Advanced Textiles for Wound Care [2 ed.] 9780081021927, 0081021925

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The Textile Institute Book Series

Advanced Textiles for Wound Care Second Edition Edited by

S. Rajendran

Woodhead Publishing is an imprint of Elsevier The Officers’ Mess Business Centre, Royston Road, Duxford, CB22 4QH, United Kingdom 50 Hampshire Street, 5th Floor, Cambridge, MA 02139, United States The Boulevard, Langford Lane, Kidlington, OX5 1GB, United Kingdom Copyright © 2019 Elsevier Ltd. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein). Notices Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library ISBN (print): 978-0-08-102192-7 ISBN (online): 978-0-08-102193-4 For information on all Woodhead publications visit our website at https://www.elsevier.com/books-and-journals

Publisher: Matthew Deans Acquisition Editor: Brian Guerin Editorial Project Manager: Katie Chan Production Project Manager: Joy Christel Neumarin Honest Thangiah Cover Designer: Victoria Pearson Typeset by TNQ Technologies

List of Contributors

Shaikh Ziauddin Ahammad Department of Biochemical Engineering and Biotechnology, Indian Institute of Technology, New Delhi, India Syed Wazed Ali Department of Textile Technology, Indian Institute of Technology, New Delhi, India S.C. Anand School of Engineering, University of Bolton, Bolton, United Kingdom Shahzad Ather Wound Healing Research Unit, Department of Surgery, Cardiff University, Cardiff, United Kingdom K. Bunko Formerly of Advanced Science and Technology Institute, United Kingdom C. Chan National University of Singapore, Singapore J.V. Edwards United States Department of Agriculture – Agricultural Research Service, New Orleans, LA, United States N. Gokarneshan Department of Textile Technology, Park College of Engineering and Tekhnology, Coimbatore, India B.S. Gupta Textile Engineering, Chemistry and Science, North Carolina State University, Raleigh, NC, United States K.G. Harding Cardiff University, Cardiff, United Kingdom Mangala Joshi Department of Textile Technology, Indian Institute of Technology, New Delhi, India J.F. Kennedy Formerly of Advanced Science and Technology Institute, United Kingdom Abhilash Kulkarni Centre of Excellence for Medical Textiles, The South India Textile Research Association, Coimbatore, India M. Kun National University of Singapore, Singapore Y. Machida Hoshi University, Tokyo, Japan

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List of Contributors

Vinay Kumar Midha Department of Textile Technology, Dr. B R Ambedkar National Institute of Technology, Jalandhar, India Arunangshu Mukhopadhyay Department of Textile Technology, Dr. B R Ambedkar National Institute of Technology, Jalandhar, India H. Onishi Hoshi University, Tokyo, Japan Roli Purwar Department of Applied Chemistry, Delhi Technological University, Delhi, India Yimin Qin State Key Laboratory of Bioactive Seaweed Substances, Qingdao, China S. Rajasekar Centre of Excellence for Medical Textiles, The South India Textile Research Association, Coimbatore, India S. Rajendran School of Engineering, University of Bolton, Bolton, United Kingdom S. Ramakrishna National University of Singapore, Singapore Erdem Ramazan Department of Textile Technologies, Serik GSS Vocational School of Higher Education, Akdeniz University, Antalya, Turkey R. Rathinamoorthy Department of Fashion Technology, PSG College of Technology, Coimbatore, India E. Santhini Centre of Excellence for Medical Textiles, The South India Textile Research Association, Coimbatore, India G. Schoukens Department of Textiles, Ghent University, Ghent, Belgium P.K. Sehgal Formerly of Central Leather Research Institute, Chennai, India M. Senthilkumar Formerly of Central Leather Research Institute, Chennai, India Mohammad Shahadat Department of Textile Technology, Indian Institute of Technology, New Delhi, India; Department of Biochemical Engineering and Biotechnology, Indian Institute of Technology, New Delhi, India Monica Puri Sikka Department of Textile Technology, Dr. B R Ambedkar National Institute of Technology, Jalandhar, India R. Sripriya Formerly of Central Leather Research Institute, Chennai, India

List of Contributors

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Parveen Sultana Department of Biochemical Engineering and Biotechnology, Indian Institute of Technology, New Delhi, India S.J. Tate Cardiff University, Cardiff, United Kingdom; Welsh Wound Innovation Centre, Wales, United Kingdom V. Team School of Nursing and Midwifery, Faculty of Medicine, Nursing, and Health Sciences, Monash University, Melbourne, VIC, Australia Steve Thomas Formerly of The Surgical Materials Testing Laboratory (SMTL), Princess of Wales Hospital, Coity RoadBridgend, South Wales, United Kingdom Giuseppe Tronci Clothworkers’ Centre for Textile Materials Innovation for Healthcare, School of Design and Biomaterials and Tissue Engineering Research Group, School of Dentistry, University of Leeds, Leeds, United Kingdom Muhammet Uzun Department of Textile Engineering, Faculty of Technology, Marmara University, İstanbul, Republic of Turkey Ketankumar Vadodaria Centre of Excellence for Medical Textiles, The South India Textile Research Association, Coimbatore, India C. Weller School of Nursing and Midwifery, Faculty of Medicine, Nursing, and Health Sciences, Monash University, Melbourne, VIC, Australia

Preface

Wound management is a complex process and the healing principally depends on the type of wounds and the selection of appropriate dressings. Advanced textiles play an important and crucial role in designing appropriate medical devices for the healthcare of people. With the rise of multidrug-resistant pathogenic bacteria and viruses (superbugs), infection control becomes a challenge for medical personnel. It has been estimated that 80% of human infections, including but not limited to endocarditis, Crohn’s disease and chronic wounds, are caused by biofilm-encased microbes. Similarly, managing difficult-to-heal wounds and other chronic conditions such as venous leg ulcers, pressure ulcers and diabetic foot ulcers are growing problems. In this situation, it is vital that new or enhanced wound dressings such as antimicrobial dressings, collagen booster dressings and electrical stimulation dressings should be developed to cope up the situation. It should be stressed that the healing of wounds depends not only on medication but also on the use of proper dressing techniques and suitable dressing materials. The market potential for textile-based medical devices is considerably high. The advanced global wound care market is expected to reach USD 13.07 billion by 2022. In 2017, the market was dominated by North America followed by Europe and this trend is predicted to continue in the forthcoming years. The European wound care market is expected to register a Compound Annual Growth Rate of 3.6% during 2018– 23. Ageing population creates increased demand for ulcer treatment. In the United Kingdom, the pressure ulcer treatment accounts for 4% of the National Health Service (NHS) annual budget. The annual cost of treating diabetic foot ulceration accounts for 5% of the total NHS budget. The treatment of venous leg ulcer creates considerable demands on healthcare professionals throughout the world. While traditional dressings currently dominate the wound care market, raising awareness of the clinical benefits provided by advanced wound dressings is bound to widen their uptake. Continued R&D into developing hi-tech wound dressings that fulfil the principal essential requirements of keeping the wound moist to accelerate healing, being nonadherent to wound bed and having antibacterial and antiodour properties not only promotes wound healing with special reference to difficult-to-heal wounds but also reduces the treatment cost considerably, which in turn has a direct impact on the economy. This interdisciplinary state-of-the art book has been designed to meet the growing challenges in advanced wound care management. The chapters are carefully written by multinational authors who have vast experience in medical and/or textile disciplines. During editing, I found that the chapters not only provide a wealth of information on wound management but also problem-solving techniques. This interdisciplinary book directly links textile and medical technologies with advances in wound care. The book

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discusses new developments and techniques related to antimicrobial dressings, the use of biopolymers in infection control management, advanced dressings for managing cavity and cancerous wounds, and the single-layer bandages for managing venous leg ulcers, application of nanofibers and novel textile structures in scaffolds, among other new areas. This updated edition also reflects recent changes in regulatory affairs. The book is essential reading for manufacturers, designers, scientists and producers of wound care materials. It is a valuable resource for professionals within the medical sector, as well as those in academia, enabling materials scientists and engineers in both academia, and at medical device companies, to stay abreast of new technology. Efforts have been exerted to edit the chapters which are easily readable by medical professionals, textile scientists and researchers, as well as wound dressing manufacturers. This book provides the readers with much needed information in interdisciplinary subject areas of nursing and textiles. I am deeply indebted to the authors of this publication and no doubt that their contribution will be a well-to-do resource document making a greater contribution to the emerging discipline. Prof. S. Rajendran Emeritus Professor Formerly Professor of Biomedical Materials and STEM Champion The University of Bolton Bolton BL3 5AB, UK September 2018

The Textile Institute Book Series Incorporated by Royal Charter in 1925, The Textile Institute was established as the professional body for the textile industry to provide support to businesses, practitioners and academics involved with textiles and to provide routes to professional qualifications through which Institute Members can demonstrate their professional competence. The Institute’s aim is to encourage learning, recognise achievement, reward excellence and disseminate information about the textiles, clothing and footwear industries and the associated science, design and technology; it has a global reach with individual and corporate members in over 80 countries. The Textile Institute Book Series supersedes the former ‘Woodhead Publishing Series in Textiles’, and represents a collaboration between The Textile Institute and Elsevier aimed at ensuring that Institute Members and the textile industry continue to have access to high calibre titles on textile science and technology. Books published in The Textile Institute Book Series are offered on the Elsevier web site at: store.elsevier.com and are available to Textile Institute Members at a substantial discount. Textile Institute books still in print are also available directly from the Institute’s web site at: www.textileinstitute.org To place an order, or if you are interested in writing a book for this series, please contact Matthew Deans, Senior Publisher: [email protected]

Recently Published and Upcoming Titles in The Textile Institute Book Series Handbook of Technical Textiles, Volume 1, 2nd Edition, A. Richard Horrocks and Subhash C. Anand, 9781782424581 Handbook of Technical Textiles, Volume 2, 2nd Edition, A. Richard Horrocks and Subhash C. Anand, 9781782424659 Geotextiles, Robert Koerner, 9780081002216 Advances in Braiding Technology, Yordan Kyosev, 9780081009260 Antimicrobial Textiles, Gang Sun, 9780081005767 Active Coatings for Smart Textiles, Jinlian Hu, 9780081002636 Advances in Women’s Intimate Apparel Technology, Winnie Yu, 9781782423690 Smart Textiles and Their Applications, Vladan Koncar, 9780081005743 Advances in Technical Nonwovens, George Kellie, 9780081005750 Activated Carbon Fiber and Textiles, Jonathan Chen, 9780081006603 Performance Testing of Textiles, Lijing Wang, 9780081005705 Colour Design, Janet Best, 9780081012703 Forensic Textile Science, Debra Carr, 9780081018729 Principles of Textile Finishing, Asim Kumar Roy Choudhury, 9780081006467 High-Performance Apparel, John McLoughlin and Tasneem Sabir, 9780081009048

Wound management and dressings Authors of the chapter: Shahzad Ather1, K.G. Harding2 1Wound Healing Research Unit, Department of Surgery, Cardiff University, Cardiff, United Kingdom; 2Cardiff University, Cardiff, United Kingdom

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Editor of the chapter: S.J. Tate1,2 1Cardiff University, Cardiff, United Kingdom; 2Welsh Wound Innovation Centre, Wales, United Kingdom

1.1   Introduction A wound is defined as a break in the epithelial integrity of the tissues. This disruption can be deeper and involve subepithelial tissues including dermis, fascia and muscle. Wounds can be caused by physical trauma where the skin is torn, cut or punctured (an open wound) or where a blunt force trauma causes a contusion (a closed wound). They may also be the result of a disease process affecting the skin. The history of wound care spans from prehistory to modern medicine and has evolved from simple wound covers ranging from vinegar-soaked dressings, through topical antibiotics to topically applied growth factors [1]. Even during early historical periods several factors were noted that speeded up or assisted the process of healing. The necessity for hygiene, the prevention of bleeding and, later on, the germ theory of disease paved the way for modern wound management.

1.2  Types of wound Wounds can be classified in many ways. Important factors in the description of a wound include the aetiology of the wound (e.g., pressure, trauma, ischaemia, heat, friction, surgery, etc), the timing and chronicity, the level of contamination, and the depth of injury to the skin and underlying tissues. These factors will all affect the management of the wound.

1.2.1  Describing the aetiology of a wound Some commonly used nomenclature that alludes to the aetiology of a wound are as follows: Abrasion: A superficial epithelial wound caused by friction or scraping. Incision: A wound made by a clean, sharp-edged object. This may be intentional, such as during surgery, or unintentional, such as an injury from broken glass. Laceration: A break in the skin that is the result of trauma exceeding the intrinsic tissue strength, for example, a skin tear after blunt trauma to the scalp. Contusion: Tissue trauma from a blunt injury or blast injury where the overlying skin remains intact, although it may later become nonviable. Advanced Textiles for Wound Care. https://doi.org/10.1016/B978-0-08-102192-7.00001-1 Copyright © 2019 Elsevier Ltd. All rights reserved.

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1.2.2  Acute and chronic wounds An acute wound may be defined as a recent wound, of any aetiology, that is expected to progress through the normal sequential phases of wound healing. In terms of biology, a chronic wound is one that is failing to progress through the stages of wound healing in an anticipated time frame [2]. Clinically, however, the word ‘chronic’ may be used to describe a wound that is more than 5 days old and therefore expected to be colonised with bacteria and unsuitable for primary closure without debridement [3].

1.2.3  Level of contamination Wounds may be classified according to the level of contamination [4]. Class I/clean:

Class II/clean–contaminated:

Class III/contaminated:

Class IV/dirty–infected

An uninfected operative wound in which no inflammation is encountered and the respiratory, alimentary, genital, or uninfected urinary tract is not entered. An operative wound in which the respiratory, alimentary, genital, or urinary tracts are entered under controlled conditions and without unusual contamination. Open, fresh, accidental wounds. Operations with major breaks in sterile technique (e.g., open cardiac massage) or gross spillage from the gastrointestinal tract and incisions in which acute, nonpurulent inflammation is encountered. Old traumatic wounds with retained devitalized tissue and those that involve existing clinical infection or perforated viscera.

1.3  Mechanism of wound healing The aim of wound healing is the restoration of tissue integrity in order that homoeostatic mechanisms can be re-established and fluid loss and the risk of infection can be minimised. It is a well-orchestrated and complex process, triggered by tissue injury and ending in regeneration or repair. It can be divided into categories based on the anticipated nature of the healing process (see Fig. 1.1).

1.3.1  Healing by primary intention Wound edges are approximated with sutures, staples or adhesive, leaving no residual discontinuity in the skin. This must be done within hours of occurrence. It enables closure to occur quickly, as minimal tissue is required to repair the defect, and scarring is usually minimal.

1.3.2  Healing by secondary intention The wound is left open without any formal closure. Healing occurs by reepithelialisation and contraction. This may be necessary because the wound is large, and the edges

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Wound healing

Scarless Foetal skin Oral mucosa

Scarring Adult skin

Nonhealing Chronic wounds

Excessive scarring Hypertrophic scars Keloid scars

Figure 1.1  Differential wound healing.

cannot be reapproximated, or because of the degree of contamination. The size of the defect and amount of disruption in the tissue integrity determines the degree of new tissue matrix and epidermal surface needed for complete closure [5] and therefore the length of time that this will take.

1.3.3  Delayed primary/tertiary healing Wound closure is delayed for several days; this is usually employed for contaminated wounds where a period of cleaning, debridement, and observation is carried out prior to closure or skin grafting.

1.4  Biology of wound healing Irrespective of the cause, acute wounds should pass through a series of overlapping stages to achieve healing. Studying this process in order to optimise it remains central to wound healing research. Tissue injury sets in motion a cascade of cellular and biochemical activities, involving a variety of blood and parenchymal cells, extracellular matrices (ECMs) and soluble mediators. Four phases are defined; haemostasis, inflammation, proliferation and remodelling. These stages are clinically indistinct and overlap in time. Fig. 1.2 summarises the stages and the important cell types and processes taking place.

1.4.1   Haemostasis The first step in the process of inflammation is haemostasis, which is characterised by vasoconstriction and coagulation. It starts soon after injury and is usually completed within the first few hours. Disruption of blood vessels and lymphatics exposes the

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Maximum response

Phases of wound repair

II Cell proliferation I Inflammation and matrix deposition

III Matrix remodelling

Fibroplasia Angiogenesis -Collagens Reepithelialization Extracellular matrix synthesis -Fibronectin -Proteoglycans Granulocytes

Bleeding

0.1

↑ Tensile strength

Phagocytosis

Coagulation Platelet activation Complement activation

0.3

Extracellular matrix synthesis, degradation and remodelling

↓ Cellularity ↓ Vascularity

Macrophages Cytokines 1

3

10

30

100

300

Days after wounding (log scale)

Figure 1.2  Wound biology: phases of wound repair.

tissue to the blood. The coagulation cascade is activated in conjunction with platelets resulting in the deposition of a haemostatic ‘plug’ [6]. The activated platelets release cytokines and growth factors including thromboxane A-2 and serotonin, which are important inflammatory mediators and also cause vasoconstriction. The clot also serves to concentrate the elaborated cytokines and growth factors including platelet-derived growth factor (PDGF) and transforming growth factor (TGF) β1 [7]. Coagulation leads to haemostasis, which initiates healing by leaving behind messengers that bring on an inflammatory process. Deficiency of clotting factors (Factor VII. IX, XII) leads to impaired wound healing [8].

1.4.2  Inflammation The stage of inflammation starts soon after haemostasis (immediate up to 2–5 days) and is usually completed within the first 48–72 h, but it may last as long as 5–7 days [9]. The initial vasoconstriction is followed by vasodilatation and increased vascular permeability in response to histamine and other vasoactive mediators.

1.4.2.1  Role of neutrophils The net result of this change in vascular permeability is an influx of polymorphonuclear cells and monocytes in the injured area in a protein-rich fluid. Neutrophils

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phagocytise debris and bacteria; they also kill bacteria by releasing caustic proteolytic enzymes and free radicals in a process called ‘respiratory burst’ [10]. The surrounding tissue matrix in the periwound tissue is protected by protease inhibitors, which can be overwhelmed and penetrated if the inflammatory response is extremely robust leading to damage to normal tissue. Unless stimuli for neutrophil recruitment persist at the wound site, the neutrophil infiltration ceases after a few days, and they undergo apoptosis, are engulfed and are degraded by macrophages [11].

1.4.2.2   Macrophages Macrophages start appearing in the wound 2 days after the injury and dominate the wound cell population over the next few days. Beside resident macrophages, the majority of macrophages at the wound site are recruited from the blood. Monocytes extravasate from the blood vessel, become activated and differentiate into mature tissue macrophages. Macrophages are crucial to wound healing and perform a number of functions. They act as antigen-presenting cells and remove debris and dead cells by phagocytosis. Perhaps their more important role in the process of healing is synthesis of numerous potent growth factors, such as TGF-α and TGF-β, basic fibroblast growth factor (bFGF), PDGF and vascular endothelial growth factor (VEGF), which promote cell proliferation and the synthesis of ECM molecules by resident skin cells [12]. These factors also help in angiogenesis, migration and activation of fibroblasts thus setting the stage of proliferation [13]. It has been shown experimentally that macrophage depletion using antisera results in a significant delay in healing [14].

1.4.2.3  Role of matrix metalloproteinases Matrix metalloproteinases (MMPs) are important throughout the inflammatory response to injury and also into the proliferation and remodelling phases. This group of enzymes are expressed by keratinocytes, fibroblasts, monocytes and macrophages in response to tumour necrosis factor α (TNF-α). In the inflammatory phase, MMPs clear debris and damaged ECM [15]. They also have a role in the activation of essential growth factors, for example, the epidermal growth factor family and the transforming growth factor family. During the proliferative phase, MMP-1, a collagenase, is involved in the cleavage of collagen-1 to enable the release and migration of keratinocytes [16]. MMP-1 and MMP-2, a gelatinase, are involved in breaking down the basement membrane to allow angiogenesis to take place under the influence of VEGF. During the remodelling phase, MMPs break down the immature ECM that was initially laid down, allowing contraction and the formation of mature scar ECM [7]. The activity of MMPs is tightly controlled, and regulation is by tissue inhibitor of MMPs, which is secreted by fibroblasts, basal keratinocytes and perivascular cells [17].

1.4.2.4  Role of inflammatory mediators Inflammatory mediators play a central and major role in the process of wound healing. They include a collection of soluble factors either present in plasma in an inactive

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form or released by damaged and nearby cells and leukocytes in an attempt to control the damage and initiate healing. They include TNF-α and interleukins, particularly interleukin 1 and interleukin 6.

1.4.2.5  Mechanisms of inflammatory resolution Inflammation performs several important functions. It clears the wound of infectious organism and debris and brings about a change in the microenvironment of the wound to set the stage for proliferation. However, successful repair after injury requires resolution of the inflammatory response. The mechanisms controlling this downregulation of the inflammatory response are poorly understood, but it is thought that the process is organised, with a series of reactions to produce stop signals referred to as ‘check point controllers of inflammation’ [18]. Lipoxins and aspirin-triggered lipoxins are the stop signals for inflammation. Autocoids also display potent anti-inflammatory actions and are termed resolvins [19]. Downregulation of proinflammatory mediators and the reconstitution of normal microvascular permeability contributes to the cessation of local chemoattractants. Synthesis of anti-inflammatory mediators, apoptosis and lymphatic drainage also play their role. An excessive or prolonged inflammatory response results in increased tissue injury and poor healing.

1.4.3  Proliferation This phase starts around the second or third day after injury and continues for up to 3 or 4 weeks. This is marked by the appearance of fibroblasts in the wound and overlaps with the inflammatory phase. As in other phases, the changes in this phase do not occur in a series but overlap in time.

1.4.3.1  Granulation tissue formation Fibroblasts start to appear in the wound from the third to fourth day, and their numbers peak between the 7th and 14th days. They migrate from the wound margins using the fibrin-based provisional matrix created during the inflammatory phase of healing. Under the influence of bFGF, TGF-β and PDGF secreted by macrophages, they proliferate and synthesise glycosaminoglycans and proteoglycans, elastins and fibronectin, the building blocks of the new ECM of granulation tissue, and collagen. As the number of macrophages diminishes, fibroblasts themselves begin to secrete bFGF, TGFβ and PDGF. They also begin producing keratinocyte growth factor and insulin-like growth factor I. Collagen molecules are secreted and organised in the form of collagen fibres, which are then cross-linked into bundles. Collagen gives the wound its tensile strength, and, in addition, cells involved in inflammation, angiogenesis and connective tissue construction attach to, grow and differentiate on the collagen matrix laid down by fibroblasts [20]. Initially collagen III and fibronectin are the most abundant matrix components, but as time progresses and the wound moves into the remodelling phase, collagen I is laid down [15].

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1.4.3.2   Angiogenesis Angiogenesis accompanies the fibroplasia phase and is essential to scar formation. Endothelial cells located at intact venules are stimulated by VEGF, which is secreted mainly by keratinocytes at the wound edge and also by macrophages, fibroblasts and platelets in response to hypoxia and the presence of lactic acid. Endothelial cells originating from parts of uninjured blood vessels develop pseudopodia and push through the ECM into the wound site. They produce the degradation agents including plasminogen activator and MMPs and invade the wound by the enzymatic degradation of fibrin clot once the new granulation tissue (i.e., ECM, collagen, capillaries) is laid down [10]. New blood vessels establish blood flow in the wound. Cells, when adequately perfused, stop producing angiogenic factors, and migration and proliferation of endothelial cells is reduced [10]. Eventually, blood vessels that are no longer needed die by apoptosis; this explains the change in colour seen in scar tissue as it matures.

1.4.3.3   Epithelialisation The initial event in epithelialisation is migration of undamaged epithelial cells from the wound margins. Keratinocytes at the wound edges are stimulated by EGF and TGF-α produced by activated platelets and macrophages [18]. They proliferate and begin their migration across the wound bed within 12–24 h after injury [5]. The first step of migration involves separation of the keratinocytes from each other and their anchors to the cell basement membrane [21]. The process of migration continues until the migrating cells from opposing sides of the wound touch each other. At the point of contact, migration ceases in a process known as ‘contact inhibition’ [21]. Once this process is complete, keratinocytes form firm attachments to each other and the new basement membrane [22]. Initially, it is the granulation tissue which is formed, consisting of inflammatory cells, fibroblasts and new vasculature in a hydrated matrix of glycoproteins, collagen and glycosaminoglycans, the components of a new, provisional ECM. The provisional ECM is different in composition from the ECM in normal tissue and includes fibronectin, collagen III, glycosaminoglycans and proteoglycans [20].

1.4.3.4   Contraction About a week after the injury, fibroblasts undergo differentiation into myofibroblasts, pulling the edges of the wound together and initiating wound contraction [23]. This process peaks at 5–15 days after injury but continues even after the wound is completely reepithelialised [24]. Contraction reduces the size of the wound and, thus, reduces the amount of ECM needed to fill the wound [25] and facilitates reepithelialisation by reducing the distance, which migrating keratinocytes must travel. At the end of the granulation phase, fibroblasts begin to undergo apoptosis, converting granulation tissue from an environment rich in cells to one that consists mainly of collagen [24].

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1.4.4  Maturation and remodelling Maturation and remodelling of the collagen into an organised and structured network is the final stage of the healing process (from day 8 up to 2 years). If this is compromised, then the wound’s strength will be greatly affected. On the other hand, excessive collagen synthesis can lead to the formation of a hypertrophic scar or keloid. The length of the maturation phase is affected by the size of the wound and whether it was initially closed or left open. This phase is characterised by the removal of type III collagen and its replacement by mature type I collagen. There is a rapid production of type I collagen, but there is no net gain, as the old collagen is being degraded by MMPs. New collagen fibres are rearranged, cross-linked and aligned along tension lines, but they can never become as organised as the collagen found in uninjured skin [17]. The second characteristic feature of this stage is programmed cell death or apoptosis, and thus the number of cell types such as macrophages, keratinocytes, fibroblasts, and myofibroblasts is reduced [5,22]. Remodelling is regulated by fibroblasts through the synthesis of ECM components and MMPs that control cell differentiation [16]. All of these changes produce a cell-deficient environment with excessive connective tissue. Blood vessels that are no longer required die by apoptosis, and the remainder acquire a basement membrane and become relatively impermeable. All of these factors lead to the increase in tensile strength and decrease in erythema and scar tissue bulk, resulting in the final appearance of the healed scar.

1.5  Factors affecting wound healing: why wounds fail to heal In most cases, wound healing is a natural, uneventful process, which leads to the restoration of tissue integrity. In some cases, wounds fail to heal and become a complex medical problem requiring specialised care and treatment. If a wound has not improved significantly in 4 weeks, or if it has not completed the healing process in 8 weeks, it is considered a chronic, nonhealing wound. Wound healing is dependent on the interaction of different cells, mediators and growth factors. Alterations in one or more of these components may account for the impaired healing observed in chronic wounds. Chronic wounds may be arrested in any of the healing phases, but most commonly disruption occurs in the inflammatory or proliferative phase [26]. There is excessive accumulation of disorganised ECM and over activation of MMPs, which results in premature degradation of collagen and growth factors [27]. An optimum microenvironment, and the absence of cytotoxic factors, is essential for healing of wounds. Many local and systemic factors have been implicated in the delayed healing of wounds.

1.5.1  Local factors 1.5.1.1  Bioburden The presence of bacteria in wounds, as on healthy skin, is normal. However, the degree to which bacteria are involved in a wound may be classified into four categories, and it is important to distinguish between them, as there are implications for management [28].

Wound management and dressings

Wound contamination Wound colonisation

Local infection/critical colonisation

Spreading infection

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Nonreplicating microorganisms present in the wound. This does not impair healing. Replicating microorganisms present in the wound but not causing injury to the host and therefore not impairing healing. Often these organisms are skin commensals. Increased bacterial burden that is causing a delay in healing. This would include the presence of a biofilm. The alternative complement pathway is activated, and the inflammatory phase of wound healing is exaggerated and prolonged. May usually be treated with topical measures. Invasive bacterial contamination that is associated with tissue destruction. Systemic therapy, in the form of antibiotics, is needed for any spreading infection. The choice of drug, route of administration and duration of therapy should be informed by a thorough clinical assessment, in combination with investigation results and local microbiology guidelines.

1.5.1.2   Ischaemia Hypoxia is detrimental to cellular proliferation and collagen production. Resistance to infection is also impaired. Numerous factors may result in local hypoxia, including the presence of foreign bodies, tissue disruption, infection, strangulation by suture material, mechanical pressure and microvascular disease. Peripheral vascular disease may result in ischaemia of the entire limb.

1.5.1.3   Oedema Chronic oedema of any aetiology results in saturation of the tissues with fluid containing growth factors, proteases and proinflammatory molecules. Additionally, macrophage and lymphocyte transport in the lymphatic system is impeded, leading to the accumulation of bacteria and debris and increased rates of infection [29]. Venous disease, obesity, lymphatic disruption from surgery or malignancy and immobility may all result in chronic oedema. Supportive hosiery can be useful in these patients. Cardiovascular and renal diseases are other common conditions associated with oedema and may require specialist input and systemic therapy to achieve control.

1.5.1.4   Neoplasia Neoplasia prevents normal healing. An ‘ulcer’ with atypical features could represent an undiagnosed skin cancer, and this should be actively excluded with a biopsy. Malignant transformation in an existing wound is also possible. A Marjolin’s ulcer refers to an ulcerating squamous cell carcinoma that presents in an existing wound, scar or area of chronic inflammation, and it is important to exclude it in longstanding ulceration, particularly in the elderly [2].

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1.5.2  Systemic factors 1.5.2.1  Ageing There are many physiological changes associated with ageing, which can lead to delayed healing. Reduced skin elasticity and collagen replacement influence healing. Reduced immunity and other chronic diseases can also affect the healing process.

1.5.2.2  Nutritional status Wound healing is an anabolic process, and as such, nutritional deficiency, whether macronutrients such as proteins and lipids or micronutrients such as vitamins, will affect the wound healing process. Proteins are required for all the phases of wound healing and are particularly important for fibroblast proliferation and collagen synthesis. In protein deficiency states, cellular and humoral immune responses are blunted and all aspects of matrix formation are delayed [30]. Vitamins have a cofactor role in many enzymatic processes, and as a consequence, their role in wound healing has been investigated [30].

Consequence of deficiency Vitamin A

Vitamin C

Vitamin K

Iron Zinc

Delayed reepithelisation, impaired collagen synthesis and stability and an increased susceptibility to infection as a result of altered B and T cell function. Absence of vitamin C as a cofactor in collagen biosynthesis leads to formation of unhydroxylated collagen. This is relatively unstable and subject to collagenolysis. Deficiency in the production of clotting factors II, VII, IX and X (vitamin K dependent) resulting in bleeding diathesis, haematoma formation and secondary detrimental effects on wound healing. Iron deficiency anaemia will result in decreased oxygen transport Increased susceptibility to infections, impaired collagen synthesis and damped fibroblast proliferation.

1.5.2.3  Diabetes and impaired glucose tolerance Glucose balance is essential for wound healing. Whilst glucose provides the energy required for cell function, there is increasing evidence that high glucose levels impair the migration of keratinocytes and fibroblasts thus impairing wound closure [31]. Insulin may also act as a fibroblast growth factor, and its deficiency therefore leads to suppression of collagen deposition in the wound [32]. Diabetes is also known to cause microvascular disease, which contributes to tissue ischaemia and neuropathy, making tissue injury is more likely.

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1.5.2.4  Other systemic diseases Arthritis, renal disease, heart disease, cancer, immune disorder, lung diseases, blood disorders and surgery all affect the process of wound healing.

1.5.2.5   Medication Many drug classes are known to affect wound healing. In some cases the mechanism is understood. Anticoagulants interrupt the clotting process. Cytotoxic and cytostatic drugs affect cell division and proliferation. Anti-inflammatory and immunosuppressive drugs affect the production of cytokines such as IL-2 and TNF-α. Other drugs are known to have deleterious effects on wound healing, but the underlying processes are not understood. The antianginal Nicorandil is one such agent. High-dose treatment has repeatedly been shown to be associated with cutaneous, peristomal, oral and gastrointestinal tract ulceration, which resolves on cessation of the drug; however, the mechanism is not yet certain [33].

1.6  Wound healing: treatment options Wound repair requires the timed and balanced activity of inflammatory, vascular, connective tissue, and epithelial cells and their mediators. In order to provide an environment that is conducive to wound healing, it is important to diagnose and manage systemic conditions, which may have contributed in the aetiology of the wound and are promoting delayed healing. This strategy is also important in the prevention of recurrence. A full history and examination is essential. In addition to addressing systemic and regional conditions, symptoms from the wound should be assessed. Pain is a frequent and troublesome sequela, which needs to be treated. Local wound management involves manipulating the wound environment to promote healing. The term ‘wound bed preparation’ has been used to describe this process, and the tissue, infection/inflammation, moisture imbalance, edge (TIME) system was developed in 2002 as a clinical tool to manage chronic wounds [34]. It originally brought together theories of wound management that had long been accepted, for example, the importance of a moist wound environment. This was first suggested in the 1960s following research by Winter on the effect of air exposure and occlusion on wound healing [35] and has been expanded as further research has been carried out into the processes involved in wound healing and the constituents of wound fluid and their roles. TIME continues to be updated [36,37]. One concept that has been incorporated more recently is the need to recognise and manage biofilms in chronic wounds. A biofilm is an aggregation of bacteria, usually of more than one species, attached to a surface and encapsulated in a self-produced ECM, which is tolerant to antimicrobial treatment and host defences. Biofilms are only visible with high-powered microscopes, but other clinical signs, such as persistent slough, may point to their presence. Ultimately, the few studies where appropriate microscopy has been used to assess for the presence of biofilm in chronic wounds have reported such a high incidence; some authors have

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recommended that it should be assumed that all chronic wounds which fail to respond to appropriate care are likely to have a biofilm and should be managed as such [38]. Tissue

Infection/ inflammation

Moisture imbalance

Edge

Clinical observations: Nonviable or deficient tissue Actions required: Nonviable tissue should be debrided as required. Foreign bodies need to be removed, and callous, exudate, slough and biofilm need to be controlled as part of treatment. Debridement may be achieved through a number of techniques, including surgical/ sharp, enzymatic, autolytic, mechanical or biological. Aim: A viable and healthy wound base Clinical observations: Excessive unhealthy granulation tissue, purulent exudate, malodour. Persistent slough or gelatinous material on the wound surface, with failure to heal despite standard local treatment, may also indicate the presence of a biofilm. Actions required: Remove infected foci. Consider topical or systemic antimicrobials and/or anti-inflammatories. Prolonged inflammation may be the result of an inflammatory disease, and a biopsy should be considered in a wound with an unusual presentation or appearance. Protease inhibition may be possible with a protease-modulating dressing. If a biofilm is suspected, then regular debridement in combination with antimicrobial treatment may be of benefit. Aim: Bacterial balance and reduced inflammation Clinical observations: A wound bed with desiccated or necrotic tissue or maceration and oedematous tissue. Actions required: Optimum wound healing occurs in a moist environment. In dry wounds, moisture-donating or -retaining dressings and debridement will be necessary. In macerated wounds, a dressing capable of managing exudate must be used and changed regularly. Compression and negative pressure wound therapy (NPWT) are alternative strategies. Aim: Moisture balance Clinical observation: A nonadvancing or undermined epidermal margin, implying that wound cells are nonresponsive. Action required: The underlying diagnosis and T, I and M factors should be reassessed. Corrective therapies may include debridement, skin grafting, biological agents or adjunctive therapies. Aim: Advancing epidermal margin

1.6.1  Wound dressings Properly selected dressings, in line with the TIME principles above, can promote healing and prevent further deterioration in the wound. Wound dressings are passive, active or interactive [39]. Passive dressings simply provide cover while active or interactive dressings are believed to be capable of modifying the physiology of the wound environment. Interactive dressings include hydrogels, hydrocolloids, alginates and foams. Table 1.1 summarises the uses of each type of dressing, and more information about the mode of action is provided below.

Wound management and dressings

Table 1.1 

13

Dressing types and their uses

Dressing type and examples

Uses

Hydrogel sheets: Intrasite, Novogel, Purilon gel, Actiform cool

Dry to minimally exudative sloughy wounds. Not recommended in infected or gangrenous wounds. Shallow cavities or flat wounds. Will maintain a moist wound environment in lightly to moderately exuding wounds and promote autolytic debridement and granulation in dry, sloughy or necrotic wounds. Flat wounds, cavities and sinuses. Highly absorbent, so suitable for moderate to highly exudative wounds and safe under compression. Flat or shallow wounds with variable levels of exudate. Cavities and sinuses. Highly absorbent, so suitable for all highly exudative wounds. They promote autolytic debridement. Secondary dressing required. Minimally exudative or dry wounds, which are flat or very shallow. Flat or shallow wounds with variable levels of exudate. Flat or shallow wounds with minimal to low exudate. Usually used as an interface dressing under an absorbent dressing.

Hydrocolloid sheets: Alione, Comfeel, Granulflex, Duoderm

Hydrofibres: Aquacel, Versiva

Foam dressings: Allevyn, Mepilex, Biatin Alginates: Kaltostat, Sorbsan, Algisite.

Semipermeable Films: Opsite, Tegaderm, Bioclusive. Capillary action: Advadraw, Cerdak Basic, Sumar Lite, Vacutex Low-adherent dressings: Atrauman, Cuticell, Jelonet, Paragauze, Paranet, Neotulle, N-A dressing, N-A Ultra, Profore, Tricotex. Soft polymer dressings: Adaptic touch, Askina Silnet, Mepitel, Physiotulle, Silflex, Sorbion Contact, Tegaderm Contact, Urgotul, Advasorb border, Allevyn gentle border, Cutimed Siltec Protease-modulating dressings: Catrix, Promogran, Tegaderm Matrix, Urgostart.

Antimicrobial dressings: PHMB, Silver, Iodine, Honey (see text for examples)

Generally suitable for light to moderately exudative wounds. Can be used on delicate skin. The plain sheet dressings can be used in combination with an absorbent secondary dressing. Chronic, moderate to highly exudative wounds. Various products available; some suitable to be used under compression, some appropriate for packing deeper wounds and some with antimicrobial components. For use in locally infected wounds. The other characteristics of the wound, e.g., depth, and exudate, as well as patient factors, such as allergies and medical comorbidities, should be taken into consideration when selecting which antimicrobial dressing to use.

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1.6.1.1  Hydrogels Made up of a matrix of insoluble polymers with a high water content. This enables them to donate fluid to the wound, ensuring a moist wound surface and promoting autolytic debridement of dry slough. As absorption of exudate is poor, they can cause maceration [40].

1.6.1.2  Hydrocolloids Hydrocolloids are composed of a matrix of cellulose and other gel-forming agents, including gelatin and pectin. These dressings promote autolytic debridement and aid granulation [40]. Hydrocolloids are available as sheets, which form a gel in the presence of exudate, paste and hydrofibres, which contain modified carmellose fibres and can therefore absorb more water.

1.6.1.3  Foam dressings These are made of a hydrophilic polyurethane foam, with or without adhesive. They have variable levels of absorbency [34]. They also provide cushioning and support to the wound.

1.6.1.4  Alginate These dressings are highly absorbent and are composed of calcium and sodium salts of alginic acid, obtained from seaweed [34]. They form a soft gel in the presence of wound exudate.

1.6.1.5  Semipermeable films These are flexible, sterile sheets of polyurethane coated with a hypoallergenic adhesive. They are variably permeable to water vapour and oxygen but impermeable to water and microorganisms.

1.6.1.6  Capillary action dressings These are multilayered dressings. The wound contact layer is perforated and permeable, and this is bonded to an absorbent viscose and polyester pad with a central wicking layer. It is designed to draw fluid off the wound surface.

1.6.1.7  Low-adherent dressings These dressings are either tulle or textiles, usually made of cotton or viscose fibres and impregnated with white or yellow soft paraffin to prevent adherence. They have no intrinsic absorbency but can be used in conjunction with an absorbent secondary dressing.

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1.6.1.8  Soft polymer dressings These are made of a soft polymer, often silicone, making them gently adherent to the wound but preventing any overlying secondary dressing becoming attached. They are either plain, and may be used with an absorbent secondary dressing, or with an integrated absorbent polyurethane foam pad backing.

1.6.1.9   Protease-modulating dressings These dressings reduce the activity of proteinases in the wound exudate, by absorbing exudate, removing enzyme cofactors or releasing inhibitors.

1.6.1.10   Antimicrobial dressings Antimicrobial dressings are good for critically colonised or locally infected wounds, especially in diabetics. They should not be a substitute for systemic antibiotics in spreading infection. A number of antimicrobial dressings with different disinfectants are available. Polyhexamethylene biguanide (PHMB) impregnated, e.g., Suprasorb X + PHMB PHMB is an antimicrobial agent, which works by disrupting cell membrane integrity. Wound cleansing gels and solutions containing this agent are also available. Silver dressings Silver ions have an antimicrobial effect in the presence of exudate. There are many types of silver dressings; alginates e.g., Sorbsan silver, hydrocolloid e.g., Aquacel Ag, foam e.g., Allevyn Ag, low adherence e.g., Acticoat, soft polymer e.g., Mepilex Ag, with charcoal e.g., Actisorb Silver. Iodine-based dressings Cadexomer iodine and povidone-iodine release free iodine when exposed to wound exudate, which has a wide spectrum of antimicrobial activity. Iodoflex and iodosorb are contraindicated in patients receiving lithium, thyroid disorders and pregnancy and breastfeeding. Inadine is contraindicated in pregnancy, breastfeeding and renal failure, and caution should be used in patients with thyroid disease. Honey dressings Medical grade honey has antimicrobial and anti-inflammatory properties. It is osmotic so promotes autolytic debridement. Caution is needed in diabetic patients, and honey should be avoided in patients who are allergic to bee stings. Examples include Activon Tulle, Actilite, Algivon and L-Mesitran.

1.6.1.11  Odour adsorbent dressings The most effective way to reduce odour in a wound is to determine and control the underlying cause of the odour, often slough and bioburden. However, dressings containing activated charcoal are available, which adsorbs chemicals released from wounds to control odour. These are designed to be used either in combination with other dressings or, if they have a suitable wound contact layer, as a primary dressing. Examples include CliniSorb, CarboFLEX and Aksina Carbosorb.

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1.6.2  Bioengineered skin Bioengineered skin is generally divided into permanent, such as autografts, and temporary, such as allografts (including deepidermised cadaver skin and in vitro reconstructed epidermal sheets), xenografts (i.e., conserved pig skin) and synthetic dressings.

Allogenic grafts are produced from neonatal fibroblasts and keratinocytes. Available in the form of dermal, epidermal or composite grafts, they are better than traditional skin grafts, as they are noninvasive, do not require anaesthesia and avoid potential donor site problems.

1.6.2.1  Epidermal grafts Cellutome and Recell are commercially available systems, which can be used to generate and apply autologous epidermal grafts. Advantages to these systems include small donor sites, with minimal discomfort relating to the harvest, and the ability to complete the procedure on an outpatient basis. They can be used to cover large skin defects, and acceptable cosmetic results have been reported in burns and leg ulcers [41,42]. Their main disadvantages include fragility and difficulty in handling owing to a lack of backing material. They are unsuitable for deep wounds and are most successful when placed on a dermal bed. A randomised controlled trial is currently underway to assess the efficacy of epidermal graft using the Cellutome system and standard care in comparison to standard care alone for venous leg ulcers (NCT02148302).

1.6.2.2  Dermal grafts Dermal grafts can be cellular or acellular and are allogenic and therefore available for immediate use. Allergy to bovine collagen, limited shelf-life and infection can limit their use [26]. Acellular dermal matrix grafts include Integra, DermACELL and Alloderm. Their use has been reported in burns, deep wounds and reconstructive surgery of the head and neck, abdominal wall and breast [2,42]. Apligraf is a commercially available bilayered cellular skin graft and is indicated for diabetic foot ulcers and venous ulcers that have not responded to conventional treatment [2]. It contains a lower dermal layer of bovine type I collagen and human fibroblasts and an upper dermal layer of human keratinocytes. It does not contain skin adnexal structures.

1.6.3  Nonsurgical innovations 1.6.3.1  Negative pressure wound therapy NPWT or Vacuum-assisted closure entails placing an open-cell foam dressing into the wound cavity and applying a controlled subatmospheric pressure. This produces negative pressure in the wound, leading to improved blood flow and oxygenation. It also helps in removing excessive fluid and slough [43]. This stimulates granulation tissue formation, wound contraction and early closure of wound. A number of options are available to meet the demands of different sized wounds with varying levels of exudate.

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1.6.3.2  Intermittent pneumatic compression This is an effective treatment for chronic ulcers on legs with severe oedema. It provides compression (at 20–120 mmHg) at preset intervals [44]. It improves lymphatic and venous flow and helps in the healing of chronic ulcers.

1.6.3.3   Oxygen Hyperbaric oxygen is thought to expedite healing, as it has been shown that ischaemic lesions heal less well [45] and certain growth factors do not work in hypoxic conditions [46]. Debate continues on its value in certain wound conditions [47]. Topical oxygen applied using a system such Natrox or TO2 has been shown to decrease wound size, and it is thought that this effect is due to the upregulation of VEGF expression [47].

1.6.3.4   Electrical stimulation The aim of electrical stimulation therapy in wound care is to restore the cellular electrical potential that normally exists at the epidermis; the ‘transepithelial potential’. This is usually between 10 and 60 mV but falls to 0 mV when the skin is wounded [48]. It is thought that the currents around a wound affect cell migration and proliferation and that electrical stimulation increases fibroblast production, cell migration and wound angiogenesis [49]. Electrical stimulation dressing devices use an externally applied current to create electrical flow through the tissues. Electrodes are placed in the wound itself or on the periwound skin. Direct or pulsed current can be used. Small randomised controlled trials have shown increased healing rates in chronic ulcers using electrical stimulation [50], and this has led to electrical stimulation being recommended as a treatment for refractory grade II pressure ulcers and any grade III and IV pressure ulcers by the National Pressure Ulcer Advisory Panel, European Pressure Ulcer Advisory Panel and Pan Pacific Pressure Injury Alliance in their joint guideline [51].

1.6.3.5   Other therapies Low-frequency ultrasound and hydrotherapy systems such as the VersaJet are methods for mechanical wound debridement [36]. Larval (maggot) therapy is another method of selective microdebridement. Laser therapy, ultrasound therapy and electromagnetic therapy are proposed to stimulate cell proliferation and thus wound healing, although the evidence for them is not conclusive [36].

1.6.4   Drug therapy 1.6.4.1   Topical Topical agents may be used to treat the wound bed and surrounding skin. This might include antimicrobials, including honey- or silver-containing ointments as well as topical antibiotic preparations, or steroids.

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1.6.4.2  Systemic Drugs affect wound healing by assisting or interfering with specific phases. Drugs can reduce peripheral vascular resistance, reduce blood viscosity and cause local or systemic vasodilatation leading to improved tissue perfusion and oxygenation. Pentoxifylline decreases platelet aggregation leading to decreased viscosity and improved capillary microcirculation. A Cochrane review in 2012 found that patients treated with pentoxifylline, with or without compression bandaging, had increased rates of ulcer healing than control subjects [52]. Iloprost, a vasodilator and prostacyclin analogue, can be used in the treatment of arterial and vasculitic ulcers [44]. Oral calcium channel blockers and glyceryl trinitrate ointment have also been used as vasodilators in cases of vasculitic ulcers caused by Raynaud’s disease and ischaemic ulcers, respectively.

1.6.5  Growth factors Growth factors are soluble signalling proteins, which influence wound healing through their inhibitory or stimulatory effects during different stages of the wound healing process. They act on inflammatory cells, fibroblasts and endothelial cells to direct the processes involved in wound healing. A lot of work has been carried out to investigate the potential of topical application of growth factors as a treatment for chronic wounds. Whilst the results in preclinical experiments have been promising, there has been only limited success in translational clinical trials. Recombinant human platelet–derived growth factor-bb (rhPDGF-BB, Becaplermin) is the only FDA-approved growth factor available for clinical use. A systematic review in 2013 found a small benefit over standard care in the incidence of complete wound closure; however, the authors commented that the strength of the evidence was low based on the quality of the clinical trials available [53]. bFGF stimulates endothelial cell migration and proliferation. In small early clinical trials, topical application led to faster granulation tissue formation and epidermal regeneration in wounds of multiple aetiologies [54]. However, conclusive benefits have not yet been shown and bFGF is not commercially available worldwide. Preclinical trials showed promising results for epidermal growth factor and keratinocyte growth factor in venous ulcers and fibroblast growth factor and PDGF for pressure ulcers. Despite this, results of the clinical trials are disappointing [55]. The inherent instability of these proteins in the hostile environment of the wound makes them ineffective. Time of application, dosage and mode of delivery or the combination of the growth factors may be incorrect and further evaluation is required.

1.7  Future trends 1.7.1  Gene therapy To be clinically effective a high concentration of growth factors is needed, which requires frequent and high dosing, but it is prohibitively expensive. Introduction of the gene rather than the product (growth factor) may be more efficient in treating

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19

nonhealing wounds. It could lead to a sustained local availability of these proteins, making it more cost-effective than repeated application of growth factors. The technology to introduce genes through physical or biological vectors exists. Successful treatment would require expression of the therapeutic gene in the wound bed for the duration of wound repair. An additional concern is that whilst upregulation of these growth factors may be beneficial in wound healing, they could have detrimental effects if upregulated systemically, for example, in promoting tumour growth in cancer [55]. Preclinical studies are ongoing in this area.

1.7.2  Stem cells therapy Stem cells have been suggested as a therapy with the potential to address the underlying pathophysiology of a chronic wound. Pluripotent embryonic stem cells have been shown to promote angiogenesis and reepithelialisation in preclinical studies, but they are sourced from discarded in vitro fertilisation embryos, making their use controversial [56]. Other sources of allogenic multipotent stem cells include human placenta and umbilical cord blood, and there are promising preclinical results demonstrating accelerated healing [56]. Autologous stem cells can be harvested from bone marrow. Badiavas et al. [57] reported the successful treatment of three patients with chronic wounds with autologous bone marrow aspirates and autologous cultured bone marrow cells. Further clinical studies have followed; however, this treatment is somewhat limited by the costs involved in the harvest, culture and processing of the bone marrow to generate the mesenchymal stem cells.

1.8  Conclusions Normal wound healing is a progressive and organised sequence of events leading to restoration of tissue integrity. A chronic wound may develop where this process fails, and there may be multiple factors involved. No single treatment is universally effective. Wound management should therefore be holistic and aim to diagnose and correct any underlying abnormalities, as well as optimise the wound environment.

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[29] C.J. Moffatt, et al., Chronic oedema: a prevalent health care problem for UK health services, Int. Wound J. (2016), p. n/a-n/a. [30] A.M. Quain, N.M. Khardori, Nutrition in wound care management: a comprehensive overview, Wounds 27 (12) (2015) 327–335. [31] C.R. Kruse, et al., The effect of local hyperglycemia on skin cells in vitro and on wound healing in euglycemic rats, J. Surg. Res. 206 (2) (2016) 418–426. [32]  W.H. Eaglstein, P.M. Mertz, “Inert” vehicles do affect wound healing, J. Investig. Dermatol. 74 (2) (1980) 90–91. [33] U. Pisano, et al., Nicorandil, gastrointestinal adverse drug reactions and ulcerations: a systematic review, Adv. Ther. 33 (3) (2016) 320–344. [34] G.S. Schultz, et al., Wound bed preparation: a systematic approach to wound management, Wound Repair Regen. 11 (2003) S1–S28. [35] G.D. Winter, Effect of air exposure and occlusion on experimental human skin wounds, Nature (200) (1963) 378–379. [36] D.J. Leaper, et al., Extending the TIME concept: what have we learned in the past 10 years?*, Int. Wound J. 9 (2012) 1–19. [37] R.L. Harries, D.C. Bosanquet, K.G. Harding, Wound bed preparation: TIME for an update, Int. Wound J. 13 (S3) (2016) 8–14. [38] World Union of Wound Healing Societies (WUWHS). Florence Congress, Position Document, Management of Biofilm, 2016, Available from: http://www.woundsinternational.com/ wuwhs/view/position-document-management-of-biofilm. [39] C. Hansson, Interactive wound dressings. A practical guide to their use in older patients, Drugs Aging 11 (4) (1997) 271–284. [40] V. Jones, J.E. Grey, K.G. Harding, Wound dressings, BMJ 332 (7544) (2006) 777–780. [41] T.E. Serena, Use of epidermal grafts in wounds: a review of an automated epidermal harvesting system, J. Wound Care 24 (4 Suppl.) (2015) 30–34. [42] M. Singh, et al., Evolution of skin grafting for treatment of burns: reverdin pinch grafting to tanner mesh grafting and beyond, Burns 43 (6) (2017) 1149–1154. [43] T.M. Fleck, et al., The vacuum-assisted closure system for the treatment of deep sternal wound infections after cardiac surgery, Ann. Thorac. Surg. 74 (5) (2002) 1596–1600 Discussion 1600. [44] S. Enoch, J.E. Grey, K.G. Harding, Non-surgical and drug treatments, BMJ 332 (7546) (2006) 900–903. [45] K. Jönsson, T.K. Hunt, S.J. Mathes, Oxygen as an isolated variable influences resistance to infection, Ann. Surg. 208 (6) (1988) 783–787. [46] L. Wu, et al., Effects of oxygen on wound responses to growth factors: Kaposi’s FGF, but not basic FGF stimulates repair in ischemic wounds, Growth Factors 12 (1) (1995) 29–35. [47] G.M. Gordillo, et al., Topical oxygen therapy induces VEGF expression and improves closure of clinically presented chronic wounds, Clin. Exp. Pharmacol. Physiol. 35 (8) (2008) 957–964. [48] International, W, Electrical stimulation in wound care, Wounds Int. 4 (Suppl.) (2013) 1–12. Available from: http://www.woundsinternational.com/supplements/view/electricalstimulation-in-wound-care. [49] L.C. Kloth, Electrical stimulation for wound healing: a review of evidence from in vitro studies, animal experiments, and clinical trials, Int. J. Lower Extrem. Wounds 4 (1) (2005) 23–44. [50] J.A. Feedar, L.C. Kloth, G.D. Gentzkow, Chronic dermal ulcer healing enhanced with monophasic pulsed electrical stimulation, Phys. Ther. 71 (9) (1991) 639–649.

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[51] National Pressure Ulcer Advisory Panel European Pressure Ulcer Advisory Panel and Pan Pacific Pressure Injury Alliance, Prevention and Treatment of Pressure Ulcers: Quick Reference Guide, Cambridge Media, Osborne Park, Western Australia, 2014. [52] A.B. Jull, et al., Pentoxifylline for treating venous leg ulcers, Cochrane Database Syst. Rev. (12) (2012). [53] N. Greer, et al., Advanced wound care therapies for nonhealing diabetic, venous, and arterial ulcers: a systematic review, Ann. Intern. Med. 159 (8) (2013) 532–542. [54] S. Matsumoto, et al., The effect of control-released basic fibroblast growth factor in wound healing: histological analyses and clinical application, Plast. Reconstr. Surg. Global Open 1 (6) (2013) e44. [55] T.N. Demidova-Rice, M.R. Hamblin, I.M. Herman, Acute and impaired wound healing: pathophysiology and current methods for drug delivery, Part 2: role of growth factors in normal and pathological wound healing: therapeutic potential and methods of delivery, Adv. Skin Wound Care 25 (8) (2012) 349–370. [56] S.N. Blumberg, et al., The role of stem cells in the treatment of diabetic foot ulcers, Diabetes Res. Clin. Pract. 96 (1) (2012) 1–9. [57] E.V. Badiavas, V. Falanga, Treatment of chronic wounds with bone marrow–derived cells, Arch. Dermatol. 139 (4) (2003) 510–516.

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2

Author of the chapter: Steve Thomas Formerly of The Surgical Materials Testing Laboratory (SMTL), Princess of Wales Hospital, Coity RoadBridgend, South Wales, United Kingdom Editor of the chapter: Muhammet Uzun Department of Textile Engineering, Faculty of Technology, Marmara University, İstanbul, Republic of Turkey

2.1   Introduction Wound healing is a multiphase and multifactorial physiological process. The complexity of this phenomenon makes the healing process very difficult and painful due to several abnormalities. Apart from cellular and biochemical components, a number of external pathways also become active during repair and help the tissue to heal. Wound dressing is one of the main external effectors during the healing process of wounds. As defined in the literature, wound is the disruption of the integrity of anatomical tissues caused by exposure to any factor. This could be whether or not wounds with tissue losses in general. For both scenarios, the wound dressings have to be applied to cover the damaged skin and protect it from external effects. The following characteristics are required for ideal modern wound dressings: bioadhesiveness to the wound surface, ease of applications, easily sterilised inhibition of bacterial invasion, biodegradability, oxygen permeability, nontoxic, etc. Although sophisticated solutions have been developed for wound healing, there are still a number of limits that are directly to affect the healing process and time. There is a growing concern about the usage of smart materials as wound dressings [1]. These are natural polymers such as polysaccharides and derivatives (e.g., carboxymethyl cellulose [CMC], alginates, chitosan [CS] and heparin), proteoglycans and proteins (e.g., collagen, gelatine, fibrin and keratin), and what is more important is that the impact of such materials on the wound healing process is still under investigation by scientists and experts in general. An intelligent, adaptive, or smart wound dressing material can alter its physical structure or properties in response to its environment [2]. It can automatically react to specific external conditions and adjust itself to bring about some useful result. The main purpose of the current chapter is to identify some common parameters suitable for testing and measuring conventional and smart wound dressings’ properties and performances. Choosing the most suitable dressing has fundamental importance to create proper tissue repair conditions in all types of wounds (Fig. 2.1). Advanced Textiles for Wound Care. https://doi.org/10.1016/B978-0-08-102192-7.00002-3 Copyright © 2019 Elsevier Ltd. All rights reserved.

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Advanced Textiles for Wound Care Permeable for oxygen

Protection from bacterial invasion

Spongy - like layer Controlled of water vapour permeability

Drug release reservoir

Skin

Drying of wound exudates

Wound bed

Figure 2.1  Schematic design of an ideal wound dressing membrane [4].

2.2  Need for prototyping and laboratory testing 2.2.1  Main properties expected from modern wound dressings An appropriate material has to be used to cover the wound to effectively heal the wound and prevent it from any infectious agent. The main functions of the wound dressings are to avoid strike-through and protect the wound areas from contamination and further injuries on the same wound area. The search for the ideal dressing is ongoing with currently available dressing that suits all patients or all wound types and at all stages of the healing process. The key requirements of wound dressings are given below and laboratory examinations for dressings are required to test before use on patients. 1. Fluid control: the ability to absorb fluid and donate water to a dry wound. 2. Physical barrier: to avoid strike-through and further physical damages. 3. Microbial control: for infected wounds. 4. Odour management: a wound often produces unpleasant and obnoxious odour. 5. Low adherences: good dressings can help eliminate adherence to a wound. 6. Space filler: for deep cavity wounds. 7. Debridement: by providing the appropriate moisture, temperature and pH. 8. Haemostatic: bleeding is stopped as early as possible to prevent blood loss. 9. Scar reduction: scar formation presents a major aesthetic problem for the patient. 10. Metal ion metabolism: deficiency in any metal ion delays wound healing. 11. Wound healing acceleration [3].

2.2.2  Prototyping and testing Prototyping is a technique for direct conversion of any data into a physical prototype using a number of techniques. Almost all industries have been prototyping and testing

Testing dressings and wound management materials

25

their new products before mass production of developed products. Prototyping means for compressing the time to market products and lowering the cost, considered as competitiveness-enhancing technologies. This also reduces product development cycle [5]. Following prototyping any products, some test methods have to be employed to determine the success of the developed products whether these products meet expectations. Above properties need to be tested before applying any wound dressings to the patients. These laboratory tests for dressings are required for a number of reasons such as the following: • To demonstrate compliance with national or international standards or specifications. • To ensure product meets ‘in-house’ manufacturing standards. • To facilitate comparisons with competitive products. • To generate data to support allocation of shelf life (stability/storage).

There are essentially three types of standards or specifications. • Structural standards, which define the structure and/or composition of a product. • Performance standards, which describe one or more key aspects of the function of a dressing. • Safety standards, designed to ensure that a product, when used appropriately, is unlikely to adversely affect the health or well-being of the individual to whom it is applied.

2.3  The development of wound dressings A considerable amount of literature has been published on the ancient medical and wound management practices. These studies show that the first written historical record was found on Sumerian clay, which is the world’s oldest medical manuscript. The ‘three healing gestures’ explained in this manuscript were (1) washing the wound; (2) applying dressings and (3) bandaging the wound [6]. Other important developments were carried out during the Egyptian civilisation. They made a great progress on primary human infections and inflammation control in ancient times [7]. Linen-based textile gauze structure was employed as the wound dressing at that time. Preliminary work on honey, gums, resins and herbal extracts in wound care application was undertaken by the Egyptians, and the linen textile structures were coated with honey to make them antimicrobial [8–10]. The contribution of ancient Greeks to medical and wound management has also been highlighted by many historians. To identify the severity of wounds, the Greeks divided the wounds into two groups, based on infected nonhealing and noninfected healing wounds. Both Hippocrates and Galen [11] recognised the two types of wounds, the first one is dry and clean, which is healed by the first intention, and the other one is dirty which requires drainage before healing took place. Galen [11,12] also suggested ‘laudable pus’ theory. In another major study in ancient Greek, some metal powder, milk, honey and wine were utilised in the gauze application for the first time. It was suggested that the metallic copper, when combined with vinegar, produced copper acetate, which had antibacterial properties and could help in the treatment of wounds and cutaneous ulcers [13].

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Advanced Textiles for Wound Care

In the 19th century, a large variety of textile fibres (such as cotton, silk and wool) and structures (knitted, nonwoven and composites) were put into service as traditional wound dressing materials. The cotton gauze impregnated with paraffin as a wound dressing was developed by Lumerie in France [14]. In the middle of the 19th century, the identification of bacteria and the use of antibiotics in the wound and wound healing took place. Semmelweis’s [15] observations on the bacteria and antibiotics were followed by Pasteur and Joseph Lister during this process. To prevent the contamination of wounds, Lister [15] began to wrap the wounds in many layers of gauze which is an important layer in a composite dressing. He placed a layer of relatively impermeable silk between the gauze layers and the wounds to prevent damage to the tissues by carbolic acid. The ‘germ-free’ wound environment theory was produced by Pasteur. Another noteworthy finding from his study was that the body fluid/exudate could not generate bacteria or infections. He suggested that the wound could be protected from environmentally infectious agents by covering and keeping it dry [16]. Following Pasteur’s discoveries, Koch [17] noted that there was a major transfer of bacteria during surgery or treatment from the surgeon’s hands, the instruments and bandages, as well as from the patients. A milestone in the history of wound care was carried out by Winter in 1962 [18]. He presented a model that changed the traditional concept of wound healing. He discovered that keeping the wound environment moist would enhance healing and come up with much better clinical results as it was compared with keeping the wound environment dry [19]. He presented a domestic pig model indicating that a moist environment was ideal for healing a wound or cutaneous ulcer. These results were confirmed in human subjects in 1963 by Hinman and Maibach, who demonstrated the beneficial effect of a moist environment on wounds (vs. air-exposed wounds) in human volunteers [20]. In recent times, the developments in cellular and molecular biology have greatly expanded and enhanced the current understanding of the biological processes involved in wound healing and tissue regeneration. A remarkable progress has been achieved and an ever-growing number of wound care products have been designed and developed to incorporate the latest understanding of cellular and molecular level phenomena involved in the dynamic and complex process of wound healing, including blood coagulation, inflammation, fibroplasias, collagen deposition and wound contraction [21]. The primary goals of innovations are to alleviate patient suffering, to shorten wound healing time periods and to resolve chronic wound healing clinical problems [22]. The investigation and innovation of novel wound dressing materials and methods are an important part of the rapidly growing biomaterials industry throughout the world [23–25]. Many dressings have been introduced during the past decade. A number of investigations have been conducted on wound-moist interactions and the results have indicated that if a wound is kept in moist conditions, it heals much faster than that in dry conditions.

2.4  Importance of performance-based specifications Test standards are used around the world to improve product quality, enhance safety, facilitate market access and trade and build consumer confidence. Surgical materials such as modern wound dressings are developed and produced in industrial scale by

Testing dressings and wound management materials

27

different processes and materials. It became necessary to develop formal standards to ensure that these were consistently produced to an agreed level of quality and properties. The 1911 British Pharmaceutical Codex (BPC) was the first two supplements and they were incorporated into the 1923 edition of same publication. In this version, over 80 products were described and the majority of them consisted of cotton fibre for medical applications and some of them were different complex cotton fabric products such as plasters and oiled silk. The standard properties of some other wound care products were also determined in first series of BPC. Barrier substances are widely used in industry to supplement other measures for the prevention of dermatitis from contact with skin irritants. The Barrier Substances Subcommittee investigated the possibility of producing suitable standard formula for a range of protective preparations of this type for inclusion in the BPC [26]. The BPC remained the principal source of standards for surgical wound dressings within the United Kingdom until 1980. The British Pharmacopoeia (BP) took place of BPC after 1980 and as a result of European legislation, wound dressings became classified as medical devices. Standards for wound prevention and management materials are presented in the different standard systems as medical devices. Overall wound dressing materials are tested and classified in terms of a framework for promoting best practice and products in wound prevention and management as they reflect current evidence. The standards are a valuable tool for guiding clinical practice and the development of policies, procedures and education programs. The aim of the standards is to facilitate quality care outcomes for individuals with wounds or at risk of wounding. However, the first standards published in the wound management area were only concentrated on testing physical and structural properties. These tests were sufficient to test traditional wound management materials and only their structural properties. We can clearly say that many test methods used in this regard are similar to the normal textile fabric test methods. In time, as new requirements emerged, these basic test methods became inadequate to test such potential contaminants. The limited specifications were analysed by such standards, although they undoubtedly had a value as quality control checks to ensure that products, which had previously been shown to meet a specific clinical need, were produced in a consistent way from a range of well-characterised materials. These materials did not facilitate comparisons between the performances of different types of dressings. In parallel with the development of new wound care products, appropriate testing methods were designed and standardized by researchers and experts. In the early 1990s, the Surgical Dressings Manufacturing Association (SDMA) formed a research group that aimed to increase the number of test standards to eliminate the limitations of current test methods. The Surgical Materials Testing Laboratory (SMTL) was one of the main research laboratories that was an introduction to recognising limitations of testing and developing much more specialised test methods for modern wound dressings. SMTL published a number of test methods on bandages and wound dressings that subsequently became incorporated into the BP and/or adopted as European Standards [3]. Currently developed test methods mainly aim to test and characterise such properties of wound dressings: exudate management/environmental control, control or prevention of infection, provide a bacterial barrier, odour control, adherence behaviour and freedom from toxicity.

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2.5  Test methods for wound dressings To obtain maximum performance from wound dressings under unlimited clinical conditions, the most suitable performance parameters to access and highlight the dressing properties need to be identified. Wound dressings are mostly classified according to their trade name; however, some researchers make such classifications by categorising wound dressings by their clinical objectives [27]. To date, there are a small number of standardised test methods available for objectively assessing the performance and properties of wound dressings on a global scale. The identification of objective parameters is very urgent because of developments in modern wound dressings. Every wound dressing company claims that they have developed the best wound dressings. The limitations of the objective test standards open a way to build in-house test methods which are developed by mostly wound dressing companies. However, this is limiting the options of professionals treating patients with wounds. For some of the test methods used for the assessing, the products are often simplistic and subjective. Currently available and mostly accepted test methods will be discussed in this chapter. The clinically relevant parameters of wound dressings are listed in Table 2.1. For each category of dressing, the parameters corresponding to its primary function are identified, and the possible tests to measure those parameters need to be evaluated in general. Wound dressing specifications and functional parameters of the main categories of dressings are generally registered under European Pharmacopoeia and BP. BS EN 13726 parts 1 to 8 (nonactive medical device) include test methods for primary wound dressing. BS EN 13726 has several subsections as listed below: Part 1: Aspects of absorbency. Part 2: Moisture vapour transmission rate of permeable film dressings. Part 3: Waterproofness. Part 4: Conformability. Part 5: Bacterial barrier properties. Part 6: Odour control. Part 7: Particle loss. Part 8: Aspects of adherence.

BS EN 13726 part 1: Aspects of absorbency are split into different characteristics of absorbency, as follows: • Free swell absorptive capacity. • Fluid handling capacity (FHC) (absorbency, moisture vapour transmission rate [MVTR] with liquid in contact). • Fluid affinity of amorphous hydrogel dressings. • Gelling characteristics.

At the SMTL (Cardiff, UK), Thomas et al. also conducted a number of researches to develop proper test methods for the wound dressings [28–31].

2.5.1  Fluid handling tests – absorbency of wound dressing Absorbent materials can be produced by two routes modification of existing structures/ polymers or using superabsorbent polymers. For wound dressing applications, mostly

Testing dressings and wound management materials

Table 2.1 

29

Parameters and the respective categories of dressings

Parameters

Category of dressings

Fluid handling capacity Free swell absorptive capacity

Waterproof foams and hydrocolloids Waterproof and nonwaterproof foams, alginate dressings, chemically modified cellulose fibres (carboxymethyl cellulose fibres [CMC] and other fibres alike CMC) and hydrocolloids Nonwaterproof foams Waterproof and nonwaterproof foams, alginate dressings, hydrocolloids and chemically modified cellulose fibres Waterproof and nonwaterproof foams, alginate dressings, hydrocolloids and chemically modified cellulose fibres Polyurethane foams Polyurethane foams, alginate dressings and chemically modified cellulose fibres Waterproof foams and hydrocolloids Polyurethane foams Hydrogels Hydrogels

Moisture vapour transmission rate Retention under pressure

Volumetric strain

Lateral and vertical spread Dispersion characteristics Waterproofness Resilience Viscosity Hydration capacity

superabsorbent fibres are implemented to produce for highly exudating wounds. The absorbency is very crucial to such wounds to protect them from external infections. Absorbent fibre–based wound dressings can absorb and retain extremely large amounts of liquid relative to their own mass. The effective management of the moisture content of a wound and of the surrounding skin is one of the most crucial requirements of any wound dressing types. In the case of exuding wounds, this implies the removal of excess wound fluid, but, in dry or lightly exuding wounds, the dressing may be required to conserve moisture [32] to maintain the exposed tissue in the optimum state of hydration to facilitate epithelialisation or promote autolytic debridement [3]. The ability to control the loss of moisture from a wound is commonly determined by the moisture vapour permeability of the dressings. Another main problem is that excessive exudate can cause maceration of the periwound skin, which in turn can lead to infection. Some of the wound dressings can cause tissue maceration, due to the pooling of the exudate at one small area of the dressing. The maceration usually is caused because of excess moisture, which can delay wound healing. An extensive attention has been given by the researchers to the development of highly absorbent products that are able to prevent fluid from spreading over the surrounding healthy tissue. Uzun et al. have developed a number of novel nonwoven fabrics produced with a combination of CMC, alginate, polylactic acid (PLA), hollow polyester (HPES), polypropylene (PP) and hollow viscose. Their research was aimed to enhance the wicking and tensile properties of nonwoven dressings for reducing the maceration and pooling of exudate and providing enough mechanical strength for painless dressing removal [33].

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Advanced Textiles for Wound Care

Some dressings such as hydrophilic polyurethane films are also very permeable to water vapour and thus permit the passage of a significant quantity of the aqueous component of exudate from the wound to the environment by evaporation. In practice, however, most permeable products are unable to cope with the volume of fluid that is produced by heavily exuding leg ulcers, burns or malignant wounds. In such situations, products that have the ability to absorb or retain significant quantities of liquid are required, although many also combine this absorptive function with a significant degree of moisture vapour permeability. These two values determine the ability of a dressing to cope with wound exudate and are described as its FHC [3]. There are a number of different tests characterising the fluid handling properties of wound dressings. They vary from simple ‘dunk and drip’ tests to more sophisticated techniques in which a suitable test fluid is applied to a sample of dressing under controlled conditions, some of which have been incorporated in the European Standard.

2.5.1.1  Free swell absorbency/absorptive capacity The absorbency of wound dressings is determined by using BS EN 13726-1:2002, 3.2 free swell absorptive capacities. This is also known as BP method. The uptake of fluid by fibrous dressings such as alginate and CMC fibre-based dressings can be measured by this basic method. For this test, 5 cm × 5 cm dressing specimens are prepared. Unless the reverse is mentioned, all absorbency tests are performed using test solution A. The test solution A (2.298 g sodium chloride and 0.368 g calcium chloride dihydrate are added to 1 L of distilled water) is prepared for the experimental studies. In other words, test solution A is a mixture of sodium chloride and calcium chloride solutions containing 142 mmol of sodium ions and 2.5 mmol of calcium ions as the chloride salts. The solution A is warmed to 37 ± 1°C and then 40 times the mass equivalent of the specimen is dispensed slowly and gently onto the specimens in the Petri dishes. The Petri dishes are then placed in an incubator for 30 min at 37 ± 1°C (body temperature). After 30 min of conditioning, the dishes are removed from the incubator and suspended by one corner by using tweezers to allow excessive solution to drip off for 30 s and reweighed for wet mass. The calculation of the results is given by:

Absorption capacity (g/g) =

(M2 − M1) M1



where M1 = mass of dry specimen and M2 = mass after water absorption.

Mass loss upon drying ( % ) = (B − A) × 100/B

where B = mass of specimens before testing and A = mass of specimens after testing. A number of factors can affect the fluid absorbency properties of the wound dressings. The absorption results of dressings tested are given in Table 2.2. It was observed that all dressings which were examined in a previous study by the author [34] absorbed at least four times their dry mass per unit area of solution A. Aquacel’s absorption of solution A was considerably higher than all other dressings. Only Kaltostat and

Testing dressings and wound management materials

Table 2.2 

31

Fluid handling properties of selected wound dressings

Dressing

Fluid handling (g/g)

Mass loss (%)

Aquacel

19.07

18

Kaltostat CarboFlex Melolin

18.44 11.11 13.56

14 11 0

CliniSorb Versiva XC Mepilex Border

3.54 4.16 7.71

6 5 20

Dressing Allevyn Gentle Border Mepilex Mepilex Lite Aquacel Surgical CombiDERM Biatain

Fluid handling (g/g)

Mass loss (%)

7.85

0

11.87 4.08 3.82

0 0 0

6.80 7.42

2 0

Melolin dressings’ values were close to that of Aquacel. Aquacel was the second thinnest product after CliniSorb, yet it was the most absorptive product and reached a peak uptake value of 19 g/g. However, mass loss of Aquacel (18%) was higher than the other products. Melolin, Allevyn Gentle Border, Mepilex, Mepilex lite, Aquacel Surgical and Biatain had no mass loss after complete drying. In general, the nonwoven dressings absorbed more fluid than foam and hydroactive dressings. The mass losses of the nonwoven dressings were also higher than the foam and hydroactive dressings due to their gelling fibres. It can be observed that the mass and thickness of the dressings did not exhibit any direct relationship with their absorption behaviours. The absorbency of dressings directly related to the fibre absorbency properties. Another important inference from these tests is that when the solution A was applied to the dressings, sandwiched foam dressing layers separated from each other, the separation fully occurred in Mepilex Border. This type of separation could affect wound healing process because of the interaction between the different layers. There are two scenarios that can explain the effect of this separation on the wound healing process. In the first scenario, the separation could have a negative impact on the wound healing process, as there is a lack of exudate transfer between the layers because of the discontinuity of the dressing resulting from their separation. The second scenario may have a positive influence on the healing process, as all the layers can continue to perform their main function individually and allow the wound to breath, thus enhancing the healing process. This aspect requires in-depth in vivo study to establish the true impact of the separation of dressing layers on the wound healing process. One of the core problems with this method is that the fibrous dressing is tested in the absence of any pressure, which means that the results obtained bear little relation to the volume of exudate that the dressing will take up under normal conditions of use. Some dressings, such as foam sheets, are like bath sponges, capable of taking up

32

Advanced Textiles for Wound Care Weight Perspex plate

Physiological saline

Dressing sample Wire rack

Figure 2.2  Set up for absorbency testing.

large volumes of fluid but unable to retain this under even light pressure. Considerable amount of research has been devoted to maximising the performance of foam dressings by casting the foam from hydrophilic polymers or the inclusion of superabsorbents within the porous structure of the foam itself [3]. These developments have resulted in the formation of a family of products that are among the most absorbent and widely used dressings available. Test systems are therefore required to compare these different dressings under varying levels of pressure in simulated clinical conditions. There are some trials done to solve this problem by measuring absorption and retention under compression. The technique used for measuring the absorbency and retention under load characteristics of dressings is a modified version of British Pharmacopoeia 1993, Volume II, Appendix XX, Methods of Test for Surgical Dressings, T. Waterretention capacity. The modification facilitates differentiation of products containing superabsorbent dressings which retain fluid under heavy loads, and the method set up is demonstrated in Fig. 2.2.

2.5.1.2  Fluid handling capacity (Payne cup method) The absorbency of the dressings can also be determined by using BS EN 13726-1:2002 Part 1: Aspects of absorbency. This method provides information on the amount of the test fluid both retained and transpired by products such as hydrogel and hydrocolloid structures. This is described in detail in the standard. The basic is that it consists of a cylinder with an internal cross-sectional area of 10 cm2 having flange at each end. In this test, the dressing specimens are prepared by making use of some hand device such as Wallace press cutter for the Payne cup type II, Fig. 2.3. The prepared Payne cub and specimens (assembled) are weighed and recorded before adding approximately 20 mL of the appropriate test fluid and then reweighed. The Payne cups are then placed in an incubator for 24 h at 37 ± 1°C. After 24 h of conditioning, the cups are removed from the incubator and allowed to equilibrate at room temperature for 30 min and reweighed. Any excess fluid is gently poured out and the cup is reweighed. The mass of moisture vapour lost, the mass of fluid absorbed by the dressing and the FHC through the dressing were then calculated using the following formulae:

MVL = W2 − W3 (g)



Fluid absorbed by dressing = W4 − W1 (g)



Fluid handling capacity = (W2 − W3) + (W4 − W1) (g)

Testing dressings and wound management materials

33

where W1 = initial mass of Payne cup + dressing, W2 = mass of Payne cup + dressing + fluid before incubation, W3 = mass of Payne cup + dressing + fluid after incubation and W4 = final mass of Payne cup + dressing. In some studies, similar apparatus known as Paddington Cup has been used to test FHC of dressings. The published results of fluid handling tests performed on 12 hydrocolloid dressings over 24, 48 and 96 h [3]. The published tables illustrate the differences between products at 24, 48 and 96 h each time point, but a comparison of the results achieved with individual products at the two time points clearly demonstrates how the products vary in terms of their rate of hydration. Some products reach full absorbency after 24 h, while others are still absorbing after 96 h. These differences undoubtedly have potentially essential clinical implications for the use of the products concerned.

2.5.2  Water vapour transmission rate Water vapour transmission rate (WVTR) has critical importance for cutaneous wound healing. The moisture permeability of wound dressings can be also determined according to the American Society for Testing and Materials (ASTM) standard. Simply, a sample is cut into a disc with a diameter of 35 mm and mounted on the mouth of a cylindrical cup with a diameter of 34 mm containing 10 mL of water. The sample is sealed with teflon tape across the edge and then placed into an incubator kept at 37°C and 50% relative humidity. The assembly is weighed every 2 h for 24 h, and the results are recorded and calculated to find out WVTR [35].

2.5.3  Moisture vapour transmission rate BS EN 13726-2 standard may also be used to determine the MVTR of permeable film dressings. Although the official method specifies that the apparatus shall be incubated with the solution in contact with the test sample, it is also possible to undertake the test with the cylinder inverted so that the dressing is not in direct contact with the liquid but exposed only to moisture vapour. This is important because the permeability of some types of polyurethane film will increase dramatically whilst in contact with liquid but revert back to previous values when this is removed – a characteristic that has obvious and important implications for its use as a wound dressing when in contact with intact periwound skin [31].

Top ring Gasket

Clamp

Knurled head screw

Permeability cup

Figure 2.3  Payne permeability cups.

34

Advanced Textiles for Wound Care

This method provides a single value for the amount of fluid which is lost through the back of the dressing during the test period. While this may be suitable for film dressings, the test has severe limitations for products such as hydrocolloids in which the permeability of the dressing changes with time as the adhesive mass on the wound contact surface gradually becomes hydrated. There is a modification to the standard test which has been described earlier [3]. A Paddington Cup is set up as described and placed on the pan of a top loading balance located in a controlled humidity cabinet which is connected to a data logger. In this way, the weight of the Paddington Cup can be continuously monitored over the test period, and from the recorded data, the change in MVTR may be determined. Depending on the product, this may be virtually zero for a number of hours and gradually increasing to reach a steady state some time during the following 24–48 h [3].

2.5.4  Development of the Wrap rig A new test system, called as the Wrap rig, has been developed by the SMTL which facilitates comparison of the fluid handling properties of most types of dressings irrespective of their structure and composition even whilst under compression. Design requirements of a new test system which could be used more closely approximated to the clinical situation and a series of key design criteria for the new model were derived previously [3]. • Fluid should be provided to the test sample by some form of pump or other suitable positive flow device. A passive uptake technique is not acceptable. • The fluid should not be presented to the test sample under excessive pressure. Previous test systems have, in effect, injected fluid into the dressing under pressure, although there is no evidence that this occurs in wounds. • There must be some suitable method for controlling the temperature of the system for the duration of the test, to reproduce the environmental conditions in the wound. • The test should provide some indication of the dynamic performance of the dressing, measuring its fluid handling capacity profile over time, and not just a single total absorbency figure. • The equipment should be capable of delivering test solution at a range of different flow rates so that the effect of different rates of exudate can be examined. • The apparatus should indicate when either vertical or lateral strike-through has occurred. • The apparatus should be suitable for testing a wide range of different types of dressings to permit direct comparison of the results. Previous methods were frequently dedicated to one type of technology, namely alginates [36]. • The equipment should be compatible with a range of different test solutions. • Where appropriate, the apparatus should permit the application of varying loads to the test samples in order to determine the effect of external pressure. • The apparatus should permit the measurement of moisture vapour transmission by the dressing as an integral part of the test. • The test should be easy to perform and provide results that can be reproduced within and between laboratories. • The equipment should not be excessively expensive to produce. • The test should ideally provide an indication of the wear time of a dressing in normal clinical use.

Testing dressings and wound management materials

35

In addition to the primary design criteria, a number of additional features were identified, which, although not essential, are considered desirable features in a wound model. • The apparatus should withstand sterilisation or disinfection. • The apparatus should permit analysis of wound fluid that has been in contact with the dressing to measure changes in ionic composition or changes in concentration of solutes such as proteins caused by selective absorption by the dressing. • The apparatus should permit microbiological examination of the local environment during the course of the test.

Prototype of the Wrap rig: The test equipment should allow the pressure beneath the dressing to be varied if this is considered desirable. A prototype test system was developed based on these criteria. The use of this rig has been described in a subsequent publication which also clearly illustrated the effects of compression on dressing performance. The Wrap rig model consists of a two-part stainless steel plate (the ‘wound bed’), mounted on a Perspex table (Fig. 2.4). An electronically controlled heating mat beneath the steel plate keeps the plate and test sample under examination within a narrow temperature band [3]. The central section of the plate is milled from solid stainless steel and includes a shallow circular recess bearing two ports on opposite ends of a 15-mm-long shallow channel. An inlet hole 3 mm in diameter and an outlet hole 7 mm in diameter permit the introduction and unimpaired exit of test solution. The diameter and depth of the circular recess are sufficient to accommodate two thin absorbent pads that ensure the effective transfer of liquid from the channel to the dressing above. Test fluid, introduced by means of a syringe pump, travels along the narrow channel and passes out through the second port, falling vertically down through a short, wide bore tube. This tube discharges into a receiver placed on the pan of an electronic balance. The liquid in the receiver is covered with a layer of oil to prevent loss by evaporation. The balance is connected to an electronic data capture device that records changes in the balance reading at predetermined intervals throughout the period of the test.

Figure 2.4  The Wrap rig.

36

Advanced Textiles for Wound Care

A dressing sample typically measuring 10 cm × 10 cm is secured on to the test plate which is set to a predetermined temperature. Test fluid applied to the test rig passes along the open channel, some or all of which will be taken up by the dressing. Any unabsorbed fluid continues to pass along the channel until it falls through the outflow pipe into the receiver, causing a change in the balance reading. The amount of fluid that accumulates in this way is inversely proportional to the absorbency of the dressing. A highly absorbent dressing may take up all the liquid that is applied to it, whereas less-absorbent products will absorb only for a short time or take a little while to reach maximum absorbency. During a test, therefore, the maximum weight of fluid that can be taken up by a dressing is determined by the flow rate of the syringe pump. As this test system is designed to simulate the normal use of a dressing, it is important to ensure that the test conditions employed are as clinically relevant as possible, particularly in relation to the production of exudate. Previous studies have found that a heavily exuding wound typically produces around 5 mL per 10 cm2 per 24 h, but in the presence of infection this value can easily double [3]. Although it is possible to run the test with these flow rates, for most tests the syringe pump is normally set to deliver a nominal 1 mL/h, as this value provides a reasonable compromise between clinical relevance and a need to keep testing times to a minimum for practical reasons. When testing cavity wound dressings, alginate fibre or hydrogel dressings, a simple modification is made to the apparatus. A piece of stainless steel tube is fixed inside the recess in the centre of the plate to form a chamber into which the dressing is placed. Although strike-through measurements are not appropriate with such dressings, it is possible to apply pressure to cavity dressings such as alginate packing by means of a weighted stainless steel piston, which forms a sliding fit in the tube. In all other respects, the test procedures remain the same. When testing hydrogel dressings, the open end of the chamber is sealed with a piece of aluminium foil held in place with impermeable plastic tape to prevent evaporation.

2.5.5  Conformability of wound dressing Dressings applied around joints or to other areas of tissue that are subject to movement or distortion must, to some degree, accommodate this movement without causing excess pressure or, in the case of adhesive products, shearing forces that can cause skin trauma. Whilst products such as bandages tend to accommodate changes in body geometry fairly readily, products such as hydrocolloids, semipermeable film dressings and self-adhesive island dressings can sometimes cause clinical problems [3]. The conformability test is carried out by using Zwick Universal Testing Machine, in accordance with BS EN 13726-4:2003 - Non-active medical devices, Part 4: Conformability. The test is designed to determine the extensibility (force required to stretch a wound dressing to known extensions) and permanent set conformability (ability to adapt to the shape and movement of the body) of a primary wound dressing by measuring its extensibility and permanent set (increase in length of the specimen after stretching and relaxing as a percentage of the original length). The test designed to assess the extensibility and permanent set conformability of primary wound dressings by measuring its extensibility and permanent set is described in BS EN 13726-4. In this test, strips of

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37

dressing 25 mm wide with an effective test length of 100 mm are extended by 20% in a constant rate of traverse machine at 300 mm/min. The maximum load is recorded and the sample is held in this position for 1 min. It is then allowed to relax for 300 s before being remeasured. Further samples taken from a direction perpendicular to the first are also tested in a similar way to account for ‘directionality’ in structure of the material. The standard requires that the test report records the maximum load, the extensibility and the permanent set, which are calculated using the formulae provided. The extensibility and permanent set can be calculated by using the following equations:

Extensibility (N/cm) = ML/2.5



Permanent set ( % ) = ((L2 − L1 ) /L1 ) × 100

where ML = recorded maximum load, L1 = length before testing (initial) and L2 = length after testing (final). The conformability characteristics of the dressings were determined by using extensibility and permanent set tests (Table 2.3). The tests were performed in both length and width directions of the dressings. These results clearly demonstrate that Opsite Post-Op showed better conformability properties for both the length and width directions in comparison with all other dressings. DuoDERM had the lowest permanent set values which could be directly related to the usage time and comfort. This is mainly because of its lower thickness and higher bulk density. Another important finding is that the hydroactive dressings had better conformability properties in comparison with the other dressings tested. An alternative test method, which eliminates the problems of directionality by extending a sample in all directions at once, has been developed using a modification Table 2.3 

Conformability of tested dressings Extensibility (N/cm)

Versiva XC Mepilex Border Allevyn Gentle Border CombiDERM DuoDERM Granuflex Biatain Aquacel Surgical Opsite Post-Op Sorbsan Plus SA

Permanent set (%)

Dressing type

Length

Width

Length

Width

Foam Foam Foam

3.56 2.18 2.41

3.99 3.03 2.90

3.74 3.89 2.81

1.84 3.48 1.51

Hydrocolloid Hydrocolloid Hydrocolloid Hydroactive Hydroactive Hydroactive Hydroactive

N/A 3.67 2.82 1.5 1.42 0.92 2.66

N/A 3.12 2.89 1.48 3.72 1.19 2.69

N/A 0.08 0.19 0.94 7.56 3.63 1.08

N/A 0.11 0.44 0.94 2.06 1.99 1.11

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Advanced Textiles for Wound Care

of the apparatus for the measurement of waterproofness described in the BP 1993. This consists of a chamber, open at one end, bearing a flange with an internal diameter of 50 mm. A retaining ring with the same internal diameter as the hole in the flange is mounted over the open end of the cylinder which can be lowered down onto the flange by means of a screw thread. A sample of the dressing under examination is placed on the flange and held firmly in place by means of the retaining ring. During the course of this test, air is slowly forced into the chamber by means of a large syringe. The resultant rise in the pressure within the chamber causes the dressing to expand and form a hemisphere which gradually increases in size until the upper surface of the dressing comes into contact with a marker placed 20 mm above the dressing surface at the start of the test. This pressure reading is then recorded by means of a transducer.

2.5.6  Dehydration rate of dressing The dehydration behaviour is determined by measuring the difference between the mass of wet and dry specimens. The mass of dry specimens is obtained before submerging them in an excess volume of solution A at 37 ± 1°C for 30 min. The specimens are taken out from the fluid and suspended by a corner for 30 s for free drainage. After draining, they are reweighed and put into Petri dishes and kept in an incubator for 24 h at 37 ± 1°C [37]. The calculation of results is given by:

Dehydration rate (g/min) = W − D/T

where W = wet mass of specimen, D = dry mass of specimen and T = test period in minutes.

2.5.7  Fluid affinity test Some hydrogel dressings, in any form, have the ability to absorb or donate liquid according to the condition of the underlying tissue. This means that they can absorb fluid from a heavily exuding wound or donate moisture to dry or devitalised tissue to promote autolytic debridement. Therefore, test systems required can be used to assess both these properties. The tested material is placed in contact with other gels made from varying concentrations of agar or gelatine representing a spectrum of tissue types, and the transfer of liquid to or from the test sample to the standard gels is measured by recording any change in weight of the sample. A moderately basic version of this technique was described earlier [3]; however, the above-method technique is progressively refined and used as the basis of a standard method described in BS EN 13726-1.

2.5.8  Rate of absorption To evaluate the rate of absorption, a drop of solution A is dropped onto the specimen using an eye dropper on the wound contact layer surface of each dressing and

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is allowed to be fully absorbed and the time taken for full absorption is recorded in seconds. Twenty drops are dropped onto each dressing and the mean time is calculated [38]. The rate of absorption of the dressings is also determined in accordance with the sinking test method [39]. It is observed that the sinking test method gives more accurate and consistent results as compared with the drop method for the fibrous dressings.

2.5.9   Vertical wicking The vertical wicking is one of the chief properties for fibrous dressings. This test can be applied only for the fibrous dressings owing to the nature of test procedure. The test specimens are prepared to 15 mm width and 100 mm length. Eosin B was added to the solution A. The specimen strips were slowly immersed into the solution vertically up to 10 mm length and left for 60 s. The vertical wicking height of dressings was determined in mm [40,41].

2.5.10  Dispersion characteristic of dressing The dispersion characteristics of the dressings are determined in accordance with BS EN 13726-2:2001. Dressing specimens of dimension 5 cm × 5 cm can be prepared and placed into a 250 mL conical flask into which 50 ± 1 mL solution A is added. The flask is slowly and gently swirled for 60 s. The specimens are removed and the dispersion is determined visually. The results are expressed as to whether there is dispersion or not in agreement with the standard [40].

2.5.11  Evaluation of swelling characteristics The swelling characteristics of fibrous dressings are determined by using Labophot-2 optical microscope at a magnification of 40x. The Proplus image software is used to obtain images of the fibres and the diameters were determined. The solution A and distilled water are introduced into the fibres without removing fibres from the microscope and the fibres were allowed to swell for 1 min and five replicate tests are carried out for each fibre types. The images of the dry and swollen fibres are captured and the diameters of both the dry and swollen fibres are calculated and compared. Wettability is also one of the essential parameters for wound dressing materials, and the contact angle measurement is used to determine this parameter by Attension Theta Lite optical tensiometer [42]. The fibre swelling results clearly demonstrate that, as expected, the Hydrofibre containing dressings Aquacel, Aquacel Surgical and Versiva XC showed very similar swelling behaviour and their swelling ratios were found to be higher than the other fibrous dressings (Table 2.4). They swelled to around three times their original diameters when they were treated with solution A. CarboFlex absorbent fibrous contact layer swelled around two times and the second layer consisting of activated charcoal cloth (ACC) fibres did not swell at all. Kaltostat swelled around 0.54 times its original diameter which was too low as compared with its absorption properties. The swelling of Melolin was determined to be around 0.15 times which was also too low as compared

40

Table 2.4 

Advanced Textiles for Wound Care

Swelling ratios of fibres used in various dressings

Dressing

Dry diameter (μm)

Swollen diameter (μm)

Swelling ratio

Aquacel Kaltostat CarboFlex Melolin CliniSorb Versiva XC Aquacel Surgical CombiDERM

10.9 12.4 12.7 15.2 8.5 10.5 10.6 14.2

42.3 19.1 35.3 17.5 9.3 40.1 39.5 18.6

2.88 0.54 1.78 0.15 0.09 2.82 2.73 0.31

with its absorption values. CombiDERM swelled 0.31 times and CliniSorb contact layer swelled 0.09 times (Table 2.5) [34].

2.5.12  Air and water vapour permeability The air permeability (cm3/s) of the wound dressings can be analysed by using the Shirley air permeability tester. The test is only applied to fibrous dressings (ASTM D737-96). The specimens are cut as a circle with 6 cm diameter and with a test area of 508 mm2. The air is admitted into the compartment on one side of the dressing and sucked using a vacuum on the other side of the compartment. The water vapour permeability (WVP) depends on the water vapour resistance which indicates the amount of resistance against the transport of water vapour through the fabric structure. The amount of fluid present in a structure (which has critical importance in the degree of comfort and absorbency for wound dressing) must be minimum. The WVP and resistance to evaporative heat loss results are given in Table 2.5. According to the test results, there is a difference between HPES and PP-blended fabrics. CMC and alginate fibre fabrics had lower WVP when they were blended with HPES and PP fibres. The WVP of HPES and PP-blended PLA fabric increased significantly. The WVP of the fabrics tested were found to be less than 35%. The resistance to evaporative heat loss should be as low as possible. As seen in Table 2.5 in most of the cases, the single-fibre fabrics had lower value than HPES and PP-blended or -reinforced composite fabrics [34].

2.5.13  Waterproofness testing of occlusive dressings The waterproofness test method for surgical dressings is described in the BP. The waterproofness test apparatus consists of the application of a hydrostatic head of 500 mm of water to a circular area about 20 cm2 of the nonadhesive side of the dressing. A filter paper (55 mm in diameter) is applied to the adhesive side. The dressing is deemed to comply with the waterproofness test if no water passes through it, in at least five of a total of six specimens tested.

Testing dressings and wound management materials

Table 2.5 

41

Thermal conductivity and permatest results

Fabrics single fibre 100% Carboxymethyl cellulose (CMC) 100% Alginate (Alg.) 100% Polylactic acid (PLA)

Water vapour permeability (%)

Resistance to evaporative heat loss (m2PaW−1)

30.2

11.8

29.1 28.6

11.6 11.5

29.5

11.9

26.5 32.3 28.2

14.1 11.0 12.7

26.7 28.0 36.7 27.1 27.8 33.0 30.7

13.7 12.9 8.6 13.4 13.1 10.2 11.5

Blended 75/25% CMC/hollow polyester (HPES) 75/25% Alg./HPES 75/25% PLA/HPES 75/25% CMC/hollow viscose

Composites CMC + HPES Alg. + HPES PLA + HPES CMC + polypropylene (PP) Alg. + PP PLA + PP Alg. + CMC + PLA

2.5.14  Measurement of the peel from stainless steel testing at 180° angle Low or nonadherent contact layer dressings are applied directly to the wound bed and do not adhere to the wound surface or cause significant trauma during dressing removal. They require a secondary dressing, usually an absorbent product. These dressings are largely silicone-based and are useful for fingertip injuries following toe nail avulsion and are also of value for patients where dressings may adhere to the wound bed such as when using a topical negative pressure therapy. Studies have shown the advantage of the use of silicone-based dressings in reducing wound pain at dressing change [43]. According to a survey [44], 81% of clinical practitioners mentioned that the highest level of pain was experienced during dressing removal. The results of an international survey also [45] identified that pain and trauma were ranked as the most important factors in considering changing dressings. A total of 3918 clinicians who responded to a written questionnaire considered that pain was most commonly associated with dressings drying out or adhering to the wound bed, factors that were also considered to be responsible for wound trauma. Some products such as alginates, hydrogels or silicone products show little propensity to adhere to granulating wounds, whereas other products such as simple gauze or nonwoven fabrics perform particularly badly in this context.

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Advanced Textiles for Wound Care

It is generally believed that there are two mechanisms of adherence. The first is the inherent ‘stickiness’ of serum which acts like a simple adhesive that forms a bond between two opposing surfaces. The second mechanism is a little more complex, involving the penetration into the dressing of serous fluid containing cellular debris which not only dries to form a solid ‘scab’ on the wound surface but also incorporates some of the structural elements of the dressing which acts like reinforcing bars in concrete. As a result, when the dressing is removed, the scab, together with underlying new epithelium, is forcibly removed leading to rewounding and delayed healing. Many dressings have therefore been developed with a wound contact surface that is designed specifically to reduce adherence, examples of which have been described previously [3].

2.5.14.1  Measurement of adherence potential A specimen size of 25 mm × 100 mm was prepared and a stainless steel plate was cleaned using a tissue dampened with acetone. The specimen is carefully placed on the stainless steel plate and a 2 kg roller is rolled forwards and backwards. The test method is used to determine the peel strength of an adhesive dressing from a stainless steel plate by using Zwick Universal Tensile Testing Machine. The results were reported to refer the average force (Lm) in units of N/cm. Texture analyser can be also employed to determine bioadhesion values and bioadhesive performance of nanofibres-based wound dressings. Mostly rabbit skin is used as the model tissue [34]. Apart from the above-mentioned test method, predicting the way in which dressings will perform clinically in terms of adherence has proved unexpectedly difficult, as no standard laboratory test system has been described for this purpose. In 1982, a method was devised by SMTL in which a cold-cure silicone rubber material was applied onto the surface of a test sample using a plastic former to control the area of application [3]. Once the rubber had set, the dressing was removed from the former containing the silicone block by means of a tensiometer to record the applied force using a 180° peel. Although no absolute values could be applied as limits, the test system was used to rank products in the order of their adherence potential. In a later modification to this test, an aqueous solution of gelatine was used to replace the silicone as this more closely represents the in vivo situation. This procedure is still used as a nonofficial ‘in-house’ test.

2.5.15  Odour adsorption test Wound odour can be a significant problem for patients, particularly those with nonhealing or malignant wounds. The malodour produced by the wounds may lower health-related quality of life and produce psychological discomfort and social isolation. A recent online survey found low overall satisfaction of odour management and the need to develop more effective strategies and guidelines in this field. The majority of the conducted studies used subjective analysis to determine presence of wound odour. In most cases, only the presence and intensity of odour were recorded; few studies evaluated the efficacy of its control. Most of the scales distinguished odour intensity

Testing dressings and wound management materials

43

as low, medium or strong. An ‘Overall Evaluation Scale’ was usually used to measure the effectiveness of a dressing to control odour rather than odour intensity [46]. Charcoal, silver, honey, sugar, metronidazole and some natural compound–based products can be effective in reducing wound odour. A range of composite wound dressings containing activated charcoal exist and their affectivity needs to be measured by a quantitative comparable method. The developed novel test equipment to determine and evaluate the odour adsorption properties of wound dressings is illustrated in Fig. 2.5. The test apparatus comprises of a horizontal stainless steel plate rig with a central circular recess of 50 mm diameter and 2 mm deep. There is a small hole in which the volatile/malodorous test solution is fed via a mechanical syringe pump. This is to simulate an exudating wound. The test solution consists of sodium/calcium chloride solution containing 142 mmol of sodium ions and 2.5 mmol of calcium ions as the chloride salts, 2% diethylamine (odorous volatile) and 10% bovine serum, simulating wound exudate. A 10 cm × 10 cm test specimen is then placed centrally over the recess and attached securely down each edge with a waterproof medical adhesive tape. The mechanical syringe pump is activated and the test solution is slowly introduced to the lower wound contact face of the test specimen. The stainless steel plate rig is fitted with an airtight perspex chamber that is placed directly over the test specimen, and the air within the chamber is consistently monitored via a Miran 1B2 ambient analyser (IR spectroscopy) every 5 s for the detection of diethylamine volatile. The collected data are measured in time or duration (minutes and/or seconds) taken to the limit of 15 ppm of the diethylamine detected in the perspex chamber directly above the test specimen. This recorded time or duration can be used to calculate the volume of test solution in mL taken up to the point of detection. From a previous study by Steve Thomas et al. [47], it was established that an exudating leg ulcer could exudate up to a rate of 0.5 mL/cm2/24 h; the test solution was set at a rate of 18 mL/cm2/24 h; therefore, it was deduced that approximately 30 min in the test rig is equivalent to 24 h in use.

Figure 2.5  Odour adsorption test equipment. Courtesy of SMTL.

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Advanced Textiles for Wound Care

Rajendran et al. modified and investigated the novel odour test method to be an efficient method for determining quantitative comparable data of a variety of wound dressings. In their study they found that the test method is flexible to test and make quantitative comparisons of numerous wound dressings. It is again shown in the literature that ACC has excellent odour adsorption properties. Their results showed that aloe vera also has comparable odour adsorption property to those of ACC-containing dressings. Unlike other dressings, it also has wound healing and antimicrobial properties and beneficial ingredients such as vitamins, minerals, enzymes, sugars, phenolic compounds, sterols and amino acids to enhance wound healing. The invention has been protected by a British patent (GB 2462678, 2010) and the know-how is licenced to Lantor (UK) Ltd, Bolton, for commercial production [48].

2.6  Microbiological tests Wounds are an ideal environment for bacterial colonisation and biofilm formation. The wound bed provides both a surface on which to grow and an ample supply of nutrients. Antimicrobial dressings that act as a pathogen barrier for the wound typically are in the form of films, foams, hydrogels or hydrocolloids. Wounds of all types represent a potential source of cross-infection, particularly if they are infected with antibiotic-resistant organisms such as Methicillin-resistant Staphylococcus aureus (MRSA). The ability of a bacterium to pass through a dressing is determined by the presence of a liquid pathway. For dry wounds, a thick layer of absorbent cotton or gauze may be sufficient to prevent contamination, but, as soon as this becomes wet, the barrier properties are lost and the dressing becomes useless in this regard. It is hence important to ensure that wounds are isolated from the environment to prevent the ingress or egress of pathogenic microorganisms. Many dressings, therefore, consist of (or include in their construction) a layer which prevents the transmission of microorganisms into or out of a wound. Most commonly, this layer consists of a piece of cast polyurethane film, but sometimes closed cell foams are used for this purpose. In the case of wound dressings that contain antimicrobial agents, manufactures need to support their claims that the antimicrobial agent provides an additional clinical benefit. Some organisation, such as the FDA, recommends performance testing (bench testing, animal studies and clinical studies) to demonstrate the antimicrobial effectiveness of the antimicrobial agent on treated medical devices such as antimicrobial wound dressings [3]. The bench or in vitro testing should simulate the clinical use of the device mimicking exposure conductions such as temperature, preconditioning the device with body fluid, dynamic environment, body contact time and microorganism contact time. The control dressing should be identical to the antimicrobial dressing minus the antimicrobial agent. The effects of antimicrobial concentration and potential elution of the antimicrobial with respect to the dressing’s antimicrobial effectiveness and the effect of the antimicrobial on the dressing surface, integrity, stability and durability should be assessed. All test methods (inoculation and recovery techniques, use of neutralizers, recovery media, incubation temperature, incubation time) must be described in detail. For textile wound dressings, the AATCC 100 – Antimicrobial Fabric Test can

Testing dressings and wound management materials

45

be used. Wound dressings that contain gels typically use the ASTM E2315 – Liquid Suspension Time-Kill Test and the Minimum Inhibitory Concentration Test (MIC) to meet these requirements. Some of the modern wound dressings contain agents that have intrinsic antimicrobial activity such as antibiotics, antiseptics, silver ions or materials which possess a significant osmotic pressure capable of inhibiting bacterial growth. In clinical practice, these materials are released from the dressing to exert an antibacterial effect. Such dressings are often recommended or promoted for the treatment or prevention of soft tissue infections. Other products contain antimicrobials that are immobilised or fixed within the structure or the wound contact surface of the dressing, i.e., not released into the local wound environment. These materials are claimed simply to prevent the proliferation of microorganisms within the dressing itself. They have no direct effect on the wound and as such are more suited for preventing cross-infection than for treating existing wound infections. In a work by the author [34], pH and antimicrobial properties of 4% ZnO/vitamin C–treated fabrics were investigated and the mean values from day 1 to day 7 for each fabric in solution A are given in Table 2.6. The Staphylococcus aureus bacteria at 10−1 dilution and the Escherichia coli bacteria at 10−3 dilution were studied to determine antibacterial activity of the 4% ZnO/vitamin C–treated dressings. The zone of inhibition values is tabulated in Table 2.6 and is depicted in Fig. 2.6. The untreated dressings did not show any zone of inhibition. It is clear from Fig. 2.6 that all 4% ZnO/vitamin C–treated fabrics demonstrate promising zone of inhibition. It can thus be concluded that the blend of collagen boosting agents, ZnO and vitamin C, can be effectively employed for achieving the main objectives of this study, which are the acidic pH and the antibacterial activity of the developed wound dressings. In all cases, the pH values of solution A decreased with the immersion of fabrics in it Table 2.6 

Mean pH and zone of inhibition values of developed dressings Mean pH (over 7 days) Solution A 100% Carboxymethyl cellulose (CMC) untreated 100% CMC 4% ZnO/VC 75/25% CMC/polylactic acid (PLA) untreated 75/25% CMC/PLA 4% ZnO/VC 50/50% CMC/PLA untreated 50/50% CMC/PLA 4% ZnO/VC

Staphylococcus aureus 10−1 (mm)

Escherichia coli 10−3 (mm)

5.72 ± 0.15 5.17.±0.11

N/A 0.0

N/A 0.0

3.49 ± 0.21 5.15 ± 0.20

9.1 0.0

8.8 0.0

3.92 ± 0.16

10.3

9.2

5.10 ± 0.25

0.0

0.0

3.85 ± 0.15

10.1

5.1

46

Advanced Textiles for Wound Care

Single-fibre CMC

Single-fibre CMC

(d)

(c)

(b)

(a)

50/50% CMC/PLA

75/25% CMC/PLA

75/25% CMC/PLA

(e)

50/50% CMC/PLA

(f)

Figure 2.6  Zone of inhibition of 4% ZnO/vitamin C–treated fabrics against Staphylococcus aureus at 10−1 (a–c) and Escherichia coli at 10−3 (d–f).

(the tested method will be discussed in the next section). The most important result to emerge from the data is that 4% ZnO/vitamin C–treated fabrics had similar pH value which was obtained with 3% vitamin C–treated fabrics. It can be concluded from these results that 1% vitamin C into the solution can also provide the desired acidic pH. A recent publication has discussed antimicrobial properties of some developed nanosilver reinforced CS fibres at various ratios (30/70%, 70/30%, 50/50% with and without nanosilver) of CS (60–120.000 g/mol). The authors have been chosen to evaluate antimicrobial activity of the samples with E. coli (ATCC 25922) and Candida albicans (ATCC 10231). In this research, the electrospun nanofibrous scaffolds were cut into small pieces (1 cm × 1 cm) and sterilized. Phosphate-buffered saline (PBS) pH 7.2 was also prepared to create a proper bacterial and fungal suspension (approximately 10 ± 5–10 ± 6 CFU/mL). It was decided to replicate each treatment three times, so 12 pieces of each sample were placed into sterile Petri dishes and 25 mL of the bacterial suspension injected onto each sample in each Petri dish. The first injection was at time zero (T0). The Petri dishes were left in the incubation chamber, at 22 ± 3°C temperature and 50 ± 5% relative humidity, at a half-covered position for 4 h (T4). After these incubation intervals, pieces of samples were put into the individual tubes that contained 5 mL of sterile PBS and shaken on a vortex mixer. After 15 s shaking, 0.25 mL was taken from the tube using a 0.5–5 mL pipette and sterile tip, added to a sterile Petri dish and the solution spread over the surface of the agar plate with a technique known as lawning. Plate count agar (PCA) plate was used for bacteria and dichloran Rose Bengal chloramphenicol (DRBC)

Testing dressings and wound management materials

47

plate for fungi. PCA plates at 37°C and DRBC plates at 25°C were then incubated for 24 h. At the end, the bacterial or fungal growth was observed and the colonies were counted in each plate [49]. An alternative test, devised within the SMTL, graphically demonstrates the ability of a dressing to kill or inhibit the growth of microorganisms that come into contact with it and thereby prevent the transfer of contaminated material into or out of a wound. In this test, an agar plate has two channels cut out of it as to effectively form two separate agar areas in the Petri dish. One of the agar blocks is sterile; the other is inoculated with the test organism. A strip of dressing under examination is placed on top of the two blocks forming a bridge. Sterile water is placed in the channel on the outer side of the contaminated agar to increase the water content of the gel and provide a ‘driving force’ to encourage the movement of moisture from the contaminated agar along or through the dressing to the sterile agar on the other side of the second channel. The Petri dish is incubated as normal with the dressings in place after which it is examined to detect the presence of growth around the margin of the test sample on the sterile agar surface [3].

