
Infection tissue
injury
Figure 1.3 Extrinsic factors contributing to the development of a chronic wound.

of atherosclerosis and small vessel disease, resulting in tissue ischaemia, as well as an

impaired immune response to infection. However, the hyperglycaemic state also has
specific effects in the wound environment which are detrimental to healing and the hyper-
glycaemia causes glycation of proteins. Glycated collagen is cross-linked, insoluble, and
stiffer than normal, which adversely affects fibril assembly. Binding with proteoglycans
is also affected, which affects matrix assembly and stability [54]. Proteoglycan binding is
essential for cell–collagen interactions with keratinocytes and fibroblasts, and adhesion and
migration of these cell types is impaired when collagen is glycated [54]. Hyperglycaemia
also stimulates MMP production by fibroblasts, macrophages, and endothelial cells, and
the extracellular matrix is broken down if MMP concentrations are too high [55].
1.5.2.2 Malnutrition
The increased activity at the site of injury means that there is an increased requirement for
macro- and micronutrients for successful wound healing. Proteins, fats, and carbohydrates
are all required, as well as vitamins and minerals.
A common problem in the elderly population is protein energy malnutrition, where an
underconsumption of protein and a calorie deficit result in weight loss, and specifically a
decrease in lean body mass. This problem is exacerbated when there is a chronic wound,
as protein is mobilised to meet the metabolic demand in the wound, and wound exudate
is protein rich. Any decrease in lean body mass will affect wound healing, with impaired
immunity and increased risk of infection in losses of 10%, thinned skin and decreased
wound closure rates in losses of up to 20%, and complete failure of wound healing and
high risk of new wounds once losses of 30% have occurred [56].
Vitamin K is essential in the production of clotting factors, and therefore vital in the
haemostasis stage of wound healing. A number of vitamins and minerals, including vita-
mins A and C, zinc, copper, and manganese, are essential in collagen synthesis [57]. Zinc
is also a co-factor in the production of other proteins, and for DNA and RNA polymerase,
and is therefore important in fibroblast proliferation [57]. Vitamin A deficiency results in
delayed re-epithelialisation.
1.5.2.3 Obesity
Obesity has been linked to a pro-inflammatory state, and it is proposed that this is an under-
lying reason for the poor wound healing in this group. Mouse and rat models of obesity,
through dietary or genetic modifications, have demonstrated delayed wound healing, and
reduced wound strength compared with non-obese controls [58]. Inhibiting the systemic
inflammatory response in genetically obese mice by treating them with neutralising anti-
bodies against TNF-α and F4/80, a macrophage cell surface protein, increased the healing
rate [59].
1.5.3 Tobacco Smoking

The negative effects of tobacco smoking on multiple organ systems are well described,
and there are many studies which have found that smoking is detrimental to wound
healing [60–63]. Smoking affects the function of many wound cell types, including
fibroblasts, neutrophils, and macrophages [64]. A number of reasons for this are proposed.
Cigarette smoke decreases the oxygen concentration in the tissues [65]. A study in current
and ex-smokers found that, in the hour after smoking a single cigarette, cutaneous and
subcutaneous blood flow, tissue oxygen tension, and tissue glucose concentration were
significantly reduced, while tissue lactate concentration significantly increased [61].
Arterial occlusion in the limb using a blood pressure cuff caused a more pronounced effect
with the same pattern of results. The effects of hypoxia are discussed further in Section
1.5.4. Cigarette smoke contains carbon monoxide, nicotine, and hydrogen cyanide, all
of which affect oxygen delivery to cells [64]. Other chemicals in cigarette smoke act as
oxidants and are thought to inhibit innate immunity, for example by affecting the ability of
macrophages to detect bacteria and inhibiting cytokine release in the presence of bacteria
[66]. Smoking inhibits the release of ROS from neutrophils and macrophages, reducing
their oxidative killing of bacteria [67]. The release of proteases (MMPs and neutrophil
elastase) from neutrophils is increased, whilst the production of TIMPs remains the same,
resulting in extracellular matrix destruction [67]. Overall, there is an increased propensity
towards chronic infection, inflammation, and failure to heal.
1.5.4 Hypoxia and Ischaemia–Reperfusion Injury