2.6.1  Tests for antimicrobial agents released from dressings For products that are designed to kill bacteria within the wound, alternative test systems are required based on the following considerations. The ability of an antimicrobial dressing to exert a beneficial clinical effect is dependent on three factors: • The nature and spectrum of activity of the agent concerned • The concentration of the material present in the dressing • The release characteristics

In its simplest form, the test can consist of the application of a piece of dressing applied to an agar plate that has previously been seeded with the test organism. Antibacterial activity is indicated by the presence of a halo or zone of inhibition around the sample, the size of which is determined at least in part by the concentration and solubility of the active ingredient. Such tests are easy to perform and can involve the use of different test organisms [3]. A possible criticism of this type of simple test is that the moisture content of the agar may be insufficient to facilitate extraction of the active agent from the dressing or that the affinity of the dressing for moisture may be such that it effectively retains the moisture within its structure and thus limits the amount that is released onto the agar to exert an inhibitory effect. It is also possible that the active agent may require the presence of sodium or calcium ions normally present in exudate or serous fluid to release or activate the biocidal agent within the dressing. Both of these problems may be overcome by a modification to the method in which a well is cut in the agar plate into which the dressing sample is inserted. The residual volume within the well is then filled with solution A (used in absorbency testing) or, for research purposes, calf or horse serum. Alternatively, it is possible to make an extract of the dressing sample using an appropriate solution and place this into the well. A further test involves the incubation of a piece of dressing with a suitable volume of a bacterial suspension

48

Advanced Textiles for Wound Care

containing a known number of microorganisms. Following incubation, the dressing sample is extracted with an appropriate recovery medium and a total viable count performed on the extractant to determine the decrease in the number of viable organisms present. This test has the advantages that it can be conducted over various time intervals and that it provides a quantitative result. The tests have been described in detail previously in laboratory-based comparisons of silver-containing dressings. Unlike previous test systems, which gained fairly rapid acceptance by the industry enabling them to become adopted as official standards, it is more difficult to reach a consensus on tests for antimicrobial activity. Whilst there is a reasonable prospect of achieving agreement on the experimental techniques which can be used, there remains a problem in the interpretation of the results, the levels of activity that are required clinically and, therefore, the limits which should be attached to each method [3].

2.7  Modified test methods for wound dressings 2.7.1  pH measurement test method Currently, the evaluation of wounds is a qualitative rather than a quantitative issue. The main issue with this is that the local treatment cannot be well quantified on how effective the healing process is. Wound size, colour, wetness and smell can be reported in most of the cases because these parameters are easily attainable. However, the detection of wound colonisation by bacteria and microbes is not always easy to manage. The pH assessment of wound area is also one of the difficult methods during the wound care procedures. Especially, the healing phases of chronic wounds need to be monitored to foster the proper treatment. The pH of the wound area has direct effect on the healing process and it has to be controlled by using different therapy types. Some of the wound measurements, such as wound colonisation and pH, are much more time-consuming and painful for the patients. There are some studies done to measure such properties. Schaude et al. have developed an indicator cotton swabs that enable faster, less expensive and simpler information gathering of wound status [50]. The direct measurement of a wound pH is limited by the availability of suitable probes; even needle-style pH probes create tissue disruption and result in localised cell death. Because of these limitations, the available data are restricted to the measurement of wound surface pH or wound exudate pH. The wound pH measurement should be simple, accessible, sensitive, precise and reproducible and should cause minimal or no discomfort to the patient [51]. The British Standard test method BS 13726:2002 appears to have attempted to test and analyse only the physical characteristics of the wound dressings but not their pH. A novel pH measurement method was developed by Uzun et al. [52] and different types of commercial wound dressings are evaluated [34]. Method: The test specimens of size 5 cm × 5 cm (0.5 g) are taken from the centre of the dressings and their effect on the pH of two different solutions was determined. The fluids used in this study are distilled water and the test solution A (2.298 g sodium chloride [NaCI] and 0.368 g calcium chloride [CaCI2] dihydrate added to 1 L of distilled water). To simulate the different mechanisms of exudate production, both from

Testing dressings and wound management materials

49

highly exuding wounds and slowly exuding wounds, two different methods for dosing the fluid with the dressings are used: 1. Highly exuding wounds – the dressings were fully immersed into the Petri dishes containing 35 mL solution. 2. Slowly exuding wounds – 5 mL of each fluid was added dropwise onto the dressing’s absorbent pad, on a daily basis. In total 35 mL of fluid (5 mL × 7 days) was dropped onto each dressing.

The pH measurements were taken over a test period of 7 days, which represents the maximum recommended usage period for most of the dressings investigated in this work. The measurements were taken on a daily basis for the immersed dressings and on the day 7 for the dropwise method. They were obtained from the fluid in which the dressing was immersed, not from the dressings themselves (Fig. 2.7), using the Hanna HI 8424 pH metre (Fisher, UK) at room temperature. The metre is calibrated for each group of measurements, using buffer solutions with pH 4.01 and pH 7.01, and has an accuracy of ±0.01 at 20°C. The overall mean pH and range of values from day 1 to day 7 for each dressing in solution A are given in Table 2.7. The pH value of solution A, without any dressing (control), ranged from 5.38 to 6.25 over the 7-day period, with a mean value of 5.81. As given in the table, pH of the solution A (control) gradually increased over time, without immersion of any dressing. With the dressings, an increase or decrease in the pH value was observed, depending on the dressing type. Kaltostat and Versiva XC gave the highest mean pH value of 6.52 after 7 days, while DuoDERM Signal and Granuflex gave the lowest mean pH values, which were 4.67 and 4.77, respectively. All silver dressings (Aquacel Ag, Algisite Ag and Mepilex Border Ag) lowered the pH value of solution A. The tested nonwoven specimens generally decreased the pH value, compared with the control, with only the sodium and calcium dressing (Kaltostat) having an appreciably higher pH value than the control.

Test fluid

The pH of the fluid was measured

The dressing was immersed in the fluid

Figure 2.7  pH measurement area.

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Table 2.7 

Mean, standard deviation (SD), range and t-values for pH value of solution A after immersion of dressings Dressings Solution A (control) Aquacel Aquacel Ag Algisite Ag Kaltostat CarboFlex CliniSorb Melolin Versiva XC Mepilex Border Allevyn Gentle Border Mepilex Border Ag DuoDERM Signal Granuflex Biatain Aquacel Surgical Mepore Mepore Ultra Primapore Opsite Post-Op Sorbsan Plus SA

Mean (over 7 days)

SD

Range

t-value

5.8114

0.339

5.38–6.25

N/A

5.6371 5.6700 5.8929 6.5171 5.5243 6.3800 6.3357 6.5171 6.1429 5.7229

0.642 0.619 0.513 0.310 0.586 0.101 0.321 0.559 0.142 0.340

4.95–6.51 5.04–6.47 5.20–6.39 6.03–6.91 4.86–6.44 6.23–6.49 5.88–6.62 5.45–7.02 5.95–6.29 5.23–6.30

0.708 0.605 0.264 3.950 1.200 4.100 2.860 2.770 2.240 0.598

5.8300

0.192

5.53–6.02

0.970

4.6714

0.224

4.38–4.96

7.550

4.7743 5.8771 4.9386

0.170 0.355 0.219

4.57–5.07 5.17–6.31 4.67–5.30

7.380 0.247 5.850

5.3914 5.5343 5.5214 5.5957 5.5700

0.486 0.242 0.257 0.259 0.077

4.81–6.09 5.19–5.85 5.02–5.81 5.15–5.86 5.47–5.66

1.960 1.890 1.930 1.460 1.990

The foam-based dressings’ pH values (Versiva XC and Mepilex Border) increased gradually over time (5.45–7.02 and 5.95–6.29, respectively). Hydrocolloid dressings, DuoDERM Signal and Granuflex, reduced the pH value of the solution A compared with the control, with both hydrocolloid dressings decreasing the pH of the solution A by nearly 20%; this reduction did not change significantly over the 7 days (4.38– 4.96 and 4.57–5.07, respectively). The mean values of the hydroactive dressings were found to be lower than the control mean pH value [34].

2.7.2  Lateral area wicking The lateral area wicking property of the wound dressings is one of the most central parameters for preventing the wound area from tissue maceration and pooling; still, there is no standard test method for the testing of the lateral wicking. This developed

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250 g of weight

Plastic vial

Test specimen

Figure 2.8  The fluid lateral wicking test.

in-house test method would be beneficial to the wound dressings, particularly for the high absorbent fibrous wound dressings. Method: The fluid lateral area wicking test draws attention to the rate of transportation of the absorbed horse serum within the structure. The test is performed by using a plastic vial containing 20 mL of horse serum which is placed at the centre of the dressings and held in place for 60 s under 250 g weight (Fig. 2.8). After 60 s, the nonabsorbed horse serum is removed, and the images of the wicked area of the dressings are analysed by using the Image Tool software (such as ImgTool Classic v0.91.7).

2.8  Biological tests Because dressings come into intimate contact with damaged tissue, blood or body fluids, it is important to ensure that they are free from any agents that can adversely affect wound healing or otherwise cause an adverse reaction within the wound. The standard approach to testing medical devices is described in BS EN ISO 10993. This standard is divided into 18 parts, each of which describes a particular type of test or procedure that may be relevant to specific types of medical devices. For topical wound dressings, the most relevant parts are as follows.

2.8.1  Part 5: tests for in vitro cytotoxicity This part of the standard describes test methods to assess the in vitro cytotoxicity of materials using techniques in which cultured cells (typically L-929 mouse fibroblasts) are either exposed to an extract of the test sample or brought into intimate contact with the sample itself using an agar diffusion or filter diffusion method. Cytotoxicity is graded on a 4-point scale from nontoxic to severely cytotoxic according to the damage occasioned to the cell system used.

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2.8.2  Part 10: tests for irritation and sensitisation This part of the standard describes a technique in which extracts of the dressing are injected subcutaneously into multiple sites on the backs of rabbits, following which the injection sites are examined visually for evidence of irritation (erythema and oedema) immediately and after 24, 48 and 72 h. The sensitisation potential is determined by intradermally injecting and occlusively patch testing multiple sites on 10 guinea pigs. The treated sites are examined visually for evidence of a skin reaction after 24, 48 and 72 h.

References [1]  S.C. Anand, J.F. Kennedy, Miraftab, et al., Medical Textiles and Biomaterials for Healthcare, Woodhead, Cambridge, 2006. [2] S. Thomas, Wound dressings, in: T.D. Rovee, H.I. Maibach (Eds.), The Epidermis in Wound Healing, CRC Press LLC, New York, 2004. [3] S.T. Thomas, Testing dressings and wound management materials, in: S. Rajendran (Ed.), Advanced Textiles for Wound Care, The Textile Institute and Woodhead Publishing, 2009. [4] E. Kamoun, R.S. Kenawy, C. Chen, A review on polymeric hydrogel membranes for wound dressing applications: PVA-based hydrogel dressings, J. Adv. Res. 8 (2017). [5]  A.K. Kamrani, E.A. Nasr, Engineering Design and Rapid Prototyping, Springer Science+Business Media, 2010. [6] G. Majno, The Healing Hand - Man and Wound in the Ancient World, Harvard University Press, Cambridge, 1975. [7] P.T. Nicholson, S. Ian, Ancient Egyptian Materials and Technology, Cambridge University Press, Cambridge, 2000. [8] G. Majno, The Swnw (Egypt): The Healing Han. Man and Wound in the Ancient World, Harvard University Press, Cambridge Massachusetts, 1975. [9] T. Wang, et al., Hydrogel sheets of chitosan, honey and gelatin as burn wound dressings, Carbohydr. Polym. 88 (2012) 75–83. [10] J.W. Meri, J.L. Bacharach, Medieval Islamic Civilization, an Encyclopaedia, Routledge, 2006. [11] C. Dealey, Wound healing in Moorish Spain, EWMA J. 34 (2002) 32–34. [12] S.L. Gorbach, Good and Laudable Pus, vol. 96, The American Society for Clinical Investigation, Inc., December 1995. [13] M.D. Caldwell, Topical wound therapy-an historical perspective, J. Trauma 30 (1990) 116–122. [14] M. Cavendish, Inventors and Inventions, Marshall Cavendish Coorp, New York, 2007. [15] J.A. Savin, Joseph Lister: a neer of investigative dermatologyglected mas, Br. J. Dermatol. 132 (1995) 1003–1007. [16] G. Lawrence, Surgery (traditional), in: in: W.F. Bynum (Ed.), Companion Encyclopedia of the History of Medicine, vol. 2, Routledge, London, New York, 1993, pp. 961–983. [17] T.S. Wells, Some Cause of Excessive Mortality after Surgical Operation, Medical Times and Gazette, October 1, 1864, pp. 349–352. [18] G.D. Winter, Formation of the scab and the rate of epithelization of superficial wounds in the skin of the young domestic pig, Nature 193 (1962). [19] J. Bryan, Moist wound healing: a concept that changed our practice, J. Wound Care 13 (2004) 6.

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[20] D. Hinman, H. Maibach, Effect of air exposure and occlusion on experimental human skin wounds, Nature 200 (1963). [21] Y.H. Lee, et al., Acceleration of wound healing in diabetic rats by layered hydrogel dressing, Carbohydr. Polym. 88 (2012) 809–819. [22] J. Bentley, Understanding the wound healing process, Pract. Nurs. 15 (4) (2004) 181–188. [23] K.C. Dee, D.A. Puleo, R. Bizios, An Introduction to Tissue-Biomaterial Interactions, Wiley&Sons, New York, 2002. [24] P. Zahedi, et al., A review on wound dressings with an emphasis on electronicspun nanofibrous polymeric bandages, Polym. Adv. Technol. 21 (2010) 77–95. [25] Y. Qin, Advanced wound dressings, J. Text. Inst. 92 (2001). [26] Anon, British pharmaceutical codex, barrier substances, Br. Med. J. 30 (1954). [27] N. Mennini, A. Greco, A. Bellingeri, et al., Quality of wound dressings: a first step in establishing shared criteria and objective procedures to evaluate their performance, J. Wound Care 25 (8) (2016). [28]  S. Thomas, Exudate-Handling Mechanism of the Cutimed Cavity Range of Foam Dressings: Laboratory Report 2, BSN Medical, London, 2009. www.medetec.co.uk. [29] S. Thomas, P. McCunnin, An in vitro analysis of the antimicrobial properties of 10 silver containing dressings, J. Wound Care 12 (8) (2003) 101–107. [30] S. Thomas, A guide to dressing selections, J. Wound Care 6 (1997) 327–330. [31]  S. Thomas, et al., An ‘In-Vitro’ Comparison of the Physical Characteristics of Hydrocolloids, Hydrogels, Foams, and Alginate/cmc Fibrous Dressing, Surgical Materials Testing Laboratory, Bridgend, S.Wales, 2005. [32] L.L. Bolton, K. Monte, L.A. Pirone, Moisture and Healing: Beyond the Jargon, Ostomy and Wound Management, 2000, p. 46. [33] M. Uzun, S. Anand, T. Shah, A novel approach for designing nonwoven hybrid wound dressings: processing and charaterisation, J. Ind. Text. 45 (6) (2016). [34] M. Uzun, Development of Novel and Responsive Structures for Wound Management Incorporating Gelling Materials, The University of Bolton, 2012. [35] ASTM Standard E96-00. Standard Test Methods for Water Vapour Transmission, 2016. [36] S. Thomas, Alginate dressing in surgery and wound management, J. Wound Care 9 (2) (2000). [37] D. Parsons, M.J. Waring, Physico-chemical characterisation of carboxylated spun cellulose fibres, Biomaterials 22 (2001) 903–912. [38] M. Swenson, N. Atwood, S. Solfest, Physical Performance Characteristic Comparisons Adhesive Bordered Foam Wound Dressings, 3M Health Care, Minnesota, USA, 2004. [39] J.E. Both, Principles of Textile Testing: An Introduction to Physical Methods of Testing Textile Fibers, Yarns and Fabrics, Newnes-Butterworths, London, 1968. [40] D. Parsons, et al., Silver antimicrobial dressings in wound management: a comparison of antibacterial, physical, and chemical characteristics, Wounds 17 (2005) 222–232. [41] A. Meftahi, R. Khajavi, A. Rashidi, et al., The effects of cotton gauze coating with microbial cellulose, Cellulose 17 (2010) 199–204. [42] S. Ryu, J. Chung, S. Kwak, Amphiphobic meta-aramid nanofiber mat with improved chemical stability and mechanical properties, Eur. Polym. J. 91 (2017). [43] K. Vowden, P. Vowden, Wound dressings: principles and practice, Surgery 35 (9) (2017). [44]  S. Asghari, S. Logsetty, S. Liu, Imparting commercial antimicrobial dressings with low-adherence to burn wounds, Burns 42 (2016). [45] C. Moffatt, The principles of assessment prior to compression therapy, J. Wound Care 7 (7) (1998). [46] A. Akhmetova, T. Saliev, I. Allan, et al., A comprehensive review of topical odor-controlling treatment options for chronic wounds, J Wound Ostomy Cont. Nurs. 43 (6) (2016).

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[47] S. Thomas, B. Fisher, M. Waring, Odour adsorbing dressings: a comparative laboratory study, J. Wound Care 7 (5) (1998). [48] S. Rajendran S.C. Anand, G. Lee, et al., A Novel Odour-adsorbing Biopolymer Dressing for Managing Infected Wounds. The University of Bolton, 2008. s.l. [49] R. Erdem, M. Akalın, Characterization and evaluation of antimicrobial properties of electrospun chitosan/polyethylene oxide based nanofibrous scaffolds (with/without nanosilver), J. Ind. Text. 44 (4) (2015). [50] C. Schaude, E. Frohlich, C. Meindl, et al., The development of indicator cotton swaps for the detection of pH in wounds, Sensors 17 (2017). [51] V.K. Shukla, et al., Evaluation of pH measurement as a method of wound assessment, J. Wound Care Vol. 16 (7) (2007) 291–293. [52] U. Uzun, S.C. Anand, T. Shah, The effect of wound dressings on the pH stability of fluids, J. Wound Care 21 (2) (2012).

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B.S. Gupta1, J.V. Edwards2 1Textile Engineering, Chemistry and Science, North Carolina State University, Raleigh, NC, United States; 2United States Department of Agriculture – Agricultural Research Service, New Orleans, LA, United States 

3.1   Introduction In a human’s fast-paced life, characterised by external hazards and physiological neglects, physical injury of one or the other form is a commonly encountered event. Additionally, ailments of many different types require access to internal tissues through removal or incision of derma. The skin, whether damaged involuntarily through injury or voluntarily through surgical intervention, must be attended to for protecting body health, function and appearance. The primary procedure used is the application of a dressing which mainly protects the site against external assaults and aids in generating the needed physiological environment for efficient repair. The dressing can be as simple as a strip of plain textile or as complex as an engineered composite that contains layers of different geometries and reactive materials, including medicines. The type of dressing depends on the type and the condition of the wound. Wound repair may be simple and inconsequential and performed by the patient oneself or it may be complex enough to warrant surgery and hospitalisation. An effective treatment requires a thorough understanding of wound types and healing mechanisms and knowledge of the interventions that are available and would ideally assist in the repair process. A major increase in the understanding of the requirements for a dressing emerged in the 1970s when the pioneering work of Winter [1] showed that the wounds healed faster and more satisfactorily if the environment at the site was kept moist. Until then, the primary function of a dressing was considered as one or more of absorbing the exudate, keeping the wound dry and protecting it against external pathogens and further injury. The structure was also required to be comfortable. With the progress already made in terms of the understanding of the healing steps and requirements for different types of wounds, a wide variety of dressings are now available. A minor wound may be defined as one that is not chronic and also not seriously acute. However, if not attended to early or properly, the same wound could become infected, enlarged and acute enough to require advanced dressing and medical procedure. The first line of treatment of a minor wound is a passive dressing, which is a product that is textile in origin and may be made by a weaving, knitting or nonwoven process. The dressing can also be a solid film, cast directly from a polymer. If there is bleeding and potential for swelling, a bandage may be required in conjunction with absorbent gauze to exert transverse pressure and control both the haemorrhage Advanced Textiles for Wound Care. https://doi.org/10.1016/B978-0-08-102192-7.00003-5 Copyright © 2019 Elsevier Ltd. All rights reserved.

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and the oedema. Like the passive dressings, the bandages are also primarily textile structures that are made by one of the fabric-forming technologies. In the first part of this chapter, after a general review of wounds, healing and dressing requirements, a brief description of the various types of dressings and the bandages available to choose from is given. A more in-depth coverage of some of the advanced dressings, touched on here, may, however, be found in other chapters of the book. In the second half of this chapter, a detailed discussion of the fibre materials and the textile structures and processes used in producing the dressing and bandage products is presented.

3.2  The role of dressings Skin is the largest organ of the body and has multiple components and, therefore, multiple functions: the epidermis, which is the outer layer and composed of dead cells, is hydrophobic and responsible for protecting against the environment [2]; the dermis, or the middle layer, which is made up of living cells with a network of blood vessels and nerves, is responsible for registering external stimulus, i.e., touch/feel, and thermal regulation of the enclosed body; and the subcutaneous layer, which is mainly made up of fat, is responsible for insulating the body against shock. The cells on the surface are constantly replaced by those below, causing the top layer to slough off. The repair of an epithelial wound then is essentially a scaling up of this process by the use of interventions. Much has been learnt during the past half a century about wounds, the healing process and the nature of the products required to successfully treat the lesion. A wet environment, composed of isotonic saline and wound fluids, has been shown experimentally to be most favourable for rapid healing of wounds. The inflammatory and proliferative phases of dermal repair in healing are also accelerated [3]. It was realised that bacteria did not generate in the wound but were acquired from an external source; thus, simply washing with soap and water alleviated much of the risk of infection. Use of a protective covering formulated the simple but effective aseptic means for the treatment. An essential part of any wound management is dressing, important considerations for which are the extent to which it restricts evaporation of water from the wound surface, buffers pain and trauma, manages exudates and protects against bacterial invasion. Although wound healing which is the stated part of a wound management protocol has been described in recorded history, our understanding of its basic principles has grown more in the past half century than in the preceding two millennia [4]. The recent outstanding growth in our knowledge about healing is highly promising and has already led to introduction of new and exciting concepts, novel therapeutic modalities and innovative wound management products. As new materials are discovered, new dressings have emerged which promise to play an active role in modifying healing of all types of wounds [5,6]. As the products become more sophisticated, they also tend to become more ‘wound-specific’. Accordingly, to select an optimum treatment for a wound and for different stages during the healing process, it is important that we understand the types

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of wounds we encounter, the sequence of events that take place during repair and the treatment options we have available to choose from.

3.3  Categorisation of wounds Wounds have been categorised in many different ways, but they are all based on the differences that exist in the required treatment and in the expected time and the prospects of healing. The classification of wounds recognises the type of injury (blunt contusion, sharp laceration, thermal, chemical, etc.), the extent of tissue loss and the presence of infection, foreign bodies and underlying structural injuries (fracture of bone, exposure of vital parts such as tendons and blood vessels). A general classification of wounds is as follows: Wounds with no tissue loss. Wounds with tissue loss. This generally includes three types of wounds: (1) caused by burning, trauma or abrasion; (2) the result of secondary events involving chronic ailments, as, for example, venous stasis, diabetic ulcers and pressure sores; or (3) induced as a part of the treatment of the wound itself, as, for example, the wound arising at the donor site for skin grafting or the wound caused by derma-abrasion.

From the standpoint of the extent of injury, a wound may also be classified in terms of the layers involved: (1) superficial wounds, involving only the epidermis; (2) partial-thickness wounds, involving also the dermis; (3) full-thickness wounds, involving, additionally, the subcutaneous fat or deeper tissue.

Most wounds can also be broadly characterised as acute or chronic. In the former type, that may or may not have tissue loss, healing tends to proceed through a timely and orderly reparative process. In the chronic wounds, however, healing has failed to proceed through this process or it has proceeded without establishing a sustainable anatomical and functional result. The chronic wounds are classically subdivided into venous stasis ulcers, pressure ulcers and diabetic ulcers. To a lesser extent, the traumatic wound with extensive cutaneous loss that has not been replaced for some reasons also may fall in the category of chronic wounds [4,7].

3.4  Minor wounds Most wounds encountered in life are minor, i.e., one that has no tissue loss and is not chronic. Such wounds have high prospects of healing with minimum scarring. Minor wounds often occur as the result of unanticipated trauma and may include injuries, such as lacerations, abrasions and blisters, and even more serious injuries, such as skin tears and bites. In many instances, such as superficial wounds, the skin may only require protection from further injury and can be treated at home with due regard given to the possibility that infection may be present or could arise. Infection is usually one

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of the biggest risks for minor traumatic wounds. A visual check for the presence of foreign material, its removal and careful cleansing may precede the application of a dressing. If, however, the wound is deep, as for example caused by penetration, then the possibility that an underlying structure may have been damaged needs to be considered. Some of the causes of minor wounds are [8]: Lacerations. This wound occurs when soft body tissue has become torn and it is often irregularly shaped and jagged. It is highly common for this type of wound to be contaminated with debris and/or bacteria by the object that caused it. Abrasions or grazes. These are more exactly superficial wounds in which the top layer of the skin is damaged or removed, e.g., by the skin sliding across a rough surface. Small blood vessels may become visible and bleed. These injuries often contain dirt and gravel. Abrasions are considered the most common type of wound, and perhaps the least dangerous [9]. Blisters. These are usually the result of friction between the top two layers of the skin. Puncturing the blister, draining the fluid and removing the top layer often allows the area to heal more quickly. In many cases, the blister will burst on its own accord. In both instances, a protective dressing is required. Cut (incision). Such wounds usually have clean edges which are the result of surgery, or injury caused by a sharp-edged object. Because blood vessels are cut straight across, there can be profuse bleeding. Among all types of wounds, incisions are the least likely to become infected, because the abundance of flowing blood serves to protect against the pathogens finding their way in. Puncture. A puncture wound typically occurs when the skin is pierced by a cylindrical object, such as a needle or a nail. These wounds can be dangerous, as one cannot easily identify the depth to which the puncture has reached; they can be particularly dangerous if the wound is located on the abdomen or thorax [9]. With this type of wound, bleeding will occur, in a similar way to the wound caused by a knife. Fig. 3.1 depicts the difference between a laceration and a puncture wound [10].

Figure 3.1  Wound types: (a) laceration, (b) puncture [9].

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Penetration. A penetration is a type of puncture but the damage is deeper such as it happens when a knife or bullet enters the body. Bites. These may be human or animal and are of special concern, especially if caused by an animal, as bacteria from the mouth can enter and result in an increased risk of tetanus and infection. Most animal bites are sustained from pets, usually dogs, and can cause abrasions, deep scratches and lacerations and puncture wounds. Cat bites are considered more serious because of the high incidence of infection.

3.4.1  General treatment strategy for minor wounds Cleaning the wound and the surrounding skin is usually the first stage in treating a minor wound. This step removes debris and other foreign material, which, if left, could cause infection. Abrasions require thorough irrigation as dirt is frequently embedded in the ruptured skin. An antiseptic solution may be used to cleanse the area. Clean surgical wounds that have been sutured simply require the cleaning of old blood before the application of a dry dressing. In some cases it may be necessary to debride the wound before proceeding; in others, repair to underlying structures may need to be addressed before applying a dressing. Wounds greater than 6–8 h old have an increased risk of infection. In all cases of traumatic injuries, the patient’s tetanus status needs to be assessed for coverage. Following this, an assessment of the wound in terms of the location, size and depth, and any additional trauma to the underlying structures needs to be determined. Animal bites need to be monitored for 24–48 h for signs of infection. After thorough cleansing and assessment, a choice of dressing is then made, which may be a simple low-adherent or an advanced multilayer composite to not only protect the wound but also absorb blood or exudate and keep the wound moist. A detailed discussion of dressings is given later in this chapter.

3.5  Healing mechanisms The various phases involved in wound healing described below are seen in all wounds, irrespective of whether it is a carefully opposed, clean and incised wound that heals by primary intention or one that is not opposed, has tissue loss, is infected and exuding, and heals by secondary intention. The length of each phase varies with wound type and extent and can be manipulated to some extent to influence healing. The body’s natural healing process can be broken down into several steps: haemostasis, inflammation, proliferation, and maturation or remodelling. Immediately after injury, the platelets from the severed blood vessels begin to aggregate and form a platelet plug. This reduces bleeding. A clot forms in the opening of the wound, which dehydrates in contact with the air and forms a scab. In the second phase, neutrophils, monocytes and macrophages emerge, which tend to demolish or debride any devitalised tissue and foreign bodies present, such as bacteria. The phagocytes act to clear debris and destroy the ingested material [11]. In the third stage, new vessels are formed which carry the oxygenated blood to the site bed. The fibroblast cells lay down

60

(a)

Advanced Textiles for Wound Care

(b)

Skin surface Red blood cell Wound

Platelet

PMN

Fibrin

Epidermis and dermis of skin

Macrophage

(c)

(d) TGF-β PDGF

Macrophage

(e)

Collagen

Fibroblast

PMN

(f)

Figure 3.2  Phases of cutaneous wound healing (a) injury, (b) coagulation, (c) early inflammation (24 h), (d) late inflammation (48 h), (e) proliferation (72 h), (f) remodelling (weeks to months) [12].

a network of collagen fibres surrounding the neo-vasculature of the wound. In the final stage, the process of remodelling of the collagen fibres laid down in the proliferation phase occurs, and this may take a long time (Fig. 3.2) [12]. A problem arises in the last steps of the healing process for large or cavity wounds as the body is not able to completely seal the site with a scab-like formation. The cavity must be plugged with an appropriate dressing to assist in the process. Depending on the type of wound, healing treatment is considered to be by one of three processes: primary, secondary or tertiary (often called delayed primary) [6]. Healing by primary intention occurs in most surgical wounds in which the edges have been adequately approximated. Such wounds are usually clean and heal rapidly. Large wounds with significant tissue loss are allowed to heal by secondary intention. Such wounds are often encountered following massive trauma, surgical ablation of large tumours, or deep burns. Tertiary or, more appropriately, delayed primary healing is induced by reconstruction using skin grafts or flaps. Tissue gaps and poorly approximated edges will

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ultimately heal by secondary intention accomplished by re-epithelialisation from the wound edges and mostly by wound contraction. Clearly, primary or delayed primary wound healings are by far preferable and superior to secondary healing.

3.6  Chronic wounds Wounds that suffer stalled healing are termed chronic and result from the disruption of the wound healing process in the inflammation phase for a minimum of 4 to 6 weeks [13–15]. Various factors contribute to chronic wounds, including local (infection, tissue ischaemia, and poor surgical technique) and systemic (ageing, nutritional disorder, vitamin deficiency, underlying diseases and medication) factors. However, massive accumulation of neutrophils in the wound is an indication of chronic wound and results in the release of matrix metalloproteases (MMPs) and neutrophil serine protease (human neutrophil elastase, HNE), which degrade beneficial growth factors and extracellular matrix (ECM) proteins. Chronic wounds are most often very treatable, especially if they are stage I and II pressure ulcers. Slow healing is often attributable to age, diet, care and the patient’s overall health. However, despite appropriate care, some pressure ulcers may not be preventable, and adoption of measures to prevent their progression to stage IV is important to reduction in mortality. Results from preclinical studies show that wounds in patients with certain illnesses such as diabetes [16] or patients taking medications such as steroids [17–21] are at a higher risk for developing into a chronic condition [22]. During the inflammation stage of a chronic wound, elevated protease levels have a deleterious effect on the affected bed by disrupting the healing cascade [23–25]. Examples of chronic wounds include venous, pressure, arterial, leg and diabetic ulcers [15,23].

3.7  Wound dressings 3.7.1   Historical Historically, early humans made use of materials from their natural surroundings, including resin-treated cloth, cobwebs, leaves and wool-based materials with a variety of substances including eggs and honey [26–28]. Some of these ancient remedies, for example, honey, were probably more than passive treatments because it is now used in advanced dressings with interactive properties. The modern history of surgical wound management indicates how, with research and understanding of wounds and their healing, dressings have evolved over time and set the criteria for the design of new and better products and effective wound management. Until the research by Winter [1], which illustrated the benefits of a moist environment for healing in the second half of the twentieth century, relatively few advances have taken place in wound care management. Since the early nineteenth century, advances in wound treatment occurred largely as a result of experience gained in military surgery. These observations brought out the benefits of a sterile environment in healing and led

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to clean and sterile gauze replacing the non-sterile products. In 1880, Joseph Gamgee developed the famous composite dressing consisting of absorbent cotton or rayon fibre enclosed in a retaining sleeve [29]. The dressings used were sometimes medicated with iodine or phenol. Gauzes impregnated with paraffin were introduced as non-adherent materials for the treatment of burns and other similar wounds. Medicated versions of these, the so-called ‘tulle gras’, were subsequently introduced and some of these are still being used. The work of Winter led to the development of a whole range of new dressings: films, gels, foams, polysaccharide materials and chitosan. These have revolutionised the treatment of wounds of all types. Some of the requirements for ideal wound dressing mentioned are listed below [30–33]: Absorbing exudates and toxic components from the surface of the wounds Maintaining a high humidity at the wound–dressing interface Allowing gaseous exchange Providing thermal insulation Protecting the wound from bacterial penetration Being non-toxic Easily removable without causing trauma to the wound.

Properties that were added later include (1) having acceptable handling qualities and (2) being sterilisable and comfortable [9]. Having acceptable handling qualities meant that the product will not tear easily and disintegrate into wound.

3.7.2  Case for moist environment The most significant advance in wound care resulted from the work of Winter [1], which showed that the occluded wounds, that is, those in a moist environment, healed faster than the dry wound. An open wound, which is exposed to air, dehydrates and results in the formation of a scab or a scar. The latter forms a mechanical barrier against migrating epidermal cells, causing them to move through a deeper level of tissue, retarding healing (Fig. 3.3) [34]. A moist environment prevents the formation of scab and allows the cells to move unhampered [35]. If exudate is present, such as from an ulcer, it should be absorbed by the dressing, so that it does not solidify in the wound.

Occlusive dressing

No dressing Normal scab

Moist exudate Wound Surface

Epidermis Dry exudate Wound surface Dry dermis

Figure 3.3  Healing under a moist environment [34].

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3.7.3  Dynamic nature and requirements Each wound is different from any other even on the same individual, occurring because of the same reason, and in about the same region. Although it may fall in a given category, it still itself remains unique. This is because a wound is influenced by so many variables within the host and the environment that each will act independent of all others [36]. This is exacerbated by the facts that both the wounds and the hosts are dynamic, i.e., in a state of constant change. Thus, there is the ongoing challenge faced in selecting the wound care dressing at each stage for each different person, and this requires a frequent reassessment of the lesion. Surgical wound assessment is an ongoing nursing responsibility that should be conducted every time a dressing is changed, until the healing is complete. Assessment tools are available that determine the following aspects [37,38]: • Type of wound – superficial or cavity. • Age of wound – fresh, days, weeks, dehisced (split along a natural line). • Stage of healing – granulating, epithelialising. • Progress of wound – healing, deteriorating, become necrotic, infected or static.

3.7.4   General classification Broadly, dressings may be classified as (1) passive, (2) interactive and (3) bioactive, based on the nature of dressing action required. However, as illustrated above, the concept of wound occlusion to promote moist healing has probably impacted dressing design as much as any other development over the last 30 years. Wound occlusion does require careful regulation of the moisture balance at the site with vapour permeability helping the dressing to stay within its absorption limit. Thus, occlusive dressing types have been developed depending on the nature of the wound and the accompanying exudate. The theory of moist wound healing has led to approximately eight or nine separate types of materials and devices (Table 3.1), useful for different treatment indications. Each material type that represents these distinct groups has molecular and mechanical characteristics that confer properties to promote healing under specifically defined clinical indications. For example, it has been recommended that wounds with minimal to mild exudate be dressed with hydrocolloid, polyurethane and saline gauze and wounds with moderate to heavy exudate be dressed with alginate dressings. Dressings may also be selected based on wound tissue colour, infection and pressure ulcer grade [39]. When taken together, the combined properties of the dressing materials given in Table 3.1 would constitute an ideal dressing. Improvements in dressings that function at the molecular or cellular level to accelerate healing or monitor wound function are included among the ideal characteristics and may be termed interactive and intelligent materials, respectively. For example, a dressing that removes harmful proteases from the wound to enhance cell proliferation is an example of an interactive product. A dressing having a detection device in the material signalling ‘time-to-change’, because the material has reached its capacity for deleterious protein levels, or reached a pH or temperature imbalance, may be termed ‘intelligent’. Currently, there is not a universal

Table 3.1 

Classes of occlusive wound dressings with a description of their properties, clinical indications, and contraindications Dressing and fibre type

Description

Properties

Indications

Thin films

Semipermeable, polyurethane membrane with acrylic adhesive

Permeable to water and oxygen providing a moist environment

Sheet hydrogels

Solid, non-adhesive gel sheets that consist of a network of cross-linked, hydrophilic polymers which can absorb large amounts of water without dissolving or losing structural integrity. Thus, they have a fixed shape. Semipermeable polyurethane film in the form of solid wafers; contain hydroactive particles such as sodium CMC which swells with exudate or forms a gel. Soft, open cell, hydrophobic, polyurethane foam sheet 6–8 mm thick. Cells of the foam are designed to absorb liquid by capillary action.

Carrier for topical medications. Absorbs its own weight of wound exudate. Permeable to water vapour, and oxygen, but not to water and bacteria. Wound visualisation Impermeable to exudate, microorganisms, and oxygen. Moist conditions produced promote epithelialisation

Minor burns, pressure areas, donor sites, post-operative wounds Light to moderately exudative wounds. Autolytic debridement of wounds. Stage II and III pressure sores.

Hydrocolloids

Semipermeable foam

Amorphous hydrogel

Similar in composition to sheet hydrogels in their polymer and water make-up. Amorphous gels are not cross-linked. They usually contain small quantities of added ingredients such as collagen, alginate, copper ions, peptides and polysaccharides

Permeable to gases and water vapour, but not to aqueous solutions and exudate. Absorbs blood and tissue fluids while the aqueous component evaporates through the dressing. Cellular debris and proteinaceous material is trapped. Gels clear, yellowish or blue from copper ions. Viscosity of the gel varies with body temperature. Available as tubes, foil packets and impregnated gauze sponges

Shallow or superficial wound with minimal to moderate exudate.

Used for leg and decubitus ulcers, sutured wounds, burns and donor sites.

Used for full-thickness wounds to maintain hydration. It may be used on infected wound or as wound filler

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Table 3.1 Continued Dressing and fibre type Fillers

Contact layer dressings (tulle gauze with petroleum jelly)

Gauze packing

Wound vacuum-assisted closure

Description

Properties

Indications

Calcium alginate which consists of an absorbent fibrous fleece with sodium and calcium salts of alginic acid (ratio 80:20). Dextranomer beads consist of circular beads, 0.1–0.3 mm in diameter, when dry. The bead is a threedimensional cross-linked dextran, and long-chain polysaccharide Greasy gauzes consisting of tulle gauze and petroleum jelly. Siliconeimpregnated dressing sheet consists of an elastic transparent polyamide net impregnated with a medical-grade cross-linked silicone Cotton gauze used both as a primary and secondary wound dressing. Gauze is manufactured as bandages, sponges, tubular bandages and stockings. Improvement in low-linting and absorbent properties. Gauze is still a standard of care for chronic wounds

Heavily exudating wounds, including chronic wounds as leg ulcers, pressure sores, fungating carcinomas. Wounds containing soft yellow slough, including infected surgical or post-traumatic wounds

Heavily exudating wounds

The dressing which is porous, nonabsorbent and inert is designed to allow the passage of wound exudate for absorption by a secondary dressing

Shallow or superficial wounds with minimal to moderate exudate

Cotton gauze may be wetted with saline solution to confer moist properties. Possesses a slight negative charge, which facilitates uptake of cationic proteases. Absorbent and elastic for mobile body surfaces

Polyurethane foam accompanied by vacuum negative pressure in the wound bed

Wound filled with foam and sealed with a film. Vacuum is obtained over wound

For chronic wounds it fills deep wound defects and is useful over wound gel to maintain moist wound; needs to be packed lightly. May traumatise wound if allowed to dry Deep wound to stimulate the growth of granulation tissue

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dressing that will work for all wound types. Therefore, a dressing for a wound should be chosen on a case-by-case basis. When choosing a product, there are several factors to consider, such as: (1) location, (2) size, (3) wound depth, (4) amount of exudate, (5) infection, (6) frequency and difficulty of dressing change, (7) cost and (8) comfort. Traditional products like gauze and tulle that account for the largest market segment are passive products. Interactive materials composed of polymeric film products are mostly transparent, permeable to water vapour and oxygen but impermeable to bacteria. These film products are recommended for low exuding wounds. Bioactive dressings are ones that deliver substances active for healing, either by delivery of bioactive compounds or the dressing is constructed from a material having endogenous activity. These materials include proteoglycans, collagen, non-collagenous proteins, alginates or chitosan.

3.7.5  Wound occlusion, environment and healing Occlusive dressings are impermeable and prevent exudate loss, whereas semi-occlusive dressings are permeable [40]. The use of occlusive dressings tends to increase scabbing, generate a drier wound and increase pain upon the removal of the bandage. Studies show that using occlusive dressings for wound care may increase bacterial growth and tissue maceration [40,41]. Occlusive dressings are usually effective in controlling haemostasis depending on their composition. For example, a dressing with high absorption capacity and rapid wicking that also promotes clotting is appropriate in controlling bleeding in an acute wound. However, when used for a chronic wound, semi-occlusive dressings have the ability to maintain moisture, allow gas exchange at the wound bed and inflict little to no pain during the removal of the bandage. Maintaining a moist wound environment facilitates fibroblast proliferation and epithelialisation growth [3,42]. Commercially available semi-occlusive dressings include hydrocolloids, hydrogels, thin films and semipermeable foam dressings that are able to absorb fluids, remove exudates and act as a bacterial barrier. There are different categories of semi-occlusive dressings based on the requirements for moisture control and the management of wound exudates. The dressings may also be categorised based on general functional properties and here we have subdivided them into passive/active, interactive, bioactive and intelligent dressings [13,43]. The concept of intelligent dressings was first demonstrated in polyurethane products based on their ability to respond to wound exudate volume by self-adjusting the moisture vapour transmission rate (MVTR) to maintain a moist wound environment [44]. The mechanism of action of MVTR in polyurethane films and foams has also been examined in recent years [45]. More recently, Xu et al. have reported a polyurethane-based dressing with moderate porosity that demonstrates biochemical and cellular markers for a peak accelerated healing rate at the optimal MVTR of 2038  g/m2 /day in full-thickness wounds [46]. This report constitutes the first study that conclusively demonstrates the benefit of an optimal MVTR. The work further suggests that the dressing selected, aided by moisture or dressing sensors, should modulate the moist wound environment to this optimum MVTR level for enhanced cell proliferation and healing.

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3.8  Types of dressings available The range of dressing products available is so large that there is potential for confusion when deciding which one to use. No single product is suitable for all types of wounds, therefore, when deciding which dressing to use, it is important to assess the wound and the stage of healing. Specific objectives must be identified; for example, if a wound is sloughy, the prime objective will be to de-slough by absorbing exudate; if the wound is clean and granulating, the aim will be to provide a moist environment to aid in healing. If the wound has a large cavity, it must be plugged. Based on considerations such as these, the available range of wound care materials can be described as below [47–51].

3.8.1   Gauze dressings A gauze is a traditional dressing and is still one of the most widely used product. It is used for many purposes: skin preparation, cleansing, wiping, absorption and protection. It can be either woven or nonwoven. Cellulose fibres (cotton and rayon) are the typical materials used in making gauze. Synthetic fibres, in particular polyester, are also employed to modify properties and reduce cost. If woven, the pattern used is plain but it can vary from loose to tight. The nonwoven dressings are highly homogeneous and soft. Fig. 3.4 shows a comparison between a woven gauze and a nonwoven sponge. Gauze comes in pad, strip, roll and ribbon form and is easy to handle; it packs easily which makes it a good choice when the wound is located in hard to reach areas. Gauze can be dry, moist or impregnated. There are some disadvantages associated with the use of gauze: it is not a good thermal insulator and also, when removed, it can cause pain and damage to the wound. The damage occurs because the fibres of the gauze get embedded into the wound exudate and when removed it often peels off some of the newly formed epithelium. Impregnation of the fabric in a suitable compound alleviates this issue.

Figure 3.4  Woven and nonwoven gauze [52]. The woven is an Army field standard dressing for US military units. The nonwoven cotton gauze (20× mag.) illustrates hydro-entangled fibres at 23 mesh.

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3.8.1.1  Dry gauze Dry gauze, which is perhaps the most widely employed material in home care, is used as a cover, as a means to prevent contamination, or to trap and lessen exudate. It is used as a primary absorbent material on a wound with a high amount of exudate. It is also used on closed wounds to prevent infection or additional trauma. The main problem encountered with gauze is that it tends to adhere to the wound and when removed from a large lesion may pull some of the newly formed tissues with it. If not being used for mechanical debridement as described below, it should be moistened before removal if it appears to be dry and adhered to the wound.

3.8.1.2  Moist gauze This type of product is used to help maintain a moist environment and most often to promote granulation or protect a granulating wound, which is one of the first visual signs of healing [53]. It has been noted that ‘wet-to-dry’ and ‘wet-to-moist’ gauze dressings are often used in practice in a way that makes them indistinguishable [54]. In fact, it should be noted, they have two different end purposes. Wetto-dry dressings have been traditionally used as a means of mechanical debridement. The Agency for Healthcare Research and Quality has promoted the use of these for the debridement function. Devitalised tissue will not fully granulate; therefore, the removal of slough, which is a mixture of fibrins, ECM protein, exudates, white blood cells and bacteria, is often done by mechanical debridement using a wet-todry dressing. The less desirable part of this method of debridement is that it causes pain to the patient on removal. However, there are a variety of alternative methods for debridement, for example, surgical debridement (when such is possible) and debridement using proteases, including collagenase-based and papain/urea-based formulations. Noteworthy as well is that there are other dressing types specifically designed to promote autolytic debridement, which include thin films, honey, alginates, hydrocolloids and polymeric membrane dressings (hydrophilic polyurethane membrane matrix with a continuous semipermeable polyurethane film backing) [43]. The other moist gauze, i.e., the wet-to-moist gauze, is used for creating moist wound healing. For treatment of open ulcerating wounds, gauze is made moist by soaking in normal saline. Normal saline dressings, which are still a standard of in-home and nursing home care, appear to act as an osmotic dressing. It has been shown that the osmolarity, sodium and chloride concentrations in dressings, placed on chronic wounds, remain relatively isotonic with time. The reason for this is that the dressing as a result of evaporation increases its tonicity. This draws fluid from the wound into the product so that a dynamic equilibrium occurs and the dressing regains isotonicity. Thus, the dressing remains functional for as long as it removes fluid from the wound.

3.8.1.3  Impregnated gauze Further work has been done to fix the limitations of gauze by impregnating it with substances that promote wound healing. Substances currently used include hydrogels,

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saline and antimicrobial agents and a wide variety of other materials, including paraffin wax. One such gauze, known for its vast improved function, is referred to as ‘Smart Gauze’ and has been found to be both super-absorbent and non-adherent to the tissue. Both the moist and the impregnated gauzes fall into the category of advanced occlusive dressings.

3.8.2   Impregnated dressings With the work of Lister in 1867, in which bandages were impregnated with carbolic acid, the use of antiseptic treatment arose, and, shortly thereafter, Joseph Gamgee produced the first composite product containing cotton or viscose fibre medicated with iodine [26]. Some of these dressings are still in use. These materials include gauzes and nonwoven sponges, and ropes and strips, saturated with saline, hydrogel or other wound-healing promoting compounds, including peptides, polysaccharides, alginate, copper ions and collagen. They are non-adherent and require a secondary dressing.

3.8.3  Transparent film dressings Films are homogeneous materials, which come in different thicknesses and consist of a polymer sheet (typically polyurethane in composition) that has one adhesive side. Film dressings are acceptable coverings for superficial wounds; being impermeable to liquids, water and bacteria, but permeable to moisture vapour and atmospheric gases, makes them suitable for use as occlusive structures. This material has a low absorption capacity, low MVTR, ranging 472–862 g/m2 /day, and is semipermeable to gas, such as oxygen (O2), with O2 permeability rates lying in the range 0.54–2.00 L/m2 /day [55–57]. It is noteworthy that films are not absorptive dressings, and skin covered by the dressing may macerate if fluid is allowed to collect in the dressing. Because of their transparent nature, the films facilitate visual inspection without having to remove the dressing. They are applied to partial-thickness wounds with little to no exudate. They are also used to manage intravenous sites, lacerations, abrasions and second-degree burns.

3.8.4   Composite dressings These dressings combine physically different components into a single product and provide multiple functions, such as bacterial barrier, absorption and adhesion. The dressings, comprising multiple layers, have a semi-adherent or non-adherent contact layer that covers the wound and may include an adhesive border. The inner is the contact layer that is designed to accept the fluid and allow it to pass into the layer above where it is absorbed and held. The outermost layer is designed for protection and to secure the dressing to the skin. They are used as primary or secondary dressing; the latter, for example, for daily applications of creams, ointments, etc. An example of how different types of carbohydrate combinations, involving cellulose, alginate and other components, can be designed into composite dressings is shown in Fig. 3.5.

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ds

nd su g dress ar-based ings

i ollo

Fillers a

roc yd dh

ea

an

uz

els

Ga

r og

ings dress

Crosslinking chemistry

d Hy

Cotton dressing

rbing r-abso Odou

nd dre con ssi tact ng lay er

Carbohydrate-based dressing

Carbohydrate-based Alginates and Charcoal cloth hydrogels and dextranomer beads/ dressing carboxymethyl cellulose sucrose and honey

Composite dressings that enhance the properties of both alginate and cotton while incorporating proteasesequestering properties

Figure 3.5  Various materials from carbohydrate sources present in wound dressings may be combined to form composite dressings with enhanced properties.

The combination of drug delivery (active agents) and tissue engineering properties into one dressing represents a new approach to composite dressing design. For instance, Mittal et al. performed an in vivo study to evaluate a bioactive gel dressing consisting of cytomodulin immobilised on a poly-d,l-lactide-co-glycolide (PLGA) microsphere scaffold as a composite graft treated with gentamicin [58]. Immobilising the cytomodulin, a synthetic tumour growth factor beta mimic [59], onto the PLGA microsphere enables a single application by preventing the degradation of the growth factor. The antibiotic gentamicin imparts a broad-spectrum antibacterial activity against gram-negative and gram-positive microorganisms. The cytomodulin–PLGA scaffold and gentamicin are mixed with a hydrogel-based carrier, gelatin, to ensure the bioactive scaffold and antibiotic drug would remain at the wound site [58].

3.8.5  Biological dressings The concept of a biological dressing based on the use of living cells is considered to have been initiated by the work in 1975 by Rheinwald and Green [60] who developed a method that made it possible to cultivate human keratinocytes so that a 1–2 cm2 keratinocyte-cultured graft could be generated in about 3 weeks. This work paved the way for the eventual development of skin substitutes and biomaterials with wound interactive properties and biological activity, which have progressed from the mid1990s through the present. Biological dressings are derived from a natural source. Collagen dressings, derived from bovine, porcine or avian sources, fall in this group. All these products are meant to accelerate healing. The biological dressings are available in many forms, including gels, solutions or semipermeable sheets. While gels and solutions can be applied directly to the wound surface and covered with a secondary

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dressing, the sheet form can be simply used as a membrane and left in place for undisturbed healing. Biological dressings are indicated to be used for partial-thickness wounds such as burns, abrasions, donor sites, skin tears, etc. Skin substitutes that also fall under this category are being increasingly used. These contain both cellular and acellular components that appear to release or stimulate important cytokines and growth factors that have been shown to be associated with accelerated healing [61]. Some basic materials may also play a role in up-regulating growth factor and cytokine production and blocking destructive proteolysis. In this regard, the biochemical and cellular interactions that greatly promote healing have only recently been elucidated for some of the occlusive dressings described in Table 3.1. Some carbohydrate-based dressings stimulate growth factors and cytokine production. For example, certain types of alginate dressings have been shown to activate human macrophages to secrete pro-inflammatory cytokines [62]. Interactive dressing materials may also be designed with the purpose of either entrapping or sequestering molecules from the wound bed and removing the components responsible for deleterious activity from it as the product is removed, or stimulating the production of beneficial growth factors and cytokines through unique material properties. They may also be employed to improve recombinant growth factor applications. The impetus for material design of these dressings derives from advances in the understanding of the cellular and biochemical mechanisms underlying healing. With the knowledge of the interaction of cytokines, growth factors and proteases in acute and chronic wounds [62–65], the molecular modes of action have been elucidated for dressing designs as balancing the biochemical events of inflammation. The use of polysaccharides, collagen and synthetic polymers in the design of new fibrous materials that optimise wound healing at the molecular level has stimulated research on dressing material interaction with wound cytokines [61], growth factors [66–68], proteases [69–72], reactive oxygen species (ROS) [73] and ECM proteins [72].

3.8.6   Absorptive dressings Absorptive dressings are usually multilayer materials which provide either a semi-adherent quality or a non-adherent layer. They are combined with highly absorptive layers of fibres, such as cotton, rayon, etc. These dressings are designed in a way so as to minimise their adherence to the wound so that the secondary trauma is minimum. These products are generally used as primary or secondary dressings for surgical incisions, lacerations, abrasions, burns, skin grafts or any draining wound.

3.8.7   Alginate dressings These advanced absorbent dressings are nonwoven, non-adherent pads and ribbons composed of natural polymers derived from brown seaweed. Alginates provide many benefits for use as dressings: they swell and retain large amounts of water (100% to over 1000% of their dry mass), thus providing an optimal moist environment; the act of swelling and diffusion throughout the gel allows the wound exudates to be absorbed, which, in turn, speeds up healing; and, because of the wet structure, the

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dressing does not stick to the wound bed and cause secondary trauma upon removal. The alginate dressing can be applied either pre-wetted, to supply a desiccated wound with moisture, or dry, to aid in the absorption of exudates. They must, however, be used with a secondary dressing. As for the mechanism, when a dry mass of the material is applied to the site, it begins to absorb exudates during which a reversal in the ion-exchange process (from calcium ion in the dressing to sodium ions in the blood and exudates) occurs. This transforms the water-insoluble calcium alginate into water-soluble sodium alginate, thus absorbing a large amount of fluid [74]. The moist gel formed fills and covers the wound. The process is also said to make the dressing an excellent haemostatic agent, thus promoting clotting [75]. For dressings, alginates are made as ropes for packing deep wounds and as sheets for treating shallow wounds. Alginate dressings act as antimicrobial materials that absorb microorganism-infected exudates, which are then removed when the dressing is changed [74].

3.8.8  Chitosan dressings Chitosan is well known for its haemostatic properties and its bacteriostatic and fungistatic behaviours, all of which are particularly useful for wound treatment. As a haemostat, chitosan helps in natural blood clotting and in blocking of nerve endings, thereby reducing pain. The polymer gradually depolymerises to release N-acetyl-β-dglucosamine, which initiates fibroblast proliferation, helps in ordered collagen deposition and stimulates an increased level of natural hyaluronic acid synthesis at the site. These processes aid in increased wound healing and decreased scar formation. Fig. 3.6 gives a schematic representation of the mechanism by which chitosan works. It shows

Figure 3.6  Haemostatic properties of chitosan [76].

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that chitosan, which is a polymeric amine, becomes positively charged when wet and attracts the negatively charged ions in blood and exudates [76]. Such attraction allows the material to clot blood quickly and also to act as an antibacterial agent on account of it attracting the negatively charged particles, including bacteria (Fig. 3.6), which are then removed at the dressing change [74]. An increase in healing rate of as much as 75% has been reported [75]. Because of the similarities in the chemical structures between chitosan and cellulose, the two are frequently mixed, which can be done at both the polymer and the fibre levels. Such blending allows a manufacturer to engineer products with desired properties at lower cost. An example of a commercial product is 25% chitosan and 75% rayon. The improved fibre properties obtained allow the material to be converted into dressing by knitting, weaving or one of the available nonwoven processes or by casting the polymer into a film. The functionality of the polymer also allows it to have built-in compounds that provide additional antimicrobial, and even deodorising, characteristics [77]. One of the largest uses of chitosan is in making dressings for use by military in the combat zone. The claim of a product is that it will bond with the blood in 1–5 min and will also form an adhesive-type structure to protect the wound until access to a medical facility becomes available. Such quick response is needed in managing combat-related injuries, as nearly 80% of all battlefield deaths result from bleeding in less than 10 min [76]. More specifically, chitosan has been developed as a sponge for use in controlling lethal haemorrhages in extremity arteries [78]. Chitosan is among a number of currently deployed haemostatic agents used within the armed services and has recently been contrasted with other materials for its efficacy in this application [79,80]. Chitosan-based haemostatic products have also been compared with the more highly ordered crystalline structures of glycosaminoglycan materials [81] to learn more about the relative roles that carbohydrate structure and charge play in eliciting haemostatic activity. In addition to its use in fabric or film form, the material may also be incorporated into dressings in the form of powder and beads, and it has been grafted onto cotton to study its antimicrobial and haemostatic activities.

3.8.9  Chitosan/alginate bicomponent fibre dressings Some wound products even combine chitosan and alginate to form a fibre [82]. With these bicomponent fibres (Fig. 3.7), the positively charged chitosan on the outside attracts the negatively charged microbes on the skin, promoting antimicrobial activity [83]. The alginate polymer inside is still able to absorb the exudate. Thus, a nontoxic, biocompatible, absorbent and anti-microbial wound dressing could be made that combine the best attributes from both polymers to generate a faster healing product for large exuding wounds. The strategy of combining a positive and a negative material in this manner has been termed polyelectrolyte complexes. Potential biomedical applications of PECs as prepared through wet-spinning methods have been lately reviewed [84].

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Figure 3.7  Core-sheath alginate/chitosan [83].

A new family of tissue adhesives, based on a bioinspired protein, secreted in defensive mucus found in slugs (Arion subfuscus) also employs a chitosan and an alginate derivative, which involve interfacial covalent bridging (the amino functionality in chitosan) into the tissue substrate. The ability of this polysaccharide-based adhesive to bond at unprecedented high breaking strengths on highly wetted tissue surfaces is the prominent feature of this biomaterial. This flexible material, termed by the authors, ‘Tough Adhesive’, functions by conferring high strength on wet tissue surfaces, similar to that found between cartilage and bone and shows promise for multiple organ types of tissue scaffolding and wound dressing applications [85].

3.8.10  Hydrocolloid dressings Hydrocolloid dressings can have various compositions, but the most common has a backing (outer layer) of either a vapour-permeable film or thin sheet of foam on which a mixture of sodium carboxymethyl cellulose (CMC), elastomers, adhesives and gelling agents are coated. Once the product is fixed on the wound, the warmth softens the lining of the dressing providing a gel cover for the wound bed. Hydrocolloid dressings are able to absorb a minimal amount of exudate and once its capacity is reached the remainder may leak out from under the dressing, termed ‘strike-through’. The strike-through can be fast and, therefore, these dressings are best suited for rehydrating dry black/brown necrotic tissues and wounds containing dry yellow slough. The hydrocolloid dressings are available in many shapes and some also have an additional adhesive border to prevent leakage or sliding of the dressing over the wound.

3.8.11  Hydrogel dressings There are two types of these dressings.

3.8.11.1   Amorphous gels Amorphous gels donate moisture to a dry wound and are, therefore, used for rehydrating dry necrotic or sloughy tissues and keeping granulation tissues moist – in much the same way as do the hydrocolloids. If the wound is sloughy and wet, this dressing will not be suited for the application. The amorphous gels come in a variety of forms and some have hydrocolloid or alginate added in an attempt to make them better at

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debriding or coping with wet wounds. The amorphous gels require a secondary dressing, usually a vapour-permeable film. The viscosity of amorphous hydrogels contributes to its function, and its ability to maintain integrity after absorbing wound fluid determines its role in moist wound healing. Less viscous types liquefy after absorbing small amounts of exudate, and thereby add fluid to the wound. However, the more viscous types maintain their structure and form a protective barrier over the site, thereby sequestering wound fluid and increasing the bioavailability of the exudate constituents, including proteases, for autolytic debridement and wound repair.

3.8.11.2  Sheet gels (non-amorphous gels) The non-amorphous gels provide a moist interface at the wound bed but do not donate as much water as do the amorphous gels and are, therefore, not the first choice for rehydrating a wound. However, they do provide a moist cover for granulating wounds. They are very soothing to wounds, making the dressings particularly suitable for use on superficial burns, including those caused by radiotherapy reactions. Because they are gentle on removal, they are also suitable for use on easily damaged skin. The sheet gels come in adhesive and non-adhesive versions.

3.8.12  Foam dressings Foam dressings usually consist of coatings of foamed solutions of polymers on sheets. The foam has small and open cells capable of holding fluids. Their absorption capacity depends on the thickness of the layer and the material. Foams are permeable to gases and water vapour, but not to aqueous solutions and exudate. Foams absorb blood and tissue fluids while the aqueous component evaporates through the dressing. Cellular debris and proteinaceous material are trapped in the material. These dressings are generally used on partial- and full-thickness wounds.

3.8.13  Antimicrobial dressings Almost any type of dressing, i.e., sponge, gauze, film or absorptive, can be made to have antimicrobial properties by incorporating agents such as silver and iodine. Silver is easily incorporated into chitosan and alginate products, thus it can greatly enhance their antimicrobial protection for the wound. A unique benefit of using silver in dressing is that it is highly effective in minute amounts (∼1 ppm) [74]. Interest in the antimicrobial properties of honey dates back to ancient Egyptian times [86,87]. Honey is a viscous and hygroscopic liquid consisting of glucose hydrolysates and a mixture of complex polysaccharides in the presence of various flavonoids and polyphenols. Honey has indicated ability to effectively inhibit more than 60 pathogenic bacterial strains [88]. Honey displays an osmotic effect because of its hygroscopic nature wherein its high sugar concentration (76 g/100 mL) dehydrates bacterial cells and the acidity (pH = 3.6–4.2) inhibits microbial growth [87,89,90]. The bacteriostatic and bactericidal properties of honey are enhanced by a combination of antioxidants, flavonoids and polyphenols, which generate hydrogen peroxide (H2O2), causing chemical oxidation of the organelles within the bacterial membrane [91].

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A concentration of 0.52–2.68 mM of H2O2 releases the reactive oxygen species, which eliminate bacterial cell growth [92,93]. It is notable that wounds treated with honey either alone or as incorporated in a dressing is able to initiate healing in infected situations that would typically not respond to conventional antibiotic and/or antiseptic therapy; therefore, the use of honey is a favourable treatment for ulcers, bed sores and burns irrespective of whether it is infected with bacteria [93,94]. The use of the same in chronic wounds counteracts hypoxia, by increasing oxygen in the lesion via H2O2 and may account for a wounds lack of healing when handled with conventional antibiotic and antiseptic therapy [95].

3.8.14  Silicone dressing These are atraumatic dressings (they do not cause trauma to newly formed tissue or tissue in the peri-wound area) based on soft silicones, which are a particular family of solid silicones, that are soft and tacky, and which, therefore, tend to adhere to dry surfaces. A silicone dressing consists of a contact layer that is coated with silicone. These materials are inert and their main attribute is that they can be removed from a sensitive wound without causing trauma. The exudates can also be absorbed but this is accomplished by using an absorbent dressing that is given a silicone coating. These dressings are particularly recommended for use as the first-line prophylactic treatment against development of hypertrophic scar and keloid after surgery [96]. A mechanism proposed for use of silicone in treating hypertrophic scars is that it causes reduction in production of collagen associated with scar formation and wound remodelling [97,98].

3.8.15  Categories based on the management of moisture The dressings discussed above can be further grouped into three main types [32]:

3.8.15.1  Dressings that absorb exudates Absorbent dressings have a very high capacity for holding fluid. Hence, for a wound generating high levels of exudate, absorbent dressings will require fewer changes within a set period of time. Two of the materials that can support this function are the alginate and the foam products.

3.8.15.2  Dressings that maintain hydration As a wound heals more, its exudate generation becomes less. This is when the wound starts to granulate or fill in with new connective tissue. When exudate levels decrease, it is not advisable to use absorbent dressings as they may result in the dehydration of the tissues. In such a situation, all that is required is to maintain the hydration level. The hydrocolloid and the film products are suited for this application.

3.8.15.3  Dressings that donate moisture When wounds are completely dry, they become covered with a layer of dead tissue, which must be removed to allow the wound to heal optimally. Often such tissues

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are removed by autolysis debridement, which is slow digestion of the dead cells by enzymes. In such cases, maintaining a moist environment helps the process. The dressing should actively add moisture to the wound, and this is best achieved with a hydrogel material.

3.9  Healing-mechanism based specialty dressings The continued growth and development of wound healing science over the last 25 years has afforded knowledge on wound pathology and healing mechanisms that have been an impetus to insights into designing better healing dressings. For example, the role of growth factors in healing and the deleterious action of excessive proteases are two subject areas in the healing science that have led to concepts used in designing protease-modulating dressings. Some examples of mechanistic designs that are based on an optimal healing environment include the use of growth factors, an optimal MVTR, mentioned earlier, and low-level hydrogen peroxide generation, all associated with enhanced cell proliferation.

3.9.1   Protease-modulating dressings On a molecular level, chronic wound fluid comprises cytokines, chemokines, growth factor electrolytes and proteolytic enzymes, which are imbalanced and delay the normal healing cascade that should typically complete within 21 days [99–101]. In a chronic wound, healing can be stalled at the inflammatory phase indefinitely. Proteolytic enzymes, in particular, the MMPs and neutrophil serine proteases (HNE), are responsible for degradation of growth factors and of the ECM proteins [102]. In general, acute wounds have normal levels of MMPs (matrix metalloproteinases) and HNE (human neutrophil elastase), which facilitate the clearance of cellular debris [103,104]. However, chronic wounds have elevated levels of MMPs (0.1–0.2 U/mL) and HNE (0.02–0.1 U/ mL) depending on their type, e.g., diabetic, venous, pressure or arterial ulcers [105]. Elevated concentrations of MMPs and HNE not only delay the healing process but are also considered biomarkers for chronic wound treatment [22,106,107]. The reduction of harmful levels of proteases in chronic wounds has been a topic of increasing interest and focus in the design and preparation of dressings for non-healing wounds over the last two decades. The molecular features of a protease-sequestrant dressing material target protease size, charge, active site or protein conformation, to affect the selective binding of the protein to the dressing material and removing proteases from the wound bed. Previously reported active dressings designed to redress the biochemical imbalance in a chronic wound have been composed of collagen and oxidised regenerated cellulose [69], nanocrystalline silver–coated high-density polyethylene [72], which also serves as an antimicrobial, deferrioxamine-linked cellulose [108], electrophilic and ionically derivatised cotton [70], peptide [71] or its carbohydrate conjugates [109], or sulfonated ion exchange derivatives of hydrogel polymers [110]. Electrostatic uptake mechanisms have been demonstrated with in situ fluorescence

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hydrogels that both detect and trap proteases [111]. Phosphorylated cotton was shown to sequester both HNE and collagenase and was developed as an FDA-approved dressing by Edwards et al. [112,113]. More recently, the role of polyphosphates when incorporated into a foam matrix has been shown to sequester metalloproteases (MMPs) derived from Pseudomonas aeruginosa [23]. Interestingly, when combined with silver in a hydrogel base, polyphosphate was also found to give rise to anti-biofilm activity [114]. Also noteworthy is the work reported by several authors that addresses the mechanism of protease-lowering activity of phosphorylated analogs of dressings functionalised with active site inhibitors of elastase and MMP [112,115,116]. It is interesting that only recently has phosphate-mediated mechanism of actions been considered. A noteworthy finding is that phosphorylated surfaces may improve the accumulation of macrophages on the surface of dressing because they contain a mannose-6-phosphate receptor, which binds to phosphate and can support targeted macrophage-mediated wound therapies. Accordingly, a better understanding of the mechanism of healing involved at the molecular level and of the roles the biological, the material and the environmental factors play in influencing it can be expected to lead to the development of newer and better dressings, specially needed for the slow and non-healing chronic wounds.

3.10  Bandages The functions of bandages are to (1) hold a dressing in place, (2) apply compression in some applications, such as to arrest bleeding in heavily haemorrhaging wounds or to treat varicose vein or leg ulcers, (3) immobilise fractures, (4) tie anaesthetic tubes and (5) hold cuffs, masks and other parts of textiles worn by a healthcare person for personal protection, safety or ease of mobility. Commonly, bandages performing a load-bearing function are made up of knitted or woven textiles, some containing elastomeric threads for required stretch and recovery properties. Many types of products are available, including relatively inextensible, highly extensible, adhesive/cohesive, tubular and medicated paste bandages [117]. The non-extensible bandages, essentially woven with open weave for breathability and low weight, are used for holding an absorbent pad or dressing in place at sites where stretch is not required, for example, finger, arm or lower leg, tying anaesthetic tubes and drains in position, and holding up a surgeon’s trousers. The extensible bandages are used for retaining a dressing and applying compression for control of oedema and swelling in the treatment of venous disorders of the lower limb. The bandage should keep the dressing in close contact with the wound and not inhibit movement or exert significant pressure that causes pain or restricts blood flow. The compression dressing falls in a class by itself and is used primarily for treatment of varicose vein ailment. The optimum pressure needed varies with condition and place on the leg. The highest pressure is required at the ankle and the lowest on the upper thigh. Stockings in different sizes and having various mechanical properties are now available to fit a range of patients and provide gradient pressures of magnitudes suited for different specific categories of venous disorders. The pressures used are as low as 14 and as high as 40 mmHg. Mathematical analysis gives the bandage pressure

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P (Pa) on the surface as a function of the bandage tension T (N) – itself a function of the extension and the elastic modulus, the radius of curvature of the limb R (m) and the width of the bandage W (m) as:

P=

T RW

(3.1)

As the effects of superimposed layers are additive, a configuration involving two turns of a bandage will essentially double the pressure. Because the bandage pressure is inversely proportional to R, wrapping a bandage at a given tension T will give the highest pressure at the ankle, where R is lowest, medium pressure at the calf, and the lowest pressure at the thigh. Adhesive bandages are made of woven cotton or rayon fabric that is coated with a suitable adhesive. Highly twisted or crepe yarns in warp provide a degree of stretch and elasticity to the bandage that can serve as a structure for treatment of varicose veins and for immobilising orthopaedic fractures resulting from sport and other injuries. Cohesive bandages combine some of the characteristics of ordinary stretch bandage with those of adhesive products. While they do not adhere to the skin, a special coating on the surface enables layers to adhere to each other, thus preventing slippage and untying during use, including sports activity. The simplest form of a tubular bandage consists of a knitted tube of a lightweight fabric. These are used under orthopaedic casts or placed over arms or legs that are covered with a medication. Clearly, bandages are more directly textile structures that supplement dressings in treatment of wounds, both external and internal.

3.11  Fibrous materials used in dressings and bandages A number of polymeric materials are used as films, fibres and other structures for developing wound-dressing products. Some of the primary materials employed are cotton, rayon, polyester, nylon, polyolefins, acrylic, polyurethane, chitosan and alginate. No doubt some other materials have been considered, for example, recombinant silk, but for economic or technical reasons, they have either not passed beyond the experimental stage or are used in a limited way. A brief introduction to the chemical nature, the physical structure and the properties of the materials used in wound management products follows. An understanding of these can provide the manufacturer with a means of selecting the most appropriate material for a dressing for each different application.

3.11.1  Cotton The fibre that has been historically the most highly used in construction of dressings, absorbent pads and bandages is cotton, which still accounts for a significant volume of wound-care products in the world. The chemical structure of one repeat unit of the cellulose chain is shown in Fig. 3.8. Each repeat has three hydroxyl groups that

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Cellulose (cotton, rayon, lyocell)

CH2OH HH O O OH H

H OH OHH HH O CH2OH

H OH

O

H

O C N R' N C O ( R O )n C N R' N C O

Elastomer

H

O

RO – aliphatic structure (n ~ 10–30) R' – ring structure CH2OH HH O O OH H

Chitosan

H

Polyester (PET)

NH2

H

OHH HH O CH2OH

NH2

O CH2 CH2 O

O

O

C

C n

O

Polyamide

C (CH2 )5 NH

NH

Nylon 6

O

O C

Nylon 66

Polyacrylonitrile Polyolefin UHMWHD polyethylene

Polypropylene (iPP)

Alginic acid

O

(CH2 )4

H

H

C

C

H

CN

H

H

C

C

H

H

NH (CH2 )6 NH

C

n

n

CH3

CH3

C

C

CH2

CH2

H

H

O HO O

C n

OH O OH

O O HO m

Figure 3.8  Molecular structures of fibres.

n

OH OH O

O

n

n

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are capable of linking with neighbouring chains by hydrogen bonds. These groups, when free or weakly bonded, also attract and bond with water. The oxygen bridges between the repeat units allow chains to bend and twist, making the polymer flexible. The chains are quite long, and the fibre has over 60% crystalline structure. The most commonly used cotton in wound products is short (97% nucleic acid removal while retaining biomechanical strength. Both these products have been indicated for the treatment of non-healing ulcers and dermal wounds and have demonstrated the ability to reduce time to complete wound closure and increase healing rates compared with conventional care. In these processed acellular dermal matrices, the removal of

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the cellular components reduces the risk of rejection and the critical dermal proteins that remain minimise inflammation and facilitate cell infiltration and tissue revascularisation. Minimally manipulated human tissue products are classified as human cell, tissues and cellular and tissue-based products by the FDA. As a result, there are fewer restrictions on the applications for which these devices can be used and viewed as tissue transplants. Integra (Integra Life Sciences) and Promogran (Systagenix Wound Management) are two wound-healing products synthesised using extracted and polymerised collagen. Integra is a bilayer composite matrix of cross-linked collagen type I from bovine sources and a glycosaminoglycan (chondroitin 6-sulphate) isolated from shark skin. It has a semi-permeable silicone membrane that functions as a temporary epidermal layer by controlling water vapour loss and providing structural integrity. Promogran is a combination matrix composed of 55% bovine type I collagen and 45% oxidised regenerated cellulose that is freeze dried and formed into a 3-mm-thick sheet that is applied directly to the wound bed. Upon application, the composite matrix absorbs wound exudate to form a biodegradable gel that enhances fibroblast migration and proliferation. Clinical studies demonstrate a significant reduction in the concentration and activity of proteases in the wound exudate treated with Promogran and a greater reduction in wound size.

5.4.10  Composite dressing Composite dressings are versatile and convenient for both partial- and full-thickness wounds. A composite or combination dressings has multiple layers and each layer is physiologically distinct. Most of the composite dressings possess three layers. Composite dressings may also include an adhesive border of non-woven fabric tape or transparent film. They can function as either a primary or a secondary dressing on a wide variety of wounds and may be used with topical medications [95]. The outermost layer protects the wound from infection, middle layer is usually composed of absorptive material which maintains moist environment and assists in autolytic debridement and bottom is layer composed of non-adherent material which prevents from sticking to young granulating tissues. Composite dressings have less flexibility and they are more expensive and contain 3–4 layers. Each layer has its own function in absorbing and retaining the fluid and creating the correct environment for rapid healing. The first layer of superabsorbent composite dressing is the layer which is in direct contact with the wound and prevents adhesion to the wound. The second layer is the distribution layer and usually called wicking layer. This wicking layer ensures the proper distribution of the fluid across the dressing. The wicking layer is a fabric which is usually used for the uniform distribution of fluid. The third layer contains the SAP and is called absorbent layer. As soon as the exudate comes in contact with the SAP, the polymeric layer expands after absorbing, retaining the moisture and forming a gel. The formation of gel confirms the permanent retaining of exudates. As a result of this fact, a single dressing can be used for several days. Finally, the fourth layer is the outer layer covering of the dressing which is in contact with the clothing, bed sheets, etc., and should be hydrophobic. These layers as discussed above are jointly used as wound

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dressing which are packed with the help of adhesives. Market available products based on SAP technology are Mextra, Zetuvit Plus and Xtrasorb.

5.5  Example of bioactive dressing: di-O-butyrylchitin 5.5.1  General description of DBC An original method of synthesis of di-O-butyrylchitin, the soluble derivative of chitin, was worked out at the Technical University of Łódź, Poland [65,66]. The proposed method applied to chitin of different origin (crab, shrimp and krill shells and insect chitin) gave the products of definite chemical structure with a degree of esterification very close to 2 (Fig. 5.2). DBC is easily soluble in common organic solvents and has both film- and fibre-forming properties [67–72]. Such properties of DBC created the possibility of manufacturing a wide assortment of DBC materials suitable for medical applications in the form of films, fibres, non-woven, knitted materials and woven fabrics. It was also stated that the treatment of finished materials made from DBC, carried out under mild alkaline conditions, led to chitin regeneration without destroying their macrostructure [72]. Moreover, the regeneration of DBC to chitin resulted in improving the mechanical properties of the newly obtained materials containing regenerated chitin (RC) [74,75]. Thus, O-butyrylation of chitin, preparation of several forms of dressings from DBC and then returning to pure chitin in the process of alkaline hydrolysis of DBC materials gives the possibility of practically unlimited manufacturing of DBC and chitin-based dressing materials comfortable and easy in use. The first investigations of biological properties of DBC and RC materials, carried out in vitro and in vivo in accordance with the European standards EN ISO 10993 (‘Biological evaluation of medical devices’), showed good biocompatibility of both polymers [75,77,78,96,97] and their ability to accelerate wound healing [74,98]. The recent investigations published by Muzzarelli et al. [99] confirm the biocompatibility of DBC. The presented results indicated that DBC is not cytotoxic for fibroblasts and keratinocytes. The first clinical investigations into medical properties of DBC have been carried out at the Polish Mother’s Health Institute in Łódź, Poland. DBC samples under investigation have been used in the form of non-woven materials made at Technical

2

2 2

& 2

& + 

2

2 2

1+

& 2

& 2

& + 

&+

2 2

& &+

2 & 2

&+

2

2

2

1+

2

&

& 2

&

&+

&+

2

& + 

1+ 2

& 2 &+

Figure 5.2  Chemical structure of DBC after complete O-butyrylation (degree of substitution = 2).

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University of Łódź using krill chitin as a source of DBC. Results of their clinical investigations were presented on the sixth International Conference of the European Chitin Society [100] and published [101]. Further results have been received using non-woven dressing materials with DBC which were obtained from shrimp shell chitin. Combined results of clinical investigations of DBC non-woven dressing materials are used and explained in this chapter.

5.5.2  Biological properties of DBC: in vitro and in vivo assays The realisation of clinical investigations was preceded by the determination of biological properties of DBC fibres and wound dressings in the form of neutral polypropylene sheets covered bilaterally by DBC films. The investigations were carried out in accordance with the requirements of the standard EN ISO 10993 (‘Biological evaluation of medical devices’). They included investigation of cytotoxic effects of aqueous extracts of DBC fibres and wound dressings coated with DBC, investigation of haemolytic effects of aqueous extracts of DBC fibres, fulfilment of intracutaneous reactivity tests of aqueous extracts and evaluation of local tissue reactions after implantation of DBC fibres into the gluteal muscles of the Wistar rats and peritoneal cavity of mice BALB/C. Based on the results of biological investigation, the following final conclusions were drawn: • Tests of aqueous DBC extracts from fibres performed in vitro proved that cytotoxicity and haemolytic effects were not stated [77,97]. • After animal tests conducted in vivo on rabbits, no reaction could be noted as the result of the application of intradermal DBC fibres [77,97]. • No intensification of the tissue reaction after implantation of DBC fibres into the gluteal muscles of the Wistar rats [99] and into the peritoneal cavity of mice BALB/C [77] could be stated. The results of microscopic observation were the same, as those obtained in investigation of the reactions in the surrounding of the Maxon surgical threads [77]. • Tests of IL1β and IL6 interleukin levels in the peritoneal fluids of the experimental mice BALB/C have not proved the existence of statistically essential differences when comparing two animal groups: the group represented by animals with DBC fibres inserted into the peritoneal cavity with those of peritoneal implanted the Maxon surgical threads [77]. • It was confirmed, that the polypropylene non-woven materials coated with DBC do not demonstrate cytotoxicity and primary irritation effects; do not cause an increase in the activities of tumour necrosis factor-α, interferons or the nitrogen oxide level; and have an active positive influence on the wound healing process [74,97]. • DBC materials showed the activity of blood procoagulation and have no influence on the activity of the plasma protein coagulation system [102].

5.5.3  Rationale for the possible provision of butyrate Short-chain fatty acids, especially butyrate, play central metabolic roles in maintaining the mucosal barrier in the gut. A lack of butyrate, leading to endogenous starvation of enterocytes, may be the cause of ulcerative colitis and other inflammatory conditions. The main source of butyrate is dietary fibre, but they can also be derived from structured biopolymers like DBC. Butyrate has been shown to

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increase wound healing and to reduce inflammation in the small intestine [103]. In the colon, butyrate is the dominant energy source for epithelial cells and affects cellular proliferation and differentiation by yet unknown mechanisms. Recent data suggest that the luminal provision of butyrate may be an appropriate means to improve wound healing in intestinal surgery and to ameliorate symptoms of inflammatory diseases. It was also suggested that butyrate may inhibit the development of colon cancer [104,105]. Butyrate has a relatively short metabolic half life. The half-life of butyrate in plasma is extremely short, as peak plasma butyrate concentrations occurred between 0.25 and 3 h after application and disappeared from plasma by 5 h after the application.

5.5.4  Interaction between DBC and enzymes The enzymatic susceptibility of DBC and RC to enzymes and consequences on their polymer structure is an important characteristic for its use as bioactive wound dressing material. When dealing with DBC, the chemical nature of the modified chitin, an ester, suggests that it would be susceptible to enzymatic attack by lipases insofar as the removal of butyryl groups is concerned. DBC does not seem particularly prone to enzymatic hydrolysis; in fact, it is not hydrolysed by lysozyme and it is not degraded by lipases. Lysozyme and lipase being the main enzymes that could release oligomers of N-acetylglucosamine in case of use of chitin-based textiles and non-wovens in wound management, it seems that the biochemical significance of DBC is scarce. Collagenase and amylase do not appear to be able to remove any significant portion from the fibres; however, it should be said that collagenase has a certain tendency to adhere to the fibres while exerting poor activity on them. Even crude cellulase and pectinase preparations exerted very little hydrolytic activity on DBC over the extended period of 48 days at 25°C. It can thus be added that DBC seems to be relatively resistant to biodegradation. This resistance to biodegradation will be further discussed in the chapter describing the clinical experiments. These clinical experiments indicate a complete biodegradation of DBC when applied as bioactive material in wound dressings.

5.5.5  Haemocompatibility The contact angle value for untreated human blood decreased with time from the initial value of 60–42 degrees in 21 min. The contact angle values for heparinised blood were slightly but significantly lower, because of the addition of heparin, and decreased with time at a comparable rate, from 53 to 42 degrees. The relatively modest values for the angles observed indicated that DBC is wettable by human untreated and heparinised blood. However, DBC is less wettable than glass. On glass slides, the contact angle decreased from 23 to 16 degrees for heparinised blood in 17 min. The fact that the drops of untreated blood deposited on DBC film maintained their shape after 21 min is indicative of the absence of thrombogenic or coagulation-enhancing capacity in DBC. The values for saline (9 g/L NaCl) were the following: DBC 75 degrees, chitin 56 degrees and chitosan 64 degrees.

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5.5.6  Radical scavenging activity of DBC DBC was submitted to the action of free radicals to detect its scavenging activity. The radicals were benzyl radical C6H5CH2% and adamantyl radical C9H13%, both generated in situ by photoactivation from stable precursors. Because of their very short life, they were stabilised with the spin trap dimethyl pyrroline N-oxide (DMPO). DBC solutions in dichloromethane containing a precursor of benzyl radicals were exposed to sun light or UV under inert atmosphere. The spectra were recorded with a Bruker EPR spectrometer in water–acetonitrile DMPO solution. The NMR spectra obtained on the chromatographic fractions from a silica gel column showed the formation of adducts of DBC and benzyl group. Similar preliminary results were obtained with the adamantyl radical. The EPR spectra recorded in water– acetonitrile DMPO solution for adamantyl radicals, the same with added DBC and for irradiated DBC in the absence of radical precursors show the following: • DBC alone does not produce radicals upon irradiation • DBC is a free radical scavenger because it modifies the radical species of the adamantan type. • DBC forms adduct with the benzyl radicals.

These results are in agreement with published results [85] which found that oligomeric species of chitosan exhibit radical scavenging activity towards a number of radicals (other than those used here). Normally, the radical scavenging activities of chitin or chitosan are strongly dependent on the degree of acetylation. Chitosan with the highest degree of deacetylation is characterised by the highest radical scavenging properties, as a result of the high amount of free amino groups. The scavenging mechanism of chitosan on free radicals may be related to the fact that free radicals can react with the residual amino groups NH2 to form stable macromolecule radicals and the NH2 groups can form ammonium groups NH3 + by absorbing hydrogen ion from the solution. The good results of DBC as free radical scavenger and antioxidant is the result of a totally different mechanism because most of the NH2 groups are acetylated in the used DBC, degree of acetylation equals 89%. Probably, the free radicals are reacting with the CH2 groups of the o-substituted butyryl groups. These radical-containing CH2 groups are stable for a long time and are consequently neutralised by the reaction with other compounds containing a radical. The free radical scavenger action and antioxidant capacity of DBC is related to the presence of the bytyryl groups and their stable radical substances. This antioxidant capacity of DBC can be an important factor for non-healing acute wounds. Whereas healing acute wounds have low levels of protein-degrading enzymes, exudates from non-healing chronic wounds contain elevated levels of proteases, like matrix metalloproteinases and elastase [4–6]. Moreover, the concentrations of proinflammatory cytokines [7] and reactive oxygen species [8] are significantly higher, compared with the concentrations in acute wounds. Reactive oxygen spe− cies, such as superoxide radicals (O2 ) and hydroxyl radicals (OH%), and reactive nitrogen species, such as nitric oxide (NO%), arise from inflammatory cells [9–11]. Overproduction of reactive oxygen and nitrogen species results in an imbalanced oxidant/antioxidant static in wounds and especially in chronic wounds [8,11,12]. As a

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result of the resulting disproportion between degradation and remodelling processes, chronic wounds persist in the inflammatory phase of the normal healing process for months or even years. The reduction in reactive oxygen and reactive nitrogen species in the wound fluid by the free radical scavenger action of DBC seems to be a logical way to stop the inflammation process, diminish epithelisation and to start the normal healing process.

5.5.7  In vitro and in vivo investigations The main reason of research in wound dressing material made form DBC is to understand the mechanism of wound healing by DBC-based material. The in vitro and in vivo investigations were released in cooperation with the Medical Academy in Wroclaw, Poland. Conducted experiments describe main biomedical characteristics like cytotoxicity, intradermal reactivity and immunological response. Also the biodegradability was investigated. Obtained results show that DBC has got comparable properties as chitin or RC, and all requirements described by European Standards are fulfilled. Clinical investigation conducted in Polish Mother Memorial Hospital shows a positive influence of DBC fabric onto wound healing. The following conclusions were obtained from these experiments: 1. DBC exerts not only local but also general effects on animal organism (influence on thermoregulation) 2. Similar phenomena were seen in animals treated with RC. 3. In the wounds, several beneficial effects of implanted inserts containing DBC dressings were seen: increase of granulation tissue weight, anti-edematic properties, elevation of the glycosaminoglycans content and improvement of collagen quality in the wounds 4. Results of the present experiments and clinical studies strongly support suggestion that DBC is a good dressing material in improving the healing process.

5.5.8  In vivo animal experiments The healing of surgical wounds after polypropylene non woven materials coated with DBC (DBC-MP) implants in rats followed the regular course; thus, the presence of DBC did not delay the early stages of the healing process. Clear indications of resorption were obtained. The role of DBC is essentially confined to imparting better handling and mechanical resistance; it does not seem that DBC has any relevant role in promoting the ordered regeneration of the wounded tissues, in consideration of its scarce susceptibility to enzymatic hydrolysis by lysozyme, lipase, collagenase and amylase. The information that DBC is also poorly degraded by other enzymes, such as raw cellulase and pectinase might be important in other fields: DBC appears to be particularly resistant in the environment, taking into account that chitin and chitosan were recognised as promptly degradable by both enzyme preparations and in particular by Aspergillus niger pectinase. Additional experiments indicated that when DBC is put into an alkaline medium, a slow hydrolysis of the DBC took place until the medium is returned to a neutral

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pH. DBC may be an important material to control and regulate the pH of the wound during the healing process. As already mentioned, the pH is an important parameter for wound healing and the control of the pH until neutral constitutes an important positive effect of DBC on wound healing. The objectives of the in vivo animal experiments were to evaluate the in vivo behaviour of the material with regard to: • their anti-inflammatory properties • their wound healing properties • their biodegradation.

To investigate the wound healing efficiency of DBC dressing materials, the dressings were placed on the wound bed of critical size skin defects. Twelve Wistar Han rats (6 male, 6 female, 60 days old) were used. Histological evaluation of the wound area and surrounding healthy tissue at different time points post-injury was performed. The wounds covered with the DBC dressing and the SeaSorb alginate showed the best wound healing: dens collagen in the connective tissue with a lot of blood vessels and some skin appendages at day 35 post-injury. The main difference was that the DBC material was degraded (complete absorption of the material was noticed after 35 days). The DBC material could stay on the wound during the healing process, while this alginate should be removed after a couple of days. As a result of this biodegradable property, DBC-based dressing has advantage compared with other available wound dressing materials. In contrast with the laboratory tests of DBC with different enzymes to study the enzymatic hydrolysis of DBC, DBC is completely degraded in this application of wound dressing material. This difference will be discussed later on, after the description of the clinical experiments. The best choice for solubility and bioactive dressing materials based on acetylated chitosan seems to be around 50% substitution. This follows also from the absorption of chitin or chitosan fibres into wounds as a function of the degree of substitution as represented in Fig. 5.3. The fast absorption, in vivo, of chitin fibres into treated wounds is obtained with chitin containing 50% acetylglucosamine. These fibres are completely absorbed in 1 week against 4 weeks for the used chitin fibres with 90%–100% acetyl groups. The

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Figure 5.3  Time for complete absorption of chitin fibres into wounds.

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complete absorption of the chitin fibres into the wounds is a result of the combined action of two enzymes, lipases for the hydrolysis and lysozymes for the breakdown of the hydrolysed chitins into his basic monomers or oligomers. This time for complete absorption of the chitin fibres corresponds with the time necessary for the complete absorption of the DBC-based fibres.

5.5.9  Results of clinical investigations As far as thermal burn patients are concerned, the depth of the wound was evaluated as 2a in all cases. It means there was no necrotic tissue and no indication for operative treatment. In all cases, healing was quick and uneventful, and in no case infection developed. Regarding the only child with electric burn – the first step of procedure was the removal of necrotic tissue. The application of DBC, as preparation for surgery, and operation itself followed. The non-septic wounds are by definition an indication for surgical treatment. As a matter of fact, all patients presented were primarily treated this way. In three of them, after plastic operation, small unhealed patches with granulation were stated. No signs of infection and no necrotic tissue were indicated. All these places healed up soon after the application of DBC. Another four children suffered mechanical injury, and the wounds were complicated by the presence of necrotic tissue. The first stop in all cases was the removal of necrosis followed by the use of DBC. Two of them were considered as candidates for further surgery, but this was the case only in one patient. Surprisingly, the other one healed up soon enough to avoid surgery. The greatest surprise was the uneventful progress, which took place by two children repeatedly operated for open, complicated leg fracture. The wounds were clean, without necrosis but with exposed bone in the centre. Despite this, they healed up quickly. The third such patient hopefully will be going the same way. DBC was also applied in three other children with various entities. They all have two things in common: the lesion of the skin/epidermis and the absence of necrosis and infection. In all cases, DBC dressings have been applied to the clean wound and not removed till the end of the healing process, while DBC has been disintegrated in the area of the wound. No other medical products have been applied for the wound healing. Summarising, it is possible to conclude the following: • Preliminary results of DBC application are highly promising: DBC seems to promote wounds’ healing. • Selection of the patients for this treatment has to be meticulous: the tissues to be covered with DBC should be viable, possibly without infection. Otherwise, the results are doubtful as it was achieved in the case with bed sores. •  Further randomised trials with referential groups should be completed to obtain evidence-based proofs of beneficial effects of DBC wound dressings.

5.5.10  Biodegradation of DBC in wound dressings Research results show that matrix metalloproteinases are present at elevated levels during early wound healing and suggest that matrix metalloproteinases may play a significant role in wound healing. The matrix metalloproteinases are a family of zinc metallo-endopeptidases that can collectively cleave all components of the ECM.

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Early research work in the porcine skin model [106,107] identified changes in matrix metalloproteinases during wound healing. Collagenase activity was high early after wounding and declined with postoperative time, returning to baseline levels when epithelialisation was complete. Gelatinase activity followed a similar pattern. The activity of matrix metalloproteinases returns to normal as healing progresses [4]. A known enzyme that catalyses the deacetylation of N-acetylglucosamine to form glucosamine and acetate is a zinc-dependent enzyme [104], UDP-3-O-((R-3hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC). LpxC functions via a metalloprotease-like mechanism by using zinc-bound water as nucleophile. In the clinical experiments with DBC-based wound dressings, the matrix metalloproteinases will probably catalyse the deacetylation of DBC in the presence of zinc-bound water. The final result of this deacetylation reaction is the formation of O-butyrylated chitosan. Now, it is known from other research results that O-butyrylated chitosan is soluble in water [108]. So, a possible explanation for the complete resorption of DBC during the wound healing experiments is because of the deacetylation of DBC by the action of matrix metalloproteinases in combination with zinc-bounded water and the formation of a complete water-soluble derivative, O-butyrylated chitosan. This water-soluble derivate is completely absorbed in the wound and probably hydrolysed afterwards by other enzymes. The clinical experiments with DBC-based bioactive wound dressing materials elucidate a totally different action of wound healing and possible other approaches for bioactive wound dressing materials.

5.6  Future trends The role of bioactive dressing materials is to deliver substances active in wound healing. Wound dressing and wound management is an active area of research developing biocompatible dressings with more focus on bioactive materials incorporating growth factors. Speciality absorbents are the need for treatment of chronic wounds or highly exudating wounds. Most of the commercially available so-called bioactive wound dressings are based on the principle of occluding the wounds. Most of the bioactive wound dressing materials prevent the formation of scab by the action of absorbing the wound exudate secreted from the ulcer. These dressings keep a moist environment on the wound and prevent exposure to air and dehydration. In addition, they give the possibility to control the pH of the wounds, mostly because of their intrinsic acidic nature and the partial pressure of oxygen. Some of the commercially available bioactive wound dressing materials contains bioactive substances such as calcium, zinc or silver ions. More and more observed is the use of silver-based antiseptics. The new, advanced dressings are impregnated with silver-based antiseptics linked to their broad-spectrum activity and their lower propensity to induce bacterial resistance than antibiotics. Chitosan, chitin and their derivatives have been studied widely as bioactive wound dressing materials; however, wound-dressing materials based on these products are still not fully commercially available as the other bioactive dressing materials, such as alginates. Probably, the future trends of bioactive wound dressing materials will be

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found in the materials based on chitin, chitosan and their derivatives. A better knowledge and understanding of the action of these dressing in wound healing will be the basis for future developments of more bioactive dressing materials. As described, some of these materials are completely absorbed in the healing wound, must not be changed during the healing process and are characterised by an excellent antioxidant activity and some of them by a good anti-bacterial activity. So, there are a lot of possibilities for future developments of really bioactive dressing materials. Because of their complete resorption into the healing wounds, the use of powder instead of fibres or films is possible and can be an important factor for the price of the bioactive dressing materials and their final cost in the treatment of wounds. Also, the use of these materials can be expanded to individual use in addition to the classical clinical use. Examples of such bioactive dressing materials are dressings made from blends of chitosan and alginate [99], blends of alginate and water-soluble chitin [23]. Flexible, thin, transparent, novel chitosan-alginate polyelectrolyte complex membranes caused an accelerated healing of incision wounds in a rat model compared with conventional gauze dressing. Water-soluble chitin, or half-deacetylated chitin, can be prepared from chitosan by N-acetylation with acetic anhydride. Alginate and water-soluble chitin-blend fibres can be obtained by solution spinning into a coagulation bath. There is good miscibility between alginate and the water-soluble chitin. The introduction of water-soluble chitin in the fibres improves water-retention properties of the blend fibres compared with pure alginate fibre. The use of these blends based on alginate and chitin or chitin derivatives may be a further and next step in the development of new bioactive dressing materials. Another type of experimental bioactive dressing material is based on a blend of collagen and chitosan [107]. Wound dressing materials were obtained from these blends by electrospinning by using poly(ethylene oxide) as third component. Poly(ethylene oxide) was necessary to improve the processability of the blends and to obtain fibres by electrospinning. Electrospinning is a simple and effective method for preparing nanofibres with diameters ranging from 5 to 500 nm. Wound dressings from electrospun fibres potentially offer many advantages over conventional processes. With its huge surface area and microporous structure, the electrospun fibres could quickly start signalling pathway and interact with the enzymes present in the wound exudate. From animal studies, the membrane produced from the electrospun collagen/chitosan/ poly(ethylene oxide) fibres was better than gauze and commercial sponge in wound healing. The future development will be the production of nanofibres from chitin derivatives, by electrospinning of the aqueous solutions or ethanol solutions or by the direct production of nanoparticles from those derivatives. This will probably increase the biochemical activity of those derivatives. As also demonstrated by the example, the O-butyrylation of chitin or chitosan is an important modification of chitin and increases the biochemical activity of chitin or chitosan. Even water-soluble derivatives of chitin or chitosan can be obtained by O-butyrylation. Probably, an optimum choice of the acetylation degree of the starting chitin for O-butyrylation is still necessary to increase the bioactive action of those compounds. The increased biochemical activity of chitin derivatives by O-butyrylation

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is also supported by the wound healing activity of an ointment containing dibutyryl cyclic adenosine monophosphate [4]. Not only the degree of O-butyrylation but also the degree of N-acetylation or N-butyrylation and the porosity of the materials may be very important to obtain bioactive dressing materials with still better wound healing properties [109–111]. N-butyrylglucosamine has shown healing properties for bone and articular cartilage in animal models of arthritis [112,113] and can be a very interesting candidate for wound dressings. Partially butyrylated chitosan is a source of N-butyrylglucosamine and be easily obtained by a heterogeneous reaction in suspension. The fine particles of chitosan are suspended in a water/ethanol mixture (1 part water/2 parts ethanol) and reacted with butyric anhydride at room temperature (private communication). Although the butyrylation was the result of a heterogeneous reaction, acid-soluble chitosan could be obtained and easily transformed into fibres.

Acknowledgments The study on DBC has been supported by the European Commission in the form of the Project CHITOMED, QLK5-CT-2002-01330. My thanks go to all companies, universities and collaborators involved in the research project and their references are cited in the publications and references concerning DBC.

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[81] A. Anitha, S. Sowmya, P.T. Sudheesh Kumar, K.P. Chennazhi, H. Erhlich, Chitin and chitosan in selected biomedical applications, Prog. Polym. Sci. 39 (9) (2014) 1644–1667. [82] A.C.A. Wan, B.C.U. Tai, CHITIN – a Promising Biomaterial for Tissue Engineering and Stem Cell Technologies, vol. 31, 2013, pp. 1776–1785. [83] K. Azuma, R. Izumi, T. Osaki, S. Ifuku, M. Morimoto, H. Saimoto, S. Minami, Y. Okamoto, Chitin, chitosan, and its derivatives for wound healing: old and New Materials, J. Funct. Biomater. 6 (1) (2015) 104–142. [84] R.A.A. Muzzarelli, Human enzymatic activities related to the therapeutic administration of chitin derivatives, Cell. Mol. Life Sci. 53 (1997) 131–140. [85] N. Inamdar, V. Mourya, Chitosan and low molecular weight chitosan: biological and biomedical applications, in: Advanced Biomaterials and Biodevices, John Wiley and Sons, 2014, pp. 182–242. [86] M. Kucharska, M.H. Struszczyk, A. Niekraszewicz, D. Ciechanska, E. Witczak, S. Tarkowska, K. Fortuniak, A. Gulbas-Diaz, A. Rogaczewska, I. Ploszaj, A. Pluta, T. Gasiorowski, Tromboguard® - first aid wound dressing, in: Progress on Chemistry and Application of Chitin and its Derivatives, vol. XVI, 2011, pp. 121–130. [87] http://www.aspenmedicaleurope.com/wp-content/uploads/2013/10/Denyer-J.-GibsonE.-Kytocel Severe-EB-Wounds-UK-2014-550L10.14.pdf. 30.01.2016. [88] A. Niekraszewicz, Chitosan medical dressings, Fibres Text. East. Eur. I3 6 (54) (2005) 16–18. [89] M.H. Struszczyk, J.K. Struszczyk, Medical applications of chitin and its derivatives, in: Polish Chitin Society Monograph, vol. XII, 2007, pp. 139–147. [90] K. Skolucka-Szary, P. Rieske, S. Piaskowski, Practical aspects related to applications of chitin and its derivatives in wound management, CHEMIK 70 (2) (2016) 89–98. [91] S. Dhivya, V.V. Padma, E. Santhini, Wound dressings – a review, Biomedicine 5 (4) (2015) 24–28 Article 4. [92] B. Liesenfeld, D. Moore, A. Mihaylova, J. Vella, R. Carr, G. Schultz, et al., Antimicrobial wound dressings – mechanism and function, in: Symposium on Advanced Wound Care, 2009. [93] L. Zaulyanov, R.S. Kirsner, A review of a bi-layered living cell treatment (Apligraf (®)) in the treatment of venous leg ulcers and diabetic foot ulcers, Clin. Interv. Aging 2 (2007) 93–98. doi:10.2147. [94] D.C. Aduba Jr., H. Yang, Polysaccharide fabrication assessment as candidate wound dressing materials, Bioengineering 4 (2017) 1–16. doi:10.3390. [95] S. Sharma, A. Dua, A. Malik, Third generation materials for wound dressings, IJPSR 5 (6) (2014) 2113–2124. [96] D. Paluch, L. Szosland, J. Staniszewska-Kuś, L. Solski, M. Szymonowicz, E. Gębarowska, The biological assessment of chitin fibres, Polym. Med. XXX (V) (2000) 3–32. [97] L. Szosland, I. Krucińska, R. Cisło, D. Paluch, J. Staniszewska-Kuś, L. Solski, M. Szymonowicz, Synthesis of dibutyrylchitin and preparation of new textiles made from dibutyrylchitin and chitin for medical applications, Fibres Text. East. Eur. 9 (34) (2001) 54–57. [98] Polish Patent P 370755, 2004. [99] R.A.A. Muzzarelli, M. Guerrieri, G. Goteri, C. Muzzarelli, T. Armeni, R. Ghiselli, M. Cornellisen, The biocompatibility of dibutyryl chitin in the context of wound dressings, Biomaterials 26 (2005) 5844–5854. [100] A. Chilarski, L. Szosland, I. Krucińska, A. Błasińska, R. Cisło, Non-wovens made from dibutyrylchitin as novel dressing materials accelerating wound healing, in: Proceedings of 6th International Conference of the European Chitin Society, EUCHIS’04, Poznań, Poland, 2004.

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[101] A. Chilarski, L. Szosland, I. Krucinska, A. Błasinska, R. Cisło, The application of chitin derivatives as biological dressing in treatment of thermal and mechanical skin injuries, in: The Annual of Pediatric Traumatic Surgery, the Devision of Pediatric Traumatic Surgery, vol. 8, 2004, pp. 58–61(XXXII). [102] M. Szymonowicz, D. Paluch, L. Solski, S. Pielka, A. Błasińska, I. Krucińska, L. Szosland, Evaluation of the influence of dibutyrylchitin materials for activation of blood coagulation system, Eng. Biomater. 7 (2004) 123–125. [103] A. Wächtershäuser, J. Stein, “Rationale for the luminal provision of butyrate in intestinal diseases”, Eur. J. Nutr. 39 (2000) 164–171. [104] B.F. Hinnebusch, S. Meng, J.T. Wu, S.Y. Archer, R.A. Hodin, The effects of short-chain fatty acids on human colon cancer phenotype are associated with histone hyperacetylation, J. Nutr. 132 (2002) 1012–1017. [105] N.J. Emenaker, G.M. Calaf, D. Cox, M.D. Basson, N. Qureshi, Short-chain fatty acids inhibit invasive human colon cancer by modulating uPA, TIMP-1, TIMP-2, Bcl-2, Bax, p21 and PCNa protein expression in an in vitro cell culture model, J. Nutr. 131 (suppl. 11) (2001) 3041S–3046S. [106] M.S. Agren, C.J. Taplin, J.F. Woessner Jr., W.H. Eaglestein, P.M. Mertz, Collagenase in wound healing: effect of wound age and type, J. Investig. Dermatol. 99 (1992) 709–714. [107] M.S. Agren, Gelatinase activity during wound healing, Br. J. Dermatol. 131 (1994) 634–640. [108] H.S. Grant, G. Blair, G. McKay, Water-soluble derivatives of chitosan, Polym. Commun. 29 (1988) 342–344. [109] G. Schoukens, I. Krucinska, A. Blasinska, M. Chrzanowski, L. Szosland, P. Kiekens, Review of techniques for manufacturing Dibutyrylchitin nonwoven biomaterials, in: General Lecture, 2nd International Technical Textiles Congress, Instanbul/Turkey, July 2005, pp. 13–15. [110] G. Schoukens, Bioactive materials from butyrylated chitosan, in: 11th Annual Seminar and Meeting Ceramics, Cells and Tissues, October 2–5, 2007. Faenza, Italy. [111] G. Schoukens, P. Kiekens, I. Krucinska, New bioactive textile dressing materials from dibutyrylchitin, in: 3rd International Technical Textiles Congress, December 1–2, 2007. Istanbul, Turkey. [112] T. Anastassiades, K. Rees-Milton, H. Xiao, X. Yang, T. Willett, M. Grynpas, N-acylated glucosamines for bone and joint disorders: effects of N-butyryl glucosamine on ovaiectomized rat bone, Trans. Res. 162 (2013) 93–101. [113]  I. Brockhausen, D.G. Nair, M. Chen, X. Yang, J.S. Allingham, W.A. Szarek, T. Anastassiades, Human acetyl-CoA; glucosamine-6-phosphate N-acetyltransferase 1 has a relaxed donor specificity and transfers acyl groups up to four carbons in length, Biochem. Cell. Biol. 94 (2) (2016) 197–204.

Further reading [1] L. Yu, Biodegradable Polymer Blends and Composites from Renewable Resources, John Wiley and Sons, 2009, p. 136. [2] R.A.A. Muzzarelli, Chitins and chitosan for the repair of wound skin, nerve, cartilage and bone, Carbohydr. Polym. 76 (2) (2009) 167–182. [3] S. Pelka, D. Paluch, J. Staniszewska-Kuś, B. Zywicka, L. Solski, L. Szosland, A. Czarny, E. Zaczyńska, Wound healing accelerating by a textile dressing containing dibutyrylchitin and chitin, Fibres Text. East. Eur. 11 (2003) 79–84.

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[4]  M. Terbojevich, A. Cosani, Molecular weight determination of chitin and chitosan, in: R.A.A. Muzzarelli, M.G. Peter (Eds.), Chitin Handbook, European Chitin Society, Ancona, Potsdam, 1997, pp. 87–101. [5] J. Szumilewicz, L. Szosland, Determination of the absolute molar mass of chitin and dibutyrylchitin by means of size exclusion chromatography coupled with light scattering and viscometry, in: T. Uragami, K. Kurita, T. Fukamizo (Eds.), Chitin and Chitosan, Kodansha Scientific Ltd., Tokyo, 2000, pp. 99–102. [6] I. Krucińska, A. Błasińska, A. Komisarczyk, M. Chrzanowski, L. Szosland, Nowe materiały włókninowe wytwarzane bezpośrednio z roztworu dibutyrylochityny, Przegląd Włókienniczy 11 (2003) 3–5. [7] A. Błasińska, I. Krucińska, M. Chrzanowski, Dibutyrylchitin nonwoven biomaterials manufactured using electrospinning method, in: Proceedings of World Textile Conference - 4th AUTEX Conference Roubaix, France, 2004. [8] A. Komisarczyk, I. Krucińska, L. Szosland, W. Strzembosz, Influence of the rate of air flow onto the structure of nonwovens made from dibutyrylchitin solution, in: Proceedings of International Conference on “Magic World of Textiles”, Dubrovnik, Croatia, 2004. [9] M. Hernick, A. Genndios, D.A. Whittington, K.M. Rusche, D.W. Christanson, C.A. Fierke, UDP-3-O-((R)-3-hydroxymyristoyl)-N-acetylglucosamine Deacetylase functions through a general acid-base catalyst pair mechanism, J. Biol. Chem. 280 (17) (2005) 16969–16978. [10] C.J. Knill, J.F. Kennedy, J. Mistry, M. Miraftab, G. Smart, M.R. Groocock, H.J. Williams, Alginate fibres modified with unhydrolyzed and hydrolyzed chitosans for wound dressings, Carbohydr. Polym. 55 (2004) 65–76. [11] J.P. Chen, G.Y. Chang, J.K. Chen, Electrospun collagen/chitosan nanofibrous membrane as wound dressing, Coll. Surf. A Physicochem. Eng. Asp. 313–314 (2008) 183–188. [12] L.J. Zhou, I. Ono, Stimulatory effects of dibutyryl cyclic adenosine monophosphate on cytokine production by keratinocytes and fibroblasts, Br. J. Dermatol. 143 (2000) 506–512.