The initial cellular activity in the early phases of wound healing is triggered by the hypoxic
environment that develops where there has been vascular injury and then vasoconstriction.
However, following this, oxygen is an essential requirement for wound healing, and demand
is increased by the raised metabolic activity at the site of injury.
Hypoxia is detrimental to cellular activity. As already discussed in Section 1.4.3, the
ability of neutrophils and macrophages to move to the wound site and carry out oxidative
killing is impaired when tissue oxygen concentrations are low. In addition to dysfunction
in the inflammatory phase of healing, hypoxia also affects the ability of cells to proliferate
and synthesise extracellular matrix components [27]. In addition to in vitro and animal
experiments which suggested that the production of collagen by fibroblasts is dependent
on tissue oxygen tension, Jonsson et al. [68] found that, in postoperative surgical wounds,
collagen deposition was proportional to wound oxygen tension.
Ischaemia–reperfusion injury is thought to be a factor in the aetiology of many chronic
wounds, including arterial and venous leg ulcers and pressure ulcers. It occurs when the
delivery of oxygen to the wound bed is intermittently impaired, for example when there
is weight bearing on a pressure ulcer or when a leg with impaired circulation is dependent
and then elevated. When the tissue is ischaemic, an abnormal inflammatory environment
develops, and then when reperfusion occurs there is additional influx of inflammatory
cells and exudate and a resulting increase in proteases and ROS, compounding the
damage to the tissue [27]. An experimental rat model of pressure ulceration found that
ischaemia–reperfusion from repeated pressure cycles was more damaging than a prolonged
period of ischaemia [69].
1.6 Concluding Remarks

Regardless of the aetiology, an acute wound must progress through a series of overlap-
ping stages in order to achieve healing. Numerous cell types are involved, and must be
carefully orchestrated. The important growth factors have been briefly discussed in this
chapter. Inflammation and degradation of extracellular matrix proteins are essential to clear
pathogens and debris, and to enable neovascularisation and migration of cells into the
wound. However, these potentially destructive processes must be controlled, and balanced
with constructive actions such as the deposition of new matrix proteins and the proliferation
of cell populations. Disruption of this complex set of interactions will result in failure of
the wound healing process and the development of chronic (non-healing) wounds.
Chronic wounds represent a huge unmet clinical need, resulting in significant morbidity
and mortality, and a burden on healthcare resources. Understanding the molecular and
cellular processes at play in the wound environment is important in our quest to develop
better treatments for chronic wounds. As described above, many changes in cell phenotype
have been observed in non-healing wounds, leading to altered behaviour, which affects
the synthesis of growth factors, enzymes, and matrix proteins, with chronic infection
and a persistent inflammatory response frequently observed. In order to be able to
convert a chronic wound into a healthy healing wound, the underlying mechanisms
of both situations must be understood and these processes optimised in the chronic
wound. The complexity of the wound environment means that this remains a challenging
field.
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2
Clinical Perspectives for Treating
Chronic Wounds
Diabetic Leg Ulcer Case Studies
Barun Majumder1 , Kirstie Lane2 , Diane Beck1 , Sandeep Singh1 and Duniya Majumder3
1
Ashford and St Peter’s Hospitals NHS Foundation Trust, Chertsey, UK
2
West Byfleet Health Centre, West Byfleet, UK
3
Lanarkshire, Glasgow, UK
2.1 Background
This chapter will review the management of diabetic leg ulcers with respect to dressings
that are commonly available within the UK, but excluding dressings that are still in phase
II and III trials. The mechanism of action of dressings will be described only briefly, as
they are covered extensively elsewhere in the book. Finally, the chapter will highlight a few
clinical cases of diabetic ulcers that are commonly seen in the diabetic foot clinic, their
treatment with dressings, and other relevant interventions.
It is expected that, by 2030, 552 million people worldwide will be affected by diabetes
[1]. The projection is that 25% of patients with diabetes will develop a foot ulcer within
their lifetime, with 60% of these patients going on to develop infections that increase their
chance of undergoing possible subsequent amputation [1, 2]. Patients with diabetes usually
suffer from neuropathy, ischaemia, and immune suppression, which can lead to ulceration
or infection and result in catastrophic amputations [3, 4].
Diabetic foot ulcers can deteriorate rapidly without prompt referral to a multidisciplinary
(MDT) foot clinic to assess and treat these ulcers, before the cost rises, because of the
Therapeutic Dressings and Wound Healing Applications, First Edition. Edited by Joshua Boateng.
© 2020 John Wiley & Sons Ltd. Published 2020 by John Wiley & Sons Ltd.
complexity of treating these ulcers. According to the UK National Institute for Health and
Care Excellence (NICE) guidelines that were updated in 2016, all patients should have
access to a foot protection service, the role of which is to prevent deterioration of diabetic
foot complications, avoiding hospital admissions and the need for escalation of treatment
[5]. It is also now a requirement in the UK to commission an MDT foot clinic in each
hospital that provides a diabetic service to its local population.
The objectives of an MDT foot clinic are to:
• reduce the number of minor and major amputations arising from a ‘foot attack’
• reduce unnecessary admissions to hospital in the event of a ‘foot attack’
• provide a seamless care pathway with the Foot Protection Service in the community [5].
In the UK, general practitioners, tissue viability nurses, and practice nurses at the primary
care facility usually play a key role in coordinating patient care and thus act as gatekeepers
of patient access to diabetes foot care and timely referral to an MDT foot clinic.
2.2 Aetiology of Diabetic Foot Ulcers