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6

Authors of the chapter: S. Rajendran, S.C. Anand School of Engineering, University of Bolton, Bolton, United Kingdom Editor of the chapter: S. Rajendran School of Engineering, University of Bolton, Bolton, United Kingdom

6.1   Introduction It has been predicted that there is a substantial market potential for advanced wound dressings. The advanced global wound care market is expected to reach USD 13.07 ­billion by 2022. In 2017, the market was dominated by North America followed by Europe and this trend is predicted to continue in the forthcoming years. The European wound care market is expected to register a compound annual growth rate of 3.6% during 2018–23. Ageing population creates increased demand for ulcer treatment. In the United Kingdom, the pressure ulcer treatment accounts for 4% of the National Health Service (NHS) annual budget. The annual cost of treating diabetic foot ulceration accounts for 5% of the total NHS budget. The treatment of venous leg ulcer creates considerable demands upon healthcare professionals throughout the world. The annual cost of treating patients with venous leg ulcers in the United Kingdom has recently been reported to be £1938 million [1,2]. The cost per healed wound ranged from £698 to £3998 per patient and that for unhealed wound ranged from £1719 to £5976 per patient. In the United States, venous leg ulcer affects 3.5% of people over the age of 65 and the estimated annual cost is from USD 1.9 to USD 2.5 billion. In the EU, the annual cost for treating patients with venous leg ulcers accounts for 1%–2% of the overall healthcare expenditure. In Australia, around 1% of the adult population suffer from venous ulceration. Venous ulcers are the most common type of chronic leg ulceration. Chronic ulcers are defined as those lasting 6 weeks or more [3]. In the United Kingdom alone, about 1% of the adult population suffers from active ulceration during their life time [4]. However, the precise prevalence of venous leg ulcers is currently unclear and the prevalence varies from 0.1% to 1.1% [2]. Approximately 400,000 patients have initial symptom of leg ulcer and 100,000 have open leg ulcers that require treatment [5]. About 80% of patients who have leg ulceration suffer with a venous ulcer. Some patients may have more than one episode of venous ulceration with estimated recurrence rates ranging from 6% to 15% [6]. The prevalence of leg ulcers increases with age affecting 1.69% of patients aged between 65 and 95 years. The incidence rate for patients in this age group is estimated at 0.76% for men and 1.42% for women [7]. It has been established that compression therapy by making use of compression Advanced Textiles for Wound Care. https://doi.org/10.1016/B978-0-08-102192-7.00006-0 Copyright © 2019 Elsevier Ltd. All rights reserved.

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bandages is an efficient treatment for healing various leg ulcers, despite surgical strategies, electromagnetic therapy and intermittent pneumatic compression (IPC).

6.2  Elastic compression bandages Bandages can be used for many purposes and include retention, support and compression. • Retention bandages are used to retain dressings in the correct position. • Support bandages provide retention and prevent the development of a deformity or change in shape of a mass of tissue because of swelling or sagging. • Compression bandages are employed mainly for the treatment of leg ulcers and varicose veins.

Elastomeric compression bandages made with rubber were first used in the late 19th century. However, these have now been replaced by lighter, stronger, more comfortable and washable bandages made from Lycra or other elastane fibres. Modern bandages are either woven or knitted and are designed to provide prescribed levels of compression in accordance with specified performance-based standards (Table 6.1). Table 6.1 

Types of bandages

Bandage

Commercial name

Remark

Retention bandage

Slinky, Stayform, K-Band, Easifix, Slinky, Crinx, Tensofix Crepe BP, Elastocrepe

Exerts very little pressure on a limb

Support bandage Compression bandages Light compression (3a)

J-Plus, K-Crepe

Moderate compression (3b)

Veinopress, Granuflex adhesive Compression Setopress, Tensopress Surepress Bilastic Forte, Blue line webbing Zincaband, Tarband, Quinaband, Icthaband

High compression (3c) Extra high compression (3D) Paste bandages

Tubular Bandages Elasticated Foam padded

Tubifast, Tubigrip, Netelast Tubipad

Prevents formation of oedema and supports joints Exert various pressure, according to the type on a limb Gives sub-bandage pressures of between 14 and 17 mmHg at the ankle Sub-bandage pressures between 18 and 24 mmHg 25–35 mmHg Up to 60 mmHg Woven cotton fabric impregnated with a medicated cream or past. Used for the treatment of eczema and dermatitis Dressing on awkward sites Provides padding and protection against physical damage

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6.3  Venous leg ulcers 6.3.1  Venous leg ulcers: problem It is important that the arterial and venous systems should work properly without causing problems to blood circulation around the body. Pure blood flows from the heart to the legs through arteries taking oxygen and food to the muscles, skin and other tissues. Blood then flows back to the heart carrying away waste products through veins. The valves in the veins are unidirectional, which means that they allow the venous blood to flow in upward direction only. If the valves do not work properly or there is not enough pressure in the veins to push back the venous blood towards the heart (chronic venous insufficiency), the pooling of blood in the veins takes place and this leads to higher pressure to the skin. Because of high pressure and lack of availability of oxygen and food, the skin deteriorates and eventually the ulcer occurs. The high venous pressure causes oedema followed by tissue breakdown. The initial indications of venous leg ulcers are oedema, swollen veins (varicose veins), stasis eczema, fibrosis, lipodermatosclerosis, atrophie blanche, ankle flare and blood clots in veins (deep vein ­thrombosis – DVT). DVT is a growing problem for long-haul flights. DVT blocks blood from flowing towards the heart. Venous ulcers appear in the gaiter area of the lower limb between the ankle and midcalf. They can vary in size ranging from very small to large ulcers that extend beyond the gaiter area. The wound is characteristically shallow, irregular in shape and has sloping well-defined borders. Typically, the skin surrounding the wound is thickened and hyperpigmented indicating lipodermatosclerosis [8]. With chronic ulcers, a yellow-white exudate is observed signifying the presence of slough. A shiny appearance indicates a fibrinous base, which inhibits new tissue formation and wound healing. Varicose veins and ankle oedema often accompany a venous ulcer [9]. Approximately 80% of patients who have a venous leg ulcer suffer from some form of discomfort, while 20% experience severe or unremitting pain [10].

6.3.2  Diagnosis of venous leg ulcers The diagnosis of lower limb ulceration must start by determining the patient’s full clinical history together with a physical examination of the condition. It is essential to identify possible risk factors that could cause ulceration or impact on the treatment of the ulcer. These risk factors could include arterial disease, trauma and malignancy [11]. A number of noninvasive test methods are available to the clinician for investigating the cause of leg ulceration and venous insufficiency. These test methods help to assess the arterial and venous circulation of the patient and can provide information on the location of blood reflux or an obstruction within the veins.

6.3.2.1   Doppler ultrasonography Doppler ultrasonography is used to measure the ankle-to-brachial blood pressure index (ABPI) of the patient. The ultrasound technique produces a signal that identifies the presence of blood flow within the arteries. The ABPI is obtained by measuring

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the systolic blood pressure within the dorsalis pedis or posterior tibial artery of the lower limb and the ipsilateral brachial artery of the arm [12]. The ratio between the ankle systolic pressure and the brachial systolic pressure provides the ABPI value. Measurement of the ABPI is important to exclude arterial disease as the cause of ulceration or as a possible risk factor that might inhibit treatment. Patients with the ABPI of >0.80 are suitable for high-compression bandage therapy for managing venous leg ulcers [13]. An index of about 0.8 or below is generally considered indicative of significant arterial disease. These patients should be excluded from high-compression bandage therapy because its use could lead to further ulcer complications or even limb amputation [14]. The Doppler ultrasonic measurement technique produces elevated readings when diagnosing patients who may have diabetes and other conditions with calcified arteries [15].

6.3.2.2  Ultrasound scanning and other therapies Colour duplex ultrasound scanning is currently the technique of choice to assess the venous system of the lower limb. The technique combines ultrasound imaging with pulsated Doppler ultrasound and provides detailed anatomic information of the superficial, deep and perforating venous systems. It can identify specific veins in which blood reflux occurs or obstructions which may be contributing to venous hypertension. A recent Cochrane study concluded the uncertainty of using the ultrasound (either high or low frequency), which improves the healing of venous leg ulcers [16]. The effectiveness of Electric Stimulation Therapy (EST), which facilitates the healing of venous leg ulcers for those who do not use moderate-to-high levels of compression (>25 mmHg), has been investigated and it was found that an average reduction in wound size of 23.15% was noted for the control group compared with 32.67% for the intervention [17] group. A study at the University of Leeds established that IPC therapy, a mechanical method of delivering compression to swollen limbs that can be used to treat venous leg ulcers and limb swelling because of lymphoedema increases venous leg ulcer healing compared with no compression [18].

6.3.2.3  Photoplethysmography and air plethysmography Photoplethysmography and air plethysmography are simple tests designed to evaluate calf muscle dysfunction and degree of venous reflux. The techniques are used to observe the change in blood volume within the lower limb before and after exercise. Application of a tourniquet to restrict blood flow within the superficial system allows the deep venous system to be assessed for a potential obstruction. Invasive venous tests such as ascending and descending phlebography are also used to assess venous insufficiency. Phlebography combines electromagnetic radiation (X-rays) and fluorescent materials to provide a technique that allows the veins to be clearly visualised. These immunofluorescence methods can detect venous outflow obstructions, provide information of valvular incompetence and also highlight the presence of pericapillary fibrin [19]. Phlebography is usually used before a patient undergoes valvular surgery.

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6.4  Venous leg ulcer treatment It should be stated that venous leg ulcers are chronic and there is no medication to cure the disease other than compression therapy. A sustained graduated compression mainly enhances the flow of blood back to the heart, improves the functioning of valves and calf muscle pumps, reduces oedema and prevents the swelling of veins. Mostly elderly people are prone to develop DVT, varicose veins and venous leg ulcers. Venous leg ulcers are the most frequently occurring type of chronic wound accounting for 80%–90% of all lower extremity ulceration. And compression remains the mainstay of treatment [20]. Compression treatment has been extensively covered in a Cochrane review [21].

6.4.1   Compression bandages Compression bandaging is the ‘Gold standard’ for managing venous leg ulceration and treating the underlying venous insufficiency [22]. The main function of a compression bandage is to exert external pressure onto the leg, and this is determined by its elastic properties. A recent study investigated the degree of pressure required to narrow and occlude the superficial and deep veins of the calf when a subject is in different body positions. For compression therapy to be effective, it has to exceed the hydrostatic pressure within the veins to narrow the vessels and achieve a subsequent increase in blood flow. Initial narrowing of the veins occurred at a pressure of 30–40 mmHg in both the sitting and standing positions and complete occlusion occurred at 20–25 mmHg (supine position), 50–60 mmHg (sitting position) and 70 mmHg (standing position) [23]. In a further study, Partsch [24] compared the different haemodynamic effects that are achieved when using compression stockings and compression bandages. The study concluded that compression stockings which exert external pressures of up to 40 mmHg are effective in increasing blood flow velocity (supine position) and reducing oedema after extended periods of sitting and standing. In addition, short-stretch and multilayered compression bandages which exert pressures of over 40 mmHg reduce venous hypertension during walking and improve the venous pumping function.

6.4.1.1   Classification Compression bandages are mainly classified as elastic and inelastic. Elastic compression bandages (Table 6.2) are categorised according to the level of pressure generated on the angle of an average leg. Class 3a bandages provide light compression of 14–17 mmHg, moderate compression (18–24 mmHg) is imparted by class 3b bandages and 3c type bandages impart high compression between 25 and 35 mmHg [25]. The 3d type extra high compression bandages (up to 60 mmHg) are not often used because the very high pressure generated will reduce the blood supply to the skin. It must be stated that approximately 30–40 mmHg at the ankle which reduces to 15–20 mmHg at the calf is generally adequate for healing most types of venous leg ulcers [26]. Compression stockings provide support to treat DVT and varicose veins and to prevent venous leg ulcers. They are classified as light support (Class 1), medium support (Class 2) and strong support (Class 3) [27].

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Table 6.2 

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Elastic bandage classification

Class

Bandage type

Bandage function

1

Lightweight conforming

2

Light support

3a 3b 3c 3D

Light compression Moderate compression High compression Extra high compression

Apply very low levels of sub-bandage pressure and are used to hold dressings in place. Apply moderate sub-bandage pressure and are used to prevent oedema or for the treatment of mixed-aetiology ulcers. Exert a pressure range of 14–17 mmHg at the ankle. Exert a pressure range of 18–24 mmHg at the ankle. Exert a pressure range of 25–35 mmHg at the ankle. Exert a pressure of up to 60 mmHg at the ankle.

6.4.1.2  Compression hosiery Elastic stockings are used for the treatment of DVT, which is associated with a risk of pulmonary embolism and post-thrombotic syndrome [28]. The recent introduction of two-layered high-compression hosiery kits may have provided an alternative solution for the treatment of venous ulceration because they are easier and safer to apply than traditional compression bandages and improve patient concordance [29]. The hosiery kits consist of two knee-high garments; a light compression (10 mmHg) understocking and a Class 3 compression-hosiery overstocking providing 25–35 mmHg. The understocking is applied on to the leg first and because of its smooth surface allows the overstocking to slip over it for ease of application. Compression stockings (antiembolism stockings) are the most commonly available and accepted methods for DVT treatment. Compression hosiery contains elastomeric yarns that are capable of recovering their size and shape after extension giving similar performance properties to longstretch compression bandages. There are three classification standards for graduated compression hosiery: the British Standard [30], French Standard [31] and German Standard [32]. It will be mentioned that attempts were made to produce a European Standard (draft ENV 12718:2001) but consensus could not be achieved and consequently the standard was cancelled [33]. The above standards generally classify compression hosiery according to the level of pressure exerted around the ankle (Table 6.3) [30–32]. Patients are advised to wear elastic stockings every day after the ulcer has healed to prevent recurrence [34]. However, in everyday practice patients are reluctant to wear compression hosiery on a long-term basis [35]. A systematic review concluded that there is circumstantial evidence to suggest that compression hosiery does reduce ulcer recurrence but there is no strong evidence to support this. In addition, high-compression stockings may be more effective than moderate compression in preventing ulcer recurrence [36]. Compression stockings (static graduated compression stockings – sGCS) are also used for most surgical and intensive care unit (ICU) patients to prevent venous thromboembolism mainly because sGCS enhance the blood flow in the deep vein system by creating a graduated pressure gradient from distal to proximal. However, some complications associated with the use of sGCS in ICU

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Table 6.3 

175

European classification of compression hosiery

Class

Support

British standard BS 6612:1985

French standard ASQUAL

German standard RAL-GZ 387:2000

1 2 3 4

Light Medium Strong Heavy

14–17 mmHg 18–24 mmHg 25–35 mmHg Not reported

10–15 mmHg 15–20 mmHg 20–36 mmHg >36 mmHg

18–21 mmHg 23–32 mmHg 34–46 mmHg >49 mmHg

have been reported elsewhere [37]. Accordingly, a study involving 1787 ICU patients revealed that a total of 40 patients (2.2%) developed sGCS-associated pressure injury.

6.4.1.3   Compression system Compression can be exerted to the leg either by a single-layer bandage or multilayer bandages. In the United Kingdom, four-layer bandaging system is widely used while in Europe and Australia the inelastic, two-layer, short-stretch bandage regimen is the standard treatment. A typical four-layer compression bandage system comprises padding bandage, crepe bandage, high-compression bandage and cohesive bandage. Both the two-layer and four-layer systems require padding bandage (wadding or orthopaedic wool) that is applied next to the skin and underneath the short-stretch or compression bandages. A plaster type inelastic bandage, Unna’s boot is favoured in the United States. However, compression would be achieved by three-layer dressing that consists of Unna’s boot, continuous gauze dressing followed by an outer layer of elastic wrap. It should be realised that Unna’s boot, being rigid, is uncomfortable to wear and medical professionals are unable to monitor the ulcer after the boot is applied. Unna’s boot provides a high working pressure when the calf muscle contracts, but very little pressure while the patient is at rest [38]. The high working pressure serves to increase blood flow, while the low resting pressure facilitates deep venous filling. The Unna’s boot is only effective in ambulatory patients and requires constant reapplication as leg volume decreases because of a reduction in oedema. Used widely in the United States, the Unna’s boot system is uncomfortable to wear because of its rigidity and is both expensive and difficult to apply. A multicentre study compared the venous ulcer healing rates between Unna’s boot and CircAid in 38 patients [39]. The time to heal for the Unna’s boot group of patients was 9.69 ± 3.28 weeks in comparison with the CircAid device group, for which it was 7.98 ± 4.41 weeks. The study data supported a trend towards more rapid ulcer healing in the CircAid device group but the results did not reach statistical significance as a result of the small number of patients studied. Short-stretch bandages function in a similar manner to the rigid/ inelastic Unna’s boot. They consist of 100% high twisted cotton yarns and are applied onto the limb at full extension. Unlike elastic bandages, short-stretch bandages firmly hold the calf thereby providing a high working pressure when the patient walks [40].

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A trial involving 40 legs from 36 patients with untreated venous oedema found that adjustable Velcro compression devices are more effective than inelastic bandages in reducing venous oedema [41].

6.4.2  Padding bandages (orthopaedic wool or wadding) Padding bandages play a significant role in the successful treatment of venous leg ulcers. A variety of padding bandages are used beneath compression bandage system as padding layers to evenly distribute pressure and give protection. They absorb high pressure created at the tibia and fibula regions. It will be noticed that the structure of a padding bandage is regarded as an important factor in producing a uniform pressure distribution. Research has shown that the majority of the commercially available bandages do not provide uniform pressure distribution [42,43]. A padding of at least 2.5 cm thickness is placed between the limb and the compression bandage to distribute the pressure evenly at the ankle and the calf region. Wadding helps to protect the vulnerable areas of the leg from the high compression levels required along the rest of the leg [44]. Padding can also be used to reshape legs which are not narrower at the ankle than the calf. It makes the limb more like a cone shape so that the pressure is distributed over a pressure gradient with more pressure at the foot and less at the leg. Generally, the longer a compression bandage system is to remain in place, the greater is the amount of padding needed. An ideal padding bandage should meet the following requirements: • light weight and easy to handle; • soft and impart cushioning effect to the limb; • capable of preventing tissue damage; • capable of distributing pressure evenly around the leg; • good absorption and wicking properties; • comfortable and should not produce irritation or any allergic reaction to the skin on prolonged contact; • should tear easily by hand and • should be cheap.

6.4.3  Ideal compression bandages It should be noted that compression bandages may be harmful if not applied properly. They provide high tension and high pressure. A thorough assessment involving several criteria is therefore essential before applying a compression bandage on a limb. For example, it is important to consider the magnitude of the pressure, the distribution of the pressure, the duration of the pressure, the radius of the limb and the number of bandage layers. The ability of a bandage to provide compression is determined by its construction and the tensile force generated in the elastomeric fibres when extended. Compression can be calculated by Laplace’s law, which states that the sub-bandage pressure is directly proportional to the bandage tension during application and the number of layers applied but inversely proportional to limb radius [45]. Subbandage pressure is a function of the tension induced into the compression bandage

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during application. Applying the bandage with a 50% overlap effectively produces two layers, which generates twice the pressure. When a compression bandage is applied at a constant tension on a limb of increasing circumference, it will produce a sub-­bandage pressure gradient with the highest pressure exerted on the ankle. The sub-bandage pressure will increase for people with smaller ankles. The ability of a bandage to maintain sub-bandage pressure is determined by the elastomeric properties of the yarns, the fabric structure and the finishing treatments applied to the fabric. The structure of a compression bandage is regarded as an important factor in producing a uniform pressure distribution. An ideal compression bandage should exhibit the following qualities: • provide compression appropriate for the individual; • provide pressure evenly distributed over the anatomical contours; • provide a gradient pressure diminishing from the angle to the upper calf; • maintain pressure and remain in position until the next change of dressing; • extend from the base of the toes to the tibial tuberosity without gap; • function in a complimentary way with the dressing and • possess nonirritant and non-allergenic properties.

6.4.4  Ideal bandage pressure Compression bandages are mostly used during the initial therapy phase where the aim of treatment is to reduce oedema and overcome venous insufficiency. A number of different types of compression bandage systems are commercially available and, as discussed, the bandages are classified as rigid/inelastic, short-stretch, long-stretch or multilayered. The type of fabric construction influences the degree of extensibility that the bandage will have. At some point, the bandage will not be able to extend or stretch any further (lockout) under a predetermined tension. Evidence suggests that a sub-bandage pressure of 35–40 mmHg at the ankle, which gradually reduces to 17–20 mmHg at the knee, is required to overcome venous hypertension and successfully treat venous leg ulcers [46]. A recent study investigated the degree of pressure that is required to narrow and occlude leg veins when a subject is in different body positions. The authors found that initial narrowing of the veins occurred at a pressure of 30–40 mmHg in both the sitting and standing positions. Complete occlusion of the superficial and deep leg veins occurred at 20–25 mmHg (supine position), 50–60 mmHg (sitting position) and 70 mmHg (standing position) [23].

6.5  Applications of bandages The elastic properties of the bandages help to provide a high recoiling force, which serves to increase venous flow and reduce venous hypertension. In addition, they conform easily around the lower limb and allow for frequent dressing changes. Skill is required to apply compression bandages at the correct tension and to avoid excessive sub-bandage pressures [47]. Application of high sub-bandage pressure on patients with any type of microvascular disease can lead to further occlusion and pressure

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necrosis of these vessels [48]. Some manufacturers supply compression bandages with a series of geometric markers printed onto the bandage surface. The markers assist in the application of a predetermined level of compression by visually distorting when the bandage is stretched to a specific tension. For example, printed rectangles become squares when the correct bandage tension is reached. In multilayer bandaging system, three or four layers of different types of bandage are used to provide external compression. Multilayer system may include a combination of nonwoven padding bandage, inelastic creep bandage, elastic compression bandages and cohesive (adhesive) bandage. The different properties of each bandage type contribute to the overall effectiveness of the bandage system. The elastic bandage component provides sustained compression while the cohesive bandage offers rigidity, thereby enhancing calf muscle pump function. The four-layer high-compression system developed by a clinical group at Charing Cross Hospital (London) has gained wide acceptance of use in the UK hospitals. The four-layer system was developed specifically to incorporate different bandage types and properties to overcome the clinical issues of exudate, protection of bony prominences and the ability to sustain sub-bandage pressure over a period of time [49]. In addition, the system was designed to apply the required 40 mmHg of pressure at the ankle, overcome disproportionate limb size and shape and to remain in position on the leg without slippage. Application of the four-layer system involves first applying a padding bandage layer from the base of the toes to just below the knee. A crepe bandage is applied next followed by an elastic compression bandage. Finally, a cohesive layer is applied to add durability and to complete the overall pressure profile. Examples of different types of compression bandages, cohesive bandages, padding bandages and multilayer compression systems are shown in Table 6.4. A multilayer high-compression bandage system has been shown to provide a safe and effective treatment option for uncomplicated venous leg ulcers. Ulcer healing rates of up to 70% at 12 weeks have been obtained [50]. The four-layer bandaging technique has been shown to heal chronic ulcers that have failed to respond with traditional adhesive plaster bandage systems [51]. A recent review on compression therapy for venous leg ulcers concluded that multilayer compression system is more effective than low-compression or single-layer compression [52].

6.6  Present problems and novel bandages During the past few years, there have been increasing concerns relating to the performance of bandages especially pressure distribution properties for the treatment of venous leg ulcers. This is because the compression therapy is a complex system and requires two-layer or multilayer bandages, and the performance properties of each layer differ from other layers. The widely accepted sustained graduated compression mainly depends on the uniform pressure distribution of different layers of bandages in which textile fibres and bandage structure play a major role. The padding bandages commercially available are nonwovens that are mainly used to distribute the pressure, exerted by the short-stretch or compression bandages, evenly around the leg otherwise higher pressure at any one point not only damages the venous system but also

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Table 6.4 

179

Illustration of bandages used in compression therapy

Bandage name

Function

Manufacturer

Tensopress Setopress SurePress Adva-co Dauerbinde K Silkolan Tensolan Comprilan Actiban Actico (cohesive) Rosidal K Co-Plus Tensoplus Coban Surepress Soffban K-soft Softexe Advasoft Flexi-ban Cellona Ultra-soft Ortho-band Formflex Profore Proguide Ultra Four System 4 K-four

Type 3c Long-stretch bandage Type 3c Long-stretch bandage Type 3c Long-stretch bandage Type 3c Long-stretch bandage Long-stretch bandage Type 2 Short-stretch bandage Type 2 Short-stretch bandage Type 2 Short-stretch bandage Type 2 Short-stretch bandage Type 2 Short-stretch bandage Type 2 Short-stretch bandage Cohesive bandage Cohesive bandage Cohesive bandage Padding bandage Padding bandage Padding bandage Padding bandage Padding bandage Padding bandage Padding bandage Padding bandage Padding bandage Padding bandage Multilayer compression system Multilayer compression system Multilayer compression system Multilayer compression system Multilayer compression system

Smith + Nephew Medlock Medical ConvaTec Advancis Medical Lohmann + Rauscher Urgo Limited Smith + Nephew Smith + Nephew Activa Healthcare Activa Healthcare Lohmann + Rauscher Smith + Nephew Smith + Nephew 3M ConvaTec Smith + Nephew Urgo Limited Medlock Medical Advancis Medical Activa Healthcare Lohmann + Rauscher Robinsons Healthcare Millpledge Healthcare Lantor (UK) Limited Smith + Nephew Smith + Nephew Robinsons Healthcare Medlock Medical Urgo Limited

promotes arterial disease. Therefore, there is a need to distribute the pressure equally and uniformly at all points of the lower limb and this can be achieved by applying an effective padding layer around the leg beneath the compression bandage. In addition, the padding bandages should have the capability to absorb high pressure created at the tibia and fibula regions. Wadding also helps to protect the vulnerable areas of the leg from generating extremely high pressure levels as compared with those required along the rest of the leg. The research carried out at the University of Bolton involving 10 most commonly used commercial padding bandages produced by major medical companies showed that there are significant variations in properties of commercial padding bandages [42,43], more importantly, the commercial bandages do not distribute the pressure evenly at the ankle and the calf region (Fig. 6.1). In addition, the integrity of the nonwoven bandages is also of great concern. When pressure is applied using compression bandages, the structure of the nonwoven bandages may collapse and the

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Figure 6.1  A spacer structure.

bandage would not impart cushioning effect to the limb. The comfort and cushioning effect are considered to be essential properties for padding bandages because they stay on the limb for several days. Twelve padding bandages which consist of single component fibres, binary blends and tertiary blends incorporating polyester, bicomponent fibres and natural fibres such as cotton and viscose have been designed and developed at the University of Bolton (Table 6.5). The salient properties of the developed bandages are the following: • all the developed padding bandages possess suitable bulkiness; • none of the bandages has lower tensile strength or breaking extension that hinders the performance characteristics of an ideal padding bandage; • the tear resistance of bandages, except 100% hollow viscose (NPB5), is high and this means that the bandage cannot be easily torn by hand after wrapping around the leg. However, making perforations at regular intervals across the bandage facilitates easy tearing; • the absorption of solution containing Na+ and Ca++ ions (artificial blood) is significantly high, irrespective of fibre type and structure; • the rate of absorption of all the developed bandages is also high and • the pressure distribution of all the novel bandages is good up to 60 mmHg (Fig. 6.2).

In the United Kingdom, multilayer compression systems are recommended for the treatment of venous leg ulcers [53]. Although multilayer compression bandages are more effective than single-layer bandage in healing venous leg ulcers [52], it is generally agreed by the clinicians that multilayer bandages are too bulky for patients and the cost involved is high. A wide range of compression bandages is available for the treatment of leg ulcers but each of them having different structure and properties and this influences the variation in performance properties of bandages. In addition, longstretch compression bandages tend to expand when the calf muscle pump is exercised, and the beneficial effect of the calf muscle pump is dissipated. It is a well-established practice that elastic compression bandages that have the extension of up to 200% are applied at 50% extension and at 50% overlap to achieve the desired pressure on the limb. It has always been a problem for nurses to exactly stretch the bandages at 50%

Novel padding bandages

Identification code

Product

Fibre type

Fibre dtex; length (mm)

NPB1 NPB2 NPB3 NPB4 NPB5 NPB6 NPB7 NPB8 NPB9 NPB10 NPB11

Single component Single component Single component Single component Single component Single component Binary blends Binary blends Binary blends Binary blends Tertiary blends

NPB12

Tertiary blends

Polyester Polyester (bleached) Hollow polyester Viscose Hollow viscose Lyocell Polyester/viscose Polyester/viscose Polyester/viscose Polyolefin/viscose Polyester/viscose/ cotton (bleached) Polyester/viscose/ polyolefin

3.3; 40 5.3; 60 3.3; 50 3.3; 40 3.3; 40 3.3; 38 3.3; 40/3.3; 40 3.3; 40/3.3; 40 3.3; 40/3.3; 40 2.2; 40/3.3; 40 3.3; 40/3.3; 40/1.8; 22 3.3; 40/3.3; 40/2.2; 40

Blend ratio

Structure

100% 100% 100% 100% 100% 100% 75%/25% 50%/50% 25%/75% 20%/80% 33%/33%/33%

Needlepunched (both sides) Needlepunched (both sides) Needlepunched (both sides) Needlepunched (both sides) Needlepunched (both sides) Needlepunched (both sides) Needlepunched (both sides) Needlepunched (both sides) Needlepunched (both sides) Needlepunched (both sides) and Thermal bonded Needlepunched (both sides)

60%/25%/15%

Needlepunched (both sides) and Thermal bonded

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Table 6.5 

181

182

Advanced Textiles for Wound Care 6.00

Pressure transference (mmHg)

5.00

4.00

7.3 (mmHg) 14.6 (mmHg) 21.9 (mHg) 29.3 (mmHg)

3.00

36.6 (mmHg) 43.9 (mmHg) 51.2 (mmHg) 58.6 (mmHg)

2.00

1.00

0.00 0

10

20

30

40

50

60

70

80

90 100 110 120 130 140 150

Fabric extension (%)

Figure 6.2  Effect of extension on pressure transference of spacer bandages – black 1.

and apply without losing the stretch from ankle to calf, although there are indicators for the desired stretch (rectangles become squares) in the bandages. The elastic compression bandages are classified into four groups (Table 6.3) according to their ability to produce predetermined levels of compression and this has always been a problem to select the right compression bandage for the treatment. The inelastic short-stretch bandage (Type 2) system, which has started to appear in the UK market, has the advantage of applying at full stretch (up to 90% extension) around the limb. The short-stretch bandages do not expand when the calf muscle pump is exercised and the force of the muscle is directed back into the leg which promotes venous return. The limitations of short-stretch bandages are that a small increase in the volume of the leg will result in a large increase in compression and this means the bandage provides high compression in the upright position and little or no compression in the recumbent position when it is not required. During walking and other exercises, the sub-bandage pressure rises steeply and while at rest the pressure comparatively drops. Therefore, patients must be mobile to achieve effective compression and exercise is a vital part of this form of compression. Moreover, the compression is not in close contact with the skin when reduction in limb swelling takes place during healing because the short-stretch bandage is inelastic, and it has already been stretched to its full extent. The main comparisons between elastic and inelastic bandages are published elsewhere (Table 6.6) [54]. The application of multilayer bandage system requires expertise and knowledge. Nurses must undergo significant practice-based training to develop appropriate bandage application skills needed for multilayer compression system. Successful bandaging relies upon adopting good technique in both stretching the bandage to the correct tension and ensuring proper overlap between layers. In addition, nurses need to have knowledge of the different performance properties of each bandage within the multilayer system and

Advanced textiles for wound compression

Table 6.6 

183

Comparison between elastic and inelastic bandages

Elastic bandages

Inelastic bandages

Elastic materials contain elastomeric fibres that are able to stretch by over 100% of the original length. Elastic bandages are generally applied at 50% stretch (see manufacturer’s instructions). Elastic bandages have a low static stiffness index, therefore exert a more constant pressure with little change in pressure on movement. Multilayer elastic systems can function in a similar way to inelastic systems as a result of the number of layers.

Inelastic or short-stretch materials contain few or no elastic fibres, increasing when stretched by considerably less than 100%. Inelastic bandages are commonly applied at 100% stretch (see manufacturer’s instructions). Inelastic bandages have a higher static stiffness index, generating higher working pressures on movement and lower resting pressures.

how each bandage combine is to achieve safe and adequate compression. The ability of multilayer bandage systems to maintain adequate compression levels for up to 1 week has reduced the necessity for frequent dressing changes and has therefore decreased treatment costs. However, the cost of multilayer compression system is still relatively high because of the requirement for specific bandage for each layer. Tolerance to multilayer compression system is generally good but non-compliance in some patients often results in prolonged or ineffective treatment. Some patients are unable to wear footwear because of the bulkiness of multilayer compression regimen. These patients often refuse treatment because the requirement to remain house-bound is totally unacceptable. At night patients find compression bandages too uncomfortable and often remove them to sleep. Because the application of multilayer compression systems is complex, most patients are unable to reapply the bandages themselves. It has been concluded from a recent review that the compression bandage system which contains both elastic and inelastic components (mixed-component systems) are comparably effective in enhancing the ulcer healing rates to alternative compression systems. In addition, it : • is easy to apply; • has similar abilities to maintain pressure as four-layer bandages and better abilities than short-stretch bandages; • has less slippage than alternative systems and • is significantly associated with several favourable quality of life outcomes [55].

To address some of the problems as mentioned above, a novel Nonwoven Varistretch Compression Bandage (NVCB) has been designed and developed at the University of Bolton. The principal features of the NVCB are listed below [56,57]: • Novel nonwoven technology was used to develop the variable compression bandages. It should be mentioned that no nonwoven compression bandages are listed in Drug Tariff. In the United Kingdom, the availability of wound dressings and bandages for use in patients’ homes is dictated by the Drug Tariff;

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• The performance and properties of the novel bandages are superior to existing multilayer commercial compression bandages. This fulfils the requirement of ideal variable pressure from ankle to below knee positions of the limb for the treatment of venous leg ulcers; and • Vari-stretch nonwoven bandages also meet the standards and the tolerances stipulated by BS 7505.

A recent innovation highlights the incorporation of colour changing pressure-­ sensing photonic fibres into the woven bandage structure [58]. These fibres change colour when the bandage is stretched and the desired right pressure can be achieved by using a calibrated colour chart.

6.7  Three-dimensional spacer compression bandages Recently, spacer technology has been increasingly used to produce three-dimensional (3D) materials for technical textiles sectors such as automotive, medical, sports and industrial market. The spacer technology is flexible, versatile, cost-effective and an ideal route to produce 3D materials for medical use. It is identified that spacer is the right technology to produce novel compression bandages that meet the prerequisites of both ideal padding and compression bandages. The main reasons for the current interest in 3D spacer fabrics for producing novel compression bandages are several-fold. In 3D spacer fabrics, two separate fabric layers are combined with an inner spacer yarn or yarns using either warp knitting or weft knitting route (Fig. 6.3). The two layers can be produced from different fibre types such as polyester, polyamide, polypropylene, cotton, viscose, lyocell, wool, etc., and can have completely different structures [59]. It is also possible to produce low-modulus spacer fabrics by making use of elastic yarns. Elastic compression could be achieved by altering the fabric 4.50

Pressure transference (mmHg)

4.00 3.50 3.00

7.3 (mmHg) 14.6 (mmHg)

2.50

21.9 (mHg) 29.3 (mmHg)

2.00

36.6 (mmHg) 43.9 (mmHg) 51.2 (mmHg) 58.6 (mmHg)

1.50 1.00 0.50 0.00

0

10

20

30

40

50

60

Fabric extension (%)

70

80

90

100

Figure 6.3  Effect of extension on pressure transference of spacer bandages – blue 4.

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185

structure. It should be mentioned that 3D structure allows greater control over elasticity and these structures can be engineered to be unidirectional, bidirectional and multidirectional. Unidirectional elasticity is one of the desired properties for compression bandages. The 3D nature of spacer fabrics makes an ideal application next to the skin because they have desirable properties that are ideal for the human body [60]. 3D fabrics are soft, have good resilience that provides cushioning effect to the body, are breathable and have the ability to control heat and moisture transfer [49]. For venous leg ulcer applications, such attributes together with improved elasticity and recovery promote faster healing. It must be stated that 3D spacer fabrics can also be produced using double-jersey weft knitting machines [59]. The main advantages of weft-knitted spacer fabrics over warp-knitted fabrics include cost-effectiveness because there is no need to prepare a number of warp beams and spun yarns and coarser count hairy yarns can be used on weft-knitting machines. Because of the problems associated with the currently available bandages for the treatment of venous leg ulcers as discussed in Section 6, ‘Present Problems and Novel Bandages’, it is vital to research and develop an alternative bandaging regimen that meets all the requirements of an ideal compression system. The research at the University of Bolton with an ultimate aim of developing a single-layer compression therapy regimen for the treatment of venous leg ulcers imposes significant challenges in developing 3D spacer bandages for compression therapy. There is no doubt that there would be substantial savings for the NHS in the United Kingdom and other health services in the world because the ultimate goal of the research programme is to replace the multilayer bandages with a single-layer bandage. A single-layer system simplifies and standardises the application of compression, is more patient friendly, reduces the nursing time and significantly decreases the treatment cost.

6.7.1  Effect of pressure transference of spacer bandages Four spacer fabrics identified as Black-1, White-2, White-3 and Blue-4 were used to study the pressure transference at various pressure ranges. Four padding bandages (PB1a to PB4a) recently available at Drug Tariff were also used for comparison. Pressure transference apparatus and extension test rig were used to study the pressure transference of spacer bandages both at unrestrained and stretch conditions. It will be observed in Fig. 6.4 that the pressure transference of different spacer bandages at any one point varies, and it mainly depends on the structure and fibre content of the material. It is interesting to note that spacer bandages distribute the applied pressure uniformly around the leg than the commercial padding bandages (Fig. 6.5). For instance, the White-2 spacer bandage absorbed the applied pressure of 43.9 mmHg and transfer 2 mmHg at one point. In other words, the absorbed pressure of 41.9 mmHg is uniformly distributed inside the fabric structure which is one of the essential requirements for venous leg ulcer treatment. On the other hand, the commercial padding bandage (PB4a) absorbed 43.9 mmHg and transferred 35 mmHg at one point (Fig. 6.5) and this means the bandage distributed only 8.9 mmHg uniformly inside the structure. The higher output pressure from the bandage at one point is undesirable and may slow down and/or block the blood flow in arteries.

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Advanced Textiles for Wound Care 10.00

Pressure transference (mmHg)

9.00 8.00 7.00

7.3 (mmHg) 14.6 (mmHg)

6.00

21.9 (mHg) 29.3 (mmHg)

5.00

36.6 (mmHg) 43.9 (mmHg)

4.00

51.2 (mmHg) 58.6 (mmHg)

3.00 2.00 1.00 0.00

0

10

20

30

40

50

60

70

80

90

Fabric extension (%)

Figure 6.4  Effect of extension on pressure transference of spacer bandages – white 2.

Pressure transference (mmHg)

7.00 6.00 5.00 7.3 (mmHg) 14.6 (mmHg)

4.00

21.9 (mHg) 29.3 (mmHg) 36.6 (mmHg) 43.9 (mmHg)

3.00

51.2 (mmHg) 58.6 (mmHg)

2.00 1.00 0.00

0

10

20

30

40

50

60

70

80

90

100

110

120

Fabric extension (%)

Figure 6.5  Effect of extension on pressure transference of spacer bandages – white 3.

Figs 6.6 to 6.9 represent the pressure transference of spacer bandages at known pressures under extension up to 120%. It is noticed that increase in applied pressure does not influence the pressure transference at any one point and the variation is marginal in all the samples. This affirms that these spacer fabrics can be used as ideal padding bandages, and by controlling the tension, it will be possible to generate the required pressure for the treatment of venous leg ulcers.

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187

Measured pressure (mm Hg)

60.00

50.00

40.00

PB1 PB2 PB3 PB4 PB5 PB6 PB7 PB8 PB9 PB10

30.00

20.00

10.00

0.00

2.93 5.86 8.79 11.72 14.6517.58 20.5123.4426.3729.22 32.1535.08 38.0140.9443.8746.8049.73 52.6655.6658.5259.99

Applied pressure (mm Hg)

Figure 6.6  Pressure distribution of commercial padding bandages.

Measured pressure (mm Hg)

60.00

NPB1

50.00

NPB2 NPB3

40.00

NPB4 NPB5 NPB6

30.00

NPB7 NPB8 NPB9

20.00

NPB10 NPB11 NPB12

10.00

0.00

2.93 5.86 8.79 11.72 14.6517.58 20.5123.44 26.37 29.2232.1535.08 38.0140.9443.8746.8049.7352.6655.6658.5259.99

Applied pressure (mm Hg)

Figure 6.7  Pressure distribution of novel padding bandages.

A pilot user study was conducted at the University of Bolton and the results show that the sustained graduated compression of the novel single-layer 3D spacer bandage is comparable with the two-layer compression bandage systems currently used [61]. The pressure profiles signify the desirable pressure graduation from the ankle to the knee. 3D spacer fabrics also have inherent excellent cushioning and pressure distribution characteristics, therefore dispensing with the necessity for the bulky padding bandage. Spacer bandages have many other attributes that can be beneficial in this type of application as they are lightweight, non-fraying, breathable, provide protective cushioning and have enhanced thermophysiological properties. The developed 3D single-layer bandage system for compression therapy not only simplifies the treatment but also reduces the application time and minimises the possible elements of error during application, not to mention potential cost-savings in time and materials.

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Advanced Textiles for Wound Care 60

Measured pressure (mmHg)

50

40

PB1a PB2a PB3a PB4a

30

20

10

0 0

2.94 5.9 8.81 11.8 14.7 17.6 20.6 23.5 26.4 29.3 32.2 35.2 38.1 41.1 44 46.9 49.9 52.8 55.7 58.6 60.1

Applied pressure (mmHg)

Figure 6.8  Pressure transference of commercial padding bandages. 12.00

Measured pressure (mmHg)

10.00

8.00 Black (1) White (2)

6.00

White (3) Blue (4)

4.00

2.00

0.00 7.3

14.6

21.9

29.3

36.6

43.9

51.2

58.6

Applied pressure (mmHg)

Figure 6.9  Pressure transference of spacer bandages – relaxed.

6.8  Conclusions Compression-delivery systems have an important role in the treatment of venous leg ulceration because they can reduce venous reflux, increase venous and arterial blood flow, improve microcirculation and reduce ankle oedema. There are a variety of compression bandaging systems available, the advantages and disadvantages of each are constantly reviewed and debated. In the United Kingdom, for example, four-layer

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189

bandaging system is popular and has shown to provide a safe and effective treatment option. Other countries, such as the United States prefer the rigid characteristics of the Unna’s boot. The success of any compression bandage system relies upon the skill and expertise of the clinician applying it. Besides, the effective management of venous leg ulcer involves careful selection of bandages to reverse the venous blood flow back to the heart. The chapter discussed the significant contribution of padding and compression bandages in healing the ulcer. The advantages and limitations of the existing two-layer and four-layer bandaging regimens are discussed in this chapter. It is obvious that the pressure transference of commercial padding bandages varied and none of the padding bandages investigated satisfied the requirements of an ideal padding bandage. On the other hand, the novel padding bandages exhibited a uniform pressure distribution around the leg. The chapter also demonstrated the need for developing a single-layer bandaging regimen for the benefit of elderly and cutting the cost of treatment. 3D spacer technology has been investigated and the results affirmed that spacer bandages would be utilised to design and develop a single-layer system that could replace the currently used cumbersome four-layer system. A suitable spacer structure can combine the desirable attributes of both the padding and 2-dimensional compression bandages into one composite 3-dimensional structure.

References [1] J.F. Guest, N. Ayoub, T. McIlwraith, I. Uchegbu, A. Gerrish, D. Weidlich, K. Vowden, P. Vowden, Health economic burden that different wound types impose on the UK’s National Health Service, Int. Wound J. 14 (2) (2017) 322–330. [2] B.A. Alexandra, W.B. Richard, Venous leg ulcers in the UK: the local burden of illness and the allocation of resources, Wounds U.K. 13 (2) (2017) 8–13 (Review). [3]  J. Reichenburg, M. Davis, Venous ulcers, Semin. Cutan. Med. Surg. 24 (4) (2005) 216–226. [4] W.A. Martson, R.E. Carlin, M.A. Passman, M.A. Farber, B.A. Keagy, F.N. Parent III, Healing rates and cost efficacy of outpatient compression treatment for leg ulcers associated with venous insufficiency, J. Vasc. Surg. 30 (3) (1999) 491–498. [5] P.K. Sarkar, S. Ballentyne, Management of leg ulcers, Postgrad. Med. J. 76 (2000) 674–682. [6] A.N. Nicholaides, Investigation of chronic venous insufficiency: a consensus statement (France, March 5–9, 1997), Circulation 102 (20) (2000) E126–E163. [7] D.J. Margolis, W. Bilker, J. Santanna, M. Baumgarten, Venous leg ulcer: incidence and prevalence in the elderly, J. Am. Acad. Dermatol. 46 (3) (2002) 381–386. [8] J.E. Naschitz, D. Yeshurun, I. Misselevich, J.H. Boss, The pathogenesis of lipodermatosclerosis: facts, uncertainties and theories, J Eur. Acad. Dermatol. Venereol. 9 (3) (1997) 209–214. [9] S.E. Zimmet, Venous leg ulcers: modern evaluation and management, Dermatol. Surg. 25 (3) (1999) 236–241. [10] P.J. Franks, C.J. Moffatt, N. Bosanquet, M. Oldroyd, R.M. Greenhalgh, C.N. McCollum, M. Connolly, Community leg ulcer clinics: effect on quality of life, Phlebology 9 (2) (1994) 83–86.

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[ 11] N.J.L. London, R. Donnelly, Ulcerated lower limb, BMJ 320 (2000) 1589–1591. [12] R.G. Sibbald, Venous leg ulcers, Ostomy Wound Manag. 44 (9) (1998) 52–64. [13] D.S. Sumner, Non-invasive assessment of peripheral arterial occlusive disease, in: K.S. Rutherford (Ed.), Vascular Surgery, third ed., WB Saunders, Philadelphia, 1998, pp. 41–60. [14] M.J. Callam, C.V. Ruckley, D.R. Harper, J.J. Dale, Chronic ulceration of the leg: extent of the problem and provision of care, Br. Med. J. (Clin. Res. Ed.) 290 (6485) (1985) 1855–1856. [15] M. McGuckin, M. Stineman, J. Goin, S. Williams, Draft guideline: diagnosis and treatment of venous leg ulcers, Ostomy Wound Manag. 42 (4) (1996) 48–54. [16] N. Cullum, Z. Liu, Therapeutic ultrasound for venous leg ulcers, Cochrane Database Syst. Rev. 5 (2017) CD001180, https://doi.org/10.1002/14651858.CD001180. [17] C. Miller, W.B. McGuiness, S.A. Wilson, K.C. Cooper, T.D. Swanson, D.E. Rooney, N.F. Piller, M.G. Woodward, Venous leg ulcer healing with electric stimulation therapy: a pilot randomised controlled trial, J. Wound Care 26 (3) (2017) 88–98. [18] E.A. Nelson, A. Hillman, K. Thomas, Intermittent pneumatic compression for treating venous leg ulcers, Cochrane Database Syst. Rev. 5 (2014) CD001899. [19] I.C. Valencia, A. Falabella, R.S. Kirsner, W.H. Eaglstein, Chronic venous insufficiency and venous leg ulceration, J. Am. Acad. Dermatol. 44 (3) (2001) 401–424. [20] S.D. Blair, D.D.I. Wright, C.M. Backhouse, E. Riddle, C.N. McCollum, Sustained compression and the healing of chronic ulcers, BMJ 297 (1988) 1159–1161. [21] N. Cullum, E.A. Nelson, A.W. Fletcher, T.A. Sheldon, Compression for venous leg ulcers, Cochrane Database Syst. Rev. 2 (2004) CD000265. [22] M. Choucair, T.J. Phillips, Compression therapy, Dermatol. Surg. 24 (1) (1998) 141–148. [23] B. Partsch, H. Partsch, Calf compression pressure required to achieve venous closure from supine to standing positions, J. Vasc. Surg. 42 (4) (2005) 734–738. [24] H. Partsch, Do we still need compression bandages? Haemodynamic effects of compression stockings and bandages, Phlebology 21 (3) (2006) 132–138. [25] S. Thomas, Bandages and bandaging: the science behind the art, Care Sci. Pract. 8 (2) (1990) 56–60. [26] D. Simon, Approaches to venous leg ulcer care within the community: compression, pinch skin grafts and simple venous surgery, Ostomy Wound Manag. 42 (2) (1996) 34–40. [27] Anon, The complete Scholl guide to health care for legs, Scholl, Luton, 1996. [28] V. Hach-Wunderle, M. Du¨x, A. Hoffmann, F. Pra¨ve, M. Zegelman, W. Hach, Treatment of deep vein thrombosis in the pelvis and leg, Dtsch. Arzteblatt 105 (2008) 23–34. [29] R. Polignano, G. Guarnera, P. Bonadeo, Evaluation of SurePress Comfort: a new compression system for the management of venous leg ulcers, J. Wound Care 13 (9) (2004) 387–391. [30] British Standards Institution, Specification for Graduated Compression Hosiery. BS 6612, BSI, London, 1985. [31] Certificat de qualite-produits. Referentiel technique prescrit pourles ortheses elastiques de contention des membres, ASQUAL, Paris, 1999. [32] Deutsches Institut für Gütesicherung und Kennzeichnung. Medizinische Kompressions­ strümpfe RAL-GZ 387, Beuth, Berlin, 2000. [33]  M. Clark, G. Krimmel, Lymphoedema and the Construction and Classification of Compression Hosiery. Lymphoedema Framework. Template for Practice: Compression Hosiery in Lymphoedema, MEP Ltd, London, 2006. [34] C. Williams, Leg ulcer after care: the role of compression hosiery, Br. J. Nurs. 9 (13) (2000) 822–828.

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[35] K.R. Vowden, P. Vowder, Preventing venous ulcer recurrence: a review, Int. Wound J. 3 (1) (2006) 11–21. [36]  E.A. Nelson, S.E.M. Bell-Syer, N.A. Cullum, Compression for preventing recurrence of venous ulcers, Cochrane Database Syst. Rev. 4 (2000) CD002303, https://doi. org/10.1002/14651858.CD002303. [37] D.B. Hobson, T.Y. Chang, J.K. Aboagye, B.D. Lau, H.M. Shihab, B. Fisher, S. Young, N. Sujeta, D.L. Shaffer, V.O. Popoola, P.S. Kraus, G. Knorr, N.E. Farrow, M.B. Streiff, E.R. Haut, Prevalence of graduated compression stocking-associated pressure injuries in surgical intensive care units, J. Crit. Care 40 (2017) 1–6. [38] H. Partsch, Compression therapy of the legs: a review, J. Dermatol. Surg. Oncol. 17 (10) (1991) 799–805. [39] R.G. DePalma, D. Kowallek, R.K. Spence, Comparison of costs and healing rates of two forms of compression in treating venous ulcers, Vasc. Surg. 33 (6) (1999) 683–690. [40] L. Hampton, Venous leg ulcers: short stretch bandages for compression therapy, Br. J. Nurs. 6 (17) (1997) 990–998. [41] G. Mosti, A.B. Cavezzi, H.C. Partsch, S.D. Urso, F. Campana, Adjustable Velcro® compression devices are more effective than inelastic bandages in reducing venous edema in the initial treatment phase: a randomized controlled trial, Eur. J. Vasc. Endovasc. Surg. 50 (3) (2015) 368–374. [42] S. Rajendran, S.C. Anand, Design and development of novel bandages for compression therapy, Br. J. Nurs. (Tissue Viability Suppl.) 12 (17) (2003) S20–S29. [43] S. Rajendran, S.C. Anand, Development of novel bandages for compression therapy, Wounds U.K. (November 2002) 19–20 Harrogate. [44] B. Gibson, V. Duncan, S. Armstrong, Know how: ischaemic leg ulcer, Nurs. Times 93 (36) (1997) 34–36. [45] C. Moffat, P. Harper, Leg Ulcers, Churchill Livingstone, Edinburgh, 1997. [46] R. Stemmer, Ambulatory-elasto-compressive treatment of the lower extremities particularly with elastic stockings, Derm. Kassenarzt 9 (1969) 1–8. [47] R.A. Logan, S. Thomas, E.F. Harding, G. Collyer, A comparison of sub-bandage pressures produced by experienced and inexperienced bandagers, J. Wound Care 1 (3) (1992) 23–26. [48] D.A. Simon, L. Freak, I.M. Williams, et al., Progression of arterial disease in patients with healed venous ulcers, J. Wound Care 3 (4) (1994) 179–180. [49] C.J. Moffatt, D. Dickson, The Charing Cross high compression four-layer bandaging system, J. Wound Care 2 (2) (1993) 91–94. [50] O. Nelzen, D. Bergqvist, A. Lindhagen, Leg ulcer etiology – a cross sectional population study, J. Vasc. Surg. 14 (4) (1991) 557–564. [51] D. Buchbinder, G.M. McCullough, C.F. Melick, Patients evaluated for venous disease may have other pathological considerations contributing to symptomatology, Am. J. Surg. 166 (1993) 211–215. [52] N. Cullum, E.A. Nelson, A.W. Fletcher, T.A. Sheldon, Compression for venous leg ulcers, Cochrane Database Syst. Rev. 2 (2001) CD000265, https://doi.org/10.1002/14651858. CD000265. [53] EHC, Compression Therapy for Venous Leg Ulcers, vol. 3, University of York NHS Centre for Review and Dissemination. Effective Healthcare, 1997, pp. 1–12. 4. [54] Best Practice Statement Holistic Management of Venous Leg Ulceration (2018). http:// www.wounds-uk.com/pdf/content_12022.pdf. [55] L. Welsh, What is the existing evidence supporting the efficacy of compression bandage systems containing both elastic and inelastic components (mixed-component systems)? A systematic review, J. Clin. Nurs. 26 (9–10) (2017) 1189–1203.

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[56] S. Rajendran, S.C. Anand, The contribution of textiles to medical and healthcare products and developing innovative medical devices, Indian J. Fibre Text. Res. 31 (2006) 215–229. [57] S. Rajendran, S.C. Anand, Challenges into development of woundcare medical devices, FiberMed 6 (June 7–9, 2006) Tampere, Finland. [58] Engineers design colour-changing compression bandage, 2018. http://news.mit.edu/2018/ color-changing-compression-bandage-signal-pressure-level-0529. [59] S.C. Anand, Spacers – at the technical frontier, vol. 110, Knit Inter, 2003, pp. 38–41. [60] Anon, Spacer fabric focus, vol. 109, Knit Inter, 2002, pp. 20–22. [61] G. Lee, S. Rajendran, S.C. Anand, New single-layer compression bandage system for chronic venous leg ulcers, Br. J. Nurs. (Tissue Viability Suppl.) 18 (15) (2009) S4–S18.

Antimicrobial textile dressings to manage wound infection

7

Yimin Qin State Key Laboratory of Bioactive Seaweed Substances, Qingdao, China 

7.1   Introduction Wounds are characterised by skin damage with the loss of the normal skin functions, in particular, its self-defence capabilities. In addition to being unable to serve as a barrier for bacterial invasion, the injured part of the body generally exudes a large amount of fluid, which together with the warm body temperature and rich nutritional components, serve as the ideal place for bacterial growth, leading eventually to wound infection and cross infection in hospital wards. These infections complicate patient illness, cause anxiety, increase patient discomfort and in the worst cases can lead to death of the patient [1,2]. Depending on the level of bacterial colonisation, wound infection can be classified into the following stages [3–5]: • Wound contamination: the presence of bacteria within a wound without any host reaction; • Wound colonisation: the presence of bacteria within the wound which do multiply or initiate a host reaction; • Critical colonisation: multiplication of bacteria causing a delay in wound healing, usually associated with an exacerbation of pain but with no overt host reaction; • Wound infection: the deposition and multiplication of bacteria in tissue with an associated host reaction.

Of the various types of bacteria that can cause wound infection, Staphylococcus aureus is a gram-positive bacterium that exists as a skin commensal, with the ability to cause a wide range of infections from localised skin eruptions to life-threatening conditions such as bacteraemia, endocarditis and pneumonia. S. aureus is one of the most common causes of hospital-acquired infections and its pathogenicity is caused by the production of coagulase by the organism, an enzyme that clots plasma and thus inhibits host defence mechanisms. In recent years, methicillin-resistant Staphylococcus aureus (MRSA) has attracted much attention in the medical field because of its deadly nature. Since it was first reported in the United Kingdom in the 1980s, many different strains of MRSA have been found, affecting a large number of individuals in many different healthcare settings. The degree to which people are affected ranges in severity from simple wound colonisation, which does not need to be treated aggressively, to systemic infection such as bronchopneumonia, which may be fatal. From a nursing point of view, the formation of biofilm presents a challenge for managing infected wounds because neither systemic administration of antibiotics Advanced Textiles for Wound Care. https://doi.org/10.1016/B978-0-08-102192-7.00007-2 Copyright © 2019 Elsevier Ltd. All rights reserved.

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nor topical application of antimicrobial formulation can effectively eradicate the bacteria that cause wound infection. The cost of managing the problems associated with infection is considerable. According to a report by the National Audit Office, at any given time about 9% of hospital patients have a nosocomial infection, costing the National Health Service as much as £1bn per annum and contributing to the death of an estimated 5000 people each year [6]. In 1995, the US Office of Technology Assessment reported that antibiotic-resistant infections caused by six species of bacteria in US hospitals cost the country at least $1.3bn (£709 m) a year. The report of the UK working party on hospital infection [7], and more recently the report by the National Audit Office [8], recommended that despite practical problems, where infection control facilities may be inadequate or in situations where MRSA has become endemic, active intervention to prevent the further spread of the organism is of benefit and should be encouraged. Wound dressings that readily permit strike-through or shed fibres on removal should be avoided as they may transmit contaminated particles that could easily be carried around the room on air currents, contaminating adjacent surfaces. The use of irrigation solutions to remove adherent dressings may also increase the potential for infected material to be transferred from the wound to the surrounding area, either in droplets that bounce off the wound surface when a jet of solution is applied with force by means of a syringe or even in a gentle trickle that runs down the patient’s leg. Semipermeable dressings such as films, film-foam combinations and hydrocolloids, which effectively seal off the peri-wound area, may help to prevent the passage of contaminating organisms both into and out of a wound [9]. However, the use of these products depends on whether their fluid-handling characteristics and performance are appropriate to the condition of the wound and the amount of exudate produced. The most effective way to control the spreading of bacteria from wound sites is to incorporate antimicrobial agents in wound dressings. Over the years, many antimicrobial materials have been used in wound management. These include chlorhexidine, honey, hydrogen peroxide, iodine, proflavine, silver and many other novel materials.

7.2  Topical antimicrobial agents in wound care For patients with infected wounds, two basic treatment protocols are available for medical practitioners, i.e., systemic administration of antibiotics and topical application of antimicrobial agents on the wounded area directly. While systemic antibiotics is outside the scope of the present review, over the years, many topical antimicrobial agents have been used to treat wound infection. These are briefly summarised in the subsequent sections.

7.2.1  Chlorhexidine Chlorhexidine is available as diacetate, digluconate and dihydrochloride, with digluconate being most frequently used in wound management. Chlorhexidine was

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discovered in 1946 and introduced into clinical practice in 1954 [10]. It has rapid, bactericidal activity against a wide spectrum of non-sporing bacteria by damaging outer cell layers and the semipermeable cytoplasmic membrane to allow leakage of cellular components. It also causes coagulation of intracellular constituents, depending on concentration [11]. It is widely used as an antiseptic in handwashing, and as a surgical scrub, but in wounds its application has been limited largely to irrigation.

7.2.2   Honey Honey has been used in the wound management practice for a long time and many therapeutic properties have been attributed to honey, including antibacterial activity and the ability to promote healing [12]. Evidence of antibacterial activity is extensive, with more than 70 microbial species reported to be susceptible [13]. The use of honey for infected wounds is increasing in popularity and a number of dressings or preparations containing it are now available, some of which have been shown to possess good antimicrobial activity against a wide range of pathogenic organisms, including resistant strains [14].

7.2.3   Hydrogen peroxide Hydrogen peroxide has been widely used as an antiseptic and disinfectant. A 3% solution has most often been used to clean wounds. It is a clear, colourless liquid that decomposes in contact with organic matter. It has a broad spectrum of activity against bacteria, with greater effect on gram-positive species than gram-negatives. Hydrogen peroxide functions as an oxidising agent by producing free radicals that react with lipids, proteins and nucleic acids to affect cellular constituents.

7.2.4   Iodine Iodine was discovered in 1811. It is a dark violet solid that dissolves in alcohol and potassium iodide. Its first reported use in treating wounds was by Davies in 1839 [15], and later it was used in the American Civil War. Early products caused pain, irritation and skin discoloration, but the development of iodophores such as povidone-iodine and cadexomer iodine since 1949 yielded safer, less painful formulations. Povidoneiodine is a poly-vinylpyrrolidone surfactant/iodine complex while cadexomer iodine is composed of beads of dextrin and epichlorhydrin that carry iodine. Both release sustained low concentrations of free iodine, whose exact mode of action is not known, but involves multiple cellular effects by binding to proteins, nucleotides and fatty acids. Iodine is thought to affect protein structure by oxidising S–H bonds of cysteine and methionine, reacting with the phenolic groups of tyrosine and reacting with N–H groups in amino acids, such as arginine, histidine and lysine, to block hydrogen bonding. It reacts with bases of nucleotides to prevent hydrogen bonding, and it alters membrane structure by reacting with C]C bonds in fatty acids [16]. It has a broad spectrum of activity against bacteria, mycobacteria, fungi, protozoa and viruses.

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7.2.5  Proflavine Proflavine is a brightly coloured acridine derivative that was extensively used during the Second World War in the treatment of wounds [17]. Modern use is as a prophylactic agent in surgical wounds packed with gauze soaked in proflavine hemisulphate solution. It is an intercalating agent that inhibits bacteria by binding to DNA and prevents unwinding before DNA synthesis.

7.2.6  Silver Silver has a long history as an antimicrobial agent [18], especially in the treatment of burns. Metallic silver is relatively unreactive, but in aqueous environments silver ions are released and antimicrobial activity depends on the intracellular accumulation of low concentrations of silver ions. These avidly bind to negatively charged components in proteins and nucleic acids, thereby effecting structural changes in bacterial cell walls, membranes and nucleic acids that affect viability. In particular, silver ions are thought to interact with thiol groups, carboxylates, phosphates, hydroxyls, imidazoles, indoles and amines either singly or in combination, so that multiple deleterious events rather than specific lesions simultaneously interfere with microbial processes. Hence, silver ions that bind to DNA block transcription and those that bind to cell surface components interrupt bacterial respiration and adenosine triphosphate synthesis [19]. Fig. 7.1 shows the antimicrobial mechanism of silver ions.

Capsule Cell wall Plasma membrane

Destruction of cell membranes

Inhibition of enzymes

Cytoplasm Ribosomes Plasmid Pili

Silver ion

Ag+

Bacterial flagellum Nucleoid (circular DNA)

Inhibition of DNA replication Figure 7.1  Antimicrobial mechanism of silver ions.

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In wound care, silver has been utilised in several formulations such as silver nitrate, silver sulphadiazine (SSD) and other types of silver-containing compounds. Silver nitrate is no longer widely used, but SSD and silver-releasing dressings remain popular. When introduced in 1968 [20], SSD was recommended as a topical treatment for the prevention of pseudomonad infections in burns, but it has since been demonstrated to possess broad-spectrum antibacterial, antifungal and antiviral activity [21–23].

7.2.7  Other antimicrobial agents Other agents that have been recommended for the treatment of MRSA infections include tea tree oil [24] and gentian violet ointment [25]. Extracts of tea are also said to have inhibitory effects on MRSA [26]. In addition, zinc and copper ions are also known to have strong antimicrobial capabilities [27,28,29].

7.3  Main types of antimicrobial wound dressings Wound dressings are materials used to cover the wounded skin. In this respect, wound dressings are similar to traditional textile materials because they share the same functional requirement of being able to protect the underlying object. Antimicrobial wound dressings possess an additional antimicrobial function, which is commonly achieved by incorporating antimicrobial agents into the fibres and textile structures which are processed into the final dressing. In the composite structure, the textile substrate provides the basic performance criteria such as its ability to protect the wound surface, to absorb wound exudates and the ease of application and removal, etc. Over the years, many methods have been used to combine antimicrobial agents with base textile materials. These methods are described subsequently.

7.3.1  Textile fabric soaked with antimicrobial agents A simple way to prepare antimicrobial wound dressing is to soak a traditional dressing in a formulation containing antimicrobial agents. For example, some paraffin gauze dressings are available medicated with antibiotics or antimicrobial agents for the treatment or prevention of infection. Sofra-Tulle from Hoechst contains framycetin, while Bactigras from Smith & Nephew Medical Ltd. contains 0.5% chlorhexidine acetate. Urgotul SSD dressing comprises a polyester mesh impregnated with carboxymethylcellulose, Vaseline and SSD. In these types of products, antimicrobial agents can be combined with a suitable thickening and gelling agent to prepare creams and ointment with antimicrobial properties, which are then combined with a suitable textile substrate. Betadine solution and Betadine cream contain 10% and 5% povidone-iodine, respectively. It has been shown that these products are effective against MRSA [30].

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7.3.2  Antimicrobial-coated textile substrate Antimicrobial agents can be coated onto the surface of a textile substrate to produce antimicrobial wound dressings. For example, Acticoat consists of two layers of a silver-coated, high-density polyethylene mesh, enclosing a single layer of an apertured non-woven rayon and polyester fabric. These three components are ultrasonically welded together to maintain the integrity of the dressing while in use. Silver is applied to the polyethylene mesh by a vapour deposition process which results in the formation of microscopic crystals of metallic silver. Upon activation with water, Acticoat provides a rapid and sustained release of silver ions within the dressing and to the wound bed for 3 or 7 days. Silverlon is a knitted fabric dressing that has been silver-plated by means of a proprietary autocatalytic electroless chemical plating technique (reduction–oxidation). This technique coats the entire surface of each individual fibre from which the dressing is made, resulting in a very large surface area for the release of ionic silver.

7.3.3  Textile fibres containing antimicrobial agents Antimicrobial compounds can be mixed with the spinning solution during the fibre-making process to produce fibres with antimicrobial properties. For example, AlphaSan RC5000 is a silver sodium hydrogen zirconium phosphate with an average particle size of about 1 μm. It consists of a three-dimensional, repeating framework of sodium hydrogen zirconium phosphate, with many equally spaced cavities containing silver. Silver (at 3.8% by weight) provides the main antimicrobial properties, while the framework matrix acts to distribute silver evenly without clumping or pooling throughout the individual fibres where the AlphaSan particles are added. When AlphaSan RC5000 is mixed with sodium alginate solution, the fine particles can be evenly distributed in the spinning solution under a high rate of shearing. Because the particles are very fine, they can be suspended uniformly while the solution is extruded to form fibres. Because the sodium hydrogen zirconium phosphate framework prevents the silver ions from oxidising the alginate, this type of silver-containing alginate fibre remains white even after sterilisation through irradiation [31]. Fig. 7.2 shows the photomicrograph of silver-containing fibre with AlphaSan RC5000 particles uniformly distributed inside the fibre structure.

7.3.4  Textile composite containing antimicrobial fibres Antimicrobial fibres can be mixed with traditional textile materials to produce antimicrobial wound dressings. For example, Silvercel combines the potent broad-spectrum antimicrobial action of a silver-coated nylon fibre with the enhanced exudate management properties of alginate fibres. Because of the sustained release of silver ions, the dressing acts as an effective barrier and helps reduce infection. As is shown in Fig. 7.3, the antimicrobial properties are built-in through the use of X-Static silver-coated fibres blended into the non-woven structure. Silvercel dressing has been proven effective in vitro against 150 clinically isolated microorganisms, including antibiotic-resistant strains.

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Silver containing particles

Figure 7.2  Photomicrograph of silver-containing fibre with AlphaSan RC5000 particles distributed inside the fibre structure.

Silver coated nylon fiber

Calcium alginate fiber

Figure 7.3  Photomicrograph of Silvercel wound dressing.

7.3.5  Other novel methods Actisorb Silver 220 consists principally of activated carbon impregnated with metallic silver, produced by heating a specially treated fine viscose fabric under carefully controlled conditions. The carbonised fabric is enclosed in a sleeve of spun-bonded non-woven nylon, sealed along all four edges, to facilitate handling and reduce particle and fibre loss. When applied to a wound, the dressing adsorbs toxins and wound

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degradation products and volatile amines and fatty acids responsible for the production of wound odour. Bacteria present in wound exudate are also attracted to the surface of the dressing where they are killed by the antimicrobial activity of the silver. Aquacel consists of a fleece of sodium carboxymethylcellulose fibres containing 1.2% ionic silver. In the presence of exudate, the dressing absorbs liquid to form a gel, binding sodium ions and releasing silver ions.

7.4  Silver-containing wound dressings 7.4.1  The antimicrobial properties of silver Silver has broad-spectrum antimicrobial properties and has a low level of toxicity to human body. As bacterial resistance to antibiotics becomes common and as more and more attentions are being paid to cross infection in hospital wards, wound dressings with antimicrobial properties are becoming increasingly popular. Over the past two decades, silver has proven to be an effective antimicrobial component of advanced wound dressings and modern silver-containing antimicrobial wound dressings are now widely used for the care of infected wounds and for the prevention of wound infections. The antimicrobial action of silver-containing wound dressings has been directly related to the amount and rate of silver released and its ability to inactivate target bacterial and fungal cells. In various laboratory and clinical studies, it has been found that metallic silver does not possess significant antimicrobial potency while silver ions are highly antimicrobial [32]. The oligodynamic microbicidal action of silver compounds at low concentrations probably does not reflect any remarkable effect of a comparatively small number of ions on the cell, but rather the ability of bacteria, trypanosomes and yeasts to take up and concentrate silver from very dilute solutions [33]. Therefore, bacteria killed by silver may contain 105–107 Ag+ per cell, the same order of magnitude as the estimated number of enzyme–protein molecules per cell [34]. Chemically, metallic silver is relatively inert but its interaction with moisture on the skin surface and with wound fluids leads to the release of silver ion and its biocidal properties. Silver ion is a highly reactive moiety and avidly binds to tissue proteins, causing structural changes in bacterial cell walls and intracellular and nuclear membranes [35]. These lead to cellular distortion and loss of viability. Silver binds to and denatures bacterial DNA and RNA, thereby inhibiting replication [36]. In a study of the inhibitory action of silver on two strains of gram-negative Escherichia coli and gram-positive S. aureus, it was found that silver nitrate exposure lead to the formation of electron-light regions in their cytoplasm and condensation of DNA molecules [37]. Granules of silver were observed in the cytoplasm, but RNA and DNA damage and protein inactivation seemed to be the principal mechanisms for bacteriostasis. Silver-related degenerative changes in bacterial RNA and DNA, mitochondrial respiration and cytosolic protein lead to cell death. The action of silver ion on cell walls is illustrated by reference to the yeast Candida albicans. Silver has been shown to inhibit the enzyme phosphomannose isomerase (PIM) by binding cysteine residues [38]. This enzyme plays an essential role in the synthesis of the yeast cell wall, and defects lead to the release of phosphate, glutamine and other vital nutrients.

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It was suggested that the microbicidal action of silver products is partly related to the inhibitory action of silver ion on cellular respiration and cellular function [39]. The exact nature of these silver radicals is not clear but Ovington [35] noted that nanocrystalline silver products (Acticoat, Smith & Nephew) can release a cluster of highly reactive silver cations and radicals, which provide a high antibacterial potency on account of unpaired electrons in outer orbitals. Silver and silver radicals released from Acticoat also cause impaired electron transport, bacterial DNA inactivation, cell membrane damage and binding and precipitation of insoluble complexes with cytosolic anions, proteins and sulphydryl moieties.

7.4.2  Types of silver compounds used in wound dressings Silver is a group 11 element (formerly group Ib) of the periodic table and exists as two isotopes, 107Ag and 109Ag, in approximately equal proportions. In solution, silver exhibits three oxidation states, i.e., Ag+, Ag++ and Ag+++, each capable of forming inorganic and organic compounds and chemical complexes. Compounds involving Ag++ or Ag+++ are unstable or insoluble in water. The silver compounds used in wound dressings can be divided into three groups, i.e., • Elemental silver, e.g., nanocrystalline particles or foil; • Inorganic compounds/complexes, e.g., silver nitrate, SSD, silver oxide, silver phosphate, silver chloride or a silver zirconium compound; • Organic complexes, e.g., colloidal silver preparations, silver–zinc allantoinate or silver proteins.

Colloidal silver solutions were the most common delivery system before 1960. It is in the form of charged pure silver particles (3–5 PPM) held in suspension by small electric current, where the positively charged ions repel each other, hence making it possible for the particles to remain in solution when applied topically to a wound. Although it is highly bacteriocidal with no resistance, because the solutions are unstable when exposed to light, colloidal silver offers little practical value. When the silver ions are complexed to small proteins to improve stability in solution, they become more stable. However, they are also much less antibacterial than pure ionic silver. In the 1960s, various silver salts were developed. When silver ions are complexed to AgCl, AgNO3 and AgSO4, they become more stable delivery systems. Silver nitrate was the most widely used compound but it is dangerous to use in concentrations exceeding 2%. For treating burns and infected wounds, 0.5% aqueous silver nitrate solution is the standard solution. However, nitrate is toxic to wounds and cells and appears to decrease healing. It is also unstable in light. Various studies have shown that pure silver ions and radicals produce the best antimicrobial results and optimising the wound healing environment. As a consequence, the silver salts and complexes used today were developed to maintain a sustained release of silver ions. A typical silver-containing compound is AlphaSan RC5000 developed by Milliken. As a zirconium phosphate–based ceramic ion-exchange resin containing silver, AlphaSan is effective against a range of microorganisms that can cause undesirable effects. The material is widely used in Europe, Japan and the United States, and it has been approved by the US Food and Drug Administration for contact applications. Table 7.1 shows the various types of silver compounds used in silver-containing alginate wound dressings.

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Table 7.1 

Silver compounds used in various types of alginate wound dressings Product name

Manufacturer

Base material

Silver compound

Acticoat Absorbent

Smith & Nephew Derma Sciences DeRoyal

Alginate fibre with PE film Calcium alginate fibre Calcium alginate fibre with foam backing Calcium alginate fibre

Nanocrystalline silver 1.4% silver Ionic silver

Ionic silver

Algicell Ag Algidex Ag Algisite Ag Askina Calgitrol Ag

Smith & Nephew B.Braun

Askina Calgitrol THIN Askina Calgitral Paste Invacare Silver Alginate

B.Braun B.Braun Invacare

Calcium alginate fibre with foam backing Thin alginate sheet Alginate in paste form Alginate/CMC fibre

Maxorb Extra Ag

Medline

Alginate/CMC fibre

Melgisorb Ag

Mölynlycke

Alginate/CMC fibre

Restore Calcium Alginate SeaSorb Ag

Hollister Woundcare Coloplast

Calcium alginate

Silvercel; Silvercel Non-adherent

Systagenix

Silverlon Calcium Alginate

Argentum Medical

Alginate/CMC fibre with non-adherent contact layer Calcium alginate fibre

Sorbsan Silver Flat; Sorbsan Silver Packing; Sorbsan Silver Plus NA; Sorbsan Silver Plus SA Tegaderm Alginate Ag

Aspen Medical

Calcium alginate fibre plus viscose pad or film backing

3M

Alginate/CMC fibre

UrgoSorb Silver

Urgo

Alginate/CMC fibre

CMC, carboxymethyl cellulose; PE, polyethylene.

Alginate/CMC fibre

Silver impregnated

Ionic silver Ionic silver Silver sodium hydrogen zirconium phosphate Silver sodium hydrogen zirconium phosphate Silver sodium hydrogen zirconium phosphate Ionic silver Silver sodium hydrogen zirconium phosphate Elemental silver– coated nylon fibres Metallic silver– plated nylon mesh core 1.5% ionic silver

Silver sodium hydrogen zirconium phosphate Silver sodium hydrogen zirconium phosphate

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Table 7.2 

Typical silver contents of the silver-containing wound dressings Proprietary name

Ag content (mg/100 cm2)

Silverlon Calgitrol Ag Acticoat Contreet foam Contreet hydrocolloid Aquacel Ag SilvaSorb Actisorb Silver 220 Arglaes powder

546 141 105 85 32 8.3 5.3 2.7 6.87 mg/g

7.4.3  Methods of adding silver into wound dressings The silver-containing wound dressings currently available have considerable differences between their overall structure, the concentration and formulation of the silver compounds. Overall, silver ions can be attached to wound dressings in four basic methods, i.e., • Physical treatment of the base material in which the fibres or fabrics are coated with metallic silver; • Chemical treatment of the base material in which the fibres or fabrics are treated with silver-containing solutions, whereby silver ions are attached to the wound dressing through ion exchange; • Blending. Fine particles of the silver compounds are blended with the base material. • Blending of silver-containing fibres with other types of fibres. This method is used in the production of Silvercel where alginate fibres are blended with the silver-coated X-Static fibres.

Because of the differences in the types of silver compounds and techniques in applying them to the wound dressings, different silver-containing wound dressings have considerably different silver contents. Table 7.2 shows the typical silver contents of the silver-containing wound dressings [40–42].

7.5  Applications of modern silver-containing antimicrobial wound dressings Modern silver-containing wound dressings have become widely used in the management of infected wounds. Depending on the characteristics of wounds, the profiles for silver-containing wound dressings can be divided into three main types, i.e.,

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• Products with a high silver content with a rapid silver ion release designed for wounds with heavy exudate and bacterial colonisation; • Products that maintain a more modest silver-release pattern, where silver ion is released over several days. These are claimed to be sufficient for moderate to severe pathogenic bacterial populations. The non-silver components of these dressings are attuned to wound bed management, i.e., exudate control, debridement of wound debris and management of the wound environment; • Products with a low silver content, which may be sufficient for low-grade infections in chronic wounds but are more appropriately used as a barrier to infection in acute wounds, burns and surgical injuries.

When in contact with wound exudate, silver ions are released from the silver-containing wound dressings with a corresponding rise of silver concentration in the contact solution. There are considerable differences in the release profile for the many types of commercial silver-containing wound dressings. For products with high silver loading, such as Silverlon and Acticoat dressings which are coated with a high level of metallic silver, a high level of silver release is needed because both products are intended for burn wounds where the prevention of infection is an important consideration. In other types of dressings, silver ion act as an antimicrobial agent to control bacterial growth and prevent cross infection where a relatively low concentration of silver is required. Fig. 7.4 shows the role of silver in delivering antimicrobial functions to the silver-containing alginate wound dressings. During applications, the dressing first absorbs exudate from wound bed into the dressing structure. As the dressing becomes

Wound exudate with bacteria

Nonwoven alginate with silver

Fiber swelling Bacteria trapped in nonwoven alginate

Release of silver ions

Ag

Ag Ag

Ag

Ag

Ag

Ag

Ag Ag

Ag

Ag

Bacteria killed by silver ions

Figure 7.4  Mechanism of action for silver-containing alginate wound dressings.

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wet, silver ions are activated and liberated into the contacting solution, exerting antimicrobial effect on the bacteria. In these cases, the level of silver release can be significantly lower that than in burn wound management. In a study on silver absorption and antibacterial efficacy of silver dressings, Lansdown et al. [43] made a sequential microbiological examination of wound swabs, sampling of wound exudate and wound scale from seven patients with chronic wounds. After analysing the silver content using atomic absorption spectrometry, they found that: • All silver released into the wound bed was absorbed by wound exudate or debris (wound scale etc.); • Silver uptake by wound exudate is approximately proportional to its viscosity (protein content); • Silver absorbed into the wound bed may be eliminated in the exudate for several weeks following the termination of silver therapy; • The amount of silver released from dressings is closely related to the amount of moisture absorbed; • Wounds treated with silver do not attain a germ-free status, suggesting that silver-resistant organisms such as S. aureus and Pseudomonas aeruginosa may contribute to indolence in healing.

In a detailed study on the performances of various silver-containing wound dressings, Thomas [41,42] found that when testing against S. aureus: • Acticoat exhibited a marked bactericidal effect within 2 h; • Contreet-H had an inhibitory effect; • Actisorb Silver 220 appeared to prevent the proliferation of the organism within the dressing after a minimum contact time of 4 h; • Actisorb Silver 220 removed the organisms from the suspension and bound them to the surface of the charcoal fibres. These organisms remain viable for many hours until they are progressively inactivated by the silver ions in the dressing. The inner core, which contains the silver, forms an effective barrier, whereas the outer nylon sleeve does not.

While total silver content is important, other factors also influence a dressing’s ability to kill microorganisms. These include the distribution of the silver within the dressing (whether it is present as a surface coating or is dispersed through the structure), its chemical and physical form (whether it is present in a metallic, bound or ionic state) and the dressing’s affinity for moisture, which is a prerequisite for the release of active agents in an aqueous environment. Products in which the silver content is concentrated on the dressing surface rather than ‘locked up’ within its structure performed well, as did those in which silver was present in the ionic form. An in vitro study [44] compared the antimicrobial properties of Acticoat with a solution of silver nitrate and cream containing SSD against 11 antibiotic multiresistant clinical isolates. Acticoat was the most effective at killing the organisms. A later study compared the activity of the same dressings against a spectrum of common burn wound fungal pathogens and showed that the silver-coated membrane provided the fastest and broadest-spectrum fungicidal activity [45].

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Yin et al. [46] compared the antimicrobial activity of Acticoat with silver nitrate, SSD and mafenide acetate to determine their minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC) and zone of inhibition. Although mafenide acetate produced the greatest zone of inhibition, the MBC of the product was higher than its MIC, indicating that it had a bacteriostatic rather than a bactericidal action. In contrast, the MICs and MBCs of the silver-containing products were very similar, indicating that their activity is essentially bactericidal. The authors showed that, although the MIC values for the three silver preparations were very similar when calculated in terms of their silver content, Acticoat acted more rapidly than the other two products, perhaps because the metallic silver on the surface of the dressing forms a reservoir of silver ions, which are released continuously and are therefore always available for bacterial uptake.

7.6  Future trends In developing antimicrobial textile dressings to manage wound infection, it should be noted that because wound dressings are directly in contact with broken skin, there are strict requirements for the type of applicable antimicrobial materials. These materials should meet the following requirements. • Should be non-toxic and safe to use on broken skin • Do not cause allergic reaction • Would not develop bacteria resistance • Possess broad-spectrum antimicrobial effect and • Have sustained antimicrobial effect during the material’s useful time.

In this respect, organic antimicrobial compounds commonly used for antimicrobial textiles have limited use in wound management, because in most cases, they are not suitable for use on broken skin. Two classes of materials have become increasingly used in the wound management industry as novel materials for the manufacture of wound dressings with antimicrobial function. These are briefly discussed in subsequent subsections.

7.6.1  Metal ions with antimicrobial properties While silver has been successfully used as an effective antimicrobial agent for wound management, other metal ions have also proven effective in preventing bacterial growth. In particular, zinc and copper ions, while being non-toxic to human, can be easily attached to wound dressings through salt formation with anionic groups or chelation with amine groups in the fibres and wound dressings. In this respect, zinc and copper alginate fibres possess strong antimicrobial potency highly desirable in the wound management industry and also in the development of personal care products. Similarly, chitosan fibres treated with zinc and copper compounds have the combined antimicrobial properties of the chitosan and the metal ions. Experimental results have shown that the zinc- and copper-containing chitosan fibres have excellent antimicrobial

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Table 7.3 

The antimicrobial effect against Candida albicans by different types of chitosan fibres Samples

Bacterial count, cfu/mL

Reduction, %

Control Chitosan fibre Cu(II) Chitosan fibre Zn(II) Chitosan fibre

5.4 × 103 1155 208 123

N/A 78.6 96.2 97.7

efficacy. Table 7.3 shows the antimicrobial effect against Candida albicans by different types of chitosan fibres [47].

7.6.2  Naturally occurring antimicrobial materials Melaleuca alternifolia oil, also called tea tree oil, has demonstrated promising efficacy in treating wound infections. Tea tree oil has been used for centuries as a botanical medicine. It is antimicrobial and anti-inflammatory and has demonstrated its ability to activate monocytes. There are few apparent side effects to using tea tree oil topically in low concentrations, with contact dermatitis being the most common. Tea tree oil has been effective as an adjunctive therapy in treating osteomyelitis and infected chronic wounds in case studies and small clinical trials [48]. It is reported that of the various naturally occurring antimicrobial compounds, tea tree oil is effective against skin infections. In addition to tea tree oil, honey can also be used for managing wound infections. Mastic gum can be used for helicobacter pylori gastric ulcers and cranberry juice for urinary tract infections. Many infections may prove amenable to safe and effective treatment with non-antibiotic naturally occurring compounds [49].

Sources of other information and advice For more information on wound care and wound management products, the readers can use the following references: 1. Y. Qin, Medical Textile Materials, Woodhead Publishing Ltd., Cambridge, 2016. 2. V.T. Bartels (Ed.), Handbook of Medical Textiles, Woodhead Publishing Ltd., Cambridge, 2011. 3. Y. Qin, Functional Wound Dressings, China Textile Press, Beijing, 2007. 4. A Prescriber’s Guide to Dressings & Wound Management Materials, VFM Unit, Welsh Office Health Department, 1997. 5. G. Bennett, M. Moody, Wound Care for Health Professionals, Chapman and Hall, London, 1995. 6. C. Dealey, The Care of Wounds, Blackwell Science Ltd., Oxford, 1994. 7. D.J. Leaper, K.G. Harding (Eds.), Wounds: Biology and Management, Oxford University Press, 1998.

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8. M. Morison, C. Moffatt, J. Bridel-Nixon, S. Bale (Eds.), Nursing Management of Chronic Wounds, Mosby, London, 1997. 9. S. Thomas, Wound Management and Dressings, The Pharmaceutical Press, London, 1990. 10. J. Wardrope, J.A.R. Smith, The Management of Wounds and Burns, Oxford University Press, Oxford, 1992.

References [1] D.R. Childs, A.S. Murthy, Overview of wound healing and management, Surg. Clin. North Am. 97 (1) (2017) 189–207. [2] B.H. Garner, D.J. Anderson, Surgical site infections: an update, Infect Dis. Clin. North Am. 30 (4) (2016) 909–929. [3] M. Ayton, Wound care: wounds that won’t heal, Nurs. Times 81 (46) (1985) 16–19 Suppl. [4] V. Falanga, F. Grinnell, B. Gilchrest, et al., Workshop on the pathogenesis of chronic wounds, J. Invest. Dermatol. 102 (1) (1994) 125–127. [5] A. Kingsley, A proactive approach to wound infection, Nurs. Stand. 15 (30) (2001) 50–54. [6] National Audit Office, The Management and Control of Hospital Acquired Infection in Acute NHS Trusts in England, Stationery Office, London, 2000, 121 (HC 230 Session 1999–2000. [7] G. Duckworth, B. Cookson, H. Humphreys, et al., Revised guidelines for the control of methicillin-resistant Staphylococcus aureus infection in hospitals. British Society for Antimicrobial Chemotherapy, Hospital Infection Society and the Infection Control Nurses Association, J. Hosp. Infect. 39 (4) (1998) 253–290. [8] National Audit Office, Improving Patient Care by Reducing the Risk of Hospital Acquired Infection: A Progress Report, Stationery Office, London, 2004 (HC 876 Session 2003–2004. [9] J.J. Hutchinson, J.C. Lawrence, Wound infection under occlusive dressings, J. Hosp. Infect. 17 (2) (1991) 83–94. [10] A.D. Russell, Introduction of biocides into clinical practice and the impact on antibiotic-resistant bacteria, J. Appl. Microbiol. (92 Suppl.) (2002) 121S–35S. [11] G. McDonnell, A.D. Russell, Antiseptics and disinfectants: activity, action, and resistance, Clin. Microbiol. Rev. 12 (1) (1999) 147–179. [12] P.C. Molan, The role of honey in the management of wounds, J. Wound Care 8 (8) (1999) 415–418. [13] P.C. Molan, The antibacterial activity of honey. Part 1. Its use in modern medicine, Bee World 80 (2) (1992) 5–28. [14] O.A. Moore, L.A. Smith, F. Campbell, et al., Systematic review of the use of honey as a wound dressing, BMC Complement Altern. Med. 1 (1) (2001) 2. [15] J. Davies, Selections in Pathology and Surgery. Part II, Longman, Orme, Browne, Greene and Longmans, London, 1839. [16] W. Gottardi, Iodine and iodine compounds, in: S. Block (Ed.), Disinfectants, Sterilisation and Preservations, third ed., Lea Febinger, Philadelphia, USA, 1983. [17] G.A.G. Mitchell, G.A.H. Buttle, Proflavine in closed wounds, Lancet ii (1943) 749. [18] H.J. Klasen, Historical review of the use of silver in the treatment of burns. I. Early uses, Burns 26 (2) (2000) 117–130. [19] J.T. Trevors, Silver resistance and accumulation in bacteria, Enzyme Microb. Technol. 9 (1987) 331–333.

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[20] C. Fox, Topical therapy and the development of silver sulphadiazine, Surg. Gynecol. Obstet. 157 (1968) 82–88. [21] R.O. Rahn, J.K. Setkiw, L.C. Landry, Ultraviolet irradiation of nucleic acids complexed with heavy metals. III Influence of Ag+ and Hg+ on the sensitivity of phage and of transforming DNA to ultraviolet radiation, Photochem. Photobiol. 18 (1973) 39–41. [22] W.T. Speck, H.S. Rosenkranz, Letter: activity of silver sulphadiazine against dermatophytes, Lancet 2 (7885) (1974) 895–896. [23] T.J. Wlodkowski, H.S. Rosenkranz, Antifungal activity of silver sulphadiazine, Lancet 2 (7831) (1973) 739–740. [24] C.F. Carson, B.D. Cookson, H.D. Farrelly, et al., Susceptibility of methicillin-resistant Staphylococcus aureus to the essential oil of Melaleuca alternifolia, J. Antimicrob. Chemother. 35 (3) (1995) 421–424. [25] M. Saji, Effect of gentiana violet against methicillin-resistant Staphylococcus aureus (MRSA), Kansenshogaku Zasshi 66 (7) (1992) 914–922. [26] T.S. Yam, J.M. Hamilton-Miller, S. Shah, The effect of a component of tea (Camellia sinensis) on methicillin resistance, PBP2′ synthesis, and beta-lactamase production in Staphylococcus aureus, J. Antimicrob. Chemother. 42 (2) (1998) 211–216. [27] X. Wang, S. Liu, M. Li, et al., The synergistic antibacterial activity and mechanism of multicomponent metal ions-containing aqueous solutions against Staphylococcus aureus, J. Inorg. Biochem. 163 (2016) 214–220. [28] M. Vincent, P. Hartemann, M. Engels-Deutsch, Antimicrobial applications of copper, Int. J. Hyg. Environ. Health 219 (2016) 585–591. [29] J.A. Feldpausch, R.G. Amachawadi, M.D. Tokach, et al., Effects of dietary copper, zinc, and ractopamine hydrochloride on finishing pig growth performance, carcass characteristics, and antimicrobial susceptibility of enteric bacteria, J. Anim. Sci. 94 (8) (2016) 3278–3293. [30] P.D. Goldenheim, In vitro efficacy of povidone-iodine solution and cream against methicillin-resistant Staphylococcus aureus, Postgrad. Med. J. 69 (Suppl. 3) (1993) S62–S65. [31] Y. Qin, M.R. Groocock, Polysaccharide Fibers, 2005, US Patent 20050101900. [32] A.B.G. Lansdown, Physiological and toxicological changes in the skin resulting from the action and interaction of metal ions, CRC 25 (1995) 397–462. [33] R.C. Charley, A.T. Bull, Bioaccumulation of silver by a multispecies population of bacteria, Arch. Microbiol. 123 (1979) 239–244. [34] A.J. Clarke, General pharmacology, in: A. Heffter (Ed.), Handbuch der experimentelle Pharmakologie. Ergänzung, vol. 4, Springer, Berlin, 1937. [35] L.G. Ovington, Nanocrystalline silver: where the old and familiar meets a new frontier, Wounds 13 (Suppl. B) (2001) 5–10. [36] S.M. Modak, C.L. Fox, Binding of silver sulfadiazine to the cellular components of Pseudomonas aeruginosa, Biochem. Pharmacol. 22 (1973) 2391–2404. [37] Q.L. Feng, J. Wu, G.Q. Chen, et al., A mechanistic study of the antibacterial effect of silver ions on Escherichia coli and Staphylococcus aureus, J. Biomed. Mat. Res. 52 (2000) 662–668. [38] T.N. Wells, P. Scully, G. Paravicini, et al., Mechanisms of irreversible inactivation of phosphomannose isomerases by silver ions and flamazine, Biochemistry 34 (1995) 7896–7903. [39] R.H. Demling, L. DiSanti, Effects of silver on wound management, Wounds 13 (Suppl. A) (2001) 5–15. [40] A.B. Lansdown, A. Williams, How safe is silver in wound care? J. Wound Care 13 (4) (2004) 131–136. [41] S. Thomas, P. McCubbin, A comparison of the antimicrobial effects of four silver-containing dressings on three organisms, J. Wound Care 12 (3) (2003) 101–107.

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[42] S. Thomas, P. McCubbin, An in vitro analysis of the antimicrobial properties of 10 silver-containing dressings, J. Wound Care 12 (8) (2003) 305–308. [43] A.B.G. Lansdown, A. Williams, S. Chandler, et al., Silver absorption and antibacterial efficacy of silver dressings, J. Wound Care 14 (4) (2005) 155–160. [44] J.B. Wright, K. Lam, R.E. Burrell, Wound management in an era of increasing bacterial antibiotic resistance: a role for topical silver treatment, Am. J. Infect. Control 26 (1998) 572–577. [45] J.B. Wright, K. Lam, D. Hansen, et al., Efficacy of topical silver against fungal burn wound pathogens, Am. J. Infect. Control 27 (1999) 344–350. [46] H.Q. Yin, R. Langford, R.E. Burrell, Comparative evaluation of the antimicrobial activity of ACTICOAT antimicrobial barrier dressing, J. Burn Care Rehabil. 20 (1999) 195–200. [47] Y. Qin, C. Zhu, J. Chen, D. Liang, G. Wo, Absorption and release of zinc and copper ions by chitosan fibers, J. Appl. Polym. Sci. 105 (2) (2007) 527–532. [48] L. Halcon, K. Milkus, Staphylococcus aureus and wounds: a review of tea tree oil as a promising antimicrobial, Am. J. Infect. Control 32 (7) (2004) 402–408. [49] C.F. Carson, T.V. Riley, Non-antibiotic therapies for infectious diseases, Commun. Dis. Intell (27 Suppl.) (2003) S143–S146.

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Authors of the chapter: H. Onishi, Y. Machida Hoshi University, Tokyo, Japan Editors of the chapter: E. Santhini, Ketankumar Vadodaria Centre of Excellence for Medical Textiles, The South India Textile Research Association, Coimbatore, India

8.1   Introduction Skin is the largest organ in the human body covering ∼12%–15% of the body weight with several complex functions essential for our survival. The primary function of the membranous tissue of the skin is to provide protection against the insults such as microbes, xenobiotics and dehydration. Structurally, the skin is divided into three distinct layers: epidermis, dermis and hypodermis or subcutaneous. Epidermis is the outer most layer of the skin, mostly contains dead cell population of epithelial cells called keratinocytes; dermis is the living tissue composed of fibroblast cells, a key cell responsible for the production and maintenance of the structural elements of the skin [1]; subcutaneous tissue is made of fat and connective tissue (Fig. 8.1). When a cutaneous injury occurs to these layers, the body commences a sequence of complex events to re-establish the protection and the homeostasis. Wounds resulting from any kind of injury are generally classified as either acute or chronic, depending on the time frame required to establish complete wound healing. At the time of trauma, all wounds are considered acute, irrespective of the cause of the injury. Only the duration of healing categorises the wound under acute or chronic. The wounds that heal at a predictable and expected time frame of about 8–12 weeks are classified as acute and require minimal attention as microbial colonisation is probably the only factor that interferes with the healing. In contrast, chronic wounds require longer periods of care and complex treatment regimens because they are often present with multiple interfering factors such as persistent infection, necrosis, tissue hypoxia, malnutrition, old age, underlying physiological conditions and the presence of excess levels of inflammatory cytokines. Irrespective of the size, depth and nature of the wound, the body initiates a dynamic and complex process of tissue regeneration through four different phases as soon as the continuity of the epithelial lining of the skin or mucosa is disrupted. They are (1) Haemostasis (immediately after injury), a phase resulting in vasoconstriction and fibrin clot, preventing excessive blood loss. Platelets trapped in the fibrin clot release vasodilators and chemoattractants and activate the cascade of complement pathways. (2) Inflammatory (within 24 h after injury), where the damaged tissue swells and Advanced Textiles for Wound Care. https://doi.org/10.1016/B978-0-08-102192-7.00008-4 Copyright © 2019 Elsevier Ltd. All rights reserved.

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Epidermis

Dermis

Hypodermis

Figure 8.1  Layers of human skin.

inflammatory cells and the reactive oxygen species (ROS) released by these cells destroy foreign material and remove cellular debris through phagocytosis and prepare the site for tissue repair. (3) Proliferative (approximately 3 days after inflammation), repairs the damaged tissue by forming new blood capillaries/vessel (angiogenesis), tissue (granulation) followed by collagen deposition and re-epithelialisation. This phase approximately takes 10–12 days to complete. (4) Maturation and remodelling (∼12 days after proliferation), replace weaker components of extracellular matrix (ECM) and provides strength to the re-epithelialised wounds, fibroblasts differentiate to myofibroblasts by reorganising the collagen matrix and effect connective tissue compaction and wound contraction. The strength of newly formed tissue would be maximum of 80% of the unwounded skin.

8.1.1  Burn wounds Burn injury occurs when the skin is exposed to excessive heat or caustic chemicals for extended period. The longer the exposure to the heat, more severe is the damage to the skin layer (epidermis and dermis). Based on the depth of the heat injury, the burn wounds are classified as (1) Superficial/first degree (confined to the outer epidermal layer) (2) Partial-thickness/second degree (complete destruction of epidermal layer and part of the inner dermis) (3) Full-thickness/third degree (destruction of both epidermis and dermis) and (4) Sub-dermal/fourth degree (extends to the tissue below including fat, muscle, tendons and bone). During the first day after injury, three concentric zones of tissue damage characterise a full-thickness burn: Inner zones of coagulation, characterised by necrotic tissues and consist of dead or dying cells as a result of coagulation necrosis and blood flow is absent. Here the wound usually appears white or charred; An intermediate zone of stasis, characterised by damaged cells that may or may not survive as the superficial dermis is avascular and necrotic and an outer zone of hyperaemia characterised by the stressed cells but will likely survive upon protecting the wound from infection and establishing intact blood circulation through appropriate treatment modalities. Apart from the local skin damage, heat also has generalised effect on the body including hypovolemia, anaemia, bone marrow depression, haemolysis – necessitating the blood transfusion to restore blood loss and systemic sepsis which are not observed

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in the wounds caused by other injuries. Hence, stimulating natural regenerative mechanism and restoration of damaged tissue in burn wounds are often lengthy, painful and have the potential to lead to death. Though the first- and second-degree burns heal by primary intention within 5–7 days without scar, the second-degree, deep-thickness and third-degree, full-thickness burns heal by secondary intention by involving the process of epithelialisation and contraction. Although burns are different from other wounds in the degree of systemic inflammation [2], healing of all wounds is a dynamic process with overlapping phases of haemostasis, inflammation, proliferation and remodelling. Among these phases, managing inflammation is vital for successful burn wound healing because of its crucial role in providing immune signals to recruit leukocytes and macrophages required for initiating proliferative phase [3]. In addition, the inflammatory mediators such as cytokines, kinins, lipids and so forth also activate fibroblast and keratinocyte in the proliferation phase and assist in re-epithelialisation or closure of the wound. While this shows the importance of inflammation in burn wound healing, aberrant inflammatory pathways are also found to link to hypertrophic scarring and treatments to inflammation, i.e., anti-inflammatory treatments are reported to aggravate the symptoms and delay healing [4–6]. Excessive or prolonged oedema caused by dilated blood vessels, increased extravascular osmotic activity and microvascular permeability exacerbates pain and impairs wound healing. However, in the absence of infection, inflammation might not be required for tissue repair. Because the burn patients are often at high risk of infection, especially drug-resistant infection and the inflammation has both beneficial and detrimental effect on burn wound healing, therapeutic interventions are to be based on the excessive presence of inflammation and oedema.

8.1.2  Management of burn wounds Unlike the other wounds, e.g., bite wounds, punctured wounds, crush injury, abrasion, etc., burn wounds are usually sterile in the beginning. It is only the organisms which are present in the deep epithelial appendages of hair follicles and sebaceous glands that start proliferating using eschar, a dead tissue which acts as a culture medium for bacterial growth after the fifth day of burn injury. This subeschar bacterial multiplication later invades the deeper tissue and causes sepsis in the burn wounds. Pruitt and McManus [7] studied the changing epidemiology of infection in burn patients and reported newer microbial colonisation such as virus and fungi responsible for sepsis in these patients apart from bacteria. Staphylococcus aureus accounted for 48% of lung infection while Pseudomonas aeruginosa accounted for 16%. Contributions of gram-negative organisms like Kleibsiella pneumoniae, Escherichia coli, Salmonella and Haemophilus were also reported in burn wound infection in the study. In last 20 years, there has not been a significant change in the statistics of bacterial burn wound infection after the study of Pruitt et al., except for the virulence of organism invading the wound which has increased manifold. S. aureus invariably is methicillin-resistant (MRSA) and Pseudomonas and Klebsiella are usually extended-spectrum β-lactamase enzyme-producing species. In last 8 years, incidence of multidrug-resistant gram-negative bacilli Acinetobacter baumannii is also increasing [2].

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Similarly, in a study by Sarabahi et al. [8], on changing pattern of fungal burn wound infections, Candida nonalbicans, mainly Candida krusei and Candida glabrata and Aspergillus were found to be the major infection-causing organisms against C. albicans as identified in 1991 by Becker et al. [9] in burn wound patients. These organisms exhibited 40% mortality and were resistant to the conventional azoles. The organisms were only sensitive to Echinocandins and Amphotericin B. Fochtmann et al. [10] also reported candidemia being the significant cause of morbidity and mortality in extensive burn wound patients. When these infections are not managed, it leads to pronounced immune response accompanied by invasive burn wound sepsis or septic shock, which results in hypotension and impaired perfusion of end organs including the skin – processes that delay wound healing. Furthermore, the leading causes of death following a severe burn are sepsis and multiorgan failure [11–13], so prevention and management of infection is a primary concern in the treatment of burn patients [11–13]. The general treatment modalities described are given in Table 8.1. The normal antimicrobial agents (e.g., povidone iodine, mupirocin, neomycin, etc.) and systemic antibiotics are not effective in controlling subeschar bacterial invasion, a prime reason behind sepsis in burn patients because of their in ability in penetrating the eschar. Therefore, for burn wounds, it is important to choose the antimicrobial agents and dressings having high penetration with bactericidal effect on the organisms multiplying at the subeschar level. The excessive burn wound healing takes several weeks to heal; hence, the probability of developing resistance against the antimicrobial agents is high among the organisms. Moreover, the antimicrobial agents may also be toxic when it is absorbed from the skin to the circulation. Hence, the antimicrobial dressings used on the burns are required to be non-toxic, with minimal or no history of emergence of resistance. More recently, metallic antimicrobials particularly silver-based dressings are used invariably for treating burns because their usage dates back to 1000 BC in treating various ailments. Silver sulfadiazine (Flammazine and Silvadene) and silver nitrate (Acticoat) dressings are one of the first and are still among the most commonly used dressings for the treatment of burn wounds [14]. Despite studies revealing the disadvantage and side effects caused by the use of these dressings, they are still being used for the treatment in different formulations. The toxicity associated with these dressings is not merely because of the Ag but because of its associated compound such as nitrate and sulfadiazine. Hence, pure silver-based dressings, such as Silvercel non-adherent, Mandolin strings, Allevyn Ag, etc., are used which not only lack toxicity but also possess anti-inflammatory and anti-matrix metalloproteinase (MMP) activity without compromising their broad-spectrum antimicrobial properties. Also, in contrast to nitrate- and sulfadiazine-associated silver dressings, current silver dressings are left in place for up to 7 days; hence, there is a decrease in the trauma to newly developing granulation tissues. Unlike antibiotics, till now there is no evidence of organisms developing resistance against silver-based dressings and ointments. Because the resistance development resides in the microbial genes and silver kills bacteria through physical destruction, the possibility of developing resistance to silver by the microbes is in question. Recent studies noted that the antimicrobial activity of silver starts from the lowest concentration of 10 ppm when in liquid formulation [15].

Novel textiles in managing burns and other chronic wounds

Table 8.1 

215

General management of burn wounds

S.No.

Burn type

Duration of healing

Treatments

1

Superficial

2

Partial thickness Superficial: • Face

Heals by itself in less than a week without scarring. • Duration: 1–2 weeks. • Heals by primary intention.

Skin moisturiser can be used. Eg: BIAFINE (Trolamine), Purilon gel. Topical antibiotics not required. Purilon gel. Bacitracin ointment to maintain wound moisture and control gram-positive bacteria on the face • Petrolatum-impregnated gauze covered with several layers of dry absorbent gauze.

• Hands,

upper and lower extremities and trunk.

• Dirty

wound that has not been cleansed of initial debris or a perineal or buttock wound.

• Flammazine

Deep partialthickness

Duration: 4–10 weeks (sometimes longer)

3

Full-thickness

4–10 weeks (sometimes longer)

4

Subdermal burn

>10 weeks

(Silver Silfadiazine), Beschitin W, Biseptine [Chlorhexidine gluconate, benzalkonium chloride, and benzyl alcohol] based topical antibiotics. • Temporary skin substitutes to protect the wound surface and to provide moist wound healing. • Focus of the treatment is to remove eschar. • Excision and grafting. • Silver cream or silver dressing, e.g. Flammazine. • Similar to deep-partial thickness. • Surgical debridement. • Silver-based antibiotic cream or dressing followed by skin graft or permanent skin substitute. • Affected digit or the extremity has limited or no movement. • Amputation of the involved area.

At the nano-level, silver is reported to be more potent in killing organisms as its size helps in easy penetration through the microbial cell membrane. Inside the cell, nano silver attacks mitochondrial respiratory enzyme complex, interacts with sulphur and phosphorus of DNA and interferes with cell division, finally leading to cell death. Some examples of dressings used for the management of burn/chronic wounds are given in Table 8.2.

Table 8.2 

Dressings used for the management of burn/chronic wounds Brand name

Alginate

Textile fibre

Aquacel

Sodium carboxymethylcellulose and calcium alginate

Comfeel

Sodium–calcium alginate gel Nanocrystalline form, metallic silver Silver–calcium alginate dressing Collagen alginate

Sorbsan Acticoat

Collagen

Puracol

Hydrocolloid

Polyurethane film

Duoderm Tegaderm

Hydrogel

Polyurethane membrane coated with a layer of an acrylic adhesive Saline-based hydrogel Calcium Alginate Dressing Water/Glycerine/Aloe Hydrophilic polyurethane foam Hydrophobic, polyurethane foam sheet

SilvaSorb Skintegrity Allevyn

Antimicrobial

Collagen

Polyurethane foam

Silverlon Fibracol

Dermagel

Lyofoa

Type of wound Leg ulcers, pressure areas, donor sites, and most other granulating wounds Venous leg ulcers, pressure ulcers, superficial burns, superficial partial-thickness burns Cavity wounds Burns, donor sites and graft recipient sites For moderate to heavily draining wounds Pressure ulcer Venous ulcers Diabetic, pressure, or venous ulcers Exuding wounds and minor skin injuries Minor burns, pressure areas, donor sites, post-operative wounds First- and second-degree burns, diabetic foot ulcers Heavily draining wounds Shallow/Deep, No Min Drainage Wounds of limited depth, including leg ulcers, minor burns Decubitus ulcers, sutured wounds, burns

Frequency of change

Commercial availability

Once in 7 days

ConvaTec, USA.

Every 2–3 days

Coloplast, USA.

2–3 days Once in 3 days

Mylan, USA. Smith & Nephew, UK. Argentum, USA.

Every 5 days Daily/twice daily Once per day to once per week Once in 7 days

Johnson & Johnson, NJ. Medline, USA. ConvaTec, USA.

Longer than 7 days

3M, USA.

2-3 times daily

Maximilian Zenho & Co, Belgium. Medline, USA. Medline, USA. Smith & Nephew, UK. Molnycke, Sweden.