The major causes of diabetic foot ulcers are neuropathy, peripheral vascular disease,
and neuro-ischaemia. Some 40–70% of diabetic foot ulcers are caused by neuropathy,
15–24% by peripheral vascular disease, and 15–45% by neuro-ischaemia [6]. In addi-
tion, other commonly seen diseases that can cause diabetic foot are osteomyelitis and
Charcot’s disease. People with diabetes are immunocompromised, and this can also lead to
necrotising fasciitis.
2.3 Standard of Care for Treatment of Diabetic Foot Ulcers

The International Diabetes Federation advises that the risk of amputation can be decreased
by 49–85% by implementing a care strategy combining prevention, multidisciplinary treat-
ment, appropriate organisation, close monitoring, and the education of practitioners and
patients [7].
The cornerstones of treating ulcers are:
• debridement
• offloading with orthotics, casting, or non-weight-bearing regimens
• treatment of infections
• local wound care, comprising cleansing with saline and the use of modern wound dress-
ings that promote a moist environment [8, 9].
Consideration should be given to revascularisation where necessary, and also the control
of serum glucose levels and optimisation of cardiovascular risk factors such as smoking
cessation, dietary habits, control of body mass index, hypertension, and dyslipidaemia.
2.4 Commonly Used Wound Dressings for Diabetic Foot Ulcers and Their
Mechanism of Action
Although topical treatment is an important aspect of wound care, it should always be con-
sidered secondary to surgical and systemic care [10]. Generally, the choice of dressing
Clinical Perspectives for Treating Chronic Wounds 23
is guided by the ulcer’s characteristics, patient requirements, and costs [11]. While it is
accepted that a moist wound environment promotes healing, less than 50% of chronic
wounds are treated with moist wound dressings [12]. Moist wound healing is associated
with faster healing, better tissue quality with less scarring, and less pain [13, 14]; however,
overhydration can cause maceration [10]. In creating a moist environment, dressings soothe
exposed nerve endings by bathing them in wound secretions, thereby minimising or elimi-
nating pain and allowing healing to progress more naturally [8]. Dressings that promote a
moist wound environment include films, foams, alginates, and hydrocolloids [8, 10].
2.5 Absorbent and Superabsorbent Dressings