7 days once 3 days once 4–5 days once Twice daily

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Formulation

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Product name

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After the introduction of excision and grafting in the 1980s from topical antibiotics in 1960s and silver sulfadiazine in 1970s, systemic infections and mortality have decreased significantly [13,16,17]. Split-thickness skin grafts taken from the unburned donor sites on the same patient (autograft) are the standard for rapid and permanent closure of the full-thickness burns. The size of split-thickness grafts used on the burns varies based on the level of total body surface area (TBSA). For example, in burns with less than 30% TBSA, autograft is either used as sheet or meshed with either 1:1 or 2:1. For the burns with greater than 40% TBSA, the skin grafts are meshed 3:1 or 4:1, complemented by cadaver allograft to temporarily cover the residual open wound areas. Allograft, xenograft or artificial coverings such as Integra or Dermagraft-TC are routinely used for burns involving over 40% TBSA. Donor sites for autograft require 1–2 weeks to heal. During that time, temporary burn dressings are removed and residual open wounds are closed with split-thickness skin grafts from these same donor sites. In patients with extensive burns, i.e., larger than 90% TBSA burns, up to 10 cycles of autografting is recommended to completely close the wounds [18]. Because of the insufficient or unavailable donor sites, these wounds are also covered with temporary grafts as used for 40% TBSA. These dressings protect the damaged epithelium, promote re-epithelialisation, split the area into the desired position to maximise longterm function, occlude the wound and prevent evaporative heat loss, provide comfort and increase the healing rate when compared with traditional dressings [19]. However, the care must be taken to prevent the disease transmission when using allogenic cells. Currently, a different variety of skin substitutes and dermal analogs exist [20–23], which are broadly divided into those which replace the epidermis or replace the dermis [24,25]. Epidermal substitutes normally lack dermal components which includes Alloderm (LifeCell, Bridgewater, NJ, USA), GraftJacket (KCI, San Antonio, TX, USA), Integra (Integra LifeSciences, Plainsboro, NJ, USA), Biobrane (Smith & Nephew, London, UK) and Recell (Avita Medical Europe Ltd, Melbourne, UK) [26]. These substitutes are potentially life-saving when the donor site availability is limited. However, besides its potential to provide permanent wound closure for extreme burn patients, getting a sheet of cells takes 3–4 weeks. Also, they are extremely fragile and susceptible for bacterial contamination. Uncertainty in the rate of acceptance, high cost and the scarring in deep burn injuries because of the lack of dermis are making these substitutes unsuitable for treatment. To circumvent such problems, new delivery systems have been developed. These include biocompatible carriers for grafting single-layered keratinocytes [27,28], grafting colonies of pre-confluent keratinocytes [29], epidermal cell spray directly during surgery and the combination of abrasion and the cell spray procedure. Similar to epidermal substitute, various dermal substitutes have been developed such as collagen scaffolds, synthetic materials or cadaveric skin. These substitutes are being combined with cells, mostly fibroblasts, to create a living dermal substitute. Transcyte (Smith & Nephew PLC, London, UK), a temporary skin replacement, contains allogenic neonatal fibroblasts seeded in a bioabsorbable polyglactin mesh and are reported to promote re-epithelialisation when used in partial-thickness burns in children [30]. Integra, a bovine collagen and chondroitin 6-sulfate covered by a disposable

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‘epidermal’ silicone layer, is used for treating extensive acute burns. The silicone sheet of the substitute is acting as a barrier against bacteria and water evaporation and provides mechanical support. It allows early removal of the eschar and provides direct wound coverage. Hence, it reduces the need for donor sites in the beginning, which is crucial for the optimal final treatment. Long-term results on using Integra ranges from normal to notable supple scar tissue. Matriderm (MedSkin Solutions Dr. Suwelack AG, Germany), a single-layer dermal substitute with bovine collagen and an elastin hydrolysate, is used for the management of acute burn wounds and scar reconstruction procedures. It can be applied successfully in a one-step procedure; hence, it is advantageous in scar reconstruction over Integra. Allograft is a temporary and permanent skin replacement containing natural collagen, elastic and basement membrane structures. AlloDerm Regenerative Tissue Matrix (LifeCell Corporation, Bridgewater, NJ, USA) is a commercially available product and tested for reconstruction purposes. The combination of dermabrasion and AlloDerm graft is reported to improve burn scar contractures and depigmented areas of the upper extremity. List of commercially available cellular and acellular skin substitutes is given in Table 8.3 [31]. Since the pioneering work on epidermal and dermal replacements, four decades have passed. But the products of epidermal regeneration are scarcely used in clinical practice because of the associated drawbacks: fragility, high cost and poor cosmetic quality of healed zones [32]. Recently, research on mesenchymal stem cells (MSCs) is gaining attention in treating burn injuries because of their ability to differentiate into multiple different cell lineages and also produce growth factors and cytokines important for the healing of burn injuries [33–37]. However, intense research is required before they can be used in clinical conditions as their vitality varies according to the donor age and health condition and also the suspicion of providing microenvironment for promoting tumour growth [33,38,39].

8.2  Chronic wounds In severe or chronic wounds, the dermis and panniculus adiposus are damaged and the muscle and bone are invaded sometimes (Fig. 8.2). Because deep dermal wounds and damage extending to the panniculus adiposus lack hair follicles, which are important for fast re-epithelialisation, the healing proceeds gradually. The wound is filled with granulation tissue, which shrinks gradually with healing, and is then covered by the process of re-epithelialisation. The removal of contamination and infection and the maintenance of moist conditions are important to achieve efficient granulation and re-epithelialisation [40,41]. In contrast to acute wounds, the levels of cytokines, growth factor, proteases and extracellular and cellular elements are altered in the exudates of chronic/non-healing wounds. The elevated levels of gelatinase A and B degrades denatured collages (gelatins), basement membrane collagens and several other matrix proteins [42]. The reduced levels of tissue inhibitors of MMP-1 (TIMP-1) combined with higher levels

Table 8.3 

List of commercially available skin substitutes

Skin substitute

Substrate

Commercial availability

Cellular/acellular skin substitutes EZ-Derm

A processed dermal porcine collagen graft.

Permaco

A bovine-derived isocyanate collagen crosslinked skin substitute.

Graftjacket

Acellular human cadaveric skin.

Matriderm

Acellular bovine dermis composed of type I, III and V elastin.

Alloderm

Acellular human dermis

Integra

A bilayer membrane made of primarily collagen derived from bovine tendons and a small percentage of chondroitin-6-sulfate from shark cartilage. Acellular human dermis.

Glyaderm Oasis

Derived from porcine small intestine (jejunum) submucosa. It is an acellular substitute containing Type I, III, and V collagens, glycosaminoglycans, fibronectin, proteoglycans and growth factors including TGF-β and FGF-2.

Brennen Medical, St Paul, MN. Tissue Science Laboratories, Inc., Andover, MD Wright Medical Technology, Arlington, TN Dr. Suwelack Skin and Health Care AG, Germany. LifeCell Inc., Branchburg, NJ Integra LifeSciences, Plainsboro, NJ

Euro Skin Bank (ESB), The Netherlands. Smith & Nephew Inc, USA.

Cell-based skin substitutes OrCel

Laserskin

Epicel Dermagraft Transcyte Apligraf

ICX-SKN

A bilayered cellular matrix cultured with normal human allogenic skin cells such as fibroblasts and keratinocytes in two separate layers into a type I bovine collagen. Benzyl-esterified hyaluronic acid derivative with ordered laser-perforated microholes for migration of autologous keratinocytes from the membrane to wound bed. Sheets of autologous keratinocytes ranging from 2 to 8 cell layers thick with murine fibroblasts. Polyglactin mesh scaffold seeded with allogenic human dermal fibroblasts A silicone mesh–like material cultured with allogenic human dermal fibroblasts. Type I bovine collagen gel cultured with allogenic human skin cells such as fibroblasts and keratinocytes. Human collagen–based extracellular matrix cultured with allogenic human dermal fibroblasts.

Songe form, Forticell Bioscience Inc, USA.

Fidia Advanced biopolymers, Italy.

Genzyme Corporation, USA. Organogenesis Inc, USA. Organogenesis Inc, USA. Organogenesis Inc, USA. Intercytex Ltd, UK.

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(a)

(b) Epidermis

Dermis Panniculus adiposus Hair follicle

Figure 8.2  Wound healing process in (a) non-deep and (b) deep wounds (re-epithelialisation →; granulation ⇨).

of gelatinolytic enzymes (MMP-2 and 9) destroy surrounding tissue and degrade basement membrane components such as laminin and type IV collagen. Cellular senescence also known as ‘Hayflick limit’ induced by the exudates [43] and by the increased activity of β-galactosidase [44] reduces proliferative capability, changes the cellular morphology and persuades the overexpression of certain matrix proteins such as fibronectin [45]. Based on the underlying conditions, the chronic wounds are generally classified into vascular (venous and arterial), diabetic and pressure ulcers. Despite the difference in their aetiology at the molecular level, these wounds share some common features, which include excessive inflammatory phase [46], persistent infections [47], formation of drug-resistant microbial biofilms [48] and the inability of dermal and/or epidermal cells to respond to reparative stimuli and deficiency of functional stem cells. In aggregate, these pathophysiologic phenomena stall the healing in the inflammatory phase rendering the wound chronic to heal. Hence, the wound fails to proceed to proliferation phase and lacks the mitogenic activity as seen in acute wounds. Excessive neutrophil infiltration appears to be a critical culprit in this cycle of chronic inflammation and acts as a biological marker of chronic wounds. Abundance of neutrophils disturbs the mitochondrial respiratory chain and accumulates ROS. The ROS in turn damages ECM, cell membrane and subsequently, premature cell senescence. In addition, neutrophils release serine proteases such as elastase and MMPs (neutrophil collagenase, MMP-8), where elastase degrades platelet-derived growth factor (PDGF) and TGF-β, while collagenase degrades and inactivates components of the ECM [49,50]. Hence, it decreases their availability in chronic wounds. Both neutrophils and activated macrophages produce pro-inflammatory cytokines such as interleukin (IL) 1α and tumour necrosis factor alpha (TNF-α) that not only increase MMP production but also reduce TIMPs; this imbalance augments degradation of the ECM, impairs cell migration and reduces fibroblast proliferation and collagen synthesis [51]. The breakdown products of ECM further promote inflammation, by providing an optimal niche for the growth of many bacteria, aerobes and anaerobes. The inflammatory cytokines (TNF-α) and the interleukins (IL-1 and IL-6) secreted by the cells in response to endotoxin produced by the bacteria [52] deteriorate the condition of

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the wound. Such an inappropriate inflammatory response combines with the impaired cellular and systemic host response to stress, perpetuating the deleterious cycle that must be broken through debridement and cleaning of the wound for healing to occur. At this stage, therefore, the removal of excessive exudates and necrotic tissue is important, and antimicrobial agents may be needed to prevent deterioration of the wound. Washing and debridement of the wound surface are important to promote the rate of healing. Dressings specifically designed to create such conditions are required to be chosen. Some growth factors or pharmaceutical agents can be utilised to promote granulation and re-epithelialisation. Finally, remodelling continues after the wound has closed up. Dermal remodelling reduces the scar, which is very important for cosmetic reasons.

8.2.1  Management of chronic leg ulcers and diabetic foot wounds Burns or pressure ulcers are mainly produced by exogenous factors. In contrast, endogenous factors are essentially associated with skin defects in leg ulcers and diabetic foot wounds. These are very complicated ulcers and wounds are chronic in most cases and are difficult to heal. Venous or arterial occlusion can cause ischaemic defects in the related area, leading to poor blood circulation. This results in poor nutritional conditions in the periphery of the legs, including the skin, making these areas vulnerable to infections [53]. Poor healing may necessitate leg amputation. In the treatment of leg ulcers, it is very important to improve ischaemic defects first. This improvement, including elastic compression around the ulcer area, appears to be useful in the healing process for leg ulcers. The combination of dressing application and medical compression seems to be useful in the treatment of venous leg ulcers [54]. Diabetic foot ulcers are also significantly related to ischaemic defects [55]. Diabetics can often develop foot ulcers owing to ischemic defects of the peripheral blood vessels, which, like leg ulcers, are often chronic and difficult to heal. These ulcers are often accompanied by infections and the ischaemic defects delay healing of the diseased sites. In the treatment of diabetic foot ulcers (DFUs), the most important factor is to improve the diabetic conditions. In addition, the application of dressings to the ulcers appears to be effective. The combination of dressings and antibacterial agents seems to be useful. For example, use of hyaluronate and an iodine complex produced significant improvement in ulcers of this type [56,57]. Furthermore, topical treatment with dressings containing PDGF-B (Becaplermin) and epidermal growth factor (EGF) showed positive effects in promoting the healing of chronic diabetic foot wounds [58]. In the treatment of these chronic wounds, it seems necessary to keep the wound or ulcer in moderately moist conditions; extreme moist conditions can increase the infection. It is therefore suggested that wound dressings with or without bioactive agents are useful to enhance the healing of chronic leg ulcers or DFUs. For the treatment of the deep wounds or ulcers, this chapter examines wound dressings and composites with/without pharmaceutical agents which are commercially available/not available.

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8.2.2  Normal treatment options for deep skin wounds or ulcers Moist wound healing is generally accepted today and the dressings used are based on this concept, although extreme moist conditions are not appropriate for healing chronic ulcers, such as leg or DFUs. The maintenance of wet conditions around the wound provides circumstances that allow biologically active agents, such as growth factors and cytokines, to be kept in the wound area [59,60]. Cell migration is allowed in wet conditions, but not in dry conditions. Contamination with scar tissue, caused in dry conditions, can inhibit the process of proliferation, resulting in delayed healing. Dressings designed to fulfill these conditions have recently been developed. However, moist healing can also lead to a deterioration of wound conditions, such as infection, particularly in deep skin wounds. For the treatment of deep skin wounds, therefore, some pharmaceutical agents are often necessary in addition to dressings, to support wound healing.

8.3  Traditional wound dressing Traditional wound dressing products including gauze, lint, plasters, bandages (natural or synthetic) and cotton wool are dry and used as primary or secondary dressings for protecting the wound from contaminations [61]. Gauze dressings made out of woven and non-woven fibres of cotton, rayon and polyesters afford some sort of protection against bacterial infection. Some sterile gauze pads are used for absorbing exudates and fluid in an open wound with the help of fibres in these dressings. These dressings require frequent changing to protect them from maceration of healthy tissues. Gauze dressings are less cost effective. Because of excessive wound drainage, dressings become moistened and tend to become adherent to the wound making it painful when removing. Bandages made out of natural cotton wool and cellulose or synthetic bandages made out of polyamide materials perform different functions. For instance, cotton bandages are used for retention of light dressings, and high-compression bandages and short-stretch compression bandages provide sustained compression in case of venous ulcers. Xeroform (non-occlusive dressing) is petrolatum gauze with 3% of bismuth tribromophenate used for non-exudating to slightly exudating wounds. Tulle dressings such as Bactigras, Jelonet and Paratulle are some examples of commercially available dressings which are impregnated with paraffin and are suitable for superficial cleaning of wound. Generally, traditional dressings are indicated for the clean and dry wounds with mild exudate levels or used as secondary dressings. Because traditional dressings fail to provide moist environment to the wound, they have been replaced by modern dressings with more advanced formulations [61].

8.4  Topical pharmaceutical agents Topical pharmaceutical agents used in deep skin wounds are shown in Table 8.4. In the infection and necrosis stage, contamination, infection and scar tissue are obstacles to the subsequent healing process [62]. Contamination must be removed by washing because foreign substances lead to foreign-body reactions. Drugs containing enzymes that

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Table 8.4 

Topical formulations for the treatment of severe skin wounds Classification

Formulation (commercial name)

Active ingredient

Debridement agents

Bromelain ointment Elase

Bromelain Fibrinolysin, deoxyribonuclease Trypsin, fradiomycin sulphate Trafermin Alprostadil–alfadex Tretinoin tocoferil Bucladesine sodium Sucrose, povidone iodine Lysozyme hydrochloride Solcoseryl Erythromycin Tetracycline hydrochloride Chloramphenicol Gentamicin sulphate Oxytetracycline hydrochloride, Polymixin B sulphate Bacitracin, fradiomycin sulphate Sulfadiazine silver Sodium fusidate Iodine, Cadexomer

Francetin.T.Powder Incarnate agent

Antibacterial agents

Fiblast spray Prostandin ointment Olcenon ointment Actosin ointment U-Pasta Kowa ointment Reflap Solcoseryl ointment Erythrocin Achromycin ointment Chloromycetin cream Gentacin Terramycin ointment with polymixin B

Baramycin ointment Geben cream Fucidin leo ointment Cadex ointment

hydrolyse biogenic substances are commercially available for this purpose. These allow the degradation of proteins and nucleic acids in the exudates and their easy removal, resulting in better conditions at the wound surface [63,64]. Antimicrobial agents are necessary to suppress possible infection. Various kinds of antimicrobial agents are used, and dosage forms of ointment and cream are commercially available [65–67]. Silver sulfadiazine (Geben cream) is often used because it is widely effective against gram-positive and gram-negative bacteria and fungi. These agents are useful to treat the wound in the early stage. However, prolonged use may prevent the subsequent healing process, resulting in delayed healing. After cleaning the wound surface with debridement agents and antimicrobial drugs, the promotion of proliferation, granulation and re-epithelialisation are important to accelerate the rate of wound healing. Pharmaceutical agents and growth factors are included in the promoting agents, but caution should be exercised when using them [68,69,70]. For example, excessive granulation caused by overuse can delay the completion of wound healing or produce an ugly scar. Although these agents are effective in improving the severe situation of wounds, caution has to be exercised in applying them, and overuse must be avoided to reduce side effects.

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8.5  Modern wound dressing As shown above, the misuse or overuse of pharmaceutical agents can become an obstacle to wound recovery. The concept of moist wound healing indicates that it is better to provide the conditions to help the wound tissue to recover naturally [71]. Hence, modern wound dressings have been developed to facilitate the function of the wound rather than just to cover it. These dressings are focused to keep the wound from dehydration and promote healing. Based on the cause and type of wound, numerous products are available in the market, making the selection a very difficult task. Modern wound dressings are usually based on natural and semi-synthetic or synthetic polymers. A wide range of natural polymers, viz chitosan, cellulose, alginate, collagen, gelatin, etc., are used in the forms of hydrogel, hydrocolloids, films, foams, membranes, scaffolds, microparticles and nanoparticles (NPs) for the treatment of chronic wounds. Similarly, the synthetic polymers such as poly(vinyl) alcohol (PVA), polyurethane (PU), poly(lactic-co-glycolic acid) (PLGA), poly(vinyl) pyrrolidone (PVP), etc., are used extensively in various formulations for the treatment of wounds. These dressings act as a barrier against penetration of bacteria to the wound environment [72–75]. It is possible to use a combination of dressings with pharmaceutical agents. Various commercially available dressings are shown in Table 8.5, and many are useful for deep skin wounds.

8.5.1  Dressings made of polymers 8.5.1.1  Natural polymers – chitin/chitosan derivatives Chitin is biocompatible and biodegradable and has the ability to promote wound healing [76,77]. Chitin is useful as an excellent biosynthetic material for the treatment of wounds of varying degrees of severity and is used clinically in the form of non-woven textile, cotton-like sheets or sponge forms for the treatment of various skin wounds, including deep skin ulcers [78,79]. These forms absorb exudates from the wound and provide a properly moist environment around the wound, but hardly exhibit any antimicrobial effects. Therefore, frequent changes of the forms are necessary when exudate accumulation or infectious states are observed. Chitin thread–derived artificial skin products such as Beschitin W, Beschitin W-A and Beschitin F are used invariably for the treatment of light burns, pressure ulcers and the wounds extending up to muscle or bone, respectively. These must be applied to the wound after cleaning by washing or debridement, because contamination, excessive exudates or scar tissue threaten to cause infection. In contrast, chitosan, synthesised by the alkaline deacetylation of chitin, shows antimicrobial activity to various bacteria [80]. Furthermore, chitosan exhibits good biocompatibility and appropriate moisturising effects [81]. Chitosan is far superior to chitin in these areas. Biomaterials made of chitosan have recently been utilised as a good scaffold to facilitate tissue regeneration [82]. The chitosan/sericin composite nanofibre scaffold exhibited antimicrobial activity against both gram-positive and gram-negative organisms and promoted cell proliferation [83]. The viable cell population was more than 100% when it was grown in the scaffold than the tissue culture flask after 72 h incubation. Furthermore, to improve the antimicrobial activity

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Table 8.5 

General wound dressings for the treatment of severe skin wounds Degree of wound severity

Material

Commercial name

Transparent occlusive cover

Polyurethane films

Wound reaching into dermis

Chitin film Hydrocolloid dressing

Opsite Tegaderm Beschitin W DuoActiveET Tegasorb light Absocure-surgical Viewgel NU-GEL Comfeel Duoderm RepliCare Restore DuoActive DuoActiveCGF Absocure-wound Tegasorb Jelliperm Intrasite gel Aquaform Purilon Gel Vigilon PEG Hydrogel. GranuGEL Beschitin W-A Kaltostat Sorbsan Algoderm Kurabio-AG Tegagel Tegagen HG Curasorb Aquacel Tielle Hydrosite Hydrosite AD Allevyn Curafoam PolyMem Flexan Mepilex Tielle Hydropolymer Hydrosite cavity Beschitin F

Hydrogel Wound reaching into panniculus adiposus

Hydrocolloid dressing

Hydrogel

Chitin film Alginate

Hydrofibre Hydropolymer Polyurethane foam

Wound reaching into muscle or bone

Polyurethane foam Chitin film

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of chitosan, attempts were made by many investigators using metallic antimicrobials such as silver (Ag) [84], Ag NPs [85–88], Fe3O4 NPs [89], etc. These dressings, because of their synergistic effect, exhibited bactericidal activity against a broad spectrum of microorganisms. Radhakumary et al. [90] addressed the limitation associated with the film-based chitosan dressings by combining thiolated chitosan with poly(N-isopropyl acrylamide) and ciprofloxacin. The film because of its sensitivity towards thermal condition was easily removed from the wound bed without harming the newly developing tissue. Chitin/chitosan-blended preparations are considered potentially useful in treating skin wounds. Chitin, chitosan, and chitin/chitosan films, called CN-F, CA-F and CN/ CA-F, respectively, were prepared by casting techniques, using various kinds of chitin and chitosan. They were compared for in vitro characteristics such as swelling and strength, and their in vivo effects were examined for wound states and the rate of reduction of the wound area, using rats with full-thickness burn wounds [91]. CN-F exhibited a small absorption of water, but CA-F made of chitosan with a moderate degree of deacetylation showed a high absorption of water. CN/CS-F exhibited medium water absorption. CN-F was rigid in vitro and in vivo and lacked the ability to absorb the exudates. CA-F made of chitosan with moderate deacetylation degrees showed good absorption of exudates, but their strength was not maintained in the in vitro swelling study. However, these disadvantages were improved in CN/CA-F. Although CA-F made of chitosan with a high deacetylation degree exhibited fairly good absorption of exudates, the rate of reduction of the wound area was not promoted. In contrast, CN/ CA-F made using chitosan with moderate deacetylation degrees was fairly flexible and adaptable to the wound surface and showed a significantly faster rate of reduction of the wound area. In addition, the effect of CN/CA-F on wound states and reduction of the wound area was better than with Beschitin W. CN/CA-F showed fairly good absorption of exudates and fairly good maintenance of flexibility and structure strength, leading to a good environment for tissue recovery. Furthermore, improved wound states, such as a reduction of pus, were observed in CN/CA-F, which was considered to be associated with chitosan’s antimicrobial effects. The inhibition of infection resulted in better wound states and promotion of the rate of wound healing. CN/CA-F is considered to be an excellent dressing for the treatment of severe burn wounds. Chitosan in its various forms such as hydrogel, membranes, scaffolds, microparticles and NPs have also been shown for their potential in healing chronic wounds [92,93]. Similar to chitin/chitosan, 5-methyl pyrrolidinone chitosan one of the derivates of chitosan healed the diabetic wounds alongside the reduced recovery rate. When it was incorporated with Neurotensin, a bioactive neuropeptide, improved vessel permeability, vasodilation and vasoconstriction were noted [93]. The CS-based composite bandages and membranes were proved as a non-toxic material [94,95] and promoted cell adhesion [96]. The chitosan/gamma-polyglutamic acid (PGA) polyelectrolyte complexes provided moisture environment to dry wounds and healed the wound significantly faster than the control wounds [97]. Similarly, the chitosan blended with PVA and montmorillonite nanocomposite hydrogels showed improved mechanical properties, biocompatibility and antibacterial and swelling behaviours [98].

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A chitosan sponge because of its micro-porosity absorbs exudates more than 20 times of its dry weight, which in turn helps in tissue regeneration [99]. Its biomedical application is further improved by loading it with different therapeutic agents like curcumin which, besides helping in exudate absorption also improves granulation tissue formation with well-aligned collagen [100] in full-thickness wounds. Chitosanglutamate and sericin-based dressings exert a protective effect on human fibroblast from oxidative damage and improved fibroblast proliferation in chronic skin ulcer [101]. Panoraia et al. [102] loaded chitosan sponge with Levo to exhibit the ability in managing wound infections, tolerability, safety and antibacterial protection against common susceptible and resistant wound pathogens. Recently, attempts are being made to functionalise chitosan with oil [103], metallic NPs, herbal extracts viz Salix alba and Juglena regia leaves [104–107], aloe vera [108], etc., both alone and in combination, to make the chitosan-based wound dressing material more promising in wound healing therapy.

8.5.1.2  Cross-linked alginate dressings/fibroin and alginate sponge Alginate dressings are made from the sodium and calcium salts comprising mannuronic and guluronic acid units. Textiles made from calcium sodium alginate (SA) perform the excellent function of significant absorption of exudates and haemostasis [109,110]. These dressings have the capacity to absorb up to 20 times the weight of dressing and conform to irregular surfaces. The larger absorptive capacity minimises pain and trauma caused by frequent dressing removal hence is used on moderate to highly exudating chronic and acute wounds. These dressings are available in ribbon and sheet forms, which are either dispersible or non-dispersible. The ribbon-type is suitable for the treatment of pockets in the wound. These dressings need to be changed before deterioration of the gel state. Non-woven calcium alginate fibre dressings have been used on deep skin wounds. Kaltostat and Sorbsan are typical non-woven fibre alginate dressings and provide wounds with good absorption of the exudates and an occlusive environment. However, these dressings have been shown to cause cytotoxicity and foreign-body reaction owing to remaining dressing debris, leading to severe chronic inflammation [111,112]. Non-woven fibre alginate dressings are biodegraded, but the degradation rate is very slow. Suzuki et al. [113] showed that calcium alginate fibres remained after implantation in the muscle of rabbits and severe chronic inflammation continued. This was considered to be caused by foreign-body reaction to the debris of dressings. However, an alginate gel prepared by cross-linking with ethylenediamine, using the amide-coupling reagent water-soluble carbodiimide, showed no cytotoxicity and reduced foreign-body reaction to a great extent. In experiments using pigs, cross-linked alginate gel showed a significantly higher wound closure rate in a full-thickness wound than Kaltostat and Sorbsan (Fig. 8.3). Furthermore, the biodegradation rate of cross-linked alginate gel was much faster than Kaltostat and Sorbsan, i.e., it was absorbed completely within a few months without inflammation. Because the cross-linked alginate gel has a non-fibrous structure, it is considered to be easily biodegraded because of its high-swelling with biological

228

Advanced Textiles for Wound Care Wound closure after 15 days (%) 90

92

94

96

98

100

Crosslinked alginate gel

Kaltostat

Sorbsan

Figure 8.3  Wound closure rate after 15 days. Mean ± SD (n = 10) [113].

fluid. The cross-linked alginate gel appears to overcome the disadvantages of the conventional dressings Kalostat and Sorbsan. However, weakness of the gel strength, unpredictable and uncontrollable degradation and dissolution properties may be a drawback of cross-linked alginate gel after the loss of the divalent cation cross-linkers [114]. Once alginate dressings are applied to the wound, ions present in the alginate are exchanged with blood to form a protective film. These dressings are suitable for moderate to heavy drainage wounds and are not suggested for dry wounds, third-degree burn wounds and severe wounds with exposed bone. Also, these dressings require secondary dressings because it could dehydrate the wound which delay healing [61]. In the case of DFU, calcium alginate–based dressings accelerate wound healing by absorbing wound exudates which in turn facilitates debridement [115,116]. Moreover, calcium is predominantly involved as Factor IV in the haemostatic phase of wound repair and its role in epidermal cell migration and regeneration patterns in later stages of healing, i.e., remodelling phase, need to be identified [117]. Recently, alginate-based dressings are also combined with biopharmaceuticals such as growth factors (stromal derived factor-1) and drugs like phenytoin, ibuprofen or clindamycin to improve DFU treatment. Phenytoin-incorporated alginate hydrogel healed non-healing chronic wound in 60% of diabetic patients within 16 weeks of treatment and was also found to reduce the wound infection and pain [118]. Medihoney (Derma Sciences Inc., Canada), an alginate hydrocolloid wound dressing loaded with 70% leptospermum honey or Algisite M calcium alginate dressing (Smith and Nephew Inc., Australia) stimulated re-epithelialisation and improved healing of foot ulcer in diabetic patients [119]. Similar to alginate dressings, much attention has recently been paid in material sciences to a protein: silk fibroin. In particular, it has been found that silk fibroin is an invaluable biosynthetic material in the field of biomedical engineering and wound healing [120,121]. Silk string has been used as a suture since ancient times, and silk is therefore widely known as a safe material. Silk fibroin is very biocompatible and its safety and usefulness have been demonstrated in various studies, showing that its film is very effective in wound healing and exhibits high compatibility as a vascular graft, and its sheet and sponge forms can function as a good support for the proliferation

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Epithelialization (mm2)

0.16 0.14 0.12 0.1 0.08 0.06

Control

AA-S

SF-S

SF/AA-S

Figure 8.4  Effect of wound dressings on re-epithelialisation. Mean ± SE(n = 6) [113].

of fibroblasts, epithelial cells, etc. Silk fibroin products act as a safe and strong support structure and promote granulation tissue proliferation and re-epithelialisation [122,123]. Electrospun silk fibroin scaffolds are of recent interest and gaining attention as wound dressing materials as its high surface area help better spreading of collagen and cell adhesion [124]. In contrast, alginate has the ability to absorb wound exudates effectively; hence, alginate dressings provide an appropriate moist environment to the wound. Given the advantages of silk fibroin in the promotion of proliferation and alginate’s maintenance of a moist environment, it is suggested that their combined use is useful in wound healing. A sponge made by blending silk fibroin and alginate (SF/AA-S) was prepared by mixing the solution and subsequent lyophilisation. SF/AA-S was compared with silk fibroin sponge (SF-S) and alginate sponge (AA-S) for wound closure rate, granulation and re-epithelialisation following the treatment of full-thickness wounds in rats [125]. The rate of wound size reduction was significantly faster in SF/AA-S than in the control (Nu Gauze), SF-S and AA-S. The area of new epithelialisation tissue was the largest in SF/AA-S, which showed a significantly better effect on re-epithelialisation than SF-S and AA-S (Fig. 8.4). The area of collagen deposition in the granulation tissue was significantly increased in SF-S, AA-S and SF/AA-S compared with the control, but no significant difference was observed between the treated groups. The acceleration of re-epithelialisation by SF/AA-S was also confirmed by the increase in proliferating cell nuclear antigen expression. Thus, SF/AA-S showed significant synergic wound healing effects as compared with SF-S and AA-S, mainly associated with the promotion of re-epithelialisation rather than collagen deposition. SF/AA-S may be useful clinically. Aloe vera gel extract–incorporated fibroin dressing was developed by Inpanya et al. [126] and showed its effectiveness in the treatment of chronic wounds using streptozotocin-induced diabetic rats. The aloe gel extracts/fibroin film stimulated proliferation and differentiation of skin fibroblasts in the treated groups when compared with control groups. The results of numerous investigations revealed the wound healing potential of fibroin-based dressings in the management of chronic wounds. Besides, animal origin–based biomaterials such as keratin and its derivatives are used as dressing materials and also as substrate for delivering antibiotics and growth

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factors for improving the wound healing application [127–132]. Similarly, bovine serum albumin nanofibres and Avian egg shell membrane (meshwork of fibrous proteins) are used in the management of wounds and burn injuries as they act as an ECM for the proliferation of fibroblast cells [130].

8.5.1.3  Hyaluronic acid and its derivatives, collagen and gelatin Hyaluronic acid (HA) is a chief polysaccharide component of ECM of mammalian tissue. It is a polymer of disaccharides consisting of d-glucuronic acid and D-N-acetylglucosamine linked via alternating glycosidic bonds. It is generally extracted from synovial fluid, umbilical cord, vitreous humor or from rooster combs [133]. Besides it structural function, HA plays a very important biological and physiological function in the body such as the regeneration, modulation of inflammation and wound healing processes [134]. The use of HA for the management of acute and chronic wounds is well established by many investigators in the forms of hydrogel, sponge, nanofibres, film, graft etc. HA gel accelerates the collagen deposition and re-epithelialisation and reduces the size of wound of streptozotocin (STZ)-induced diabetic rats [135]. Matsumoto and Kuroyanagi [136] developed HA sponge and functionalised it with arginine and EGF for treating diabetic wound. The functionalised HA sponge accelerated healing in STZinduced diabetic rats along with increased re-epithelialisation. Recently, HA is being explored as a carrier for delivering therapeutic agents to increase its local availability for improving the healing of chronic wound. Its biodegradability and biocompatibility favours its application in tissue engineering/tissue regeneration. In a study by Abbruzzese et al. [137], HA gel was combined with mixture of amino acids for treating non-healing ulcers (NHUs) of diabetic patients. Interestingly, the gel besides reducing the ulcer size within 3 months of its treatment also reduced microbial infection–mediated complications. In another study by Xie et al. [138], HA gel enhanced absorption and transport of vitronectin growth factor when it was complexed with HA. The increased absorption of growth factor improved the re-epithelialisation in deep dermal partial-thickness burn wound model. Similarly, antimicrobial compound loaded with HA eliminated infection and prevented undesired tissue adhesion in abdominal cavity wound when it was spun into nanofibres [139]. Babo et al. [134] achieved controlled delivery of platelet lysate, a haemoderivative rich in cytokines on loading it in HA microparticles and identified its potential in regenerative medicine application. Clinical studies of HA-based bioactive dressings such as HA cultured with autologous human keratinocytes (laser skin autograft) and keratinocyte stem cells showed greater potential in promoting healing NHU, DFU, burn wounds and large cutaneous wounds. Autologous human keratinocytes healed 79% of wound area within 7–64 days of NHU in human diabetic patients [140]. A plethora of studies confirm its capability in improving the proliferation and migration of fibroblast, keratinocytes, endothelial cells in in vitro and in vivo wound models and clinical studies, making it a new product in tissue regeneration. However, several studies found molecular weight–dependent biological function of HA. While low– and high–molecular weight HA and their by-products increase the tissue damage [141] and limit the wound regeneration, the medium–molecular weight HA enhanced wound closure through up-regulation of junctional adhesion molecules at the epidermal diffusion border [142].

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Similar to HA, collagen has also been well explored as wound dressings and are available commercially in the forms of sheet, gel, powder and membrane for the management of wounds of different types. With the advancement in tissue engineering, collagen has been used as a substrate/scaffold for delivering cells of autologous and allogenic fibroblast and keratinocytes, natural compounds, growth factors, antibiotics and metallic antimicrobials for the treatment NHU. Apligraft and dermagraft are Food and Drug Administration (FDA)–approved collagen-based bioactive dressings used for the treatment of DFU. Because collagen is a basic structural protein and provides strength and integrity to tissue matrices, reports of various in vitro, in vivo and clinical studies showed it being superior to HA in managing healing and non-healings wounds of patients with diabetes, venous and pressure ulcers and burn wounds. Arul et al. [143] delivered ROS through collagen matrices and showed promising results in healing diabetic dermal wound healing. Ulrich et al. [144] analysed the wound fluid of DFU treated with collagen/oxidised regenerated cellulose (ORC) dressing and found increased scavenged free radicals and growth factors and decreased activity of collagenase, MMP-2 and 9, and gelatinase. Collagen–ORC dressing also reduced ulcerative area within 6 weeks of its application in diabetic patients with chronic foot ulcer [145]. Gelatin is a derivative of collagen, used in various biological applications because it is biodegradable and biocompatible and has low antigenic properties. Recently attempts have been made to develop biocompatible scaffolds using collagen–gelatin and are used to deliver fibroblast growth factor (FGF) in a relayed manner [146]. The sustained release of FGF stimulated angiogenesis in diabetic mouse and accelerated granulation tissue formation. BCG, BIOSTEP, Catrix, CollaSorb and PROMOGRAN PRISMA matrix are the commercially available collagen- and gelatin-based dressings for the management of partial- and full-thickness pressure, venous, vascular and diabetic ulcers [117].

8.5.1.4  Cellulose and dextran-based dressings Cellulose is the most abundant organic polymer in the Earth and is the primary structural component of plants and natural fibres such as cotton and linen. Biomedical applications of cellulose as a covering material for wound, scaffold for tissue engineering [147] and vehicle for delivering drugs [148] is well demonstrated by many investigators. However, its application is often found limited as the body cannot resorb cellulose like other biomaterials such as collagen and HA. Currently, attempts are being made to improve its resorbability through different chemical modifications and/or cross-linking of bioresorbable moieties with water-soluble cellulosics [149,150,151]. Carboxymethyl cellulose (CMC), sodium carboxymethyl cellulose (NaCMC) and hydroxypropyl methylcellulose are the cellulose derivatives with high biodurability and are exploited majorly in wound healing applications. Some of the commercially available CMC- and NaCMC-based dressings are IntraSite Gel (Smith and Nephew), GranuGel (ConvaTec), Purilon Gel (ColoPlast), Aquacel Ag (ConvaTec) and Silvercel (Johnson & Johnson) [152]. A textile of NaCMC is used in a similar manner to calcium SA textiles [153,154]. NaCMC is a non-toxic, non-allergenic, anionic water-soluble polymer derived from cellulose. It absorbs wound fluid and transforms into a soft gel. The main characteristic of the CMC textile is its significant absorption of exudates. Hence, they are primarily used for the management of leg ulcers, pressure

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ulcers (categories II–IV), diabetic ulcers, surgical wounds, donor sites, abrasions, lacerations, first-degree and second-degree burns, traumatic wounds, painful wounds and wounds that are prone to bleeding. The CMC textile is changed before deterioration of the gel state by the absorption of exudates. As a wound dressing material, cellulose improves the healing through the release and maintenance of growth factors like EGF, basic fibroblast growth factor (bFGF) and phosphodiesterase growth factors. These growth factors in turn help in the proliferation and migration of therapeutic cells required for wound healing [155,156]. Aquacel hydrofibre is a commercially available cellulose-based wound dressing, which helps in the absorption of excess exudates, provides moist environment and impedes with the bacterial proliferation, thereby accelerating the wound healing process. Gustaite et al. [157] developed cellulose sponge with a mean pore size of 750 nm. The sponge, because of its hydrophilicity and high specific surface area, exhibited high absorption and water vapour transmission ability. Furthermore, functionalisation with different active compounds (e.g., polyphenols) and metallic antimicrobials (e.g. AgNPs) improved healing. The same group developed cellulose hydrogel through lyophilisation/ supercritical CO2 treatment and established the potential as a wound dressing material [158]. Maver et al. [159] developed cellulose-based thin films and studied its potential of using it as a platform for delivering drugs for wound healing applications. The group used diclofenac (DCF), an analgesic drug as a model drug, and observed its release pattern similar to that of viscose fibres impregnated with DCF. The drug release was controlled by laying additional cellulose layers that do not contain DCF. Mu et al. [160] developed nano-porous nitrocellulose-based liquid bandage and evaluated its cutaneous wound healing potential using mouse model. The mean pore size of the bandage was 18 nm, which was advantageous in preventing bacterial invasion and had favourable tensile strength and acceptable water vapour transmission rate. The bandage improved the healing of cutaneous wounds through reduced inflammation, rapid angiogenesis, enhanced re-epithelialisation and deposition of aligned collagen fibres. These in vivo results are supported by various clinical studies where the significant improvements in healing of foot ulcers of diabetes patients are seen. Significant reduction in the E. coli and S. aureus contaminants were noticed by Jung et al. [161] in DFU. Microbial-derived cellulose hydrogel, besides reducing the infection, helped in the removal of necrotic debris and absorbed excess fluid from exudating wounds [155] of chronic and NHUs. It is also reported to increase granulation tissue formation and re-epithelialisation and healed non-infected chronic wounds of diabetic patients within 32 days [162]. Similar to cellulose, dextran is also a natural polymer gaining significant attention in recent years as a biomaterial for dressing the wounds and scaffold for controlled drug delivery and tissue repair [163]. Especially, the strong hydrophilic property of dextran is advantageous in dry/chronic wounds because its moisture content stimulates angiogenesis and helps skin regeneration [164]. Also, it absorbs wound exudates, thereby minimising bacterial colonisation in the wound bed. Dextran, because it is a nontoxic hydrophilic homopolysaccharide with many hydroxyl groups, it allows modifications for the development of spherical, tubular and 3D network structures with specific characteristics for tissue engineering applications. The flexibility of dextran helps in precise tuning for the delivery of angiogenic signalling biomolecules to induce functional

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neovascularisation. The dextran hydrogel is reported to promote dermal regeneration with skin appendages re-growing within 3 weeks of treatment. It is also found to enable infiltration of inflammatory and angiogenic cells into the wounded area. Furthermore, neovascularisation and a mature epithelial structure with fully developed hair follicles and sebaceous glands were observed on 7th and 21st days of treatment [164]. Ribeiro et al. [165] used dextran-based hydrogel as a vehicle to deliver chitosan microparticle-loaded growth factors and studied its wound healing potential using both in vitro and in vivo models. Analysis of cytotoxicity, degradation products and histological parameters confirmed biocompatible nature of the hydrogel and its by-products. Histological analysis revealed absence of granulomatous inflammatory reaction in skin lesion and re-establishment of skin architecture. With this result, the group suggested its potential as a device for delivering bioactive agents used in regenerative medicine. Cicco et al. [166] developed microparticulate carriers through Supercritical assisted atomisation based on high-mannuronic alginate and amidated pectin blend loaded with gentamicin sulphate and studied its movement from dry to soft hydrogel. The particles with very high encapsulation efficiency and small diameter showed good flowability and high fluid uptake, enabling wound site filling and limiting bacterial proliferation. Moisture transmission of the in situ formed hydrogel was about 95 g/m2 h, thereby avoiding wound dehydration. The release ranged from burst to prolonged (4–10 days) based on the ratio between drug and polymer. It was also found to have antimicrobial activity alongside biofilm degradation capability, a key factor for proper management of infected wounds. Paunica-Panea et al. [167] developed a new composite dressing using collagen–dextran as natural polymers and zinc oxide as a metallic antimicrobial for wound healing application. Similarly, Hoque and Haldar [168] developed dextran-based antibacterial hydrogel for complete eradication of topical biofilm through extended release of biocides. The group used cationic small molecular biocides and dextran methacrylate for disturbing established biofilms. The gels, prepared via direct loading of the biocide and with highly controllable amounts, displayed 100% activity against both drug-sensitive and drug-resistant bacteria such as MRSA until 5 days. On established bacterial biofilms, it completely eradicated S. aureus, E. coli, and MRSA biofilms, the most common biofilm-forming bacteria that cause severe infections in humans. Moreover, the gels were shown to annihilate preformed MRSA biofilm with >99.99% bacterial reduction under in vitro and in vivo conditions in a superficial MRSA infection model in mice. Biocompatibility analysis confirmed the material as having excellent skin compatibility in various animal models such as a rat model of acute dermal toxicity, guinea pig model of skin sensitisation and rabbit model of skin irritation. Thus, it is suggested for treating bacterial biofilm-associated infections, especially topical infections.

8.5.2  Wound dressings made of synthetic polymers 8.5.2.1   Polyurethane PU-based films are a typical dressing used to protect wounds and keep moist conditions around the wound as an occlusive dressing [59,169]. Although water vapour and oxygen can permeate PU films, exudates can accumulate in severe wounds, leading to infection

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or delayed healing. In this case, wound dressings with higher permeability are desirable to give protection from infection and hydration. An electrospinning technique has recently been utilised, enabling the production of polymer nanofibres to manufacture nanofibrous textiles [170]. The nanofibrous PU film consists of PU fibre, a few hundred nanometers in diameter with ultra-fine porous structure. The nanofibrous PU film was non-toxic, controlled water vapour, had excellent oxygen permeation and promoted drainage of fluids caused by high porosity. Furthermore, the superfine structure allowed no invasion of exogenous bacteria. Comparison was made between the effects of the nanofibrous PU film and the control PU film (Tegaderm) on a full-thickness wound in guinea pigs. The dermis of the wound covered with Tegaderm showed a fairly long-lasting inflammatory state, while in the case of the nanofibrous PU film, the re-epithelialisation rate was increased and the dermis was well organised. Histological studies confirmed that the re-epithelialisation rate was accelerated in the nanofibrous PU film. This nanofibrous PU film prepared by electrospinning can, therefore, be proposed as a valid wound dressing. Similar to film, PU-based foam dressing is also permeable to both gases and water vapour. Its hydrophilic properties promote adequate absorbency while also providing thermal insulation. It keeps the exudates locked away from the peri-wound area, hence preventing maceration. The foam is easy to remove and protects the wound from unnecessary damage. These dressings are mainly used on moderate-to-heavy exudates, granulating or slough-covered partial- and full-thickness wounds, donor sites, ostomy sites, minor burns and diabetic ulcer but not for dry wounds. Allevyn foam dressing consists of a layer of hydrophilic PU foam bonded to a pink semi-permeable PU film. It is permeable to moisture vapour but provides an effective barrier to water and microorganism. Lyofoam consists of a soft, hydrophobic, open-cell PU foam sheet. Similar to Allevyn, it is permeable to gases and water vapour but resists the penetration of aqueous solutions and wound exudates. Shah et al. [171,172] demonstrated improved wound healing when using PU-based wound dressings. Based on the beneficial effect of this dressing, PU-based dressings are patented recently for the management of chronic DFUs. The commercial wound dressing Meliplex Ag (Molnlycke Health Care, Sweden) comprises a silicone wound contact layer, PU foam pad as an absorbent material, silver sulphate as an anti-microbial agent and a vapour-permeable waterproof film designed to absorb wound exudates, while maintaining a moist wound environment. It is mainly recommended for the effective management of chronic wounds such as lower extremity ulcers, pressure ulcers, burn wounds and DFUs [173]. To promote rapid wound healing, PU dressings loaded with different antimicrobial agents (e.g., penicillin, erythromycin, chlorhexidine, triclosan), a pain-relieving substance (e.g., ibuprofen) and protease inhibitors (e.g., MMP-9, elastase, MMP-8, MMP-12) are reported. These therapeutic agents are reported to release from its base materials such as collagen/polylactile/polyglycolide or PU upon contact with wounds [171]. Recently, Pyun et al. [174] developed rhEGF-incorporated PU-foam and evaluated its ability of healing diabetic wounds using Sprague–Dawley rat models. When compared with control groups, the rhEGF-PU treated groups healed the wound completely by promoting wound contraction, re-epithelialisation, collagen deposition and the formation of a skin appendage. Further evaluation in diabetic patients with chronic exudative wound also confirmed accelerated wound healing.

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8.5.2.2  Chitosan/PU films containing minocycline Chitin/chitosan-blended films have also been shown to be effective for the treatment of severe burn wounds [91]. In that study, the films made of chitosan with a high degree of deacetylation were also found to be more effective than chitin film and gauze alone. However, these blended or chitosan films did not necessarily demonstrate good wound states in terms of the elimination of pus, etc. Minocycline (MC) is widely and highly effective in the suppression of bacteria in skin ulcers [175] and reported to possess anti-fungal properties [176]. In fact, attempts have also been made to develop topical formulations containing MC [175,177]. However, these semi-solid formulations require frequent changing and multiple washing of the wound, leading to pain or burden for the patients. Dressings are considered to be better for usability and quality of life (QOL). Therefore, the combination of dressings and some antimicrobial agents was suggested to improve efficacy. Chitosan/PU films were produced, called CA/MC-F, in which MC powder was sandwiched between chitosan film, controlling the release of MC, and the PU film (Tegaderm) acting as a backing film [178]. The CA/MC-F, composed of chitosan with an 83% deacetylation degree and a small amount of MC (2 mg), called CA83/ MC-F, showed a gradual drug release over 2 days in vitro and in vivo. CA83/MC-F, CA83 film, MC ointment, Geben cream and Beschitin W were applied to full-thickness burn wounds in rats in the early stage (days 2 and 4), and the reduction rate of the wound area and wound states was compared between the different formulations. CA83/MC-F and CA83 film showed a faster reduction rate of the wound area than MC ointment, Geben cream and Beschitin W (Fig. 8.5). When the wound underwent complete occlusion, the wound states deteriorated owing to excessive exudates. Appropriate drainage seemed to be required to promote wound healing. When a greater amount of MC (10 mg) was contained, the sandwich film showed a worse effect because MC remained too long on and in the wound. Prolonged use and overuse of MC appeared to worsen wound states and delay wound healing. CA83 film and CA83/MC-F containing 2 mg of MC exhibited Control CA83/MC-F CA83 film Beschitin W MC ointment Geben cream

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Figure 8.5  Change of wound area after application of preparations. Mean (n = 3) [178].

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improved wound states and promoted wound closure rate when it was applied in conditions allowing appropriate drainage. Given the effect on wound states, CA83/MC-F may be more effective than CA83 film. Chitosan/PU film containing MC is suggested as a useful formulation for the treatment of severe burn wounds.

8.5.2.3  PVA- and PVP-based dressings PVA is one of the oldest synthetic polymers and has been used in different biomedical applications, e.g., wound dressing [179], wound management [180], drug delivery systems [181], artificial organs [182] and contact lenses [183]. The hydrophilic property of PVA is well exploited by the investigators and PVA-blend hydrogel, film, nanomembrane etc, have been developed. These blended materials, either natural or synthetic polymers, assemble the desirable properties of each material on its own, while blended polymer materials are always mixed with PVA for improving mechanical and physicochemical properties of obtained polymeric materials [108]. PVA sponges with various chitosan-oligosaccharide (COS) ratios, called PVA/ COS-S, were prepared by mixing them in an aqueous solution and subsequent lyophilisation. PVA/COS-S inhibited the growth of bacteria, while simple PVA sponge (PVAS) showed no antimicrobial activity. PVA/COS-S released COS gradually over several days. The rate of wound healing was examined, using rats with full-thickness wounds. When compared with cotton gauze (the control), PVA-S and PVA/COS-S showed faster closure of the wound. PVA/COS-S was more effective than PVA-S, and PVA/ COS-A with a higher ratio of COS showed a faster rate of reduction of the wound area. COS-loaded PVA-S can easily be prepared and is considered a useful formulation for wound treatment because of its high degree of effectiveness [184]. Kim et al. [185] developed nitrofurazone-loaded hydrogel wound dressing by blending PVA and SA, through the freeze–thawing method. The hydrogel was found to have increased swelling ability, elasticity and thermal stability. By increasing the SA content in PVA/SA hydrogel, decreased gel fraction % and mechanical properties were observed. Biological evaluation of the hydrogel film material showed the material as biocompatible and the wound healing ability of the dressing was proportionate to the amount of SA incorporated into PVA hydrogel film. Manju et al. [186] observed improved healing of chronic wounds in diabetic patients when they were treated with ciprofloxacin-loaded aminophenyl boronic acid/ PVA blend hydrogel. Similarly, Li et al. [187] developed a dressing by combining silver nanoparticles (AgNPs) with PVA chitosan-oligosaccharides (COS) and studied the wound healing potential through in vivo experiments. The animals treated with PVA/CS-AgNPs nanofibre scaffold were integrated well into the surrounding skin of the animals and decreased the wound area to 3% within 14 days of treatment. Li et al. group took the advantage of antimicrobial potential of AgNPs and protected the wound from microbial infection, a key factor that delays healing in majority of the wounds. Moreover, epithelialisation was seen in the treated animals within 14 days of treatment, confirming its potential as a scaffold for wound healing applications. Whereas Hassan et al. [188] used turmeric as an antibacterial agent and developed antibacterial PVA/starch hydrogel membrane–based wound dressing. The hydrogel membranes were prepared by cross-linking PVA with starch by using glutaraldehyde.

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Turmeric at the concentration of 0.5 g showed the highest anti-bacterial activity among different turmeric contents used. Similar to PVA, PVP is another biocompatible and hydrophilic polymer and has been extensively used for a wide variety of pharmaceutical applications including wound dressings [117]. Because the material is hydrophilic in nature and permits oxygen, many researchers are using PVP alone or in combination and developing dressing materials. Li and Lee [189] developed PVP- and S-nitrosothiol-based interpolymer complexes and studied its capability of releasing nitric oxide (NO). This complex released NO over a period of 10 days and accelerated healing with a single topical application. This could be because of the vasodilation function of NO which in turn might help in forming stable angiogenesis.

8.5.2.4   Poly(l-leucine) sponge loaded with silver sulfadiazine Various kinds of dressings or formulations have been developed for the treatment of wound healing, but infection is still a serious problem in clinical use. In particular, excessive exudates and the appearance of pus occur frequently in severe or chronic wounds. In these cases, quick drainage of the exudates and the supply of antimicrobial agents may be needed in addition to ensuring the moist environment. Poly(l-leucine) is insoluble in aqueous conditions, less toxic and slowly biodegradable. These characteristics may be appropriate for impregnating pharmaceutical agents and supplying them gradually to the wound. A poly(l-leucine) sponge containing silver sulfadiazine (AgSD), called PL/ AgSD-S, was prepared by mixing and subsequent lyophilisation [190,191]. The release of AgSD from the sponge was examined in vivo using mice with full-thickness dorsal skin wounds: that is, the remaining amount of AgSD was measured after application to the wound. The AgSD was gradually released over 1 week. Its in vivo antibacterial activity was examined using mice with full-thickness dorsal skin wounds, inoculated with bacteria such as S. aureus or P. aeruginosa. Twelve hours after inoculation, the formulation was applied to the wound and the number of bacteria was counted. Compared with the non-treated group, the sponge suppressed the growth of S. aureus or P. aeruginosa. This study demonstrated that the AgSD-loaded poly(l-leucine) sponge would be useful in the treatment of bacteria-infected wounds. When this sponge was clinically tested on patients with burn wounds or pressure ulcers, it showed excellent protection and suppression of infection. Ointments and creams are still used in the treatment of severe wounds such as serious burns and pressure ulcers, but they require frequent change of the formulation and gauze used as a cover, resulting in a burden for the patients. However, dressings such as PL/AgSD-S are easy to handle, provide wound protection and good suppression of infection and result in an enhanced QOL for patients. Various other types of dressings containing AgSD were also reported to show these advantages [192,193]. These formulations are considered useful for the treatment of severe or chronic wounds.

8.5.2.5  Other polymer-based dressings PHEMA, PCL and polymers of poly α esters such as PLA, PGA and PLGA are also of interest currently because they are identified as being biocompatible with the strength required for various biomedical applications. Degradation rate of these polymers

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makes it useful for drug delivery and tissue engineering applications [195–197]. Among these polymers, PLGA is the most studied and approved by FDA for several biomedical and pharmaceutical applications [197]. Dong et al. [198] studied the potential of PLGA microsphere in the delivery of rhEGF for the treatment of diabetic ulcer using a rat model. The growth factor–incorporated microsphere was prepared through solvent evaporation technique and the encapsulation efficiency was found to be 86%. Furthermore, the group compared its healing efficiency with pure rhEGF. When compared with pure growth factor, the microsphere-loaded EGF because of its sustained release showed accelerated healing. Similar results were reported by Chu et al. [199], where the growth factor was loaded through double-emulsion technique. Other polymers such as PLA [200], PCL [201], PGA [197,202] and PHEMA [203– 205] were also shown to be effective in healing wounds through in vitro and in vivo studies by many investigators. The success of these polymers are mainly based on their ability in providing the wound with the therapeutic level of growth factor, thus showing higher recovery rate alongside the complete re-epithelialisation, regeneration of skin appendages, stable capillary vessel and deposition of aligned collagen fibres.

8.6  Future trends Many dressings other than the novel dressing formulations described above have also been developed recently. Materials which not only provide appropriate environments but also function well to promote wound healing will become important in obtaining more effective dressings or formulations. Technical innovation and the discovery of better functional substances are being actively progressed. Some interesting current studies in the development of novel dressings or formulations are described below.

8.6.1  Nanofibrous non-woven matrices In the field of textiles, electrospinning method is one of the technical innovations for the production of nanofibres [206]. In addition to the nanofibrous PU membrane referred to above, nanofibrous non-woven textiles have been manufactured with chitin, collagen and silk fibroin [125,207,208]. These biosynthetic polymers are considered invaluable because of their promotion of tissue generation and wound healing. Chitin nanofibrous non-woven matrices (Ch-N) and conventional fibrous nonwoven membrane Beschitin W (Ch-M) were compared regarding their scaffold characteristics for tissue regeneration and wound healing, that is, for cell attachment and the spreading of keratinocytes and fibroblasts. The Ch-N consisted of electrospun chitin fibres of a few hundred nanometers diameter, while the Ch-M was composed of approximately 10-μm-thick chitin microfibres (Fig. 8.6). The Ch-N showed faster biodegradation than Ch-M, Ch-N–promoted cell attachment and spreading of keratinocytes and fibroblasts, more than Ch-M did, and Ch-N coated with type I collagen promoted cellular response. These results suggest that Ch-N would be useful for wound healing. Collagen nanofibrous matrices were also fabricated by the electrospinning technique

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(b)

Figure 8.6  Structures of (a) chitin nanofibre (Ch-N) (100 μm) and (b) Beschitin W(Ch-M) (100 μm) [208].

and found to be effective for wound healing. Electrospun nanomembranes of fishscale collagen peptide and COS showed fair antibacterial activity against gram-positive and gram-negative organisms alongside proliferation of skin fibroblasts [194,195]. Similarly, the composite collagen nanomembranes prepared with PLGA [209], PVA [210], PEO/gold [211], HA [212] and Zein [213] confirm the capability of collagen in healing wounds of different stage and types. Furthermore, silk fibroin nanofibrous non-woven matrices, and its surface modification with dextran [214] improved the healing of wound under in vitro condition using NIH3T3 cells. When the silk fibroin was reinforced with vitamin C, it improved skin regeneration [215] and showed antibacterial activity against E. coli under UV irradiation when it was co-electrospun with TiO2 [216]. Recently silk fibroin–based antioxidant scaffold was developed with fenugreek and was shown to have better healing activity on full-thickness excision rat wound model [217]. All these nanofibrous mats and scaffolds produced by the same technique showed good cell attachment and spreading of keratinocytes and fibroblasts under both in vitro and in vivo conditions. Thus, nanofibrous non-woven matrices manufactured with these biocompatible biosynthetic polymers are considered a very effective candidate as a novel dressing for the treatment of severe wounds because they can provide a similar structure and function to those of the natural ECM. They are now expected to offer very high potential as a technique for recovery from severe wounds and will be examined actively in the future.

8.6.2  Novel wound dressings for managing deep skin wounds or ulcers Although the widely used dressings described above are useful in treating various wounds, it is difficult to remove completely the possibility of infection and delay of wound healing. These problems tend to occur in severe wounds accompanied by excessive exudates, infection and the contamination of necrotic tissues. Biological dressings have, therefore, been the interest of many researchers. This section briefs the advancements made in the cellular and acellular therapies for the treatment of NHUs.

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8.6.2.1  Advanced therapies The standard wound care therapies explained above are often found inefficient in healing chronic wounds and, hence, are treated with advanced therapies using biopharmaceuticals. The therapies are broadly categorised according to their specific technologies or engineering, tissue types, cell types and protein content [218]. Among these therapies, proteins, i.e., growth factors, are the most studied in wound healing because of their potential in stimulating the cells involved in healing. Generally, the growth factors mediate non-haematopoetic cells such as fibroblast and keratinocytes and improve the healing. EGFs, PDGF and transforming growth factors (TGF-β) are the exhaustively studied growth factors. PDGF-BB is the only commercially available advanced therapy in the trade name of Becaplermin for the treatment of diabetic neuropathic ulcers. In the 20-week phase III clinical trial by Wieman leading to its approval, topically applied rhPDGF gel was found to significantly increase the incidence of complete wound closure by 43% and decrease the time to healing by 32% over placebo-controlled standard wound care [219]. Date from multiple sources also confirm the efficiency of growth factor in healing chronic non-ischaemic foot ulcers when combined with good standard wound care [219–221]. Several attempts are made to improve the exogenous delivery of growth factor by using various biomaterials. Sun et al. [222] incorporated PDGF in collagen membrane and demonstrated its wound healing ability using rabbit dermal ischaemic ulcer models. The PDGF at 0.64 nM concentration showed re-epithelialisation in approximately 55% animals which was 30% in the blank control after 14 days. Jin et al. [223] used PLGA microparticles incorporated into nanofibrous scaffolds for delivering PDGF of the concentrations between 2.5 and 25 μg. Increased angiogenesis and tissue neogenesis were reported in the treatment groups when compared with control groups. Li et al. [224] delivered PDGF of the concentrations of 0–11.5 μg/ mL using PU scaffold and studied its healing efficiency on rat excision wound model. PDGF-treated animals, by the 14th day post-injury demonstrated nearly 100% re-epithelialisation, while the blank control group achieved only 70% tissue recovery. Recombinant human EGF is perhaps the most studied growth factors next to PDGF in the field of wound healing as it plays a crucial role in stimulating fibronectin synthesis, angiogenesis, fibroplasia and collagenase activity required for re-epithelialisation in acute wounds. Several trials conducted by different research groups from Asia and Cuba demonstrated the healing benefits of EGF compared with control [58,225–227]. bFGF is a potent angiogenic growth factor known as keratinocyte growth factor-2 or repifermin [228]. It promotes the proliferation and growth of fibroblast cells and vascular endothelial cells and is useful to accelerate healing [229,230] of chronic wounds including DFU, venous and pressure ulcers. These functions can operate efficiently when used with dressings that provide appropriate environments for the wounds. A gelatin sponge dressing containing bFGF-loaded gelatin microspheres showed more sustained release of bFGF, as compared with a gelatin sponge containing free bFGF (Fig. 8.7), and a greater degree of reduction in the wound area in pigs with full-thickness skin defects [230].

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5

bFGF released (mg)

4 3 GS-bFGF 2

GM-bFGF

1 0

0

1

2

3

4

5

6

7

Time (days)

Figure 8.7  Release of bFGF from gelatin sponge containing free bFGF and sponge containing gelatin microspheres loaded with bFGF [230].

The dressing was biocompatible and did not cause foreign-body reaction. The newly formed dermis exhibited almost the same structure as that of normal skin. Dressings loaded with bioactive proteins are suggested as useful and novel wound formulations. Although the use of bioactive proteins is difficult owing to problems such as the determination of optimal concentrations, they are certain to be useful for wound healing and will be examined actively in the future.

8.6.2.2   Cell therapy The bioactive dressings discussed in the above section offer many advantages in improving the healing of chronic wounds. However, limitation does exist and it often results in wound recurrence, amputation, increased length of stay in hospital and poor cosmetic outcome. Also, the delivery of bioactive compounds from the polymer-based vehicles such as nano/micro-particles, sheet, film, foam, etc., is not always controllable. To overcome the limitations associated with the conventional dressings, currently human dermal allograft–based biological dressings are gaining importance in the field of wound healing for augmenting tissue regeneration in chronic lower extremity wounds such as DFU and VLUs (venous leg ulcers). These biological dressings are categorised by FDA as human cellular and tissue-based products [218]. Cell-based therapy uses cells of autologous and allogenic nature for both acute and chronic wounds. These cells besides accelerating the healing of ulcer are also reported to reduce the scar contraction, minimise donor-site morbidity and colour mismatch. Compared with conventional treatment, this treatment is simple and less time consuming and reduces the surgical burden for patients [231]. Because the epidermal portion is restored by epithelialisation induced by the migration and proliferation of adjacent epidermal cells including melanocytes, the density and activity of melanocytes and precursor melanocytes of the epidermis of the graft become similar to those observed

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in the adjacent skin. In the treatment of chronic wounds, attempts are made to convert the wound bed into the environment where maximum wound healing can be achieved by transplanting cells with an excellent wound healing capacity to the wound bed [231]. Autologous cells, because it is from the patient’s own tissue, reduce the time needed for the host cell to invade the wound tissue and allow early synthesis of new skin. However, it does not have an effect on wound contraction. Hence, these cells are grown on artificial dermis developed using natural/synthetic polymer–based scaffolds, membranes or sheets and are applied on a wound bed. These tissue-engineered artificial dermis minimise wound contraction without delaying the healing of skin and soft tissue defects. Similar to autologous cells, allogenic cells also promote migration and proliferation of cells from the wound bed and from the edges. Because these cells release components of ECM and basement membrane besides growth factor, it improves host cell proliferation which in turn replaces the transplanted allogenic cells from the wound bed. In both the therapies, fibroblast, keratinocytes and adipose-derived stromal vascular fraction cells grown on collagen/HA/polyglactin scaffolds are actively used in clinical settings. Holoderm (Tego Science, Korea), Kaloderm (Tego Science), Hyalograft 3D (ChaBio & Diostec), Apligraf (Organogenesis, Canton, MA) AND Dermagraft (Organogenesis, Canton, MA) are few of the commercially available tissue-engineered skin substitutes for the treatment of chronic ulcer. Holoderm contains approximately 1 billion keratinocytes expanded from a 1- to 3-cm2 skin biopsy for about 14–18 days which covers an entire adult body. Kaloderm contains >2 × 107 cells derived from a Korean infant’s foreskin and randomised, controlled, multicentre study on this dressing showed its efficiency of healing DFU within 12 weeks of treatment. Hyalograft 3D comprises autologous cultured fibroblasts grown on a scaffold made from the benzyl esters of HA. Similar to Kaloderm, hyalograft 3D also showed complete healing of DFU in 84% patients and 34% in the control group. The study also proved its safety and tolerability. Apligraf (Organogenesis, Canton, MA) is an allogenic dermal equivalent derived from fibroblasts cultured in a contracted type I collagen matrix and an epidermis generated by keratinocytes. It is mainly recommended for treating the full-thickness neuropathic DFUs of greater than 3 weeks duration which have not responded to conventional treatment and extended through the dermis but not exposed to tendon, muscle and bone. The collagen matrix of Apligraf acts as a substrate for the proliferation of living cells that are seeded in it and help synthesise growth factors, cytokines and ECM products [232–234]. In a clinical study conducted by Veves et al. [235], Apligraf group achieved complete healing in 56% of diabetes patients with neuropathic foot ulcer when compared with 38% in the control group (P = .0042) in the pivotal, multicenter, 12-week clinical trial. Other subsequent investigations found similar efficacy of this bioengineered product for healing chronic diabetic foot wounds and VLUs [236,237]. Dermagraft (Organogenesis, Canton, MA) is a human fibroblast-derived dermal substitute (HFDS) comprising a cryopreserved, absorbable, three-dimensional polyglactin mesh substrate seeded with living neonatal dermal fibroblasts [238]. Similar to the bilayered skin replacement, these cells secrete a host of growth factors, cytokines,

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matrix proteins and glycosaminoglycans that induce tissue regeneration through the development of granulation tissue and in-growth of host fibroblasts and keratinocytes [239,240]. It is indicated for full-thickness DFUs greater than 6 weeks duration, which extend through the dermis, but without tendon, muscle, joint or bone exposure. This dermal substitute was proven effective in healing chronic DFUs in the pivotal trial by Marston et al. [241]. A recent study investigated the incidence of amputations and bone resections within the two arms of the DFU pivotal trial and found a decreased incidence of these complications in the HFDS group, likely related to a lower incidence of infection and faster healing in the investigational treatment group [242]. These tissue-engineered skin substitutes, although cultured with allogenic cells, they have not stimulated antigenicity in the studies reported so far. Recently, stem cells, particularly bone marrow and placentas (adult), derived are of interest for enhancing the healing of chronic ulcer. The cell lineages of bone marrow and placenta are mesenchymal which lack cell surface antigens and hence would not provoke a foreign-body reaction [243]. MSCs derived from placental tissues including the umbilical cord, the amnion and the chorion is reported to heal lower extremity wounds. These cells suffer from neither age-related effects nor decreased cell counts as found in MSCs harvested from adult patients with comorbid diseases [244–247]. Amniotic membrane (AM) product (Grafix; Osiris Therapeutics, Inc., Columbia, MD) is a commercially available human MSC and contains viable cells, including fibroblasts and epithelial cells, in addition to MSCs and a natural ECM [243]. The complete DFU healing was observed at 12 weeks in the patients receiving viable human matrix than those in the control group (62% vs. 21%, P = .0001). Bone marrow–derived stem cells are increasingly being studied for use in enhancing chronic wound and cutaneous repair [248–255] based on the reports on their ability to augment repair or regeneration of tissues such as cardiac, bone, cartilage, blood vessels and skin [248,251,256,257]. Tissue or acellular therapies are basically decellularised matrix of dermal, amniotic or collagen matrix derived from human or animal. These biological acellular and/or ECMs products serve as substrates which allow cells to migrate and initiate angiogenesis, thereby promoting granulation tissue development and tissue regeneration [258]. Because ECM contains glycosaminoglycans (including hyaluronan), proteoglycans and glycoproteins [259,260,255], products based on these materials are also available. Porcine-derived small intestinal submucosa, porcine urinary bladder matrix, bovine dermis, equine pericardium and sheep (ovine) bladder [261–269] are some of the currently available non-human ECM products. Hyalomatrix (Anika Therapeutics, Inc., Bedford, MA) is a hyaluronan-based matrix dressing used in the management of burns, VLUs and DFUs [270–273]. Integra bilayer wound matrix (Integra LifeSciences, Plainsboro, NJ) is a dermal regeneration template (bovine collagen, glycosaminoglycans, and silicone layer) that is primarily used in burns, lower extremity chronic wounds and foot ulcers [274,275]. GRAFTJACKET (KCI, San Antonio, TX) is a regenerative tissue matrix that acts as a scaffold for the repair or replacement of damaged or inadequate integumental tissue, such as DFU, VLU or pressure ulcers or for other homologous uses of human integument.

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TheraSkin (Soluble Systems, Newport News, VA) is a cryopreserved real human skin allograft comprising living cells, fibroblasts, keratinocytes, fully developed ECM in its epidermis and dermis layer. Hence it contains all the relevant human biological components such as growth factors, cytokines, fibroblasts, keratinocytes and Types I, III and IV collagen required to close and replace damaged skin in hard-to-heal wounds. Available data suggest that acellular dermal matrices, in addition to basic wound care principles, may provide an effective technique for tissue regeneration in deep and cutaneous extremity wounds [276,277]. In recent years, AMs and umbilical cord tissues have gained attention in treating chronic wounds because of their rich cellular content in the native state. AMs contain a number of cytokines and growth factors bound to the ECM after decellularisation and preparation that remain available to augment angiogenesis and tissue repair when implanted into chronic wounds [278–281]. Dehydrated human amnion/ chorion membrane (Epifix; Mimedix Group, Marietta, GA) healed 92% DFU after 6 weeks of treatment when compared with control group where the healing rate was only 8% [282]. In a crossover study of unhealed patients in the control arm of the RCT, 91% healed by 12 weeks with biweekly Dehydrated human amniotic membrane (dHCAM) application [283]. Subsequent studies ascertained that weekly applications of this allograft provided more rapid healing of DFUs than biweekly application and that healing frequency with the amnion/chorion product was significantly higher than patients assigned to either a bilayered skin substitute or to standard of care treatment in another comparative trial [284,285].

8.7  Sources of further information and advice Dressings and formulations relating to the healing of severe or chronic wounds cover various fields of science, such as medical science, biomedical engineering, biomaterials, cellular biology, microbiology, pharmacology and pharmaceuticals. Information on dressings and pharmaceutics that have already been officially approved can be obtained from package inserts, brochures, publications and websites made publicly available by administrative organisations. These provide information on their application and regulation of use. Practical guides, patents and papers issued by companies or manufacturers are also very useful for obtaining detailed information. News about medicines, industries and the development and research of companies also help us to obtain current or future information. Papers from universities and research institutes provide concepts, methodologies and the evaluation of individual research studies. Many books and reviews about wound healing have recently been published. Biomaterial science is probably at the centre of this field, but various sciences are considered fundamentally or practically to promote the development of dressings and formulations for the treatment of severe wounds. Furthermore, it must not be forgotten that, along with the development of materials, dressings and formulations, the establishment of their proper use, depending on wound states and patient conditions, is also of great importance.

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Acknowledgments The authors thank Dr. Prakash Vasudevan, Director, SITRA for according permission to publish this chapter. The authors also thank Dr. K. Sajan Rao, Head, LRTC for his valuable suggestion and critical evaluation of the manuscript. Contributions of Mr. T. Sureshram, Ms. K. Shalini, project students and the staff of the biological laboratory are also highly acknowledged.

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Further reading [1] P.S. Babo, R.L. Pires, L. Santos, A. Franco, F. Rodrigues, I. Leonor, R.L. Reis, M.E. Gomes, Platelet lysate-loaded photocrosslinkable hyaluronic acid hydrogels for periodontal endogenous regenerative technology, ACS Biomater. Sci. Eng. 3 (7) (2017) 1359–1369. [2] J.S. Bae, K.H. Jang, S.C. Park, H.K. Jin, Promotion of dermal wound healing bypolysaccharides isolated from Phellinus gilvus in rats, J. Vet. Med. Sci. 67 (1) (2005) 111–114. [3] R. Lobmann, C. Zemlin, M. Motzkau, K. Reschke, H. Lehnert, Expression of matrix metalloproteinases and growth factors in diabetic foot wounds treated with a protease absorbent dressing, J. Diabetes Complic. 20 (2006) 329–335. [4] L. Negron, S. Lun, B.C. May, Ovine forestomach matrix biomaterial is a broad spectrum inhibitor of matrix metalloproteinases and neutrophil elastase, Int. Wound J. 11 (2014) 392–397. [5] S. Weikert, D. Freyer, M. Weih, et al., Rapid Ca2+-dependent NO-production from central nervous system cells in culture measured by NO-nitrite/ozone chemoluminescence, Brain Res. 748 (1997) 1–11.

Drug delivery dressings Authors of the chapter: P.K. Sehgal, R. Sripriya, M. Senthilkumar Formerly of Central Leather Research Institute, Chennai, India

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Editor of the chapter: S. Rajendran School of Engineering, University of Bolton, Bolton, United Kingdom

9.1   Introduction The administration of topical medications to the wound sites is one of the most documented areas in medical history [1]. Conventional wound therapy comprised primarily of various ointments, local antimicrobial agents, and sterile bandages [2]. In the early 1980s, very few dressing types were available; they comprised mainly traditional dressings, paste bandages and similar preparations. During the mid 1980s modern wound management products began to emerge and hospitals across the world started using them in a small way. Today their uses have increased manifold. The principle function of a wound dressing is to protect the wound from infection and dehydration and to provide an optimum healing environment. The choice of a wound dressing is dependent on the cause, presence of infection, wound type and size, stage of wound healing, cost and patient acceptability. One dressing type may not be appropriate for all wounds. An ideal wound dressing should have host of advantages which includes rapid and cosmetically acceptable healing to prevent or combat infection, inducing haemostasis, nontoxic, nonallergic and nonsensitizing nature of the material to absorb wound exudates and wound odour, to provide debridement action and thermal insulation and to allow gaseous and fluid exchange. In addition to this it should be cost-effective with long shelf life and provide maximum comfort to the patients [3]. Wound dressing materials are designed for creating and maintaining an environment which is most suitable for wound healing by providing easy gaseous exchange, absorbing exudates from the wound site and providing a sterile environment which does not support microbial growth [4]. Wound dressings are mainly employed to prevent bulk loss of tissue, and they are effective against trauma, chronic wounds such as chronic burn wounds, diabetic, decubitus and venous leg ulcers. In case of infection, the dressings without drug may not be effective because the infectious organisms preferentially target wound beneath the dressing materials and elicit serious infections requiring removal of the dressing for further treatment and healing [5–8]. Treatment of these wounds requires the suppression and control of bacterial growth. Such wounds require topical antimicrobial treatment with a dressing, for proper management and healing. In this situation, the role of drug delivery dressings can play an important role for the effective healing and proper management of wounds. Current efforts in the area of drug delivery in wound dressings include the development of targeted delivery in which the drug shows activity at the wound site. Sustained Advanced Textiles for Wound Care. https://doi.org/10.1016/B978-0-08-102192-7.00009-6 Copyright © 2019 Elsevier Ltd. All rights reserved.

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release formulations in which the drug is released over a period of time in a controlled manner are effective in such cases. Localised drug delivery technologies are emerging as a way to target an optimum dose of a bioactive substance precisely whenever it is needed, rather than distributing excessive and unnecessary drug over the wound and avoiding excessive drug throughout the body via the systemic circulation. Targeting an optimum dose can be especially useful for drugs with a narrow therapeutic index, i.e., the difference between the dose at which the drug becomes therapeutically active and the dose at which undesired side effects can occur. Dressings can be significantly more effective and safer than their intravenous or orally administered counterparts, particularly with respect to unwanted side effects. The interest in formulated dosage forms, where the drug release can be controlled, has increased steadily during the last five decades. In most cases the purpose is to make a product that maintains a prolonged therapeutic effect at a reduced dosing frequency [9]. In addition to improved efficacy and safety, the frequency of administration can be decreased with sustained delivery, thereby improving patient compliance. Controlled release system is particularly interesting for such drugs which have relatively short half-lives and require a high frequency of administration in conventional dosage forms.

9.2  Wound: definition and types A wound is a type of physical trauma wherein the skin is torn, cut or punctured to create an open wound or where blunt force trauma causes a contusion to create a closed wound. In pathology, wound specifically refers to a sharp injury which damages the skin. The types of open wound are incisions or incised wounds – incisions which involve only the epidermis are classified as cuts, rather than wounds. Lacerations are irregular wounds caused by a blunt impact to soft tissue which lies over hard tissue. Abrasions (grazes) are superficial wounds in which the topmost layers of the skin (the epidermis) are scraped off, often caused by a sliding fall onto a rough surface. Puncture wounds are caused by an object puncturing the skin, such as a nail or needle. Penetration wounds are caused by an object such as a knife entering the body. Gunshot wounds are caused by a bullet or similar projectile driving into or through the body. Because the open wound is a disruption of normal anatomic structure and function [10], it can be classified in many ways. It may call it an acute or chronic wound depending on its nature or duration or type. By definition, an acute wound is acquired as a result of trauma or an operative procedure and proceeds normally in a timely fashion along the healing pathway with least external manifestations without complications [11]. Surgically created wounds are usually managed with local wound care. Wounds that fail to heal in the anticipated time frame and often recur are considered chronic wounds. These wounds present major challenges to health-care professionals and have serious consequences for patient quality of life. These wounds are visible evidence of an underlying condition such as extended pressure on the tissues, poor circulation, or even poor nutrition. Pressure ulcers, venous leg ulcers, and diabetic foot ulcers are examples of chronic wounds. Successful management of chronic wounds demands treatment of the whole body of the person who is suffering with such wounds. It involves meticulous local wound care, an

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understanding to diagnose the reason for the specific wound and to treat the underlying cause, a working knowledge of modern wound dressings, and correction and management of the patient’s underlying conditions for effective recovery and management. Wound depth is classified by the initial level of tissue destruction evident in the wound: superficial, partial thickness or full thickness [12]. Superficial wounds involve only the epidermis, partial thickness wounds involve only epidermis and dermis and full thickness wounds involve the subcutaneous fat or deeper tissue. Before any medical or paramedical evaluation or intervention is attempted, an open wound is considered as minor if it is superficial, away from natural orifices; there is only minor bleeding and not caused by a tool or an animal. Any other wound should be considered as severe. In case of severe open wounds, there is a risk of blood loss which could lead to shock and an increased chance of infection as bacteria may enter a wound from surrounding tissue, air, etc. Because of the risk of infection, wound should be kept clean, and closed if possible until professional help is available. Closed wounds have fewer categories, but they are just as dangerous as open wounds. The types of closed wounds are contusions (more commonly known as a bruise) which caused by blunt force trauma that damage tissue under the skin. Hematoma (also called a blood tumour) is caused by damage to a blood vessel that in turn causes blood to collect under the skin. Crushing injuries are caused by a great or extreme amount of force applied over a long period of time. Wounds are also classified as, wounds without tissue loss (e.g., in surgery, cuts, incisions) and wounds with tissue loss, such as burn wounds, wounds caused as a result of trauma, abrasions or as secondary events in chronic ailments, e.g., venous stasis, diabetic ulcers or pressure sores and iatrogenic wounds such as skin graft donor sites and dermabrasions.

9.3  Wounds which require drug delivery Restoration of tissue continuity after injury is a natural phenomenon. Infection, quality of healing, speed of healing, fluid loss, and other complications that enhance the healing time represents a major clinical challenge. Acute wounds are expected to heal within a predictable time frame, although the treatment required to facilitate healing will vary according to the type, site and depth of a wound. The primary closure of a clean, surgical wound would be expected to require minimal intervention to enable healing to progress naturally and quickly. However, in a more severe traumatic injury such as a burn wound or gunshot wound, the presence of devitalized tissue and contamination with viable (e.g., bacterial) and nonviable foreign material is likely to require surgical debridement and antimicrobial therapy to enable healing to progress through a natural series of processes, including inflammation and granulation, to final reepithelialisation and remodelling. In marked contrast, chronic wounds are most frequently caused by endogenous mechanisms associated with a predisposing condition that ultimately compromises the integrity of dermal and epidermal tissue [13]. Pathophysiological abnormalities that may predispose to the formation of chronic wounds such as leg ulcers, foot ulcers and pressure sores include compromised tissue

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perfusion as a consequence of impaired arterial supply (peripheral vascular disease) or impaired venous drainage (venous hypertension) and metabolic diseases such as diabetes mellitus. Advancing age, obesity, smoking, poor nutrition and immunosuppression associated with disease such as AIDS, Hepatitis A and B, cancer or drugs (e.g., chemotherapy or radiation therapy) may also exacerbate chronic ulceration. Pressure or decubitus ulcers have a different aetiology from other chronic wounds in that they are caused by sustained external skin pressure, most commonly on the buttocks, sacrum and heels. However, the underlying pathology often contributes to chronicity, and in this situation, pressure sores such as all chronic wound types may sometime heal slowly and in an unpredictable manner. Chronic wounds involving progressively more tissue loss give rise to the biggest challenge to wound care product researchers. Second major challenge is the prevention of scarring, keloid formation or contractures and a cosmetically acceptable healing. In these cases drug delivery dressings prove beneficial for effective and proper wound management.

9.3.1  Wound infections Infection has been defined as the deposition and multiplication of organisms in a tissue with an associated host reaction. If the host reaction is small or negligible then the organism is described as colonising the wound rather than infecting it. Whether a wound becomes infected or not is determined by the host’s immune competence and the size of the bacterial inoculum. With normal host defences and adequate debridement, a wound may bear a level of 100,000 (105) microorganisms per gram of tissue and still heal successfully. Beyond this number, a wound may become infected. It is well documented that if a wound becomes infected, the normal healing is disrupted as the inflammatory phase becomes chronic, disrupting the normal clotting mechanisms and/or promoting disordered leucocyte function. These factors together or independently prevent the development of new blood vessels and formation of granulation tissue. The production of destructive enzymes and toxins by mixed communities of organisms may also indirectly affect healing. Thus, it is critical to prevent infections which may occur by normal skin wound contaminants. A prolonged inflammatory response results in the release of free radicals and numerous lytic enzymes which could have a detrimental effect on cellular processes involved in wound healing. Proteinases released from a number of bacteria are known to affect growth factors and many other tissue proteins that are necessary for the wound healing process [14,15]. The increased production of exudates that often accompanies increased microbial load has been associated with the degradation of growth factors and matrix metalloproteinases which subsequently affect cell proliferation and wound healing [16]. Some bacteria are rapidly able to form their own protective microenvironment (biofilm) following their attachment to a surface, and the ability of host to control these organisms is likely to decrease when this biofilm community matures. Also within a stable, biofilm community, interactions between aerobic and anaerobic bacteria would likely increase their net pathogenic effect, enhancing their potential to cause infection and delay healing. Some of the potential wound pathogens are classified here.

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Beta Haemolytic Streptococci (Streptococcus pyogenes), Enterococci (Entero­ coccus faecalis) and Staphylococci (Staphylococcus aureus) are the gram-positive and Pseudomonas aeruginosa, gram-negative aerobic rod bacteria are the potential wound pathogens. Enterobacter species, Escherichia coli, Klebsiella species and Proteus species are the gram-negative facultative rods, and Bacteroides and Clostridium anaerobes are classified as wound pathogens. Yeasts (Candida) and Aspergillus are fungi which are also responsible for wound infection.

9.3.2   Acute wounds 9.3.2.1  Acute soft tissue infections Cutaneous abscesses, traumatic wounds and necrotising infections are classified as acute soft tissue infections. S. aureus is the single causative bacterium in approximately 25%–30% of cutaneous abscesses [17,18] shown by microbial investigations and has been recognised as being the most frequent isolate in superficial infections seen in hospital accidents and emergency departments [19]. Contrary to this, studies have revealed the presence of polymicrobial aerobic– anaerobic microflora in approximately 30%–50% of cutaneous abscesses [20], 50% of traumatic injuries of varied aetiology [21], and 47% of necrotising soft tissue infections [22]. Necrotising soft tissue infections occur with different degrees of severity and speed of progression; they involve the skin (e.g., clostridial and nonclostridial anaerobic cellulitis), subcutaneous tissue to the muscle fascia (necrotizing fasciitis) and muscle tissue (streptococcal myositis and clostridial myonecrosis). S. aureus has been described as being the single pathogen in two patients with rapidly progressing necrotizing fasciitis of the lower extremity [23], and in a study of necrotising fasciitis in eight children [24], the presence of pure S. pyogenes in two patients and a mixed predominance of Peptostreptococcus spp., S. pyogenes, B. fragilis, C. perfringens, E. coli and Prevotella spp. in the others was reported. Potentiation of infection by microbial synergistic partnerships between aerobes, such as S. aureus and S. pyogenes, and nonsporing anaerobes has been recognised in various types of nonclostridial cellulitis and necrotising fasciitis [25] The classification of necrotising soft tissue infections is complex and based on the assumed causative microorganism(s), the initial clinical findings, the type and level of tissue involved, the rate of progression and finally the type of therapy required [26]. However, this classification of such infections serves little clinical purpose because the prognosis and treatment are the same and, consequently, differentiation is required only between pure clostridial myonecrosis [22] as it involves muscle invasion and is associated with a higher mortality rate and other nonmuscle-associated soft tissue infections.

9.3.2.2  Bite wound infections The reported infection rate for human bite wounds ranges from 10% to 50% depending on the severity and location of the bite. About 20% of dog bites and 30%–50% of cat bites become infected [27]. In a study reported by Brook [28] 74% of 39 human in animal bite wounds contained predominantly a polymicrobial aerobic–anaerobic

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microflora, with S. aureus, Peptostreptococcus spp. and Bacteroides spp. The majority of bite wounds harbour potential pathogens many of which are anaerobes. The common anaerobes in animal bite wounds are Bacteroides, Prevotella, Porphyromonas, and Peptostreptococcus spp. [29] and less common potential pathogens such as Pasteurella multocida, Capnocytophaga canimorsus, Bartonella henselae and Eikenella corrodens [30].

9.3.2.3  Burn wound infections Infection is a major complication in burn wounds, and it is estimated that up to 75% of deaths following burn injury are related to infections [31]. Exposed burnt tissue is susceptible to contamination by microorganisms from the gastrointestinal and upper respiratory tract [32]; many studies have reported the prevalence of aerobes such as P. aeruginosa, S. aureus, E. coli, Klebsiella spp., Enterococcus spp. and Candida spp. [33]. In other studies involving more stringent microbiological techniques, anaerobic bacteria have been shown to represent between 11% and 31% of the total number of microbial isolates from burn wounds [34]. Predominant anaerobic in burn wound isolates are Peptostreptococcus spp., Bacteroides spp. and Propionibacterium acnes [35]. Mousa [34] also reported the presence of Bacteroides spp. in the wounds of 82% of patients who developed septic shock and concluded that such microorganisms may play a significant role in burn wound sepsis.

9.3.3  Chronic wounds A chronic wound can be defined as a wound in which the normal process of healing has been disrupted at one or more points during the phases of haemostasis, inflammation, proliferation and remodelling of a wound. Diabetic, decubites and venous ulcers are the most common types of chronic wounds.

9.3.3.1  Diabetic ulcers These are the most common cause of foot and leg amputation. In patients with Type I and Type II diabetes, the incidence rate of developing foot ulcers is approximately 2% per year. The average cost for 2 years of treatment is $27,987 per patient [36]. The diabetic foot ulcer is mainly neuropathic in origin, with secondary pathogenesis being a blunted leucocyte response to bacteria and local ischaemia due to vascular disease. These wounds usually occur on weight-bearing areas of the foot. Plantar ulcers associated with diabetes mellitus are susceptible to infection due to the high incidence of mixed wound microflora [37] and the inability of the polymorphonuclear neutrophils to deal with invading microorganisms effectively [38]. As in most wound types, S. aureus is a prevalent isolate in diabetic foot ulcers, together with other aerobes including S. epidermidis, Streptococcus spp., P. aeru­ ginosa, Enterococcus spp. and coliform bacteria [39]. With good microbiological techniques, anaerobes have been isolated from up to 95% of diabetic wounds [40], the predominant isolates being Peptostreptococcus, Bacteroides and Prevotella spp. [41]. In view of the polymicrobial nature of diabetic foot ulcers, Karchmer and

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Gibbons [42] have suggested that the treatment could be based on a better understanding of the general microbiology of these wounds rather than defining the causative microorganism(s).

9.3.3.2  Decubitus (pressure) ulcers Decubitus ulcers develop as a consequence of continued skin pressure over bony prominences; they lead to skin erosion, local tissue ischaemia and necrosis, and those in the sacral region are particularly susceptible to faecal contamination. The wound tends to occur in patients who are unable to reposition themselves to off-load weight, such as paralysed, unconscious or severely debilitated persons. Approximately 25% of decubitus ulcers have underlying osteomyelitis [43], and bacteraemia is also common [44]. One of the few reported acknowledgments of the role of polymicrobial synergy in chronic wound infection was made by Kingston and Seal [25], who commented that because the bacteriology of decubitus ulcers is similar to that of some of the acute necrotizing soft tissue infections, the anaerobic and aerobic bacteria involved are likely to contribute to the deterioration of a lesion. The opportunity for microbial synergy in many decubitus ulcers was demonstrated by Brook [45], who reported mixed aerobic and anaerobic microflora in 41% of 58 ulcers in children; S. aureus, Peptostreptococcus spp., Bacteroides spp. (formerly members of the B. fragilis group) and P. aeruginosa were the predominant isolates.

9.3.3.3  Venous leg ulcers In the venous leg ulcer, chronic passive venous congestion of the lower extremities results in local hypoxia. One current hypothesis of the pathogenesis of these wounds includes the impediment of oxygen diffusion into the tissue across thick perivascular fibrin cuffs. Another belief is that macromolecules leaking into the perivascular tissue trap growth factors needed for the maintenance of skin integrity. Additionally, the flows of large white blood cells slow down because of venous congestion and occluding capillaries thus becoming activated and finally damaging the vascular endothelium leading to ulcer formation. Venous leg ulcers are the most common form of leg ulcers. Up to 80% of leg ulcers are the result of chronic venous hypertension, most commonly caused by valvular incompetence [46]. The microflora of chronic venous leg ulcers is frequently polymicrobial, and anaerobes have been reported to constitute approximately 30% of the total number of isolates in noninfected wounds [47]. Although S. aureus is the most prevalent potential pathogen in leg ulcers [48], Bowler and Davies [49] reported a significantly greater frequency of anaerobes (particularly Peptostreptococcus spp. and pigmenting and nonpigmenting gram-negative bacilli) in clinically infected leg ulcers than in noninfected leg ulcers (49% vs. 36% of the total numbers of microbial isolates, respectively). The same investigators also suggested that aerobic–anaerobic synergistic interactions are likely to be more important than specific microorganisms in the pathogenesis of leg ulcer infection; this mechanism is not widely recognized in the management of surgical [50] and chronic wound infections.

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9.4  Delivering drugs to wounds Once the type of wound is identified and if it is classified as a wound requiring drug, an appropriate drug which can be effectively or selectively localised on and in the diseased tissue should be the next logical step which requires immediate attention for the recovery of patient. Delivery of most drugs, whether by oral administration or through injection, follows what was known as first order kinetics. In this process, initial high blood levels of the drugs are obtained, followed by exponent fall in blood concentrations. This is problematic because therapeutic effectiveness will not ensue once blood concentrations fall below certain levels. Furthermore, some drugs are toxic at high blood level concentrations, and it is difficult to achieve a balance between effective levels and toxic levels when blood concentration fall off so rapidly. Ideal delivery of drugs should follow zeroorder kinetics, wherein blood level of drugs would remain constant throughout the delivery period. There are number of technologies currently available that have been used to provide sustained release, but not necessarily zero-order release. For example, porous polymer microcarriers that contain active pharmaceutical ingredients are trapped within interstitial pore channels. The polymers themselves are not reactive, and drug delivery is accomplished utilizing diffusion (Fig. 9.1). This approach allows delivery for extended periods, but there is no evidence that zero-order kinetics is attained [51,52]. In an attempt to achieve zeroorder kinetics, extensive work has been carried out on the attachment of biologically active peptides and proteins to poly(lactic acid), poly(lactic co-glycolic acid), and related polyesters [53]. The ideal delivery is particularly important in certain classes of medicines intended, for example, for antibiotic delivery for healing of wounds which include diabetic ulcers, decubitus ulcer, venous static ulcer, and other nonhealing wounds. Controlled release systems are most suitable for such wounds. These systems comprise a bioactive agent (a drug) incorporated in a carrier. The main objective of a controlled release device is to maintain the concentration of the drug within therapeutic limits over the required duration. Compared to conventional drug formulations, such systems typically require smaller and less frequent drug dosage and minimize side effects. The release rate is a strong function of the physicochemical properties of the carrier as well as the bioactive agent and may also depend on environmental factors such as pH, ionic strength, temperature, enzymatic concentrations changes and degree of infection at the site of delivery. The drug release mechanism in some dressings is influenced by the inflammatory enzymes or microbial proteases (which directly proportional to the rate of infection) where the polymer in the drug delivery dressings is degraded by these enzymes thereby releasing the drug from the polymer matrix (Fig. 9.2). The design and preparation of pH and temperature-sensitive drug delivery dressings is another approach in which the dressing must retain both the drug over prolonged periods and then release it relatively rapidly. Here drug is incorporated into the copolymer backbone and the solubility of the polymer is altered by temperature, protonation or deprotonation events. In the pH-sensitive linkages, they are designed to undergo hydrolysis under distinct physiological conditions to either directly release drug or alter the polymer structure to disrupt or break apart the dressing (Fig. 9.3).

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Microparticle with drug Polymeric matrix

Figure 9.1  Schematic diagram showing the diffusion of drug from drug loaded microparticle embedded in a polymeric matrix.

In ionic binding system, the release of the drug, which is already bound to the polymer backbone by ionic interaction, is regulated by the infected organisms present in the wound. Any alteration in the ionic behaviour of the wound caused by the infected organisms is controlled by the release of drug from the polymer backbone due to anion–cation interaction (Fig. 9.4) [54]. In another method, responsive drug delivery can be achieved by externally triggering the drug administration from a delivery system with magnetic or electronic pulses. An alternative approach involves mixing drugs with an excipient that is slowly dissolved and relying on this prolonged dissolution to deliver effective amount of active ingredients over an extended period [55].

9.5  Types of dressings for drug delivery There are occasions in surgery that requires the use of a temporary cover for the raw wounds. These include skin loss secondary to burns, trauma, amputation, chronic ulcers, leprosy and sites of skin transplant. The body needs its own regeneration time,

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(a)

Collagen scaffold with drug

Macrophage Neutrophil

(b) MMPs

(c)

Figure 9.2  (a) Infected wound covered with drug incorporated collagen scaffold. (b) Release of matrix metalloproteinases from the inflammatory cells and fibroblast. (c) Degradation of scaffold and release of drug to the wound site.

whereas complication consequents to loss of skin cover, wait for no one. The intact skin provides a productive layer over cutaneous nerves, and the keratin layer of skin is a very effective antimicrobial barrier. Denuded areas of skin expose the nerves and cause pain and tenderness; they cannot prevent the loss of body heat as normal skin does by controlling vasodilation and sweating formation. Denuded areas continuously loose surface fluid and electrolytes because barrier of intact skin and keratin is not present to prevent the same. However, denuded areas are devoid of this protection, thus delaying wound healing by exposing vulnerable areas of subcutaneous tissues to infection. The ingrowth of epithelium over denuded areas needs a layer of cover to act as the scaffold on which the tissues grow in order. Denuded areas are unable to provide this effectively leading to the formation of extensive scars and even keloids. Therefore

Hydrogel

Change in pH/ionic strength/increased temperature

Figure 9.3  Schematic diagram showing the drug delivery from environmentally sensitive hydrogel matrix. Succinylated collagen bilayer with drug

O (CH2)4 C O– D+ Ionic binding of drug to succinylated collagen

Wound surface with moderate infection

Wound surface with severe infection

Figure 9.4  Schematic diagram showing the release profile of ionically bound drug from the ciprofloxacin incorporated collagen bilayer dressing based on the rate of wound infection.

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the denuded areas need a temporary cover (dressing) till such times that the body is able to manufacture the cover of its own. Wound dressings can be broadly categorised as natural and synthetic polymeric dressings. Under natural polymers we have collagen, albumin and gelatine as protein-based polymers and agarose, alginate, carrageenan, hyaluronic acid, dextran, chitosan and cyclodextrins as polysaccharides, both widely used as wound-dressing materials. Both synthetic biodegradable and nonbiodegradable polymers have been used successfully in designing wound-dressing materials. Poly (lactic acid), poly (glycolic acid), poly (hydroxybutyrate), poly (ε-caprolactone), poly (β-malic acid), poly (dioxanes), poly (sebacic acid), poly (adipic acid), poly (terephthalic acid), poly (imino carbonates), polyamino acids, polyphosphates, polyphonates, polyphosphazenes, poly (cyano acrylates), polyurethanes, polyorthoesters, polydihydropyrans and polyacetals are synthetic biodegradable polymers employed currently as wound-dressing materials. Carboxymethyl cellulose, cellulose acetate, cellulose acetate propionate, hydroxypropyl methyl cellulose, polydimethylsiloxane, colloidal silica, polymethacrylates, poly(methyl methacrylate), poly hydro (ethyl-methacrylate) and ethyl vinyl acetate, poloxamers and poloxamines are synthetic nonbiodegradable polymers used for the same purpose. Cotton and synthetic gauzes are the most commonly used wound-dressing materials [56]. They are preferred because of their low cost and high absorptive capacity. However, because of their porous structure, they do not have barrier to bacterial penetration and also when in wet condition they promote migration of bacteria to wound site. This can be prevented if an antimicrobial compound is present in the gauze [57]. Gauze sticks to a wound surface and disrupt the wound bed when removed; these dressings are used only on minor wounds or as secondary dressings. Another dressing called tulle dressing is a cotton or viscose gauze dressing impregnated with paraffin with or without antiseptic or antibiotic material. Paraffin lowers the dressing adherence, but this property is lost if the dressing dries out. The hydrophobic nature of paraffin prevents absorption of moisture from the wound, and frequent dressing changes are usually needed. Skin sensitisation is also common in medicated types. Tulle dressings are mainly indicated for superficial clean wounds, and a secondary dressing is usually needed. Uses of gauze and tulle dressings as drug delivery systems are limited as they hold the drugs only for a limited period. Film dressings are highly comfortable and shower-proof, and their transparent surface facilitate monitoring of wounds without dressing removal. In these vapour-permeable films, diffusion of gases and water vapour throughout the surface is allowed when used on wounds. But these films do not adsorb wound exudates and are not preferred to use on heavily exudating wounds as fluid tends to accumulate underneath the film, leading to maceration of the wound and the surrounding skin. Film dressings are suitable for superficial, lightly exudating or epithelialising wounds. These dressings vary in size and thickness and may have an adhesive to hold the dressing on the skin. They conform easily to the patient’s body but do not hold well in high-friction areas, such as the sacrum or buttocks. Also, films are semiocclusive which trap moisture, allow autolytic debridement of necrotic wounds and create a moist healing environment for granulating wounds.

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They are impermeable to fluids and bacteria, but they are permeable to air and water vapour; control of both is dependent on the moisture and vapour transmission rate of the films, and it varies depending on the polymer used in the dressings. Permeability to water and air in these dressings creates a moist wound environment [58]. The shortcoming of film dressings can be overcome by foam dressings. They are lightweight, superabsorbent and easy to apply; they come as a highly compressed foam pad that wicks away moisture. It is a good choice for patients who have poorly vascularised, heavily draining leg wounds because it only requires changing once a day. The foam can be attached with tape, gauze, or Ace bandages. In general, it is applied on dry to wet draining wounds as it wicks away the moisture during drainage of the wound. Foam dressings are designed to absorb large amount of exudates, they also maintain a moist wound environment [59]. Hydrogel is another class of film dressings; it consists of polymers with a very high intrinsic content of water [60]. They conform to wounds with unusual shapes because of their gel-like nature. In contrast to hydrofibres, hydrogels are used primarily to donate fluid to dry necrotic and sloughing wounds, and their absorbency is limited. They are composed mainly of water in a complex network or fibres that keep the polymer gel intact. Water is released to keep the wound moist. They are used for necrotic or sloughy wound beds to rehydrate and remove dead tissue [61]. They are not used for moderate to heavily exudating wounds. Hydrocolloid dressings are indicated for minimal to moderately draining wounds. They are lightweight, with adhesive and absorbent characteristics. They are tailor-made to fit oddly shaped wounds and can be changed depending on the drainage, which may vary from a few days to as long as a week. They are composed of carboxymethyl cellulose, gelatine, pectin, elastomers and adhesives that can be formed as a gel [60]. Depending on the hydrocolloid dressing chosen, they can be used on wounds with light to heavy exudate and sloughing or granulating wounds, and it can be made available in many forms such as adhesive or nonadhesive pad, paste, and powder. The most common form is self-adhesive pads. Hydrocolloid dressings due to occlusive nature do not allow water, oxygen, or bacteria into the wound. This may help to facilitate angiogenesis and granulation at wound site [62]. Hydrocolloids also cause the pH of the wound surface to drop and the acidic environment can inhibit bacteria growth [63]. Hydrocolloids absorb wound exudates and create a warm, moist environment which promotes debridement and healing. Like hydrogels, hydrocolloid helps a clean wound to granulate or epithelialize and encourage autolytic debridement in wounds with necrotic tissue. Occlusive nature of hydrocolloids makes them unsuitable to use if the wound or surrounding skin is infected. But the hydrocolloid dressings with the antimicrobial agents may overcome this drawback [64]. Hydrofibre dressings are produced from similar materials to hydrocolloids and also form a gel on contact with the wound, but they are softer and more fibrous in appearance, with a greater capacity to absorb exudate. Moisture from the gel assists in debridement and facilitates nontraumatic removal. They are soft nonwoven pad or ribbon dressing made from sodium carboxymethyl cellulose fibres. They interact with

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wound drainage to form a soft gel, and they absorb exudate and provide a moist environment in a deep wound that needs packing [65]. Alginate dressings are called ‘seaweed’ dressing as it is derived from brown algae. Like polyurethane, it is applied dry so it can wick away moisture, making it another good choice for wet draining wounds. Alginate dressing contains calcium salt of alginic acid, and it produces highly absorbent dressing suitable for heavily exudating wounds. It is capable of absorbing up to 20 times its weight in fluid and possesses haemostatic properties. It is available as flat sheets or as rope, and can be used for packing cavities. Alginates change from soft fibrous structure to gel when it absorbs exudates. It facilitates easy removal of the dressing thus preventing contamination of wound and maintaining moist wound environment. Alginate dressings can be used for both infected and noninfected wounds. On dry wounds or wounds with minimal drainage, these dressings are suitable as they dehydrate the wound and delay the healing process [9]. Chitosan dressings are based on the natural biopolymer that is derived from a major component of crustacean outer skeletons. This material is known in the wound management for its haemostatic properties. Further, it also possesses other biological activities and affects macrophage function that helps in faster wound healing [66]. It also has an aptitude to stimulate cell proliferation and histoarchitectural tissue organisation [67]. The bacteriostatic and fungistatic properties of these dressing are useful for wound management. Both in solution and gel forms these dressings act as a bacteriostatic, fungistatic and coating agent. Gels and suspensions may play the role of carriers for slow release or controlled action of drugs, as an immobilising medium and an encapsulation material. Film and membranes are used in dialysis, contact lenses, dressings and the encapsulation of mammal cells, including cell cultures. Chitosan sponges are used in dressings, and to stop bleeding of mucous membranes. Here chitosan fibres are used as resorbable sutures, nonwovens for dressings and drug carriers in the form of hollow fibres. Collagen-based biomaterials are considered to be the most promising substitute for wound healing and skin regeneration. Collagen can be processed into a number of forms such as sheets, tubes, sponges, powders, fleeces, injectable solutions and dispersions, all of which have found use in medical practice [68]. Furthermore, attempts have been made to apply these systems for drug delivery in a variety of applications such as ophthalmology, wound and burn dressing, tumour treatment and tissue engineering. Collagen inserts and shields can be used as drug delivery dressing over corneal surface or to the cornea itself and to deliver the drug intraocularly [69]. In drug delivery dressing, collagen sponges are invaluable in the treatment of severe burns and have found use as a dressing for many other types of wounds, such as pressure sores, donor sites, leg ulcers and decubitus ulcers [70]. Major benefits of collagen covers include their ability to easily absorb large quantities of tissue exudate, smooth adherence to the wet wound bed with preservation of this moist microclimate as well as its shielding against mechanical harm and prevention of secondary bacterial infection. Besides these physical effects, collagen promotes cellular mobility and growth and inflammatory cells actively penetrate the porous scaffold [71]. This allows a highly vascularised granulation bed to

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form and encourages the formation of new granulation tissue and epithelium on the wound. Based on the tissue repair and hemostyptic properties of collagen sponges, combinations with antibiotics were developed for local delivery in the treatment and prophylaxis of soft tissue infections. Collagen films have also been used as a drug carrier for antibiotics which have application in periodontal regeneration and infected dermal wounds [72]. Composite dressings have multiple layers and can be used as primary or secondary dressings. They are appropriate for wounds with minimal to heavy exudates, healthy granulation tissue, necrotic tissue (slough or moist eschar) or a mixture of granulation and necrotic tissue. Composite dressings have two or more layers and each layer has specific function. Two-layered dressings have a dense upper and a spongy lower layer. The outer membrane prevents body fluid loss, controls water evaporation and protects the wound surface from bacterial invasion, and the inner matrix encourages adherence by tissue growth into the matrix. These dressings may be considered to constitute an ideal structure that promotes wound healing. Physical characterisation of these dressings shows excellent oxygen permeability, that it controls the water vapour transmission rate, and that it promotes water uptake capability [73]. In common, the spongy layer will be an antibiotic-impregnated polymer derived. Both collagen and chitosan bilayer dressing either alone or in combination with other polymers are widely reported [74,75]. A three-layered dressing has been developed using chitosan and synthetic polymers. The first layer prevents body fluid loss and protects the wound surface from bacterial invasion. The second layer functions to transport exudates, protect the wound, and prevent the outer gauze layer from adhering to the wound. It is the second line of defence against bacteria that may try to invade after the chitosan layer breaks down. This polymer film layer, having the consistency of a cellophane paper degrades and becomes part of the healed skin. The third layer, made of cotton or cotton-viscose, absorbs exudates and must be changed periodically. Because the wound is well-protected underneath, removing the gauze layer should not hurt as much as removing traditional adhesive bandages. In some cases three-layer dressing consists of, first, semiadherent or nonadherent layer that touches the wound and protects the wound from adhering to other material. This layer allows the dressing to be removed without disturbing new tissue growth. Exudates pass through it into the next layer, which is absorptive. If a topical agent is applied to the wound, such as an antibiotic ointment, the dressing’s inner layer will not stick to the topical product. A second absorptive layer that wicks drainage and debris away from the wound’s surface helps prevent skin maceration and bacterial growth and maintains moist healing environment. This absorptive layer is made of material other than an alginate, foam, hydrocolloid, or hydrogel. Besides protecting the intact skin from excessive moisture, the absorptive layer helps liquify eschar and necrotic debris, facilitating autolytic debridement. Bacterial barrier forms third or outer layer that may have an adhesive border. This layer allows moisture vapour to pass from the wound to the air and keeps bacteria and particles out of the wound. It also helps maintain the moist healing environment. Unlike gauze, the bacterial barrier layer prevents moisture leakage to the outside of the dressing (strike-through), meaning that the dressing can be changed less frequently.

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9.6  Applications of drug delivery dressings 9.6.1  Infection control Minor wounds usually are not serious, but even cuts and scrapes require care. Serious and infected wound requires infection control and attention. Goals of management of wounds are to avoid infection, minimize discomfort, facilitate healing and minimise scar formation. The use of topical antibiotics and antiseptics is a key approach for reducing the microbial load in wounds. There are several commercially available topical formulations (powers/creams) that release antimicrobial agents into the wound bed. Commonly used antibiotics include bacitracin, mupirocin and Neosporin. However, because of the increasing incidence of bacterial resistance, antibiotics are being used less frequently and antiseptic agents such as slow release iodine and silver ions have the advantage of rarely inducing any bacterial resistance. The combination of wound dressing with direct antibiotic release at the wound site provides obvious advantages over traditional wound dressings in preventing bacterial infection, especially in highrisk patients. Role of drug delivery dressing on infected wound is to control the bacterial proliferation, adsorb wound exudates and protect the wound from secondary bacterial contamination, thereby enhancing the healing process. A number of sophisticated dressings (dry and moist dressings) with antimicrobial properties have been introduced in the market for treating infected wounds [76]. Some occlusive dressings, such as hydrogels and hydrocolloids, have bacterial and viral barrier properties. These dressings can be used to prevent contamination of the wound and reduce the spread of pathogens and cross-infection. Hydrogels allow them to be utilised to deliver topical wound medications such as metronidazole and silver sulfadiazine by diffusion mechanism. The release of medications can be controlled by the degree of cross-linkage in the gel. Both temperature- and pH-sensitive gels have been the subject of investigation with the objective of developing new products. The biological properties of chitosan including bacteriostatic and fungistatic properties are particularly useful for the treatment of infected wound. It has been exploited in various forms, in gels and suspensions it acts as an immobilising medium and an encapsulation material for slow release or controlled action of drugs. Chitosan sponge and hollow fibres are also used as drug carrier dressings [77]. Collagen sponges impregnated with gentamicin and amikacin have been used for many years in human soft tissue and orthopaedic surgery [78].