The advantage of absorbent dressings is that they provide protection in addition to
absorbency [15]. A high exuding wound is defined as producing approximately 5 ml per
10 cm2 per 24 h [16]. In such cases, a superabsorbent dressing is desirable. The advantages
of absorbent or superabsorbent dressings are reduced nursing time and frequency of change
of dressing. Application of creams or ointment affects their performance on absorbency.
2.6 Alginates
Alginates are made from brown sea weed (Phaeophyceae), and date back to 1883 [17].
Different brands vary in their calcium or sodium salts of alginic acid and in the arrange-
ment of the fibre; they are available as either a rope or a sheet. They comprise mannuronic
or guluronic acid residues with guluronic acid residues forming a firmer gel at a slower
rate than mannuronic acid residues. Dressing changes are painless and their performance
can be enhanced by the addition of an antimicrobial constituent (silver) or phylum, which
helps liquid absorption and swelling [18]. Alginates can absorb exudate up to 15–20 times
(15–25 g/cm2 ) their weight, which makes them ideal for wounds that produce large exu-
dates, e.g. leg ulcers, cavity wounds, and diabetic foot ulcers. However, their absorptive
capacity reduces while under compression. Once in contact with exudate, calcium within
the dressing is exchanged for sodium in the exudate, and the fibres within the dressing are
converted to a hydrophilic gel by capillary action. These dressings also have haemostatic
properties to form a clot effectively, by releasing the calcium that they contain and acti-
vating platelets. They are also useful after debridement of large ulcers as a dressing for
haemostasis [19, 20]. Alginates are not suitable for dry wounds and, when used, can be left
in place for 4 days if the fibres are not saturated.
2.7 Films
Films are a frequently used dressing to cover low exudative wounds in postoperative
patients and those with minor injuries (for both diabetic and non-diabetic wounds), and
when the dressings need to be permeable or semipermeable. Films prevent ingress of
microbes from the environment but allow the wound to ventilate. The rate of gaseous
exchange permitted by films is known as the moisture vapour transmission rate (MVTR).
The MVTR is important in preventing tissue maceration of the wound by avoiding the
accumulation of moisture vapour under the dressing [21]. The manufacturers vary in their
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Que isto de pizar em saltos
É susto para quem piza,
E a quem paga é sobresalto.
Quem te curte o cordavão

Porque não te dá sapatos?
Mas eu que te rôo o osso
É que hei de pagar o pato?
Que diria quem te visse

No meu dinheiro pizando?
Diria que quem t’o deu
Ou era besta, ou cavallo.
Pois porque não digam isso,

Leve-me a mim São Fernando,
Si os der, e si tu os calçares,
Leve-te, Annica, o diabo.
De mais, que estou de caminho,
E seria mui grande asno
Estar para dar a sola,
E a ti deixar-te os sapatos.
Agora si eu cá tornar,
Trarei pelles de veado
Para dar-te umas chinelas
Duraveis, que é mais barato.
Fica-te na paz de Deus,

Saudades até quando,
Vem-te despedir de mim,
Porque de hoje a oito parto.
A UMAS MOÇAS
QUE COSTUMAVAM IR A UMA ROÇA
ROMANCE
Vamos cada dia á roça,

Si é que vai a camarada,
Que ri e folga á franceza,
E pinta á italiana.
Vamos, e fiquemos lá
Um dia ou uma semana,
Que emquanto as gaitas se tocam
Sabe a roça como gaitas.
Vamos á roça inda que
Nos fique em tantas jornadas
Cada meia sem palmilha,
E sem sola cada alparca.
Vá Mané, e vá Marcella,
Vá toda a nossa prosapia,
Excepto a que por casar
Não põe pé fóra de casa.
Case e tão casada fique,
Que nem para fazer caca
Jamais o marido a deixe,
Nem se lhe tire da ilharga.
Case, e depois de casar-se
Tanto gema, e tanto paira,
Que caia em meio das dores
Na razão das minhas pragas.
Case, e tanto se arrependa,
Como faz toda a que casa,
Que nem para descasar-se
A via da egreja saiba.
E nós vamos para a roça
Co’nosso feixe de gaitas,
Até ver-me descasada,
Para me rir de quem casa.
Á MULATA JOANNA GAFEIRA
ESTANDO QUEIXOSA DO POETA A HAVER SATYRISADO
ROMANCE
Não posso cobrar-lhes medo,

Joanna, a vossos focinhos,
Que como sois tão formosa,
Cede á verdade o fingido.
Tanta olhadura a travez,
Tanto focinho torcido,
Tanto pescoço empinado,
Tanto esguelhado beicinho,
São modos tão extrangeiros,
Alheios e peregrinos
Das perfeições naturaes
Do vosso rosto divino,
Que jámais podem fazer
No meu peito amante e fino
Retroceder as tenções,
Nem arribar os designios.
Sempre caminhando ávante,
Nunca deixando o caminho,
Ando atraz de ver si posso
Chegar a vosso captivo.
Si me ferraes esta cara
Co’um favorzinho de riso,
Me hei de rir de farto então
Do mundo e seus regosijos.
Hei de pôr-me a rir então
De sorte que a riso fito
Me hão de ter em todo o orbe
Por Democrito dos risos.
Olharei para a Beleta,
E me rirei dos meninos,
Que andam sempre a belisca-la
Qual mono com seus bugios.
Olharei para Apollonia,
E de a ver entre os corrilhos
De tanta canastra honrada,
Que é a nobreza do sitio.
Rirei de ver cada um
Ir-se d’aqui despedido,
Entonces mais carregado,
Porque entonces mais vazio.
A elles pelas estradas
Suspirando pelo sitio,
A ella pelos oiteiros
Zombando de taes suspiros.
A elles tomando o tolle
Para o sertão fugitivos,
Tanto fugindo dos amos,
Como da conta fugindo.
A ella por capoeiras
Estreando co’ os meninos
A baetinha dos pobres,
A serafina dos ricos.
Para a Ursula olharei,
E rirei de a ver no Sitio
Parafuzando pivetes
Pela tarracha do embigo.
Rirei de ver os amantes,
Rirei de ver os queridos,
Que tendo-se por ditosos,
São em seus gostos mofinos.
E só feliz eu serei,
Si lógro os vossos carinhos,
E me impingis nesta cara
Da vossa bocca um beijinho.
Tende-me na vossa graça,
E a queixa se torne em riso,
A malquerença em amor,
E o desfavor em carinho.
Á DAMAZIA
OUTRA MULATA QUE CHAMAVA SEU UM VESTIDO QUE
TRAZIA DE SUA SENHORA
ROMANCE
Muito mentes, mulatinha!

Valha-te Deus por Damazia,
Não sei quem, sendo tu escura,
Te ensina a mentir ás claras.
Tal vestido, e com tal pressa!
Não vi mais ligeira saia:
Mas como a seda é ligeira,
Foi a mentira apressada.
Tal vestido não é teu,
Nem tu tens, Damazia, cara
Para ganhar um vestido,
Que custa tantas patacas.
Tu ganhas dous, tres tostões
Por duas ou tres topadas,
Não chegam as galaduras
Para deitar uma gala.
Nem para os feitios chegam
Os troquinhos que tu ganhas,
Pois não vale o teu feitio
Mais que até meia pataca.
De soldado até sargento,
Ou até cabo de esquadra,
Não passa o teu roçagante,
Não te chega a triste alçada.
Estes que te podem dar
Mais que uma vara de cassa,
Uma cinta de baeta
E saia de persiana;
Collete de chamalote,
E de vara e meia a fralda,
Que fazem oito mil réis,
Que é valor da pobre farda.
Todos sabem que o vestido,
Que em verdes campos se esmalta,
É verdura de algum besta,
Que em tua senhora pasta.
Mas o que é d’ella teu é,
Que é outra que tal jangada,
E talvez por t’o emprestar
Se ficaria ella em fraldas.
Apostemos que não vestes
Outra vez a verde saia!
E nem de a vestires mais
Te ficam as esperanças.
Ora toma o meu conselho,
E vive desenganada,
Que emquanto fores faceira
Não has de ganhar pataca.
Á UMA DAMA
POR NOME IGNACIA PAREDES
ROMANCE
Quiz ir a festa da Cruz

Ignacia, e faltou-lhe a rede,
Como que foi força ficar
Paredes entre paredes.
Outros dizem que uma amiga

Lhe pediu o manto adrede,
Pela ter emparedada
Todo o dia, em que lhe peze.
Não sei a verdade d’isto,

Sei que eu paguei a patente,
Tendo um dia de trabalho,
Porque de festa lh’o désse.
A saber que estava em casa,