9.6.2  Healing improvement Even though the main emphasise in the making of drug delivery dressings is on the prevention and control of infection, certain nonhealing ulcers require additional care. Use of growth factors for the treatment of nonhealing human wounds holds great therapeutic potential. Cytokines and growth factors are the major regulators produced by various cell types and recruited to or present at wound site and are responsible for the successful repair of the injured tissues [79–82]. Release of some substances from the dressings stimulates the cells to release cytokines which enhance wound healing.

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For example, release of acemanna from the hydrogels has the ability to stimulate macrophages to release fibrogenic and angiogenic cytokines (Interleukin-1 and TNF-α) which result in a positive effect on wound healing. Various topical delivery systems with cytokines and growth factors to the injured tissues have been examined. These include covering the wound with a gel, cream or ointment containing a cytokine or a growth factor [83], spraying the growth factor over the wounded site [84], application of the cytokine-soaked gauze [85] to the wound, preincubation of the skin graft with a cytokine before grafting [86] and use of the genetically engineered biological bandage containing the culture of the growth hormone–producing cells [87]. Topical delivery of cytokines such as recombinant human granulocyte–macrophage colony stimulating factor and recombinant human granulocyte colony stimulating factor by using collagen and polyurethane dressings may serve as effective tools for wound healing [88]. Growth factors have also been incorporated into poly(lactic-co-glycolic acid) scaffolds successfully leading to the formation of more viable tissue structures [89,90]. Recombinant human-platelet derived growth factor-bb (rhPDGF-BB, Becaplermin) is the first approved growth factor available for clinical use. In clinical trials it has been shown to increase the incidence of complete wound closure and decrease the time to achieve complete wound healing. Collagen matrix with Bovine transforming growth factor-β2 can be used as a potential dressing on closure of venous stasis ulcers. Controlled release of biologically active fibroblast growth factor (FGF-2) molecules from chitosan hydrogels caused induction of angiogenesis and collateral circulation that occurred in healing-impaired diabetic. Some hydrocolloids have been shown to bridge the interactive and bioactive classifications by exhibiting fibrinolytic, chemotactic and angiogenic effects [62].

9.6.3  Controlling transport of biological fluid Wound exudates can pose problems in the treatment and care of the wound site and needs to be handled. In the treatment of many wounds it is beneficial to keep the wound moist while removing excess exudate. This environment provides an optimum wound healing environment, reduces pain, and provides an environment for autolytic debridement and re-epilethlialisation. Excess fluid, however, can lead to problems such as maceration (skin breakdown) and microbial infection of the wound site. For this reason, many wound dressings are sometimes designed to have absorbent pads and/or high moisture vapour transmission rates, i.e., the excess fluid is allowed to transmit or evaporate through the wound dressing during application on wound. Drug delivery dressings that contain reservoir of a suitable medicament have been developed. The reservoir is directly placed in contact with the skin, and the medicament is allowed or assisted to permeate the skin. Unfortunately, the amount of drug contained within the dressing is limited for a particular size of dressing, and these dressings do not have a capability to be recharged from a remote reservoir. Many of these dressings are not suitable for application over open wounds. For example, many transdermal drug delivery devices rely on the barrier provided by the dermis to regulate drug delivery rate.

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Hydrocolloids and hydrofibres form a gel on contact with the wound, with a greater capacity to absorb exudates. Moisture from the gel assists in debridement and facilitates nontraumatic removal. This also enhances autolytic debridement of necrotic and sloughing tissues and promotes the formation of granulation tissue. Hydrogels are used primarily to donate fluid to dry necrotic and sloughing wounds, and their absorbency is limited. In case of burn dressing, it is the most important factor to control evaporative water loss in addition to the drug delivery. Therefore, antimicrobial agent– impregnated materials are required, and wound dressing materials developed in recent years meet these requirements [91,92].

9.6.4  Haemostatic property There exists a need for a wound dressing that can safely and effectively deliver a number of pharmaceuticals (or drugs) to targeted tissue at a controlled rate, along with haemostatic function. A good example is oxidised cellulose dressing, because of their biodegradable, bactericidal and haemostatic properties, they have been used as a topical haemostatic wound dressing in a variety of surgical procedures, which includes neurosurgery, abdominal surgery, cardiovascular surgery, thoracic surgery, head and neck surgery, pelvic surgery, and skin and subcutaneous tissue procedures. Collagen, in forms such as powder, fibres, sponge, also has haemostatic properties when used as a wound dressing. Collagen in the form of fine fibres demonstrates an unexpected and entirely unique self-adhesive property when wet with blood or fluids in live warm-blooded animals and adheres to severed tissues and require no suturing. Similarly, chitosan dressing having chitosan fibre with microporous polysaccharide microspheres with therapeutic agent provides both the function of drug delivery and haemostatic property when applied on a wound. Gelatin sponge is also an absorbable, haemostatic material used in surgical procedures characterised by venous or oozing bleeding. The sponge adheres to the bleeding site and absorbs approximately 45 times its own weight in fluids. Because of the uniform porosity of the gelatine sponge, blood platelets are caught within its pores, activating a coagulation cascade. Soluble fibrinogen transforms into a net of insoluble fibrin, which stops the bleeding.

9.7  High-tech drug delivery devices 9.7.1  Tissue engineering Scaffolds are central components of many tissue-engineering strategies because they provide an architectural context in which extracellular matrix, cell and growth factor interactions combine to generate regenerative niches. Although three-dimensional porous structures have been recognised as the most appropriate design to sustain cell adhesion and proliferation, several specific applications in tissue engineering may take advantage of other design formats or combination of different materials designs. In fact, as the demand for a new and more sophisticated scaffold development, materials are being designed that have a more active role in guiding tissue development.

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Instead of merely holding cells in place, these matrices are designed to accomplish other functions through the combination of different format features and materials. A good example of this is the use of drug delivery devices that can act simultaneously as scaffolds for cells growth. Drug delivery creates appropriate chemical environment via soluble factors to direct cells. Controlled drug delivery and its applications for tissue engineering to support and stimulate tissue growth have attracted much attention over the last decade. Controlled release devices open the possibility of combining drugs and growth factors within scaffolds to promote tissue development and formation [93–97]. In other approaches, microspheres or nanospheres with encapsulated cells, growth factors or other therapeutic agents in a polymeric matrix can enhance the ability of drug delivery dressings to resemble natural human tissues and therefore perform a better functioning in vivo condition.

9.7.2  Stem cell research Stem cells have the potential to reconstitute dermal, vascular and other elements required for optimum wound healing. Through tissue engineering and drug delivery, one may recapitulate developmental cues in a manner which is more physiologically relevant than the simple addition of growth factors to two-dimensional cultures. By combining microspheres containing different drugs with unique release profiles, one can start to emulate the environment seen during development; this has profound implications for stem cell research. Thus, one may be able to gain greater control and insight into the capacity of stem cells and use this to realize the replacement and repair of complex tissues.

9.7.3  Micro- and nanotechnology in drug delivery dressings The use of microspheres for the sustained release in the drug delivery system has been of increasing interest. There are potential advantages for controlled release and absorbability. One of the most common methods in which growth factors have been incorporated into polymers is through the formation of microspheres [95,98,99]. Such microspheres releasing growth factors have been used as scaffolds, providing another means to generate tissue-engineered structures with the necessary chemical environment to foster repair [100]. Sustained release of bFGF from the gelatin microsphere incorporated in the bilayer dressing (inner gelatin sponge and outer polyurethane membrane) has shown improved healing on york pig model [101]. Cefazolin incorporated poly(lactide-co-glycolide) nanofibres as antibiotic delivery system has shown potential healing in the treatment of wounds [2]. The use of nanofibers in tissue engineering and drug delivery is increasingly focused mainly because they provide high surface area to volume besides easy modulation of drug release profile. The structure of nanofiber matrix plays a key role in drug release profile. In homogeneous nanofiber structure, the drug is dispersed throughout the polymer matrix, and in core–shell nanofiber structure, the matrix carrying the drug is covered by pure polymer [102]. In homogenous nanofiber structure, the rate of

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Nanofibers of drug timolol for glucoma, cyclosporin A for alkali injured eye and dexamethasone for eye disorders

Donepezil nanofibers, mats of biodegradable polymer to prevent neurodegeneration

Nanofiber mats of antibiotics for prevention of MSRA film deposition in otitic media Nicorandil nanofibers for instant pain relief in angina pectoris

Azithromycin nanofibers for treatment of pneumonia

Insulin and linagliptin sublingual nanofibers for better patient compliance

Curcumin, doxorubicin and cisplatin loaded nanofibers for effective cancer treatment

Voltage power supply

Nanofibers of antiinflammatory drugs for conditions like rheumatoid arthritis

Taylor cone

Metal collector Rotating drum

Drug delivery by virtue of nanofibers in diseases and disorders related to various organs

Electro-spinning setup Nano-fiber mats

Figure 9.5  Schematic diagram showing the production of nanofiber mats and their applications to drug delivery.

drug release decreases with time, because the drug must travel progressively longer distances to diffuse to the fibre periphery, which requires more time. Contrary, the core–shell design provides the delivery system with the diffusion rate of the therapeutic agent stable throughout the life. Thakkar et al. reviewed the applicability of drug nanoparticle–loaded nanofibers in the management of diseases/disorders related to the brain, eye, ear, cardiovascular system, lungs and oral cavity [103] (Fig. 9.5). Use of antibiotic-loaded nanofibers as wound dressing material serves several advantages because of porosity, high surface area to volume ratio and biocompatibility. This area of drug delivery with nanofibers is very well explored and will be described only in brief. Recently Li et al. have reported thermosensitive nanofibers loaded with ciprofloxacin as antibacterial wound-dressing materials. Ciprofloxacin was loaded in thermoresponsive electrospun fibre mats containing poly(di(ethylene glycol) methyl ether methacrylate). Postelectrospinning drug was found to be in amorphous form. By virtue of their thermal sensitivity, fibres could promote the proliferation of fibroblasts, and by varying the temperature, cells could easily be attached to and detached from the fibres. In vivo investigations on rats indicated aforementioned nanofibers to have much more potent wound healing properties than commercial gauze [4]. Alavarse et al. have reported tetracycline hydrochloride-loaded electrospun nanofiber mats based on PVA and chitosan for wound dressing. The delivery of drug during the first 2 h was reported to allow an effective antibacterial activity on the gram-negative E. coli as well as on the gram-positive Staphylococci epidermidis and S. aureus [104]. A novel poly(l-lactide-co-caprolactone)/

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collagen bioactive electrospun mat with sustained drug delivery of gentamicin has been developed [105]. The mat loaded with 10% gentamicin showed bioactivity for 15 days against gram-positive and gram-negative bacteria. The in vitro cell culture of 3T3 fibroblasts confirmed that the electrospun mat provides an increased specific interface area and hydrophilicity to enhance cell attachment, proliferation and migration.

9.7.4   Gene delivery Gene delivery is a versatile approach, capable of targeting any cellular process through localised expression of tissue inductive factors. Introduction of the gene rather than a product-like growth factor is thought to be cheaper and more efficient for treating nonhealing wounds. Polymeric scaffolds either natural, synthetic, or a combination of the two, capable of controlled DNA delivery can provide a fundamental tool for directing progenitor cell function, which has applications with the engineering of numerous types of tissue. Scaffolds are designed either to release the viral and nonviral vector into the local tissue environment or maintain the vector at the polymer surface, which is regulated by the effective affinity of the vector for the polymer. For example, DNA delivery using chitosan scaffold has been evaluated as wound-dressing materials [106], and the in vivo delivery of a plasmid DNA encoding a platelet-derived growth factor gene using a polymer matrix, poly(lactide-co-glycolide), enhanced matrix deposition and blood vessel formation in the developing tissue [107,108]. Efficiency of hydrogel formed by PEG–PLGA–PEG was evaluated as nonviral delivery of pDNA for gene therapy in a skin wound model in CD-1 mice, which has shown promising wound healing [109].

9.7.5  Environment-sensitive drug delivery dressings Some of the scaffolds under evaluation respond to several physiological stimuli such as pH, ionic strength, temperature or enzymatic concentrations changes and infection. Several studies have aimed to construct novel triggered drug delivery systems that release antimicrobials at specific locations at required times. These new systems are usually triggered by certain endogenous host infection responses such as inflammation-related enzymes, thrombin activity or microbial proteases. For example, S. aureus infection increases the local concentration of thrombin. A PVA–peptide–gentamicin conjugate was developed and investigated where the release of gentamicin depends on local thrombin concentration [110]. In the same way ciprofloxacin-conjugated polymers synthesized using 1,6-hexane diisocyanate and polycaprolactone diol releases ciprofloxacin (broad spectrum antibiotic) when the polymer degrades by an inflammatory cell–derived enzyme, cholesterol esterase [111]. Thermosensitive micelles or thermoresponsive hydrogels are self-regulating carriers because the release can be induced during small temperature differences in the human body [112,113]. Another way of achieving self-regulating drug delivery concerns the application of hydrogels, which are swelling-controlled polymers that allow release of incorporated drugs only at a certain pH [114]. Responsive drug delivery can be achieved by externally triggering the drug administration from a delivery system with magnetic or electronic pulses [115]. In a succinylated collagen bilayer system

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(outer membrane and inner sponge) with ciprofloxacin, collagen behaves as an anion after swelling and ciprofloxacin forms cations in the swelled network of sponge when applied on the wound. Because of the ionic binding, the drug diffuses slowly and its release rate remains in check. If wound exudates are greater, more drugs will be released to the wound site, which facilitate controlled delivery of drug. When PVP is used along with the drug in the bilayer system, the drug comes out as cations from PVP and gets ionically bound to succinylated collagen matrix in wet condition. It further regulates the release of drug. Because infected wounds are polar in nature, the release of the drug from the sponge is regulated because of the ionic nature of the succinylated dressing. Once the dressing gets wet, the role of PVP is negligible and the drug is released by overcoming the ionic binding between the drug and the sponge [116].

9.8  Conclusions The design and development of drug delivery dressings involve various scientific approaches. Drug delivery dressing requires the drug delivery molecule to be designed to give it an enhanced chemical stability and pharmacokinetic properties. Thus the drug can be tailored to give the required properties, in terms of its absorption, distribution, metabolism, excretion and transfer across the biological barriers targeting the site of action. Similarly, an understanding of the process by which the drugs pass through the membranes, then choose their best route of administration followed by transportation to target tissue, is essential for reliable drug delivery. Using various delivery devices, the drug reaches the site of action and stays there to repair and heal the wound. Although drug delivery dressings have their role in wound management, good nutrition is necessary for wound healing. During the healing process, the body needs an increased amount of calories, proteins, vitamin A and C and minerals to promote wound healing and prevent infection and complications. If the patient has diabetes, it is required to monitor his/her blood sugar levels at regular intervals to ensure wound healing and control infection. Patients are advised that, if their appetite remains poor and the wound is not healing well and/or they are losing weight, they should make an appointment to see a doctor. Wound healing needs an integrated approach and regular monitoring. Although drug delivery dressings play a major role in the wound healing process, other factors mentioned here are equally important and add to successful management of a wound.

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[88] J. Grzybowski, E. Oldak, M. Antos-Bielska, M.K. Janiak, Z. Pojda, New cytokine dressings. I. Kinetics of the in vitro rhG-CSF, rhGM-CSF, and rhEGF release from the dressings, Int. J. Pharm. 184 (1999) 173–178. [89] W.L. Murphy, M.C. Peters, D.H. Kohn, D.J. Mooney, Sustained release of vascular endothelial growth factor from mineralized poly(lactide-co-glycolide) scaffolds for tissue engineering, Biomaterials 21 (2000) 2521–2527. [90] T.P. Richardson, M.C. Peters, A.B. Ennett, D.J. Mooney, Polymeric system for dual growth factor delivery, Nat. Biotechnol. 19 (2001) 1029–1034. [91] P.M. Vogt, J. Hauser, O. Rossbach, et al., Polyvinyl pyrrolidone-iodine liposome hydrogel improves epithelialization by combining moisture and antisepsis. A new concept in wound therapy, Wound Repair Regen. 9 (2001) 116–122. [92] K.S. Masters, S.J. Leibovich, P. Belem, et al., Effects of nitric oxide releasing poly(vinyl alcohol) hydrogel dressings on dermal wound healing in diabetic mice, Wound Repair Regen. 10 (2002) 286–294. [93] R. Langer, Drug delivery and targeting, Nature 392S (1998) 5–10. [94] J.E. Babensee, L.V. McIntire, A.G. Mikos, Growth factor delivery for tissue engineering, Pharm. Res. (N.Y.) 17 (2000) 497–504. [95] J.P. Benoit, N. Faisant, M.C. Venier-Julienne, P. Menei, Development of microspheres for neurological disorders: from basics to clinical applications, J. Control. Release 65 (2000) 285–296. [96] M.J. Whitaker, R.A. Quirk, S.M. Howdle, K.M. Shakesheff, Growth factor release from tissue engineering scaffolds, J. Pharm. Pharmacol. 53 (2001) 1427–1437. [97] W.M. Saltzman, W.L. Olbricht, Building drug delivery into tissue engineering, Nat. Rev. Drug Discov. (2002) 177–186. [98] Y.S. Nam, T.G. Park, Protein loaded biodegradable microspheres based on PLGA– protein bioconjugates, J. Microencapsul. 16 (1999) 625–637. [99] K. Fu, R. Harrell, K. Zinski, C. Um, A. Jaklenec, J. Frazier, N. Lotan, P. Burke, A.M. Klibanov, R. Langer, A potential approach for decreasing the burst effect of protein from PLGA microspheres, J. Pharm. Sci. 92 (2003) 1582–1591. [100] M.J. Mahoney, W.M. Saltzman, Transplantation of brain cells assembled around a programmable synthetic microenvironment, Nat. Biotechnol. 19 (2001) 934–939. [101] S. Huang, Y. Jin, T. Deng, H. Wu, Wound dressings containing bFGF-impregnated microspheres: preparation, characterization, in vitro and in vivo studies, J. Appl. Polym. Sci. 100 (2006) 4772–4781. [102] H. Jiang, L. Wang, K.J. Zhu, Coaxial electrospinning for encapsulation and controlled release of fragile water-soluble bioactive agents, J. Control. Release 193 (10) (2014) 296–303. [103] S. Thakkar, M. Misra, Electrospun polymeric nanofibers: new horizons in drug delivery, Eur. J. Pharm. Sci. 107 (30) (2017) 148–167. [104] A.C. Alavarse, F.W.O. Silva, J.T. Colquea, et al., Tetracycline hydrochloride-loaded electrospun nanofibers mats based on PVA and chitosan for wound dressing, Mater. Sci. Eng. C 77 (1) (2017) 271–281. [105] C.R. Reshmi, T. Menon, A. Binoy, et al., Poly(L-lactide-co-caprolactone)/collagen electrospun mat: potential for wound dressing and controlled drug delivery, Int. J. Polymeric Mater. Polymeric Biomater. 66 (13) (2017) 645–657. [106] O. Felt, P. Buri, R. Gurny, Chitosan: a unique polysaccharide for drug delivery, Drug Dev. Ind. Pharma 24 (1998) 979–993. [107] L.D. Shea, E. Smiley, J. Bonadio, D.J. Mooney, DNA delivery from polymer matrices for tissue engineering, Nat. Biotechnol. 17 (1999) 551–554.

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Authors of the chapter: J.F. Kennedy, K. Bunko Formerly of Advanced Science and Technology Institute, United Kingdom Editors of the chapter: E. Santhini, Ketankumar Vadodaria, S. Rajasekar Centre of Excellence for Medical Textiles, The South India Textile Research Association, Coimbatore, India

10.1  Introduction A ‘smart’ textile may be defined generally as a material designed to sense and react to differing stimuli or environmental conditions. The ‘intelligent’ textile industry is expanding very quickly and developing wearable composite materials for use in fields such as sport, defence, the military, aerospace or medicine. Garments equipped with electronic units, detector devices for ailments or various sensors designed to monitor changes in body temperature and moisture are becoming increasingly real and not just the stock-in-trade of science fiction films. Smart textiles are being broadly developed in the field of sports, e.g., outdoor garments with smart membranes to allow moisture to penetrate only in one direction, to keep the wearer warm and protect against the wind. Moreover, this development of ‘smart’ textiles is facilitating advances in the area of medical textiles. The system of wearable pads designed to monitor the vital signs of mother and foetus during pregnancy is one of many ‘smart’ material approaches in the health field. In addition, special attention is being paid to the application of smart textiles in medical devices for the care of wounds. These innovative dressings have perhaps not yet been as fully investigated and developed as ‘smart’ garments, but this approach in medicine shows definite promise for improving and accelerating the healing process.

10.2  Basic principles and types of smart textiles The term ‘smart textiles’ is used to describe materials that are advanced in their structure, composition and ‘behaviour’ in special conditions. Their ‘intelligence’ is classified into three subgroups [1–3]. Passive smart textiles, which are sensors and can only sense the environment; Active smart textiles, which can sense stimuli from the environment and also react to them; simultaneously with the sensor function, they also play an actuator role; Very smart textiles, which are able to adapt their behaviour to the circumstances.

Advanced Textiles for Wound Care. https://doi.org/10.1016/B978-0-08-102192-7.00010-2 Copyright © 2019 Elsevier Ltd. All rights reserved.

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To achieve an ideal wound care product, which may be classified as ‘smart’, it is necessary to refine plain dressings. A deep understanding of the processes that occur on the injured surface (e.g., inflammation, secretion of the exudates or epidermal regeneration) is fundamental when initiating trials to design intelligent textiles for wound care [4–6]. It is very important for the healing process to provide a moist environment for wounds (a moist wound free from infection is an environment rich in white blood cells, enzymes, cytokines and growth factors beneficial to wound healing), while still enabling adequate gaseous exchange. Therefore, the occlusive and adherent properties of covering dressings must be preserved. In contrast, dressings should also be easily removable, without causing additional post-wound trauma, and they should support epithelialisation – the process of new epidermal cells moving across the wound surface and settling on it, which in turn causes wound closure and therefore healing. Epithelialisation occurs more effectively in moist environments. It is also very important to use the sort of dressing which will support healing but reduce scar size, e.g., pressure garments [7,8]. Moreover, as a cover, the dressing should protect the wounded area from secondary contamination. It will ideally also provide the antiseptic and healing agents and accelerate the regeneration process. Hence, today, textiles with controlled drug-delivery systems are one of the most investigated categories of dressings. Finally, dressings should absorb excess wound exudates so as to provide relatively stable conditions for healing [4–6]. In the light of these challenges, scientists are working to design innovative dressings which will fulfil all these functions and provide the correct responses to particular wound conditions. These dressings, described as ‘intelligent’ or ‘smart’, will be able to react in different ways in various wound environments. The aim of this chapter is to gather information on the most sophisticated wound care textiles, which accelerate and improve healing processes, and therefore provide more comfortable conditions for patients.

10.3  Biomarkers and smart wound dressing Biomarkers are indicators for confirming overlapping stages/sequential progress of any of biological phenomena/factors (such as physiological, biochemical, pathological and pharmacological) in any living creatures i.e., human, plant, animals and microbes. Biological factors and microenvironment play a crucial role in wound healing process. Understanding of wound biomarkers can help in understanding repair, regeneration and delay in wound healing process. Wound healing process involves complex processes such as haemostasis, angiogenesis, granulation, inflammation, proliferation, remodelling etc. Biomarkers can be platelet release of cytokines molecules, interleukins, growth factors, fibrinogen, fibronectin, anti-haemophilic factor, pro-accelerin; nucleic acid–based biomarkers such as gene mutations or polymorphisms and quantitative gene expression analysis, peptides, proteins, lipid metabolites; and other small molecules, carbohydrates, proteins, lipids to genes, DNA, RNA, platelets, enzymes, hormones etc. [9]. Besides, bacterial biomarkers such as sortase A [10], matrix metalloproteinase (MMPs), Lipopolysaccharide (LPS) [11], etc. are also helpful in selecting the patient-specific or personalised antimicrobial dressing. Biomarkers can be helpful in deciding patient-specific treatment. MMPs are very important enzymatic biomarkers.

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MMPs help in cell–cell, cell–matrix signalling during wound healing and degrading and removal of damaged extracellular matrix (ECM). Overconcentration of MMP inhibits wound healing process [12,13]. Smart wound dressing Tegaderm with polyhydrated ionogens (PHI), by 3M, was effective in chronic wound by controlling MMPs.

10.4  Characteristics of smart textiles 10.4.1  Sensors in smart textiles Living in the 21st century, we cannot imagine the world without electronic devices, computers and incredibly fast intercommunication. It follows that even wearable textiles might be controlled and manipulated by biosensors and that all the components of their interactive electromechanically systems (such as sensors, actuators and power sources) can be incorporated or woven directly on garments (sensing and actuating microfibres) or printed/applied onto fabrics (flexible electronics) [14]. This means that science is heading towards the development of ‘intelligent’ communication between human beings and their inanimate creations. Electroactive fabrics and wearable bio-monitoring devices are now being actively developed [15]. Because electro-sensor–monitored garments are being extensively investigated, it seems probable that such electronic devices will soon be applicable as an element of wound dressings, tracking the changes in particular wounds, such as post-operative and chronic wounds which definitely need continual monitoring, and also providing cover protection. Nowadays, dressings may contain different types of sensors, e.g., macromolecules such as stimuli-responsive polymers [15]. These chemical sensors respond to the wound environment with a change of colour, release of fragrance and swelling/ de-swelling. In contrast, the actuating mechanism for their action may be caused by different factors, e.g., changes in wound temperature, high secretion of exudates and pH changes in the local environment.

10.4.2  Sensors and dressings Because different types of sensors monitor the wound environment, their location in the structure of the dressing depends on the particular situation. The structure of the dressing itself may allow the arrangement of the sensor within it. This occurs, for instance, in newly developed technology designed to diagnose infection in the wound using a silicon-based biosensor. Traditional detection of bacteria in the wound has been carried out using technology that involved several stages. Checking the presence of gram-negative bacteria in the injured site involved making a smear slide of the wound sample, then performing staining, decolourisation and finally examining the slide under a microscope. Using cutting-edge technology based on luminescence principles, it is possible to detect gram-negative bacteria in situ, applying appropriate sensors within the dressing. This invention, developed by Miller, Fauchet and their colleagues from the Department of Chemistry, Rochester University (NY, USA) [16], uses a porous silicon wafer on which millions of tiny holes are etched. This porous structure allows contact of the target molecules with a large surface area. In addition,

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this structure comprises nanocrystals, which are photoluminescent in the visible range of the spectrum at room temperature. Moreover, for improved use of the luminescence method, it is possible to apply a proper bandwidth of light. The sensor material, therefore, is placed between further layers of porous silicon that only allow the escape of light for selected wavelengths. These devices are only a few micrometres thick and are known as porous silicon micro-cavity resonators [17]. In the detection process for lipid A, specific binding occurs between the organic receptor molecule and the diphosphoryl lipid A in the water, via the precisely shaped molecular cavity. This organic molecular receptor, known as ter-tryptophan tercyclopentane (TWTCP), is blocked by added amine. This prevents all the TWTCP binding sites from binding to the silicon substrate. Finally, when the binding of lipid A with TWTCP takes place, causing a change in the refractive index of the silicon, an 8-nm red shift occurs in the wavelength of its photoluminescence peak. Unfortunately, this is not visible to the naked eye and an expensive machine reader must be used [11]. However, when in the process of reading the peak has been improved and simplified, this potential for easier and quicker detection of wound infection and the presence of hazardous bacteria will certainly be realised.

10.4.3  Temperature-controlled textiles Keeping wounds covered provides insulation from further injuries and helps to maintain normal body temperature. It has long been known that temperature may have a beneficial influence on wound healing. All cellular functions, especially enzymic and biochemical reactions, are optimised at normal body temperature (normothermia), defined approximately as 37°C [15,17–20]. This is a very important point in the design of ‘smart’ textiles. In contrast, body temperature may also be a factor that stimulates the ‘behaviour’ of the dressing and influences wound healing. The latest investigations in the field of ‘smart’ wound dressings that are managed by temperature have revealed two directions: Textiles change their properties (e.g., forming a gel) in response to different skin temperature and dressings that may be heated by specific devices and thereby promoting wound healing.

10.4.4  Temperature-sensitive dressings The ‘intelligence’ of hydrogels has long been recognised. These smart polymers absorb high amounts of water and have a soft consistency that renders them similar to natural tissue. Moreover, the hydrogel may take up water from the surroundings under special, strictly defined conditions, e.g., the correct temperature. This means that this same polymer may exhibit hydrophobic or hydrophilic behaviour, according to the environment. When coating an area, or when embedded into membranes, hydrogels may therefore control the wettability of the surface. This feature has been exploited in the design of ‘smart’ dressings that combine hydrogel with textile. Hydrogels have been used in new cutting-edge textiles that protect the wound and support its healing. Being ‘smart’ chemical sensors, they respond to the wound environment in a special, predicted way. Poly(N-isopropylacrylamide) is a well-known

The use of ‘smart’ textiles for wound care

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Figure 10.1  The chemical structure of poly(N-isopropylacrylamide) microgel.

thermosensitive polymer, which has both isopropyl (hydrophobic) and amide (hydrophilic) groups (Fig. 10.1) [15,17,21]. The polyurethane are cross-linked with poly(N-isopropylacrylamide) and silver nanoparticles (AgNPs) to produce the thermoresponsive polyurethane wound dressing. This wound dressing has antimicrobial, temperature-sensitive wound healing and non-adherent properties [22a]. Polyurethane siloxane–based thermoresponsive wound dressings were prepared with poly(N-isopropylacrylamide), which were incorporated into the backbone of the polyurethane siloxane polymer. The wound dressing transferred the fibroblast cell sheet to skin surface of the wound and also encouraged temperature-based wound healing [22b]. Thermoresponsive drug-loaded, non-adherent chitosan-based wound dressing were prepared. The backbone of chitosan was incorporated with thiol groups after which the thermoresponsive poly(N-isopropyl acrylamide) was loaded with the drug. The drug was delivered as per temperature responsiveness [22c]. Thermo-responsive hydrogels based non-adherent wound dressings were prepared with poly(N-isopropylacrylamide) and reinforced with cellulose nanocrystals via free-radical polymerisation reaction [22d]. A multifunctional hybrid hydrogel-based wound dressing was prepared with anti-protein adsorption and antibacterial properties were applied on the wound dressing. The methacrylate arginine and N-isopropylacrylamide were polymerised by free-radical reaction and crosslinked to produce the hydrogel [22e]. This polymer is able to assimilate water under strictly defined conditions. Its lower critical solution temperature is set at 32–33°C, and below this point, it absorbs water and extends its chain conformation. In contrast, when immersed in aqueous solution above 32°C, poly-N-isopropylacrylamide (PNIPAAm) is extensively dehydrated and compact. This thermoresponsive nature of PNIPAAm microgel polymer has, therefore, found an application in wound dressing [22,23]. It may swell and shrink according to the temperature of the aqueous solution (in this case the exudate). Below the lower critical solution temperature of PNIPAAm, the swelling of the PNIPAAm microgel beads will decrease the adhesive property of the polymer, resulting in lower peel strength and finally in easier and more comfortable removal of the dressing from the wound. The studies have shown that PNIPAAm microgel beads may be embedded into films, membranes or non-woven fabrics made from various materials (e.g., chitosan, polystyrene or polypropylene) [15,24]. The membranes have nanoporous structures and are very often transparent.

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10.4.5  Applications A recently designed and studied dressing, which is sensitive to skin temperature, shows great and remarkable possibilities for the application of the PNIPAAm polymer. It is a trilayer membrane, which partially resembles artificial skin and may be applied to extensive burn injuries (Fig. 10.2) [24]. The first layer is a three-dimensional tricopolymeric sponge composed of gelatin, hyaluronan and chondroitin-6-sulphate. It has 70% porosity with a 20- to 100-μm-range pore size. This layer fulfils the function of the ECM of the skin for cell retention. It is therefore a dermis analogous layer, which stimulates capillary penetration, promotes dermal fibroblast migration and induces the secretion of an ECM. After migration of the dermal fibroblasts, which recognise the host dermis structure on the wound site, the biodegradable tri-copolymer matrix is gradually degraded by endogenous enzymes. The middle layer is composed of PNIPAAm and is called the auto-stripped layer. As explained earlier, PNIPAAm is a polymer which exhibits hydrophilic properties below lower critical solution temperature (33°C) and a hydrophobic nature above this temperature. The third, external layer is a non-woven fabric made of polypropylene. Its function is to protect the wound from infection and facilitate exudates drainage. The most important property of this dressing is that the PNIPAAm keeps the three layers together if the wound temperature is maintained in the inflammation state (above 37°C). But when the healing process is advanced, new skin is being formed and the temperature decreases to normal skin level (31°C), then the two exterior layers of dressing can be peeled off from the tri-copolymer layer. Wound dressings designed in this way can be used as biodegradable scaffolds for the induction of a ‘neodermis’ synthesis. ‘Neodermis’ is rebuilt new skin which covers the wounded areas. This dressing has huge potential application in large surface burns, where skin grafts are required [24].

10.4.6  Non-contact normothermic wound therapy It is obvious that open wounds endanger the organism as a result of the changing local environment in the body. Uncovered wounds are prone to internal contamination and

Non-woven polypropylene material PNIPAAm hydrogel

Tri-copolymer sponge

Figure 10.2  Structure of the dressing with arranged PNIPAAm microgel.

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are also being cooled, which is not beneficial to the healing process. Therefore, plain dressings such as bandages provide basic care of the injured surface, although they sometimes cause additional trauma when being applied or removed. It is very important, therefore, that the normothermic environment (at normal body temperature of about 37°C) provides optimal conditions for enzymic and other biochemical reactions and improves local circulation and tissue oxygen tension. Moreover, correct body temperature increases the availability of immune cells, e.g., macrophages, which may destroy and digest pathogens [18]. Warming the wound, therefore, may stimulate the healing process by increasing blood flow to the tissues, maintaining an optimal oxygen level and supporting the immune system [19,20,25]. In the development of sophisticated dressings, designers have invented new dressings in the form of small wearable apparatus. The product called Warm Up Active Wound Therapy (Augustine Medical, Inc., Eden Prairie, MN) is one example of a dressing device that supports heat input into the wound. This method of healing uses a non-contact radiant-heat bandage to treat chronic venous ulcers or acute injuries, when conventional treatment has failed. Warm Up Active Wound Therapy is a non-contact thermal dressing, which consists of a bandage, two plastic films, a heating element, a control unit and a power supply (Fig. 10.3). The bandage surrounds two layers of plastic film supported by and attached to an open cell pad. The pad adheres to the skin surrounding the wound. The open window in the bandage is a two-layered pocket where the heating element is situated. The window is located straight over the wound and enables direct monitoring of the wound when the heating element is removed (Fig. 10.4).

(a)

(b)

(c)

38 °C

A1 A2

A3

A4

Figure 10.3  Diagram of a non-contact normothermic wound dressing. (a) Dressing with the heating element in the pocket (A1 foam ring pad, A2 pad window with two layers of the plastic films, which form a pocket for the heating element, A3 heating element, A4 fragment of bandage that surrounds the dressing pad); (b) control unit that sets the temperature in the heating element; (c) power supply, which is also a charger for the batteries located in the control unit.

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4

1

3

6

5

Figure 10.4  Diagram of the dressing section of Warm Up Active Wound Therapy. 1: wound, 2: foam ring pad, which supports two plastic transparent films, 3: two layers of plastic films with a space between them, 4: heating element, 5: bandage around the pad, 6: connection to the heating control unit.

It is important that the heating element does not come into contact with the patient but is held above the wound by the bandage and separated by one or more insulating layers. The temperature at the heating element is automatically maintained by the control unit at 38°C. The power supply is a wall outlet pack that reduces the voltage to a safe level and recharges the batteries, which are located in the control unit. There are different ways of using Warm Up Active Wound Therapy. According to one method [26], this treatment was applied four times a day over a 2-week period. The heating element was activated for 1 h, followed by a period of 1 h of non-heating. This regime was repeated four times a day. At the end of the last daily session, the radiant-heat bandage was removed; the wounds were dressed with collagen–alginate dressing and wrapped in an elastic compression bandage that was left in place overnight. The method of use of Warm Up Active Wound Therapy described above is one of several proposed. Generally, clinical treatment indicated that heating wounds definitely accelerated healing. The following results are significant: The use of local heat delivered by the non-contact normothermic wound therapy was shown to increase subcutaneous oxygen tension by 50% above the baseline measures in normal volunteers [20]. Healing with non-contact normothermic wound therapy is faster than the use of standard dressings and no adverse effects occur [20]. From the beginning to the end of the study, pain decreased in 92% of cases, while in the control group given standard treatment, the decrease was only in 27%, and the wound size decreased in 45% (for non-healing venous stasis ulcers) [25]. This confirms the beneficial influence of non-contact normothermic wound therapy on the healing process.

10.4.7  Control of exudates from wounds It is very well known, and accepted by clinicians for more than 40 years, that a moist wound environment is beneficial during the healing process [26]. Therefore, many modern textiles used in dressings are designed to provide moist and warm conditions for wounds. Body injuries are caused as a result of different stimuli, accidents or diseases (e.g., burns, acute wounds, post-operative wounds and ulcers). Some results suggest that the secreting fluid from wounds may have a beneficial effect on healing, but in contrast, it may also inhibit this process. Studies have demonstrated that exudates

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from chronic wounds, e.g., ulcers, in fact cause deterioration of healing, whereas fluid secreting from acute wounds may support the recovery of healthy skin [26,27]. For this reason, it is common practice to manage the wound exudates and utilise its beneficial effects for the healing process [28].

10.4.8  Exudates and healing process Within the injured area of the body, various inflammatory reactions occur and fluid derived from serum passes through the vessel walls into the wound bed in the process called extravasation. Finally, the exudates emerge at the wound surface and, according to the local environment, may contain microorganisms or tissue debris [29]. However, the wound exudates are derived from body serum and are therefore rich in components such as glucose, lactic acid, inorganic salts, proteolytic enzymes, growth factors, immune cells (e.g., macrophages and lymphocytes), plasma proteins, albumin, globulin and fibrinogen. Some of these play remarkably significant roles in the healing process. For example, macrophages play an immune-defence role, thus releasing growth factors and proinflammatory cytokines. In addition, some components are a source of energy (glucose) while inorganic salts create typical pH values and cause the exudates to play the role of buffer solution [28]. Moreover, the fluid coming from the body through the wounded areas may be utilised as a medium for drugs that accelerate healing or for (other) antibacterial agents, which have bactericidal properties. When drugs have previously been administered into the digestion and circulation systems, they may subsequently appear in the exudates from the wound area [30]. Thus, it can be seen that the exudate is a heterogeneous liquid with dissolved contents, which undeniably has an influence on the healing process. Dressing selection should, therefore, be related to the type and size of wound, and most importantly, it should be chosen according to the volume, viscosity and nature of the exudates.

10.4.9  Selecting a dressing After entering the wound area, the exudates may demonstrate either a beneficial or a noxious tendency in the healing process. Depending on the wound type, the exudates may appear as a clear, straw-coloured, thin fluid, which is very similar to serum and common in acute wounds [27]. The seropurulent type of exudates, which has a characteristic yellow, cream coffee colour and creamy-thick consistency, indicates that infection is under way, as occurs in infected blisters. However, in chronic wounds the colour and consistency of the exudates may vary. In addition, an unpleasant odour from chronic wound exudates and excessive drainage on clothing or bedding are common causes of patients’ discomfort and distress [31]. The features of the wound exudates also change over time after injury. Therefore, it is very important to select the dressing which is appropriate for current wound conditions. Ideally, the wound-care product would respond in a specific ‘smart’ way to the various fluid environments, but, currently available dressings react in a predictable way to the defined circumstances and features of the exudates. Various mechanisms exist for handling the dressing of fluid: gelling, absorption and retention and moisture

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vapour transmission. Some of these mechanisms sometimes occur simultaneously in one product [27]. But all of these actions of dressing are clear objectives in the design of smart textiles, to manage the exudates and, as a result, provide the optimal environment for the quickest wound healing [32]. Today, it is still necessary for us to assess which dressing will support the healing of a particular type of wound. We have to choose with care the product that can manage appropriately the predicted amount and type of exudates.

10.4.9.1  Textiles based absorbent A wide range of dressings is available that uses gel formation as a response to interaction with the exudates. When incorporated in the dressing, the gel is the part of the system which not only protects the wound, but also accelerates the healing. The absorption and gelling functions of the dressing are very often combined and supplemented within one product. The gels applied in wound dressings might be set in sheets, pads, fibres, foams or saturated gauzes. The most commonly used are alginates (and their combinations with other contents, e.g., with gelatine), poly(N-isopropylacrylamide) gels or hydro-colloid dressings. Hydrogels applied in wound dressings are well known for their hydroaffinity properties. One very important feature of particular hydrogels is the amount of aqueous solution that they are able to absorb and maintain in which the environment is moisturised. The absorbance capacity is based on the amount and types of the absorbent materials. However, when excess exudate must be removed, a moist environment at the wound surface is still desirable [33]. A further property that promotes the beneficial use of hydrogels in dressings is the fact that gel contact with the exudate causes easier dressing removal, without additional pain and trauma for the patient [22]. Other gelling dressings in use are hydrofibres, which are soft, non-woven pads, useful for wounds with a heavy level of wound drainage and for deep wounds. It is also important that hydrogels stay firmly in contact with the wound for a long period without removal, resulting in the reduction of scar formation [26,34]. Recently, antibiotic/antimicrobial coated hydrogel are being developed to protect the wound from infection besides absorbing exudates, e.g., ciprofloxacin-loaded aminophenyl boronic acid/poly(vinyl alcohol) blend hydrogel [35]; AgNPs combined with PVA chitosan oligosaccharides [36].

10.4.9.2   Fluid-retention dressings Another type of gelling dressing absorbs the exudate and causes retention of fluid. The gel which is then formed can be directly removed from contact with the wound. However, this does not necessarily sustain the moist environment. One example of this kind of product is Hydrofiber, made from sodium carboxymethyl cellulose fibres. These are soft, non-woven pads, which are useful for a heavy level of wound drainage and for wounds that are deep and need packing [37]. Hydrofiber may be used in dressings with a combination of other layers, e.g., with a polyurethane foam/film layer (in the product Versiva) antimicrobial dressing (Aquacel Ag). The hydrofibre is impregnated with silver [37a].

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10.4.9.3  Foams and absorbent pad dressings This type of dressing is appropriate for the first stage of healing when drainage from the wound is greatest because a large amount of exudate can be absorbed. The advantage is that foams can be applied in a variety of sizes, shapes and thicknesses and are gentle on the skin. While foam pads have good adhesive properties, some of them stick too firmly to the wound or surrounding skin area, causing additional trauma upon removal. To prevent this, soft foam pads with an incorporated silicone layer have been designed [4]. This allows for repositioning or gentle removing of the dressing. Hydrophilic polyurethane foams are used to treat the chronic wounds and highly infected wounds, polyurethane made up of 2,4-toluene and 2,6-toluene diisocyanate and hydrophilic polyols. The hydrophilic polyurethane foam are flexible and stable, i.e., non-collapsible and non-sinkable, non-disintegratable [4a].

10.4.9.4  Superabsorbent spacer fabric Recent development in the field of wound dressing is the exploitation of superabsorbent spacer fabric for treating exudating wounds. The fabric consists of two outer hydrophobic layer made of polyester/spandex yarn and one superabsorbent middle layer made of superabsorbent yarns. The fabric is reported to have faster wetting speed, better absorbancy, higher air permeability and comparable water vapour permeability, thermal insulation and conformability with the existing dressings [38].

10.4.9.5  A model of moisture vapour transmission in wound dressings Moisture vapour transmission through the dressing is a very important process. Depending on the dressing’s water absorption capacity, it determines the fluid balance at the wound site [39,40]. The rate of moisture vapour transmission is a feature of all dressings which absorb and remove liquids. One type of dressing that absorbs particularly large amounts of liquid is hydrocolloid dressing, which usually has two layers. The first, which comes into contact with the wound site, is a hydrocolloid membrane with a large potential for swelling when taking up water. This layer is covered by another one, made of a polymeric material (e.g., polyurethane). Hydrocolloid dressings maintain a moist environment for healing and also allow the liquid to permeate outside the dressing and facilitate autolytic debridement of the non-viable tissue [41].

10.5  Examples of ‘smart’ wound care 10.5.1  Hydrogel dressings Hydrogels are cross-linked polymeric networks swollen in biological fluid. Two types of hydrogels that are commercially available are sheet hydrogel and amorphous hydrogel. Sheet hydrogels are formed by partially cross-linking the polymers (e.g., polyacrylamide or polyethylene oxide) to form a three-dimensional structure with sufficient water-holding sites. In case of amorphous hydrogel, water-soluble polymers

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such as cross-linked carboxymethyl cellulose (CMCH), starches, alginates, pectin, etc., are used majorly. Generally the amorphous hydrogels are thick viscous fluids and hence donate water exceptionally. The high water content of hydrogels (70%–90%) helps granulation tissues and epithelium in a moist environment and provides a soothing and cooling effect. Hydrogels are used for dry chronic wounds, necrotic wounds, pressure ulcers and burn wounds. Hydrogel dressings are non-irritant and non-reactive to biological tissue and permeable to metabolites. Many researchers have reported that hydrogel dressings are used to treat chronic leg ulcers. Some examples of hydrogels are Intrasite, Nu-gel, Aquaform polymers, sheet dressings, impregnated gauze and water-based gels, Tegagel (from 3M Health Care), Curasol Hydrogel Saturated Dressing (from Healthpoint), DuoDerm Hydroactive Wound Gel (from ConvaTec), and Carrasyn Hydrogel Wound Dressing (Carrington Laboratories). One of the examples of wound dressings that have gel formed in situ is based on oxidised alginate, gelatine and borax [42]. Each of these components has a specific function in the dressing. The gelatine has a haemostatic effect, while the alginate is well known for promoting wound healing and is supported by the antiseptic quality of borax. The combination of these functions makes the dressings very effective for moist wound healing. The alginate is oxidised, rapidly cross-links the gelatine and in the presence of borax gives in situ formation of hydrogel. It does not wrinkle or flute in the wound bed and moreover is non-toxic and biodegradable. It protects the wound bed from the accumulation of excess exudates because it has a capacity of fluid uptake that is 90% of its weight. It takes up the exudates, but still maintains the moist environment to facilitate and stimulate epithelial cell migration during the healing process [42].

10.5.2  Fluid-retention dressings Dressings that are well known for fluid retention very often contain hydrofibres. Examples are Aquacel, Hydrofiber Wound Dressing, Versiva Composite Adhesive Exudates Management Dressing (both from ConvaTec) [43], Exufiber and Mepilex Border. Versiva, for example, contains three components: a top polyurethane foam/ film layer, an absorptive non-woven fibrous blend layer (with Hydrofiber) and a thin perforated adhesive layer. All the components play specific roles in the dressing. The thin perforated adhesive layer has direct contact with the wound and accelerates the absorption of exudates. The non-woven fibrous blend layer absorbs and retains the exudates by behaving as a cohesive gel. The third layer, the outer-side polyurethane foam/film, protects the wound from contamination and manages the moisture vapour transmission of the exudates extravasation. This dressing is recommended for use in different types of ulcers (on legs, diabetic, pressure) and for surgical wounds, second-degree burns and traumatic wounds. Similarly, Exufiber is also designed to be used on wide range of highly exuding wounds, including leg and foot ulcers, pressure injuries and surgical wounds, among others. When Exufiber comes into contact with exudate, it transforms into a gel which provides moist environment for efficient wound healing and facilitates ease of removal during dressing changes [44]. Exufiber has a high absorption and retention capacity [45], reducing the risk of leakage and maceration.

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10.5.3  Film dressing (semi-permeable) Modern semi-permeable film dressings are usually made from transparent and adherent polyurethane of various compositions. It permits transmission of water vapour, O2 and CO2 from the wound, provides autolytic debridement of eschar and is resistant to bacterial entry. The moisture vapour transmission rate can be variable by modifying the polymer concentration and the structure of film. With the latest high-tech films, moisture vapour transmission of 3000 g/m2/24 h is achievable [3]. Transparency of this dressing helps monitor the wound healing without removing it and are majorly recommended for epithelialising wound, superficial wound and shallow wound with low exudates, e.g., Opsite, Tegaderm, Biooclusive [47].

10.5.4  Foam dressings These dressings are made up of hydrophobic, hydrophilic or combination of both with (e.g.: polyurethane foam) or without (e.g.: Restore foam, MPM non-bordered foam dressing) adhesive borders. If hydrophobic layer is a part of the dressings, it helps to protect the wound from liquid but allows gaseous exchange and water vapour. Depending upon the thickness of the wound, foam has the capability of absorbing varying quantities of wound drainage and hence are suitable for lower leg ulcers and moderate to highly exuding wounds and granulating wounds. They are generally used as primary dressings for absorption and secondary dressings are not required because of their high absorbancy and moisture vapour permeability [47,48]. Some of the best known foam-dressing products are Lyofoam (from ConvaTec), Polymem Non-Adhesive Dressings (from Ferris) and Allevyn Adhesive Dressings (from Smith and Nephew), Tielle (Acelity).

10.5.5  Silicone-foam pads Some brand-name dressings which contain soft silicone are Tendra Mepitel (a silicone mesh contact layer), Tendra Mepilex Lite and Tendra Mepilex Border (all from Molnlycke Health Care).

10.5.6  Hydrocolloid dressings Hydrocolloids are permeable to water vapour but impermeable to bacteria and also have the properties of debridement and absorb wound exudates [49]. They are used on light to moderately exudating wounds such as pressure sores, minor burn wounds and traumatic wounds. These dressings are also recommended for paediatric wound care management, as they do not cause pain on removal [50]. When this hydrocolloid is in contact with the wound exudate, they form gels and provide moist environment that helps in protection of granulation tissue by absorbing and retaining exudates. Granuflex, Comfeel, Tegaderm, Tegasorb DuoDERM Extra Thin CGF and Replicare* Ultra are available in the form of sheets or thin films. Disadvantage of hydrocolloids are they are not indicated for neuropathic ulcers or highly exudating wounds and are also mostly used as a secondary dressings [51].

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10.5.7  Composite dressings These dressings in general contain three key components such as the wound contact layer, the functional layer and the retention layer. The contact layer acts as an interface between the wound surface and the dressing and is low or non-adherent to the surface of wound. This layer allows wound exudates to pass into the functional layer while preventing the adherence of the dressing to a drying surface at the end of the healing process. The middle or functional layer though usually composed of absorptive material varies greatly for different products to meet the requirement of intended use. This layer besides maintaining moisture environment also assists in autolytic debridement. The bottom or retention layer is composed of non-adherent material, which prevents sticking to newly granulating tissue and helps secure the dressing onto the wound edge and provides physical protection to the wound surface, e.g., Alldress, Covaderm, Coversite plus

10.5.8  Antimicrobial wound dressings Antimicrobial dressings play an important part in wound care in the prevention and management of infection. The spread of antibiotic-resistant strains of microorganisms such as MRSA, VRSA, VRE, etc., is a major threat to the vulnerable people who spend extended time in the hospital throughout the world. It is an ever increasing threat and poses a huge economic burden on the patient. To overcome the microbial infection, currently medicated dressing materials are being developed. These dressings are incorporated with bioactive metallic ingredients such as silver ions (e.g., Acticoat, Actisorb plus) and iodine (povidone iodine). These bioactive ingredients on application kill bacteria at the cellular level and control the infection.

10.5.9  Bioactive dressings These dressings are known for their biocompatibility, biodegradability and non-toxic nature and are derived generally from human, animal or plant sources such as collagen, hyaluronic acid, chitosan, alginate and elastin etc. Polymers of these materials are used alone or in combination depending on the nature and type of wound. Biological dressings are sometimes incorporated with growth factors and antimicrobials to enhance wound healing process [52]. Please refer Chapter 12 for further details.

10.5.10  Tissue-engineered ‘skin equivalents’ One of the advanced treatments for improving the healing of chronic or non-healing ulcer is the usage of tissue-engineered skin equivalents, e.g., Dermagraft (Advanced Biohealing Inc, Lojalla, CA, USA) and Apligraft (Organogenesis, Canton, MA, USA). These dressings are polylactin and collagen-based scaffolds seeded with keratinocytes and/or fibroblasts. Some skin substitutes commercially available include Alloderm composed of normal human fibroblasts with all cellular materials removed

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and Integra artificial skin consisting of collagen/chondroitin 6 sulphate matrix overlaid with a thin silicone sheet. Other few substitutes are Laserskin, Biobrane , Bioseed, and Hyalograft3-DTM(TM). Please refer Chapter 12 – Advance therapies for further details.

10.6  Response of dressings to bacteria Wound infections caused by pathogens have always been a major problem that has slowed the healing process. Although the practice of dressing wounds dates from the start of civilisation, utilising dressings for infection control is relatively new. Dressings exist today that have specific properties to inhibit infection in the wound site. There are different ways of achieving this. Sometimes the dressing applied may release drugs or other chemical compounds, which have bactericidal properties and kill the pathogen [53,54]. In other cases, the dressings catch the whole bacterial population and close them within their own structure [43]. All these treatments exploit advanced and ‘smart’ methods of accelerating wound healing, because while removing bacteria, they reduce the state of inflammation.

10.6.1  Dressings that remove bacteria from the wound site In the early 1990s, it was shown that bacteria may be removed from the wound site within the moisture-retentive hydrocolloid [54,55]. Later, investigations demonstrated that alginate-fibre dressings, which form a gel, may also partially immobilise bacteria in the fibrous matrix and, thus, effectively remove them from the wound site [51,52]. Further investigations revealed other dressings that remove bacteria from the infected site with greater efficacy than alginate [55–57].

10.6.2  Application of textiles for removal of bacteria Wound dressings based on carboxymethylated spun cellulose, e.g., CMCH (AQUACEL Hydrofiber dressing), absorb the exudates and form a cohesive gel. Along with the exudates, whole populations of bacteria occupying the wound space are entrapped within the gel structure. In contact with the exudates, the CMCH dressing forms a coherent, continuous gel. The fibres of the dressing, therefore, become fully hydrated, swell and are indistinguishable from each other. The fluid is rapidly absorbed and the bacteria from the wound space are enclosed inside the gel. Most importantly, the great majority of the bacteria are taken into the cohesive gel structure and none are present on the non-hydrated fibres surrounding the gelled area. These investigations have all been confirmed using a scanning electron microscope [54]. This application has, therefore, the potential to inhibit wound infection without the release of drugs.

10.6.2.1  Smart bandages for pathogenic bacteria These bandages detect pathogenic bacteria responsible for wound infection based on the virulence factors such as lipases, hyaluronidase secreted by the infecting

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bacteria. The virulence factors alter the host environment and release toxins such as αhaemolysin, leukocidins and leukotoxins, and cytotoxins, which kill the healthy cells. Smart bandages are incorporated with nanocapsules containing antibiotic and/or antimicrobials and a dye which on contact with the toxin changes colour as an indicative of bacterial infection. This technology besides addressing infection also reduces the abuse of antibiotic/antimicrobials, thereby decreasing the occurrence of resistance developing bacteria. A theranostic wound dressing was developed by Zhou et al. [58] composed of biocompatible UV-photo cross-linkable methacrylated gelatin encapsulating both antimicrobial and fluorescent vesicles. This system is designed in such a way to respond only when pathogenic bacteria exist in the wound bed but not to local environment and benign bacteria. Also, the incorporated antimicrobials get released only when required and are able to kill/inhibit the growth of MRSA and Pseudomonas aeruginosa while providing a visual warning of infection, thereby offering opportunities to combat drug-resistant bacteria.

10.7  Future trends The wound dressing textile industry has a very fast rate of development. Smart devices or sensors, which may be incorporated into dressings, play a special role and are currently being investigated with particular urgency. In the past, people mostly considered the protective function of dressings, but today, they are loaded with drugs, different sensors and devices. On the basis of the achievements of current techniques and science, we can imagine that in the future, structures and applications of wound-care products will become more and more sophisticated, and patients’ recovery to health will be faster, painless and continually monitored.

10.7.1  Dressings and pathogens Dressings currently being investigated for the detection of noxious bacteria in wound sites include, for example, dressings with a silicone-based biosensor that binds lipid A, which may be detected using the photoluminescence method [11]. However, there is the potential development of new dressings, which can recognise the presence of microbiological organisms and also distinguish between particular species and strains. However, detection methods will need to be simplified and avoid becoming too expensive. There is also the potential to develop new dressings containing antibacterial agents, which will only be active in the presence of the pathogen. Dressings already exist today which are loaded with drugs and antibiotics [59]. Products containing silver as a bactericidal agent are especially popular, e.g., the nanocrystalline silver dressing Acticoat or SilvaSorb. Acticoat is a smart dressing which aims to accelerate the healing of burns. This product not only prevents wound adhesion but also acts as an antibacterial agent. The Acticoat dressing contains a rayon/polyester non-woven core, laminated between layers of silver-coated high-density polyethylene mesh. This dressing is effective against many bacterial strains, including methicillin-resistant

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Staphylococcus aureus and vancomycin-resistant Enterococci [54,60–62]. SilvaSorb is a synthetic, polyacrylate hydrophilic matrix containing dispersed or suspended microscopic silver-containing particles. In contact with the moist exudate, the silver is released into the wound [3]. These dressings are already smart because, apart from their protective function, they are also a source of antibacterial agents. The challenge for future investigations is to design a dressing capable of releasing the antimicrobial agents in a controlled way, e.g., so that the amount of antimicrobial agent released to the wound site is just sufficient for the amount of pathogen, thereby preventing the adverse effects of any excess.

10.7.2  pH-sensitive textiles The pH value of the exudates is very important and significantly influences patients’ health. A huge challenge remains for scientists to learn how the pH level may be used to accelerate the healing process and how to monitor dangerous changes in the wound environment. As described above, wound liquids are particular mixtures of dissolved biological micromolecules and macromolecules. Some of them may be noxious and some may promote the healing process. Sometimes they have a negative or positive charge, which significantly influences the pH of the exudate. There is, therefore, the possibility of designing dressings which can detect pH changes or even react to them. Studies are currently under way to investigate how pH-sensitive chemical compounds may be applied in textiles and how they react in different conditions. Some colorimetric pH sensors react very rapidly and allow detection of changes with the naked eye, which makes them particularly attractive. In contrast, fluorescent sensors are even more sensitive than colorimetric ones [63]. Fabrics which are chromic or chameleon materials and can change their colour in different conditions (e.g., light, heat, electricity, pressure, liquid, electron beam) are representative of ‘intelligent’ textiles [64]. The pH responsiveness of a polymer is highly based on the functional groups present on the backbone of the polymer. A polymer contains carboxylic acid or amine group on the backbone that can be used as a pH-responsive polymer, to undergo protonation or deprotonation and associated with changes in hydrophilicity and hydrophobicity, when in contact with different pH environments. Researchers have tailored the polymer with different functional groups in response to the wide range of pH. It is well known that fluorescent or colorimetric agents are good pH sensors [65]. These compounds are highly sensitive to environmental changes, and when they possess high fluorescence intensity with thermal and photostable properties, they may be used to dye natural or synthetic textile fibres [66] or as dyes for the structural colouration of polymer materials [66]. One of the compounds investigated, which may be embedded on to a fabric matrix, is 1-[(7-oxo-7-benzo[de]anthracen-3-ylcarbamoyl)-methyl]pyrid-inium chloride dye (BD) [62,63]. This novel water-soluble organic compound retains colorimetric pH sensor properties even when it is immobilised on viscose textile. When BD is placed in acidic solution, it occurs in protonated form and produces a bright-yellow colour. At pH 10.4, deprotonation of BD occurs and the colour becomes reddish orange. Optical fibre–based, pH-sensitive smart textiles have been developed to identify the wide range of pH on chronic wounds. Bromophenol blue, phenol red

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and bromocresol purple were coated on the optical fibre. The colour of the optical fibre will change based on the pH of the wound environment; the pH variation is measured using a photometric device [64a]. Chitosan and carbon dots hydrogel show good pH sensing; 0.1% concentration of carbon dots were mixed with chitosan and made into a film wherein chitosan exhibited antimicrobial property and carbon dots show pH-sensing property, when the film was examined under UV light, with different colours being displayed based on pH ranging from 4 to 1 [64b]. Fig. 10.5 shows two forms of electron movement as a result of deprotonation or protonation. BD may therefore occur in two canonical forms, as shown in Fig. 10.5. The absorption spectra of the dye are strongly dependent on the pH of the solution. It shows that the absorption maximum occurs at two different wavelengths for the two ranges of pH. At pH 3.3–7.3, the absorption maximum occurs at λ = 413 nm, whereas at pH 10.4–12.6 the absorption maximum is at λ = 457 nm. Reaction is very fast and reversible [60]. The example outlined above shows a dyed fabric which also plays a pH-sensor role. It would be a great challenge to investigate the textile matrix further, as an application for pH-sensitive dressings. Fabric dyeing with colorimetric agents gives a large

OH– H N ..

pH 3.3–7.3

H N ..

N

O

O

OH–

H+

OH–

H3O+ .. N

H3O+ .. N

pH 10.4–12.6 N

N ..O– ..

O

– ..O ..

N O

O

H+

OH–

O

Figure 10.5  Mechanism of protonation and deprotonation of BD dye. In acidic solution, the dye is bright yellow and in alkaline solution, a reddish orange.

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sensory area, which might be convenient in the case of wound dressings, allowing the monitoring of the whole wounded surface. Furthermore, an immediate answer indicated by a colour change would give a warning in case of any dangerous pH variations. Although the ‘smart textile’ industry is expanding greatly, ‘smart dressings’ are still a relatively new branch. Therefore, some products already under development might not be included here because they have not yet been reported in the public domain. However, this chapter provides a review of some ‘intelligent’ or advanced dressings, which have been invented and developed over the last few years. This detailed presentation of their mechanisms should encourage further investigation because it shows the potential of dressings in the treatment of particular wounds.

10.8  Sources of further information and advice Those interested in ‘smart’ wound dressings may find other sources of further information, but the following reference list gives the most accessible and fundamental resources. Smart textiles for medicine and healthcare, edited by L. Van Langen hove, is a significant source of information not only for the wound care products area but also for different smart textiles, such as intelligent garments for prehospital emergency care, smart textiles in rehabilitation or in pregnancy monitoring. The following volumes are also recommended: Medical textiles and biomaterials for healthcare, edited by S. C. Anand, J. F. Kennedy, M. Miraftab and S. Rajendran (Woodhead Publishing Limited, Cambridge, UK, 2006), which discusses issues relating to wound-care materials and intelligent textiles for medical applications. The previous editions of this book series are Medical textiles (2000) and Medical textiles 96 (1997), both edited by S. C. Anand. Conferences including discussion of topics relating to smart fabrics, textiles or dressings are an alternative source of information. During such events, changes are proposed in the functionality of textiles by applying new technologies and creating sensitive, interactive and intelligent materials. The most recent conferences and events that were held are listed below: MEDTEX 07, Fourth International Conference and Exhibition on Healthcare and Medical Textiles, the Latest Conference of a Series of MEDTEX Conferences, The Holiday Inn Bolton Centre, Bolton, UK, 16–18 July, 2007. www.bolton.ac.uk/uni/research/medtex07 Nanocomposites 2007 in Brussels, The Crown Plaza Europa in Brussels, Belgium, 14–16 March, 2007 The Middle East’s First Symposium and Exhibition, Dedicated to Non-Wovens, Dubai, United Arab Emirates, 20, 21 February, 2007 3rd International Congress on Innovations in Textiles and Fabrics, Berlin, Germany, 14, 15 February, 2007 Smart Textiles Europe, Paramount Carlton, Edinburgh, UK, 13, 14 December, 2006. www. paramount-carlton.co.uk European Conference on Textiles and the Skin, Apolda, Germany, 11–13 April, 2002. http:// www.derma.uni-jena.de/04tagung/2002ects.pdf.

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Advanced Textiles for Wound Care

More information about conferences held over the last few years on textiles, fabrics and new trends in medical applications can be found on the website http://www. technical-textiles.net.

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[17] M.-Y. Zhou, L.–Y. Chu, W.–M. Chen, X.–J. Ju, Flow aggregation characteristic of thermo-responsive poly(N-isopropylacrylamide) spheres during the phase transition, Chem. Eng. Sci. 61 (2006) 6337–6347. [18] J.D. Whitney, M.M. Wickline, Treating chronic and acute wounds with warming: review of the science and practice implications, J. WOCN 30 (4) (2003) 199–209. [19] J.D. Whitney, G. Salvadalena, L. Higa, M. Mich, Treatment of pressure ulcers with noncontact normothermic wound therapy: healing and warming effects, J. WOCN 28 (5) (2001) 244–252. [20] T. Ikeda, F. Tayefeh, D.I. Sessler, A. Kurz, O. Plattner, B. Petschnigg, Local radiant heating increases subcutaneous oxygen tension, Am. J. Surg. 175 (1998) 33–37. [21] L.M. Geever, D.M. Devine, M.J.D. Nugent, J.E. Kennedy, J.G. Lyons, A. Hanley, C.L. Higginbotham, Lower critical solution temperature control and swelling, behaviour of physically crosslinked thermosensitive copolymers based on N-isopropylacrylamide, Eur. Polym. J. 42 (2006) 2540–2548. [22] L.-S. Wang, P.-Y. Chow, T.-T. Phan, I.J. Lim, Y.-Y. Yang, Fabrication and characterisation of nanostructured and thermosensitive polymer membranes for wound healing and cell grafting, Adv. Funct. Mater. 16 (2006) 1171–1178 17.   (a) Z. Abdali, H. Yeganeh, A. Solouk, R. Gharibi, M. Sorayy, Thermoresponsive antimicrobial wound dressings via simultaneous thiol-ene polymerization and in situ generation of silver nanoparticles, RSC Adv. 5 (2015) 66024–66036.    (b) A. Rezapour-Lactoee, H. Yeganeh, S.N. Ostad, R. Gharibi, Z. Mazaheri, J. Ai, Thermoresponsive polyurethane/siloxane membrane for wound dressing and cell sheet transplantation: in-vitro and in-vivo studies, Mater. Sci. Eng. C 69 (2016) 804–814.   (c) C. Radhakumarya, M. Antonty, K. Sreenivasana, Drug loaded thermoresponsive and cytocompatible chitosan based hydrogel as a potential wound dressing, Carbohydr. Polym. 83 (2011) 705–713.    (d) K. Zubik, P. Singhsa, Y. Wang, H. Manuspiya, R. Narain, Thermo-responsive poly(N-isopropylacrylamide)-cellulose nanocrystals hybrid hydrogels for wound dressing, Polymers 9 (4) (2017) 119.   (e) D.-Q. Wu, J. Zhu, H. Han, J.-Z. Zhang, F.-F. Wu, X.-H. Qin, J.-Y. Yu, Synthesis and characterization of arginine-NIPAAm hybrid hydrogel as wound dressing: in vitro and in vivo study, Acta Biomater. 65 (2018) 305–316. [23] M.R. Guilherme, G.M. Campese, E. Radovanovic, A.F. Rubira, E.B. Tambourgi, E.C. Muniz, Thermo-responsive sandwiched-like membranes of IPN-poly-N-isopropylacrylamide/ PAAm hydrogels, J. Membr. Sci. 275 (2006) 187–194. [24]  F.-H. Lin, J.-C. Tsai, T.-M. Chen, K.-S. Chen, J.-M. Yang, P.-L. Kang, T.-H. Wu, Fabrication and evaluation of auto-stripped tri-layer wound dressing for extensive burn injury, Mater. Chem. Phys. 102 (2007) 152–158. [25] C. Robinson, S.M. Santilli, Warm-Up Active Wound Therapy: a novel approach to the management of chronic venous stasis ulcers, J. Vasc. Nurs. 2 (1998) 38–42. [26] A. Jones, D. Vaughan, Hydrogel dressings in the management of a variety of wound types: a review, J. Orthop. Nurs. 9 (2005) 51–511. [27] R. White, K.F. Cutting, Modern Exudate Management: A Review of Wound Treatments, World Wide Wound, 2006. Revision 1.0. [28] K. Lay-Flurrie, The properties of hydrogel dressings and their impact on wound healing, Prof. Nurse 19 (2004) 269–273. [29] K.F. Cutting, Exudate: composition and functions, in: R.J. White (Ed.), Trends in Wound Care Volume III, Quay Books, London, 2004.

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[30] T. Yotsuyanagi, S. Urushidate, K. Yokoi, Y. Sawada, M. Suno, T. Ohkubo, A study of the concentration of orally administered sparfloxacin found in exudates from suture wounds beneath occlusive dressings, Burns 24 (1998) 751–753. [31] S. Seaman, Management of fungating wounds in advanced cancer, Semin. Oncol. Nurs. 22 (3) (2006) 185–193. [32] T.J. Coats, C. Edwards, R. Newton, E. Staun, The effect of gel burns dressings on skin temperature, Emerg. Med. J. 19 (2002) 224–225. [33] S. Thomas, P. Hay, Fluid handling properties of hydrogel dressings, Ostomy Wound Manage 41 (54–56) (1995) 58–59. [34] D. Eisenbud, H. Hunter, L. Kessier, K. Zulkowski, Hydrogel wound dressings: where do we stand in 2003? Ostomy Wound Manage 49 (2003) 52–57. [35] S. Manju, M. Antony, K. Sreenivasan, Synthesis and evaluation of a hydrogel that binds glucose and releases ciprofloxacin, J. Mater. Sci. 45 (2010) 4006–4012. [36] C. Li, R. Fu, C. Yu, Z. Li, H. Guan, D. Hu, D. Zhao, L. Lu, Silver nanoparticle/chitosan oligosaccharide/poly(vinyl alcohol) nanofibers as wound dressings: a preclinical study, Int. J. Nanomed. 8 (2013) 4131–4145. [37] G.R. Newman, M. Walker, J.A. Hobot, P.G. Bowler, Visualisation of bacterial sequestration and bacterial activity within hydrating Hydrofiber wound dressing, Biomaterials 27 (2006) 1129–1139.   (a) Technology updates: understanding hydrofiber technology, Wounds Int. 1 (5) (2009) Products reviews, Wounds Int. 1 (5) (2010). [38] Y. Yang, H. Hu, Application of superabsorbent spacer fabrics as exuding wound dressing, Polymers 10 (2018) 210. [39] C.M. Mouës, G.J. van den Bemd, F. Heule, S.E. Hovius, Comparing conventional gauze therapy to vacuum assisted closure wound therapy: a prospective randomized trial, J. Plast. Reconstr. Aesthetic Surg. 60 (2007) 672–681. [40] P. Wu, J.D.S. Gaylor, A model of water vapour transmission in hydrocolloid wound dressing, J. Membr. Sci. 97 (1994) 27–36. [41] M. Límová, J. Troyer-Caudle, Controlled, randomised clinical trial of 2 hydrocolloid dressings in the management of venous insufficiency ulcers, J. Vasc. Nurs. 1 (2002) 22–33. [42] B. Balakrishnan, M. Mohanty, P.R. Umashankar, A. Jayakrishnan, Evaluation of an in situ forming hydrogel wound dressing based on oxidized alginate and gelatin, Biomaterials 26 (2005) 6335–6342. [43] Y. Qin, Superabsorbent cellulosic fibres for wound management, Textiles 1 (2005) 12–14. [44] P. Chadwick, J. McCardle, Exudate management using a gelling fibre dressing, Diabetic Foot J. 18 (1) (2015) 43–48. [45] Data-on-file report 20140806-001 Mölnlycke Health Care. [46] Deleted in Review. [47] T. Thomson, Foam Composite, 2006, US Patent 7048966. [48] R.E.S. Marcia, M.C.R. Castro, New dressings, including tissue engineered living skin, Clin. Dermatol. 20 (6) (2002) 715–723. [49] S. Thomas, P.A. Loveless, A comparative study of twelve hydrocolloid dressings, World Wide Wounds 1 (1997) 1–12. [50] S. Thomas, Hydrocolloids, J. Wound Care 1 (1992) 27–30. [51] J.S. Boateng, K.H. Matthews, H.N.E. Stevens, G.M. Eccleston, Wound healing dressings and drug delivery systems: a review, Indian J. Pharmacol. Sci. 97 (2008) 2892–2923. [52] S. Dhivya, V. Vijaya Padma, E. Santhini, Wound dressings – a review, Biomed. (Taipei) 5 (4) (2015) 22.

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[53] K. Moore, A. Thomas, K.G. Harding, Iodine released from the wound dressing modulates the secretion of cytokines by human macrophages responding to bacterial lipopolysaccharide, Int. J. Biochem. Cell Biol. 29 (1997) 163–171. [54] F.-L. Mi, Y.-B. Wu, S.-S. Shyu, A.-C. Chao, J.-Y. Lai, C.-C. Su, Asymmetric chitosan membranes prepared by dry/wet phase separation: a new type of wound dressing for controlled antibacterial release, J. Membr. Sci. 212 (2003) 237–254.   (a) M. Walker, J.A. Hobot, G.R. Newman, P.G. Bowler, Scanning electron microscopic examination of bacterial immobilisation in carboxymethyl cellulose (AQUACEL) and alginate dressings, Biomaterials 24 (2003) 883–890. [55] J. Lawrence, Dressings and wound infection, Am. J. Surg. 167 (1994) 21S–4S. [56] P.G. Bowler, S.A. Jones, B.J. Davies, E. Coyle, Infection control properties of some wound dressings, J. Wound Care 8 (1999) 499–502. [57] M.J. Waring, D. Parsons, Physico-chemical characterisation of carboxy-methylated spun cellulose fibers, Biomaterials 22 (2001) 903–912. [58] J. Zhou, D. Yao, Z. Qian, S. Hou, L. Li, A.T.A. Jenkins, Y. Fa, Bacteria-responsive intelligent wound dressing: simultaneous in situ detection and inhibition of bacterial infection for accelerated wound healing, Biomaterials 161 (2018) 11–23. [59] H.N. Paddock, R. Fabia, S. Giles, J. Hayes, W. Lowell, D. Adams, G.E. Besner, A silver-impregnated antimicrobial dressing reduces hospital costs for pediatric burn patients, J. Pediatr. Surg. 42 (2007) 211–213. [60] K. Kok, G.A. Georgeu, W.Y. Wilson, The acticoat glove – an effective dressing for the completely burnt hand. How we do it, Burns 32 (2006) 487–489. [61] R. Rustogi, J. Mill, J.F. Fraser, R.M. Kimble, The use of ActicoatTM in neonatal burns, Burns 31 (2005) 878–882. [62] D. Staneva, R. Betcheva, Synthesis and functional properties of new optical pH sensor based on benzo[de]anthracen-7-one immobilized on the viscose, Dyes Pigments 74 (2006) 148–153. [63] C.A. Norstebo, Intelligent textiles, soft products, J. Future Mater. (2003) 1–14. [64] D. Staneva, R. Betcheva, J.-M. Chovelon, Fluorescent benzo[de]anthracen-7-one pHsensor in aqueous solution and immobilized on viscose fabrics, J. Photochem. Photobiol. Chem. 183 (2006) 159–164.   (a) Advances in science and technology, Smart Text. Biosens. Capab. 8 (2013) 129–135.   (b) Wound dressing application of pH-sensitive carbon dots/chitosan hydrogel, RAC Adv. 7 (2017) 10638. [65] N. Ayangar, R. Lahoti, R. Wagle, Indian J. Chem. 16B (1973) 106–108. [66] T. Konstantinova, P. Meallier, H. Konstantinov, D. Staneva, Polym. Degrad. Stab. 48 (1995) 161–166.

Further reading [1] F. Dehaut, M. Maingault, Kinetic binding of bacteria on two types of dressing: algosteril (calcium alginate) and gauze, in: Poster Presentation, First European Workshop SurgeryEngineering: Synergy in Biomaterial Applications. Montpelier, France, 1994, 1994. [2] L. Martineau, P.N. Shek, Evaluation of bi-layer wound dressing for burn care. II in vitro and in vivo bactericidal properties, Burns 32 (2006) 172–179.

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Authors of the chapter: Mangala Joshi1, Roli Purwar2 1Department of Textile Technology, Indian Institute of Technology, New Delhi, India; 2Department of Applied Chemistry, Delhi Technological University, Delhi, India Editor of the chapter: Roli Purwar Department of Applied Chemistry, Delhi Technological University, Delhi, India

11.1  Introduction Wound management has recently become more complex because of new insights into wound healing and increasing need to manage complex wounds outside the hospital. Modern wound dressings are designed to facilitate the function of the wound rather than to just cover it. Healing of wounds is a biological cellular process linked to the process of repair. The physiological process of wound healing is a dynamic process and follows a complex pattern of four continuous phases, namely haemostasis, inflammation, proliferation and maturation or remodelling [1]. The best dressing is the patient’s own skin, which is permeable to vapour and protects the deeper layers of tissue against mechanical injuries and infection. The disadvantage of such dressings is their antigen properties, which limits the span of the application. A wound dressing creates a suitable microclimate for rapid and effective healing [2]. A good wound dressing prevents dehydration and scab formation; is permeable to oxygen; is sterilisable; absorbs blood and exudates; protects against secondary infections; supplies mechanical protection to the wound; and is non-adherent, non-toxic, non-allergic and non-sensitive. Besides, it should also be tear and soil resistant, should be stable in a range of temperatures, should withstand and humidity encountered in use, should have long shelf life and should be economical [3]. The wounds require several kinds of dressing, depending on the kind and dimension of the wound, its positioning on the body and in particular on the effusion intensity, the depth of tissue damage and the stage of healing. Appropriately used dressings may prevent complications such as infection, tissue maceration, excessive effusion, swelling, pain, smell, etc. The dressing supports the body’s own cleaning mechanism and provides clean conditions in the wound [4]. A traditional wound dressing comprises an absorbent pad of a fibrous material with gauze, which is in immediate contact with the wound. The diffusing wound fluid will thus extend into the inter-sticks and around the fibre of the dressing so that the dressing is eventually adhesively and mechanically anchored into the wound surface and produces a protective covering to the wound. Commonly used wound dressing comprises cotton gauze, foams, sponges, cotton wads or other fibrous materials. Gauze and other fibrous materials absorb fluid by capillary action with the disadvantage that Advanced Textiles for Wound Care. https://doi.org/10.1016/B978-0-08-102192-7.00011-4 Copyright © 2019 Elsevier Ltd. All rights reserved.

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when new tissue is formed as a part of healing process, it engulfs the fibre and is torn when the material is removed causing wound injury and disturbing new tissue growth. Consequently, removal or changing of dressing can and will cause disruptions of the healing process, delaying the healing process and being a painful procedure for the patient [5]. Moreover, cotton gauge which is generally used because of its good absorption properties and soft handle allows moisture to evaporate from the wound, which means that cotton gauze dressings do not maintain the moist environment that is said to facilitate faster wound healing. These also need frequent changing. Thus, there is a need for a dressing which is non-adherent while being absorbent. The expectation from an ideal wound dressing at times may be very demanding and cannot be fulfilled by only one layer of material. A multilayered composite dressing provides the ultimate wound protection, layer by layer. Such modern dressings have more than one layer of material that can be universally used as initial form of the treatment of the wound. They can be applied over a wound in one simple and efficient step to prevent adherence of the dressing to the wound, to help maintain a proper moisture level at the wound and to prevent disturbance of wound caused by dressing changes.

11.2  Definition Composite dressings are the products obtained by combining physically distinct components in to a single dressing that provides multiple functions. These functions must include (1) bacterial barrier, (2) absorption, (3) either semi-adherent or non-adherent property over the wound site and (4) an adhesive border. Composite dressings are extremely easy to use with ‘band-aid’ type application. Composite dressing is defined as a multilayer product with an adhesive border that comprises [6]: 1. a physical (not chemical) bacterial barrier that is present over the entire dressing pad and extends out into the adhesive border, 2. an absorptive layer and 3. a semi-adherent or non-adherent layer over the wound site

Table 11.1 summarises the commercially available composite dressings in the m ­ arket. The shape and size of the composite dressing depends on the wound size and its place.

11.3  Structure of composite dressing Composite dressings have multiple layers and can be used as primary or secondary dressings. Most composite dressings have three layers, namely semi-adherent or a non-adherent layer, absorptive layer and bacterial barrier layer as shown in Fig. 11.1. A semi-adherent or non-adherent layer touches the wound and protects the wound from adhering to other material. This layer allows the dressing to be removed without disturbing new tissue growth. Because exudates pass through it into the next layer, it must be permeable to fluids. An absorptive layer wicks the drainage and debris away from the wound’s surface, which helps prevent skin maceration and bacterial growth

Composite dressings for wound care

Table 11.1 

315

Commercially available wound dressing

Serial number

Commercial name

Manufacturing company

1.

Island Dressing

2.

Tefla plus barrier Island Dressing

Mekesson Medical Surgical Medtronic

3.

Mepore Pro

Mölnlycke Health Care

4.

Repel

MPM Medical, Inc.

5.

Jumpstart

Arthrex, Inc.

6.

Alldress

Mölnlycke Health Care

7.

Stratasorb

Medline Industries, Inc.

8.

Covaderm Plus

DeRoyal

9.

Medipore + Pad Soft Cloth Tegaderm + Pad

3M

Tegaderm Absorbent Cardinal Health

3M

Covaderm Plus VAD

DeRoyal

10.

11. 12.

13.

3M

Cardinal Health

Features • Gauze

dressing with light and moderated wound • Absorbs over 10 times its weight in exudate, waterproof film over pad surface • Contact layer protects fragile epithelial tissue • Self-adhesive absorbent surgical dressing, Protects wounds from water and contamination • Highly absorptive, waterproof dressing with adhesive border • Antimicrobial wound dressings provide broad-spectrum antimicrobial efficacy • Absorbent, vapour permeable, self-adhesive • Waterproof and bacteria-proof • Dressing has a deluxe soaker pad, non-woven adhesive border and a waterproof backing. • Adhesive barrier island with contact layer, absorption pad, polyurethane vapour transmission film and tape border • Breathable, absorbent and conforms to body contours • Sterile waterproof, absorbent wound dressing that provides a viral and bacterial barrier • Transparent wound dressing with fluid handling capacity • Soft non-woven fabric coated with hypoallergenic acrylic adhesive and an absorbent pad with a low adherent wound contact layer • Designed to cover vascular access sites • Constructed with a special V-cut tape and protective layers Continued

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Advanced Textiles for Wound Care

Table 11.1 Continued Serial number

Commercial name

Manufacturing company

Features

14.

Coverlet

BSN medical

• Flexible

15.

COVRSITE-Plus

Smith & Nephew, Inc.

16.

DermaDress

DermaRite Industries

17.

DuDress

Integra LifeSciences

18.

Gentell Comfortell

Gentell Wound and Skin Care

with central absorbent island wound pad • Seals off wound from dirt and contamination • A waterproof film layer helps protect the wound from contamination by urine or faeces • Multilayered, waterproof composite dressing for wounds with minimal to moderate drainage • Non-adherent absorbent centre pad, adhesive border, soft gauze and film top for barrier protection • Four-layer composite dressing with absorbency, barrier to contaminants and a waterresistant tape border

Bacterial barrier layer

Adsorptive layer Non adherent or semi adherent layer

Extrudate Moisture

Wound

Figure 11.1  Layered structure of composite dressing.

Composite dressings for wound care

317

and helps maintain a moist healing environment. Besides protecting the intact skin from excessive moisture, the absorptive layer helps liquefy eschar and necrotic debris, facilitating autolytic debridement. A bacterial barrier layer may have an adhesive border. This outer layer allows moisture vapour to pass from the wound to the air and keeps bacteria and particles out of the wound. It prevents moisture leakage to the outside of the dressing (strike-through), meaning that the dressing could be changed less frequently [7].

11.4  Materials and textile structures used in composite dressing 11.4.1  Non-adherent or semi-adherent layer In the composite dressing, the first layer needs to be a fine mesh ‘non-adherent’ type material. ‘Non-adherent’ is a misnomer because the goal of this layer is to allow the stuff that comes out of the wound to go through this layer and then be removed with the dressing change. The major function of non-adherent layer is that it reduces shearing of epithelium, permits passage of blood and fluids, does not trap heat or moisture and is non-adsorbent and non-adhesive. This layer does not promote or speed up the healing process. Instead, it just allows simple dressing changes without disturbing the healing process. The non-adherent material is generally only one layer thick [8]. Various textile materials such as nylon, cotton, polyester, polypropylene, rayon, silk and cellulose derivatives in the form of woven, non-woven, net and perforated film structure can be used as a non-adherent layer as shown in Fig. 11.2. Initially paraffin gauze was used as non-adherent material for dressing. Jelonet, Paranet, Paratulle and Unitulle are some of the commercial paraffin gauze based non-adherent dressing, which consist of a cotton or rayon cloth impregnated with white or yellow soft paraffin. The soft paraffin in the dressing reduces adherence to the wound bed, if applied in sufficient layers. However, these dressing will require frequent changing to prevent drying out and incorporation into the granulation tissue in the wound [9]. The main drawback of the natural polymer-based textile structure is that, though they are non-adherent relative to the adsorbent layer, they are not completely non-adherent. Woven or net structures have interstices in which the exudates can dry. Moreover, in certain situations such as pressure dressing or a packing dressing, the dressing is pressed on to the treatment area causing non-adherent material to be pressed into the wound so that granulation tissue and epithetical cells are forced into the interstices of the non-adherent material. The non-adherent layer of composite dressing can be prepared by changing the texture of the surface. The non-adherent surface can be prepared by impregnating non-woven fabric with minute particles or globules of polythene which then passes through a hot calendar to provide a smooth surface covered with film-like patches of polythene and free of projecting fibres [10]. In general, non-adherent layer comprises a highly porous, self-sustaining and discontinuous film of fused and coalesced non-­ woven, inert, thermoplastic, synthetic polypropylene [11]. N-TERFACE (high-density

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Advanced Textiles for Wound Care

Non woven

Perforated film

Woven net

Woven gauge

Figure 11.2  Basic textile structures for non-adherent layer of composite dressing.

polyethylene sheeting) by Winfield laboratory can be used as a non-adherent layer for composite dressing [12]. More recently, a polyamide fabric partially embedded into the biosynthetic silicon films has been used. Collagen is incorporated in silicon and polyamide components. Mepitel is a non-adherent silicon dressing made of a medical-grade silicon gel bound to a soft and pliable polyamide net. Another example is a fine polyamide net containing pores of 50 μm in diameter under trade name of Tegapore. These pores are big enough to permit the free passage of exudates into the secondary absorbent layer but are too small to allow the ingress of granulation tissue. The perforated net prevents the dressing from adhering to the surface of the wound while the holes allow the passage of exudates to the absorbent layer. The net dressings themselves do not absorb any body fluids. A non-adherent dressing layer is also produced by coating them with a thin layer of aluminium by vacuum deposition. Such dressings are commercially available under the trade name Metallene [13]. In general, non-adherent layer comprises a porous polyethylene film having a thickness of about 3.5–5.0 mills.

11.4.2  Absorptive layer As the name suggests, the second layer comprises an absorbent material for absorbing exudates, blood, moisture and other fluid materials from the inner layer and maintains the wound in moist environment. The absorbent layer may contain one or more layers of absorbent material in an adequate quantity. Many non-toxic conventionally known

Composite dressings for wound care

Spun bonded

319

Air laid

Woven fabric

Figure 11.3  Various textile structures used for absorptive layer.

absorbent materials are readily available. The mostly used adsorbent materials are gauze, non-woven sheet materials such as needle-punched non-woven rayon, cellulosic pulp, synthetic pulp, cotton rayon, creped cellulose wadding and airfelt or airlaid pulp fibres and absorbent sponges. Fig. 11.3 shows some of the absorptive layers used in composite dressing. Absorptive layer needs to be flexible, soft and approximately 0.1–0.5 cm thick. The absorptive layer size and shape will vary with the size and shape of the wound. It should be large enough to cover the wound and can absorb at least 2–20 cc/g of exudate [12]. Super-absorbents are water-insoluble materials capable of absorbing and retaining large amounts of water or aqueous fluid in comparison with their own weight. A ­ cellulose matrix containing a super-absorbent, e.g., carboxymethyl cellulose, sodium polyacrylate in powder form, is generally used for absorbent layer in the composite dressing. Other absorbents used comprise alginic acid, dextran, carboxymethyl dextran, starch, modified starch, hydroxyethyl starch, hydrolysed polyacrylonitrile, polyacrylamide, carboxymethyl cellulose and their derivatives. The most preferred super-absorbent material is a cross-linked dextran derivative which absorbs between 2 and 10 g of water per gram of dry material. These are commercially under trade names – Sephadex from Sigma Chemical Co. (St. Louis, MO), Debrisan.RTM from Pharmacia of Sweden and Separan.RTM AP30 from Dow Chemical Co. It is preferable that the absorbent is uniformly laid to wick the blood and body fluids away from the wound surface and prevent the pooling of fluids next to the

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wound to prevent maceration of the wound. The absorbent should breathe and not trap excessive heat. The absorbent can be designed to dispense microencapsulated medication or traditional medication to the wound. The absorbent can be moistened with various medications or solutions before application or can be impregnated with a desired medicament. Examples of medicaments that may be absorbed into the absorbent are antimicrobial drugs, analgesics, metal oxides, enzymes, etc. The absorbent should readily wick away any fluids before they dry, thereby helping to prevent any bonding or adherence of the contact component to the wound surface. Commercially available absorbent textiles such as Sunbeam Process absorbent materials (Gelman Technology), the Composite Air Laid Superabsorbent Pad (Dry Forming Processes) and Polyester Superabsorbent Fiber Flock SAFF (Hanfspinnerei Steen & Co.) are the mostly preferred materials for making composite dressings [12]. US patent 5167613 [14] and 5465735 [15] disclose the combination of high-­density and low-density adsorbent pad structure to absorb the exudates. Such structures consist of two separate but contiguous elements, namely a lower high-density woven or non-woven fabric having optimum spreading or wicking characteristics and upper low-density fabric having optimum absorption capacity. The high-density fabric will have a density of the order of 0.1–0.2 g/cm3, while the low-density fabric will have a density 0.05 g/cm3. The high-density and low-density fabric can be prepared by using rayon, rayon/polyester blend, polyester/cotton blend or cellulosic material. US patent 6077526 [16] discloses the gradient density needle punch felt of polyester and viscose fibre, which absorbs a large quantity of exudate. Material with varying densities across its depth is achieved by varying the degree of needle penetration and thus fibre entanglement across the material depth. Thus, a graded density felt may have a relatively loose voluminous central region and more dense surface layers. The increased density of surface layer is achieved by more entanglement with the result that there is less spacing at its surface. This construction of graded density felt acts as a regulator or gate. Another US patent [17] claims a composite wound dressing having an outer layer having controlled permeability and an absorptive layer which is highly blood and exudate absorbent and comprises a Polytetrafluoroethylene (PTFE) fibril matrix having hydrophilic absorptive particles enmeshed in a matrix and optionally a partially occlusive film coated on one surface of the matrix.

11.4.3  Bacterial barrier layer The third or outer layer comprises a bacterium-impermeable and air-permeable cover sheet. The cover sheet also consists of a layer of pressure-sensitive adhesive in its peripheral as shown in Fig. 11.4. The adhesive layer may be of the order of 1 mil thick. This layer helps to seal the cover sheet in liquid and bacteria tight relationship around their common periphery so that neither exudate escapes through the edges of the dressing nor can any external contaminants, including bacteria, enter the dressing and then pass through the slits to the underling wound. The bacterial barrier layer comprises a flexible, waterproof and breathable material which protects the injury from exposure to contaminants from the outer atmosphere, while preventing leakage of any moisture

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Bacterial barrier layer

Adhesive layer Air permeable

Figure 11.4  Function of bacterial barrier layer along with adhesive layer.

from the injury. In general, this layer comprises a waterproof, breathable polyurethane film of approximately 0.5–1.5 mil thickness. Polypropylene or polyethylene such as a low-density, opaque polyethylene film or waterproof and breathable films are other suitable materials for bacterial barrier layer. The bacterial barrier layer may be of the order of about 1.0 to 3.0 mils thick [18]. A bacterial barrier air filter can also be used as an outer layer and is commercially available as Nucleopore.RTM, Millipore.RTM or Gellman.RTM, etc.

11.5  Types of composite dressing Various types of composite dressing depending on the absorbance of wound exudates have been patented and are commercially available. The major classification includes (1) island composite dressings and (2) layered composite dressings.

11.5.1  Island composite dressing Island dressing consists of an absorbent layer sandwiched between the semi-­ permeable backing sheets as shown in Fig. 11.5. The absorbent pad is substantially centrally disposed on an adhesive layer of greater dimension so that the free adhesive surface surrounds the periphery of the absorbent pad for securing the dressing to the skin. The backing sheet thus extends outwardly from the edges of the absorbent layer for the attachment of the dressing over a wound by adhesion to the skin surrounding the wound. US patent 6566577 [19] discloses a low adherent island dressing for a bleeding or low exuding wound. The wound dressing consists of an absorbent layer cover with a thermo plastic film. The film has a textured perforated surface on the front side and

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(a)

(b) Semi permeable Backing sheet

Sandwiched adsorbent material

Non adherent layer Adsorbent layer Adhesive layer

Bacterial barrier layer

Figure 11.5  Schematic representation of (a) island dressing and (b) island composite dressing.

a smooth perforated surface on the rear side. The rear side is covered with a semi-­ permeable backing sheet. This sheet is extended outwardly as an adhesive material. US patent 6168800 [20] discloses the antimicrobial multilayer island dressing, which includes an inner absorbent assembly having a first layer comprising a wound contacting non-absorbent, non-adhering porous polymeric film, which is impregnated with an antimicrobial agent, a second layer comprising a semi-permeable continuous polymeric film joined to the first layer to form a sealed interior reservoir compartment, an absorbent material positioned within the interior reservoir compartment to collect discharged exudate from a wound and an outer layer extending beyond the peripheral edges of the inner absorbent assembly, the outer layer having at least a portion coated with an adhesive material for adhering the island dressing to the wound area. US patent 5607388 [21] discloses liquid- and pathogen-impermeable island wound dressing, which can be adhesively bonded to the skin surrounding a wound and is provided with a liquid- and gas-permeable exudates-absorbing pad, and a plurality of sequentially removable liquid- and microorganism-impermeable, gas- and moisture vapour–permeable cover sheets disposed adjacent to and covering the pad.

11.5.2  Layered composite dressing In the layered composite dressing, the multiple layers of same size are stacked over each other. These dressings consist of minimum two layers to maximum five layers with distinguishing properties. All layers are sealed together from the periphery to make a composite structure. US patent 6348423 [22] discloses a multilayer wound dressing which includes a fibrous absorbent layer for absorbing wound exudate, an odour layer for absorbing odour and a barrier layer. The odour layer is sandwich between the fibrous absorbent and barrier layers. The barrier layer is vacuum perforated and the fibrous absorbent layer is of highly absorbent fibres capable of absorbing 25 g of exudate per gram of dressing. US patent 4875473 [23] discloses a multilayer wound dressing which facilitates wound healing by creating hypoxia followed, after 3–72 h, by an aerobic environment. The dressing is made of (1) a low-oxygen permeability outer layer; (2) an oxygen-­permeable inner layer, affixed on one side to the outer layer; and (3) an adhesive applied to the other side of the inner layer. The entire dressing is applied to the

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wound and creates a hypoxic environment. The outer low–oxygen permeability layer is removed after 3–72 h. The oxygen-permeable layer is left on to provide protection during a subsequent aerobic healing phase. An antiseptic release multilayer dressing is patented by Bioderm Inc. The bottom wound-contacting layer covered with tapered aperture contacts a wound area to discharge exudate from the wound area and transmit exudate via a guiding layer to an absorbent layer. The absorbent layer is formed of high-molecular polymeric fibres and is mixed with a certain concentration of water-soluble agents, such as antiseptic agents, enzymes and growth factor agents, in a suitable proportion. After the exudate passes into the absorbent layer, the polymeric fibres expand forming the shape of gel to avoid exudates flowing backwards to the wound area and to release the antiseptic agents. The absorbent layer is covered by the translucent layer which contains micropores for air venting [23]. CarboFlex is a non-adhesive five-layered dressing. The first layer is an absorbent wound contact layer consisting of fibres of Aquacel and Kaltostat. This layer absorbs and retains exudate, so the problem of maceration and excoriation is reduced as the retention of exudate controls the lateral wicking. As this layer forms a soft gel, a moist environment is maintained and so should allow pain-free removal of the dressing. The second layer is an ethylene methyl acrylate (EMA) film that contains one-way water-resistant microvalves, which delays strikethrough to the charcoal layer. This mechanism prolongs the action of the odour-absorptive properties of the dressing. The third layer is an activated charcoal cloth for the adsorption of odour. The fourth layer consists of a soft non-woven absorbent pad that will absorb any excess exudate, thus delaying the strikethrough and gives extra softness to the dressing for patient comfort. It is also thought that patients may dislike the appearance of a black’ dressing, so this layer makes it aesthetically pleasing to patients. The final fifth layer is another layer of EMA film, which again delays strikethrough of exudate and makes the dressing soft, smooth and water resistant [9]. The Triosyn T40‴ Antimicrobial Wound Dressing is a sterile, primary wound dressing. It is a multilayer composite dressing consisting of an absorbent polyester non-­ woven pad, a permeable adhesive, a single layer of Triosyn-iodinated resin beads and a non-adherent high-density polyethylene mesh.

11.6  New trends in wound dressings 11.6.1  Embroidery technology for wound dressing Embroidery technology is being widely used for medical textiles and tissue engineering. Non-healing wounds need intensive wound care for a very long time. In textile-based implant materials, tissue formation and vascularisation depend on the size and distribution of pores and fibres. An arrangement of pores of different orders of magnitude will favour the tissue growth and the formation of new blood vessels and capillaries. St. Gallen, Switzerland, have developed a wound dressing TISSUPOR as shown in Fig. 11.6 based on embroidery for treatment of chronically non-healing wounds.

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Figure 11.6  Embroidery technology for wound dressing [23].

Embroidery technology allows achieving a three-dimensionally structured textile architecture that combines pores for directed angiogenesis and elements for local mechanical stimulation of wound ground. In TISSUPOR pad, the layers of dense fabric and spacer fabric are made of polyester and the super-absorbing material used is polyacrylate [24]. Wound dressings based on the woven fabric have the disadvantage that it has a hard surface, which adapts poorly to the wound. For this reason, many wound dressings are made up of knitted structures which are soft because of the movements of the threads within the interfacing. However, the disadvantage is that they harden because of exudates emerging from the wound and thus lose their flexibility. Monfilaments, multifilaments or mixtures of these can be used in the embroidery process. The advantage of embroidery over knit structure is that the thread cannot move in the interfacings. The mechanical properties of the embroidery are defined by the arrangements of the interfacings and hardly affected by the incorporation of exudates or extracellular matrix into the thread, which leads to interfacings sticking together. In knitted structure, the mechanical properties are mainly defined by the movability of the thread in the open interfacing. Thus, adhesive exudate leads to an increase in the rigidness of the textile in some circumstances far more than an order of size. Stiffness can cause local loading conditions, which can lead to local tissue necrosis [25].

11.6.1.1  Multilayer dressings using nanofibres Electrospinning is a simple and cost-effective technique used to fabricate fibres with a diameter on the nanometre scale. Wound dressings with nanofibrous materials contribute to improved haemostasis, absorption of exudates from the wound, flexibility in the designed dressing mat and maintenance of moisture in the wound environment, allowing for oxygen and water permeability. Their greatest potential, however, lies in their

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physical features as electrospun nanofibres have large surface area to volume ratios, high porosity containing small pores and a matrix morphology that resembles the natural extracellular matrix of the human body [26,27]. Sirc et al. [28] have prepared a multilayered structure of the nanofibres using Nanospider needleless technology. The mat consisted of two polyurethane layers sandwiching a poly(vinyl alcohol) layer, which held the antibiotic gentamicin. Mats with differing polyurethane thickness values were fabricated, demonstrating that an increase in layer thickness contributed to the prolonged release of gentamicin. Chen et al. [29] created a nanofibrous multilayered structure of poly(d,l)-lactide-co-glycolide and collagen that contained vancomycin, gentamicin and lidocaine to repair infected wounds. This multilayered mat proved to be effective at facilitating wound healing at an early stage. More recently, Tan et al. [30] developed a bilayered wound dressing consisting of polyurethane and gelatin; the double layer used in their investigation showed desirable performance in terms of water vapour transmission rate and water absorption ratio with haemostatic and antibacterial properties. Hassiba et al. [31] have developed a double-nanocomposite nanofibrous mat consisting of an upper layer of polyvinyl alcohol and chitosan loaded with silver nanoparticles and a lower layer of polyethylene oxide or polyvinylpyrrolidone nanofibres loaded with chlorhexidine as antiseptic. The purpose of the upper layer is to protect the wound site against environmental germ invasion. The lower layer, which is in direct contact with the injured site, inhibits bacterial growth at the wound site.

11.6.1.2  Multilayer dressing using negative-pressure wound therapy Negative-pressure wound therapy is a therapeutic technique utilising humidity control of a wound in the proliferation phase to promote the intricate process of the wound healing. The negative-pressure wound therapy typically uses a negative-pressure source, such as a vacuum pump in connection with an airtight seal, suction member and biocompatible porous dressing to generate a negative-pressure environment around the wound area to drain the excess wound fluids and exudates, encourage the migration of the healthy tissue, maintain moisture in the surrounding tissue and increase the blood flow to accelerate the wound healing. Negative-pressure wound therapy utilising the intricate process of wound healing can effectively promote the blood flow to the area, stimulate the formation of granulation tissue and encourage the migration of healthy tissue over the wound. The negative-pressure wound therapy removes the exudates from the wound tissue to inhibit the bacterial growth. The common systems for use in negative-pressure wound therapy are mainly two types, one is the system with fluid storage container and the other is the system with absorptive wound dressing [32]. BenQ Material Corporation [33] have patented a negative-pressure wound dressing including an enclosure housing and a wound contact layer. The enclosure housing has an opening. The opening of the enclosure housing has a barrier layer which separates the enclosure housing into an exudate receptacle and a contact layer receptacle. The wound contact layer is contained in the contact layer receptacle. The exudate receptacle of the enclosure housing includes a negative pressure delivery tube connecting the exudate receptacle and a negative-pressure source and a discharging tube disposed in

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the vicinity of the barrier layer for discharging exudates stored in the exudate receptacle. The barrier layer includes at least one conduit with openings respectively towards the exudate receptacle and the wound contact layer for draining wound exudates from the wound contact layer to the exudate receptacle when a negative pressure is delivered from the pressure source via the negative-pressure delivery tube. Smith & Nephew Inc. [34] have patented a multilayer wound dressing which generates negative pressure at a wound site. The dressing has three layers comprising (1) a sealing layer with at least one orifice, (2) an absorbent layer over the sealing layer for absorbing wound exudate and (3) a liquid-impermeable, gas-permeable filter layer over the absorbent layer. With the help of pump element, which pumps wound exudate and air from a wound site, a peripheral region around the wound site is sealed with a sealing layer of a wound dressing, collecting wound exudate pumped from the wound site, through at least one orifice in the sealing layer, in an absorbent layer of the wound dressing and exhausting gas from the wound dressing through a filter layer between the absorbent layer and a cover layer extending over the wound dressing.

11.7  Summary Composite dressing is a multilayered product, which is a combination of different textile structures such as woven, non-woven, knitted, net film, spacer, etc. Each layer has its distinct property to enhance the wound healing process. Research and new developments in composite dressing is mainly focused on enhancing the functionality of its different layers so as to promote rapid wound healing and reduction in pain associated with wound treatment and all this at a reduced cost. The improvement in non-­adherent, absorbent and bacterial barrier layer can thus reduce the frequent changes of the dressing, which helps in better wound healing.

References [1] G. Han, R. Ceilley, Chronic wound healing: a review of current management and treatments, Adv. Ther. 34 (2017) 599–610. [2] R.F. Diegelmann, M.C. Evans, Wound healing an overview of acute, fibrotic and delayed healing, Bioscience 9 (2004) 283–289. [3] V. Jones, J.E. Grey, K.G. Harding, Wound dressings, BMJ 332 (2006) 777–780. [4] N.F.S. Waston, W. Hodgkin, Wound dressings, Surgery 23 (2005) 52–56. [5] B. Griffiths, E. Jacques, S. Bishop, Wound Dressing, US Patent No. 6458460, 2002. [6] G.W. Cummings, R. Cummings, Composite Dressing with Separable Components, US Patent No. 6255552 B1, 2001. [7] H.K. Payne, G.H. Devenish, Honey Impregnated Composite Dressing Having Super Absorbency and Intelligent Management of Wound Exudate and Method of Making Same, US Patent No. US 9107974, 2015. [8] S. Thomas, Primary wound contact material, in: Wound Management and Dressing, The Pharmaceutical Press, London, 1990.

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[9] D. Morgan, Formulary of Wound Management Products, eighth ed., Haslemere Euromed Communication Ltd., 2000. [10] D.D. Endres Davies, Non-adherent Surgical Dressing, US Patent No. 3441021, 1967. [11] Eldredge, et al., Ophthalmic Pressure Bandage, US Patent No. 3285245, 1966. [12]  G.W. Cummings, R. Cumnmings, Composite Wound Dressing with Separable Components, US Patent No. 5910125, 1999. [13] R. Pudner, J. Community Nurs. 15 (8) (2001). [14] H. Karami, R.F. Vitaris, Composite Vented Wound Dressing, US Patent No. 5167613, 1992. [15] H.A. Patel, Wound Dressing, US Patent No. 5465735, 1994. [16] D.C. Scully, C. McCabe, Wound Dressing, US Patent No. 6077526, 2000. [17] L.A. Errede, J.D. Stoesz, G.D. Winter, Composite Wound Dressing, US Patent No. 4373519, 1981. [18] W.L. Andrews, R.C. Hammett, Medical Dressing of a Multilayered Material, US Patent No. 5437621, 1993. [19] D. Addison, J.S. Mellor, M.W. Stow, M.C. Biott, Wound Dressings Having Low Adherency, US Patent No. 6566577, 2003. [20] J.A. Dobos, R. D Mabry, Antimicrobial Multi-layer Island Dressing, US Patent No. 6168800, 1998. [21] R. Ewall, Multi-purpose Wound Dressing, US Patent No. 5607388, 1994. [22] B. Griffiths, E. Jacques, S. Bishop, Multilayered Wound Dressing, US Patent No. 6348423, 1999. [23] O.M. Alvarez, Multi-Layer Wound Dressing Having Oxygen Permeable and Oxygen Impermeable Layers, US Patent No. 4875473, 1986. [24] E. Karamuk, M. Billia, B. Bischoff, R. Ferrario, B. Wagner, R. Mose, M. Wanner, J. Mayer, Eur. Cell. Mater. 1 (1) (2001) 3–4. [25] E. Wintermantel, J. Mayer, Medicinal Product with a Textile Component, US Patent No. 6737149, 2004. [26] A.J. Hassiba, M.E. Zowalaty, G.K. Nasrallah, Review of recent research on biomedical applications of electrospun polymer nanofibers for improved wound healing, Nanomedicine 11 (6) (2016) 715–737. [27] K.A. Gholipour, B.S. Hajir, Review on electrospun nanofibres scaffold and biomedical applications, Trends Biomater. Artif. Organs 24 (2) (2010) 93–115. [28] J. Sirc, S. Kubinova, R. Hobzova, Controlled gentamicin release from multi-layered electrospun nanofibrous structures of various thicknesses, Int. J. Nanomed. 7 (2012) 5315–5325. [29] D.W.C. Chen, J.Y. Liao, S.J. Liu, E.C. Chan, Novel biodegradable sandwich-structured nanofibrous drug-eluting membranes for repair of infected wounds: an in vitro and in vivo study, Int. J. Nanomed. 7 (2012) 763–771. [30] L. Tan, J. Hu, H. Zhao, Design of bilayered nanofibrous mats for wound dressing using an electrospinning technique, Mater. Lett. 156 (2015) 46–49. [31] A.J. Hassiba, M.E. El Zowalaty, T.J. Webster, A.M. Abdullah, G.K. Nasrallah, K.A. Khalil, A.S. Luyt, A.A. Elzatahry, Synthesis, characterization, and antimicrobial properties of novel double layer nanocomposite electrospun fibers for wound dressing applications, Int. J. Nanomed. 12 (2017) 2205–2213. [32] P. Vikatmaa, V. Juutilainen, P. Kuukhasjarvi, A.Malmivaara, negative pressure wound therapy: a systematic review on effectiveness and safety, Eur. J. Vasc. Endovasc. Surg. 37 (6) (2009) 740–741. [33] S.-W. Chao, Negative Pressure Wound Dressing, US Patent No. 20160199546, 2016. [34] G.C. Adie, S.J. Collinson, C.J. Fryer, E.Y. Hartwell, D. Nicolini, Y.L. Peron, Wound Dressing and Method of Use, US Patent No. US 9061095 B2, 2015.

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Authors of the chapter: M. Kun, C. Chan, S. Ramakrishna National University of Singapore, Singapore Editors of the chapter: Abhilash Kulkarni, Ketankumar Vadodaria Centre of Excellence for Medical Textiles, The South India Textile Research Association, Coimbatore, India 

12.1  Introduction: principles of tissue engineering Tissue engineering is the application of engineering and life science principles in the development of biological substitutes for restoration, maintenance or improvement of tissue function or a whole organ [1]. There are three essential components as shown in Fig. 12.1. Firstly, a porous matrix or scaffold, preferably biocompatible, i.e., absorbable, is required to serve as an extracellular matrix (ECM) support structure for self-organisation of cells. Secondly, various cell types including autologous, allogeneic, xenogeneic cells or cell lines can be cultured on scaffolds for proliferation, differentiation or other biomedical purposes. Lastly, key biomolecules such as growth factors, differentiation factors or other cytokines can also be incorporated into the scaffolds for the desired molecular cues or cellular signals imparted to the seeded cells. Besides the above-mentioned triad, various tissue engineering parameters, such as two-dimensional (2D) cell expansion, three-dimensional (3D) tissue formation, in vitro cell culture conditions, e.g., static, stirred or dynamic flow conditions with or without bioreactors, can be manipulated to enhance the performance of the biological functions of the engineered tissue in an artificial matrix. With no base layer available, the tissue engineered scaffolds act as a template for the keratinocytes to migrate by providing required elasticity and strength. Various factors such as mechanical properties, pore size, microstructure, biocompatibility, biodegradability and surface morphology need to be considered for the design of the scaffold. With respect to this, many important clinical milestones have been reached in the past decade with many tissue-engineered scaffolds produced for its application in various areas such as bone [2,3] bladder (Atala et al., 2006), skin (Yannas et al., 1989) [4] and airway [5]. Textiles in different forms are used as tissue scaffolds for various applications because of its versatility, unique structural behaviour to adapt different surfaces offering porosity and majorly mechanical anisotropy in a wide range to resemble biological issues. Textile structures offer low bending rigidity and are usually anisotropic with high in-plane stiffness, as well as their superior control over the design, manufacturing precision and reproducibility [6]. Textiles offer architecture to tailor the properties needed by varying or controlling the fibre properties such as its size, orientation, geometry, surface Advanced Textiles for Wound Care. https://doi.org/10.1016/B978-0-08-102192-7.00012-6 Copyright © 2019 Elsevier Ltd. All rights reserved.

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Cells

A scaffold Regulators: growth factors, cytokines, etc.

Cell–matrix interaction: attachment, migration, proliferation, differentiation

Triad

Figure 12.1  Elements of tissue engineering (a triad): cells, a scaffold/matrix and regulators.

topography, pore size and pore interconnectivity. These properties in return dictate the behaviour of the cells, its distribution and the physical properties of the scaffolds. Fibres are the building blocks of the textile substrates that determine the characteristics of the final construct. Based on the origin, the fibres are classified as natural and synthetic fibres. This chapter is divided into six sections. The first section provides a brief overview of principles of tissue engineering. The second section is concerned with the major functions, specific requirements and current materials used for fibrous scaffolds, as well as the relationship between textile architecture and cell behaviours. The third section presents various types of textiles classified by fabrication methods and intended applications. The fourth section covers an ever-expanding range of applications of tissue engineering for replacement and repair of various organs or tissues. This section also introduces several novel smart scaffold devices. The fifth section offers insight into new trends and future directions for tissue engineering developments. The last section is a survey of some important sources of information and references.

12.2  Properties required for fibrous scaffolds Of the three key components in tissue engineering, scaffolds is the one that can be manipulated to the greatest extent. A 3D scaffold similar to natural ECM topography is considered to be a critical component for a successful tissue engineering strategy. The desirable scaffold is a regeneration substrate with special properties such as architectures and functions that are similar to natural ECM; a pore size within a critically defined range; and a degradation rate that matches the rate of tissue regeneration at the host bed.

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12.2.1  Functions of fibrous scaffolds Living cells in tissue engineering are generally seeded into an artificial architecture capable of retaining cells and guiding their growth and tissue regeneration in three dimensions. This artificial ECM plays an important role in mimicking the in vivo milieu to allow cells to interact in their own microenvironments. The fibrous scaffolds fabricated may have a branched configuration extending outwardly from a central stem [7] and serve at least one of the several purposes. Firstly, fibrous scaffolds with hierarchical structures can provide a superior surface area for cell attachment, migration, proliferation and differentiation. Secondly, they can also serve as a carrier for biochemical factors to deliver the biochemical factors to the target organs for therapeutic purposes. In addition, these highly porous fibrous scaffolds allow free entrance of vital cell nutrients such as oxygen and cell growth factors, as well as easy diffusion of secreted biomolecules during cell growth. Recently, scaffolds fabricated from nanofibres, referred to here as fibres with diameters below 1000 nm, are gaining increasing attention. It is being recognised that nanofibres when used as scaffold materials in tissue engineering exhibit superior functions when compared with macrofibres. Some of the attributed advantages are as follows [8,9]: The high surface area-to-volume ratio of nanofibrous scaffolds has enhanced absorption of adhesion molecules such as vitronectin and fibronectin which are important for cell adhesion to the scaffold. Nanofibres being smaller by two orders than a cell create a 3D environment that resembles ECM favourable for cell interaction. Nanofibrous scaffolds provide a favourable environment for proliferation and maintenance of certain cell phenotypes. Stem cells maintained in nanofibrous scaffolds can be induced to differentiate into different cell lines, thus offering the possibility of engineering complex tissue consisting of different cell lines starting from a single stem cell line. It appears that nanofibrous scaffolds can provide physical and spatial cues that are essential to mimic natural tissue growth.

12.2.2  Specific requirements for fibrous scaffolds To achieve successful tissue restoration and organ functions, a fibrous scaffold must meet certain fundamental criteria. First, the pore size must be adequate and the porosity sufficiently high to facilitate cell seeding and allow for an efficient exchange of cell nutrient and metabolic waste between the adherent cells and the host bed. Cells residing in a fibrous scaffold are capable of amoeboid movement pushing the surrounding fibres aside and thus expanding pores within the scaffold. In this way, fibrous scaffold offers cells the opportunity to optimally adjust the pore diameter and migrate into areas where some of the initial pores are relatively small [9]. The relationship between pore diameter and tissue ingrowth will be discussed in Section 12.4. In addition, mechanical properties of a fibrous scaffold are another contributor to its success in tissue engineering because a scaffold not only provides a substrate for cell residence but also assists to maintain the mechanical stability at the defect site of the host [9]. An effective tissue-engineered scaffold has to meet at least two

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mechanical requirements. First, it must be sufficiently stable for a physician to handle and implant the scaffold into the target site of the host. Second, after transplantation, the architectures of the scaffold in the process of biodegradation need to provide sufficient biomechanical supports during tissue regeneration [9]. The mechanical properties of an engineered scaffold are determined not only by intrinsic factors such as chemical compositions of the material but also by extrinsic factors, such as construction geometry or architectural arrangement of the building blocks [9]. For certain applications such as vascular grafts involving pulsatile stress, there will be special requirements in terms of compliance and elasticity of the materials [10]. If the graft’s compliance and distensibility are not met, blood flow disturbance would occur and endothelial injuries would be caused by the increase in mechanical stress near the anastomotic sites [11]. However, incorporation of elastic fibres or polymers in scaffolds for vascular grafts will enhance the compliance of the scaffolds to haemodynamic pressure [10]. Scaffolds interact with the cellular components and act as a platform for the cells to attach, grow and finally repair the system. All the scaffolds developed for tissue engineering must exhibit biocompatibility, i.e., cells must adhere to the scaffolds and function as normal, laying down a new matrix without causing any inflammatory response due to immune reaction, which impedes the healing process and ultimately rejected by the body. Last but not least, biodegradability is an important consideration for selecting a scaffold material. Ideally, a biodegradable scaffold is absorbed by the surrounding tissues and metabolised in the body after fulfilling its intended purposes. For example, poly-(d,l-lactide-co-glycolide) (PLGA) is a widely used biomaterial that can hydrolyse into monomers of lactide and glycolide, which subsequently break down into water and carbon dioxide through the Krebs cycle [12]. The degradation rate should match the rate of tissue formation. This means the residing cells should proliferate, differentiate and build up ECM sufficient for tissue reconstruction, while the scaffold materials gradually degrade over time. An ideal skin substitute is expected to have certain characteristics: Easy to manipulate for transplantation and readily adherent to wound sites. Impervious to bacteria, but porous for nutrients and oxygen diffusion. Sterile, nontoxic and nonantigenic. Have physical and mechanical properties appropriate to wound coverage. Have a controlled degradation rate. Ability to regain lost skin functions, including sensitivity, elasticity, normal physiological function and pigmentation. Assimilated into the host with minimal scarring and pain. Readily vascularised.

The ultimate goal of the skin tissue engineering is to satisfy most if not all of the criteria, and meeting these criteria can be better achieved with novel, smart skin substitutes [13].

12.2.3  Materials used for scaffolds Currently, there are a variety of biomaterials suitable for the fabrication of scaffolds. Biomaterials can be defined as any biocompatible substances other than those used

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for food or drugs [14]. Owing to their functional properties and design flexibility, polymers are the primary class of materials for fabrication of scaffolds [15]. The polymers used in scaffold fabrication can be classified into two groups: naturally derived polymers and synthetic polymers. The naturally derived polymers are biodegradable, such as collagen, dextran, elastin, fibrin, hyaluronic acid (HA), fibronectin, polypeptides, hydroxyapatites, chitosan and glycosaminoglycans (GAGs) [13,16–18]. Such materials have the advantage that they facilitate biological recognition and provide a better environment for tissue regeneration. However, rapid absorption and weak mechanical strength often compromise efficient applications of natural biomaterials. They may also elicit inflammatory and allergic responses. Amongst the naturally derived polymers, collagen elicits the least immunological response. Synthetic polymers can be classified further as either biodegradable or nonbiodegradable. Biodegradable polymers are of great interest in the development of tissue engineering. Synthetic polymers such as poly-l-lactide (PLA), polyglycolide (PGA), polycaprolactone (PCL) and polyglactin are biodegradable. The degradation rate of these synthetic polymers varies greatly, with PGA degrading in weeks, whereas PCL may take up to several years. As the seeded cells begin to break down the scaffold, the surface of the polymer is continuously replaced by ECM secreted by the cells. This is a dynamic process of cell–substrate interactions [1]. Recently, copolymers such as PLGA and poly-(l-lactic acid-co-ε-caprolactone) (PLLA-CL) are increasingly used for fabricating tissue-engineered scaffolds or as implants because the degradation rates can be readily controlled by adjusting the ratio of their components. Another advantage of synthetic polymers lies in their potential to be produced in large quantities with controlled properties in terms of strength, degradation rate and microstructure. However, compared with natural polymers, synthetic polymers lack biological recognition signals for cellular interaction. Current strategies to address this problem include immobilisation of naturally derived polymers on the surface of synthetic polymer matrix or simply physically blending a natural polymer with a synthetic polymer before fabrication. This is to improve biocompatibility of the hybrid scaffold while preserving their mechanical strength [16,19,20].

12.3  Relationship between textile architecture and cell behaviour Cellular responses to fibrous scaffolds as discussed previously are influenced by various characteristics of the scaffold, including surface chemistry and texture. The following properties are of particular importance.

12.3.1  Scaffold topography Microarchitecture of a porous scaffold is known to affect cell behaviours. For example, from 5–500 nm to 7–10 μm, topographic alterations on 2D substratum can result in different cell responses [21,23]. In addition, it is well documented that cell responses to

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200.00 µm

Figure 12.2  Laser scanning confocal microscopy image of immunostained α-actin filaments in SMCs after 1 day of culture on aligned PLLA-CL nanofibrous scaffold [27].

2D and 3D environment are quite different. Compared with 2D substrates, cells loaded within a 3D matrix display enhanced biological activities and a lower requirement of integrin usage for cell adhesion [24]. Other reports also observed that epithelial cells and fibroblasts are more likely to proliferate in 3D than 2D culture conditions [25,26]. This is attributed to the 3D environment being similar to natural ECM in terms of structural dimension. Fibre orientation within a fibrous scaffold is also found to affect cellular behaviour. In our studies, smooth muscle cells (SMCs) tended to orientate and elongate themselves along the alignment of the fibres and to express a spindle-like contractile phenotype, as shown in Fig. 12.2 [27].

12.3.2  Fibre diameter Cells are able to organise around the fibres with diameters smaller than themselves [28]. Sanders and coworkers showed that, for 5 weeks, after polypropylene fibres were implanted in the subcutaneous tissue in the dorsum of rats, small fibres with diameters less than 6.0 μm had significantly less macrophage density than those fibres between 6.0 and 27.0 μm in diameter, which had substantial fibrous encapsulation, a sign of a foreign body reaction [26]. This may be because of the reduced cell–material contact surface area or because of a curvature threshold effect that triggers certain cell signalling [26]. Induction of a fibrous layer between a scaffold implant and host soft tissue can create unstable mechanical coupling at the material–tissue interface. This can trigger local stress responses and fibrous capsule formation. It has been shown that the threshold value of microfibres to form fibrous capsules is 5.9 μm in diameter [29]. One explanation why fibres with diameters above this threshold value can elicit capsule formation is that the larger fibres may separate from collagen fibres in ECM, thus

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creating dead space regions adjacent to themselves, and recruit inflammatory cells to stimulate fibrous capsule formation [25].

12.3.3  Scaffold porosity Porosity is a measure of void spaces in a material. The volume of void spaces and the distribution of pore size are two important parameters that characterise the scaffold porosity. Of particular importance in tissue engineering is the interconnectivity of the pores. Most studies have focused on the effect of the pore size. A scaffold with a high porosity tends to have a large surface area for cellular attachment and formation of multiple focal adhesion points on the interconnected fibres [28]. The relationship between pore diameter and tissue ingrowth has been extensively investigated. For percutaneous implants, it was reported that epithelial migration was significantly improved when pore size is 0.025–3 μm [29]. For corneal implants, stratification was more often observed for materials with a pore size of 0.1–0.8 μm than for 0.8–3.0 μm [31–33]. In addition, a pore size of 40–50 μm was shown to facilitate migration of endothelial cells cultured on vascular grafts [34,35]. Another study indicated that the optimal pore dimensions for encouraging neovascularisation is 0.8–8.0 μm [36], whereas for effective osteoblast ingrowth for bone graft, the optimal pore diameter is 75–150 μm [37]. The porosity of fibrous scaffolds can also affect the degradation rates. Highly porous fibres degrade more slowly because acidic by-products secreted by cells would be removed from the implanted sites at a faster rate [10]. Porosity, fibre diameter and mechanical strength are interrelated parameters for nanofibrous scaffolds. It has been shown that a decrease in the porosity of a nanofibrous scaffold is associated with a decrease in fibre diameter and an increase in mechanical strength and density [10].

12.3.4  Surface property Surface properties of a fibrous scaffold, such as surface hydrophobicity, charge and roughness, are largely dominated by free functional groups of the materials used in fabricating the scaffolds. Chemical composition and biological functions of these materials play an important role in determining cell–scaffold interactions. Hydrophobic surfaces are usually considered initiators of the foreign body reaction and reduced biocompatibility [29]. Therefore, a preferred current approach for scaffolds that are constructed from hydrophobic synthetic materials is to either incorporate hydrophilic natural materials or modify the surface of the material to make it less hydrophobic. For instance, it was reported that grafting concentrated hydrochloric acid on a PGA fibrous scaffold enhanced the surface hydrophilicity of the scaffold, indicated by increased attachment and proliferation rates of rat cardiac fibroblasts cultured on it [38]. Similarly, incorporation of chitosan in fibrous scaffolds was used in skin tissue engineering because chitosan can improve the biocompatibility of the scaffold and have wound healing effects and antimicrobial properties as well [10]. Some in vitro studies have shown the effects of surface charge of scaffolds on cell adhesion and expansion. The proliferation rate of fibroblasts is greater on positively charged copolymers such as hydroxyethyl methacrylate and amine-containing

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N,N-dimethylaminoethyl methacrylate hydrochloride; hydroxyethyl methacrylate and trimethylaminoethyl methacrylate chloride than on negatively charged copolymers (such as methacrylic acid and hydroxyethyl methacrylate) or on a neutral homopolymer such as hydroxyethyl methacrylate [39]. Another group demonstrated that the preferred scaffold surface charge for endothelial cells is in the following order: a positively charged hydroxyethyl methacrylate copolymer (with trimethylaminoethyl methacrylate HCl) > tissue culture polystyrene (TCP) (slightly negative charge) > a negatively charged hydroxyethyl methacrylate copolymer (with methacrylic acid) [40]. However, this is not always the case. The interaction between seeded cells and a scaffold surface can vary with different surface materials. For example, the proliferation rate of endothelial cells on either negatively charged or positively charged methylmethacrylate copolymers (with methacrylic acid and trimethylaminoethyl methacrylate HCl salt, respectively) was observed to be higher than that on the TCP surface. In contrast, positively charged hydroxyethyl methacrylate copolymer (with trimethyl-aminoethyl methacrylate HCl) was found to support attachment of endothelial cells, while the same copolymer, when being negatively charged (with methacrylic acid), would not facilitate endothelial cell adherence [40]. Subtle differences in the surface roughness of fibrous scaffolds can affect cellular responses. It has been observed by seeding human coronary artery endothelial cells (HCAECs) on a smooth solvent-cast film and on an electrospun PLA nanofibre mesh that there is an inverse relationship between surface roughness of substrates and adhesion and proliferation rates of HCAECs. Cells on the smooth film exhibited round morphology and can organise into capillary-like microtubes, which is the expected functional phenotype. In contrast, cells on the nanofibre mesh have an undesired spread-out morphology [10]. However, different cell types have different preferences for surface roughness. Another group reported that the attachment and expansion of human umbilical vein endothelial cells (HUVECs) were significantly enhanced when the surface roughness was increased. This roughness was created by grafting polyethylene glycol (PEG, mol. wt. 2000) and a cell surface peptide Glycine-­Arginineglycine-aspartate (GRGD) onto the polyurethan surface [41]. Similarly, vascular SCMs have lower cell adhesion and proliferation on the smooth PLA surfaces [42]. However, each of the above-mentioned properties is only a component factor rather than an exclusive determinant for directing cell–matrix interactions. It should also be kept in mind that the overall effects of fibrous scaffolds on behaviours of their resident cells can be tailored by adjusting these component factors.

12.4  Textiles used for tissue scaffolds and scaffold fabrication A multitude of research work on various types of optimum scaffolds for tissue engineering has been carried out in the last decade. According to processing methods, these scaffolds can be broadly categorised into three groups: (1) foams/sponges, (2) 3D printed substrates/templates and (3) textile structures [43]. Textile structures form an important class of porous scaffold in tissue engineering.

Textile-based scaffolds for tissue engineering

Table 12.1  Various

Tissue engineered biological substitutes Bladder Blood vessel

Bone Cartilage Cornea Dental Heart valve Ligament Liver Nerve Skin Tendon

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scaffolds used in tissue engineering [44]

Examples of scaffold materialsa PGA Polyester(Dacron); PETE; polyurethane; PGA; PTFE; PLA; PLGA (Vicryl), PLLA-CL PGA; PLLA; PLGA + hydroxyapatite; polyethylene PGA; PLLA; PLGA Collagen, fibrin, polyester, copolymer of PDMS and PNIPAAM PLA; PLGA (Vicryl) PGA Collagen; PETE; polyethylene; PGA; PLGA PGA; PLA; PLGA; polyorthoesters; Polyanhydride; PLGA; viscose rayon Collagen-glycosaminoglycan; PGA PGA, PLGA, nylon, collagen-glycosaminoglycan; chitin/chitosan, alginates PGA; PETE; silk

Scaffold structures: yarn (y), weave (w), braid (b), knit (k), nonwoven (n) Textile (n) Textile (n, w, b, k)

Textile (n), foam Textile (n) Foam Textile (n), foam (porous membrane) Textile (n, w) Textile (y, b, n, k), foam Textile (n), foam, 3D printed Textile (n), foam Textile (n, w, k), foam Textile (n, y)

aPDMS,

poly(dimethyl siloxane); PETE, polyethylene terephthalate; PGA, poly(glycolide); PLA, poly(l-lactide); PLGA, poly(dl-lactide-co-glycolide); PLLA-CL, poly(l-lactic acid-co-ε-caprolactone); PNIPAAM, poly(N-isopropylacrylamide); PTFE, polytetrafluoroethylene.

12.4.1  Textile structures for medical application Textile structures including nonwoven, weave, braid and knit have been applied in the medical field for many years, from the initial uses, in sutures, wound gauze, plasters, vessel prosthesis and hernia nets, etc., to current applications, in vascular implants, artificial liver, tendons, skin and other vital organs or tissues. Table 12.1 shows a wide range of applications of textile structures in tissue-engineered scaffolds.

12.4.1.1  Microstructural aspects of textile structures Textile structures can be customised to give the required porosity in terms of size, amount and distribution pattern. In textiles, a pore is considered as the space surrounded by fibres, generally characterised by an irregular shape. The distribution of the pores can be manipulated by fibre size, fibre diameter, its cross-sectional shape, crimp in microscale, yarn size in macroscale and type of textile structure formation (i.e., knitting, weaving, nonwoven). Table 12.2 lists the microstructural aspects of different textiles and their wide uses in health care–related fields.

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Table 12.2 

Microstructural aspects and medical applications of textile scaffolds [44] Nonwoven

Woven

Braided

Knitted

Pore size (μm) Porosity (%) Pore distribution Reproducibility of porosity Pore connectivity Processability Medical applications

10–1000 40–95 Random Poor

0.5–1000 30–90 Uniform Excellent

0.5–1000 30–90 Uniform Excellent

Good

Excellent

Excellent

50–1000 40–95 Uniform Good to excellent Excellent

Good Surgical gowns, incontinence pads, nappies, sanitary wear, artificial ligament, tissue engineering scaffold

Excellent Artificial ligaments, sutures, vascular implants

Good Vascular implants, artificial tendons and ligaments, stents, compression bandages

Others

High equipment cost, questionable control over porosity

Excellent Surgical gowns, vascular implants, dressing, plasters, tissue engineering scaffolds, hospital bedding and uniforms Limited shape

Only tubular or uniform crosssectional shapes

Limitations of low-bending properties of current biodegradable fibres

The porosity of scaffolds is governed by the construction of textile fabrics. A typical textile scaffold shows three levels of porosity that can be selectively controlled. The first level is the interfibre gap that can be controlled by changing the number of fibres in the yarn and the yarn-packing density. The gap between yarns forms the second level of porosity. For knitted scaffolds, variations in stitch density and stitch pattern can affect this level of porosity, whereas in the case of woven scaffolds, the porosity can be changed by controlling the interyarn gaps through a beating action. The third level of porosity is created by subjecting the textile structures to secondary operations, including crimping, folding, rolling and stacking.

12.4.1.2  Mechanical properties of textile structures For certain applications, the scaffold is more than a simple vehicle for cell delivery. It must maintain its structural integrity and a certain amount of load carrying capacity for the desired amount of time, for example, in bone, cartilage and ligament reconstruction [45]. Table 12.3 compares the mechanical properties of various textile structures.

Textile-based scaffolds for tissue engineering

Table 12.3 

Strength Stiffness Structural stability Others

339

Mechanical properties of textile scaffolds [44] Nonwoven

Woven

Braided

Knitted

Low Low Poor to good

High High Excellent

High High Excellent

Low Medium Poor to good

Isotropic behaviour

Anisotropic behaviour

Anisotropic, with good properties in axial direction and poor properties in transverse direction

The behaviour can be tailored from anisotropic to isotropic

In general, nonwoven fabrics are webs of nonaligned filaments allowing for the largest variation in pore characteristics, whereas woven fabrics possess a dimensionally stable structure, characterised by pores of regular size and shape. Warp-knitted fabrics, in which threads are laid along the direction of fabric production, have been proven to be suitable for the demand of high-elastic deformation, for example, in vascular grafts applications; the grafts are required to resist continuous dynamic stress. Braided fabrics are formed by interlacing three or more threads so that threads cross one another in a diagonal formation. They can be made either flat or tubular to meet for different purposes [46,47]. Compared with woven or knitted fabrics, the braided textile composites can better resist twisting, shearing and impact. However, they show their poor stability under an axial compression [47,48].

12.4.2  Technologies for fabrication of textile scaffolds 12.4.2.1   Knitting Interlacement of loops of yarn produces knitted structures. They are generally categorised into weft and warp knitting. Products such as hernia mesh, heart valves and products for incontinence treatment make use of knitted structures. For most of the medical applications, warp-knitted structures are commonly used when compared with weft-knitted structures. This is because of the fact that warp-knitted structures offer excellent structural stability, cannot unravel easily, have high suture retention strength and 3D geometries can be easily developed using knitting technologies with tuneable mechanical properties. Different knitting structures are widely employed to design and construct tissue-engineered scaffolds. Tissue engineering with different knitting structures and its application is reviewed by Wang et al. [49]. Lieshout et al. have developed a biocompatible PCL and fibrin-based knitted aortic heart valve that lasted even after 10 million loading cycles without any rupture. In a similar experiment conducted by Lieshout et al., two types of scaffolds were developed using two different techniques, i.e., knitting and electrospinning. The cells penetrated well in the knitted structure in contrast with electropsun scaffold and

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the electrospun scaffold tore in 6 h during the physiological flow test. Apart from aortic value, knitted structures are used in ligament/tendon [50] and blood vessel tissue engineering [51], suitable knitted meshes can be developed to prepare different biomimetic meshes.

Embroidery technology Recently, embroidery technology in which thread direction can be arranged at almost any angle has elicited great interests in the design and fabrication of tissue-engineered scaffolds. The process involves a needlework pattern of sewing reinforcing fibres onto a ground material. The arrangement of these reinforcing fibres is computer controlled and, thus, almost any desired textile forms can be produced. Various materials including woven and nonwoven fabrics or foils mentioned above can be used as the ground material. By stacking the embroidery, a multilayered construct can be built to form 3D textile scaffolds [43]. Custom-made embroidery technology has been widely employed to design and construct tissue-engineered scaffolds. For example, Ellis and coworkers have successfully developed hernia patches, stents for the repair of abdominal aortic aneurysms and implants for intervertebral disc [43]. Another group has developed a 3D embroidered substrate for the improved regeneration of skin tissue in chronic wounds. Besides, Mai et al. [46], observed that osteoblast-seeded poly-3-hydroxybutyrate embroidery can successfully induce ectopic bone formation. Embroidery technology is particularly attractive for making tissue-engineered scaffolds. The degree of construction of the embroidery can be controlled and, therefore, a broad spectrum of scaffolds with a wide range of properties is possible.

Braiding Braiding is one of the old textile technologies used to manufacture braided yarns or fabrics that are made by intertwining three or more strands of yarns or fabric strips in a diagonal formation. Recently, braiding is also used in the new family of medical textiles; some of the products that take advantage of this technology are sutures, stents, artificial ligaments or tendons, dental floss, etc. Braided technology is an excellent candidate when the demand is for high tensile strength and mechanical flexibility. Braiding provides the highest axial strength among all other fibre-based techniques which makes it the preferred method for engineering connective tissues. Scaffolds produced by braided technology have found application in vascular grafts [53] and nerve regeneration [54]. Besides, they have grabbed a lot of attention in the area of cartilage such as artificial tendons and ligaments. More work is done in this area to develop scaffolds that are produced by using braiding. Braiding structures present more load-bearing capacities unlike nonwovens, providing high radial expansion and strength, with flexibility and controlled porosity. Hence, they can be used in the areas where the demand for mechanical properties is very high. Generally, the porosity of the braided structures is lower than the knitted structures. Different polymer systems, braiding angles and fibre diameters have an effect on the cell behaviour. Tenogeneic cell differentiation is greatly influenced by the braiding angle used in the scaffold. Several parameters such as type of fibre, interactions between these fibres

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including the yarn diameter, choice of material and braiding process parameters need to be adjusted to obtain the optimum pore size for TE applications [55,56] (Laurencin CT 2009 patent). Goretex has developed a scaffold that is composed of thousands of fibres braided together to provide enough strength that acts as a replacement for ligaments. Recently, many researchers have started to build braided structures using strands of electrospun nanofibres as a substitute for ligaments. Among the various polymer systems used for ligaments and tendons, poly-l-lactic acid (PLLA)–braided scaffold was inferior in load bearing when compared with PCL-braided scaffolds. Cells on the braided scaffolds were distributed heterogeneously and were localised on the surface only unlike stacked scaffolds, which displayed a homogenous distribution.

Embroidery The South India Textile Research Association (SITRA) has developed wound dressings using embroidery technology for the mechanical stimulation of angiogenesis. Spunlace nonwoven acted as the base layer with incorporation of the embroidery design onto them using polyester (PET) monofilament with different pore sizes to stimulate the growth of cells, capillaries and blood vessels.

Three-dimensional printing 3D printing is another method for producing the tissue scaffolds with better control of pore size, complex shapes, size and porosity when compared with other fabrication technologies. 3D printing works on the principle of laying down of successive layers of the polymer to form the 3D scaffold. There are different methods in 3D printing available such as fused deposition modelling, inkjet printing, and selective laser sintering, colorjet printing and steriolithography. 3D printing technology has been tried to produce different scaffolds for trachea [57,58], bone [59,60], oesophagus [61] and aortic valve [62]. Advances in 3D printing have led to bioprinting recently. Bioprinting is a 3D printing technology using living cells with the preservation of the viability of the cells within the scaffold. One of the fully functional human tissue that was bioprinted is Organovo’s exVive3D Liver that has been used to provide toxicity assessment that is supplementing in vitro and preclinical animal testing.

12.4.2.2  Technologies for fabrication of textile nanofibres The processing of fibres with diameters less than 1000 nm plays an increasingly important role in the construction of tissue-engineered scaffolds. Several fabrication techniques such as electrospinning, phase separation, meltblown, template synthesis and self-assembly have been used to produce suitable polymer nanofibres for various purposes [51,63]. Among the techniques mentioned above, electrospinning is the most commonly used method to fabricate nanofibres because it is relatively easy to set up in the laboratory and the resultant scaffolds have a large surface area-to-volume ratio and

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interconnected pores. Synthetic and natural polymers, as well as ceramics, have been electrospun into nanofibres. The fabrication process involves an electrostatic field of the order of 5–30 kV between a collector and the spinneret (usually in the form of a needle). The polymer melt or solution is pumped out of the spinneret at a controlled rate. When the sufficiently high electric field overcomes the polymer solution surface tension, a thin jet of liquid flies towards the collector plate. The thin jet of liquid solidifies owing to evaporation of the solvent or cooling of the molten polymer, and nanofibres are collected on the collector. The fibre morphology is controlled by adjusting the electrospinning conditions, such as applied voltage, feed rate, types of collector, diameters of needle (spinneret) and distance between the needle tip and the collector. It is observed that the shorter the distance between needle tip and collector, the more beads are formed along the fibres. It has been reported that increased voltage correlates with increased beads density, and at an even higher voltage, the beads will join to form a thicker diameter fibre [64–66]. For a given voltage and a given needle–collector distance, reducing the internal diameter of the needle orifice or reducing the feed rate often leads to a decrease in the fibre diameter or size of beads. In addition, the type of collectors will influence the morphology of the collected nanofibres. For instance, collectors made from conductive materials such as aluminium foil are observed to have a higher fibre-packing density than nonconductive ones. Thus, nanofibres collected on a nonconductive plate are more likely to form a 3D structure, such as honeycomb architecture, owing to the repulsive forces of the accumulated charges on the nonconductive collector [67]. Additionally, experiments on collectors with smooth surfaces such as metal foils showed a high fibre-packing density compared with collectors with porous surfaces such as metal mesh. Moreover, the texture of the fibres formed can also be varied by using a patterned collector like a braided Teflon sheet, on which the yield fibres take a topography that follows the surface pattern of the Teflon sheet [68]. Additionally, whether or not the collector is static, moving may have an effect on the morphology of fibres. A rotating cylinder collector can be used to obtain unidirectional nanofibres with alignment along the rotating direction. Other ambient parameters that would influence the evaporation rate of the solvent, including concentration of the polymer solution, temperature and humidity, also influence fibre morphology. By varying those parameters synergistically, several special morphologies can be achieved, for instance, porous nanofibres [69], flattened [70], ribbon-like fibres [71], helical fibres [72] and hollow fibres [72,73]. Nanofibres have an extensive application in tissue engineering.

Nonwoven ISO standard 9092 and CEN EN 29092 defines nonwovens as ‘a web formed by a sheet of fibres or continuous filaments that includes chopped yarns of any origin bonded together by chemical, thermal or mechanical means, with the exception of weaving or knitting’. Two set of processes are involved in the manufacturing of the nonwovens, i.e., web formation and bonding. Generally, nonwoven fabrics are highly porous in nature and offer a wide pore size distribution in a given area. The prevalent advantage that the nonwovens possess is the control of the pore size distribution and

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the fibre diameter during its manufacturing and the interconnected pores available in the structure [74]. Various properties of the fabric such as mechanical, tensile and fluid transportation can be manipulated during the fibre orientation process. There are many ways that the nonwoven structures can be used as scaffolds, despite the only constraint of controlling the pore size precisely to obtain well-defined pore structures internally. Besides their limitation, they can act as a supporting structure that host cells from different tissues [75,76]. Apart from stand-alone supporting structures, the nonwoven-based scaffolds can also be used with a combination of bioactive molecules that perform as a carrier medium, different material or various cells to achieve the native physiology of the tissues or organs such as chondroinduction, angiogenesis, osteogenesis and osteoinduction [77]. Various nonwoven manufacturing techniques such as meltblown, spun bond, needle punching and carding have been tried to create scaffolds of different polymer systems as per industry standards with a focus on establishing the commercial feasibility to manufacture the tissue scaffolds. Until now, researchers have worked on various polymers to produce nonwovens and have used them as scaffolds for tissue engineering with various pore sizes. Based on the cell size, migration requirements and transportation properties, scaffolds need a minimum pore size depending on the area of application. For example, scaffolds for bone engineering need a minimum pore size of 100 nm [78]. Takahashi et al. [79] proved that the fibre diameter of PET fibres and the porosity greatly affected the proliferation and differentiation of mesenchymal stem cells (MSC). They could observe that an optimum fibre size was needed for the cells to attach onto them as shown in Fig. 12.3. The fibre size was 2 μm, where the attachment of the cells with fibres was observed, anything below that size the cells could not attach. Fibres with higher diameter had more pore space allowing the

Cell number (cells/mm2)

800

600

400

200

0

2.0

4.4

9.0

12.0

22.0

42.0

Fibre diameter (µm)

Figure 12.3  Relationship between fibre diameter and cell attachment.

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cells to seed, higher attached number and proliferation rate. Bone differentiation of cells is greatly affected by the fibre size and the spatial property of the nonwoven fabric. Smaller diameter fibres generally promote proliferation, whereas larger diameter fibres encourage tenocytic phenotype. Apart from MSC, human adipose-derived stem cells (hASC) also demonstrated that attachment onto scaffolds was dependant on the fibre size. When comparing the scaffolds of meltblown, carded, electrospun and spunbonded nonwovens of different fibre size, it was evident that cellular attachment of carded nonwovens exhibited lower cell attachment as the fibre diameter was above 20 μm [80]. These scaffolds produced from different techniques displayed that the hASC were viable, attached, proliferated and enhanced adipogenesis and osteogenesis. Proving that the ability of cells to attach on scaffolds and proliferate totally rely on the fibre size, pore size, pore interconnectivity and thickness of the scaffold, suggesting that these methods are suitable for cell growth and differentiation and also provide high production rate in terms of commercial viability. Another factor that also influences the attachment and proliferation of cells is the fibre shape, i.e., cross section. Nonwoven scaffolds produced with round and trilobal cross sections demonstrated good cell attachment and proliferation when compared with snowflake-shaped fibre that has high surface area than round and trilobal. This is because surface patterning reduces the area for focal adhesion, thereby reducing cellular attachment. Polyvinylidene fluoride (PVDF) porous nonwoven scaffolds were produced by needle punching using different cross sections of the fibres such as round, trilobal and snowflake as shown in Fig. 12.4(a). The size of the pores in the scaffold corelates with the cell density and its interaction with the fibre. Scaffolds with wide open structure offering large pores enhance cell growth because of mass transport of nutrients and

Figure 12.4  (a) Different cross-sectional features of polyvinylidene fluoride fibres. (b) Texturised fibre with 10, 16 and 28 needles/inch.

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gases to cell, and better migration of cells throughout the scaffold is achieved as cells prefer to grow on the areas of fibre intersections [81], despite less cell seeding. With this regard, the scaffolds produced with 10 needles/inch had the highest proliferation rate than 16 and 28 needles/inch [82]. Refer Fig. 12.4(b) for the fibre crimp using different needles/inch. This indicates that the choice of needle punched process with less needles per inch as a technique can be considered to manufacture the tissue scaffold and the use of PVDF as a suitable biomaterial. Another way of producing these pores inside the nonwoven structures is the use of a template or a porogen to create these pores. In this context, Durham et al. [83] have fabricated well-defined microtubular-channelled PLA nonwoven scaffold by using a template in combination with hydroentanglement. These channels are created to provide uniform pore size within the scaffold that assisted in the penetration of the dermal fibroblast cells and the openings remained open for the better transport of nutrients and molecular diffusion.

12.5  Applications of textile scaffolds in tissue engineering The range of tissue engineering applications has expanded in recent years. Some typical examples, with special emphasis on the use of textile scaffolds, are described here.

12.5.1  Skin grafts Skin grafts are perhaps the most successful tissue-engineered constructs, and several have been approved by the US Food and Drug Administration (FDA) and commercially manufactured. For example, in 1998, Advanced Tissue Science, Inc. introduced Dermagraft→, a cryopreserved dermal substitute, in which human fibroblast cells derived from newborn foreskin tissue were seeded on a biodegradable polyglactin mesh scaffold. The fibroblasts were found to proliferate and fill interstices of the scaffold and secrete dermal collagen, matrix proteins, growth factors and cytokines suitable as dermal substitute. Some commercialised skin graft substitutes employ natural ECM molecules in their fibrous scaffolds, such as collagen (Biobrane, Integra, Alloderm), fibrin (Bioseed), HA (Laserskin), fibronectin (TransCyte) and GAGs (TransCyte). Although there have been considerable improvements in tissue-engineered skin grafts, none of them could reproduce the normal architecture of natural skin, including hair follicles, Langerhans cells, sebaceous glands and sweat glands. Therefore, intensive research is still ongoing to improve existing skin graft substitutes to regenerate the important properties of natural skin.

12.5.2  Vascular grafts An important requirement for tissue-engineered vascular grafts is that the tubular conduits are made of materials capable of incorporating into host tissues with a

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Figure 12.5  Electrospun PLLA-CL nanofibrous vascular conduit (length 3.8 cm, diameter 3 mm) [19,20].

functioning self-renewing endothelial layer. Scaffold materials can be either synthetic or natural polymers. Synthetic materials for fabricating vascular grafts include biodegradable polymers such as PGA, PLA and PLGA or nonbiodegradable polymers such as polyurethanes [84–86] and polyethylene terephthalate (Dacron). Biological materials that have been used in vascular grafts can be generally classified into three groups: acellular xenogeneic grafts [87–89], acellular allogeneic grafts [90–94] and prefabricated grafts made with natural polymers [75,76]. Major disadvantages of natural material-based scaffolds are their rapid absorption rate and poor mechanical strength. To improve both biocompatibility and mechanical strength, many novel grafts use a combination of synthetic and biological materials. For example, a collagen-coated PLLA-CL (70: 30) nanofibre vascular conduit is shown in Fig 12.5. It demonstrated in such a construct that there are enhanced attachment, proliferation and viability of HCAECs and, more importantly, the cellular phenotype is preserved [19,20]. Traditional problems associated with vascular grafts, including clotting and scar tissue formation, are still a problem for current vascular grafts and this has prevented new grafts from entering clinical trials [26]. Recently the US FDA has approved a vascular graft (Gore Propaten), made of expanded polytetrafluoroethylene (ePTFE)-heparin for treatment of peripheral artery disease. The addition of heparin to the luminal surface of the graft via proprietary endpoint covalent bonding was intended to reduce the occurrence of thrombosis in clinical performance between synthetic and vein grafts. Other strategies such as embedding antibiotics and antithrombotic agents in the graft materials have also been attempted to improve the performance of vascular substitutes [96–98].

12.5.3  Tissue-engineered liver Several extracorporeal bioartificial liver (BAL) systems have been developed to support essential hepatic functions. In a typical BAL device, patient’s plasma or blood is

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circulated through a bioreactor with immobilised primary hepatocytes or hepatoma cell lines between artificial plates and capillaries [99,100]. From 1990, nine BAL systems have been tested clinically and most of them performed well in preclinical tests [101]. The BAL devices may be based on hollow fibre technologies such as Extracorporeal liver assist device (ELAD) [102] and [103,104], HepatAssist [105], Liver support systems (LSS) [87,88] and Bioartificial Liver Support System (BLSS) [108]; porous matrix systems such as RFB-BAL [109], AMC-BAL [110–112], encapsulation systems such as UCLA [100] and AHS-BAL [113] or flat membrane systems such as flat membrane bioreactor (FMB)- bioartificial liver (BAL) [114]. For instance, the HepatAssist liver device, developed by Demetriou [105], consists of a microcarrier for attachment of primary porcine hepatocytes, two charcoal filters, a membrane oxygenator and a pump. The hollow fibre open membrane has a pore size of 0.2 μm, small enough to prevent the passage of hepatocytes, but large enough to allow an exchange of proteins and protein-bound toxins between plasma and hepatocytes. The hepatocytes are housed in the extracapillary space [105]. As liver is a vital and complex organ, investigation into a BAL with the broader essential functions of liver is ongoing.

12.5.4  Nerve grafts Neural tissue engineering involves the use of biomaterials as scaffolds with tissue-specific architecture and a controlled pore structure that facilitates growth and organisation of resident cells for nerve repair [115]. Nerve guidance conduits to bridge the gap between the nerve stumps and to direct nerve regeneration have been developed recently [116–119]. For example, Bini et al. [120], fabricated a peripheral nerve conduit made of micro-braided PLGA biodegradable polymer fibres. Fibrin matrix cable formation was observed 1 week after implantation into the right sciatic nerve of the rat and nerve generation was seen in 9 out of 10 rats tested 3 weeks later. Many biodegradable and nonbiodegradable materials have been investigated to construct nerve conduits such as collagen [121–124], polyethylene [125–127], PLGA [128,129], polyphosphoester [130,131], silicone [132,133] and PTFE [133]. Electrospun biodegradable PLA nanofibres have been used to fabricate a nerve conduit. Neural stem cells seeded on these conduits were observed to attach and interact favourably with the aligned nanofibre ECM [77]. For future research, the challenge is to develop more efficient nerve conduits so that nerve generation can occur across extended gaps.

12.5.5  Bone grafts Tissue engineering in bone has also undergone major advances in recent years. Natural materials such as collagen [134–136], fibrin [137–139], chitosan [140,141], HA [142] and the synthetic polymers such as PCL [143,144], poly(propylene fumarates) [145,146], poly(phosphazenes) [147–149] and PLGA (Osteofoam) [150] have been applied to establish 3D bone scaffolds. Cell sources include osteoblasts [151,152], adult stem cells from bone marrow [142] [153–155] or periosteum [156]. Meanwhile, a plethora of growth factors including bone morphogenetic proteins (BMPs), transforming growth factor beta, fibroblast growth factors, insulin growth factor

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I and II, platelet-derived growth factor and chrysalin have been incorporated into scaffolds for ingrowth and differentiation of osteoblasts and bone tissue formation [157–161].

12.5.6  Other organs Besides the applications mentioned above, rapid developments in tissue engineering have extended its scope to encompass many other important human organs, such as cartilage [162–165], ligament [166–168], heart [169–171], pancreas [172–174], larynx [175–177] and cornea [178–180]. However, further research and development are still required before ‘off-the-shelf’ products are available.

12.5.7  Examples of smart textile scaffolds The convergence of information technologies and advances in textile materials has created smart textile fabrics. Smart textiles are intelligent textile structures or fabrics that can sense and react to environmental stimuli, which may be mechanical, thermal, chemical, biological and magnetic amongst others [44]. The initial application was in military and defence systems, and it is currently being introduced in biomedicine and tissue engineering; two examples are described here. The incorporation of miniature electronic devices into textiles promises to have a tremendous impact on tissue engineering and medical textiles. Calvert and his team created an electronic sensor-studded textile using inkjet printers [181]. In the process, ‘wires’ made of the conducting polymer, poly(3,4-ethylenedioxythiophene)–poly(4-styrene sulfonate), were printed between the silver lines on the fabric. This intelligent textile device has been used to sense body motions such as twisting of a wrist and bending of a knee using its piezoresistive properties [182]. Another example is smart textile scaffolds made of shape memory materials. These shape memory scaffolds can be transferred into memorised, permanent shapes from their original temporary configuration on an external stimulus, e.g., an increase in temperature. Therefore, such a smart textile scaffold made of biodegradable materials such as PCL and copolyesters of diglycolide and dilactides may be introduced into the human body through a small incision and the implanted device then returns to its original shape to fulfil the desired functions. Such a device would degrade after successfully completing the desired function [44].

12.6  Future trends The burgeoning research in tissue engineering has impacted significantly on how tissue replacement and restoration will be done in the future. Further developments in material sciences, molecular biology, and scaffold fabrication technologies, as well as further understanding of stem cells and controlled manipulation of cell differentiation, will further broaden and enhance successful applications of tissue engineering. Advances in intelligent materials will give textile scaffolds greater functions and allow novel materials to be fabricated. For example, electroactive polymers and elastomers could

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be used in artificial muscles [44]. Auxetic fibres made from polymers such as PTFE, polypropylene and nylon can be constructed into knitted and woven textiles that are particularly suitable for skin grafts, as these scaffolds will expand in response to wound swelling [183]. Growth factors, drugs or monitoring devices may also be incorporated into textile scaffolds and implanted in the human body to perform certain functions that are not possible today. For example, a novel temperature-sensitive and biodegradable glycidyl methacrylated dextran (Dex-GMA)/gelatine scaffold containing microspheres loaded with BMP has been developed. The phase transition temperature of the resulting scaffold could be tailored for controlled release with a half-life ranging from 18 days to more than 28 days by changing the ratio of Dex-GMA to gelatine. Such smart hybrid scaffolds have both self-regulated drug delivery and tissue scaffold functions [184]. The electrospinning technique is versatile and relatively cost-effective and therefore is likely to continue to be used in the future for fabrication of nanofibres. Applications of nanofibres in the biomedical and biotechnological fields are increasingly important, as these applications exploit some of the unique properties attributable to the nanoscale effects. It is envisaged that more natural polymers will be incorporated into nanofibrous scaffold designs to improve biological compatibility and enhance functional performance. The challenge of scaling up and making better-quality fibres is being met with the introduction of novel and improved electrospinning techniques. Progenitor or stem cells with high capabilities of self-renewal and multilineage differentiation have a remarkable potential to develop into many different cell types in various tissues. For instance, embryonic stem cells could give rise to almost all cells deriving from three germ lines [185]. Adult stem cells, residing in the fully differentiated or adult tissues, e.g., bone marrow, periosteum, muscle, fat, brain and skin, can differentiate into a specific cell lineage from which they derive [185]. Moreover, recent studies found higher plasticity of adult stem cells than what was previously expected. For example, it was indicated that adult stem cells derived from the dermis could differentiate into muscle, brain and fat cells [186], and another group found that adult stem cells isolated from bone marrow would differentiate into keratinocytes in vivo [187]. MSC have been used for regeneration and repair of tendon [188], bone [189] and heart [190]. Loading these multipotent cells onto textile scaffolds and directing them to differentiate into desired lineages broadens the potential applications of textile scaffolds. Gene modulation will make possible the seeding of recombinant proteins or genetically modified cells on textile fabrics for specific therapeutic applications. For example, one recent group loaded the Bcl-2-transduced HUVECs on a skin substitute. Enhanced vascularisation and engraftment were observed after transplanting to immunodeficient (C.B-17SCID/Bg) mice. The improved angiogenesis was attributed to Bcl-2 resulting in secretion of an antiapoptotic protein which increases the capacity of HUVEC to form mature vessels [191]. Therefore, it is hoped that, by loading genetically modified cells on textile scaffolds as skin graft substitutes, improved functions, including those provided by hair follicles, sebaceous glands, sweat glands and dendritic cells, will be achieved in the near future [34]. In addition, the transgenic approach may be employed to produce biomaterials with unique characteristics for fabricating fibrous textile scaffolds. For example, in 1999, Nexia Biotechnologies Inc. succeeded in extracting recombinant spider silk proteins

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(BioSteel→) from the milk of transgenic goats. Although the strength of BioSteel→ is far from satisfactory, its ductility is unique as it can undergo a high degree of elongation before it breaks. Following this, a research group has successfully co-electrospun this spider silk protein with carbon nanotubes. Such a combination enabled tailoring nanofibres with mechanical properties superior to that of natural spider silk. The feasibility of using such ‘super silk’ as tissue engineering scaffolds has been explored [192]. However, there are a number of potential risks that are not fully addressed at this time including the toxic effects of textiles with nanoscale texture and the unknown risks of nanopolymer materials on human health. Other issues of contention are the ethics of using stem cells and genetically modified cells. As there is no single ideal scaffold for all tissue types, rapid advances in fibrous textile scaffold research will allow more flexibility in tailoring scaffolds for different requirements. The unique properties attributable to nanoscale effects are just beginning to be exploited in textile scaffold. We expect that further developments will progress along this line.

12.7  Sources of further information and advice 12.7.1  Books D. Cohn, R.L. Reis, Polymer Based Systems on Tissue Engineering, Replacement and Regeneration, The Netherlands, Kluwer Academic Publishers, 2002. Y. Ikada, Tissue Engineering: Fundamentals and Applications, UK, Elsevier Ltd, 2006. K.U. Lewandrowski, Tissue Engineering and Biodegradable Equivalents: Scientific and Clinical Applications, New York, Marcel Dekker, Inc., 2002. P.X.Ma, J.H. Elisseeff , Scaffolding in Tissue Engineering, Boca Raton, FL, US, CRC Press, 2005. N.A. Peppas, J.Z. Hilt, J.B. Thomas, Nanotechnology in Therapeutics: Current Technology and Applications, UK, Horizon Bioscience, 2007. S. Ramakrishna, An Introduction to Electrospinning and Nanofibers, Singapore, World Scientific Publishing Co. Pte. Ltd., 2005. R.L. Reis, J.S. Román, Biodegradable Systems in Tissue Engineering and Regenerative Medicine, USA, CRC Press, 2005. W.M. Saltzman, Tissue Engineering: Engineering Principles for the Design of Replacement Organs and Tissues, New York, Oxford University Press, Inc., 2004. Selcuk I. Güceri, Vladimir Kuznetsov, Nanoengineered Nanofibrous Materials, Netherlands, Kluwer Academic Publishers, 2004. I.V. Yannas, Tissue and Organ Regeneration in Adults, New York, Springer, 2001.

12.7.2  Trade and professional bodies CellTran Limited, UK, http://www.celltran.co.uk/index.php. Degradable Solutions AG, http://www.degradable.ch/. Exploit Technologies Private Limited, Singapore, http://www.exploit-tech.com/Home.aspx/. Japan Tissue Engineering Co., Ltd., http://www.jpte.co.jp/english/index.html. Nanomatrix, http://www.nanomatrix.biz/.

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The Japanese Society for Tissue Engineering, http://www.jste.net/english.htm. Tissue Engineering Inc. (TEI), www.tissueengineering.com. Tissue Engineering International and Regenerative Medicine Society, http://www.termis. org/. Tissue Engineering Sciences (TES), www.tissueeng.com. Transtissue technologies, www. transtissue.com.

12.7.3  Research groups Centre for Biomaterials and Tissue Engineering, University of Sheffield, UK. http://www. cbte.group.shef.ac.uk/. Center for Biomedical Engineering, Massachusetts Institute of Technol-ogy, USA. http:// web.mit.edu/afs/athena.mit.edu/org/c/cbe/www/. Charité Tissue Engineering Laboratory, Germany. http://ctel.tissue-engineering.net/index. php?seite=Startseite. Healthcare and Energy Materials Laboratories. http://www.bioeng.nus.edu.sg/seeram_ ramakrishna/. Polymeric Biomaterials and Tissue Engineering Laboratory, University of Michigan, USA, http://www.dent.umich.edu/depts/bms/personnel/faculty.php?uname=mapx. Tissue Engineering and Organ Fabrication Laboratory, Boston, USA, http://www.mgh. harvard.edu/tissue/. Tissue Engineering Laboratory, National University of Singapore, http://www.bioeng.nus. edu.sg/research/tissueengineering/.

12.7.4  Websites http://www.ameriburn.org. http://www.collagenesis.com/documents/products.htm. http://www.collagenmatrix.com/. http://www.lifecell.com. http://www.netdoctor.co.uk/diseases/facts/footandlegulcers.htm. http://www.organogenesis.com. http://www.ortecinternational.com. http://www.synthecon.com/products/bioscaffold.htm. http://www.tissue-engineering.net/. http://www.worldwidewounds.com.

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[174] K.K. Papas, R.C. Long, A. Sambanis, I. Constantinidis, Development of a bio- artificial pancreas: I. Long-term propagation and basal and induced secretion from entrapped beta TC3 cell cultures, Biotechnol. Bioeng. 66 (1999) 219–230. [175] K. Blaimauer, E. Watzingera, et al., Effects of epidermal growth factor and keratinocyte growth factor on the growth of oropharyngeal keratinocytes in coculture with autologous fibroblasts in a three-dimensional matrix, Cells Tissues Organs 182 (2006) 98–105. [176] P.J. Kingham, G. Terenghi, et al., Tissue engineering strategies for reinnerva-tion of the larynx, Clin. Otolaryngol. 31 (3) (2006) 245. [177] R.L. Ringel, J.C. Kahane, P.J. Hillsamer, A.S. Lee, S.F. Badylak, The applica- tion of tissue engineering procedures to repair the larynx, J. Speech Lang. Hear. Res. 49 (2006) 194–208. [178] M. Alaminos, M.D. Sanchez-Quevdo, J.I. Munoz-Avila, et al., Construction of a complete rabbit cornea substitute using a fibrin-agarose scaffold, Investig. Ophthalmol. Vis. Sci. 47 (2006) 3311–3317. [179] J.Y. Lai, K.H. Chen, W.M. Hsu, G.H. Hsiue, Y.H. Lee, Bioengineered human corneal endothelium for transplantation, Arch. Ophthalmol. 124 (2006) 1441–1448. [180] P. Zorlutuna, A. Tezcaner, I. Kiyat, A. Aydinli, V. Hasirci, Cornea engineering on polyester carriers, J. Biomed. Mater. Res. Part A 79A (2006) 104–113. [181] A. Sawhney, A. Agrawal, P. Patra, P. Calvert, Piezoresistive sensors on textiles by inkjet printing and electrufess plating, Mater. Res. Soc. Symp. Proc. 920 (2006) 103–111. [182] H. Bethany, Materials science blossoms in Boston, Sci. Technol. 83 (2005) 49–52. [183] K.L. Alderson, Auxetic polypropylene fibers. Part 1. Manufacture and characterisation, Plast Rubber Compos. 31 (2002) 344–349. [184] F.M. Chen, Y.M. Zhao, H.H. Sun, et al., Novel glycidyl methacrylated dextran (DexGMA)/gelatin hydrogel scaffolds containing microspheres loaded with bone morphogenetic proteins: formulation and characteristics, J. Control. Rel. 118 (1) (2006) 65–77. [185] A.J. Salgado, O.P. Coutinho, R.L. Reis, et al., Bone tissue engineering: state of the art and future trends, Macromol. Biosci. 4 (2004) 743–765. [186] J.G. Toma, M. Akhavan, K.J.L. Fernandes, et al., Isolation of multipotent adult stem cells from the dermis of mammalian skin, Nat. Cell. Biol. 3 (2001) 778–784. [187] X. Borue, S. Lee, J. Grove, et al., Bone marrow-derived cells contribute to epithelial engraftment during wound healing, Am. J. Pathol. 165 (2004) 1767–1772. [188] A.K.S. Chong, D. Abel, H.P. James, et al., Bone marrow-derived mesenchymal stem cells influence early tendon-healing in a rabbit achilles tendon model, J. Bone Joint Surg. Am. 89 (2007) 74–81. [189] P.A. Rust, P. Kalsi, et al., Will mesenchymal stem cells differentiate into osteoblasts on allograft? Clin. Orthop. Relat. Res. 457 (2007) 220–226. [190] X. Zhou, R. Liao, M.S. Kelly, et al., Collagen–GAG scaffolds grafted onto myocardial infarcts in a rat model: a delivery vehicle for mesenchymal stem cells, Tissue Eng. 12 (9) (2006) 2467–2478. [191] D.R. Enis, B.R. Shepherd, Y. Wang, et al., Induction, differentiation, and remodeling of blood vessels after transplantation of Bcl-2-transduced endothe-lial cells, Proc. Natl. Acad. Sci. U.S.A. 102 (2005) 425–430. [192] F.K. Ko, M. Gandhi, C. Karatzas, Carbon nanotube reinforced spider silk – a model for the next generation of super strong and tough fiber, in: Proceedings of the 19th American Society for Composites Annual Technical Conference, October, Atlanta, GA, 2004, pp. 17–20.

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Further reading [1] M. Akbari, et al., Textile technologies and tissue engineering: a path toward organ weaving, Adv. Healthc. Mater. 5 (2016) 751–766. [2] E. Ekevall, C. Golding, R.R. Mather, Design of textile scaffolds for tissue engineering: the use of biodegradable yarns, Int. J. of Cloth. Sci. Technol. 16 (2004) 184–193. [3] M.F. Pittenger, A.M. Mackay, S.C. Beck, et al., Multilineage potential of adult human mesenchymal stem cells, Science 284 (1999) 143–147.

The application of collagen in advanced wound dressings

13

Giuseppe Tronci Clothworkers’ Centre for Textile Materials Innovation for Healthcare, School of Design and Biomaterials and Tissue Engineering Research Group, School of Dentistry, University of Leeds, Leeds, United Kingdom 

13.1  Introduction Chronic wounds, also referred to as hard-to-heal ulcers, fail to proceed through an orderly and timely self-healing process, resulting in cutaneous damage with full thickness in depth. Chronic wounds typically take longer than 3 months to heal and can originate from prolonged application of pressure to the skin (pressure ulcers), diabetes-related reduced nerve function and poor blood circulation (diabetic ulcers), improper functioning of venous valves (venous ulcers) and arterial narrowing at the lower extremities (arterial insufficiency ulcers). Clinical complications arising from this pathology include infection, gangrene, haemorrhage and lower-extremity amputations, potentially resulting in permanent disabilities and pain for patients. Chronic wounds are a major healthcare and economic burden worldwide. In the United Kingdom alone, 200,000 patients suffer from a chronic wound, while more than 6 million people are affected in the United States [1,2]. As a result of the increasing rates of diabetes and obesity and an ageing population, it is estimated that 1%–2% of the general population will develop a chronic wound, and up to 25% of the patients with diabetes will be affected by an ulcer in their lifetime [3]. Consequently, the global advanced wound care market, including advanced wound dressings, negative-pressure wound therapy, wound care biologics and other products, is expected to reach nearly $11 million in 2022, growing at a Compound Annual Growth Rate (CAGR) of 5% from 2016 to 2022 [4]. Because of their easy applicability and availability and clinical competence, advanced wound dressings accounted for the largest market share of the advanced wound care technology market in 2015. Therefore, there is growing attention towards the design of advanced dressing devices that can accelerate healing in chronic wounds by recapitulating aspects of the wound healing microenvironment and that can be customised according to stratified wound populations, to improve patients’ quality of life, to reduce healthcare costs and to create patient-friendly solutions.

13.1.1  Clinical need of advanced wound dressings Wound healing is a dynamic process, which proceeds via overlapping phases of inflammation, epidermal restoration, wound contraction and remodelling (Fig. 13.1). This process relies on the dynamic interaction of cells, soluble factors and the extracellular Advanced Textiles for Wound Care. https://doi.org/10.1016/B978-0-08-102192-7.00013-8 Copyright © 2019 Elsevier Ltd. All rights reserved.

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Self-healing wound

Angiogenesis granulation

Haemostasis Inflammation ▪ Platelets ▪ Cytokines

▪ ▪ ▪ ▪ ▪

▪ ▪ ▪ ▪ ▪

Neutrophils Macrophages ROS MMPs Soluble factors

↑ MMPs ↑ ROS ↓ Soluble factors ↑ pH ↑ Bacteria contamination

▪ ▪ ▪ ▪ ▪

Fibroblasts Macrophages Endothelial cells MMPs Soluble factors

Prolonged inflammation

Re-epithelialisation Tissue remodelling ▪ Keratinocytes ▪ Endothelial cells ▪ Fibroblasts ▪ Collagen fibres ▪ Crosslinking ▪ Soluble factors

Chronic wound

Figure 13.1  Typical healing and impaired healing phases in normal and hard-to-heal wounds, respectively.

matrix (ECM) so that inflammation can rapidly be resolved to allow for the ingrowth of fibroblasts and keratinocytes [5]. Activation of platelets and secretion of inflammatory cytokines, migration of macrophages, fibroblasts and keratinocytes, and expression of matrix metalloproteinases (MMPs) and growth factors are key to promote wound contraction and closure, ultimately leading to mature ECM and the formation of functional neo-tissue. Especially the release of MMPs in a balanced and coordinated fashion is crucial to enable phagocytosis, angiogenesis, cell migration (during epidermal restoration) and tissue remodelling. Such cascade of timely events is impaired in chronic wounds and results in a persistent inflammation state, which is associated with upregulated MMPs and reactive oxygen species (ROS), impaired growth factor expression and increased risks of bacterial contamination [6]. MMP activity has been reported to be up to 30-fold higher in chronic compared with acute wound fluids, suggesting that new ECM is continuously broken down because of the imbalanced ratio between MMPs and tissue inhibitors of MMPs. In light of the orchestrated nature of the wound microenvironment, observed MMP upregulation negatively affects fibroblast response and differentiation and causes growth factor denaturation at the wound site, so that the subsequent healing steps are halted. The use of topical wound dressings is a recognised way to wound healing (Fig. 13.2). Initially intended to keep the wound dry to minimise wound infection, conventional dressings were subsequently designed to absorb and retain wound exudate to enhance healing rates. Highly hydrated fibrous assemblies have therefore been realised [7], yet a narrow trade-off between dressing exudate absorbency and hydrated mechanical properties is commonly observed in situ. Consequently, self-adhesive oxygen-permeable film dressings have been developed to allow for moisture evaporation from intact periwound skin. Ultimately, with the advances in biomaterials science, textile manufacture and skin biology, a technology design shift has been pursued from dressings intended as purely skin-protecting bandages to advanced wound dressings, aiming to regulate wound microenvironment with regards to, e.g., pH, proteolytic activity and ROS

The application of collagen in advanced wound dressings

External environment

365

MMPs ROS Bacteria

Advanced wound dressing

Wound exudate

Wound bed

Figure 13.2  Design concept of an advanced wound dressing regulating wound exudate levels at the macroscopic scale and pH and overexpressed MMPs and ROS at the biochemical level.

concentrations. An array of approaches of varying efficacy has therefore been pursued, including MMP-cleavable sacrificial substrates [8], metal-chelating chemistries [9], cell [10] and soluble factor [11] delivery strategies, keratinocytes migration-­inducing peptides [12], bio-responsive systems [13] and growth factor–delivering vehicles [14]. Despite the extensive research efforts so far, clinically approved therapies for chronic wound management are still time-consuming, economically unaffordable and present restricted customisation. In this chapter, the role of collagen in the ECM of biological tissues and wound healing will be discussed, together with its use as building block for the manufacture of advanced wound dressings. Commercially available collagen dressings and respective clinical performance will be presented, followed by an overview on the latest research advances in the context of multifunctional collagen systems for advanced wound care.

13.2  Collagen as building block of advanced wound dressings Collagen is the most abundant protein in the human body. As a structural protein produced by fibroblasts, it plays a major role in all phases of the wound-healing cascade, stimulating cellular activity and contributing to new tissue development [15]. The presence of collagen in wound dressings is therefore highly advantageous to promote healing in hard-to-heal wounds, by encouraging the migration of macrophages and fibroblasts to the wound site, leading to the deposition of new collagen matrix. Other than its chemotactic effect on wound specific cells, collagen is also highly hydrophilic, so that respective collagen dressings promote the uptake of growth factor–rich and MMP-rich wound exudate [16]. Collagen-driven uptake of wound exudate is key not only to keep

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the wound hydrated but also to bind and protect wound exudate–carried growth factors and to inactivate upregulated, tissue-detrimental chronic wound MMPs, so that neo-­ tissue is not constantly enzymatically degraded. With the increased elucidation on the role that biochemical factors play in chronic wounds and in light of recent advances in biomaterials science, a great deal of attention has therefore been devoted to the development of advanced collagen-based dressing formulations aiming (1) to provide dressings with superior enzymatic stability at the macroscopic level, (2) to regulate the chronic wound microenvironment at the biochemical level and (3) to successfully enable their customisation to fulfil the requirements of a wide range of chronic wound populations.

13.2.1  Protein composition and organisation in vivo Collagen accounts for about one-third of the proteins in humans and two-thirds of the skin dry weights. As the most abundant protein in mammals, collagen has provided mankind with widespread applicability. In vivo, it plays a dominant role in maintaining the biological and structural stability of various tissues and organs. Ex vivo, collagen has been widely employed in the development of leathers and glues, food, cosmetic and pharmaceutical formulations and in medical devices [17]. So far, 28 genetically distinct types of collagen have been identified, with all of them displaying a triple helical structure at the molecular level (Fig. 13.3). Of these, type I (found in skin, tendon and bone), II (found in cartilage) and III (found in skin and vasculature) are mostly employed for biomedical applications and are characterised by collagen triple helices assembled into fibrils at the nanoscale, which are responsible for tissue architecture and integrity. The remarkable industrial versatility of collagen can therefore be largely attributed to its hierarchical organisation. The collagen molecule is based on three left-handed polyproline II-type (PPII) helices, which are staggered from one another by one amino acid residue and are twisted together to form a right-handed triple helix (TH, 300 nm in length, 1.5 nm in diameter). THs can be either homo- or heterotrimers, depending on the tissue and collagen type. With regards to collagen type I, which is widely used in wound care and regenerative medicine, the TH consists of a heterotrimer of two α1(I) chains and one α2(I) chain [18]. At the molecular level, each TH-forming PPII helix contains c. 1000 amino acid residues and is characterised by the repeating unit Glycine-X-Y, whereby X and Y are predominantly proline and hydroxyproline, respectively. The high content of both stiff (hydroxyl-)proline and small glycine residues explains the folding of each polypeptide into a PPII helix and the consequent arrangement of three PPII helices in the right-handed TH. Depending on the location in the human body and the specific biological tissue, THs can assemble into fibrils, fibres and fascicles. Besides secondary interactions, collagen assemblies, i.e., THs, fibrils, fibres and fascicles, are stabilised via covalent cross-links, which are formed between (hydroxy-) lysine residues under the influence of lysyl oxidase via either aldol condensation or Schiff base–mediated mechanism [19]. These naturally occurring intra- and intermolecular cross-links are formed in the non-helical, telopeptide regions of the collagen molecule; they are responsible for the proteolytic resistance of collagen in vivo and contribute to the mechanical properties and biological function of tissues.

Triple helix

NH2

Aldol crosslink Collagen Fibronectin

Integrin

Cytoskeleton

Intracellular

Polyproline-II helix

Collagen

Amino acidic

Molecule

Sequence

Collagen fibril 67 nm

(CH2)4

NH2

(CH2)2

CH(OH)

CH2

OH

CH2

CH(CH3)

CH2

NH2

The application of collagen in advanced wound dressings

Extracellular

OH

COOH

Figure 13.3  Stabilised collagen fibril assemblies present in skin’s ECM.

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Above-mentioned chemical composition and structural organisation explain the importance of collagen in wound healing and its widespread use for the manufacture of advanced wound dressings. The presence of the integrin recognition amino acid sequences RGD and GFOGER along PPII helices enables collagen to control many cellular functions of fibroblasts and keratinocytes, including cell shape, differentiation and migration. Type I collagen has been reported to stimulate angiogenesis in vitro and in vivo, whereby the binding of endothelial cell α2β1 integrin to the GFPGER502-507 sequence of the collagen TH was suggested to play a critical role [20]. The amino acid sequences of collagen also serve as binding sites for a number of chronic wound–upregulated inflammatory cytokines and MMPs, making collagen biodegradable. Besides promoting the migration of skin cells towards the wound, the application of collagen dressings can also divert tissue-detrimental action of aforementioned enzymes and soluble factors from the chronic wound to the dressing, offering an inherent mechanism of wound microenvironment regulation towards healing.

13.2.2  Extraction of collagen ex vivo Aiming to use collagen as the building block of advanced wound dressings, collagen is extracted from biological tissues, e.g., tendons, in acidic environments or via enzyme-catalysed extraction. Collagen fibres in vivo are stable enough to withstand the disruptive influence of thermal agitation but capable of the assembly and disassembly of the component molecules. However, irreversible disassembly of collagen can be induced ex vivo by several agents, such as heat, pH and enzymatic action. In these situations, the weak bonds (hydrogen bonds, dipole–dipole bonds, ionic bonds and van der Waals interactions) are initially broken, followed by the chemical cleavage of covalent cross-links. Collagen molecules in the form of triple helices become therefore soluble and diffuse away from the tissue to the extracting medium. Consequently, the unique hierarchical organisation of collagen found in vivo is lost ex vivo, resulting in a water-soluble product with limited solubility in organic solvents. Extracted collagen triple helices can be reconstituted in vitro (pH 7.4, 37°C) into in vivo–like fibrillary structures, resulting in viscoelastic gels at the macroscopic level; yet poor mechanical stability and uncontrollable volumetric swelling are usually observed in aqueous environment. While the extraction of collagen is typically carried out in mild conditions, so that collagen triple helices can be preserved and collected, excessive heating and extremely acidic solution pH can lead to denatured collagen, whereby triple helices unwind into single random coils and cleavage of pristine collagen polypeptides into smaller chains occurs. Such denatured form of collagen is called gelatin, which is a heterogeneous mixture of water-soluble polypeptide chains of varied molecular weights. Gelatin usually binds more water than collagen in light of its randomly coiled conformation, whereby an increased number of functional groups are exposed to water, leading to new hydrogen bonds. Based on their chemical similarities and compatibility within the body, collagen and gelatin are both widely used as building blocks for the design of multifunctional biomaterials and the manufacture of advanced wound dressings. Gelatin is a much cheaper raw material than collagen and that is why it is often

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employed in place of collagen. Because of the presence of triple helices and higher molecular weight of PPII helices, collagen shows restricted solubility compared with gelatin, although collagen-based materials typically exhibit increased mechanical competence in hydrated conditions. Consequently, flexible chemical and manufacturing processes should be developed to enable collagen applicability in clinical settings towards the development of in vivo–like covalently cross-linked collagen networks, which are water-insoluble, elastic and that can be configured in bespoke macroscopic formats, such as nonwoven fabrics, coatings and pads.

13.2.3  Collagen sources and antigenicity Type I collagen has been successfully extracted from bovine, equine or porcine tissues and employed in commercial advanced wound dressings, e.g., Promogran, Biopad and Biostep. However, the use of animal-derived collagen is associated with religious constraints, potential allergies and concerns of transmissible diseases, especially bovine spongiform encephalopathy (‘mad cow disease’). Synthetic research approaches leading to either collagen-like macromolecules or collagen TH-mimicking peptides have been proposed as chemically viable ‘artificial’ collagen [21,22]. Likewise, genetic engineering strategies have been successfully pursued to achieve type I recombinant human collagen as pathogen-free, economically affordable and quality-controlled raw material [23]. In contrast, alternative collagen sources, such as fish [24,25] and chicken [26] skin, have been explored to address above-mentioned issues in translation and commercialisation settings and to comply with current regulatory framework. Tissue source is known to affect the extraction yield and the chemical composition and clinical performance of resulting collagen [27], whereby differences in amino acid composition (e.g., lower imino acid and lysine content in fish compared with bovine collagen) have been found to impact on thermal, structural and mechanical properties, covalent cross-linking and, above all, antigenicity [28]. With regards to the latter point, the use of a human collagen would minimise the probability of interspecies variability and immune rejection, while the concept of material purity should also be carefully considered. Therefore, reliable extraction and manufacturing processes should be developed, to minimise the contamination of collagen products with unwanted residues related to non-collagenous proteins, cells, cross-linking compounds or microbial components, i.e., endotoxins [29]. The selection of collagen sources with minimal antigenicity is prerequisite to enable clinical use of collagen dressings in humans and to minimise the potential to evoke immune and adverse reactions. Macromolecular features present in the collagen backbone not common to the host species are more likely to interact with antibodies and to encourage an immune response than shared features, thereby acting as antigenic determinants. Interspecies amino acidic variation is therefore inherently linked to the issue of collagen antigenicity. Hence, the immunological closeness to humans supports the widespread use of bovine collagen for the development of commercial wound dressings with minimal antigenicity. Antigenic determinants of collagen can be found in the (triple) helical regions, with variations in the amino acid sequences not exceeding more than a few percent between mammalian species [30]. A far greater degree of

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variability is found in the non-helical terminal regions of collagen, i.e., telopeptides, with up to half of the amino acid residues in these regions exhibiting interspecies variation. Telopeptide-free collagen, also called atelocollagen, can be obtained via pepsin-induced extraction [31], whose yield is reported to be higher compared with acidic extraction [32]. The introduction of pepsin in the extraction medium allows for the selective cleavage of peptide bonds located in the terminal non-helical regions, potentially reducing collagen antigenicity. The telopeptide ends of the collagen molecule are dissected, while the triple helices remain preserved. In contrast, the removal of telopeptides may result in the inability of reconstituted product to display characteristic collagen fibril patterns because of the role amino acid and carboxyl telopeptides play in cross-linking and fibril formation [28,30].

13.3  Commercial collagen dressings Collagen has been widely investigated as building block of commercially advanced wound dressings, whereby varied protein and chemical configurations have been proposed to achieve superior wound healing dressing function. The application of hydrophilic dressings with appropriate exudate management capability is a recognised route to chronic wound healing [33]. Transparent collagen dressings have been developed in the form of membranes, pads and gels, allowing for wound monitoring and uptake of growth factor–rich wound exudate, while providing a barrier to exogenous bacteria. With the increasing understanding of the chronic wound microenvironment, multiphase formulations have also been pursued aiming to integrate collagen-based dressing devices with multiple functions, such as antibacterial activity, drug release and wound cleansing and MMP management capabilities (Table 13.1).

13.3.1  Non-hydrolysed collagen formulations Non-porous dressing pads made of 100% type I equine non-hydrolysed collagen have been developed and commercialised (Biopad) for the therapeutic treatment of burns and wounds [34]. Here, the hydrophilic behaviour of collagen was exploited to promote absorption (up to 15 times of the material dry weight) of wound exudate and aqueous biological media in the dressing. The dressing product consists of a nonfibrous pad of chemically unmodified collagen, which is prepared by sequential collagen acidic solubilisation, filtering and drying. The fact that the material is non-porous and chemically unmodified may be beneficial (1) to control and slow down the rapid dressing-induced exudate uptake (because of the presence of a compact, pore-free structure), which may otherwise lead to detrimental and excessive wound evaporation; (2) and to preserve the native collagen biological function and TH structure in resulting product. Especially the retention of triple helices is key to allow for collagen binding with wound exudate growth factors and cytokines and to ensure mechanical competence in the hydrated state [35]. The resulting collagen dressing pad is amenable to surgical cutting to fit the size of the wound. Before application in situ, the dressing should be partially hydrated to gain elasticity and to conform to the wound, likely

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371

Table 13.1 

Examples of patented, commercially available collagenbased advanced wound dressings

Product ID

Composition

Biopad

100% type I native equine collagen 100% bovine collagen, Manuka honey Bovine (mainly type I) collagen, glycerine Bovine (type I-III) collagen, oxidised regenerated cellulose Gelatin, sodium alginate, carboxymethyl cellulose, EDTA, plasticisers

Puracol

Stimulen

Promogran

ColActive

Collagen conformation

Collagen content (wt%)

Format

References

Triple helix

100

Pad

[34]

Triple helix

88

Pad

[38]

Hydrolysed

52

Gel

[48]

Hydrolysed

55

Pad

[51]

Denatured

50–90

Mesh

[53]

because of the glassy-like behaviour of collagen in the dry state and the absence of any plasticising phase in the dressing [36]. Following hydration with wound exudate in situ, the collagen dressing is claimed to be transparent, allowing for continuous wound monitoring, so that frequent dressing removal and replacement can in principle be avoided (although a secondary dressing is normally applied to maintain the dressing pad at the wound site). Besides the inherent advantages associated with its 100% non-hydrolysed TH-preserved collagen composition, this dressing was also reported to exhibit optimal structural compromise with regards to the extension of the collagen areas and the thickness of the collagen strands. Although no information on the MMP regulation capability was disclosed, these dressings proved to retain the same overall structure during exposure to collagenase [37]. Aiming at a dressing device with additional biochemical and wound cleansing capabilities, a non-hydrolysed collagen-based formulation (Puracol) was proposed containing Manuka honey (MH) [38]. The use of MH in the dressing is rationalised by the fact that wound cleansing of necrotic tissue is typically required before wound dressing treatment; this is usually carried out via surgery or sharp debridement, which may cause patient pain and require additional nursing time. Here, bovine collagen was employed to induce MMP regulation via collagen binding and cleavage with MMPs and was still applied in its non-hydrolysed, TH and non–cross-linked state. Other than controlling MMP overexpression in chronic wounds, the use of collagen was also expected to increase the viscosity of MH aiming to achieve localised delivery to the wound site,

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minimising MH spillage out of it. The use of MH was first intended to promote debridement of necrotic tissue following dressing application in situ, although MH activity is expected to positively impact on wound healing over different levels: (1) its acidity induces temporal denaturation of MMPs, which are responsible for wound chronicity; (2) MH osmolarity draws wound exudate out of the wound bed, resulting in an outflow of fluid, which helps in dissolving necrotic tissue and cleansing the wound [39]; (3) MH has broad-spectrum antibacterial activity even when in contact with high amounts of wound exudate, largely attributed to the presence of methylglyoxal [40,41]. The proposed formulation combining the advantages associated with collagen and MH can be employed as wound-contacting layer within a multilayer dressing comprising a (non) woven fabric, an absorbent layer made of, e.g., polyurethane foam or cellulose fibres, and a fluid impervious, adhesive cover layer designed to contain the wound exudate absorbed by the dressing. The wound cleansing and healing performance of the collagen layer was successfully investigated in patients with hard-to-heal wounds. Here, decrease in depth, increase in granulation tissue and decrease in the overall wound size provided evidence of the wound conversion from a chronic to a proliferative state within a 3-week time window [42]. These findings demonstrated the beneficial function of the native collagen dressing towards the preparation of an optimal wound bed, ultimately leading to accelerated wound re-epithelialisation. In contrast, the dressing potential to manage MMP upregulation in situ was not specifically addressed. Non-hydrolysed type I equine collagen has also been recently combined with hyaluronic acid (HA) [43] aiming to realise a dressing pad capable to promote cell proliferation, migration, differentiation and angiogenesis, while also inducing hydration of the wound [44]. The use of HA is rationalised because HA is a glycosaminoglycan found in the ECM that plays a central role in controlling water content and mechanical function of connective tissues, while also regulating several processes related to cell physiology and biology via interaction with specific cell receptors [45]. Aiming to preserve both collagen proteolytic activity and HA biofunctionality and keep the dressing pad manufacture simple, the formulation is prepared with no covalent cross-links or chemical functionalisation at the molecular level. Solutions containing specific ratios of HA and collagen are freeze-dried so that the final dressing pad is achieved ready for sterilisation. The application of freeze-drying to the polymer solution enables the formation of pores in resulting dressing internal architecture [46], thereby enhancing the exudate absorption capacity of the dressing (Fig. 13.4). Despite the absence of any covalent cross-link between the two phases, carboxylic acid groups of HA are expected to electrostatically interact with the amino groups of collagen, resulting in the formation of a physical network at the molecular scale. In light of the addition of HA, resulting dressing is mechanically strong yet flexible, in contrast to the case of collagen only pad [34], and can promptly conform to topical wounds. Other than wound dressing pads, the HA–collagen formulation can also be delivered in the hydrogel state for the treatment of cavity wounds. Culture of 3T3 fibroblasts with both collagen–HA and collagen control formulations confirmed that the use of HA promoted increased adherence of seeded cells to the material with respect to the collagen control, within a 5-day time window. Also in this case, the performance of the HA–collagen dressing prototype in contact with MMPs was not addressed.

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Figure 13.4  Manufacture and scanning electron microscopy (SEM) of a dressing pad obtained via freeze-drying of a gelatin aqueous solution.

13.3.2  Hydrolysed collagen-based formulations Extraction of collagen with preserved triple helices requires defined and controlled experimental conditions. Once extracted ex vivo, collagen in its TH state is known to present limited solubility and time-consuming solubilisation in aqueous conditions, which limit the creation of scalable customised material format. To overcome above-mentioned constraints and identify cost-effective biochemically comparable alternatives, extensive research and development has been carried out with derived, either hydrolysed or denatured, forms of collagen, which have been successfully integrated in several commercially available advanced wound dressings. In contrast to native collagen, hydrolysed or denatured (i.e., gelatin) derivatives consist of a wide mixture of predominantly linear polypeptides. These random coils can, however, refold into collagen-like triple helices, depending on the environmental conditions and polypeptide molecular weight, so that uncontrollable structure–property relationships may be observed [47]. A modified collagen gel (MCG) formulation (Stimulen) comprising non–cross-linked, hydrolysed bovine collagen mixture of long and short polypeptides dispersed in a matrix of water and glycerine has been disclosed for the treatment of ischemic wounds [48]. Preclinical investigations in an excisional wound swine model showed that MCG-treated wounds displayed longer rete ridge structures compared with untreated wounds, suggesting improved biomechanical properties of the healing wound tissue. The hydrolysed collagen formulation also proved to improve recruitment of neutrophils and release of inflammation-related cytokines into the wound site [49]. Despite lacking its native TH structure, the application of hydrolysed collagen in situ was still effective in promoting an initial boost in macrophage concentration and inflammatory response, followed by rapid return of macrophage count to control values and inflammatory resolution, so that healing could take place [50]. Consequent to these results, hydrolysed collagen was blended with oxidised regenerated cellulose (ORC) to create a dressing pad (Promogran) combining superior water absorption properties of cellulose with wound-regulating biochemical functionalities of collagen [51]. The dressing preparation involved the solubilisation of bovine hydrolysed collagen (BHC) and ORC in an aqueous solution, followed by one-pot freeze-drying and dehydrothermal cross-linking process. The final material therefore consists of a mechanically strong pad, which can be surgically cut to fit the wound size, yet displaying restricted elasticity, likely consequent to the presence of covalently cross-linked, low–molecular weight collagen polypeptides. In contrast

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to previously discussed products, results on the BHC/ORC dressing performance in diabetic foot ulcers wound fluid confirmed the material’s ability to successfully bind and rapidly inactivate chronic wound proteases [52], although no information on the potential dressing mass loss consequent to proteolytic cleavage was provided. Overall, these results underline that the BHC/ORC formulation could remove excess proteases from the wound bed, so that the enzyme-induced tissue degradation could be reduced and tissue synthesis promoted. Despite hydrolysed rather than TH-preserved collagen employed in this dressing, these results demonstrate that the collagen polypeptide can still act as a competitive enzymatic substrate with respect to the neo-tissue. Other than the collagen-based mechanism, the addition of ORC in the dressing was demonstrated to provide an additional means for MMP regulation via electrostatic complexation of ORC negatively charged functional groups with positively charged metal ions found in physiological conditions and essential for MMP activity. Hydrolysed collagen was also demonstrated to bind with and protect platelet-derived growth factor (PDGF) from proteolytic degradation, suggesting the potential applicability of the BHC/ORC dressing as controlled delivery system. Moreover, the dressing was also demonstrated to serve as free radical scavenger, which is key to control the excessive upregulation of reactive oxygen species responsible for the prolonged inflammatory state in chronic wounds. The multiple biochemical functions exhibited by the BHC/ORC dressing proved key to induce significantly increased wound closure in diabetic mice in contrast to dressing-free control wounds [8]. These results were found in agreement with histological analysis of wound tissue 14 days post-wounding, whereby enhanced formation and maturation of granulation tissue was observed in BHC/ORC-treated wounds. Other than hydrolysed collagen, porcine gelatin has been employed for the manufacture of flexible mesh dressings, together with a biocompatible plasticiser, such as polyethylene glycol (PEG), carboxymethyl cellulose (CMC), sodium alginate and ethylenediaminetetraacetic acid (EDTA) [53]. During manufacture, the dressing-forming aqueous mixture is poured on to a fibrous substrate of, e.g., cellulose before freeze-drying. The use of the plasticiser in the dressing formulation provides the dressing with enhanced elasticity in the dry state, in contrast to previously mentioned collagen-based dressing pad products, while CMC and sodium alginate are employed as hydrophilic components to enhance the absorption capacity of the material in situ. Despite gelatin is cross-linked by carbodiimide-induced intramolecular cross-linking, a 20 wt% mass loss was recorded following 24-h incubation with collagenase. To further control collagenase activity, EDTA is introduced in the dressing as soluble metal chelator, aiming to induce complexation with the active zinc site of upregulated MMPs, thereby providing an additional mechanism for MMP inactivation. Although the extent of degradation was reduced in the presence of alginate, the structure was observed to collapse following 5-h exposure to collagenase at body temperature [37], while a water uptake of up to 34-time the initial dressing dry weight was observed following 24-h incubation (0.01 M Phosphate buffered saline [PBS], pH 7.4, 37°C). The presence of plasticisers effectively enhanced the elasticity of the material following 1-h soaking in PBS (0.01 M, pH 7.4), resulting in a measured elongation at break of more than 190%. Ultimately, resulting dressing mesh could be loaded with

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Sirolimus as exemplary anti-inflammatory drug for the controlled delivery to the surface of tissues, whereby less than 2% drug was released after 3 days in vitro (0.01 M PBS, pH 7.4, 37°C).

13.4  Design of multifunctional collagen systems with customised formats Despite wound management collagen solutions have been commercialised to respond to the pressing needs of an increasing diabetic population, limitations in biochemical functionalities, manufacturing processes and customisation of dressing properties, functions and format prevent us from developing cost-effective technologies personalised for a wide range of chronic wounds. To address this challenge, widespread research has been pursued to design multifunctional systems with bespoke architecture and integrated bioactive formulations, aiming to correct chronic wound biochemical imbalances and achieve dressing-induced orchestration of the wound healing microenvironment. Research strategies to realise this have focused on three main streams: (1) cell-based therapies, whereby cells are encapsulated in the dressing material to promote tissue repair [54,55]; (2) drug-loaded systems enabling controlled and staggered release of soluble factors to prevent wound infection and accelerate healing [56,57] and (3) cell-free and soluble factor–free dressing devices whereby the healing functionality is inherently accomplished by dressing physical properties and chemical configurations at the molecular scale [58,59]. The design of inherently multifunctional wound dressings may be preferable to achieve constant clinical performance in vivo, irrespective of temporal factors ruling, e.g., the release of active compounds or metabolic activity of encapsulated cells, while also minimising regulatory framework burdens and time required for regulatory approval and translation to market.

13.4.1  Synthesis of network architectures to achieve dressing multifunctionality Despite collagen being an ideal biomaterial for wound dressing application, the inherent MMP-induced degradation in vivo of collagen-based dressings raises concerns in terms of dressing form-stability, non-controllable swellability and poor hydrated mechanical properties. Incorporation of soluble MMP-chelating agents, i.e., EDTA, has been exploited for the development of commercially advanced wound care products. Yet, loading of the dressing with soluble factors may involve additional considerations with regards to controlled release kinetics, sustained MMP modulation and medicinal product-related translation pathway. Either glutaraldehyde [60,61], genipin [62], or carbodiimide chemistry [63] or physical factors [64,65] have been employed to stabilise collagen in biological environments, although issues remain with regards to material cytotoxicity and restricted control of cross-linking reaction and material properties. To overcome these limitations, a great deal of attention has been given towards the development of flexible cross-linking strategies of collagen.

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By introducing cross-links between collagen molecules, water-insoluble networks are accomplished that swell in contact with wound exudate, so that defined moist environment is established in situ, while enhanced dressing biodegradability and hydrated mechanical properties can be expected. Most importantly, additional biofunctionalities can be introduced in resulting materials depending on the characteristics of the cross-linking segment. Type I bovine collagen has been cross-linked with tannic acid (TA) in an effort to introduce the antimicrobial and anti-inflammatory activities of TA within a covalent collagen matrix [66]. TA is a plant polyphenol consisting of a glucose moiety core with hydroxyl groups being esterified with five digallic acids. Resulting materials proved to display about 10 wt% mass loss following 42-h incubation in a collagenase-containing medium, in contrast to more than 60 wt% mass loss observed in TA-free collagen controls in the same conditions. Following application to full-thickness wounds in rats, TA–cross-linked samples proved to support enhanced wound closure and nearly complete re-epithelialisation following 12-day treatment, in comparison with the collagen control, while no commercial benchmark was employed in the study. Results obtained in vitro and in vivo therefore support the hypothesis that TA carboxylic and hydroxyl groups within the collagen matrix can mediate the formation of non-covalent netpoints with the functional groups of the collagen molecules, explaining the decreased degradation yield. Digallic acid units are also known to act as metal ion chelators; they can therefore bind with and inhibit collagenases [67], contributing to the accelerated healing observed in wounds treated with TA-based collagen formulations. Building on the knowledge developed with this system, Francesko et al. analysed the enzymatic modulation activity of plant polyphenol–loaded type I bovine collagen-based conetworks prepared via carbodiimide-catalysed cross-linking reaction with either HA or chitosan [68]. Hydrogels displayed an averaged swelling ratio of 1500–2500 wt% and an averaged Young’s modulus of 60–160 kPa, depending on the specific formulation. Here, the addition of HA proved to significantly impact on the water uptake capability of resulting samples, in agreement with the well-known swellability of HA in vivo. Despite that, increased material stability was observed in enzymatic media, whereby collagen degradation was measured in the range of 10–30 wt% following 1-day incubation with collagenases. The release profile of loaded polyphenols was not addressed, yet no toxic response and spread-like cell morphology was observed following 3-day culture with L929 fibroblasts. Following similar line of thinking, either Macrotyloma uniflorum or Triticum aestivum were loaded as anti-inflammatory and antibacterial plant extract onto fish collagen–fibrin composites [69] and goat tendon collagen aerogels [70], respectively. Collagen-based composites displayed more than 40 wt% mass loss following 24-h incubation in enzymatic media, partially explained by the absence of any covalent cross-links; yet, they induced accelerated healing of full-thickness wounds in albino Wistar rats via suppression of cyclooxygenase-2, inducible nitric oxide synthases and MMP-9 expressions [71]. In contrast, T. aestivum was shown to promote chemical cross-linking of collagen lysines [70], so that T. aestivum–loaded collagen aerogels displayed proangiogenic effect resulting in complete wound closure in female Wistar rats following 18 days post-wounding. Besides the biochemical modulation of the wound microenvironment, sponges of denatured collagen and HA

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were realised and loaded with epidermal growth factor (EGF), aiming to stimulate cell proliferation for the treatments of burns [72]. The absence of covalent cross-links between the two biopolymers was likely responsible for the quick dissolution of the sponge within 7-day incubation, although the consequent quick EGF release proved beneficial in promoting angiogenesis and re-epithelialisation in a dermal burn model in rats [73] and in a full-thickness dorsal skin defect in diabetic mice [74]. Other than loading with soluble bioactives to achieve specific modulation of the wound microenvironment, a family of functionalised (atelo)collagen networks has recently been developed, whereby inherent control of MMP activity is accomplished via the introduction of chemically coupled photoactive compounds [75,76]. The covalent functionalisation of (atelo)collagen triple helices with photoactive compounds enables the formation of photo-induced covalent networks with bespoke macroscopic properties and the complexation of introduced adducts with the active site of MMPs, yet avoiding the use of any soluble factor. This synthetic strategy proved to enable customisation of hydrogel elastic modulus depending on the type of chemically coupled photoactive adduct (Fig. 13.5), while an averaged swelling ratio of up to nearly 2000 wt% was observed [77]. Preclinical investigations with a Hydrogel of Functionalised ateloCollagen (HyFaCol) indicated increased neodermal response in full-thickness wounds created in diabetic mice, compared with wounds treated with a polyurethane commercial control in the same experimental conditions [78].

13.4.2  Customisation into single fibrous component for wound dressing manufacture The clinical performance of multifunctional collagen-based formulations would be greatly accelerated if delivered in material formats relevant to the wound dressing manufacturing industry. Fibrous architectures, e.g., nonwovens, are widely used for the development of healthcare materials, including wound dressings, because of their high porosity, easy manufacture and advantageous fluid adsorption properties [79]. Consequently, the creation of single collagen fibres has been widely pursued aiming to accomplish libraries of dressing building blocks with customised molecular architecture, properties and biofunctionalities, to fulfil the complex requirements of stratified chronic wounds. To deliver on this vision, specific manufacturing routes need to be developed enabling preservation of collagen proteinic architecture in the fibrous state, while allowing for clinically acceptable material purity and manufacturing yield relevant for industrial scale up. Among the different fibre manufacturing processes available, wet spinning has the potential to convert collagen solutions into single fibres. From a protein preservation standpoint, this fibre spinning process is highly benign because there is no involvement of harsh organic solvents, electrostatic voltage or high temperature [80]. In these experimental conditions, the risk of spinning-induced collagen TH denaturation is minimised, so that wet spun fibres consisting of preserved collagen triple helices can be obtained. Wet spinning was developed by the textile industry in the early 1900s as a means of producing man-made fibres such as viscose rayon. Mechanistically, this fibre

378

H 2N

(a)

(1) Collagen

I.

Lysine H 2N

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II.

OH Collagen

(b)

O

NH (2)

(d)

10000

EAFM /kPa

1000

100

1

GMA*

4VBC*

MA*

Figure 13.5  (a) Synthesis of UV-cured (atelo)collagen networks via lysine functionalisation with photoactive compounds. (b) Resulting (atelo) collagen networks swell in water and present an internal porous architecture (c) by scanning electron microscopy. (d) Atomic force microscopy on collagen hydrogels reveals significantly different elastic modulus (EAFM) depending on the specific network architecture.

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spinning mechanism relies on (1) the phase separation of a fibre-forming (bio)polymer solution against a suitable (bio)polymer non-solvent and on (2) the spinning rate of the phase-separating solution jet. The (bio)polymer solution is extruded through a spinneret into a non-solvent coagulation bath, whereby (bio)polymer solution streams turn into solid filaments, because of the non-solvent–induced (bio)polymer phase separation. For each (bio)polymer system, fibre properties can therefore be manipulated by adjusting solution and coagulating bath characteristics, wet-spinning parameters (e.g., spinneret diameter, solution injection flow rate and drawing ratio) and post-spinning fibre conditioning (e.g., covalent cross-linking, washing and drying). Silver et al. pioneered the formation of high-strength, dehydrothermally crosslinked, wet-spun collagen fibres using concentrated rat tail collagen solutions in diluted hydrochloric acid [81,82]. Wet spinning was carried out in a neutral buffer system at 37°C, whereby resulting fibres were washed in isopropyl alcohol and distilled water before dehydrothermal cross-linking. Remarkably, hydrated wet spun fibres exhibited a maximum tensile strength and elongation at break of up to 92 MPa and 20%, respectively, although the density of the covalent cross-links could not be quantified. Using a PEG-containing coagulating bath, Zeugolis et al. successfully wet spun bovine atelocollagen fibre with in vitro reconstituted fibrillary organisation and increased tensile strength [83]. Post-spinning incubation in isopropanol induced a decrease in fibre diameter compared with fibres conditioned in aqueous environment, likely related to fibre dehydration in the former case and water-induced fibre swelling in the latter case. Hydrated wet-spun fibres displayed an elastic modulus of more than 16 MPa when incubated in PBS and of nearly 4 MPa when incubated in distilled water, suggesting that PBS incubation induced folding of collagen triple helices into fibrils. In another account, wet-spun collagen was incubated with cross-linking agents, resulting in fibres resembling the tensile properties of native tissues. Either ethylene glycol diglycidyl ether or hexamethylene diisocyanate proved suitable in enhancing the mechanical properties of wet-spun collagen, although concerns were also raised regarding potential material cytotoxicity and side reactions [47]. To minimise the extent of superficial drying-induced irregularities, e.g., ridges and crevices, and to increase molecular alignment and fibre tensile properties, Caves et al. applied drawing to wet-spun fibres. A dual syringe pump system was developed where isolated collagen solution and PEGbased wet spinning buffer were mixed in 1-m fluoropolymer tubing before entering in a 2-m ringing bath of 70% ethanol solution [84]. Resulting filaments displayed retained TH organisation, while reconstituted collagen fibrils were also observed following 48-h incubation in PBS at 37°C and washing in distilled water, before fibre cross-linking with glutaraldehyde. Hydrated fibres displayed a fibre diameter in the range of 20–50 μm and an averaged ultimate tensile strength of nearly 94 MPa. Treatment with glutaraldehyde proved successful in decreasing the extent of fibre degradation following subcutaneous implantation in C57BL/6 mice, although a mild local inflammatory response was observed. Integrated wet spinning cross-linking processes have also been attempted, whereby fibre-forming collagen was wet spun (with no drawing) in a mineral salt aqueous coagulation bath containing glutaraldehyde [85]. Despite grooved surface morphology being observed, resulting fibres could be successfully assembled in a carded nonwoven architecture. This study therefore supported the use of wet

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spinning for the formation of fibrous assemblies based on TH-preserved collagen, in contrast to the use of, e.g., melt spinning, whereby fibres of completely denatured collagen are obtained [86]. Other than animal-derived collagen, recombinant human type I collagen derived from a transgenic tobacco plant was recently applied in a novel fibre spinning method, involving drawing and cross-­linking [23]. Smooth, highly aligned wet-spun fibres with a fibre diameter as small as 8 μm could be successfully accomplished. Also in this case, potentially toxic glutaraldehyde and carbodiimide-induced cross-linking was pursued, whereby the former treatment led to fibres with increased wet-state stress at break (∼140 MPa) compared with carbodiimide cross-linked fibres (∼40 MPa). To address the cytotoxicity issues associated with glutaraldehyde or carbodiimide, a photoactive collagen system has been recently developed and employed as fibre building block [87]. Photoactive collagen proved to be compatible with the wet spinning process in either alcohol or water-based coagulating baths. Water-insoluble, mechanically competent fibres could be prepared via post-spinning UV-curing process and successfully assembled into a three-dimensional porous fabric (Fig. 13.6). Other than wet spinning, microfluidics-based approaches have also been proposed for the fabrication of reconstituted type I collagen fibres with fibre diameters of only 3 μm and an averaged tensile strength of 383 MPa [88]. Despite the remarkable performance of resulting fibres and the absence of cross-linking step, further research may be required into this process to increase its 19 m/h production rate towards wet spinning-like fibre production rates of 1000 m/h [23] to enable industrial scale up.

13.4.3  One-step manufacture of multifunctional collagen-based meshes Together with the multiscale manufacture of fabric dressings via controlled customisation of multifunctional molecular systems into single fibres and consequent fibre assembly into three-dimensional structures, one-step spinning processes have also been extensively investigated for the creation of fibrous meshes from collagen-based solutions. Such research approaches undoubtedly offer a faster manufacturing route to the fibrous prototype, although reduced control over fibre characteristics, protein organisation and production yield is expected [36,80,86]. Electrospinning and wet electrospinning of collagen-based materials have been extensively employed for the formation of either mono- or multi-layered nonwoven fabrics, while other strategies involving physical or chemical deposition of collagen coatings onto fibrous supports have also been pursued. Electrospinning is considered as a simple and effective fabrication method to prepare nanofibrous membranes with diameters ranging from 5 to 500 nm, i.e., about 100 times smaller than the fibre diameters observed in wet or melt spun fibres. Electrospinning involves the application of voltage to a syringe containing a polymer solution [89]. Following ejection of the polymer solution and solvent evaporation, a nonwoven mesh is formed on a grounded collector. Despite fibre and web characteristics can be manipulated by adopting appropriate experimental parameters, such as solvent, polymer concentration and flow rate, common process limitations include the

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381 (1) Photoactive collagen H N

Lysine

+

TEA

N H

H N

CI

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(2) Collagen staples UV (346 nm)

Fibre-forming collagen triple helix Coagulating bath

Dry laying Collagen fibre suspended in a turbulent air flow

(3) Collagen fabric

Air laid forming fabric Support rollers

Vacuum

Figure 13.6  Manufacture of a collagen fabric with retained triple helices. 4VBCfunctionalised collagen (1) is dissolved in acidic solution and wet spun. UV-cured staples (2) are water insoluble and mechanically competent and can be assembled into a three-­ dimensional fabric via, e.g., dry laying (3).

limited fabric thickness and restricted fabric porosity. Furthermore, given that electrospinning requires volatile solvent to allow for prompt fibre formation, organic solvents are usually used. In the case of collagen, both applications of electrostatic voltage and organic solvents are well known to induce unwinding of collagen triple helices into randomly coiled polypeptide chains, so that the resulting mesh is effectively composed of gelatin rather than collagen [90,91]. Because of the loss of collagen triple helices, resulting samples are readily soluble in aqueous environment, preventing their use in biological environments. Consequently, the formation of water-stable collagen-based electrospun membranes has attracted widespread research attention and has so far been typically accomplished via blending of collagen solution with other polymers [35], manufacture of multi-layered structures [92–94], chemical cross-linking of

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resulting fibres [95–97] or combination thereof. These approaches proved successful towards the creation of ECM-mimetic fabrics integrated with growth factor retention and release functionality [58]. Here, a polysaccharide component allowed for the effective sequestration of endogenous PDGF while the enzymatic cleavage of gelatin in the electrospun matrix triggered the release of sequestered growth factor, so that accelerated repair of a full-thickness skin wound was observed in C57BL/6 mice. To overcome the cytotoxicity issues with conventional cross-linking methods, e.g., glutaraldehyde, Dhand et al. have recently proposed the addition of naturally occurring catecholamines in collagen-based electrospinning solutions, so that fibre stabilisation is accomplished via latent oxidative polymerisation initiated by exposure to ammonium carbonate [98]. In another recent report, wet electrospinning has been proposed to address the limited thickness, porosity and pore size observed in electrospun fabrics [99]. Wet electrospinning proceeds by spraying electrospun nanofibres into a liquid bath, which is used to separate the fibres. By controlling the area of nanofibre deposition, resulting wet electrospun webs revealed a porosity of about 90 vol%, in contrast to 60–80 vol% porosity observed in electrospun samples. Other approaches have also been investigated to avoid inherent electrospinning-associated denaturation of triple helices. Collagen has been deposited as physical coating onto polyester/gelatin electrospun meshes, yet rapid collagen degradation was observed during 24-h enzymatic incubation. Chemical immobilisation of collagen coating has therefore been proposed by using polypropylene (PP) meshes as inert substrate for biomimetic functionalisation [100]. Plasma modification of PP was applied to enable the incorporation of acrylic moieties, which could then be activated with carbodiimide to covalently couple collagen. Although the enzymatic stability of the coating was not addressed, application of resulting material on to a full-thickness wound model in SD rats revealed increased wound closure with respect to wounds treated with PP controls. Similar approach was also pursued in an N-isopropyl acrylamide (NIPAM)-grafted PP nonwoven fabric, whereby covalent glutaraldehyde-mediated covalent linkages were proposed between collagen and NIPAM was proposed [101].

13.5  Outlook Different advanced wound care concepts will continue to be developed to support chronic wound healing, whereby new antibiotic-free antibiofilm technologies, multifunctional material design and flexible and scalable manufacture processes will play a crucial role. A strong focus will be given to integrated collagen-based dressings that will allow remote monitoring of wound conditions and visual indications of chronic state changes. This approach will enable timely and prolonged application of cost-effective dressing devices promptly customised to the targeted chronic wound, ultimately resulting in economically affordable wound healing times, and minimised dressing changes. Flexible design and manufacturing concepts should therefore be developed, which can enable systematic variations in dressing properties and functions, while also allowing for late-stage device assembly at the bed side.

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Especially in out-of-hospital healthcare, collagen devices that are able to adjust to and regulate changes in chronic wound microenvironment, while also displaying easy removability, are expected to reduce patient pain, therapeutic time and wound infection risks. These requirements could be fulfilled by building biomimetic architectures tailored across length scales that are able to perform and display more than one function according to defined biochemical shifts. Advances in collagencompatible fibre spinning and assembling technologies will be paramount to realise high-value building blocks with integrated sensing units and to enable the material conversion into appropriate structures depending on the chronic wound type, state and size. Patient- and clinician-assisted device development will continue to be key to de-risk late-stage clinical and technology uptake failure and to identify appropriate clinical models for first-in-man evaluations, before clinical trials.

Acknowledgments The author gratefully acknowledges financial support from the Clothworkers’ Centre for Textile Materials Innovation for Healthcare, the EPSRC-University of Leeds Impact Acceleration Account and the EPSRC Centre for Innovative Manufacturing in Medical Devices (MeDe Innovation Fresh Ideas Fund).

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Speciality dressings for managing difficult-to-heal wounds

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Arunangshu Mukhopadhyay, Monica Puri Sikka, Vinay Kumar Midha Department of Textile Technology, Dr. B R Ambedkar National Institute of Technology, Jalandhar, India 

14.1  Introduction The development of new and effective interventions in wound care remains an area of intense research. Wound dressings are one important aspect that promotes wound healing apart from treating the underlying cause and other supportive measures. There are a wide variety of dressing techniques and materials available for management of both acute wounds and chronic non-healing wounds. The primary objective in both the cases is to achieve a healed closed wound. However, in a chronic wound the dressing may be required for preparing the wound bed for further operative procedures such as skin grafting [1]. An ideal dressing material should not only accelerate wound healing but also reduce loss of protein, electrolytes and fluid from the wound and help to minimise pain and infection. It can be quite a challenge for any physician to choose an appropriate dressing material when faced with a wound. Because wound care is undergoing a constant change and new products are being introduced into the market frequently, one needs to keep abreast of their effect on wound healing. The importance of assessment of the wound bed, the amount of drainage, depth of damage, presence of infection and location of wound cannot be denied [2]. These characteristics help any clinician decide on which product to use and where to get optimal wound healing. A hard-to-heal wound has been defined as one that fails to heal with standard therapy in an orderly and timely manner [3]. This definition applies equally to both acute and chronic wounds and is independent of the wound type and aetiology. Successful treatment of difficult wounds requires complete assessment of the patient and not just the wound. Systemic problems often impair wound healing; conversely, non-healing wounds may herald systemic pathology. There are a number of factors that contribute to delayed wound healing, including patient related factors, such as underlying pathology and comorbidities; wound-related factors, such as ulcer size, duration and location; and clinical competency factors, such as the knowledge and skill of the clinician. Additionally, resource- and treatment-related factors, such as dressing availability and selection, can influence how long the wound will take to heal. Recognition of non-healing wounds demands a careful assessment and reassessment of both the patient and the wound and reviews of systems of care so that both intrinsic and extrinsic barriers to healing are identified and addressed. Every chronic wound is a new challenge, so before deciding on a dressing solution, the concerns related to odour, exposure, infection prevention, comfort and moisture need to be addressed. Each wound is a unique problem Advanced Textiles for Wound Care. https://doi.org/10.1016/B978-0-08-102192-7.00014-X Copyright © 2019 Elsevier Ltd. All rights reserved.

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to solve and it may require one or several of the available speciality dressings to properly deal with any given injury. Many chronic wounds can be healed with conventional dressings but complex wounds may require speciality dressings, growth factors or bio-engineered tissue products. The selection of speciality dressings used for chronic wounds currently available to medical professionals is broad, with several options to choose from in treating patients. But by evaluating an individual wound’s needs, it can be relatively easy to find the right approach with the right dressing. The speciality dressings are more useful for difficult-to-heal wounds but few of these can also be used to accelerate wound healing process in normal wounds. The understanding of the pathophysiology of wound healing, wound and patient assessment is necessary before proceeding to the selection of the appropriate speciality dressing.

14.1.1  Pathophysiology of wound healing A wound is described as a defect or a break in the skin caused by physical, chemical or thermal damage or as a result of an underlying physiological or medical condition resulting in disruption of normal anatomical structure and function of skin [4]. The physiological process of wound healing is achieved through four temporarily and spatially overlapping phases as shown in Fig. 14.1 [5,6]: 1. Haemostasis – Immediately after injury, haemostasis occurs and is characterised by vasoconstriction and blood clotting, which prevents blood loss and provides the provisional matrix for cell migration. Platelets secrete growth factors and cytokines attract fibroblasts, endothelial cells and immune cells to initiate the healing process. 2. Inflammation – The subsequent inflammation phase lasts up to 7 days. The predominant cells at work in this phase are phagocytic cells, such as neutrophils and macrophages. Neutrophils release reactive oxygen species and proteases that prevent bacterial contamination and cleanse the wound of cellular debris. Blood monocytes arrive at the wound site and differentiate into Wound healing phases

Hemostasis (immediate)

Inflammatory (2–7 days)

Vascular constriction

Opening of blood supply

Platelets aggregation, degranulation and fibrin formation (thrombus)

Neutrophil infiltration

Formation of a scab

Lymphocyte infiltration

Monocyte infiltration and differentiation to macophages

Cleansing of the wound

Proliferative

(5 days to 3 weeks)

Granulation New collagen tissue is laid down Angiogenesis New capillaries fill in defect Contraction Wound edges pull together Epithelialization Cells cross over the moist surface Cells travel about 3 cm from point of

Figure 14.1  Wound healing phases.

Remodelling/maturation (3 weeks to 2 year)

Collagen remodeling Collagen forms which increases tensile strength to wounds Vascular maturation and regression Scar tissue is only 80 percent as strong as original tissue

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tissue macrophages. The latter not only remove bacteria and nonviable tissues by phagocytosis but also release various growth factors and cytokines recruiting fibroblasts, endothelial cells and keratinocytes to repair the damaged blood vessels. As the inflammatory phase subsides accompanied by apoptosis of immune cells, the proliferation phase begins. 3. Proliferation – This phase is primarily characterised by tissue granulation, formation of new blood vessels (angiogenesis) and epithelialisation. 4. Remodelling phases – The last phase occurs once the wound has closed and may last 1–2 years or longer. During this phase, the provisional matrix is remodelled into organised collagen bundles [7,8].