Visitara-a como sempre,
E fizera o que costumam
Casados in facie Ecclesiæ.
Fôra-me pôr á janella,

Porque o calor me refresque,
Fallára co’as Guapas sujas,
Que são limpas guapamente.
Marianna se agastára,
Que tudo escuta e attende,
Por isso diz o adagio:
Manso, que ouvem as paredes.
Sabendo d’este ciume
Foram as Guapas contentes,
Que inda que mulheres feias,
São feias, porém mulheres.
Ignacia se socegára,
Que é moça mansa e alegre,
E com dous mimos se põe,
Sendo Ignacia, uma clemente.
Da sua amiga me queixo,

Que cão de horta me parece,
Pois em todo o dia nunca
Comeu, nem deixou comer-me.
Com Ignacia já não quero

Lançar mais barro á parede,
Que de mui sêcca receio
Que alli meu barro não pegue.
Uma mãe com duas filhas

Na verdade é pouca gente,
Para que eu possa cantar
Prêso entre quatro paredes.
Tres só não fazem prisão,

Porque um triangulo breve,
Que um sino Salmão figura,
Mais enfeitiça que prende.
Mas a parede de Ignacia,

Com ser uma tão sómente,
Como é tão forte e tão rija,
Bastou só para prender-me.
Perdi o ganho essa tarde,
E cuido que para sempre,
Quem m’a pegou uma vez,
Não quero que outra me pegue.
Da Sancta Cruz era a festa,

E a maldicta da Paredes,
Com cruz e sem cruz receio
Me faça calvarios sempre.
Eu perdi moça que agrade,

Ella velho que aconselhe,
Ambos ficámos perdidos,
Quem o vê que o remedeie.
Á UMA MOÇA POR NOME BARBARA
ROMANCE
Babú, como ha de ser isto?

Eu me sinto já acabar,
E estou tão intercadente,
Que não chego té amanha.
Morro da vossa belleza,
E si ella me ha de matar,
Como eu creio que me mata,
Formosa morte será.
Mas seja formosa ou feia,
Si o Deão me ha de enterrar,
Por mais formosa que seja,
Sempre caveira será.
Todos já aqui desconfiam,
Tudo é já desconfiar,
Da minha vida os doutores,
E eu de vosso natural.
Desconfio de que abrande
Vosso rigor pertinaz;
E a minha vida sem cura
Sem duvida acabará;
Porque si estaes incuravel,
E tão sem remedio está
O achaque de não querer-me,
E o mal de querer-me mal:
Que esperança posso eu ter,
Ou que remedio ha capaz,
Si vós sois a minha vida,
E morreis por me matar?
Amor é união das almas
Em conformidade tal,
Que porque estaes sem remedio,
Por contagio me mataes.
Curai-vos de mal querer-me,
E do fastio em que estaes
A minha triste figura,
Que ao demo enfastiará.
Comei, e seja o bocado,
Que com gosto se vos dá,
Porque em vós convalescendo,
Hei de eu também melhorar.
Assim sararemos ambos,
Porque si vós me enfermaes
Pelo contagio, o remedio
Por sympathia será.
Vós, Babú, viraes-me as costas,
Pois eu faço outro por tal:
Estou ás portas da morte,
A falla me falta já.
Quero fazer testamento,
Mas já não posso fallar,
Que vós por costume antigo
Sempre a falla me quitaes.
Mas testarei por acenos,
Que tudo em direito ha,
E si por louco o não posso,
Posso por louco em amar.
Todos meus bens, si os tivera,
Os deixára a vós não mais;
Mas deixo-vos para outrem,
Que é o mais que posso deixar
Si hei de deixar-vos a vós
Quantos bens no mundo ha,
Em vos deixar a vós mesma,
Arto herdada assim ficaes.
Em suffragios da minha alma
Não gasteis o cabedal,
Que aos vossos rigores feita
Penas não ha de extranhar.
Mas si por minhas virtudes,
E si por vos jejuar,
E si por tantas novenas,
Que á vossa imagem fiz já,
Vos mereço algum perdão
Dos peccados que fiz cá,
Assim em vos perseguir,
Como em vos desagradar:
Com as mãos postas vos peço
Que no vosso universal
Juizo mandeis minha alma
Ao vosso Céu descançar
Não a mandeis ao Inferno,
Que arto inferno passou cá:
Adeus, e apertae-me a mão,
Que eu me vou a enterrar.
SATYRISA
ALLEGORICAMENTE A VARIOS LADRÕES DA REPUBLICA
ROMANCE
Hontem, Nise, á prima noite