Many complicated and delicate interactions are involved in wounds successfully transitioning from an acute inflammatory phase to the subsequent proliferation and remodelling phases. Abnormal wound healing becomes evident when optimised local and systemic conditions are absent, leading to a ‘non-ideal’ wound healing environment. Acute wounds have the potential to move from acute wound to chronic wounds, requiring the clinician to have a thorough understanding of outside interventions to bring these wounds back into the healing cascade.

14.1.2  Patient and wound assessment The care for chronic wounds therefore relies upon basic tenets that aim to not only remove the causes but also address underlying systemic and metabolic perturbations such as infection or peripheral arterial disease. Proper care of the hard-to-heal wound is facilitated initially by employing thorough patient and wound assessment. Factors contributing to the development of the wounds are to be addressed accordingly. Concurrent with the management of associated complications, wound bed preparation plays a key role in encouraging the proper environment in which tissue repair can take place. Notwithstanding, appropriate diagnosis is mandatory to establish the aetiology of the non-healing wound.

14.1.2.1   Patient assessment Patient assessment starts with a thorough patient history to determine medical comorbidities, contributing factors possibly leading to the chronic wound, prior trauma and prior history of wounds, current medications and allergies. For example, the presence of diabetes mellitus with neuropathy will be important to note for those patients presenting with a diabetic foot ulcer (DFU) as will a history of deep venous thrombosis for those presenting with a suspected venous leg ulcer (VLU). The importance of taking a medical history cannot be overemphasised [9]. An assessment of the patients’ living situation and their likely reliability in following prescribed treatments is important in the actual determination of which therapies should be employed to manage the wounds.

14.1.2.2   Wound assessment Assessment of the wound actually begins during the initial encounter with the patient, whereby his/her general appearance is noted and that of the wound itself. Morbid obesity or, conversely, a painfully thin patient body habitus is a clue to nutritional status that will have a bearing on treatment protocols and possibly on outcomes. A visual inspection

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of the wound will immediately identify very important attributes that will guide further evaluation and treatment. The depth, extent (size), location, general appearance, odour and notation of exudates are all essential components of wound evaluation and need to be recorded at baseline [10]. Ascertainment of infection and determination of its severity are also critical for appropriate wound management and classification. When signs of infection at the wound are present, tissue cultures are indicated to guide specific antimicrobial treatment [11].

14.1.2.3  Principles of wound bed preparation It is important to ensure adequate oxygenation and nutrition for wound bed preparation. The usual reason for inadequate tissue oxygenation is local vasoconstriction as a result of sympathetic overactivity. This may occur because of blood volume deficit, unrelieved pain or hypothermia, especially involving the distal extent of the extremities. Adequate nutrition is an often-overlooked requirement for proper wound healing. In addition, to the above, debridement has long been recognised as a critical component for wound care and has been shown by several investigators to expedite healing. Thorough debridement converts the chronic wound from one that is excessively inflamed to more of an acute profile that can jump start the wound towards a healing trajectory. Regardless of the method used, effective debridement of chronic wounds is accepted as an essential component of care throughout the wound healing continuum. Nonetheless, healing can be delayed if debridement is performed too frequently and/or extensively. The importance of off-loading the chronic wound cannot be overemphasised [10,12–15]. In fact, when this component of wound care is neglected, the chances of a successful outcome are extremely low. For example, when one recognises that most wounds, especially DFUs, have excessive pressure as their proximate cause, it is quite understandable that the high pressures must be ameliorated before healing can take place. Along the same lines, compression therapy for chronic VLUs is equally important. For ulcerated patients with significant venous insufficiency and associated chronic lymphoedema, intermittent pneumatic compression pump therapy can also be recommended [16,17].

14.2  Hard-to-heal wounds Recognition of non-healing wounds demands a careful assessment and reassessment of both the patient and the wound and reviews of systems of care so that both intrinsic and extrinsic barriers to healing are identified and addressed. There are a number of factors that contribute to delayed wound healing which need to be identified as early as possible. The impact of hard-to-heal wounds on the patient and resources also need to be addressed.

14.2.1  Reason of non-healing wounds One of the characteristics of multicelled organisms is the ability to replicate and self-repair. The normal healing process is a well-orchestrated, complex and interlinked

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series of four well-recognised overlapping phases of haemostasis, inflammation, proliferation and remodelling, as discussed in the previous Section 14.1.1. In this process, components of the extracellular matrix, interacting with recruited cells, play an important role in coordinating key processes in healing [18]. The normal process can be interrupted at any stage and is vulnerable to a variety of intrinsic and extrinsic inhibitory factors. For non-healing wounds, the negative effects to be considered are endocrine diseases (e.g., diabetes, hypothyroidism), haematologic conditions (e.g., anaemia, polycythaemia, myeloproliferative disorders), cardiopulmonary problems (e.g., chronic obstructive pulmonary disease, congestive heart failure), gastrointestinal problems that cause malnutrition and vitamin deficiencies, obesity and peripheral vascular pathology (e.g., atherosclerotic disease, chronic venous insufficiency, lymphoedema).

14.2.2  Identifying a hard-to-heal wound In most wounds, healing progress should be visible within a 4 week period. Much can be gleaned from a detailed initial wound and patient assessment when issues such as ischaemia, associated comorbidities and infection, amongst others, may be identified and a broad idea of healing potential derived. Such assessments must, however, be accurate and reproducible if treatment is to be delivered effectively [19]. Recognition of non-healing wounds demands a careful reassessment of the wound, the region of the wound, the patient and the systems of care so that both extrinsic and intrinsic barriers to healing may be identified. For many wounds one or more of the following three key intrinsic abnormalities will be present and delay or prevent healing: • Ischaemia • Infection • Abnormal or persistent inflammation.

14.2.3  Early recognition of hard-to-heal wounds [19] Recognition of a hard-to-heal wound requires regular reassessment with measures taken towards healing. It does, however, also demand that: • The assessment and diagnostic process is correct. • Appropriate treatment has been applied to deal with both the requirements of the wound and the management of any underlying medical conditions that may impact on healing. • The outcome of treatment has been evaluated within a time frame that is appropriate for a specific wound type.

14.2.4  Impact of hard-to-heal wounds on the patient Chase et al. [20] introduced the concept of ‘forever healing’ and other work has led to the concept of permanent ‘wounding’. For the patient this requires learning to live with the pain, emotional problems and social isolation associated with delayed healing [21,22]. The more wound healing is delayed, the more it impacts on the patient.

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Symptom control is important in all wounds, but particularly for those of long duration. Pain management, exudate control and odour management are some of the main issues that impact on both the patient and his/her family’s quality of life [23,24]. Failure to control these issues will adversely affect concordance and increase the chance of non-healing.

14.2.5  Impact of hard-to-heal wounds on resources Reducing health costs is a recurring global issue. Wound management is a major area where there is a drive for improved cost-effectiveness. Costs are higher for hard-toheal and long duration wounds as the frequency of therapy, staff time and product use increases [25,26]. Reducing costs while optimising the quality of life for patients with delayed wound healing requires the following: • Early identification of hard-to-heal wounds • Targeted use of advanced wound care products.

14.3  Classification of wound dressings Skin has a remarkable tendency to repair itself. But when the damage is severe or occurs in a larger area, appropriate and immediate coverage of the wound area with an optimal device or adequate dressing is essential to protect the wound and accelerate the healing process [4,27]. Materials that are used to cover wounds and burns are also known as artificial skin, as they fulfil the functions of normal skin in the areas of wound and destroyed skin [28]. The various dressings used for wound healing are classified as follows.

14.3.1  According to nature of action Based on the nature of action, wound dressing materials can be classified as follows: 1. Passive products – gauze and gauze-cotton composites 2. Interactive products – polymeric films and foams offering transparency, water vapour permeability, permeability to oxygen and sometimes biodegradability 3. Bioactive products – advanced dressing having the ability to transport active substances to the wound site by delivery of active substances in wound healing, e.g., collagen, chitosan and alginates [29].

14.3.2  According to the nature of materials used [28,30] According to the nature of materials, wound dressing materials can be classified as follows: 1. Traditional dressings – The most common traditional dressings are gauze and gauze-cotton composite. The main functions performed by these dressings are to absorb exudates, cushion

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the wound, allow for a dry site, hide the wound from view, provide physical protection and protect it from contamination. These traditional dressing have several disadvantages as follows [31]: a. Unable to prevent microbial invasion; low absorption of wound exudates leading to accumulation of exudates at wound surface, which is prone to microbial attack. b. Exudate leaking from the saturated surface increases the risk of infection. c. Provide a dry environment to wound; it has been observed that would healing in a wet environment is faster than with the dry environment. d. Leads to trauma to the patients at the time of removal, as they adhere to the wound bed, besides possible bleeding and damage to the newly formed epithelium [28,32,33]. e. Do not provide permeability to gases. f. Used for minor wounds and not for chronic wounds. 2. Biomaterial-based dressings – Biomaterial based dressings are classified into following [28]: a. Allografts – Most common source is fresh or freeze-dried skin fragments taken from the patients ‘relatives or cadavers’. However, there is a great risk of immune reaction and the body may reject the tissue. Suppression of immune system carried out to prevent the body’s rejection of transplanted tissue leads to increased risk of infection also. The disadvantage of these dressings is the difficulty in preparation, lack of donors, high cost and limited shelf life. b. Tissue derivatives – These materials derived from different forms of collagen, have low contamination risk, weak antigenic features and easy to prepare. However, greater risk of infection, particularly in long-term use is the main disadvantage. c. Xenografts – These are commercially available materials like the ones derived from pig skin, contrary to autografts and allografts. They can be easily sterilised and have a long shelf life. However, risk of triggering an immune response because of a foreign tissue is the main disadvantage. 3. Artificial dressings – To overcome the limitations of traditional dressings and risk of infection in biomaterial-based dressings, artificial dressings having ideal features for the treatment of wounds and burns are being developed. However, because of the difference in the pathophysiology of the wound and burn, it is very difficult to develop an artificial dressing material that meets all the requirements for an optimum healing. A lot of research is underway using natural and synthetic polymers, to develop wound dressings that can provide optimum healing conditions [28]. a. Natural polymers – collagen, chitosan, fucoidan, hyaluronic acid and its derivatives, poly-N-acetyl glucosamine b. Synthetic polymers – polyurethanes and their derivatives, Teflon, proplast, methyl methacrylate, silicon.

14.3.3  According to the physical form [28] Many pharmaceutical formulations have been developed as synthetic dressing material for wound and burn treatment. According to physical form, wound dressing materials can be classified as follows: 1. Film/membranes – These pharmaceutical dosage forms are prepared from different methods using one or more polymers. These dressings are permeable to water vapour and oxygen but not to water or microorganism.

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2. Foam dressings – Foams are highly absorbent, semipermeable dressings that help protect the surrounding skin from maceration (the softening and breaking down of skin resulting from prolonged exposure to moisture) and promote healing. This dressing normally contains hydrophilic polyurethane foam and is designed to absorb wound exudate and maintain a moist wound surface. Some foam dressings include additional absorbent materials, whereas others are silicone-coated for non-traumatic removal. They are highly absorbent and semipermeable and can help to keep surrounding skin from maceration by supporting autolytic debridement. 3. Gels – Gels are viscous, semi-solid preparations formed by dispersion of inorganic or organic substances that have larger size than colloidal particles in a liquid phase. Hydrogels are semi-solid preparations consisting of cross-linked insoluble polymers and up to 96% water. They are designed to absorb wound exudate or to rehydrate a wound, depending on wound moisture levels. These polymer dressings create and maintain a moist wound environment, provide absorption and have cleansing, desloughing and debriding capacities for necrotic and fibrotic tissues.

Within each category, the dressings are further divided into [30]: • Primary dressing – a dressing which is in physical contact with the wound bed. • Secondary dressing – a dressing that covers the primary dressing. • Island dressing – a dressing constructed with a central absorbent portion surrounded by an adhesive portion.

The dressings may not be misunderstood with the bandage; the bandage is primarily used to hold a dressing in place. In this chapter, our focus will be on the speciality wound dressings for hard-to-heal wounds.

14.3.4  Characteristics of an ideal wound dressing Because a hard-to-heal wound is the one that fails to heal with standard therapy in an orderly and timely manner so the dressings should provide optimal environment for wound healing. Characteristics of an ideal wound dressing are the following [28,30,33–38]: • Ease of application • Comfortable to remove • Bio-adhesiveness to the wound surface • Sufficient water vapour permeability • Easily sterilised • Inhibition of bacterial invasion • Elasticity and high mechanical strength • Compatibility with topical therapeutic agents • Optimum oxygen permeability • Biodegradability • Non-toxic and non-antigenic properties • Maintains moist environment around the wound • Long shelf life • Cost-effective and cosmetically acceptable • Removes excess exudates, but prevents saturation to the outer surface.

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14.4  Speciality wound dressings for hard-to-heal wounds Different types of wounds, acute or chronic, have different pathophysiology and therefore require different dressings. It is very difficult to develop a dressing which can have all the above characteristics and is suitable for all types of wounds. Difficult-toheal wounds require bioactive dressings made from different materials for serving the needs of different types of wounds. These dressings may or may not be applied along with a special therapy for faster healing of wounds. Speciality dressings are those that heal the wound by physical or chemical means or by means of physiologically active components or with more complex adjunct therapies. When addressing the needs of any individual chronic wound, we can simplify the array of speciality dressings down into a handful of broader categories based on their wound healing benefits as summarised in Table 14.1. An ever-growing population in need calls for new scientific innovations in dressings, topical devices and procedures to help better manage a variety of wound care issues. To combat factors that impede the healing process, recent research has produced promising examples of advanced technology used for chronic wounds. Commonly used advanced speciality dressings include the following.

14.4.1  Speciality dressings for controlled drug release Most often, difficult-to-heal wounds do not heal because topical medications cannot be administered in a controlled fashion and at appropriate time. To apply a drug onto a chronic wound, the dressing has to be removed, exposing the wound to potential infections and causing a good deal of discomfort to the patient. New speciality dressings have been invented that can release the drugs in a controlled manner. The bandage is made of cotton threads wrapped by a conductive shell (Fig. 14.2). The cotton threads can be encapsulated with hydrogel coatings containing antibiotics, growth factors or other drugs that can be safely embedded. The conductive, drugladen threads are laid out in a criss-cross pattern [39]. Electric current is then passed through any two threads that are perpendicular to each other, heating up the area where the threads intersect and melting the hydrogel coating, releasing the encapsulated drugs. The researchers have embedded antibiotics and vascular endothelial growth factor (VEGF) within the hydrogel and successfully tested its antibiotic properties in an in vitro study. They also evaluated the effectiveness of VEGF being delivered through the new bandage on live rats with diabetic wounds, demonstrating its ability to speed up healing in living beings [39]. In another research, scientists at the Massachusetts Institute of Technology have created a glue-coated polymer bandage that mimics the way that gecko feet (Fig. 14.3) can adhere to vertical surfaces. The glue-coated polymer consists of hundreds of thousands of nanopillars offering high surface area. Bandage is stretchy, sticks to wet places and can dissolve in the body over time at rates that can be adapted as needed, and could incorporate antibiotics or other drugs [40]. The bandage can be used for outside and inside the body, such as to repair tears, prevent leaks and replace sutures.

Table 14.1  Various

types of speciality bandages

Type

Function

Speciality dressings for controlled drug release

Release the drugs in a controlled manner

Speciality dressings for rapid control of bleeding Speciality dressing for detecting/inhibiting bacterial infections

Treat deep wounds and limit life-threatening blood loss

Speciality dressings for stimulating healing by electric current Speciality dressings for debridement Speciality dressing for extracellular matrix Stem cell dressings

4D printed structures

Regenerative bandage

Speciality dressing to combat odour

Speciality dressing for easy removal to prevent trauma and epithelial tissue damage Speciality dressing for moisture management

Detect the presence of bacterial infection Ability to kill a broad spectrum of wound-related microbes in the dressing Speed up healing by using electric current The removal of dead tissue and other potentially harmful debris Binds to the cells around the wound and promotes the growth of new skin. Deliver stem cells directly to wounds, thus greatly improving overall healing Unique hydrogels fitted with living cells that can grow, can integrate into wounds and create vital tissue structures much faster Antioxidant properties and delivers a protein that hastens the body’s own ability to heal itself. Remove deep-seated exudate and debris, which helps reduce the bulk of the odours

Aids in debridement and epidermal repair

Provides active moisture management for an optimal wound environment.

The name of the manufacturer is given in parentheses.

Commercial names and manufacturer Acticoat family of dressing with SILCRYST nanocrystals (Smith & Nephew) Celox Rapid gauze (Medtrade Products Ltd.) Axiostat (Axio Biosolutions) PuraPly (Organogenesis Inc.) KerraCel Ag3+ (Crawford Healthcare)

PosiFect (Biofisica, LLC)

Debrisoft (Lohmann & Rauscher) CollaSorb (Hartmann USA) Integra (Integra Life Sciences) Not commercialised

Not commercialised

Living Bandage (Integrated Orthopedics) Not yet commercialised Iodosorb (Smith & Nephew) Actisorb Silver 220 (Johnson & Johnson) Exuderm Odorshield Hydrocolloid (Medline Industries Inc.) Algisite M (Smith & Nephew)

HydroTac (Hartmann) BeneHold TASA (Vancive Medical Technologies) Biatain Alginate dressings (Coloplast)

Speciality dressings for managing difficult-to-heal wounds

401 Conductive coating

Hydrogel coating Cotton thread

Figure 14.2  Structural design of threads in smart bandage for controlled drug release. From P. Mostafalu, G. Kiaee, G. Giatsidis, A. Khalilpour, M. Nabavinia, M.R. Dokmeci, S. Sonkusale, D.P. Orgill, A. Tamayol, A. Khademhosseini, A textile dressing for temporal and dosage controlled drug delivery, J. Control. Release 238 (28) (September 2016) 114–122.

Figure 14.3  Photo of the underside of a foot of the house gecko (Hemidactylus frenatus) showing the expanded adhesive pads on the toes. This image was first published by T. Gamble, E. Greenbaum, T.R. Jackman, A.P. Russell, A.M. Bauer, Repeated origin and loss of adhesive Toepads in Geckos. PLoS One 7(6) (2012) e39429. Available at: http://dx.doi.org/10.1371/journal.pone.0039429.

14.4.2  Speciality dressings for rapid control of bleeding After a traumatic accident, it is vital for victims to receive treatment as soon as possible. To properly treat deep wounds and limit life-threatening blood loss, it is imperative to stop bleeding immediately. Often, the compresses found in first aid kits are not powerful enough to stop profuse bleeding. Celox Rapid gauze, Chito-R made of proven Celox Chitosan granules plus a small amount of proprietary bio-adhesive makes the dressing hold in place on the wound 50 times stronger than other dressings (Fig. 14.4). This results in a significantly faster plug formation that stops bleeding with less treatment time [41]. The new bio-adhesive is a well-known added “NF”–grade ingredient – meeting the US National Formulary requirements to add to pharmaceuticals – and is widely used in medical and drug products. Military and Law Enforcement customers in the United States and NATO allied nations have chosen Celox Rapid through their selection process for its effectiveness and rapid treatment time.

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Figure 14.4  Celox Rapid gauze. From N.R. Kunio, G.M. Riha, K.M. Watson, J.A. Differding, M.A. Schreiber, J.M. Watters, Chitosan based advanced hemostatic dressing is associated with decreased blood loss in a swine uncontrolled hemorrhage model, Am. J. Surg. 205 (5) (May 2013) 505–510.

Axio Biosolutions, a medical start-up located in Bengaluru, India, has developed a smarter emergency wound haemostat. The company’s recently released dressing, Axiostat, is gaining popularity across Indian hospitals and in military as an important tool to stop bleeding after trauma. The haemostat uses chitosan, a polymer found in shellfish, to halt bleeding within the first few minutes of injury [42]. HemCon products are fabricated from chitosan, a naturally occurring, biocompatible polysaccharide. Chitosan is a positively charged polysaccharide that attracts blood cells which are negatively charged. This attraction causes an extreme adherence when in contact with blood. The red blood cells form a very tight coherent seal over the wound as they are drawn into the bandage (Fig. 14.5). As the red blood cells and platelets are drawn towards the bandage through this ionic interaction, a strong seal is formed at the dermal wound site. This supportive, primary seal allows the body to effectively activate its coagulation pathway, initially forming organised platelets. The platelets and red blood cells continue to be drawn towards the bandage and travel up the access tract to strengthen the initial seal [43].

14.4.3  Speciality dressing for detecting/inhibiting bacterial infections in healing wound Sometimes the healing process is stopped because of the growth of infection in the wound. Therefore, it is very important to clean the wounds before infections develop further. A team of British scientists has developed a smart wound dressing that can detect the presence of bacterial infection by glowing green (as shown in Fig. 14.6), when in contact with a bacterial film, an encapsulated mass of bacteria protected by a film through which passing the drugs is difficult [44]. The dressing is made of a hydrated agarose film in which the fluorescent dye–containing vesicles are mixed with agarose and dispersed within the hydrogel matrix. The static and dynamic models of wound biofilms, from clinical strains of Escherichia

Speciality dressings for managing difficult-to-heal wounds

Nonstick backing

Blood vessel

403

Chitosan pad

Blood cells

Area of detail HemCon bandage

Figure 14.5  Working of a HemCon bleeding control bandage. From HemCon®BandagePROTricol Biomedical, 2018, Available at: https://www.tricolbiomedical.com/product/the-hemostatichemcon-bandage.

Figure 14.6  Dressing for detecting bacterial infections. From N.T. Thet, D.R. Alves, J.E. Bean, S. Booth, J. Nzakizwanayo, A.E. Young, B.V. Jones, A.T. Jenkins, Prototype development of the intelligent hydrogel wound dressing and its efficacy in the detection of model pathogenic wound biofilms, ACS Appl. Mater. Interfaces 8 (24) (June 22, 2016) 14909–14919.

coli, Pseudomonas aeruginosa, Staphylococcus aureus and Enterococcus faecalis were established on nanoporous polycarbonate membrane for 24, 48 and 72 h, and the dressing response to the biofilms on the prototype dressing was evaluated. The dressing indicated a clear fluorescent/colour response within 4 h only, observed when in contact with biofilms produced by a pathogenic strain. The sensitivity of the dressing to biofilms is dependent on the species and strain types of the bacterial pathogens involved, but a relatively higher response was observed in strains considered good biofilm formers.

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Figure 14.7  Crab shell bandage. From Press Release: Novel Antibacterial Wound Cover Could Prevent Thousands of Infections Each Year, May 1, 2017. Taken from https://en.wikipedia.org/wiki/ Crustacean#/media/File:Shrimps_at_market_in_Valencia.jpg

Massachusetts-based medtech company Organogenesis Inc. has developed PuraPly, their new anti-biofilm wound matrix. The wound dressing uses collagen and antibacterial Polyhexanide (polyhexamethylene biguanide) as a barrier that, in conjunction with biofilm debridement, can halt biofilm reproduction and prevent infection [45]. For years, doctors have used alginate – derived from actual seaweed – to create effective and powerful bandages. Researchers from the University of Bolton have unveiled another bandage created from sea life, i.e., crab shells [46]. The bandage is made from chitosan, a mineral that’s found in most crustacean shells (Fig. 14.7). The antimicrobial hydrogel wound dressing has been developed by means of radiationinitiated cross-linking of hydrophilic polymers, i.e., by well-established technology comprising gel manufacturing and its sterilisation in one process. The approach included an admixture of chitosan of relatively low molecular weight dissolved in lactic acid (LA) into the initial regular components of the conventional hydrogel dressing based on poly(N-vinyl pyrrolidone) and agar. Presence of LA in the system influenced essential radiation and technological parameters of hydrogel manufacturing. Nevertheless, essentially physical characteristics of the hydrogel was not affected, except for somewhat increased water uptake capacity, which in turn improves functionality of the dressing as extensive exudate for the wound can be efficiently absorbed. Preliminary microbiological studies showed antimicrobial character of the chitosan-containing hydrogel towards gram-positive bacterial strain [47]. Silver is a widely used antimicrobial agent, yet, when impregnated in macroscopic dressings, it stains wounds, can lead to tissue toxicity and can inhibit healing. Recently, polymeric nanofilms containing silver nanoparticles have exhibited antimicrobial activity at loadings and release rates of silver that are 100 times lower than conventional dressings. The dressing is fabricated from a silver nanoparticle–loaded polymeric nanofilm that is laminated with a micrometer-thick soluble film of polyvinyl alcohol (PVA). When placed on a moist wound, the PVA dissolves, leaving the silver-loaded nanofilm immobilised on the wound bed [48]. Leading UK wound Care Company Crawford Healthcare has developed a wound dressing, KerraCel Ag3+ which is a carboxymethyl cellulose bandage that acts as a

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quick-absorption gel [49]. Crawford claims that this particular silver ion is six times more powerful in disrupting biofilms and killing bacteria than traditional silvers. AQUACEL Ag Extra dressings provide controlled release of ionic silver as the wound exudate is absorbed into the dressing [50]. The dressing has good strength, absorbency, wear time and the ability to kill a broad spectrum of wound-related microbes in the dressing. A naturally grown bandage for minor skin cuts, scrapes and burns has advantages over those generic bandages that can be bought in a box at a drugstore. Plants such as lamb’s ear and marsh woundwort have built-in antibacterial properties that can be directly applied to the skin, and an animal product like egg membrane can heal a burn faster than sutures.

14.4.4  Speciality dressings for stimulating healing by electric current Electrical stimulation has been the most studied biophysical device for healing chronic wounds to date, primarily utilised by physical therapists and physiatrists [51–54]. When a cut or scrape occurs, the body releases a slight electric signature at the edges of the wound to signal the surrounding cells to begin replicating into the cut. The electrical bandage mimics this signature across the whole wound, causing the cells under the scrape to begin replicating up as well. This means that rather than just the edges healing, the whole wound heals at the same pace. The different metal dots on the bandage cause voltage to move between them when wet, mimicking the body’s own response and stimulating growth (Fig. 14.8). An abundance of studies advocate the beneficial healing effect of electrical stimulation at various modes and frequencies for a variety of chronic wounds [55–58]. Extracorporeal shock wave therapy (ESWT) has been used for a number of years for a variety of musculoskeletal conditions and has recently been adapted for the treatment of cutaneous wounds human or veterinary surgical wounds, accidental or military trauma and in sports injuries. Several recent reviews and one study comparing ESWT with HBOT on DFU healing support its potential role in expediting wound repair [59–62]. Researchers at the University of Manchester have developed an electronic bandage that can speed up healing by using electric current [63]. They recruited 40 volunteers who had two identical wounds created on their inner arms using a punch biopsy. One was allowed to heal naturally, while the other was treated with electric current delivered in pulses over a period of 2 weeks. The researchers showed substantial increase in new vascular growth within the treated wound that healed faster than the untreated one. NASA has also developed a new material that uses electricity to significantly promote healing of injured wounds (Fig. 14.9). In conditions of non-earth gravity, human blood displays behaviour quite different from that on earth. Wounds are likely to heal much more slowly and considering the survival risks and the cost of space missions, healing wounds as fast as possible is crucial. The new material generates a small amount of electricity when interacting with another surface, including human skin. The material, called polyvinylidene fluoride (PVDF) has numerous possible applications, including wound healing. It is proven that wounds tend to heal much more

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Figure 14.8  Electronic bandage. From S. Ud-Din, A. Sebastian, P. Giddings, J. Colthurst, S. Whiteside, J. Morris, et al., Angiogenesis is induced and wound size is reduced by electrical stimulation in an acute wound healing model in human skin, PLoS One 10 (4) (2015) e0124502, Available at: https:// doi.org/10.1371/journal.pone.0124502.

Polyvinylidene fluoride, or PVDF

Figure 14.9  NASA Electroactive bandage. Reprinted from NASA Langley’s Technology Gateway, Electroactive Material for Wound Healing, after copyright permission “Image Credit: NASA”.

quickly if small amounts of electricity are applied to the surrounding tissue. However, the gauze pattern is also essential to the healing process. If the PVDF fibres are aligned correctly, cells on a wound use it as a scaffold, helping the wound to heal faster. The easiest way to align the fibres is to make gauze, which also creates an additional layer of protection against infection. The electroactive device can also be used for military personnel wounded in the battlefield, surgical incisions and serious wounds. Another bioelectric wound dressing, named the PosiFect, has been used in treating pressure and venous ulcers [64,65]. This dressing contains a miniature electrical circuit delivering a micro-current to the wound bed for a minimum of 48 h and has shown promise in treating these chronic wounds.

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14.4.5  Speciality dressings for debridement The removal of dead tissue and other potentially harmful debris known as ‘debridement’ is a vital component for any effective wound healing. There are already several kinds of debridement, including surgical, mechanical and those debridement procedures involving maggots. Researchers from Australia have created a new fast-acting vacuum plaster. Vacuums have been used in wound healing to some extent for several years. However, these required small battery packs, which needed frequent recharging and made travelling difficult. This new plaster, called ‘Nanova’, is small and lightweight and connects to a vacuum pump that is the size of a standard smartphone [66]. It works by creating an area of negative pressure that removes dead tissue and other debris. The added pressure also encourages increased blood flow, which causes the wound to heal faster. Ultrasound, most frequently used for diagnostic and musculoskeletal therapy purposes, has also assumed a role in wound management. Several lower frequency devices are currently available for debridement that uses the delivery of sound waves to generate cavitation at the wound bed [67]. Wounds with thick fibrinous slough and necrosis can thereby be very aggressively debrided with low-frequency ultrasound devices, although trials to show improved healing rates have not been conclusive [67–69]. One of the ‘old’ techniques in wound care is maggot debridement therapy (MDT). MDT is also known as maggot therapy, bio-debridement or larval therapy. In MDT, live and ‘medical-grade’ fly larvae are applied to the patient’s wounds to achieve debridement, disinfection and, ultimately, wound healing [70]. MDT is indicated for open wounds and ulcers that contain gangrenous or necrotic tissues with or without infection [71]. The beneficial effects of using larvae were first noted in 1557 [72], but with the introduction and widespread use of antibiotics in the 1940s, it was gradually neglected by doctors. In recent years, with the rising incidence of drug resistance, there has been renewed interest in using maggots in chronic wound management [73], particularly in treating wounds infected with methicillin-resistant S. aureus and other drug-resistant pathogens. MDT not only shortened the healing time but also improved the healing rate of chronic ulcers; therefore, it may be a feasible alternative in the treatment of chronic ulcers [74].

14.4.6  Speciality dressing for extracellular matrix The use of dried and processed fish skin works as an extracellular matrix that binds to the cells around the wound and promotes the growth of new skin. Fish skin contains omega-3 fatty acids that offer natural anti-inflammatory properties that can speed-up healing. Fish skin not only poses lower viral disease risk than other natural human and animal skin substitutes but also requires little processing. Others include pig intestines, foetal cow skin and human allograft (the epidermal and dermal skin layers of human cadavers). A group of researchers in China [75] were able to speed up skin wound healing on mice using collagen (Fig. 14.10) obtained from the skin of tilapia fish K.

14.4.7  Dressings through tissue engineering A revolutionary dissolvable scaffold for growing new areas of skin could provide a safer, more effective way of treating burns, diabetic ulcers and similar injuries.

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Figure 14.10  Fish skin for wound healing. From T. Zhou, N. Wang, Y. Xue, T. Ding, X. Liu, X. Mo, J. Sun, Development of biomimetic tilapia collagen nanofibers for skin regeneration through inducing keratinocytes differentiation and collagen synthesis of dermal fibroblasts, ACS Appl. Mater. Interfaces 7 (5) (2015) 3253–3262.

Ultra-fine, 3-dimensional scaffold, which is made from specially developed polymers, looks similar to tissue paper but has fibres 100 times finer. Before it is placed over a wound, the patient’s skin cells (obtained via a biopsy) are introduced and attach themselves to the scaffold, multiplying until they eventually grow over it. Researchers from the Newcastle University in United Kingdom have found a novel way to deliver stem cells directly to wounds, thus greatly improving overall healing [76]. The team suspended the cells in alginate dressing, which allows for a timereleased schedule and much more adaptability. The healing process in both severe burns and pressure ulcers can be faster using these dressings. Moreover, these special bandages (Fig. 14.11) can be stored at much lower temperatures, thus prolonging their shelf life and helping to lower total costs.

14.4.8  4D-printed structures Wound dressing made from 4D-printed structures made of unique hydrogels fitted with living cells that can grow [46], can integrate into wounds and create vital tissue structures much faster have been developed for hard-to-heal wounds. The technology could also be used to create new surgical tools less prone to infection because they are made of biodegradable materials.

14.4.9  Regenerative bandage A research team of biomedical engineers from North-western University has devised a novel therapeutic regenerative bandage (Fig. 14.12), which has antioxidant properties and delivers a protein that hastens the body’s own ability to heal itself. The regenerative bandage is composed of a thermo-responsive, biocompatible material, which when applied to the wound as a liquid, solidifies into a gel at body temperature. The

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Figure 14.11  Stem cell dressing. From S. Swioklo, A. Constantinescu, C.J. Connon, Alginateencapsulation for the improved hypothermic preservation of human adipose-derived stem cells, Stem cells Transl. Med. 5 (3) (2016) 339–349.

Figure 14.12  An immunofluorescence image showing regenerated dermal tissue (in pink) in wounds treated with regenerative dressing. From Y. Zhu, R. Hoshi, S. Chen, J. Yi, C. Duan, R.D. Galiano, H.F. Zhang, G.A. Ameer, Sustained release of stromal cell derived factor-1 from an antioxidant thermoresponsive hydrogel enhances dermal wound healing in diabetes, J. Control. Release 238 (September 28, 2016) 114–122.

researchers incorporated a protein, called stromal cell–derived factor-1, into the gel [77]. The human body innately uses this protein to elicit the homing of repair cells (stem or progenitor cells) to the site of injury, where they produce new blood vessels, thus increasing blood flow and promoting wound healing. The slow release of this protein from the biocompatible material mimics the body’s innate healing response. The thermo-responsivity of the material enables safe wound dressing changes by rinsing with cool saline, thereby preventing re-injury of the healing tissue during bandage replacement. The study shows that the regenerative bandage promotes diabetic wound healing four times quicker than a conventional bandage, without side effects. The researchers showed increased blood flow to the wound with the use of the regenerative bandage,

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Self-healing via ion-dipole interaction

Transparent, self-healing artificial muscle

Figure 14.13  Self-healing dressing. Reproduced from Y. Cao, T.G. Morrissey, E. Acome, S.I. Allec, B.M. Wong, C. Keplinger, C. Wang, ATransparent, self-healing, highly stretchable ionic conductor, Adv. Mater. 29 (10) (2017) 1605099, with Copyright permission Wiley-VCH Verlag GmbH & Co. KGaA.

suggesting that the biological wound repair process, which is impaired in diabetic patients, is partially restored by the regenerative bandage. In another innovation, a transparent, self-healing, highly stretchable ionic conductor has been developed, which autonomously heals after experiencing severe mechanical damage (Fig. 14.13). The design of this self-healing polymer uses ion–dipole interactions as the dynamic motif [78]. This phenomenon is an attraction between ions and molecules with two magnetised poles. Even when pulled apart, the ion and molecule are eventually drawn back together. It can be stretched up to 50 times without losing its durability. When it is finally cut or torn, the material will heal in just less than 24 h, and it can be stretched again right after it is finished healing. It is worth noting that the material works best at room temperature, and the impact of cold has yet to be fully established. Cellular and tissue-based products (CTPs) are another type of speciality dressing having particular benefit to chronic non-healing wounds as they work to stimulate wound healing by utilising the patient’s own cells to rebuild tissues [79]. These products can be acellular, containing no cells, or cellular, containing living cells. Acellular products consist of a porous matrix that functions by binding to the patient, allowing matrix–cell interactions that produce growth factors which encourage regenerative cell growth. Cellular products usually contain fibroblasts and keratinocytes (epidermal cells) embedded in a collagen dressing that works to form an epidermal skin layer. While initiating the healing process, CTPs are also successful at maintaining a moist wound bed, which is the key to proper healing.

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14.5  Allied developments for wound management There are various speciality dressings and therapies that were evolved not only for healing the chronic wounds but also to accelerate healing of common wounds.

14.5.1  Speciality dressing to combat odour Iodosorb is a unique gel formulation of cadexomer iodine and used to treat a number of wound types, including pressure sores, DFUs and venous stasis ulcers [80]. By layering over the entire surface of a given wound, Iodosorb can remove deepseated exudate and debris, which helps reduce the bulk of the odours. Additionally, the gel absorbs any accompanying fluids and drainage. Because the gel can help reduce the entire bacterial load within a wound, patients experience less intense pain and improved healing times. Iodosorb also changes from dark red to white when it is time for a change, offering patients and caregivers an especially handy notification tool. Actisorb Silver 220 is another dressing specifically designed to help treat the most malodorous of infected wounds, including leg ulcers, faecal fistula and fungating lesions [81]. It comprises carbon fibre suspended in nonwoven nylon. This allows the dressing to absorb several of the key components responsible for foul odours, namely fatty acids, harmful toxins and stagnated wound degradation substances like hyaluronic acid. The dressing can also help cut back the size and spread of bacterial colonies, which not only further helps with odour but also reduces the likelihood of infections. When it comes to smaller wounds, mainly various cuts and lesions, the Exuderm Odorshield Hydrocolloid [82] is the preferred option for many physicians and caregivers. This is especially true when it comes to minimal-drainage sacral wounds like leg and pressure ulcers, among others. The Exuderm works on cyclodextrin, an industrial-grade odour absorber that is also used in many home-based cleaning products. The Hollister Restore Dressing [83] is built specifically to combat intense woundbased scents with less emphasis on wound healing or bacterial load capacity. But it does have one of the more pronounced usage rates, as the dressing can fight odours for up to 40 h depending on size and severity. The dressings feature a porous plastic composition and design aesthetic that contours to individual body parts, both of which offer added comfort for the patient.

14.5.2  Speciality dressing for easy removal to prevent trauma and epithelial tissue damage during healing A team of scientists from Boston University have created a new burn dressing that can be wiped off painlessly. The dressing is made by combining a polyethylene glycol cross-linker and a lysine-based dendron, resulting in a specialised form of hydrogel [84]. Over the last several years, hydrogels have become increasingly popular in wound care, as the material aids in debridement and epidermal repair. There have been a number of other hydrogel-based dressings released over the last decade or so, but not all of them have been geared towards easy removal or the unique needs of burn patients.

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So, rather than being cut or removed via mechanical debridement, this hydrogel can be applied to patients’ burns and then washed off as needed, as the wound dressings dissolve with a liquid form of the compound cysteine methyl ester. The dressings also help maintain moisture within the wound site, absorb excess fluids and can prevent bacterial infection. Calcium alginate dressings are made from salts of alginic acid obtained from algae (Phaeophyceae sp.) found in seaweed. They are known for absorbing excess wound exudate and forming a non-adherent gel, which accelerates wound healing by promoting a moist wound healing environment, facilitating debridement and helping to prevent trauma to the wound bed and the surrounding skin [85]. Calcium alginate dressings are used on moderate to heavily exudative wounds during the transition from debridement to repair phase of wound healing [86,87].

14.5.3  Speciality dressing for moisture management Lamke et al. [88,89] reported that the rate of water loss at a surface temperature of 35°C from normal skin is 204 ± 12 g/m2 per day, whereas it is 279 ± 26 g/m2 per day for first-degree burn and 5138 ± 202 g/m2 per day for granulating wound. Therefore, water loss from a severely burnt skin is 20 times more than the normal skin. The water vapour permeability of a wound dressing should prevent both excessive dehydration and build-up of exudates. Wong [89] has recommended that a water loss of 2000– 2500 g/m2 from the injured skin is optimum for a risk-free healing of the wound. It has been observed that wound healing is faster in moist environment, with the hydrogel dressings as compared with gauze dressings [88,89]. HydroTac is a foam dressing with a gas-permeable, waterproof and bacteria-proof cover film. On the wound side, the dressing is coated with net-shaped hydrogel. For moist wounds, the exudate is absorbed by a layer of foam, while dry wounds are kept moist with active moisture release [90]. It provides active moisture management for an optimal wound environment. BeneHold (Fig. 14.14) Thin Absorbent Skin Adhesive (TASA) is a new adhesive technology that represents an innovative implementation of the traditional hydrocolloid adhesive concept [91]. Wound dressings made using TASA resembles semipermeable film dressings: they are thin, transparent and highly conformable. However, unlike semipermeable film dressings, they are also able to absorb and retain fluids such as wound exudate, and in that sense their function is as a hydrocolloid. TASA dressings combine two different moisture management mechanisms in one material: whereas most semipermeable film dressings rely entirely on moisture vapour transmission and most hydrocolloids rely entirely on moisture retention, TASA handles moisture in both ways. The way that TASA combines hydrophilic and hydrophobic material results in a material that remains integrated (i.e., does not break down) even after absorbing fluid, does not have an odour and allows for visualisation of the underlying wound throughout the entire wear time. Alginate dressings are absorbent wound care products that contain sodium and calcium fibres derived from seaweed. They come in the form of flat dressings that can be placed over open ulcers and rope dressings that are used for packing the wound, which

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Figure 14.14  BeneHold TASA. From BeneHold™ TASA™ Thin Absorbent Skin Adhesive – Vancive Medical, 2017, Available at: https://vancive.averydennison.com/content/.../TASA%20Clinical%20 Handout.pd.

absorb fluids and promotes healing with pressure ulcers, DFUs, or venous ulcers. An individual dressing is able to absorb up to 20 times its own weight. These dressings, which are easy to use, mould themselves to the shape of the wound, which helps ensure that they absorb wound drainage properly. This also makes these dressings ideal for using on ulcers in areas that are difficult to dress, such as heels and sacral areas. Alginate dressings are dry when initially placed on an open wound and become larger and more gel-like as they draw in fluids. This helps clear out the wound, prevents it from becoming dry and protects it from harmful bacteria, which helps lower the risk of infection. These dressings also help promote new skin growth during the wound healing process by ensuring that the wound area stays moist. This encourages natural debridement via enzymes, which supplements the wound care provided by wound care practitioners in a clinical setting. Alginate dressings can also help wounds that are bleeding. The calcium in these dressings helps stabilise blood flow, which slows bleeding [92].

14.5.4  Negative-pressure wound therapy Negative-pressure therapy has assumed a major role in the management of traumatic, acute and chronic wounds and for stabilising skin grafts, flaps and surgical incisions. In this therapy, wound is sterilised and sealed with the application of a dressing. After that a pump is attached to create an adjustable negative pressure inside the sealed wound [92–98]. Negative pressure aims to pull dangerous pathogens from the wound to ensure the faster healing of wound with a lower risk of infection. NPWT very efficiently manages wound drainage and can provide expedited granulation tissue development, wound area contraction/reduction, preparation for delayed closure or grafting or primary healing for managing open amputation wounds, DFUs, VLUs and other wounds. NPWT is also quite useful as a bolster to enhance the incorporation of skin grafts onto recipient wound beds [99]. Overall, negative pressure treatment offers several advantages to patients and healthcare providers. However, careful selection of those undergoing the therapy is crucial to its success.

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14.5.5  Bacteriophage therapy Bacteria are seen as the enemy of most wound care regimens, the cause of so much pain and issues with delayed healing. However, researchers in the United States and Europe have used these microbes as a treatment option in the so-called phage therapy option [100]. This is because of antibiotic-resistant bacteria, which have developed immunity to many of today’s most powerful drugs. These microphages, taken from sewers in Paris and rivers in India, are an unknown quantity to most of these microbes and are thus quite effective at diminishing whole colonies.

14.5.6  Hyperbaric oxygen therapy Often used as a last resort, hyperbaric oxygen therapy (HBOT) is extremely effective wound care technology that reduces the risk of amputation, particularly for patients with diabetes. During hyperbaric oxygen therapy, the body is exposed to 100% oxygen at a high pressure to expedite healing. Hyperbaric oxygen therapy is delivered in a hyperbaric oxygen chamber in which the patient is completely immersed, or through a gas mask delivering 100% oxygen to the lungs. Although not as effective as the other methods, topical hyperbaric oxygen therapy can be applied to one part of the body, e.g., the leg – by wrapping it in a plastic bag that is filled with pressurised oxygen. HBOT has been advocated as being beneficial for a wide variety of chronic wounds like DFUs and VLUs for over two decades. The recent Cochrane review in 2012 indicated significant short-term improvement for healing DFUs over controls at 6 weeks. However, this benefit was not evident at 1 year or longer [101–108].

14.6  Future of wound care Despite all the above-mentioned options, there are many wounds resistant to treatment and a variety of new techniques are being researched. These include tissue engineering techniques like stem cells and gene therapy for achieving wound closure [109,110]. Stem cells have the ability to migrate to the site of injury or inflammation, participate in regeneration of damaged tissue, stimulate proliferation and differentiation of resident progenitor cells, secreting growth factors, remodelling matrix, increasing angiogenesis, inhibiting scar formation and improving tensile strength of the wound [111–114]. Adipose-derived stem cell alone or with platelet-rich plasma is a promising tool in chronic wound healing but the delivery techniques and complete effect needs to be studied and refined [115]. Recently, stem cell–based skin engineering along with gene recombination represents an alternative tool for regenerative strategy for wound therapy [116,117]. Current drug delivery strategies cannot control loss of drug activity because of physical inhibition and biological degradation. So to optimise the delivery of factors for maximum efficacy, a molecular genetic approach is being researched in which genetically modified cells synthesise and deliver the desired growth factor in a time-­ regulated and locally restricted manner to the wound site to promote wound healing. Their action may be further strengthened by implanting them in a biomaterial scaffold

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which promotes cell adhesion, proliferation, migration and differentiation. Stem cells might emerge as an exciting target for gene transfer in tissue repair [118–120]. If stem cells could be instructed to differentiate into one particular lineage and functionally integrate into injured tissue environment, they can replace cells that have been lost.

14.7  Conclusion Chronic wounds include, but are not limited, to DFUs, VLUs, and pressure ulcers. They are a challenge to wound care professionals and consume a great deal of healthcare resources around the globe. Although often difficult to treat, an understanding of the underlying pathophysiology and specific attention towards managing these perturbations can often lead to successful healing. Overcoming the factors that contribute to delayed healing are key components of a comprehensive approach to wound care and present the primary challenges to the treatment of chronic wounds. Basic tenets of care need to be routinely followed, and a systematic evaluation of patients and their wounds will also facilitate appropriate care. Underlying pathologies, which result in the failure of these wounds to heal, differ among various types of chronic wounds. A better understanding of the differences between various types of chronic wounds at the molecular and cellular levels should improve our treatment approaches, leading to better healing rates, and facilitate the development of new more effective therapies and speciality wound dressings. More evidence for the efficacy of current and future advanced wound dressings is required for their appropriate use. Dressings should provide the optimal environment for wound healing. For the purpose of this, speciality dressings do this by simple physical or chemical means, controlling drug delivery, rapid control of bleeding, speciality dressings for debridement, concept using tissue engineering, regenerative bandage, typically by controlling moisture levels, incorporating antimicrobial agents such as iodine, honey or silver, employing other types of topical treatments such as ointments and larvae or using physiologically active components (for example, growth factors, collagen or hyaluronic acid) or with more complex adjunct therapies (such as topical negative pressure and electrical stimulation). However, few of these dressing materials can also be used to accelerate wound healing process in normal wounds.

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[65] S. Hampton, F. Collins, Treating a pressure ulcer with bio-electric stimulation therapy, Br. J. Nurs. 15 (2006) S14–S18. [66] Acelity - NANOVA™ Therapy System, 2017, Available at: www.acelity.com/products/ nanova-therapy-system-uk. [67] M.E. Wendelken, L. Markowitz, O.M. Alvarez, A closer look at ultrasonic debridement, Podiatry Today 23 (2010) 23–28. [68] S. Amini, A. Shojaeefard, Z. Annabestani, et al., Low-frequency ultrasound debridement in patients with diabetic foot ulcers and osteomyelitis, Wounds 25 (2013) 193–198. [69] M.M. Stanisic, B.J. Provo, D.L. Larson, L.C. Kloth, Wound debridement with 25 kHz ultrasound, Adv. Skin Wound Care 18 (2005) 484–490. [70] R.A. Sherman, Maggot therapy takes us back to the future of wound care: new and improved maggot therapy for the 21st century, J. Diabetes Sci. Technol. 3 (2009) 336–344. [71] L.J. Van Veen, Maggot debridement therapy: a case study, J. Wound Ostomy Cont. Nurs. 35 (2008) 432–436. [72] H.I. Goldstein, Maggots in the treatment of wound and bone infections, J. Bone Joint Surg. Am. 13 (1931) 476–478. [73]  K.Y. Mumcuoglu, Clinical applications for maggots in wound care, Am. J. Clin. Dermatol. 2 (2001) 219–227. [74] W.D. Beasley, G. Hirst, Making a meal of MRSA—the role of biosurgery in hospital-­ acquired infection, J. Hosp. Infect. 56 (2004) 6–9. [75] T. Zhou, N. Wang, Y. Xue, T. Ding, X. Liu, X. Mo, J. Sun, Development of biomimetic tilapia collagen nanofibers for skin regeneration through inducing keratinocytes differentiation and collagen synthesis of dermal fibroblasts, ACS Appl. Mater. Interfaces 7 (5) (2015) 3253–3262. [76] S. Swioklo, A. Constantinescu, C.J. Connon, Alginate-encapsulation for the improved hypothermic preservation of human adipose-derived stem cells, Stem cells Transl. Med. 5 (3) (2016) 339–349. [77] Y. Zhu, R. Hoshi, S. Chen, J. Yi, C. Duan, R.D. Galiano, H.F. Zhang, G.A. Ameer, Sustained release of stromal cell derived factor-1 from an antioxidant thermoresponsive hydrogel enhances dermal wound healing in diabetes, J. Control. Release 238 (September 28, 2016) 114–122. [78] Y. Cao, T.G. Morrissey, E. Acome, S.I. Allec, B.M. Wong, C. Keplinger, C. Wang, ATransparent, self-healing, highly stretchable ionic conductor, Adv. Mater. 29 (10) (2017) 1605099. [79] SchaumKD, 2016 Update: cellular and/or tissue-based products for wounds, Adv. Skin Wound Care 29 (4) (April 2016) 152–154. [80] Iodosorb Cadexomer Matrix Dressings Containing Iodine, 2017, Available at: www. smith-nephew.com. ‘Key Products’ Advanced Wound Management. [81] Acelity - ACTISORB™ Silver 220 Antimicrobial Binding Dressing, 2017, Available at: www.acelity.com/products/actisorb-silver-220. [82] Exuderm Odorshield Hydrocolloid | Medline Industries, Inc, 2017, Available at: https:// www.medline.com/.../Exuderm-Odorshield-Hydrocolloid/Hydrocolloids. [83] Restore Calcium Alginate Dressing | Hollister US, 2017, Available at: www.hollister. com. ‘Wound Dressings’ Calcium Alginate Dressings. [84] M.D. Konieczynska, J.C. Villa-Camacho, C. Ghobril, M. Perez-Viloria, K.M. Tevis, W.A. Blessing, A. Nazarian, E.K. Rodriguez, M.W. Grinstaff, On-demand dissolution of a dendritic hydrogel-based dressing for second-degree burn wounds through thiol-thioester exchange reaction, Angew Chem. Int. Ed. 55 (34) (2016) 9984–9987.

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[85] D. Fanucci, J. Seese, Multi-faceted use of calcium alginates. A painless, cost-effective alternative for wound care management, Ostomy Wound Manag. 37 (November– December 1991) 16–22. [86] J. Seymour, Alginate dressings in wound care management, Nurs. Times 93 (44) (October 29–November 4, 1997) 49–52. [87] J. Belmin, et al., Sequential treatment with calcium alginate dressings and hydrocolloid dressings accelerates pressure ulcer healing in older subjects: a multicenter randomized trial of sequential versus non sequential treatment with hydrocolloid dressings alone, J. Am. Geriatr. Soc. 50 (2) (February 2002) 269–274. [88] L.O. Lamke, G.E. Nilsson, H.L. Reithner, Burns 3 (1977) 159. [89] P. Wong, Physical Evaluation of Hydrogel as a Burn Wound Dressing (MSc. thesis), University of Strathclyde, Glasgow, UK, 1980. [90]  HydroTac® - HARTMANN, 2017, Available at: https://hartmann.info/en-AU/ our-products/Wound-Management/.../HydroTac®. [91] BeneHold™ TASA™ Thin Absorbent Skin Adhesive – Vancive Medical, 2017, Available at: https://vancive.averydennison.com/content/.../TASA%20Clinical%20Handout.pd. [92] D.G. Armstrong, A.J. Boulton, P. Banwell, Negative pressure wound therapy in treatment of diabetic foot wounds: a marriage of modalities, Ostomy Wound Manag. 50 (2004) 9–12. [93] P.E. Banwell, Topical negative pressure therapy in wound care, J. Wound Care 8 (1999) 79–84. [94] M.J. Morykwas, J. Simpson, K. Punger, A. Argenta, L. Kremers, J. Argenta, Vacuumassisted closure: state of basic research and physiologic foundation, Plast. Reconstr. Surg. 117 (2006) 121S–126S. [95] N. Petrie, M. Potter, P. Banwell, The management of lower extremity wounds using topical negative pressure, Int. J. Low. Extrem. Wounds 2 (2003) 198–206. [96] A.P.S. Smith, K. Whittington, R.G. Frykberg, J. DeLeon, Negative pressure wound therapy, in: D.L. Krasner, G.T. Rodeheaver, R.G. Sibbald, K.Y. Woo (Eds.), Chronic Wound Care 5: A Clinical Source Book for Healthcare Professionals, HMP Communications, Malvern, PA, 2012, pp. 271–299. [97] V. Saxena, C.W. Hwang, S. Huang, Q. Eichbaum, D. Ingber, D.P. Orgill, Vacuum-assisted closure: microdeformations of wounds and cell proliferation, Plast. Reconstr. Surg. 114 (2004) 1086–1096 Discussion 1097–1088. [98] S.S. Scherer, G. Pietramaggiori, J.C. Mathews, M.J. Prsa, S. Huang, D.P. Orgill, The mechanism of action of the vacuum-assisted closure device, Plast. Reconstr. Surg. 122 (2008) 786–797. [99] A.L. Isaac, J. Rose, D.G. Armstrong, Mechanically powered negative pressure wound therapy as a bolster for skin grafting, Plast. Reconstr. Surg. Glob. Open 2 (2014) e103. [100] S. Reardon, Phage therapy gets revitalized, Nature 510 (7503) (June 5, 2014) 15–16. [101] W.A. Zamboni, L.K. Browder, J. Martinez, Hyperbaric oxygen and wound healing, Clin. Plast. Surg. 30 (2003) 67–75. [102] A. Abidia, G. Laden, G. Kuhan, et al., The role of hyperbaric oxygen therapy in ischaemic diabetic lower extremity ulcers: a double-blind randomised-controlled trial, Eur. J. Vasc. Endovasc. Surg. 25 (2003) 513–518. [103] G. Baroni, T. Porro, E. Faglia, et al., Hyperbaric oxygen in diabetic gangrene treatment, Diabetes Care 10 (1987) 81–86. [104] E. Faglia, F. Favales, A. Aldeghi, et al., Adjunctive systemic hyperbaric oxygen therapy in treatment of severe prevalently ischemic diabetic foot ulcer. A randomized study, Diabetes Care 19 (1996) 1338–1343.

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[105] C. Hammarlund, T. Sundberg, Hyperbaric oxygen reduced size of chronic leg ulcers: a randomized double-blind study, Plast. Reconstr. Surg. 93 (1994) 829–833. [106] L. Kessler, P. Bilbault, F. Ortega, et al., Hyperbaric oxygenation accelerates the healing rate of nonischemic chronic diabetic foot ulcers: a prospective randomized study, Diabetes Care 26 (2003) 2378–2382. [107] W.A. Zamboni, H.P. Wong, L.L. Stephenson, M.A. Pfeifer, Evaluation of hyperbaric oxygen for diabetic wounds: a prospective study, Undersea Hyperb. Med. 24 (1997) 175–179. [108] P. Kranke, M.H. Bennett, M. Martyn-St James, A. Schnabel, S.E. Debus, Hyperbaric oxygen therapy for chronic wounds, Cochrane Database Syst. Rev. 4 (2012) CD004123. [109] S.E. Hanson, M.L. Bentz, P. Hematti, Mesenchymal stem cell therapy for nonhealing cutaneous wounds, Plast. Reconstr. Surg. 125 (2010) 510–516. [110] J. Cha, V. Falanga, Stem cells in cutaneous wound healing, Clin. Dermatol. 25 (2007) 73–78. [111] A. Stoff, A.A. Riviera, N.S. Banerjee, S.T. Moore, T.M. Numnum, A. Monteros, et al., Promotion of incisional wound repair by human mesenchymal stem cell transplantation, Exp. Dermatol. 18 (2009) 362–369. [112] T. Yoshikama, H. Mitsumo, I. Nonaka, Y. Sen, K. Kawanishi, Y. Inada, et al., Wound therapy by marrow mesenchymal cell transplantation, Plast. Reconstr. Surg. 121 (2008) 860–877. [113] S.H. Ko, A. Nauta, V. Wong, J. Glotzbach, G.C. Gurtner, M.T. Longaker, The role of stem cells in cutaneous wound healing: what do we really know? Plast. Reconstr. Surg. 127 (Suppl. 1) (2011) 10S–20S. [114] M. Cherubino, J.P. Rubin, N. Miljkovic, A. Kelmendi-Doko, K.G. Marra, Adipose derived stem cells for wound healing applications, Ann. Plast. Surg. 66 (2011) 210–215. [115] K. Lau, R. Paus, S. Tiede, P. Day, A. Bayat, Exploring the role of stem cells in cutaneous wound healing, Exp. Dermatol. 18 (2009) 921–933. [116] G.G. Gauglitz, M.G. Jeschke, Combined gene and stem cell therapy for cutaneous wound healing, Mol. Pharm. 8 (2011) 1471–1479. [117] L.K. Branski, G.G. Gauglitz, D.N. Herndon, M.G. Jeschke, A review of gene and stem cell therapy in cutaneous wound healing, Burns 35 (2009) 171–180. [118] R. Langer, Biomaterials in drug delivery and tissue engineering: one laboratory’s experience, Acc. Chem. Res. 33 (2000) 94–101. [119] M. Korbling, Z. Estron, Adult stem cells for tissue repair –a new therapeutic concept? N. Eng. J. Med. 349 (2003) 570–582. [120] S.A. Eming, T. Kreig, J.M. Davidson, Gene therapy and wound healing, Clin. Dermatol. 25 (2007) 79–92.

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R. Rathinamoorthy1, S. Rajendran2 1Department of Fashion Technology, PSG College of Technology, Coimbatore, India; 2School of Engineering, University of Bolton, Bolton, United Kingdom 

15.1  Introduction Medical devices are becoming more important in the healthcare sector. Currently, there are more than 8000 generic medical devices available in the market, where some devices contain drugs [1] and these demands for countries to constantly review and regulate the regulatory frameworks. This ensures that the products are delivering the benefits as intended and are safe to use to humans. One of the major issues for companies developing and producing medical devices is that the current regulatory needs are to be updated as per the regulatory requirements and these have to be implemented during the manufacturing process [2]. The global value of medical device market is estimated at 228 billion USD and is projected to reach around 440 billion USD by 2018 from 164 billion USD in 2010. It is growing approximately at 4.4% compound annual growth rate per year. The United States is one of the largest medical devices market in the world and the value is worth about 125.4 billion USD, which represents 38% of the global medical device market in 2012 [3]. The European Union (EU) dominates the second largest medical devices market in the world, which is estimated at 100 billion Euros. The major driving countries are Germany, France, Italy, the United Kingdom and Spain [4]. China is the third largest medical devices market in the world with an average growth of 20% annually since 2009 and is valued at over 48 billion USD in 2012 [5]. The global market share of medical devices is illustrated in Fig. 15.1 [6]. Table 15.1 shows the world’s leading top 20 medical devices manufacturing companies. Medtronic Plc is the leading medical device company in the world, generating revenue of 28.8 billion USD in 2016 followed by Johnson & Johnson with the sales value of 25.1 billion USD in the second place. General Electric Healthcare is the third largest market share holder with 18.3 billion USD followed by Siemens Healthineers with a share of 15.2 billion USD [7].

Advanced Textiles for Wound Care. https://doi.org/10.1016/B978-0-08-102192-7.00015-1 Copyright © 2019 Elsevier Ltd. All rights reserved.

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Advanced Textiles for Wound Care Market share of medical devices 12.7 7.9

3.8 3.4 3.4

2.7 2.4

47.3

2.2

Dental fittings Hearing aids Computed tomography devices Ophthalmic devices and instruments Mechaniotherapy and psychological aptitude test Medical furniture Dental devices and instruments

4.4 2.2 2.2

Other medical devices Parts and accessories for medical device

Pacemakers Syringes and needles

2.2 1.8 1.4

Therapeutic respiration devices X-ray devices Orthopaedic and fracture devices

Figure 15.1  Market shares of different medical devices. Table 15.1 

Top 20 medical device manufacturing companies in the world, based on the sales report for FY 2016 Rank

Company

Value in billion $

1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20.

Medtronic Plc Johnson & Johnson GE Healthcare Siemens Healthineers Becton Dickinson Cardinal Health Philips HealthTech Stryker Baxter Abbott Laboratories Boston Scientific Danaher Zimmer Biomet Essilor B. Braun St. Jude Medical Alcon 3M Health Care Fresenius Olympus

28.8 25.1 18.3 15.2 12.5 12.4 12.4 11.3 10.2 10.1 8.4 7.8 7.7 7.5 6.8 6.0 5.8 5.5 5.4 5.4

15.2  Medical devices Medical device is defined as any instrument, apparatus, appliance, material or other article, whether used alone or in combination, including software necessary for its proper application intended by the manufacturer to be used for human beings. A medical device is a product which is used for medical purposes in patients (diagnosis,

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therapy or surgery). If applied to the body, the effect of the medical device is primarily physical, in contrast to pharmaceutical drugs, which exert a biochemical effect. A medical device does not achieve its principal intended action in or on the human body by pharmacological, immunological or metabolic means, but which may be assisted in its function by such means [8]. This definition includes devices intended to administer a medicinal product, such as a syringe driver, or which incorporates a substance defined as a medicinal product, such as a drug-eluting stent. World Health Organisation defines medical devices as any instrument, apparatus, implement, machine, appliance, implant, reagent for in vitro use, software, material or other similar or related article, intended by the manufacturer to be used, alone or in combination, for human beings, for one or more of the specific medical purpose(s) of: Diagnosis, prevention, monitoring, treatment or alleviation of disease, Diagnosis, monitoring, treatment, alleviation of or compensation for an injury, Investigation, replacement, modification, or support of the anatomy or of a physiological process, Supporting or sustaining life, Control of conception, Disinfection of medical devices providing information by means of in vitro examination of specimens derived from the human body; and does not achieve its primary intended action by pharmacological, immunological or metabolic means, in or on the human body, but which may be assisted in its intended function by such means [9].

Examples of medical devices range from simple wound dressings to life-saving devices: • Blood pressure monitors, blood sugar meters, thermometers, electrodes, external prostheses, fixation tapes, compression bandages, wound dressings, contact lenses, urinary catheters, intravaginal and intraintestinal devices [stomach tubes, sigmoidoscopes (inspect S-shaped colon), colonoscopes (inspect colon), gastroscopes (inspect stomach)], endotracheal tubes (inspect trachea), bronchoscopes (inspect bronchi), dental prostheses, orthodontic devices, intrauterine devices, ulcer, burn and granulation tissue dressings or healing devices and occlusive patches; • Devices that measure electric filed strength generated by nerves and muscles such as electrocardiograph (ECG), bioelectric impedance – commonly used in apnoea (cessation of breathing) monitoring for infants, laparoscopes, arthroscopes (inspect interior of a joint, such as the knee), draining systems, dental cements, dental filling materials and skin staples; • Cardiac pacemakers, defibrillators, heart valves, vascular grafts, internal drug delivery catheters, ventricular-assist devices, neuromuscular sensors and simulators, replacement tendons, breast implants, artificial larynxes (respiratory tract between the pharynx and the trachea), extracorporeal oxygenator tubing and accessories, orthopaedic pins, plates, replacements joints, bone prostheses, intraosseous device (a needle is injected through the bone’s hard cortex and into the soft marrow interior which allows immediate access to the vascular system); • Incontinence products (e.g., adult nappies), breast pumps for treatment of inverted nipples, muscle toning products with medical claims (such as treatment of incontinence), slimming products indicated for the treatment of clinical obesity and external heat pads claiming pain relief; • Assistive technology products such as wheelchairs, walking/standing frames, walking sticks, mobility aids for the visually impaired, rehabilitation tricycles/mobility carts, orthopaedic footwear, external limb prostheses and accessories and orthoses (lower/upper limb, spinal, abdominal, neck, head);

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• Sport support products: Heat/cold pads, bandages for sprains, compression bandages, gym equipment placed on the market specifically to measure, for example, heart rate or breathing rate – blood pressure monitors, even if intended to be used in a gym, however, would be considered to be medical devices; • Software, for instance, software intended to enhance images from X-ray or ultrasound would be considered to be medical devices. Software that is simply a patient management system or a records storage system would not, however, be considered to be a medical device; and • Products which become an accessory to a medical device: example includes steriliser for use with medical equipment, pouches for packaging re-sterilised medical devices, specific battery chargers for battery-driven electromedical devices, contact lens care products, disinfectants specifically intended for medical devices, specialised water treatment devices for use with dialysis machines and gas cylinders/pressure-release devices for use in conjunction with anaesthesia machines.

It is also important to mention that specially made devices are usually unique devices manufactured specifically for one person on the base of written prescription from a health professional. Dental appliances, prostheses and hearing aid inserts are some of the examples of the custom-made devices. The items such as dental alloys, dental ceramics and modular components for prostheses are some of the specific purpose–indented custom-made devices. It should also be noted that products which are not intended for a ‘medical purpose’ are not considered to be medical devices, although they look like medical devices. Examples include: • Baby nappies, feminine hygiene products (sanitary towels, tampons), breast pumps, tooth brushes, dental sticks, dental floss, tooth whitening/bleaching products, mattress protectors and hand-cleansing wipes; • Masks for the protection of the user (e.g., from the environment) are not medical devices. However, surgical masks (for use in an operating theatre) are medical devices as they are intended to protect the patient rather than the user. Mouth guards are only medical devices when intended for a specific ‘medical’ purpose, for example as a retainer following orthodontic treatment; and • Latex/rubber gloves – examination gloves and surgical gloves are medical devices. Gloves for other purposes would not be devices (e.g., for use in the home or in a laboratory). There is no provision under the medical device regulations for disinfectants intended primarily for use with medical devices to have subsidiary claims for multipurpose use; therefore, such products may only be CE marked where they are intended for use on medical devices.

15.3  Phases in the life span of a medical device The phases in the life of a medical device are given in Fig. 15.2, from the conception of a medical device to its disposal [10]. The activity phases are simplified to make it easier to understand the regulatory system. For example, the development phase includes development planning, design verification/validation, prototype testing and clinical trials. The stages in the life span of medical devices are controlled by different persons. In general, the producers control and manage the first three phases of the medical device’s life span, from the concept of the product to design. The vendor of the medical devices controls the second portion of the life of medical device from advertising to sales.

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Pre market control

Conception and development Manufacture

Manufacturer

Post market control

On market regulation and control

Packaging and labelling Advertising Vendor Sales Use User Disposal

Figure 15.2  Major phases in the life span of a medical device [10]. Table 15.2 

Common framework for medical device regulation [10]

Stage

Control/Monitor

Person/s

Activities regulated

Pre-market

Product

Manufacturer

Placing on Market

Sale

Vendor

Post market

After sale/Use

Vendor/User

Device attributes – Safety and performance Manufacturing – Quality systems Labelling – Accurate description of the product and Clear instruction for use. Establishment registration – List of products available and the regulation requires the vendor to fill after-sales obligations Advertising – Prohibits misleading or fraudulent activities Surveillance – After-sale obligations, Clinical performance of the devices and problem identifications

Here, the term ‘Vendor’ includes importers, distributors, retailers and manufacturers who sell medical equipment. ‘Use and Disposal’ is the third and final phase of the medical device which is usually performed or controlled by the user. The complication in the part is because of the reason that the user is usually a professional in a healthcare facility or may be a patient sometimes. It is important to recognise that any of these phases can affect the safety and performance of a medical device (Table 15.2).

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Along with the above mentioned controlling factor, the regulations implemented by the government also controls the different phases of the medical device. In terms of government policies, the life span of the medical device is broadly classified into three sections namely, Pre-market control, On-market regulations and control and Postmarket surveillance. The premarket control phase controls the proper placement of the developed medical product in the market by satisfying the regulatory requirements of the country. Labelling and advertising control is maintained for correct product representation. Placing-on-market control ensures establishment registration, device listing and after-sale obligations. Post-market surveillance/vigilance ensures the continued safety and performance of devices in use.

15.4  European Medical Devices Directive Regulations The European medical devices market is the second largest medical device market in the world with the estimated value of 100 billion Euros [11]. It is estimated that, next to US market, the European market occupies about 31% of the world medical device market [12]. In 2014, around 11,000 patent applications were filled in the medical technology field with European Patent Office. This is a huge amount with a proportion of 7% of the total applications. Of these patent applications, 41% were filed from European countries (28 EU member countries, Norway and Switzerland) and 59% from other countries [13]. Within the European market, the biggest medical textile markets in Europe are Germany, France, the United Kingdom, Italy and Spain. These countries are the major (top 5) contributors of In vitro Diagnostic Device (IVD) markets in Europe [14]. Fig. 15.3 shows the medical device market share in EU. Medical Device Directive (MDD) regulates the safety and marketing of medical devices in Europe since 1990s. Medical devices are classified based on the degree of risk associated with the device usage, the amount of time the device is in contact with the human body and the degree of invasiveness of the device. In contrast to the United States, the EU adopts the following classification:

Market share in %

3 4

3

14

2 3

28

5 16

10 12

Germany France UK Italy Spain Netherlands Swiz Sweden Belgium Austria Others

Figure 15.3  European medical device market by country, based upon manufacturer prices.

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• Class I: Devices with low risk such as gloves, bandages, stethoscopes, hospital beds, wheelchairs and other patient support systems; • Class IIa: Devices with medium risk (low to medium) such as hearing aids, ECGs, ultrasonic diagnostic equipment and other electro-medical devices; • Class IIb: Devices with greater risk (medium to high) such as surgical lasers, infusion pumps (non-implantable), ventilators, intensive care monitoring equipment, etc., and • Class III: Devices with highest risk such as catheters, prosthetic heart valves.

Medical devices cannot be marketed in the EU without adhering to the stringent regulations of the MDD. One of the regulations is the affixation of the CE marking [15]. Since 14 June 1998, no medical device covered by the MDD 93/42/EEC shall be placed on the market that does not carry a CE mark. The only devices not requiring a CE mark are ‘custom-made devices’ and ‘devices intended for clinical investigations’, where the manufacturer must keep documentation in accordance with MDD.

15.4.1  Classification of medical devices The medical devices are classified as Class I, Class II (IIa and IIb) and Class III devices. The required level of the assessment will be higher for a class II device than the class I device. For a class III device the assesment creteria will be more critical than a class II device. The classification rules are set out in Annex IX of the directive. This annex includes definitions of the terminology used in the classification rules. The classification of a medical device will depend up on a series of factors, including: • The intended duration of use of the device • The nature of the device, whether the device is invasive/surgically invasive or not. • The type of application of the device, is it implantable or active? • Whether or not the device contains a substance? which in its own right is considered to be a medicinal substance and has action ancillary to that of the device.

It is usually the ‘Intended Purpose for Use’ that determines the class of the medical device and not the particular technical characteristics of the device. It is the ‘Intended Purpose for Use’, assigned by the manufacturer to the device that determines the class of the medical device and not the class assigned to other similar products manufactured by the same manufacturer or different manufacturers [16].

15.4.2  Application of the classification rules Classification of the device is determined on the basis of claims contained in the information provided with the device. The manufacturer must be sufficiently specific to devices. The manufacturer must provide a minimum requirement, either appropriate positive or negative indications, for use [17]. For any device to be mentioned as ‘Specifically intended’ as per any classification rule, the product manufacturer should evidently point out that the product or medical device is proposed for such a specific purpose in the information associated with the device. Else, the device might be considered as a normal device for general medical practice, for which it is principally designed and used. Examples of such devices

430

Table 15.3 

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Medical device rules classification

Rules

Device

Rules 1–4 Rules 5–8 Rules 9–12 Rules 13–18

Non-invasive devices Invasive devices Active devices Special rules, e.g., devices containing tissue of animal origin, drug-device

are laser printers and identification cameras, which may be used in combination with medical devices. These devices will be considered as a medical device only when the manufacturers of the device place them on the market with specific intended purpose. There are 18 rules outlined in Annex IX of the Directive and related Regulation that lay down the basic principles of classification. In MEDDEV 2.4/1 Rev. 8, these rules are further explained and descriptive examples are provided. The 18 rules are subdivided into 4 groups as shown [17] in Table 15.3: It should be stressed that there are practical issues in classifying certain devices, for instance, wound dressings are classified as either Class 1 or Class 11a or Class 11b depending on the actual application: • Intended to use as a mechanical barrier – Class 1 (absorbent pads, sticking plasters and bandaid). These dressings act as a barrier, maintain wound position or absorb exudates from the wound. • Intended to use for microenvironment of wounds – Class IIa: Devices that possess specific additional healing properties. For example, dressings intended for managing moisture at the wound bed but not intended for extensive wounds requiring healing by secondary intention. • Intended to use for exposed wounds – Class IIb: Wounds are healed by secondary intention such as granulation. • Dressings for cavity wounds, burn wounds and chronic ulcer wounds are Class IIb.

15.4.3  Compliance requirements There are three directives related to medical devices [18,19]: • Medical Device Directive (MDD) – 93/42/EEC • Active Implantable Medical Device (AIMD) Directive – 90/385/EEC • In vitro Diagnostic Device Directive (IVDD) – 98/79/EC.

The Directives 90/385/EWG (AIMD) and 93/42/EC (MDD) have been changed by Directive 2007/47/EC of the European Parliament and the Council of 5 September 2007. These changes are being applied from 21 March 2010. The following exposition refers to the MDD, although most provisions are much the same under the other two MDD. • The Medical Devices Directive (MDD) (93/42/EEC and 2007/47/EEC): Applies to all general medical devices not covered by the Active Implantable Medical Devices Directive or the In vitro diagnostic medical devices and any products of human and animal origin. The general medical devices include simple bandages to high-tech radiology equipment.

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• The Active Implantable Medical Devices Directive (AIMDD) (90/385/EEC and 2007/47/ EEC): Applies to all active devices and related accessories intended to be permanently implanted in humans. This covers all powered medical devices implanted and left in the human body such as pacemakers, implantable defibrillators, implantable infusion pumps, implantable neuromuscular stimulators and bladder stimulators • The In vitro Diagnostics Directive (IVDD) (98/79/EEC): Applies to all devices and kits used away from the patient to make a diagnosis of patient medical conditions. This covers any medical devices, reagents, reagent product kits, instruments, apparatus which is intended to be used for in vitro examination of substances derived from the human body [18].

The main purpose of these directives is to ensure device safety and performance and allow free movement of medical devices throughout EU. Twelve annexes of MDD define the compliance requirements of medical devices [20]: •  Annex I – The essential requirements which consist of general requirements and design and construction requirements.   General requirements state that the medical devices are designed and developed in such a way that, when used under the conditions and purposes intended, they will not compromise the health or safety of patients, users or other personnel. Safety, transport and storage condition are also included in this annex. Chemical, physical and biological properties such as infection and microbial contamination, protection against radiation, electrical, mechanical, thermal risks, energy supplies or energy substances and labelling requirements and instructions for use are some of the requirements covered in design and construction requirements annex. • Some of the key features listed in Annex II: EC Declaration of Conformity (Full quality assurance system) are listed below:   The manufacturer’s quality system must be registered to the applicable ISO 9000 and EN46000 standards and be subject to routine surveillance assessments. The manufacturer must declare its conformity to the MDD and affix the CE mark in compliance with Article 17 and Annex XII. The manufacturer is required to maintain its declaration of conformity for at least 5 years after the last product has been manufactured. •  Annex III: EC Type-Examination: Requires the notified body to test and evaluate a representative sample of the device to ensure that the device fully complies with the MDD’s applicable requirements and the appropriate technical standards •  Annex IV: EC Verification: This includes the EC verification conformity which requires the manufacturer of the medical device (or its authorised agent) to declare that the product complies with all appropriate MDD requirements and applicable technical specifications. • Compliance with Annex V must be coupled with the procedures defined in either Annex III or Annex VII (depending upon product classification). •  Annex VI: EC Declaration of Conformity (Product quality assurance): The manufacturer must obtain a product-quality assurance registration (final testing only) in accordance with the appropriate ISO 9000 or EN46000. •  Annex VII: EC Declaration of Conformity: Manufacturers are required to prepare appropriate technical documentations to demonstrate full compliance with the requirements of the directive and associated technical standards. •  Annex VIII: Statement Concerning Devices for Special Purposes: Manufacturers must provide specific documentation related to the intended use of custom-made devices or devices designed for clinical investigation. •  Annex IX: Classification Criteria: includes definitions, procedures for implementing rules and the classification rules themselves.

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•  Annex X: Clinical Evaluation: Requirements pertinent to devices intended for clinical investigation. These mandates include compilation of data, statements of confidentiality and documentation •  Annex XI: Criteria to be met for the Designation of Notified Bodies: Defines the selection criteria, conduct and responsibilities of those organisations designated as notified bodies. •  Annex XII: CE Marking of Conformity: Defines the physical dimensions and appearance of the CE mark.

15.4.4  CE marking Medical devices covered in one of the three EU MDD must have the CE marking before placing them in the market. CE marking is a declaration by the manufacturer that the product meets the requirements of the applicable European Directive(s). CE marking gives companies easier access into the EU and European Free Trade Area to sell their products without adaptation or rechecking. Some of the salient features related to CE markings are: • The device producer/agent should affix the CE marking. • The affixed CE marking must be visible, legible and permanent. • The identification number provided by the notification body must be provided along with the CE conformity marking. • If the CE marking is reduced or enlarged, the proportions given in the above graduated drawing must be respected. Where the directive concerned does not impose specific dimensions, the CE marking must have a height of at least 5 mm. • CE marking is required in 31 countries in Europe (28 EU member countries plus 3 signatories of EEA Treaty – Iceland, Liechtenstein and Norway). Switzerland is non-EU/EEA but it adopts EU MDD into law. • CE marking does not guarantee the quality of the products but it certifies that the device complies with the essential requirements and provides assurance to users that the products perform as intended by the manufacturers and are safe when used as intended.

A flow chart of the steps involved in marketing the medical devices is depicted in Fig. 15.4.

15.4.5  Notifying bodies Notifying Body (NB) is an independent examining board that is authorised by the regulatory body of respective courtiers (Health Ministry) to perform conformity assessment activities within the directives. Examples of NB in the United Kingdom are BSI, Amtac Certification Services Ltd, Intertek Testing and Certification Ltd, Lloyd’s Register Quality Assurance Ltd, SGS United Kingdom Ltd, UL International (UK) Ltd. The list of EU-NB are published periodically in the Official Journal of the European Communities under a List of Bodies Notified Under Directive 93/42/EEC. NB will carry out evaluation of medium- and high-risk devices (Class IIa, IIb and III) and not low-risk devices. High-risk Class IIb and III devices are to be evaluated by the NB in an experimental test setting. Some of the services of NB are the following: • Product testing • Examination certificate issue

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Manufacturer with medical device

Choose the proper directives and annexes the products apply Choose the proper conformity assessment procedure/route Prepare Design dossier (if required) Technical document Declaration of conformity Notified boby certification and register with competent authorities

CE marketing for the product and market the product

Figure 15.4  CE marking process overview.

• Technical file and design dossier evaluation • Surveillance of product and quality system and • Identification of standards.

It must be noted that the manufacture himself is fully responsible for Class I low-risk devices for the evaluation of the production process and the product itself. The NB must be impartial in its judgement of a product that is assessing. It must not engage in the design, manufacturing, maintenance or distribution of a product that is assessing.

15.4.6  Technical file The manufacturer must prepare a technical file showing that the product complies with the MDD and confirms to the essential demands. Technical file is required for all the three classes of devices. The expression ‘Technical Files’ applies to Class I, Class IIa and Class IIb devices but ‘Design Dossier’ to Class III devices. Typically, there are 12 sections in Technical File or Design Dossier as illustrated in Table 15.4. Technical File is audited by a NB. Design Dossier has to be submitted to the NB for review before CE marking of the product. After successful review, the NB issues a design examination certificate according to the Annex II.4 of the Council Directive certifying compliance with the relevant provisions of the Annex I of the MDD.

15.4.7  Conformity assessment procedure A conformity assessment procedure demonstrates that the device complies with the requirements of Directive 93/42/EEC. Compliance is a legal binding document, which is stated by establishing a Conformity Declaration. The compliance document

434

Table 15.4 

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Different sections of a design dossier or technical file

Content number

Content details

1. 2. 3. 4. 5.

Introduction Essential Requirements Checklist Risk Analysis Drawings, Design, Product Specifications Chemical, physical and biological tests 5.1 In vitro Testing – Preclinical Studies 5.2 Biocompatibility Tests 5.3 Biostability Tests 5.4 Microbiological Safety, Animal origin tissue 5.5 Coated Medical Devices Clinical Data Package Qualification and Shelf life Labels • Instructions for use • patient information • advertising materials Manufacturing Sterilisation Conclusion Declaration of Conformity (Draft)

6. 7. 8.

9. 10. 11. 12.

must contain the required and adequate information to trace the product from the user to manufacturer or the EU representative of the product. It may include a list the Directives and Standards that the product conforms to, product identification and the manufacturer’s name, address and signature. It must be verified by a Certificate of Conformity issued by a NB. The conformity assessment procedures for Class I, Class IIa, Class IIb and Class III medical devices are shown in Figs. 15.5–15.8, respectively [15]. Class I devices are not required to subject to Quality System and Technical File is not needed to be audited by NB. Instead it must be declared in Declaration of Conformity. Full Quality System is applicable to Class IIa, IIb and III medical devices.

15.4.8  Wound dressings and regulatory norms As discussed in the preceding sections, wound dressings are also classified as medical devices and are regulated by the European MDD. The European standard EN-13795 covers all the missing technical parts of MDD. It also covers aspect of the product from the design, development and production to their safe use condition, storage and packaging, including transportation, labelling and other physicochemical and microbial properties of the medical device.

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Device Declaration of conformity

Annex VII (module A) EC declaration of conformity + technical documentation

No

Is device sterile and/or have a measuring function?

Apply CE marking

Market device

Annex IV (module F) EC verification (NB verifies and certifies that every product/batch conforms with requirements of the directive) Annex V (module D) production quality assurance (NB assesses and monitors manufacturer’s quality system

Yes Manufacturer’s choice

Annex VI (module E) product quality assurance (NB assesses and monitors manufacturer’s quality system - which must undertake to examine each product or representative batch) Annex II (module H) full quality assurance. Audit by NB to ISO 13485 or similar standard

Declaration of conformity

Apply CE marking and notified body number

Market device

Figure 15.5  Class I conformity assessment procedures.

Device

Either

Or Annex VII (module A) EC declaration of conformity + technical documentation

Manufacturer’s choice

Annex II (module H) full quality assurance. Audit by NB to ISO 13485 or similar standard Annex IV (module F) EC verification (NB verifies and certifies that every product/batch conform with technical file) Annex V (module D) production quality assurance (NB assesses and monitors manufacturer’s quality system of production to ensure conformity to the directive)

Annex VI (module E) product quality assurance (NB assesses and monitors manufacturer’s quality system for at least one representative sample to ensure conformity to the directive)

Declaration of conformity

Apply CE marking and notified body number

Market device

Figure 15.6  Class IIa conformity assessment procedures.

15.4.8.1  Class I wound dressing All non-invasive devices are in Class I under classification rule 1. For example: non-sterile dressings used to aid the healing of a sprain, plaster of Paris, cervical collars, gravity traction devices, compression hosiery. All non-invasive devices which come into contact with injured skin are in Class I. However, if they are intended to be used as a mechanical barrier, compression or absorption of exudates, then rule 4 applies.

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Device

Either

Annex II (module H) full quality assurance. Audit by NB to ISO 13485 or similar standard

Or Annex III (module B) type examination (NB verifies and certifies a representative sample of the production)

Annex IV (module F) EC verification (NB verifies and certifies that every product/batch conforms with the directive)

Declaration of conformity

Annex V (module D) production quality assurance (NB assesses and monitors manufacturer’s quality system for production to ensure products conform to ‘type’)

Manufacturer’s choice

Annex VI (module E) product quality assurance (NB assesses and monitors manufacturer’s quality system - which must undertake to examine each product or representative batch)

Apply CE marking and notified body number

Market device

Figure 15.7  Class IIb conformity assessment procedures.

Device

Either

Or

Annex II (module H) full quality assurance. Audit by NB to ISO 13485 or similar standard

Design dossier examination by NB

Annex III (module B) type examination (NB verifies and certifies a representative sample of the production)

Manufacturer’s choice

Declaration of conformity Annex IV (module F) EC verification (NB verifies and certifies that every product/batch conforms with the directive)

Annex V (module D) production quality assurance (NB assesses and monitors manufacturer’s quality system for production to ensure products conform to ‘type’)

Apply CE marking and notified body number

Market device

Figure 15.8  Class III conformity assessment procedures.

For example: absorbent pads, island dressings, cotton wool, wound strips, adhesive bandages (sticking plasters, band-aid) and gauze dressings which act as a barrier, maintain wound position or absorb exudates from the wound.

15.4.8.2  Class IIa wound dressing All non-invasive devices which come into contact with injured skin are in Class IIa but the dressings, including devices principally intended to manage the micro-environment of a wound, fall under classification rule 4. Dressings that are intended to assist the healing process by controlling the level of moisture at the wound (moisture-healing concept) during the healing process and to generally regulate the environment in terms of humidity and temperature, levels of

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437

oxygen and other gases and pH values or by influencing the process by other physical means are also classified as Class IIa devices. For example: Adhesives for topical use, Polymer film dressings – Hydrogel dressings – Non-medicated impregnated gauze dressings.

15.4.8.3  Class IIb wound dressing • All non-invasive devices which come into contact with injured skin are in Class IIb if they are intended to be used principally with wounds, which have breached the dermis and can only heal by secondary intention under classification rule 4.

For example: dressings for chronic extensive ulcerated wounds – dressings for severe burns having breached the dermis and covering an extensive area – dressings for severe decubitus wounds – dressings incorporating means of augmenting tissue and providing a temporary skin substitute.

15.4.8.4  Class III wound dressing • All devices incorporating, as an integral part, a substance which, if used separately, can be considered to be a medicinal product as defined in Article 1 of the Directive 2001/83/EC and which is liable to act on the human body with action ancillary to that of the devices, are in Class III. Under classification rule 13.   For example: Dressings incorporating an antimicrobial agent where the purpose of such an agent is to provide ancillary action on the wound • All devices manufactured utilising animal tissues or derivatives rendered nonviable are Class III except where such devices are intended to come into contact with intact skin only, Under rule 17   For example: Implants and dressings made from collagen.    Fig. 15.9 represents the general medical device approval process followed in EU countries.

15.5  MDD in the United States In the United States the majority of medical device clusters are located in California, Massachusetts, New York and Minnesota regions. In the United States alone, there are more than 7000 medical device companies. The annual sales is around 110–116 billion USD per annum [21]. The US medical device market is the world largest and was estimated to 147.7 billion USD in 2016. The medical device market in the United States is projected for a growth rate at a CAGR of 6.1% over 3 years [22]. The US medical device sector directly employed 400,000 Americans and indirectly employed 2 million foreigners [23].

15.5.1  Premarket review process The federal agency responsible for regulating medical devices in the United States is the Food and Drug Administration (FDA) – an agency within the Department of Health and Human Services. A manufacturer must obtain FDA’s prior approval or clearance

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Manufacturer

Determine classificaion - as per annex VII of the medical device regulation (MDR)

Class I, IIa, IIb & III Class I - self certified

Quality management system (QMS)

Quality management system (QMS) as per annex VIII. eg. EN ISO 13485 Clinical evaluation, post market surveillance (PMS) and post market clinical follow-up (PMCF) plans must be ready Notified body audits CE technical file or design dossier (class III)

Technical file with CER (annex II)

Intented purpose of device along with testing reports, clinical evaluation report (CER), risk management plan, IFU, labeling details. Unique device identifier (UDI).

Notification body audit

CE marking certificate QMS certificate

Declaration of conformity for MDR Device registration

Figure 15.9  Medical device approval process in EU.

before marketing many medical devices in the United States. FDA’s Centre for Devices and Radiological Health (CDRH) is primarily responsible for medical device premarket review. However, the Centre for Biologics Evaluation and Research regulates devices associated with blood collection and processing procedures, cellular products and tissues [24]. It is mandatory for the medical product manufacturers to register their facilities and list their devices with FDA and follow general regulatory requirements. FDA classifies medical devices according to the risk they pose to consumers. Low-risk medical devices like plastic bandages and ice bags present no risk to the users. These devices can be marketed directly after the legal registration alone, without undergoing any regulatory procedure of the FDA. But, a device with moderate or high risk must go through all the regulatory procedures of the FDA before marketing. This approval will be granted to the manufacturer by FDA only if the products comply all the regulatory requirements like premarket and necessary post-market requirement.

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15.5.2  Code of federal regulations The Code of Federal Regulations (CFR) is a codification of the general and permanent rule published in the Federal Register by the executive departments and agencies of the Federal Government [25]. The rules of FDA are listed under Title 21 of the CFR. Each title (or volume) of the CFR is revised once in a calendar year. A revised Title 21 is issued on approximately April 1st of each year. The main parts used in the medical device acceptance are listed below [26], • 21 CFR part 800 – GENERAL • 21 CFR part 801 – LABELLING • 21 CFR part 803 – MEDICAL DEVICE REPORTING • 21 CFR part 807 – ESTABLISHMENT REGISTRATION AND DEVICE LISTING • 21 CFR part 808 – EXEMPTIONS FROM FEDERAL PREEMPTION OF STATE AND LOCAL MEDICAL DEVICE REQUIREMENTS • 21 CFR part 809 – IN VITRO DIAGNOSTIC PRODUCTS FOR HUMAN USE • 21 CFR part 810 – MEDICAL DEVICE RECALL AUTHORITY • 21 CFR part 812 – INVESTIGATIONAL DEVICE EXEMPTIONS • 21 CFR part 814 – PREMARKET APPROVAL OF MEDICAL DEVICES • 21 CFR part 820 – QUALITY SYSTEM REGULATION • 21 CFR part 821 – MEDICAL DEVICE TRACKING REQUIREMENTS • 21 CFR part 822 – POSTMARKET SURVEILLANCE • 21 CFR part 830 – UNIQUE DEVICE IDENTIFICATION

The FDA categorises and organises over 1700 distinct medical devices into Medical Speciality ‘Panels’. These panels are documented in Title 21 of the Code of Federal Regulations (21 CFR), Parts 862–892. In general, there are two different paths available for a medical device manufacturer to bring in their devices into market, if their device falls under moderate- and high-risk devices category, with FDA’s permission [27]. Path 1: Conducting clinical studies, submitting a premarket approval (PMA) application and requiring evidence providing reasonable assurance that the device is safe and effective. The PMA process is generally used for novel and high-risk devices and results in a type of FDA permission called approval. Path 2: In this process, submission of a 510(k) notification is required, by mentioning and representing a significantly equivalent device which is already exists in the market (a predicate device) that does not require a PMA. This is comparatively cheap and short path. This path is shorter and less costly. The 510(k) process is unique to medical devices and results in FDA clearance. Substantial equivalence is determined by comparing the performance characteristics of a new device with those of a predicate device.

15.5.3  Device classification Under the terms of the Medical Device Amendments of 1976 (MDA, P.L. 94-295), FDA classified all medical devices that are on the market at the time of enactment – the pre-amendment devices into one of three classes. Congress provided definitions for the three classes Class I, Class II and Class III based on the risk (low, moderate

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Table 15.5 

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Medical device classification by FDA

Device classification

Examples

Safety controls

Class I

Elastic bandages, examination gloves, hand-held surgical instruments

General controls

Class II

Powered wheel chair, infusion pumps, surgical drapes

General controls and special controls

Class III

Heart valves, silicone gel breast implants, implanted cerebella stimulator Metal on metal hip joints, certain dental implants

General controls and premarket approval General controls

Required submission Registration only unless 510(k) specifically required 510(k) notification unless exempt Investigational device exemption (IDE) possible PMA Application IDE Probable

510(k) notification

and high risk, respectively) to patients posed by the devices. Examples of each class are listed in Table 15.5. Class I – Under current law, the Class I devices are devices which are sufficient to provide reasonable assurance of the safety and effectiveness of the device. Many Class I devices are exempt from the premarket notification and/or the Quality System regulation requirements [27]. Class II – Class II includes devices that pose a moderate risk to patients and may include new devices for which information or special controls are available to reduce or mitigate risk. Special controls are usually device specific and may include special labelling requirements, mandatory performance standards and post-market surveillance. Class III – These devices are ‘represented to be for a use in supporting or sustaining human life or for a use which is of substantial importance in preventing impairment of human health’, or present ‘a potential unreasonable risk of illness or injury, to be subject to PMA to provide reasonable assurance of safety and effectiveness’. [27].

15.5.4  Premarket approval Premarket approval is one of the methods used for the totally new or high-risk devices. It is one of the strictest methods of device approval process by FDA. The product approval through PMA system is basically based on the valid scientific evidence(s), which provide a reasonable assurance that the device is safe and effective for its intended use provided in the application. In contrast to a 510(k), PMAs generally require some clinical data before FDA approval [28].

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PMA

Traditional PMA

Modular PMA

As per 21CFR 814.20b

Similar Procedure like traditional PMA

Two step process, acceptance review in 15 days and filling review in 45 days

Submit documents as different modular stages

FDA will inspect manufacturing site Out come - approvel or denial Time line : 180 days

After final modular submission, PMA number will be allotted

Streamline PMA

Product dev. process (PDP)

Used for well known technology for well known diseases. For this process, already 2–3 similar PMAs should be approved

It is a combined process of IDE and PMA Time line : 120 days after the completion of clinical study

Time line : 180 days

Time line: 90 days for each module and 180 days after final module

Figure 15.10  Classification of different PMA procedures.

The medical devices must have an investigational device exemption (IDE) before the clinical study is initiated. The process of IDE allows an unapproved device (most commonly an invasive or life-sustaining device) to be used in a clinical study to collect the data required to support a PMA submission [29]. A PMA must contain (among other things) the following information: • Summaries of nonclinical and clinical data supporting the application and conclusions drawn from the studies; • A device description including significant physical and performance characteristics; • Indications for use, description of the patient population and disease or condition that the device will diagnose, treat, prevent, cure or mitigate; • A description of the foreign and U.S. marketing history, including if the device has been withdrawn from marketing for any reason related to the safety or effectiveness of the device; • Proposed labelling; and a description of the manufacturing process

PMA procedures are shown in Fig. 15.10.

15.5.5  PMA supplements If a manufacturer wants to make an amendment to an approved PMA device, it is mandatory to submit one of several different types of PMA supplements to FDA. The various types of PMA supplements are briefly described in Table 15.6 [27,30]. The manufacturer is also required to pay a user fee, except in the case of the Special PMA Supplement. FDA provides information about approved PMA supplements on the FDA website.

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Table 15.6 

Different PMA supplements procedures in the United States Type of supplement

Type of changes to device

Data required

Reviewer

Panel-track

Significant design change; new indication

Clinical, limited preclinical data in some cases

1990

180 day

Significant design change; labelling change

Real-time

Minor design changes to device, software, sterilisation or labelling Manufacturing change Labelling change that enhances device safety

Preclinical; Confirmatory clinical data in some cases Preclinical only

Panel of subject matter experts and/ or FDA staff FDA staff

FDA staff

1997

FDA staff

1997

FDA staff

1986

30-day notice Special

No specific data required No specific data required

Year introduced

1986

15.5.6  510(k) notification For a moderate-risk medical device that is not exempt from premarket review process are the devices which generally require the 510(k) submission. This 510(k) could also be used for currently marketed devices for which the manufacturer seeks a new indication (e.g., a new population, such as paediatric use, or a new disease or condition), or for which the manufacturer has changed the design or technical characteristics such that the change may affect the performance characteristics of the device. The PMA and 510(k) pathways of approvals are fundamentally different in the review process. The safety and effectiveness of the devices are determined in a PMA review by FDA, but in case of the 510(k) review, FDA determines if the device is substantially equivalent to another device already on the market. But the safety and effectiveness of the existing device may not have been assessed previously [27,31]: •  510(k) should be submitted while • Introducing a new device in the market • Changing the indications for the use of a previously cleared device and • Making a significant modification in the previously cleared device. •  510(k) is must for • Manufacturers • Specification developers • Re-packers who change device or its labelling and • Anyone who both manufacture and distribute a medical device.

Regulatory bodies and their roles associated with medical devices and wound dressings

Sponsor prepares 510(k) application

Substantive interaction and interactive review

Submit to CDRH document control centre (DCC)

Acceptance of review

Assigned a unique k number

Hold or acknowledgement letter

443

Document control centre (DCC) checks for user fees and e copy of the proposal

Figure 15.11  510(k) Submission process.

Traditional 510(k)

Types of 510(k)

Abbreviated 510(k)

21 CFR 807 Used for any original 510(k) or for a modification to a previously cleared device under 510(k) May be used under any circumstance This process selected when, A guide document exists A special control has been established, or FDA has recognized a relevant consensus standard Use of design controls or quality system regulations to assure the substantially equivalent for device modification

Special 510(k)

May be submitted for a modification to a device, which has no affect on the intended use or alter the fundamental technology No data is evaluated by FDA Examples - changes in environmental specification, performance specification, ergonomics of the patient user interface, dimensional specification, software or firmware.

Figure 15.12  Classification of 510(k) process types.

•  510(k) is not required for • Private label distributor • Re-packers who do not change device or its labelling and • Distributors or importers who furthers marketing of the legally marketed device and does not alter the label or device.

510(k) submission and classification processes are depicted in Figs 15.11 and 15.12, respectively. The difference between 510(k) and Premarket Approval Process (PMA) is shown in Table 15.7.

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Table 15.7 

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Difference between PMA and 510(k) process

PMA process

510(k) process

Safety and efficacy Medical Device Classes: III Scientific evidence Always clinical data required Detailed lengthy application Product will be approved Timeline: 180 days

Substantial equivalent Medical Device Classes: I, II and some III Comparison with predicate device 10%–15% Application require clinical data Short application process Clearance will be given Timeline: traditional and abbreviated: 90 days special 510(k): 30 days No pre-approval inspection No post-marketing activity

Pre-approval inspection Post-marketing activities (supplements) require Not easy to replicate Advisory panel review required but not for all PMA

Easy to replicate Rare advisory panel review

15.5.7  The medical device review process: post-market requirements Once approved or cleared for marketing, manufacturers of medical devices must comply with various regulations on labelling and advertising, manufacturing and post-marketing surveillance. According to the CDRH report, the ‘current United States medical device post market surveillance system depends primarily upon’ the following sources for detecting potential problems with medical devices [27]: • Medical Device Reporting (MDR) • Medical Product Safety Network • Post-Approval Studies • Post-market Surveillance Studies • FDA Discretionary Studies and • Other Tools.

There are limitations associated with the above sources of information on post-market problems caused by medical devices.

15.5.8  Regulations pertaining to wound dressing in the United States According to FDA-Title 21 of CFR 800, the following are a few examples of Class I, Class II and Class III wound dressing devices.

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15.5.8.1  Class I wound dressing Fabric dressings that are simple and minimally invasive are designated as Class I devices. In Code of Federal Regulation, the wound dressings are sectioned under Title: 21 CFR, Part 878, General and Plastic surgery devices, Subpart E – Surgical devices [32]. • In 878.4018 – Hydrophilic wound dressings are classified under Class I (general control). • In 878.4020 – Occlusive wound dressings are classified under Class I (general control) these devices are exempted from the premarket notification procedures in part 807. • Under 21 CFR, Part 880 – General Hospital and Personal Use Devices, the bandages are listed as: • 880.5090 Liquid bandage – Class I (general controls) • 880.5075 Elastic bandage – Class I (general controls) • 880.5240 Medical adhesive tape and adhesive bandage – Class I (general controls) • 878.4014 Non-resorbable gauze/sponge for external use. • 878.4450 Non-absorbable gauze for internal use.

15.5.8.2  Class II wound dressing Medical textiles/wound dressings, which are used either as non-implantable devices (e.g., antimicrobial agents consisting of dressings or patches produced from fibres or fabrics) or as implantable devices (e.g., cardiovascular grafts) are categorised in Class II. This is because when antimicrobial agents are applied on a fibre or fabric (textile), they are considered as a drug, and the resulting device that includes the antimicrobial drug will be considered a combination product as defined in 21 CFR 3.29(e) in the EN 13795 [33]. • In 878.4015 – Wound dressing with poly (diallyl dimethyl ammonium chloride) additive is classified under Class II (Special control). • 878.4011 Tissue adhesive with adjunct wound closure device – A tissue adhesive with adjunct wound closure device intended for the topical approximation of skin.

15.5.8.3  Class III wound dressing Products containing biomaterials of human or animal origin are in Class III. Examples of Class III dressings are • 878.4010 Tissue adhesive for non-topical use. This dressing is used for adhesion of internal tissues and vessels. • 878.4490 Absorbable haemostatic agent and dressing – The intended use of the dressing is to produce haemostasis by accelerating the clotting process of blood.

Table 15.8 shows the regulatory pathways associated with different wound dressings. A flowchart of the medical device approval process in the United States is depicted in Fig. 15.13.

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Table 15.8  Wound

Advanced Textiles for Wound Care

care product categories [34]

Category of products

Examples

Regulatory pathway

Traditional Wound Management Products Wound Closure Products

Adhesive bandages, topical ointments, gauzes Internal staplers, skin staplers, surgical/ligature clips, sutures Alginate dressing, film dressing, foam dressing, hydrocolloid dressing, hydrogel dressing Skin replacements, cell-based replacement, collagen dressings, growth factors Cleansers and sealants Silver antimicrobial dressing, non-silver antimicrobial dressing

510k or monographs

Advanced Moist Wound Healing Products Active Wound Healing Products Debriding Products Antimicrobial Dressings

510k 510k or Premarket Approval (PMA) application PMA, New Drug Application or Biologics License Application 510k 510k or Premarket Approval (PMA)

15.6  Medical device regulations in Canada Canada has one of the largest economies in the world and the eighth largest medical device market. It was valued at 6.2 billion USD in 2015 and is projected to grow steadily, increasing to approximately 8.6 billion USD by 2020. Medical device imports account for 80% of the medical device market. Canada’s total healthcare expenditure is 10.4% of total GDP and the average healthcare expenditures per capita is 5292USD [35]. Medical devices in Canada are regulated by Therapeutic Products Directorate (a branch of Health Canada) and are subject to the Canadian Medical Devices Regulations [CMDR (SOR/98-282)] under Food and Drugs Act (F&D Act) (R.S., 1985, c. F-27). The Canadian Medical Device Regulation largely combines the best features of the EU’s regulations and that of the United States. The Canadian Medical Devices Regulation classifies the devices based on the risk factors similar to European regulations and assists in assigning class and determining requirements of evolving technology. The manufacturers’ quality systems are reviewed by third parties. The medical device database is accessible to the public and this allows them to identify the properly licensed devices by the regulatory authorities [36]. The manufacturing, sales, advertising for sale and importation of medical devices, including IVDs, are regulated by the Health Canada, a Canadian agency that regulates medical devices through the Medical Devices Regulations. Manufacturers must ensure that their medical devices meet the safety and effectiveness requirements as defined in the Medical Devices Regulations (SOR/98-282, Section 9).

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Manufacturer

Determine classification - as per food and drug administration (FDA) database

Class II & III Class I

ISO 13485:2003 compliant quality management system.

FDA quality system regulation (QSR)

FDA quality system regulation (QSR) found in 21 CFR part 820. Pre-submission for new/innovative product lnvestigational device exemption (IDE) - if required

Class II

Submit 510(k) premarket notification

Class III

Submit premarket approval (PMA) application.

510(k) approval

Factory audit at all facility by FDA PMA approval

Register the product in FDA database as per 21 CFR part 807 Approval for medical device

Figure 15.13  Medical device approval process in USA.

The Food and Drugs Act defines a medical device as: any article, instrument, apparatus or contrivance, including any component, part or accessory thereof, manufactured, sold or represented for use in: the diagnosis, treatment, mitigation or prevention of a disease, disorder or abnormal physical state, or its symptoms, in a human being; the restoration, correction or modification of a body function or the body structure of a human being; the diagnosis of pregnancy in a human being; or the care of a human being during pregnancy and at and after the birth of a child, including the care of the child. It also includes a contraceptive device but does not include a drug [37].

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Table 15.9 

Canada medical device classifications and regulatory requirements [38] Device Class

Risk

Examples – non-IVDD

Example – IVDD

Class I

Lowest

Manual reusable surgical instruments, hospital beds, stretchers, wheelchairs, adhesive bandages, surgical drapes, cell culture media

Microbiology and cell culture media, General diagnostic reagents

Class II

Low

Contact lenses. endoscopes, hydrogel dressing, blood bags, surgical drills

Class III

Moderate

Orthopaedic, dermal and dental implants, haemodialysis machine, surgical lasers, bone cements

Class IV

High

Cardiac pacemakers, angiography catheters, cranial shunts, replacement heart valves, closed-loop therapeutic system, cardiac sutures

Home-use pregnancy kits, lab-use arrays for glucose, complete blood count and therapeutic drug monitoring Near patient blood glucose monitors and test strips, drugs of abuse screening, diagnostic cancer marker. Transmissible diseases makers for life-threatening diseases and donor screening. E.g.: HIV

License requirements Medical device establishment license – for manufacturer, importer and distributor Medical device license manufacturer Medical device establishment license – for importers and distributors

15.6.1  Classification of medical devices The Health Canada’s Medical Devices Bureau also delivers the premarket portion of the medical devices programme to regulate the medical devices by doing product assessment and device classification, quality systems and medical device licensing. The Classification of Medical devices are assigned to Class I, II, III or IV using rules set out in Schedule 1 of the CMDR, with Class I representing the lowest risk and Class IV the highest. Separate sets of rules address IVDs. Table 15.9 shows CMDR.

15.6.2  Quality systems The manufactures must submit their medical device license application to the Health Canada for Class II, III and IV medical devices. It is mandatory to submit the ISO 13485:2003

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quality systems certificate along with the license application. The licence for the medical device is issued by a registrar recognised by the Standards Council of Canada according to the Canadian Medical Device Conformity Assessment System (CMDCAS) [39]. The license is issued after completion of the third-party audit for compliance with the Standards and CMDR and the requirements specific to the CMDCAS program. The expenses for this registration and quality audit must be borne by the manufacturer. Manufacturer’s Class I, custom-made and investigational devices are exempt from this requirement. All medical devices sold in Canada must meet the safety and effectiveness requirements of CMDR and must be labelled in compliance with the regulations [40].

15.6.3  Labelling Under the Medical Devices Regulations (SOR/98-282, Sections 21-23), all labelling on medical devices imported into Canada must be ‘legible, permanent, and prominent’ and must contain the following minimum data: • Device name • Manufacturer name and address • Control number for Class III and IV devices • Content information on the package, if the package is not transparent • For device needs to be sold in sterile condition, the word ‘Sterile’ should be printed • The date of expiry of the device • The uses and purpose of the device must be provided unless it is self-evident to the intended user and the medical conditions • Storage and usage directions

For the device which is to be sold for the public, the label information should be legible and printed outside of the package, which should be visible under normal conditions. Labelling must be in English and French and directions for use must be supplied in both official languages at the time of purchase.

15.6.4  Post-market regulation The manufacturers and distributors of all classes of medical devices are subject to the post-market regulations of Canada. The inspectors of food branch and health products conduct the post-market surveillance activity by addressing the mandatory problem reporting and recalls. Manufacturers and importers are also responsible for mandatory problem reporting. The Mandatory Problem Reporting requirement [41] pertains to any occurrence may be of normal or abnormal cases, involving with the officially sold device like 1. Related to the malfunction or stoppage of the device or a drop in its efficacy, or any insufficiency in its labelling or in its way for application. 2. Device had led to has led to the loss or a serious deterioration in the state of health of a patient, user or other person or could do so were it to recur.

In case of any serious after-effect like death, the manufacturers and importers must submit this report within 10 days to Health Canada. In case of non-serious issues, manufacturers and importers are expected to submit the Mandatory Problem Report within 30 days of the date.

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15.6.5  Regulations pertaining to wound dressings in Canada For common devices that are used as mechanical barriers or for compression or absorption of exudates, the regulation is detailed in sub-rule (1) and that is classified under Class I. Furthermore, the Class I category also consists of non-invasive devices that come into contact with injured skin [42]. As per medical device classification rule 4: (i) subject to sub-rule (ii), all non-invasive devices that are intended to come into contact with injured skin are classified as Class II. Non-invasive devices with any other intended mechanism of action or indication (e.g., promote healing, provide relief of pain and provide a moist wound healing environment), which come into contact with injured skin, are Class II. Other than the above mentioned classes, the Therapeutic Products Classification Committee also classified the combination products. Either the Medical Devices Regulations or the Food and Drug Regulations will be used for the evaluation of the combination product based on their principal mechanism of action. The general procedures for medical device approval process in Canada are provided in Fig. 15.14.