Vi sôbre o vosso telhado,
Assentados em cabido,
Cinco ou seis formosos gatos.
Estava a noite mui clara,
Fazia um luar galhardo,
E porque tudo vos diga,
Estava eu em vós cuidando.
O presidente ou deão,
Na cumieira assentado,
Era um gato macilento,
Barbirruço e carichato.
Os demais em boa ordem,
Pela cumieira abaixo,
Lavandeiros de si mesmos,
Lavavam punhos e rabos.
Tão profundo era o silencio,
Que não se ouvia um miau,
E o deão interrompeu
Dando um mio acatarrado.
Tossiu, tossiu, e não pôde
Articular um miau,
Que de puro penitente
Traz sempre o peito cerrado.
Eis que um gatinho Reinol,
Muito estitico e mui magro,
Relambido de feições,
E de tono afalcetado,
Quiz por primeiro fallar,
E fallára em todo o caso,
Si outro gato casquiduro
Lhe não sahira aos embargos.
«Eu sou gato de um meirinho,
Disse, que pelos telhados
Vim fugindo a todo o trote
Do poder de um saibam quantos.
Com que venho a concluir
Que servindo a taes dous amos,
Hei de fallar por primeiro,
Porque sou gato de gatos.
Falle, disse o Presidente,
Pois lhe toca por anciano,
E elle tomando-lhe a venia
Foi o seu conto contando.
Em casa d’este escrivão
Me criei com tal regalo,
Que os demais gatos de casa
Eram commigo uns bichanos.
Mas cresci e aborreci,
Porque se cumprisse o adagio
Que official de teu officio
Teu inimigo declarado.
Foi-me tomando tal odio
Porque foi vendo e notando,
Que era eu capaz de dar-lhe
Até no officio um gatazio.
Topou-me em uns entreforros,
E tirando-me porraços,
Eu lhe miava os narizes,
Quando elle me enchia os quartos.
Fugi, como tenho dito,
E me acolhi ao sagrado
De uma vara de justiça,
Que é valhacouto de gatos.
Sahe meu amo aos prendimentos,
E eu fico em casa encerrado
Por caçador de balcões,
Onde jejuo o trespasso.
Porque em casa de um meirinho,
Nas suas arcas e armarios,
É quaresma toda a vida,
E temporas todo o anno.
Não posso comer ratinhos,
Porque cuido, e não me engano,
Que de meu amo são todos
Ou parentes ou paisanos.
Porque os ratinhos do Douro
São grandissimos velhacos:
Em Portugal são ratinhos,
E cá no Brazil são gatos.
Eu sou gato virtuoso,
Que a puro jejum sou magro:
Não como por não ter que,
Não furto por não ter quando.
E como sobra isto hoje
Para me terem por sancto,
Venho a pedir que me ponham
No calendario dos gatos.»
Acabada esta parlanda,
Muito ethico de espinhaço
Sôbre as moletas das pernas
Se levantou outro gato,
Dizendo: ha annos que sirvo
Na casa de um boticario,
Que a recipe de pancadas
Me tem os bofes purgados.
Queixa-se que lhe comi
Um boião de unguento branco,
E lhe bebi nessa noite
Um cangirão de rhuibarbo.
Diz bem, porque assim passou,
Mas eu fiquei tão passado,
Como de tal solutivo

Therapeutic Dressings and Wound Healing Applications Boateng Full Chapter

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Therapeutic dressings and wound

healing applications Boateng

Titles in the Series

Limit of Liability/Disclaimer of Warranty

Library of Congress Cataloging-in-Publication Data applied for

Hardback ISBN: 9781119433262

Cover design: Wiley

Set in 10/12pt, TimesLTStd by SPi Global, Chennai, India

List of Contributors xiii

1 Chronic Wound Healing: Molecular and Biochemical Basis 1

2 Clinical Perspectives for Treating Chronic Wounds 21

3 Prediction, Prevention, Assessment, and Management of Skin Tears in

4 Importance of Debriding and Wound Cleansing Agents in Wound

5 Treatment of Mixed Infections in Wounds 91

6 Treatment of Biofilms in Infected Wounds 115

6.5 Treatment of Biofilms in Wounds 126

7 Freeze-Dried Wafers for Wound Healing 137

8 Silver and Silver Nanoparticle-Based Antimicrobial Dressings 157

9 Hydrogel Dressings 185

9.1.4 Classification Based on the Shape and Dimensions of

10 Gene Therapy for the Treatment of Chronic Wounds 209

11 Honey in Wound Healing 235

11.4 Medical Grade Honey 237

12 Regeneration Using Tissue Engineered Skin Strategies 255

13 Local Delivery of Growth Factors Using Wound Dressings 291

14 Electrospinning Technologies in Wound Dressing Applications 315

14.4.3 Needle-to-Collector Distance 320

15 The Place of Biomaterials in Wound Healing 337

16 Wound Dressings and Pressure Ulcers 367

17 3D Printed Scaffolds for Wound Healing and Tissue Regeneration 385

Asif Ahmed, School of Science, Faculty of Engineering and Science, University of

Annalisa Bianchera, Interdepartmental Centre Biopharmanet-TEC, University of Parma,

Joshua Boateng, School of Science, Faculty of Engineering and Science, University of

Maria Cristina Bonferoni, Department of Drug Sciences, University of Pavia, Italy

Karen Campbell, Western University, London, ON, Canada

Carla Caramella, Department of Drug Sciences, University of Pavia, Italy

Ovidio Catanzano, Department of Life Sciences, University of Trieste, Italy

Gwendolyn Cazander, Wound Expertise Center (WEC), Ikazia, Rotterdam,

Mariana T. Cerqueira, 3B’s Research Group, I3Bs – Research Institute on Biomaterials,

Lucília P. da Silva, 3B’s Research Group, I3Bs – Research Institute on Biomaterials,

Philip Debrah, Department of Pharmaceutics and Microbiology, School of Pharmacy, Uni-

Bianca K. den Ottelander, Wound Expertise Center (WEC), Ikazia, Rotterdam,

Martijn C.H.A. Doomen, Wound Expertise Center (WEC), Ikazia, Rotterdam,

Dennis Douroumis, School of Science, Faculty of Engineering and Science, University of

Lisa Elviri, Food and Drug Department, University of Parma, Italy

Franca Ferrari, Department of Drug Sciences, University of Pavia, Italy

Mansa Fredua-Agyeman, Department of Pharmaceutics and Microbiology, School of

Marcos Garcia-Fuentes, Center for Research in Molecular Medicine and Chronic

Atabak Ghanizadeh Tabriz, School of Science, Faculty of Engineering and Science,

Keith Harding, Division of Population Medicine, Cardiff University School of Medicine,

Galiya S. Irmukhametova, Faculty of Chemistry and Chemical Technology, al-Farabi

Vitaliy V. Khutoryanskiy, School of Pharmacy, University of Reading, UK

Awo Afi Kwapong, Department of Pharmaceutics and Microbiology, School of Pharmacy,

Kirstie Lane, West Byfleet Health Centre, West Byfleet, UK

Kimberly LeBlanc, Wound Ostomy Continence Institute/Association of Nurses Special-

Duniya Majumder, Lanarkshire, Glasgow, UK

Emi Maruhashi, University of Lisbon, Lisbon, Portugal

Grigoriy A. Mun, Faculty of Chemistry and Chemical Technology, al-Farabi Kazakh

Silvia Rossi, Department of Drug Sciences, University of Pavia, Italy

Giuseppina Sandri, Department of Drug Sciences, University of Pavia, Italy

Sophia Tate1 and Keith Harding2

1.2 Acute Wound Healing

The first step, haemostasis, is characterised by vasoconstriction and coagulation; it takes