15.7  Medical device regulations in Australia Australian medical device market is one of the slow-growing markets in the world. The market was valued at 4 billion USD in 2016, down from 5 billion USD in 2014. The major reason behind this is that 80% of the medical devices used in Australia are imported [43]. In Australia, the Therapeutic Goods Administration (TGA) regulates the supply of medical devices according to criteria prescribed by the Therapeutic Goods Act of 1989 and related regulations [44]. These acts were regulated in line with the EU laws by global harmonisation approach through the Global Harmonization Task Force [45].

15.7.1  Medical device classifications Medical devices are classified into five levels based on the level of risk and the intended purpose of the device (Table 15.10), in accordance with the Therapeutic Goods (Medical Devices) Regulations 2002, Regulation 3.2 and Schedule 2, and the Therapeutic Goods Act 1989, section 41BD. The low-risk devices like hospital beds, stethoscopes, crepe bandages and wheelchairs are classified under the Class I devices. These devices can be registered using online applications in Australia. The Class I medical devices are further classified into two categories, namely Class I sterile or Class I measuring device based on their applications. The marketing of these Class I sterile or Class I measuring devices required a conformity assessment certificate. This certificate must be obtained from TGA or under any other regulatory system that is accepted by TGA [45]. Monitoring equipments, surgical instruments, stents and catheters are the devices which fall under the Class IIa and Class IIb. The marketing application of these devices must be supported by TGA’s conformity assessment certificate. The manufacturer can also produce the

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Manufacturer

Determine classificaion - as per canadian medical device regulation (CMDR)

Class II, III & IV Class I ISO 13485:2003 compliant quality management system which includes the addtional specific requirements of the CMDR. Medical device establishment license (MDEL)

Notified body audits or quality system audits by canadian medical device conformity assessment system (CMDCAS).

Canadian medical devicelicense (MDL) applicaion Class II and III equal to US 510(k) application. Submit MDEL application to health Canada

Class IV equal to US PMA.

Class II

Class III

Submit MDL application ISO 13485 certificate, labelling (information for use) and declaration of conformity to health Canada

Class IV

Submit MDL application, ISO 13485 certificate, IFU, declaration of conformity and premarket review document to health Canada Summary technical documentation (STED) format, clinical data for the device Submit both electronic and paper format

Review of MDL applications Time line: MDEL - 60 days; class II - 15 days; class III - 75 days and class IV - 90 days

Approval for medical device Class I - MDEL certificate posted in website and emailed manufacturer Class II, III and IV - MDL certificate posted in website and emailed manufacturer

Figure 15.14  Medical device approval process in Canada.

452

Table 15.10 

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Classification of Medical devices in Australia

Class

Level of risk

Device examples

I IIa

Low Low-medium

IIb III

Medium-high High

AIMD (Active Implantable Medical Device)

High

Scalpels, compression bandages, dental kits Hearing aids, masks for providing anaesthesia Condoms, blood bags, infusion pumps Cardiovascular stents, joint prostheses, heart valves Pacemakers, implantable defibrillators

conformity assessment certificate obtained under different regulatory system but the system must be accepted by TGA. The Class III devices like heart valves and AIMD device like pacemakers require not only evidence of conformity assessment but also a detailed and certified assessment of their design dossier. As mentioned earlier, the marketing application of the any imported Class III device must be complimented by evidence of conformity assessment by the TGA or any other regulatory system that is accepted by TGA. But in the case of Class III devices that contain a medicine, human blood or plasma, or material of animal, microbial or recombinant origin, the TGA undertakes full conformity assessment. TGA assesses the manufacturer’s quality management system, which may include an onsite audit in addition to reviewing the technical documentation.

15.7.2  Conformity assessment The classification of a medical device determines the conformity assessment procedure. The medical device manufacturer needs to satisfy the conformity assessment requirements of therapeutic good legislation act, by providing proper evidence related to the product and also for the manufacturing process of the medical devices. The conformity assessment certificate will be provided to the manufacturer, once they provide enough documents to meet the requirement of the therapeutic good legislation act, known as conformity assessment evidence. This confirms that the manufacturer has the proper system in place to produce the products. The conformity assessment certificate is a declaration of conformity of the medical device. The certificate also acts as an application to include the device in the ARTG list. A manufacturer can select the required conformity assessment procedure to ensure that the device is adequately evaluated to conform to the particular requirements for the class of device. Devices in higher classifications are required to undergo a more stringent form of conformity assessment than those in lower classes. The detailed conformity assessment procedures were given in Fig. 15.15 [46].

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15.7.3  Essential principles The TGA’s Essential Principles set out the requirements relating to the safety and performance characteristics of medical devices. The Essential Principles require the following: • Use of a medical device must not compromise health and safety. • Design and construction of a medical device must conform to safety principles. • Medical device is appropriate for its intended purpose. • Long-term safety of user has been ensured. • Benefits of a medical device outweigh any side effects.

Based on the nature of the medical device, its design, function and purpose of manufacture, some specific essential principles may or may not apply for it. They include requirements for biological safety, electrical safety, sterilisation, materials of biological origin, mechanical and radiation safety and labelling requirements. The manufacturers of standard medical device will choose their appropriate standards as the means of representing the compliance with the essential principle. Examples of these regulatory standards are: • ISO 14971 – Application of risk management to medical devices • ISO 13485 – Quality management systems – Requirements for regulatory purposes • ISO 11137 – Sterilisation of healthcare products – Radiation, Parts 1–3 • The manufacturer should identify the relevant standards and document testing to show compliance in a device’s technical files.

There are many key players in Australian medical devices regulatory system as shown in Table 15.11.

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Table 15.11 

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Key players of Australian regulatory system

People

Role

Responsibilities

Manufacturers

Perform design, production, packaging, refurbishment and labelling of the product. (Not individuals)

• Determines

Sponsors

Imports, exports or manufacture medical device in Australia (Not individuals)

Therapeutic Goods Administration (TGA) Agents

Government body that regulated therapeutic goods and medical devices Persons acting on behalf of sponsors or manufacturers to include medical device in Australian register of TG (ARTG)

classification, intended use and Global Medical Device Nomenclature (GMDN) • Ensures compliance with Essential Principles • Selects suitable conformity assessment procedures • Declaration of Conformity • Provide information to TGA from manufacturers • Submits conformity assessment details • Includes medical device in ARTG • Provides samples to TGA and allows TGA to inspect and reports adverse events to TGA –

–

15.7.4  Regulations pertaining to wound dressing in Australia The Australian Regulatory Guidelines for Medical Devices classifies the wound dressing in the above-mentioned five categories. The different examples of wound dressing are provided for better understanding [47].

15.7.4.1  Class I wound dressing • Adhesive dressing strip – not sterile, sterile, under classification rule 2.4.3(c) Compression bandage used for sprains – under Rule 2.4(3) (b) • Absorbent pads, island dressings, cotton wool, wound strips and gauze dressings – A noninvasive device to be used as a mechanical barrier or for compression or for absorption of exudates under rule 2.4.3 (c) • Dressing for nose bleeds – invasive devices that are for short-term use in the oral cavity as far as the pharynx, in an ear canal to the ear drum, or in a nasal cavity under rule 3.1(2) (b) (ii)

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15.7.4.2  Class IIa wound dressing •  polymer film dressings, hydrogel dressings and non-medicated impregnated gauze dressings – A non-invasive device to be used in contact with injured skin (including a device the principal intention of which is to manage the microenvironment of a wound) – under classification rule 2.4 (1)

15.7.4.3  Class IIb wound dressing • Dressings for chronic extensive ulcerated wounds, severe burn, severe decubitus wounds or dressings providing a temporary skin substitute. A non-invasive device to be used for wounds that have breached the dermis and where the wounds can only heal by secondary intent, under classification rule 2.4 (4) • A wound dressing for deep wounds and ulcers that have breached the dermis containing alginate to absorb exudates – Contains alginate of non-microbial origin. Heals by secondary intent, under classification rule 2.4 (4)

15.7.4.4  Class III wound dressing • Dressings incorporating an antimicrobial agent. – Contains a medicine under classification rule 5.1 (2) • A wound dressing for deep wounds and ulcers that have breached the dermis containing alginate to absorb exudates – Contains alginate of microbial origin, by Rule 5.5(1) (a) • A wound dressing including materials of biological origin, such as collagen, sodium hyaluronate, chondroitin sulphate, recombinant plant expressing human collagen genes under classification rule 5.5.1 (a). The medical devices approval process is depicted in Fig. 15.16.

15.8  Recent changes in EU medical devices regulations The following new regulations on medical devices are adopted from 5 April 2017 [48]. This replaces the existing directives, they are namely: • Regulation (EU) 2017/745 of the European Parliament and of the Council of 5 April 2017 on medical devices, amending Directive 2001/83/EC, Regulation (EC) No 178/2002 and Regulation (EC) No 1223/2009 and repealing Council Directives 90/385/EEC and 93/42/ EEC. • Regulation (EU) 2017/746 of the European Parliament and of the Council of 5 April 2017 on in vitro diagnostic medical devices and repealing Directive 98/79/EC and Commission Decision 2010/227/EU.

The applicability of the new rule will be after a transition period of 3 years (2020) for medical device regulation, after entry into force and 5 year (2022) after entry into force for the in vitro diagnostic medical devices regulations [49].

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Manufacturer Determination of classification using schedule 2 of the australian therapeutic goods (medical devices) regulations 2002

Class I non sterile, non measuring

Class I sterile, measuring

Class II a, class II b

Class III

Submit files like, Technical file or design dossier australian declaration of conformity

Sponsor must submit files to TGA CE - marking Initial certification audit report Examination reports issued by the notified body

Class I, sterile, measuring class II a, class II b

Class III

TGA review the design dossier

Medical device registered by TGA Australian register of therapeutic goods (ARTG) listing number will be issued Product listed in ARTG database on the TGA website

Figure 15.16  Medical device approval process in Australia.

The two new Regulations bring a number of improvements for medical and in-vitro devices: 1. Improve the quality, safety and reliability of medical devices: a. For the high-risk device like implants and etc., the new law enforces strict and tight regulations, which ultimately impose the manufacturers to undergo a severe review process before placing their medical device into the market. b. Compared with the previous regulation the rules became more crucial and tight for the clinical trials.

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c. Devices like coloured contact lenses (which will not correct vision), which is an aesthetic product, was not covered by previous regulation, but were also included in the new set of regulation. d. For the in vitro diagnostic medical devices, a new risk classification system is introduced in line with the international guidelines. 2. Strengthen transparency of information for consumers: a. The development of comprehensive EU database on medical devices along with the Unique Device Identification system for medical device traceability has improved the overall transparency in the process. b. The regulation mandates a unique device identifier for every product listed in the new European database of medical devices (EUDAMED). For example, a patient with the implanted medical device must have an ‘implant card’ which contains all details of his/ her implant. 3. Enhance vigilance and market surveillance: a. More detailed requirements and a more systematic approach is taken with regard to the post-market surveillance system, the post-market clinical follow-up systems, the vigilance system and the risk management system [50]. b. Other requirements of the notified body include the following: i. An audit expert should not audit the same facility for more than three successive years. ii. For all Class III devices, it is must to include a surveillance assessment report for the approved parts and/or materials. iii. The notified body should build up a scheme for unannounced audits. iv. The notified body might have adequate staff with significant clinical skill, and have them permanently available. c. A two-fold safety mechanism has been introduced: step (1) a pre-market clinical consultation procedure and step (2) a post-market scrutiny procedure for high-risk devices, i.e., implantable Class III devices and Class IIb devices intended to administer and/or remove a medicinal product. d. Based on Global Harmonization Task Force model, a rule-based new classification system has been implemented in ‘In vitro Diagnostics Regulations’. The new classification utilises all the classes namely A, B, C and D types. As per this new method, only 20% devices can utilise the conformity assessment within the current directives, the rest 80% of in vitro diagnostics must need conformity assessment by the notification body [51].

15.9  Challenges in medical device regulations The major players in the medical device regulations are Europe and the United States. Though there are many fundamental differences existing between the regulations of these countries, both jurisdictions face similar outstanding challenges to effective medical device regulation. For manufacturing industries, changing regulatory environments continue to present the biggest business challenge for a majority of medical device companies. As per the survey conducted by Emergo Groups, a leading medical device regulatory consultancy in Europe, majority of the company representatives identified that the regulatory changes are their biggest challenge [52]. A chart (Fig. 15.17) depicts the challenges faced by the medical device manufacturers.

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Changes in regulatory standards Reduction in reimbursement

Complexity of the requirement

Increased expenses for R&D

Manufacturers of medical device

Diverse customer requirements

Reduced funding for smaller firms

Pricing and competition with market leaders

Figure 15.17  Challenges for medical device manufacturers.

15.10  Summary It is crucial for the medical devices manufacturing companies, academics and others dealing with medical devices to learn various medical devices regulatory requirements in the EU, United States, Canada and Australia. This review provides an opportunity for them to understand the regulatory process and complexity involved in obtaining CE markings in EU and other related approval process in the United States, Canada and Australia. It is obvious from the review that the severity of approval process depends mainly on the risk factors associated with specific medical devices such as simple wound dressings to life-saving devices. The chapter describes the similarities and dissimilarities of medical device regulations between countries, specific requirements for approval and marketing the devices, recent changes in regulations and challenges ahead for manufacturers.

References [1] World Health Organisation, Sixtieth World Health Assembly, Provisional Agenda Item 12, March 22, 2007, p. 19. [2] P. Landvall, Medicintekniskaprodukter – Vägledning till CE märkning, SIS Förlag AB, Stockholm, 2007. [3] Espicom, The medical device market: USA, in: Espicom, 2015. Available from: http:// www.espicom.com/usa-medical-device-market.html.

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[4] Klass Consulting, Boost your business in Europe. Find your medical distributor, in: Klass Consulting, 2015. Available from: http://www.klaasconsulting.com/medical-devices/. [5] Export, Medical devices overview, in: Export, 2014. Available from: http://export.gov/ china/doingbizinchina/leadingsectors/eg_cn_081028.asp. [6] PRNewswire, Medical device markets in the world to 2018-market size, trends, and forecasts, in: Prnewswire, 2014. Available from: http://www.prnewswire.com/newsreleases-medical-device-markets-in-the-world-to-2018–-market-size-trends-and-forecasts-267415491.html. [7] Top 30 Medical Device Manufacturers, 2018. http://www.mpo-mag.com/heaps/ view/3670/1/253218. [8]  ISO 13485:2016 Plus Redline, Medical Devices - Quality Management Systems Requirements for Regulatory Purposes, 2017. http://webstore.ansi.org/RecordDetail. aspx?sku=ISO+13485%3A2016+Plus+Redline&gclid=Cj0KEQjwkN3KBRCu2fWmy9LLqN4BEiQANP9-WpvczyauQ9RkFRdRb-676rnLQX35odF S4u-4HYySABkaAuuX8P8HAQ. [9] Medical Device – Full Definition, World Health Organisation, Geneva, 2017. http://www. who.int/medical_devices/full_deffinition/en/. [10] Medical Device Regulations, Global Overview and Guiding Principles, World Health Organisation, Geneva, 2003. [11] WHO Global Health Expenditure Database, 2017. www.medtecheurope.org/sites/default/ files/.../MEDTECH_FactFigures_ONLINE3.pdf. [12] Espicom, Eucomed calculations, Manufacturer Prices. Medical Technology Excluding in Vitro Diagnostics, 2017, Europe http://archive.eucomed.org/medical-technology. [13]  European Patent Office, Eucomed calculations, European Countries Refer to EU + Norway, 2017, Switzerland www.medtecheurope.org/sites/default/files/.../MEDTECH_ FactFigures_ONLINE3.pdf. [14] EDMA- European IVD Market Statistics Report, 2014. www.medtecheurope.org/sites/ default/files/.../MEDTECH_FactFigures_ONLINE3.pdf. [15] E. French-Mowat, J. Burnett, How are medical devices regulated in the European Union? J. R. Soc. Med. 105 (Suppl. 1) (2012) S22–S28. https://www.ncbi.nlm.nih.gov/pmc/ articles/PMC3326593/. [16] Which Classification Does a Medical Device (MD) Fall Into? 2017. http://www.ce-marking.com/medical-devices.html#whichclassification. [17] Medical Devices: Guidance Document, MEDDEV 2. 4/1 Rev, June 9, 2010. http://ec.europa. eu/consumers/sectors/medicaldevices/files/meddev/2_4_1_rev_9_classification_en.pdf. [18] Council of the European Communities, Council Directive of 20th June 1990 on the Approximation of the Laws of the Member States Relating to Active Implantable Medical Devices. 90/385/EEC, 2007. [19] European Parliament and the Council of the European Union, Directive of the European Parliament and of the Council of 27th October 1998 on in Vitro Diagnostic Medical Devices. 98/79/EC, 1998. [20]  Basic Information about the European Directive 93/42/EEC on Medical Devices, Medical Device Certification, Germany, 2017. http://studylib.net/doc/8362192/ basic-information-about-the-european-directive-93-42-eec-on. [21]  G.W. Daniel, 5 Questions about the medical device tax and its potential for repeal, in: Brookings, 2014. Available from: http://www.brookings.edu/research/ opinions/2014/11/12-medical-device-tax-daniel. [22] Espicom, The medical device market: USA, in: Espicom, 2014. Available from: http:// www.espicom.com/usa-medical-device-market.html.

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[23] EY, Pulse of the industry: medical technology report 2013, in: Ey, 2013. Available from: http://www.ey.com/Publication/vwLUAssets/Pulse_of_the_industry_%E2%80%93_ medical_technology_report_2013_-_Redefining_innovation/$FILE/Pulse_Redefining_ medical_technology_innovation.pdf. [24] FDA, Devices Regulated by the Center for Biologics Evaluation and Research, 1991. http:// www.fda.gov/BiologicsBloodVaccines/DevelopmentApprovalProcess/510kProcess/ ucm133429.htm. [25]  Electronic Code of Federal Regulations, 2017. https://www.ecfr.gov/cgi-bin/ ECFR?page=browse. [26] Code of Federal Regulations, Title 21, 2017. https://www.ecfr.gov/cgi-bin/text-idx?SID=dce57918e474f38a11b2367fffc8525d&mc=true&tpl=/ecfrbrowse/Title21/21cfrv8_02. tpl#0. [27]  J.A. Johnson, FDA Regulation of Medical Devices,Congressional Research Service, R42130, 2017. https://fas.org/sgp/crs/misc/R42130.pdf. [28] FDA, Medical Devices, Premarket Approval (PMA), 2017, Available at: http://www. fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYourDevice/ PremarketSubmissions/PremarketApprovalPMA/default.htm. [29] FDA, Device Advice: Investigational Device Exemption (IDE), July 9, 2009. http://www. fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYourDevice/ InvestigationalDeviceExemptionIDE/default.htm. [30] B.N. Rome, D.B. Kramer, A.S. Kesselheim, FDA approval of cardiac implantable electronic devices via original and supplement premarket approval pathways, 1979-2012, J. Am. Med. Assoc. 311 (4) (2014) 386 (January 22/29, 2014). [31] FDA, Medical Devices, 510(k) Submission Methods, 2017, Available at: http://www. fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYourDevice/ PremarketSubmissions/PremarketNotification510k/ucm134034.htm. [32]  CFR - Code of Federal Regulations Title 21, 2017. https://www.accessdata.fda.gov/ scripts/cdrh/cfdocs/cfCFR/CFRSearch.cfm?CFRPart=878. [33] M. Azam Ali, A. Shavandi, Medical textile testing and Quality assurance, in: L. Wang (Ed.), Performance Testing of Textiles: Methods, Technology and Applications, Woodhead Publication, Elsevier, UK, 2016. [34] M. Kumar, Development of Wound Management Products for the US: An Anomaly for Global Product Development Model, 2017. www.raps.org/WorkArea/DownloadAsset. aspx?id=4111. [35] Canada – Overview of Medical Device Industry and Healthcare Statistics, 2017. https:// www.emergogroup.com/resources/market-canada. [36] Medical Devices Regulations, SOR/98–282, Food and Drugs Act, 2017. http://laws-lois. justice.gc.ca/eng/regulations/SOR-98-282/page-1.html#footnotea_e-ID0EFBAA. [37] Food and Drugs Act of Canada, R.S., c. F-27, s. 1, Interpretation, Definitions, 2017, The Food and Drugs Act is available at: http://www.hc-sc.gc.ca/fnan/legislation/acts-lois/actloi_reg-eng.php. [38] Guidance on Medical Device Establishment Licensing and Medical Device Establishment Licence Fees (GUI-0016), 2017. https://www.canada.ca/en/health-canada/services/ drugs-health-products/compliance-enforcement/establishment-licences/directives-guidance-documents-policies/guidance-medical-device-establishment-licensing-medical-device-establishment-licence-fees-guide-0016.html. [39] ISO 13485:2003 Medical Devices – Quality Management Systems – Requirements for Regulatory Purposes, 2017. https://www.iso.org/standard/36786.html.

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[40] Guidance Document. How to Complete the Application for a New Medical Device Licence, Health Canada, 2017. https://www.emergogroup.com/sites/default/files/guidance_how_to_complete_the_application_for_a_new_medical_device_licence.pdf. [41] Nancy Ruth, RAC, CQA (ASQ), Device Registration Pathways in Canada, Regulatory Focus, February 2010, pp. 32–39. [42] Medical Devices Regulations, SOR/98–282, Sections 59-61, 2017. http://laws-lois.justice. gc.ca/eng/regulations/SOR-98-282/page-6.html#h-42. [43] Australia – Overview of Medical Device Industry and Healthcare Stats, 2017. https:// www.emergogroup.com/resources/market-australia. [44] Commonwealth of Australia, Therapeutic Goods (Medical Devices) Regulations, 2002. http://www.comlaw.gov.au/ComLaw. [45] J. Bingham, MHSc, FSHP, GAICD, Regulation of Medical Devices in Australia and New Zealand, Regulatory Focus, 2010, pp. 24–30. [46] Therapeutic Goods Administration. Australian Medical Devices Guidelines: 3. Conformity Assessment Procedures, 2003. http://www.tga.gov.au/docs/html/devguid3.htm. https:// www.tga.gov.au/sites/default/files/consult-devices-cab-thirdparty-081222.pdf. [47] Australian regulatory guidelines for medical devices (ARGMD). Version 1.1 May 2011. TGA Health Safety Regulation, 2017, Available from: http://www.tga.gov.au/pdf/devices-argmd-01.pdf. [48]  Regulation (EU) 2017/745 of the European Parliament and of the Council of 5 April 2017 on Medical Devices, 2017. http://eur-lex.europa.eu/legal-content/EN/ ALL/?uri=uriserv:OJ.L_.2017.117.01.0001.01.ENG. [49]  Revisions of Medical Device Directives, 2017. https://ec.europa.eu/growth/sectors/ medical-devices/regulatory-framework/revision_en. [50] New EU Rules on Medical Devices to Enhance Patient Safety and Modernise Public Health, 2017. http://ec.europa.eu/growth/tools-databases/newsroom/cf/itemdetail. cfm?item_id=9119&lang=en. [51] The New EU MDR Implementation in May 2017, 2017. http://www.andamanmed.com/ eu-medical-device-regulations/. [52] Emergo Survey: Regulatory Issues Remain Biggest Challenge for Most Medical Device Companies, 2017. https://www.emergogroup.com/blog/2017/02/emergo-survey-regulatory-issues-remain-biggest-challenge-most-medical-device-companies.

The role of biopolymers and biodegradable polymeric dressings in managing chronic wounds

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Monica Puri Sikka, Vinay Kumar Midha Department of Textile Technology, Dr. B R Ambedkar National Institute of Technology, Jalandhar, India 

16.1  Introduction In an increasingly health-conscious society, there is a greater demand for naturally derived materials for medical treatment. Wound dressing integrating naturally derived biomaterials is the need of the hour. Wound dressings have become increasingly critical in promoting wound healing and wound management. They are critical for wound care because they provide a physical barrier between the injury site and outside environment, preventing further damage or infection [1]. They also manage and even encourage the wound healing process for proper recovery. There are greater demands for the wound dressing to actively play a role in the wound healing process. Therefore, incorporation of bioactive components in wound dressings helps improve wound exudate absorption and remove the aetiologies of exudate production [2]. Wound healing represents a major health burden and the variety of wound types has resulted in a wide range of wound dressings with new products frequently introduced to target different aspects of the wound healing process. These wound dressing biomaterials play an active role in the healing process, thus accelerating the process. There are variety of wounds that are generated worldwide each year because of surgical procedures and trauma and as the result of non-healing ulcers and burns [3]. Many types of materials have been utilised to develop wound dressings and have been commercialised in the market. These wound dressings provide an environment for the wound to heal at the maximum rate under particular pathological conditions while achieving a cosmetically acceptable appearance [4]. An ideal dressing should achieve rapid healing at reasonable cost with minimal inconvenience to the patient. The selection of an appropriate dressing plays an important role in both recovery and aesthetic appearance of the regenerated tissue. Among the various wound dressing materials, biomaterial or natural polymer–based dressing are gaining importance because of their unique properties [5].

Advanced Textiles for Wound Care. https://doi.org/10.1016/B978-0-08-102192-7.00016-3 Copyright © 2019 Elsevier Ltd. All rights reserved.

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16.2  The wound healing process Wound healing progresses through a series of interdependent and overlapping stages with the primary aim to re-establish the integrity of damaged tissue and replacement of lost tissue [6]. There are four stages in a normal wound healing process: • Haemostasis • Inflammation • Proliferation • Remodelling

Depending on the healing time, wounds are classified as acute or chronic. Acute wounds like surgical incisions, thermal wounds, abrasions and lacerations heal within 3 weeks while chronic wounds persist for a minimum of 3 months [7]. Acute wounds can be superficial involving both the epidermis and superficial dermis, or full thickness in which the subcutaneous layer is compromised [7]. Acute wound healing is regulated by cytokines and growth factors released proximal to the wound. Chronic wounds can result by destructing all the layers in skin including epidermis, dermis and underlying subcutaneous fat tissue. Chronic wounds typically result as complications of other disease processes, i.e., foot ulcers from diabetes, pressure ulcers resulting from spinal cord injuries and even as a result of neurodegenerative processes like Pick’s ­disease [8]. The peculiarity of the wound type and the degree of damage demand different approaches for its treatment. However, it has been observed that a warm, moist wound environment with proper wound healing material can rapidly heal a wound. So most of the wound dressings function to preserve hydration within the wound to optimise regeneration, protect against infection and avoid disruption of the wound base [9–13]. The basic properties required for a wound dressings are maintenance of moisture and nutrients at site, oxygenation, inflammation control, fibroblast proliferation and epithelialisation. Different types of dressings having different types of materials or physical form are being used for the treatment of different types of wounds, some of which have a micro- and nano-particulate delivery system. The use of biopolymers (Fig. 16.1(a)) from different sources has been investigated for many years for pharmaceutical and biomedical applications. The multifunctional behaviour and tunability of biopolymers facilitate their application to a wide variety of wound types. Polymers from natural origin, such as polysaccharides, proteoglycans and proteins, and polymers from synthetic origin, like polyglycolic acid (PGA), polylactic acid (PLA), polyacrylic acid, poly-ε-caprolactone, polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA) and polyethylene glycol (PEG), have exhibited in vitro and in vivo wound healing properties with enhanced epithelialisation and display hydrogel forming ability. The most currently available wound dressings are made using chitosan, hyaluronic acid (HA), collagen and silicon [14–19]. In addition, other biomaterials that are currently being investigated for wound dressings consist of alginates, heparin, cellulose and gelatin [20–24].

16.3  Role of natural biopolymers as wound dressings Natural polymers are widely used to develop wound dressing materials and scaffolds because of their immense biocompatible and biodegradable properties. Such polymer

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(a)

465

Protiens & peptides

Polysaccharide

Natural

Proteoglycans

Bio polymers

Polycaprolactone Synthetic

Polyvinylpyrrolidone Poly (lactide-co-glycolide) Polyethylene glycol Poly (vinyl alcohol Polyurethanes

(b)

Collagen Gelatin Proteins & peptides

Pectin & gums Cellulose

Natural polymers

Neutral Polysaccharide

Dextran Alginates

Acid

Basic Sulphated

Beta glucans

Hyaluronic Chitin Chitosan

Fucoidan Chondroitin

Proteoglycans

Glycosaminoglycans

Heparin Keratin

Figure 16.1  (a) Classification of biopolymers. (b) Categorisation of natural polymers.

templates provide means of imparting three-dimensional (3D) structures and deliver ­physical and chemical integrity to the cell tissue constructs. Because of their biocompatibility, biodegradability and similarity to macromolecules recognised by the human body, the natural polymers such as polysaccharides (alginates, chitin, chitosan, heparin and chondroitin), proteoglycans and proteins (collagen, gelatin, fibrin, keratin, silk fibroin and eggshell membrane) are extensively used in wounds and burns management (Fig. 16.1(b)).

16.3.1  Polysaccharide biopolymers Polysaccharides have been primarily used in food, textile or cosmetic products, but their potential utility as wound dressings is vast because of their abundance, inexpensive,

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absorbent, high-tensile strength, non-toxic, non-immunogenic and ability to form fine fibrous network. They also exhibit a diversity of molecular weights, charge, chemical composition and structures that influence their overall material properties especially suitable for wound aetiology. Natural polysaccharides play a role in wound healing because of their ability to promote non-specific activation of the immune system by activating macrophages that clean up the wound site after injury. Some polysaccharides are extensively used for the management of wounds when administered in the form of hydrogels: neutral (cellulose, dextran and β-glucan), acidic (alginic acid and HA), basic (chitin and chitosan) or sulphated polysaccharides (chondroitin sulphate, dermatan sulphate, heparin and keratan sulphate). Polysaccharide biopolymers have also been processed into biomimetic platforms that offer a bioactive component in wound dressings to aid the healing process. Polysaccharides can also be functionalised to influence their antimicrobial, fluid retention and gel strength properties [25].

16.3.1.1   Neutral polysaccharides •  Cellulose is a naturally occurring polysaccharide having glucose-based repeat units connected by b-1,4-glucosidic linkages. In case of chronic wounds, it has been found that use of scaffold/ matrix made from bioengineered cellulose as wound dressing reduces the healing time and pain. In case of partial- or full-thickness wounds, these materials have been found to support the process of epithelialisation and granulation. The cellulose-based wound dressing materials can be modified by incorporation of active molecules like antimicrobial drugs, antioxidants, hormones, enzymes and vitamins [26]. Microbial cellulose synthesised by Acetobacter xylinum (Acetobacteraceae) also can be used as wound dressing and as tissue-engineered skin [27]. It has been used in regenerative medicine as wound healing scaffold for damaged skin because of its excellent physico-chemical properties, nanostructure, biodegradability, mechanical strength, antimicrobial property and biocompatibility. It has also been reported as an alternate dressing material for superficial partial-thickness burn wounds. Some of the commonly used cellulose derivatives include carboxymethyl cellulose (CMC), hydroxyl ethylcellulose, hydroxyl propyl cellulose, hydroxyl propyl methyl cellulose, cellulose acetate and bacterial cellulose. Bacterial nanocellulose (BNC) has been reported to be a good wound dressing material in biomedical applications. Porous nanofibrous BNC has been used for large-area skin transplantation, tissue repairing and remodelling. These materials possess special properties like biocompatibility, biodegradability, chirality, hydrophilicity, broad chemical modifying capacity, ability to form various semi-crystalline fibre types making it suitable for such applications. Cellulose derivatives have also been used as film coatings, gel base, bioadhesives, as base material for controlled drug release and also for tissue regeneration applications [28–34]. •  Dextran is a bacterial derived polysaccharide generally produced by enzymes from certain strains of Leuconostoc or Streptococcus. More recently, dextran hydrogels have been considered for biomaterial applications and investigated as drug delivery vehicles. They are particularly used as scaffolds for soft tissue engineering applications because dextran is resistant to both protein adsorption and cell adhesion allowing cell adhesion to be achieved by specific derivatisation with extracellular matrix (ECM)–based peptides. Carboxymethyl benzylamide sulfonate dextran, a soluble polymer, has been reported to stimulate wound healing, affect proliferation and metabolism of different cells [35]. Hydrated cyclodextrin possesses the ability to capture lipophilic odour molecules and have been used in odour control dressings. These are found to be active for a longer time and further serum proteins help in enhancing the property of odour absorption.

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•  β-Glucans (beta-glucans) comprise a group of β-d-glucose polysaccharides naturally occurring in the cell walls of cereals, bacteria and fungi, with significantly differing physic-chemical properties dependent on source. Recent studies highlight that highly purified yeast-derived insoluble (1→3)-d-glucan (Glucan 300) strongly inhibits adipogenic differentiation, supports wound healing and significantly lowers skin irritation [36].

16.3.1.2   Acidic polysaccharides •  Alginates are suitable for highly exudative wounds because they are capable of absorbing 20 times of their weight, allow moist wound environment and prevent microbial contamination. These dressings are highly absorbent, non-adherent, biodegradable, contain non-woven fibres derived from brown seaweed and may contain controlled-release ionic silver. They contain alginic acid from seaweeds and are available as calcium alginate, calcium–sodium alginate, collagen–alginate and gelatin–alginate [37–40]. When placed on a wound, sodium and calcium ions interact with serum to form a hydrophilic gel. These dressings are particularly effective for managing highly draining wounds, pressure/vascular ulcers, surgical incisions, wound dehiscence, tunnels, sinus tracts, skin graft donor sites, exposed tendons and infected wounds.   These dressings are contraindicated for dry wounds as they readily promote absorption and have no hydration qualities. In clean wounds, alginate dressing may be kept in situ for up to 7 days or until the gel loses its viscosity, but for infected wounds, they must be changed frequently. The majority of alginate dressings are produced in sheet form, which is beneficial for superficial wounds, and are also available in the form of a ribbon or rope [41], useful for packing deep wounds and cavities.   Different alginate-based materials as a result of their antimicrobial properties and wounds/ burns healing applications have been obtained including zinc alginate, silver alginate [42], asiaticoside-loaded alginate films, sodium alginate–chitosan two-ply composite membranes [43] and sodium alginate–chitosan based films combined with laser therapy. Alginate scaffolds have been used in conjunction with another weaker material to reinforce the mechanical properties [44,45]. Alginic acid and its salts are used for the treatment of wound and burn because of their haemostatic properties. Their first applications were in the form of a gel, but sponges produced from calcium alginate are also used effectively in the treatment of wounds. It is also indicated that calcium alginate increases cellular activity properties such as adhesion and proliferation [46]. •  Hyaluronic acid (HA) is a natural polysaccharide found in the ECM of mammalian tissue. It is composed of glucuronic acid and N-acetyl-glucosamine and the molecular structure facilitates the movement of cells within the ECM providing a substrate for cell migration and proliferation thus enhancing dermal repair. Biodegradation of HA produces by-products that also aid in epithelial cell proliferation and migration. It also plays even more significant role in angiogenesis and the inflammatory response, further supporting cellular growth [14,47–51].   It has been used extensively as a drug delivery system for numerous therapeutic modalities and as a biopolymer for structural support and stem cell delivery in bone regeneration [47]. Recent success in its use as an in vitro culture template for proliferation of keratinocytes has made it an exciting new product for use in wound regeneration. The limitations in wound repair with HA grafts are likely related to co-morbidities found in high-risk patients. Arterial occlusion and wound site infection have a negative impact on graft survival and wound repair [52].

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16.3.1.3   Basic polysaccharides •  Chitin- and chitosan-based dressings Chitin is the second most abundant biopolymer after cellulose and is the main constituent of the exoskeleton in animals, particularly crustaceans, molluscs and insects. Deacetylation of chitin yields chitosan, which makes it insoluble in neutral or basic pH because of its free amino groups; while in acidic pH, protonation of amino groups leads to its solubility in water. Chitosan provides a substrate for cell attachment because of its polymer structure exhibiting similarities to glycosaminoglycans (GAGs) that are major component of the ECM [53]. Thus, the extent of its application ranges from surgical sutures, artificial skin and controlled drug delivery devices. Unfortunately, chitosan is difficult to electrospin because of its highly charged nature from deacetylation of its N-acetyl-d-glucosamine group that induces aggregation, making it insoluble in various solvents [54]. However, photo cross-linked electrospun mats containing quartinised and carboxyethyl chitosan/poly (vinyl alcohol) nanofibres have been prepared for wound dressing applications [55,56].

Chitosan has intrinsic antimicrobial properties on bacteria, algae and fungi and is also haemostatic. The antimicrobial effects are affected by various intrinsic factors including type of chitosan, the degree of polymerisation, the host, the chemical or nutrient composition of the substrates and many environmental conditions [57–66]. The antimicrobial effect of the chitosan wound dressing can be further enhanced by using another antimicrobial agent like aloe vera. The antibacterial potential of nanosilver-incorporated chitosan hydrogel composite bandage showed excellent blood clotting ability, high swelling ratio and controlled biodegradation with excellent antibacterial activities against Staphylococcus aureus and Escherichia coli [67]. Chitosan is produced in several forms such as powder, paste, film and fibre. Further, because of its abundance, it can be a low-cost solution for an effective wound dressing material. Additionally, chitosan being derived from chitin, the second most abundant biopolymer on earth [54] thus, their availability can be leveraged to produce a low-cost and effective wound dressing material.

16.3.1.4   Sulphated polysaccharides •  Fucoidan is a sulphated polyfucose polysaccharide and has attracted considerable biotechnological research interest since the discovery that it possessed anti-coagulant activity similar to that of heparin and is also reported to possess other properties including anti-thrombotic, anti-inflammatory, anti-tumoural and antiviral effects [68]. Many of these effects are thought to be because of its interaction with growth factors such as basic fibroblast growth factor and transforming growth factor-β. Fucoidan may, therefore, be able to modulate growth factor– dependent pathways in the cell biology of tissue repair [69]. In recent years, the research on drug and gene delivery systems, diagnostic microparticles and wound and burn healing formulations of fucoidan has been increasing in course of time [70–72]. •  Chondroitin sulphate is a sulphated GAG composed of a chain of alternating sugars (N-acetylgalactosamine and glucuronic acid). It is usually found attached to proteins as part of a proteoglycan. A chondroitin chain can have over 100 individual sugars, each of which can be sulphated in variable positions and quantities. Chondroitin sulphate is an important structural component of cartilage and provides much of its resistance to compression. Materials made from this GAG are biocompatible and non-immunogenic.

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Chondroitin sulphate acts as a surrogate ECM, serving as a repository for cytokines and growth factors, important bioentities for the healing process, and they provide structural frameworks for fibroblasts during epithelial regeneration [73,74]. •  Heparin-coated aligned nanofibres increase endothelial cell infiltration in 3D scaffolds and tissue remodelling in vitro and in vivo, in full-thickness dermal wound models. Heparin was also incorporated into non-covalently assembled, polymeric hydrogel networks based on its interactions with known heparin-interacting peptides and proteins. PEG star polymers functionalised with heparin-binding peptide motifs have been reported to assemble with heparin into viscoelastic solutions with tuneable properties. These can also be mixed with star–PEG–heparin conjugates to form non-covalent hydrogels capable of growth factor delivery via hydrogel erosion. Such erosion strategies, although passive, may offer opportunities to modulate growth factor activity via co-release of the growth factor with heparinised macromolecules [75]. •  Keratin is an environment-friendly polymer which has 3D mesh-like structure. It is composed of structural fibrous protein and is the main constituent in corneous tissues like hair, feather, wool, horns and nails and in vertebrate epithelia. It can be easily shaped in the form of hydrogel [24]. Keratin derivatives can interact with polyelectrolyte wound environment to facilitate healing process. It has high water intake capacity and can be used as dressing material at the wound site to prevent loss of biological fluid to the environment and to minimise wound exudate. The biocompatibility, soft and wet nature of keratin makes it one of the promising dressing materials to treat wounds and burns. This hair-based polymer facilitates epithelialisation, vascularisation and reconstruction of skin tissue [24,76]. Keratin loaded with mupirocin serves dual purposes by providing compatibility for cell support and growth and initiates release of antibiotics in a sustained manner at the wound site [77].

16.3.2  Proteoglycans Natural polysaccharides contain GAGs that are present in the ECM. Furthermore, GAGs have been demonstrated to improve the wound healing process through re-­ epithelialisation and increased vascularisation. GAGs are the most important components of ECM and are essential to bone and skin regeneration. According to the structure (polymer length, degree of sulfation), they modulate the attraction of skin and bone precursor cells and have potential in tissue engineering for wounds and burns [78]. It has been reported that HA (linear polysaccharide made from N-acetyl-dglucosamine and glucuronic acid) interacts with proteins, proteoglycans, growth factors and tissue components called biomolecules which has vital importance in healing of various types of wounds [73]. This interaction plays an important role in acceleration of tissue repair and wound healing. Biomimetic hydrogels specifically designed to promote tissue repair (wound healing applications) contain chemically modified HA cross-linked by photo-polymerisation with glycidyl methacrylate groups [79] functionalised with thiol cross-linking sites [80] or cross-linked with DNA for gene delivery [81]. Also heparan sulphate glycosaminoglycans (HS-GAGs) and a polymer engineered to mimic HS-GAGs properties have shown to decrease inflammation and stimulate neovascularisation (angiogenesis) and collagen maturation in wounds and burns healing process [82].

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16.3.3  Proteins and peptides Among proteins, collagen and hydrolysate derivatives (i.e., gelatins) show vast potential for efficient wound treatment as dressings and drug delivery systems.

16.3.3.1   Collagen Collagen is a natural protein substrate for cellular attachment, growth and differentiation and promotes cellular proliferation and differentiation. Collagen serves as an excellent wound dressing material because of its negligible immunogenicity, excellent biocompatibility and mechanical stability. Collagen dressings encourage the deposition and organisation of newly formed collagen, creating an environment that fosters healing because of the chemotactic properties of the dressings on wound fibroblasts. It can stimulate and recruit specific cells, such as macrophages and fibroblasts, along the healing cascade to enhance wound healing and also provide moisture or absorption, depending on the delivery system. The first medical usage of collagen in humans was to provide co-reaction of contour deformities. Bovine collagen was used as suture and haemostatic agents after years. Today, collagen formulated from bovine, porcine or avian sources is used for treatment of partial- or full-thickness wounds with minimal to moderate exudates including collagen suspensions for dermal injection, topical haemostatic agents, wound dressing materials, collagen suture and catguts, collagen gels for periodontal reconstruction, collagen sponges for the haemostasis and coating of joint, artificial skin substitutes for management of severe burns, and collagen-rich pig skin wound dressing materials [83–90].

16.3.3.2   Gelatin Gelatin is a protein, derived from collagen, also known as denatured collagen. Unlike collagen, it has low antigenicity and is inexpensive [91]. Gelatin is used for preparation of biocompatible and biodegradable wound dressings. It can be fabricated in the form of film or sheath for cutaneous wound repair. Gelatin film is quite effective for wound closure purposes by exhibiting re-epithelialisation of the epidermis and repair of ECM in the dermis. Gelatin sheaths are used to cure deep partial thickness wounds in the skin. The limitation of gelatin is its mechanical properties and is preferred to be used as a blending agent with other polymers to treat burns, diabetic and venous stasis ulcers and trauma [91,92]. Recent research suggests that gelatin is definitely an effective biomaterial for wound dressing and it has a positive biological response to facilitate cell adhesion and proliferation [74]. Gelatin/PEG composites in the presence of dialdehyde CMC have been developed to serve as wound healing materials with low cytotoxicity [93].

16.3.3.3  Pectins and gums Chemically, gums are polysaccharides containing acidic groups. The acidic groups interact with small amounts of (especially) calcium, magnesium and potassium. Gums make viscous solutions or gels in water. These polysaccharides stabilise emulsions, retain moisture, thicken liquids and suspend particles. Pectins are water soluble and make

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viscous solutions or gels, similar in composition to the gums. Pectins also form gels under certain conditions. Pectin is a biocompatible and biodegradable natural polymer widely used in the food industry, targeted drug delivery, wound healing and tissue engineering applications. Hydrocolloids such as pectins and gums both are used as occlusive and semi-occlusive moist dressings (gels) for wounds management. Pectin–gelatin hydrogel membranes, cytocompatible with B16 melanoma cells, are also used for moist wound care applications. The increase in gelatin ratio significantly improves the microporous nature of the membranes with highly interconnected honeycomb-type architecture and enhanced thermal stability as compared with reference pectin alone [93,94].

16.4  Role of synthetic biopolymers as wound dressing Synthetic polymers are used mainly as platforms for actuation and delivery of active agents, but they also provide an optimal microenvironment for cell proliferation, migration and differentiation when used in dressings and biosynthetic skin grafts. Some synthetic polymers obtained by the electrospinning technique, such as biomimetic ECM microscale and nanoscale fibres based on PGA, PLA, polyacrylic acid, poly-ε-caprolactone, PVP, PVA and PEG, are biocompatible, biodegradable and have good mechanical properties [21]. Features of some of the most used synthetic polymers in wound healing are summarised subsequently.

16.4.1  Poly (lactide-co-glycolide) Poly (lactide-co-glycolide) (PLGA) is a copolymer of PLA and PGA. It is a Food and Drug Administration (FDA)–approved biodegradable polymer with immense potentials in skin tissue engineering. It is physically strong, biocompatible and can be fabricated into desired shape and size. Skin substitutes prepared from PLGA are in great demand because of their controlled degradation and tuneable mechanical properties [95]. Polymer degradation synchronises with the rate of epithelialisation, thus achieving successful repair in a scheduled time frame. Moreover, PLGA/PLA mesh when cultured with human fibroblasts gives rise to a template to treat diabetic foot ulcer. The limitation of PLGA lies in its hydrophobicity and it fails to act as an appropriate platform for cell adherence. PLGA can be fabricated in the form of knitted mesh to support uniform cell distribution. PLGA entangled with collagen serves as an excellent 3D mesh for homogenous distribution of cells and ECM synthesis of dermal fibroblasts in skin tissue engineering. Hybrid electrospun scaffold from PLGA and natural polymer like silk has synergic effect on wound healing [95–97].

16.4.2  Polyethylene glycol Polyethylene glycol (PEG) is a hydrophilic polymer of ethylene oxide. The non-­ immunogenic, biocompatible and flexible nature of PEG makes it a suitable synthetic dressing material for wound healing. The low toxic PEG macromers are well bonded

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with growth factor like EGF and can be delivered at the wound site [98]. The mechanical stability of PEG can be enhanced by blending PEG with chitosan and PLGA. Blending also increases thermal stability and crystallinity of the particular polymer [99]. Such PEG-based dressings have been widely used to treat a diabetic wound by promoting and inducing growth of skin cells and collagen deposition. It also reduces scar formation [100]. The injectable hybrid hydrogel dressing system is developed from PEG-based hyperbranched multiacrylated co-polymer and HA in combination with adipose-derived stem cells to support the viability of cells in vitro and in vivo. It prevents wound contraction and enhances angiogenesis by acting as temporary hydrogel for wound healing purpose [101].

16.4.3  Polyurethanes Polyurethanes (PUs) are copolymers with repetitive urethane groups in their structures. These polymers are non-toxic, elastomeric with good toughness, tear resistance, abrasion resistance and biocompatibility. Such materials favour epithelialisation during wound healing. PUs possess good barrier properties and oxygen permeability [102]. To overcome the limitation of adherence of PU, collagen or collagen-based peptides are coated on the PU mesh to support the adherence of cells on it and improve tissue biocompatibility [103]. Foam dressings can be designed to form a film with adhesive borders. Lyofoam (Conva Tec) and Allevyn (Smith and Nephew) are well-established foam dressings with additional wound contact layers to avoid adherence with scab or dry wound. They are highly absorbent and the unique porous structure of the dressings makes them suitable for treating partial- or full-thickness wound. Foam is superior to gauze in reducing pain and comforts in healing wound in patients [103–105].

16.4.4  Poly (vinyl alcohol) PVA is a semi-crystalline copolymer of vinyl acetate and vinyl alcohol. It is non-toxic, non-carcinogenic, biocompatible and hydrophilic in nature and can absorb a huge amount of water. It can be tailored to the desired shape and size like fibres, sponges and films for skin tissue engineering, drug delivery or diabetic wound treatment. PVA can be blended with other polymers to improve its physical or clinical properties. Low mechanical strength of PVA can be improved by blending with chitosan and HA. It can be cross-linked with glutaraldehyde or succinyl chloride to increase its flexibility. PVA blended with collagen enhances the quality of granulation tissue and improves the strength and flexibility of cells at the wound site. Blending with alginate, dextran and chitosan improves its clinical properties [106–111].

16.4.5  Polyvinylpyrrolidone PVP is also a well-known biocompatible polymer used as one of the main components of hydrogel preparations for temporary skin covers or wound dressings. PVP is used in the production of medicines, and it serves as a blood substitute and blood detoxifier. PVP hydrogel itself does not exhibit good swelling properties, but when blended with

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polysaccharides such as CMC, chitosan or other polysaccharides such as agar or alginate, the swelling properties improve. PVP is an excellent binder for active agents to dressing materials [112,113].

16.4.6  Polycaprolactone Polycaprolactone (PCL) is a synthetic polyester obtained by susceptible autocatalysed bulk hydrolysis and slow degradation of linear aliphatic polyester. It possesses perfect biocompatibility, biodegradability, non-toxicity and bioresorbability with unique mechanical properties and can be processed into different shapes and forms. Electrospun PCL fibres mimic the fibrous structure of ECM and act as suitable templates to treat acute and chronic wounds. The limitation of PCL material lies in its poor antimicrobial properties. Therefore, silver nanoparticles are incorporated into PCL matrix to ensure its resistance to microbial invasion. In addition, the template has sufficient wound exudates uptake and water retention capacities. PCL–collagen matrix serves as an excellent template that triggers the way to regulate the growth of fibroblasts and initiates wound healing [114–116].

16.5  Polymer-based composite wound dressings More than 3000 dressing types are available in the wound management market. The characteristics of the various types of dressings depend on the intrinsic properties of the polymers used for their preparation. The resulting products may be used individually or in combination to absorb exudate, combat odour and infection, relieve pain, promote autolytic debridement and/or provide and maintain a moist environment at the wound surface. Unfortunately, no single dressing can accomplish all these goals. Thus, the selection of the appropriate dressing to a specific wound type is a difficult task and depends on factors related to the product itself, the patient’s health status, wound type and location and economic considerations. Modern wound dressings frequently include a combination of polymeric layers with different functions that provide particular characteristics to the dressing as shown in Table 16.1. Both synthetic polymers and biopolymers can be easily processed into the desired shape and design and stabilised using different techniques for extended shelf life and performance. The commercial dressings are the engineered skin substitutes, which are fabricated by modifying synthetic and bioactive natural polymers. They are manufactured by using advanced techniques and are cultured with skin cells to give rise to appropriate dressings to heal the wound. Some of these dressings are discussed here.

16.5.1  Silicone dressings Abnormal wound healing can lead to a hypertrophic or keloid scar. Historically, these have often been treated with long-term application of pressure garments. In 1981, it was found that the benefits of pressure therapy could be enhanced or replaced by applying a

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Table 16.1 

Advanced Textiles for Wound Care

Composite polymer dressings

Dressings

Composition

Biological efficacy

Films

Chitosan, gelatin, cellulose

Foams

Gel film–coated foam or PU

Hydrogels

Cellulose derivatives HA

Hydrocolloids

Cellulose derivatives, elastomer and alginates Sodium alginate, calcium alginate, polysaccharides

Fabricated for acute, partial- and full- thickness wound with low exudates. Perfect for graft donor site, minor burns and to cover surgical incision Designed for chronic and partial-thickness and deep-cavity wounds Mainly for acute and chronic wounds with moderate exudates. Perfect for chronic ulcers and superficial burns Designed for acute, chronic, partial- and full-thickness wound and can be applied on burns and dermabrasions Fabricated for post-operative wounds. Suitable for wounds with moderate exudates, chronic ulcers and as skin grafts

Alginates

Costeffectiveness Relatively inexpensive

Relatively inexpensive Relatively inexpensive

Moderately inexpensive

Moderately inexpensive

sheet of silicone gel made from polydimethylsiloxane. This would relax or soften scar tissue, thereby allowing a levelling effect on the hypertrophied area [117,118]. There has been an increasing trend to use silicone as a non-traumatic adhesive component in many existing dressing categories to reduce procedural pain associated with dressing changes. Silicone is inert and therefore does not chemically interact with the wound or have any effect upon the cells responsible for healing, but rather because of the ease of removal of soft silicone, it does not traumatise the wound or the surrounding skin. Biobrane is a biosynthetic material made of silicone film attached to porcine collagen cross-linked nylon matrix, used for burns or sometimes in ulcers and blistering disorders [119–121]. Biobrane is attractive for use in burns as its make up allows blood and sera within the wound to form a clot, naturally affixing it to the wound bed while re-epithelialisation occurs. The outer silicone layer augments the wound environment by reducing water loss through evaporation. The unique composition of Biobrane gives it numerous advantages with regard to standard dressings. The material is typically used for coverage of partial-thickness burns that contain no associated debris or eschar because it is unable to debride dead tissue from the wound [122,123]. There are limitations to Biobranes for clinical use [124]. Additional studies found Biobrane to be more expensive and led to increased infection rates. The increased rates of infection seen with Biobrane are likely because of partial adherence to the wound bed leading to bacterial overgrowth.

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Advanced Wound Bioengineered Alternative Tissue (AWBAT), performance-­ improved product similar to Biobrane, has been cleared by FDA in 2010 [93,125,126]. In this product, the limitations in Biobrane have been improved by making the silicone membrane more porous and excluding the use of toxic cross-linking agents to make covalent bond between collagen peptide to the silicone–nylon composite.

16.5.2  Hydrogels Hydrogels are synthetic cross-linked polymers that are usually made from polymethyl methacrylates and polyvinyl pyrrolidine and are capable of absorbing and retaining a significant amount of water when placed at the wound site [127]. They are considered as ideal dressings as they clean, rehydrate dry and necrotic tissues and initiate autolytic debridement. It has been reported that they promote moist healing and are used to treat venous leg ulcers [128]. But, these dressings cannot absorb sufficient wound exudates and therefore support bacterial proliferation and lead to foul smell in the infected wound. Hence, they are blended with natural polymers to form composites that balance the advantages of each material. Such dressings also possess low mechanical strength and are quite difficult to handle. Therefore, gauze coverings are used along with them to hold them appropriately on the wound. PurilonTM (Coloplast) and Nu-gel TM (Johnson and Johnson) are widely recognised hydrogels for wound healing purposes [127–129].

16.5.3  Hydrocolloid dressings Hydrocolloids constitute colloidal material (gel)-like CMC, alginate and elastomers or adhesives used extensively as wound management products [130,131]. They can be fabricated in the form of films or sheets and are mainly used for treating light-exuding wounds such as minor burns, traumatic sores and injuries. Hydrocolloids are susceptible to swell when coming in contact with wound exudate and form a gel to cover the wound. Removal of such dressings is painless. AquacelTM and GranuflexTM (Conva Tec, Hounslow, UK) are efficient hydrocolloids and their performance is superior to tulle gauze in acute inflammatory response. Hydrocolloid dressings possess occlusive outer covering which prevents water vapour transmission and reduces oxygen supply to the wound for faster healing [11,33,97].

16.5.4  Smart silk dressings – for treating chronic wounds Silk sericin is a biocompatible, biodegradable and non-toxic protein derived from Bombyx mori (insert Fig. 16.2). It is composed of 18 amino acids and has hydroxyl, carboxyl and amino groups that can increase cell density, cell lines and activate collagen formation at the wound site by significantly increasing the growth and proliferation of fibroblasts of the human skin. Silk has been extensively used with PGA network to enhance physico-chemical, mechanical, swelling and biological properties of the hydrogels. Recombinant spider silk protein can be treated as wound dressing material to cover deep, second-degree burn wounds [132–134].

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Figure 16.2  Silk sericin dressing. From Pornanong Aramwit, Silk Proteins for Wound Healing materials In Silk: Properties, Production and Uses, 2012, Nova Science Publishers. Used with permission from Nova Science Publishers Inc.

16.5.5  Hydroconductive dressings Hydroconductive dressings (SteadMed Medical’s Drawtex, Fort Worth, TX) are a relatively new and novel class of products that use a capillary action to lift and move exudates away from a wound into the core of the dressing for dispersing into a second layer. They also have the additional benefit of moving debris from the wound surface besides restricting the growth of bacteria in the wound. Levafiber, the proprietary name of the Drawtex dressing technology, utilises two types of absorbent, cross-action structures that facilitate the ability to move large volumes of exudates and debris through the dressing. These dressings can move fluid in a horizontal or vertical vector into the dressing and hold fluids up to 30–50 times their own weight. The hydroconductive debridement component helps to lift and loosen adherent slough tissues, allowing for easy removal when the dressing is changed. These dressings are versatile and can be tailored to fit different sizes and shapes. The material does not shed fibres or break apart and can be utilised for a 7-day wear time [135,136].

16.5.6  Oxidised regenerated cellulose and collagen Oxidised regenerated cellulose (ORC) is a bioabsorbable topical haemostatic woven material used to control bleeding. It has been used as a surgical and dental haemostat for almost half a century, proving to be effective in controlling capillary, venous and small arterial bleeding in various settings. When applied to a bleeding surface, it forms a gelatinous mass, which eventually is absorbed within 2–7 days. ORC may also exert moderate bacteriostatic effects by creating an acidic pH. ORC can also be manufactured in combination with a collagen matrix. Collagen is a major protein of the body and necessary in wound healing and repair. Commonly, 55% bovine collagen is combined with 45% ORC. In the presence of exudates, this dressing transforms into a gel matrix and binds to MMPs to help inactivate some of these overproduced enzymes [137,138].

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16.5.7  Polyhexamethylene biguanide and honey dressings There are several well-known antimicrobial dressings that have been on the market for years. Polyhexamethylene biguanide is an antiseptic that is currently attracting interest for biocellulose dressings, although it has a long history of use in things such as contact lens cleaning solutions and wet wipes. In a concentration of 0.3%, it has proven to be both non-cytotoxic and a non-irritant, with a very low risk of sensitisation [126]. It has also been found to be effective against a broad spectrum of bacteria, fungi, moulds, yeasts, methicillin-resistant staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE). Manuka honey is an ancient remedy for the treatment of infected wounds and was first recognised as a topical antibacterial agent in 1892. Since this time, there have been many published reports describing the effectiveness of honey against a broad spectrum of bacteria and fungi, including S. aureus, Pseudomonas aeruginosa MRSA, and VRE. Honey may also have a role in reducing malodour, providing an autolytic debridement environment, whereby the osmotic action of honey encourages exudates to move away from the wound bed and have an anti-inflammatory and immune-modifying effect [139,140].

16.5.8  Neem and aloe vera dressings Azadirachta indica (AI) A. Juss (the neem tree), member of the Meliaceae family, is a popular and common tree. Active compounds such as nimbidin, nimbin, and nimbidol present in neem, which have anti-inflammatory, antimicrobial activities help in accelerating the wound healing process. Neem also consists of a large amount of amino acids, vitamins and minerals that plays a major role in proliferation phase of wound healing process [141]. In a study [142], the topical use of Neem (A. indica) oil and systemic use of Haridra (Curcuma longa) in both groups were found effective in healing the chronic wound. Both drugs have proven value in the management of non-healing wounds. They have also angiogenic property and potency to increase DNA content as well. The combination of Neem and Haridra is best to treat diabetic chronic wounds in a better way, both drugs showed a remarkable effect in leprotic, venous and decubitus ulcer as well. In view of no any adverse effects and affordable economically by all, it can be recommended in combination for the treatment of chronic wound. Aloe Vera is a cactus-like plant, which readily grows in hot and arid conditions. Aloe Vera gel is obtained from the mucilaginous part of the centre of the leaf. It has been used for many centuries and comprises the major ingredient in various commercial skin-care and wound-care products. It can be used orally and topically to treat a wide range of health-related disorders. The Aloe Vera gel contains vitamins A, B, C, E, enzymes, polysaccharides, amino acids, sugars and minerals. In the management of acute and chronic wounds, several reports using Aloe Vera have demonstrated variable results [143–147]. Though there is supporting evidence that Aloe Vera can improve wound healing rates, further large randomised control trials are needed to substantiate this.

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Aloe Vera gel has also been combined with natural polymers to produce blend films for wound-healing applications. A thin hydrogel film has been developed composed of calcium alginate and AV gel (5%, 15%, and 25%) for applications in both exuding and dry wounds [148]. These films create the optimal conditions for an improved healing process, and simultaneously release the AV compounds directly to the wound site, according to specific release profiles.

16.6  Polymer nanomaterials for wound healing Biocompatible and biodegradable polymer micro- and nano-fibre devices fabricated from nanofibre materials with sizes less than 1 μm or 1 nm replicate the molecular components of in vivo cellular and bimolecular environment. The large surface area of nanofibre dressings not only allows increased close interaction of therapeutic agents and exchange of O2 and CO2 with tissues but also provides a mechanism for sustained release and localised delivery of antiseptic remedies, analgesics and growth factors needed for burn and wound healing. In addition, the high porosity of nanofibre dressings permits diffusion of nutrients and removal of waste products from the application site. Owing to their multifaceted properties, the nanofibre dressings created from both natural and synthetic polymers have attracted the attention of surgeons, physicians, biomedical researchers and industry. Their envisioned potential applications are because of the optically transparent functional materials and nanocomposites required for making scaffolds to grow stem cells, wound healing dressings and mats, transdermal patches, targeted drug-delivery systems, tissue compatibility and biodegradability, improved cell adherence and relatively lower manufacturing cost [149–152].

16.7  Bioprinting Three-dimensional printing technology has made it possible to create patient-specific wound dressings with design freedom using computerised models. Threedimensional printing of polysaccharides is realised by a process called bioprinting that uses selective deposition of a gelatinous ink in 3D space to create controlled geometric structures. Pescosolido et al. (2011) have incorporated HA and dextran into cross-linked hydrogels reprocessed into 3D scaffolds using bioprinting [153,154]. Three-dimensional bioprinting has been developed to effectively and rapidly pattern living cells and biomaterials, aiming to create complex bioconstructs. However, placing biocompatible materials or cells into direct contact via bioprinting is necessary but insufficient for creating these constructs. Therefore, ‘4D bioprinting’ has emerged recently, where ‘time’ is integrated with 3D bioprinting as the fourth dimension, and the printed objects can change their shapes or functionalities when an external stimulus is imposed or when cell fusion or post-printing self-assembly occurs [155].

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16.8  Stem cell therapy The bioengineers, cell biologists and clinicians are facing challenges towards further development of ideal wound dressing template with ongoing interaction and collaborations. Stem cell therapy is a new milestone and strategy with the characteristics of self-renewal and multilineage differentiation. Identification and location of stem cells in skin have already been achieved and ongoing research proved the potential contribution of stem cells in the reconstitution of skin at the wound site. Epidermal keratinocytes have a poor regenerative capacity which can be overcome by utilising self-renewing keratinocyte stem cells. In the next decade, stem cell therapy will be a breakthrough in skin tissue engineering to generate skin substitutes that will completely mimic structures and function of the native skin [156–160].

16.9  Conclusion Wound dressings should have properties and delivery characteristics that are optimised for specific wound types with minimum or no inconvenience to the patient and at reasonable cost. To achieve such objectives, manipulation of the physical characteristics of the identified systems is necessary so the use of composite dressings which combine the different characteristics of various polymers is required. This will be helpful for targeting many aspects of the complex wound healing process, to ensure effective, complete wound healing and shorter healing times for chronic wounds and other difficult to heal wounds. Recent studies about biocompatible and biodegradable natural/synthetic polymers has led to a substantial development of novel types of wound dressings and their outstanding applications in the biomedical area particularly for regenerative medicine. The effectiveness of these can be improved further by incorporating wound healing–accelerating molecules like growth factors, peptides or various natural substances like honey, aloe vera and various plants and peel extracts. Various polysaccharides have been used either alone or in combination or in derivative forms for wound healing applications. Most of these are biodegradable in human body, which makes it more attractive. The biopolymers are more effective as a wound-healing accelerator than synthetic polymers. The wound treated with biopolymers and biomaterials shows faster healing. Also the structural arrangement of the biopolymers is similar to that of normal skin. Consequently, the biopolymers are considered to be one of the ideal materials with biocompatibility, biodegradability and wound healing property and easy application. Although biopolymer dressings interact with dermal tissue and cells to accelerate the acute healing process, they have no or minimal effect on the healing of complex wounds. In contrast, synthetic polymers have good mechanical properties; near-limitless supply and are easy to process into suitable designs for wound repair, including appropriate pore size and scaffold geometry. These advantages are countered by their minimal intrinsic bioactive properties. Therefore, advanced wound repair is currently directed towards stimulation of physiological repair at the molecular level. Combining synthetic and/or biopolymer dressing with the therapeutic potential of bioactive molecules has emerged as an exciting field of research for enhanced wound repair.

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Further reading [1] K. Kawai, S. Suzuki, Y. Tabata, Y. Nishimura, Accelerated wound healing through the incorporation of basic fibroblast growth factor-impregnated gelatin microspheres into artificial dermis using a pressure-induced decubitus ulcer model in genetically diabetic mice, Br. J. Plast. Surg. 58 (8) (2005) 1115–1123. [2] S.E. Kim, D.N. Heo, J.B. Lee, J.R. Kim, S.H. Park, S.H. Jeon, et al., Electrospun gelatin/ polyurethane blended nanofibers for wound healing, Biomed. Mater. 4 (4) (2009) 044106, https://doi.org/10.1088/1748-6041/4/4/044106. [3] J.M. Anderson, M.S. Shive, Biodegradation and biocompatibility of PLA and PLGA microspheres, Adv. Drug Deliv. Rev. 64 (2012) 72–82. [4] R.K. Mishra, A.B.A. Majeed, A.K. Banthia, Development and characterization of pectin/ gelatine hydrogel membranes for wound dressing, Int. J. Plast. Technol. 15 (2011) 82–95. [5] F. Munarin, M.C. Tanzi, P. Petrini, Advances in biomedical applications of pectin gels, Int. J. Biol. Macromol. 51 (2012) 681–689.

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Syed Wazed Ali1, Mohammad Shahadat1,2, Parveen Sultana2, Shaikh Ziauddin Ahammad2 1Department of Textile Technology, Indian Institute of Technology, New Delhi, India; 2Department of Biochemical Engineering and Biotechnology, Indian Institute of Technology, New Delhi, India

17.1  Introduction Healing reestablishes the integrity of wounded tissue and prevents deregulation of homeostasis in organisms. The main aim of dressings is to inhibit bleeding and shield the injured part from ecological irritants, water and electrolyte disorder. Skin is a natural barrier with the environment which prevents dehydration [1] and plays a key role in homeostasis and controlling the entry of microorganisms into wounds. Thus skin must be covered with a dressing without delay after injury. Wound dressings can be categorized into synthetic, biological and biologic–synthetic. Biological dressings are frequently employed clinically, but they are associated with some disadvantages (high antigenicity, limited supplies, poor adhesiveness and risk of cross-contamination). Synthetic dressings have a long shelf life and create minimal inflammatory response without any risk of pathogen transmission. Biologic–synthetic dressings are bilayered structures with high polymeric and biological content [2,3]. The most important characteristics of an ideal dressing are that it can maintain moisture and allow gaseous exchange as well as acting as a barrier for microorganisms and removing excess exudates at the wound interface. Additionally, it should be non-allergenic, non-toxic and easily removed without trauma, and be fabricated with minimal processing from biomaterial which has antimicrobial properties and endorses wound healing.

17.2  Nanostructure wound dressings In dressings and other biomedical applications, silver nanoparticles (Ag NPs) play a key role because of their excellent antibacterial activity, good anti-inflammatory action and ability to enhance fast wound healing. Ag NPs are clusters of Ag in the size range of 1–100 nm, and are attractive in paramedical applications as antibacterial and antimicrobial agents. Clothing manufacturers have started incorporating Ag NPs into fabrics such as socks to neutralize odour-forming microorganisms [5,6]. The potential of Ag NPs has been exploited to control infection. Based on their anti-inflammatory and fast wound-healing action, Ag NPs have been employed since ancient times (Hippocrates used Ag preparations, and it was used in early treatment of ulcers and Advanced Textiles for Wound Care. https://doi.org/10.1016/B978-0-08-102192-7.00017-5 Copyright © 2019 Elsevier Ltd. All rights reserved.

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Prophylactic environmental effect. Silver NPs are added into antibacterial. Paints and disinfectants to ensure an aseptic environment for the patient.

Prophylactic antibacterial effect. Silver NPs are added as a surface coating for neurosurgical shunts and venous catheters.

Prophylactic antibacterial effect. Silver NPs are added to bone cement and other implants.

Infection protection. SilverNP-impregnated wound dressings prevent infection and enhance wound heading.

Advanced Textiles for Wound Care

Cauterization. Silver nitrate used to stop epistaxis.

Antibacterial effect. First medical use: Crede’s 1% silver nitrate eyedrops were used to prevent mother-to-child transmission of gonococcal eye infection.

Inflammatory effect (causes deliberate adhesion). Silver nitrate is used in pleurodesis.

Regenerative effect. Silver sulfadiazine cream is used as a dressing for burns and ulcers. It also improves skin regeneration. Cauterization. Silver nitrate is used to stop the growth of post-traumatic granulomas, or ‘wild flesh’.

Figure 17.1  Uses of silver and silver NPs in treatment of different diseases. From K. Chaloupka, Y. Malam, A.M. Seifalian, Nanosilver as a new generation of nanoproduct in biomedical applications, Trends Biotechnol. 28 (2010) 580–588.

by C.S.F. Crede for gonococcal infections in newborns) [7,8]. The uses of Ag NPs in various parts of the body for the treatment of diseases are shown in Fig. 17.1 [9]. Generally, Ag, Ag NPs and nonwoven forms of chitin and chitosan (composites, nanofibrils, films, sponges and scaffolds) are employed in treatment of wounded tissues, and a number of articles related to wound dressing materials made of chitin and chitosan are reported. However, very few studies on chitin- and chitosan-based biodegradable wound dressings have been performed [10–13]. It should be taken into account that the prepared dressing should be biodegradable as well as biocompatible, to accelerate the healing process and target the wound without affecting healthy tissues. Nanomedicine, and especially NPs, have opened an innovative way to improve healing efficiency: NPs have performed better than current dressings in providing sustainable and effective dressing in wound treatment. This chapter deals with the role of various nanostructures, especially Ag NPs, chitosan and chitosan–Ag NP-based dressings, in the treatment of wounds and burns. Some commercially available Ag-based dressings and their manufacturers are listed in Tables 17.1 and 17.2.

17.2.1  Mechanism of antimicrobial action of silver nanoparticles The mechanism of the antimicrobial action of Ag NPs (Ag ions) is still not properly reported. However, according to the morphological and structural changes, possible

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Table 17.1 

Different antimicrobial dressings and their manufacturers [4] Dressing name

Antimicrobial ingredient

Dressing format

Manufacturer

Acticoat Absorbent

Ionic Ag

Calcium alginate

Actisorb Silver 220

Ionic Ag and activated charcoal

Ag-impregnated activated charcoal cloth

Arglaes

Ionic Ag

Transparent film or powder

Aquacel AG

Ionic Ag

Hydrofibre

Contreet H

Ionic Ag

Hydrocolloid

Contreet F

Ionic Ag

Foam

Iodosorb

Molecular iodine

Gel or paste

Silvasorb Antimicrobial Silver Dressing Kerlix AMD Gauze

Ionic Ag

Hydrogel sheet or amorphous gel

polyhexamethyl biguanide

Gauze

Smith & Nephew, Largo, FL, USA Johnson & Johnson Wound Management, Somerville, NJ, USA Medline Industries, Mundelein, IL, USA Convatec, Skillman, NJ, USA Coloplast, Marietta, GA, USA Coloplast, Marietta, GA, USA HealthPoint, Ft. Worth, TX, USA Medline Industries, Mundelein, IL, USA Tyco Healthcare/ Kendall, Mansfield, MA, USA

mechanisms have been suggested in terms of interaction between Agand thiol groups present in respiratory enzymes of bacterial cells. Ag could also get bound with bacterial cells and inhibit the respiratory function [14]. The mechanism action of Ag ions can be explained by alterations to the structure and morphology of the bacterial cell wall. It was found that in a relaxed state the DNA molecule has replication potential, but in condensed form DNA loses this potential, leading to damage or death of the cell. The reaction of metal ions with proteins (thiol group) has also been observed to inactivate proteins [15]. Ag NPs show significant antimicrobial activity as compared to other metal salts; this might be due to the large surface area of NPs, which generates maximum interaction with the cell wall of microorganisms. Attached NPs penetrate and easily enter the cell walls of bacteria and interact with sulphur- and phosphorus-containing proteins (DNA). Thus Ag NPs attack the respiratory chain and prevent cell division, resulting in bacterial death. Release of Ag ions from NPs also effectively enhances antimicrobial activity [16,17].

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Table 17.2 

Commercially available Ag-based products and their uses in wound dressings Product

Company

Application

Uses

Acticoat

Smith & Nephew

Nanocrystalline Ag wound dressing

Silverline

Spiegelberg

SilvaSorb

Medline Industries and AcryMe

ON-Q SilverSoaker

I-Flow Corporation

Polyurethane ventricular catheter impregnated with Ag NPs Antibacterial products including cavity filler, wound dressings and hand gels Ag NP-coated catheter used in drug delivery

Dressing for ulcers and burns; stops bacterial infection Controls catheter-associated infections Stop bacterial infections; hand gels used for clinical and hygiene purposes Antibiotic treatment; delivery of medication

17.2.2  Treatment of wound healing using silver nanoparticles Ag is clinically effective in treatment of burns [18]. An aqueous solution of Ag and Ag NPs discharges Ag ions, which have a potential bactericidal effect [19–21]. Ag ions can interact with cell walls of bacteria via the plasma membrane [22] and the peptidoglycan cell wall [23]; bacterial proteins [20] and the enzyme which are mainly involved in cellular activity, resulting in a bactericidal effect (causes lysis). Comparative antimicrobial studies of Ag and nanoparticles of Ag (Ag NPs) reveal that Ag NPs have higher antibacterial activity than Ag ions [24]. This might be due to the comprehensive interaction of Ag NPs with bacterial cell walls, ensuring lysis [25]. The Ag NPs generate reactive oxygen species, which confirm their antibacterial activity and also their toxicity of Ag NPs to human beings [26]. The mechanism of Ag NPs in terms of antibacterial activity has been investigated from the cells of Ag NP-treated Escherichia coli by proteomics, using two-dimensional electrophoresis in conjunction with mass spectroscopy of protein samples [27]. The results of rigorous studies confirmed the inactivity of outer-membrane protein precursors (OmpA, OmpC, OmpF) after Ag NP treatment had destroyed bacterial cell walls completely [28]. Damage to cell walls also results in the failure of proton transfer, which stops the synthesis of Adenosine triphosphate (ATP) [27]. For over a decade Ag-supported nanocrystalline wound dressings like Acticoat have been successfully used to treat wounds and burns [29,30], toxic epidermal necrolysis [31], chronic ulcers [32], Steven–Johnson syndrome [33] and pemphigus. Acticoat is a typical nanocrystalline dressing with a 900 nm thick coating consisting of 10–15 nm crystallite applied on a polyethylene layer [34]. Based on randomised clinical trials (RCTs), Ag NPs have demonstrated exceptional wound healing potential among the existing Ag sulphadiazine (SSD) and gauze dressing regimes in burns treatment [8]. Improvement in wound-healing capacity (by an average of 3.35 days) in infected wounds has been

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Figure 17.2  TEM micrographs of P. aeruginosa without silver nanoparticles (a) and treated with silver nanoparticles (b and c). From J.R. Morones, J.L. Elechiguerra, A. Camacho, K. Holt, J.B. Kouri, J.T. Ramírez, M.J. Yacaman, The bactericidal effect of silver nanoparticles, Nanotechnology 16 (2005) 2346.

observed using nanocrystalline Ag dressings [35]. Another RCT study of Ag NP dressings in the treatment of burns using SSD (1%) revealed outstanding performance of Ag NPs to heal burns rapidly [29]. Additionally, Ag NPs improved the capacity of epithelisation to regenerate tissue (proliferation and angiogenesis). Ag NP-supported dressings have the potential to cause argyria (skin staining) and argyremia (raised Ag content in blood). But, for example, chitosan–Ag NP dressings deposit far less Ag than conventional SSD and thus demonstrate the safer use of Ag NPs in reducing the incidence of argyria and argyremia. Due to their significant effectiveness in treatment of burns, Ag NPs have also been incorporated in medicine for treatment of wounds [36]. The effect of the size of Ag NPs on the antimicrobial activity of Gram-negative bacteria has been studied using advanced techniques like annular dark field (HAADF) scanning transmission electron microscopy (TEM) [16]. Ag NPs in a size range of 1–10 nm showed superior antimicrobial activity: they attached easily and penetrated into bacterial cell walls to interrupt the function of sulphur- and phosphorus-containing compounds (DNA). These Ag NPs also release ions, which had direct bactericidal effects [8]. HAADF and TEM analyses both established the existence of Ag NPs on the surface and interior of bacteria cell walls. The TEM images clearly demonstrated the bactericidal effect of SNs on Pseudomonas aeruginosa samples in the impairment of cell membranes (Fig. 17.2). The environmental impact of Ag NPs has been improved using starch and bovine serum albumin (BSA) as capping agents [37]. Synthesized BSA-capped Ag NPs were employed to observe the lethal effects in zebrafish embryos (Danio rerio) in terms of hatching, mortality, pericardial oedema and heart rate. A delayed rate of mortality and hatching was detected in embryos with increasing concentration of BSA Ag NPs, which results in slow blood flow, abnormal body axes, twisted notochord, cardiac arrhythmia and pericardial oedema. However, no significant effect in developed embryos was found using Ag+ ions and stabilizing agents individually. TEM study confirmed distribution of Ag NPs in blood, brain, heart and yolk embryos, and this

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Figure 17.3  TEM images of normally developed embryos as the control (a); BSA–Ag (5 μg/ mL) treated embryos with slimy fluid containing brown flakes inside the chorion of live embryos (b); cloudy appearance indicating dead embryos at 24 hours post fertilisation (hpf) (c). From P. Asharani, Y.L. Wu, Z. Gong, S. Valiyaveettil, Toxicity of silver nanoparticles in zebrafish models, Nanotechnology 19 (2008) 255102.

was further apparent in the electron-dispersive X-ray analysis (EDS). Acridine orange staining also used to improve the toxic effect of Ag NP-treated embryos (Fig. 17.3). Controllable-size colloidal Ag NPs ([Ag(NH3)2]+) have been synthesized using glucose, galactose, maltose and lactose [38]. Under different ammonia concentrations and pH (0.005–0.20 mol/L, 11.5–13.0), the particle sizes of colloidal Ag NPs were achieved using the lowest ammonia content (1.69 μg/mL Ag), which was confirmed by dynamic light scattering, TEM and ultraviolet-visible spectroscopy (UV-vis) analyses. Reduction of [Ag(NH3)2]+ by disaccharides (maltose) produced a narrow size distribution of NPs with high antimicrobial activity with respect to Gram-positive and Gramnegative bacteria as well as for multiresistant strains (S. aureus) [39]. Antimicrobial activity of some important reported microorganisms is listed in Table 17.3.

17.2.3  Silver-based ceramic and organic polymeric nanomaterials Ceramic NPs containing inorganic materials such as silica, calcium and phosphate salts were tested for skin wound healing. Calcium-based NPs regulate calcium homeostasis, which controls the inflammatory process, fibroblast proliferation and keratinocyte migration [40,41]. The acidic pH of a wound also plays a key role in NP degradation, which results in discharge of calcium ions. A strong antibacterial effect and fast healing rate in healthy, diabetic and immunocompromised rodents have been observed using NPs releasing nitric oxide. Quick wound healing might be due to stimulation of proliferation and migration of fibroblasts, angiogenesis and tissue remodelling (by collagen deposition) [15,16,42,43]. The NPs associated with antibacterial drugs (curcumin) had good therapeutic action to stimulate healing in infected mice burns as compared to commercially available drugs [17,44]. Liposomes are employed in wound therapy due to their lipophilic and hydrophilic nature, and to control side effects of massive drug doses during conventional administration [45]. Liposomes are the most widely used agent for wound therapy, as they are biodegradable and safe to

The role of nanostructures in various wound dressings

Table 17.3  Antibacterial

495

potential of Ag NPs towards

microorganisms Microorganisms

Findings

References

E. coli, S. typhi, S. aureus E. coli, P. aeruginosa, Vibrio cholera, S. typhi E. faecalis, S. aureus, E. coli, P. aeruginosa, S. epidermidis, E. faecium, K. pneumoniae

Higher antimicrobial activity for E. coli and S. typhi than for S. aureus Smaller NPs showed better antibacterial activity; octahedral and decahedral shapes had more highly reactive faces Different reducing saccharides were used to form Ag NPs of different sizes; smaller-size Ag NPs exhibited higher antibacterial activity against different bacteria using Minimum Inhibitory Concentration (MIC) of ammonia (1.69–54.00 mg/mL) E. coli showed higher resistance to bactericidal effects of Ag NPs than S. aureus, while earlier reports demonstrated more sensitivity to Ag of Gram-negative than Gram-positive bacteria based on using a single strain (previous studies) compared to multiple strains

[20]

E. coli (4 strains), Bacillus subtilis (3 strains), S. aureus (3 strains)

[16,37]

[38]

[39]

use in long-term drug release as well as being less toxic. Nanostructured lipid carriers have been effectively applied to carry recombinant human epidermal growth factor, which improves the wound closure rate by stimulating the four stages of the wound healing process. To improve antimicrobial efficiency of wound dressings, hydrogels of Ag–graphene reacted with acrylic acid and N, N′-methylene bisacrylamide have been prepared under various mass ratios of reactants [46]. Among all the prepared hydrogels, the maximum antibacterial performance was achieved by a mass ratio of 5:1 of Ag to graphene; this also gave outstanding biocompatibility, good extensibility and high swelling ratio. In practical application, silver–graphene hydrogel demonstrated fast healing of artificial wounds in rats within 15 days. Thus an Ag–graphene nanocomposite-based antibacterial dressing could be a promising candidate for wound applications. Another nonwoven web wound dressing, poly(vinyl alcohol) (PVA)/AgNO3, was prepared by the reaction of a PVA and AgNO3 aqueous solution using an electrospinning technique [47]. The existence of Ag NPs on the surface of nonwoven dressings was confirmed by scanning electron microscopy (SEM), TEM and XPS analyses. The effect of heat treatment and UV radiation reduced the Ag ion (Ag+) into Ag and the heat treatment improved the crystallinity of (PVA)/AgNO3, which could be a good dressing owing to its structural stability in moisture and good antimicrobial activity. In another study, different concentrations of phytosynthesised Ag NPs in cotton dress fabrics were used to heal burn wounds of rats and compared to commercially available ointment on cotton fabrics [48]. The wound-healing capacity of

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phytosynthesised Ag NP cotton dress fabric (100 μg/kg of body weight) was found to be higher (higher wound contraction area) than dressings containing commercial ointment, which established the better wound-healing performance of cotton containing Ag NPs. To prepare an effective wound dressing, polyurethane (PU) containing silver ions was fabricated by electrospinning followed by reduction of Ag ions to Ag NPs [49]. The electrospun PU NP-supported coating showed high surface area-to-volume ratio, good fluid drainage ability, controlled evaporative water transmission and outstanding antimicrobial efficiency. To enhance the wound-healing capacity of the dressing, collagen was grafted on the fibre surface by plasma treatment (at low temperature oxygen). Collagen-assisted PU–Ag NP fibre (diameter ∼159 nm) covered an increment in surface hydrophilicity, and ∼100% inhibition of bacterial growth was found with the improvement in membrane water absorption capacity. Animal study results confirmed significant wound-healing effects of collagen-assisted PU–Ag as compared to gauze and commercially available collagen sponge wound dressings. Findings related to Ag-containing dressings have confirmed release of Ag+ into the wound without adsorption [50]. Detection of Ag in blood (120 μg/L), urine and tissues of the human body was found after treatment of skin burns with 0.5% AgNO3 [51]. Another study reported deposition of 50 μg/L Ag in 6 h and maximum concentration of 310 μg/L in body parts (corneal tissue, liver and kidney) of SSD-treated burn patients [52]. Existence of Ag NPs has also been observed in the mid-dermis and deep dermis of treated burn wounds, with dressings causing argyria [53]. A proposed scheme for the interaction of Ag ions and Ag NPs with biological cells at cytotoxic level is shown in Fig. 17.4.

17.3  Chitin/Chitosan–Ag NP-based wound dressings In paramedical applications chitin- and chitosan-supported dressing materials have been effectively employed as antifungal and bactericidal agents as well as for their oxygen permeability in the treatment of wounds. A number of chitin and chitosan forms (e.g., sponges, scaffolds, hydrogels, membranes, fibres, etc.) have been developed to use in wound dressings [55,56]. In the early 1980s glycosaminoglycan and collagen-based skin membranes were used as the planar substrate to culture human epidermal keratinocytes [57]. The prepared membrane demonstrated significant results for the culture of human epidermal keratinocytes, along with cells yielding hybrid material which mimics skin [58]. Yannas et al. [59] developed a silicon-supported collagen sponge layer containing glycosaminoglycans to use as artificial skin. More recently attention has been paid to developing significant wound dressings using synthetic and modified biocompatible dressings [60]. Biocompatible materials, namely cellulose, chitin and their derivatives, are used for their quick potential to heal wounds at cellular and molecular levels. Chitin is a low-cost, biocompatible, ecofriendly material obtained from animal, plant and fungal cell walls (Fig. 17.5). It is linearly linked via a 1,4-polymer linkage composed of N-acetyl-d-glucosamine residues. The derivatives of chitin and chitosan are biodegradable, biocompatible, non-toxic,

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Figure 17.4  A proposed scheme for the interaction of silver ions and silver nanoparticles with biological cells at cytotoxic level. From N. Li, T. Xia, A.E. Nel, The role of oxidative stress in ambient particulate matter-induced lung diseases and its implications in the toxicity of engineered nanoparticles, Free Radic. Biol. Med. 44 (2008) 1689–1699.

hydrating and antimicrobial agents which have demonstrated significant effects in fast wound healing [61]. Chitosan consists of a three-dimensional matrix for tissue growth which stimulates macrophages towards tumoricidal functionality. It also assists blood clotting and stops nerve endings to reduce pain by releasing depolymerize (N-acetyl-β-d-glucosamine) which increase the function of fibroblast proliferation resulting collagen deposition and amplified the synthesis of hyaluronic acid at the wound site [62]. Other important characteristics of chitin and chitosan are that they can be shaped as nanofibres [63], hydrogels [64], beads [65] and scaffolds [66] for different biomedical applications like wound healing [63], gene and drug delivery [67] and tissue engineering [68]. Different chitin- and chitosan-supported wound dressings materials are listed in Table 17.4. The antibacterial activity, blood-clotting efficiency and cytotoxic behaviour of chitin/nanosilver (Ch–Ag) composite scaffolds have been investigated [70]. The prepared scaffolds demonstrate antibacterial activity against S. aureus and E. coli and good

498

Advanced Textiles for Wound Care COCH3 H OH H O HO

H

O

H

HO

H O

NH

H

H O

H

O

NH2 H

H

HO

H H

NH H

H3COC

H

NH2

H H

Chitin

H OH

H

H O

O HO

H OH

H H3COC

HO

H OH

NH H

H

H OH

O

H O

H O HO

H H

NH2

H

Chitosan

Figure 17.5  Chemical structures of chitin and chitosan.

blood-clotting potential. Tests carried out using Cell viability/proliferation (MTT assay) with L929 under in vitro conditions revealed good cytotoxicity. However, satisfactory in vivo cytotoxicity was also observed in mouse fibroblasts using a Ch–Ag dressing [71]. A dressing containing chitosan-supported Ag NPs was prepared for wound-healing applications [72]: the prepared chitosan–Ag dressing achieved better healing efficiency (∼89%) than native SSD dressings (∼68%) and pure chitosan (∼74%). Nanofibrous membranes of cellulose nanocrystal–ZnO (CNC-ZnO) nanohybrids incorporated with biodegradable poly(3-hydroxybutyrate-co-3-hydroxy-valerate) (PHBV) have been prepared to use as wound dressings [73]. Significant improvements in mechanical and thermal stability (150% tensile strength and a 112.5% Young’s modulus) of nanofibrous membranes with 5.0 wt% CNC–ZnO–PHBV were found as compared to neat PHBV. The composite nanofibrous membrane of CNC–ZnO demonstrated considerable absorbency (8.4 g/g) of simulated fresh blood and had almost 100% antimicrobial activity against E. coli and S. aureus bacteria. In another study, egg white was used to prepare Ag inlaid with gold (Au) NPs with an average size of 10 nm [74]. Prepared Au–Ag NPs were embedded on a matrix of chitosan (CS–Au–Ag) to use as a wound dressing. Enhanced antibacterial efficiency of CS–Au–Ag was found due to the higher and faster release of Ag ions from CS– Au–Ag compared to a native chitosan dressing, which showed restricted application of Ag NPs through reduction in the Ag content. The CS–Au–Ag nanocomposite had good mechanical stability and improved swelling and retention characteristics owing to the presence of residual egg white. In comparison to CS–Ag in vivo, CS–Au–Ag established its significant potential as a dressing in wound healing. Bacterial cellulose (BC) nanocomposite films made of poly(2-hydroxyethyl methacrylate) (PHEMA) have been fabricated using in situ radical polymerization of

The role of nanostructures in various wound dressings

Table 17.4 

499

Chitin- and chitosan-supported wound dressing materials

Material

Name

Company

References

Chitin-supported dressing

Syvek-Patch

Marine Polymer Technologies Eisai, Japan Eisai, Japan Unitika, Japan 3M 3M HemCon IMS Medafor

[69]

Chitosan-supported dressing

Chitopack C Chitopack S Beschitin Tegasorb Tegaderm HemCon Bandage Chitodine Trauma DEX

2-hydroxyethyl methacrylate [75]. These thin films provide good biocompatibility, cell adhesion and proliferation for human adipose-derived mesenchymal stem cells as compared to native BC and PHEMA. Nanocomposites supported by thin films are a promising wound dressing in biomedicine with a stem-cell-mediated tissue regenerative capability. Electrospun chitosan/polyethylene oxide-based randomly oriented smooth and beadless nanocrystal fibre (ChNC) mats have been used for wound dressing [76]. The porous characteristics of smooth and beadless ChNC fibres (223 and 966 nm diameters) were confirmed by Scanning Electron Microscopy (SEM) and Atomic force microscopy (AFM) analyses. ChNC was found to have mechanical stability and a cross-linked morphology with 64.9 MPa strength and 10.2 GPa modulus, due to the addition of chitin in the matrix of polyethylene. A high surface area (35 m2/g) and appropriate evaporation rate (1290 and 1548 g/m2 per day) contributed to improving the healing of skin wounds. The compatible nature of chitosan/polyethylene nanocrystal fibre confirmed its applicability as a wound dressing to repair and recover adipose-derived stem cells. The polyethylene oxide matrix was reinforced with cellulose to fabricate nanocrystal cellulose (CNC) by electrospinning [77]. Isolation of CNC was carried out from hydrochloric acid and sulphuric acid, and the CNC was used to form electrospun mats. The diameter of electrospun CNC was decreased by the addition of polyethylene oxide and cellulose, which simultaneously decreased the porosity of CNC mats. After cross-linking, the tensile strength and tensile modulus (58 MPa, 3.1 GPa) of CNC mats improved due to the addition of CNCHCl-supported mats. The as-spun CNCHCl-based mats had average pore diameters of 1.6 μm and porosity of 38%. Additionally, mixing of CNCHCl increased permeability for water vapour and O2/CO2 transmission. In practical utility, CNCHCl nanocrystals were nontoxic towards adipose-derived stem cells and could be used as a wound dressing. SSD-doped chitosan composite (CS/AgSD) sponges have been developed to treat wounds [78]. The high porosity and swelling characteristics and the presence of functional groups of CS/AgSD were established by infrared resonance spectroscopy (FTIR), SEM and X-ray diffraction (XRD) analyses. Composite sponges had a wide

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range of antibacterial activity towards E. coli, C. albicans, S. aureus and B. subtilis. Cytotoxicity investigation of composite sponges using MTT viability assay and fluorescence staining on HEK293 cell lines tested for E. coli, C. albicans, S. aureus and B. subtilis, and showed that the sponges had significant antimicrobial efficiency as wound dressings. In another study, antibacterial activity of Spanish broom fibres impregnated with chitosan NPs loaded with vancomycin was examined against S. aureus and in vitro cytotoxicity on HaCaT cells [79]. The chitosan NPs were prepared by ionic gelation using different weight ratios of chitosan and tripolyphosphate; the best formulation of chitosan/tripolyphosphate was chosen as 4:1. Spanish broom fibres loaded with chitosan NPs showed improved antibacterial activity against S. aureus compared to the same fibres containing vancomycin without NPs. Another preparation was chitosan cross-linked with genipin by the addition of partially oxidized Bletilla striata polysaccharide biomaterials [80]. Prepared chitosan cross-linked with genipin/Bletilla striata (CSGB) had less gelling time, higher water retention, more uniform distribution, better mechanical strength, higher cell production and better L929 cell production compared to chitosan cross-linked only with genipin. Blockage of free amino groups of chitosan in CSGB showed no antibacterial activity; the antimicrobial efficiency was incited by the reaction of CSGB with Ag NPs to fabricate a CSGB–Ag composite, which was found by in vivo study to heal cutaneous wounds in mice. The in vivo observation found better recovery of epidermisation with fewer inflammatory cells in 7 days. Ag NPs containing hydrogel are also considered as an excellent antimicrobial material for wound dressing [81]. The hydrogel was prepared by polymerising acrylamide in the presence of poly(vinyl sulfonic acid sodium salt) and a trifunctional cross-linker (2,4,6-triallyloxy 1,3,5-triazine) using a redox initiator and ammonium persulphate/N,N,N′,N′′-tetramethylethylenediamine (TMEDA), followed by in situ reduction with sodium borohydride. The shining sun shape (ball) (∼5 nm) of Ag NPs (∼1 nm) was observed by SEM/TEM analyses. The composite hydrogel was loaded with a natural compound (curcumin) and a comparative antimicrobial study was made: the hydrogel demonstrated significant antimicrobial efficiency and has potential to be a good wound dressing material. To remove the drawback of hydrogels (poor mechanical stability), gelatin methacrylate (GelMA) was synthesized by the reaction of skin gelatine (Type A porcine) with methacrylic anhydride at 50°C. The prepared GelMA monomer containing polyethylene glycol protected AgNPs was subsequently copolymerized with 2-hydroxypropyl methacrylate by redox reaction. The obtained hydrogel copolymer demonstrated optimal mechanical stability and moisture retention along with inhibition of microbial contamination by S. aureus. Microcomputed tomography and FTIR analyses confirmed the improvement in the pore size (32 m to 48–64 m after incorporation of Ag NPs) and copolymer formation, respectively. A degradation study of the composite hydrogel established its degradation after 42 days in the presence of a phosphate buffer solution containing the collagenase enzyme. The absence of cytotoxicity and the non-adherence of the hydrogel to dermal fibroblasts was observed by in vitro culture study. Another study reported the antibacterial activity of Ag NPs loaded on to cotton wool using a convenient solution-dipping technique which involved the soaking of cotton in an Ag

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2-ethylhexylcarbamate solution at 120°C [82]. Homogeneous and high-density deposition of Ag NPs (20–80 nm) on the surface of the cotton wool was confirmed by XRD, SEM and energy-dispersive X-ray analyses. Studies of blood-clotting efficiency, antibacterial inhibition, saline absorption and UV protection of Ag-loaded cotton wool confirmed significant antibacterial activity against S. aureus and E. coli, faster blood clotting and better absorption of 0.9% (w/v) saline solution, and showed excellent UV protection (due to the presence of Ag NPs) as compared to native cotton. An ultrafine gelatine fibre mat containing Ag NPs of 11 and 20 nm size was prepared by electrospinning and made a good antibacterial agent [83]. To improve stability in an aqueous solution, the Ag-containing gelatine mat was further cross-linked with moist glutaraldehyde. Decline in weight loss and the water retention of the Ag/gelatine mat in an acetate buffer (pH 5.5), distilled water (pH 6.9) or simulated body fluid (pH 7.4) was found with increasing cross-linking time. The Ag/gelatine mats achieved quite good antibacterial activity against P. aeroginosa, followed by S. aureus, E. coli and methicillin-resistant S. aureus. Besides wound dressings supported with chitosan–Ag NPs, cerium oxide (CeO2) NPs conjugated with poly(ε-caprolactone) (PCL) and gelatine have been prepared using electrospinning [84]. The PCL/gelatine–CeO2 was used as a potent wound dressing. Among all prepared PCL/gelatine–CeO2 dressings, the wound dressing containing 1.50% CeO2 demonstrated almost 100% healing capacity in an in vivo study (excisional wounds in rats) in comparison with sterile gauze (63%), as shown in Fig. 17.6. Thus CeO2 NPs incorporated in a PCL/gelatine dressing could be effectively employed in wound treatment. The antimicrobial efficiency of Ag and ZnO has been increased by the fabrication of an Ag/ZnO nanohybrid on the surface of chitosan using lyophilisation [76]. Better porosity, swelling, blood-clotting potential and in vitro antibacterial activity against drug-sensitive and drug-resistant pathogens make chitosan–AgZnO composite dressings an exceptional candidate to replace pure Ag and ZnO-based wound dressings. The main cause for the improvement in the observed wound healing, reepithelialisation and collagen deposition was formation of chitosan–Ag/ZnO composite junctions. Fibrous mats of ZnO NPs embedded with sodium alginate (SA)/PVA were prepared using electrospinning [85]. Various samples of ZnO–SA–PVA were fabricated with different concentrations of ZnO (0.5%, 1%, 2% and 5%). The cytotoxicity performance results indicate that the composite fibers of SA–PVA had better cytocompatibility with 0.5% and 1% ZnO as compared to bare SA–PVA. ZnO–SA–PVA showed better antimicrobial activity against S. aureus and E. coli owing to the presence of ZnO in the SA–PVA matrix. Based on its significant antimicrobial activity, ZnO– SA–PVA can be effectively used as a biocomposite material for wound dressing with minimal toxicity. Chitosan NPs loaded with SSD were fabricated to control bacterial growth and for use in wound treatment [86]. The best formulation was found by using chitosan NPs and SSD in 1:1 molar ratio because of their appropriate particle size, polydispersity index and morphology and association efficiency. The proposed molar ratio showed the best characteristics for the preparation of SSD-loaded chitosan NP wound dressings by a padding process with/without using any cross-linker. The antimicrobial

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7 days

14 days

Figure 17.6  Skin of rat wounds treated with sterile gauze (control) and PCL/gelatine–CeO2 wound dressing for 7 and 14 days post-wounding. From M. Naseri-Nosar, S. Farzamfar, H. Sahrapeyma, S. Ghorbani, F. Bastami, A. Vaez, M. Salehi, Cerium oxide nanoparticle-containing poly (ε-caprolactone)/gelatin electrospun film as a potential wound dressing material: in vitro and in vivo evaluation, Mater. Sci. Eng. C 81 (2017) 366–372.

activity of the chitosan–SSD dressing was shown by its efficient inhibition of growth of Gram-positive, Gram-negative and Candida bacteria on an infected wound. Electrospinning is considered one of the advanced techniques to fabricate dressing materials. In this regard, a bioactive nanohybrid membrane of CNC and ZnO fibres was fabricated to use as a reinforcing agent [73]. Significant improvement in thermal stability and mechanical strength and reduced PHBV nanofibre diameter and porosity (14%–56%) were found after the incorporation of CNC–ZnO in the PHBV matrix. Incorporation of CNC–ZnO (5.0 wt%) considerably improved the uniformity and reduced the diameter of PHBV nanofibres, with better porosity in the range of 14%– 56%. Significant enhancement in mechanical strength (Young’s modulus 112.5%) and thermal stability were achieved. The CNC–ZnO-supported membrane had a positive influence on the barrier properties and absorbency (8.4 g/g) for simulated fresh blood, and almost 100% antibacterial activity was achieved against E. coli and S. aureus. The membrane is thus a potential antibacterial wound dressing.

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PVA has been used to develop PVA–chitosan–Ag NPs composite fibrous mats by electrospinning [87]. The presence of 15–22 nm diameter Ag NPs on the surface of chitosan associated with PVA was confirmed by SEM, TEM, UV-vis, FTIR and XRD analyses. The results for in vitro antibacterial activity and in vivo wound-healing potential confirmed effective inhibition of E. coli and S. aureus growth, resulting in high wound-healing potential as compared to a gauze control. Another thermally and chemically stable wound dressing based on poly(N-vinylpyrrolidone) (PVP) associated with chitosan and titanium dioxide (TiO2) NPs was prepared to deter antimicrobial activity [88]. The PVP–chitosan–TiO2 nanocomposite dressing had potential to cover outstanding antimicrobial activity, good biocompatibility against NIH3T3 and L929 fibroblasts and quick healing capacity in albino rats as compared to commercially available soframycin skin ointment and chitosan-treated groups.

17.4  Conclusions Healing of wounds using Ag NPs and chitosan–Ag NP dressings is a multifaceted process involving a number of integrated steps to ensure fast and proper construction of tissue architecture. In many reported studies, chitin/chitosan–nanoparticles of silver (NS) appears to be an exceptional nanostructured dressing material for wound healing and burns. In comparison with the partially cytotoxic nature of pure Ag (in bulk), Ag NPs and chitosan–NS have shown high durability and better biocompatibility to produce wound dressings with low toxicity, high moisture absorbency and antibacterial efficiency. The properties of nanostructured wound dressings accelerate effective healing of wounds and burns. Chitosan–NS-supported dressings could be effectively employed to heal wounds and encourage fast proliferation of tissues as a result of better healing efficacy and bactericidal effects. Moreover, the high moisture permeability of chitosan–NS wound dressings may have extraordinary potential to act in a very satisfactory way to handle accumulated fluid in heavily exudating wounds.

Acknowledgements Dr Mohammad Shahadat expresses appreciation to the Science and Engineering Research Board (DST) Fast Tract Young Scientist Scheme (SB/FT/CS-122/2014) for his postdoctoral fellowship.

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Erdem Ramazan Department of Textile Technologies, Serik GSS Vocational School of Higher Education, Akdeniz University, Antalya, Turkey 

18.1  Introduction Healthcare is a critical aspect of human survival. Polymeric materials and textile structures in different forms and properties helped the scientists to develop functional new biomaterials. Wound management has recently become more complicated because of new insights into wound healing and requirements to manage complex wound either in the medical departments or outside the hospitals. Therefore, the development of new and effective wound healing devices remains an area of intense research. Main target of wound management is to enable rapid wound healing with satisfactory results in terms of tissue regeneration and cosmetic appearance [1]. Nowadays, plenty of novel textile-based wound treatment products are available that combine the traditional textile characteristics with modern multifunctionality. The wound care market is estimated to be worth $6.7 billion worldwide, and it is estimated to accumulate rapidly within the following 10 years. The growth of the market is associated with the incrementing number of chronic wound patients. In the United States, approximately 6.5 million people suffer from chronic wounds, and US$25 billion is spent every year on offering appropriate therapy [2,3]. Many patent applications are still being filed, and it has recently been reported that Smith & Nephew, KCI, Johnson & Johnson, Human Genome Sciences and Paul Hartmann A. G. were ranked as the top five applicant companies based on the number of applications. So, designing and inventing novel wound dressing structures are very hot topics [3]. The substantial properties of textiles that help to design effective wound dressings can be stated as absorption, porosity, capillarity, strength, extensibility, flexibility, drapeability, air and moisture permeability, availability in three-dimensional (3D) structures, variety in fibre (or filament’s) types and lengths, fineness, cross-sectional shape and geometry, manipulability to incorporate medicine etc. [4]. Most preferred textile structures used for modern wound dressings are fibres, slivers, yarns, woven, nonwoven, knitted, crochet, braided, embroidered fabrics, composites and electrospun nanofibrous materials. Wound care also applies to dressing materials such as hydrogels, matrix (tissue engineering), films, hydrocolloids and foams [5]. Ideal wound dressings should possess the following properties: being a barrier to microorganisms to protect against infection; create clean and moist environment in the wound bed; provide thermal insulation and comfort; protect exposed nerves to Advanced Textiles for Wound Care. https://doi.org/10.1016/B978-0-08-102192-7.00018-7 Copyright © 2019 Elsevier Ltd. All rights reserved.

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diminish associated wound pain; eliminate dead space within the wound bed to prevent premature wound closure; remove debris, necrotic tissue and foreign material; provide adequate gas exchange between the wound and environment; being easily removed from the wound surface without causing any trauma during healing; being able to manage exudates and fluid without causing maceration or irritation; provide cushioning effect; being biocompatible, non-toxic, non-allergic, non-irritating and biodegradable (if it is necessary); not release particles and fibres in the wounded area; being cost-efficient; able to be manufactured and used easily [4,6]. In the 1960s George D. Winter from the Department of Biomechanics and Surgical Materials at the University of London experienced an extraordinary situation during the study on the treatment of pig wounds in an occlusive condition. It was observed that when the wound was kept under a moist condition, epithelialisation of the wound surface occurred much faster than if the wound was reserved under dry condition. Further experimental efforts on humans proved that wounds heal rapidly when they are kept under a moist condition. So this important finding opened the doors to develop modern ‘moist healing or occlusive wound dressing’ materials [7]. Some natural polymers such as polysaccharides (alginates, chitin, chitosan, heparin and chondroitin), proteoglycans and proteins [collagen, gelatin (GT), fibrin, keratin, silk fibroin (SF), eggshell membrane] are widely preferred for preparing the products suitable for wounds and burn management because of their structural similarities to human macromolecules, biocompatibility and biodegradability. By using biomimetic techniques, some synthetic polymers such as polyglycolic acid, polylactic acid, polyacrylic acid, poly-ε-caprolactone, polyvinylpyrrolidone, polyvinyl alcohol and polyethylene glycol were also applied to improve healing and enhance re-epithelialisation. Through fibrous matrix formation, these polymers provide an optimal microenvironment for cell proliferation, migration and differentiation and also possess good micromechanical properties [8]. This chapter discusses briefly the wound healing process and deals extensively with the production of various wound dressing fabric structures and also the recent developments in novel wound dressing structures.

18.2  Classification of the wounds According to the nature of the repair process, wounds can be defined as acute or chronic. Acute wounds are usually tissue injuries that heal completely within the expected time period of 8–12 weeks with minimal scarring. These types of wounds include mechanical injuries (abrasions, tears, penetration, incision and burn) and chemical injuries caused by corrosive agents. Chronic wounds, on the other hand, are related to tissue injuries that heal slowly and often reoccur because of the repeated trauma which depends on the physiological conditions of the patients, immunological defects or persistent infection [9,10]. Wounds are also characterised based on the number of skin layers and area of skin influenced. If only skin surface is affected by the injury, this is referred to as superficial wound, whereas injury involving both the epidermis and the deeper dermal layers,

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Figure 18.1  Wound types: (a) necrotic, (b) sloughy, (c) granulating, (d) epithelialising and (e) infected wounds [12,13]. (e) Taken From: https://en.wikipedia.org/wiki/Infection#/media/File:Dit_ del_peu_gros_infectat.jpg.

including blood vessels, sweat glands and hair follicles is expressed as partialthickness wound. Full-thickness wounds occur when epidermis, dermis and the underlying subcutaneous fat or deeper tissues are damaged [9,11]. On the basis of their physiological conditions and appearance, wounds can be divided into five groups, each with a symbolic colour code: necrotic wounds (black), sloughy wounds (yellow), granulating wounds (pink or red), epithelialising wounds (red) and infected wounds (green). Fig. 18.1 exhibits the five types of wounds [9,12]. Necrotic wounds are hard and dry to touch. They are covered with devitalised epidermis and tend to shrink. In this condition, autolysis is inhibited and separation of the necrotic tissue may be delayed indefinitely. Burns, leg ulcers and pressure sores are some of the examples of sloughy wounds. In this condition, necrotic covering is removed and a glutinous yellow covering occurs on the wound surface. This is not dead tissue, but a composition of fibrin, protein, serous exudate, leucocytes and bacteria. Granulating tissue is the new matrix form occurring on the surface of wound during healing. Colour is bright, condition is moist and plenty of tiny blood vessels are observed. For epithelialising wounds, it is characteristic that epithelium is formed over a denuded surface. Isolated pink-coloured islands are observed on the wound surface. If the wound is infected, cloudy, green and smelling fluid drainage occurs [9,14].

18.3  Healing phases of the wounds Selection of a proper wound dressing material for a specific type of wound requires detailed knowledge of the wound healing process. Wound healing is a complex and dynamic process managed by cytokines and growth factors (Table 18.1) and can be categorised into four continuous phases: (1) homeostasis, (2) inflammation, (3) proliferation and (4) maturation or remodelling (Fig. 18.2).

Table 18.1 

Major growth factors and cytokines that take part in wound healing with cell types and their main roles [15] Growth factors

Cells

Function

Epidermal growth factor Fibroblast growth factor-2

Platelets, macrophages and fibroblasts Keratinocytes, mast cells, fibroblasts, endothelial cells, smooth muscle cells, chondrocytes Platelets, keratinocytes, macrophages, lymphocytes, fibroblasts

Re-epithelialisation

Transforming growth factor-β

Platelet-derived growth factor

Platelets, keratinocytes, macrophages, endothelial cells, fibroblasts

Vascular endothelial growth factor

Platelets, neutrophils, macrophages, endothelial cells, smooth muscle cells, fibroblasts Neutrophils, monocytes, macrophages, keratinocytes Neutrophils, macrophages

Interleukin-1 Interleukin-6 Tumour necrosis factor-α

Neutrophils, macrophages

Granulation tissue formation, re-epithelialisation, matrix formation and remodelling Inflammation, granulation tissue formation reepithelialisation, matrix formation and remodelling Inflammation, granulation tissue formation, reepithelialisation, matrix formation and remodelling Granulation tissue formation

Inflammation re-epithelialisation Inflammation, re-epithelialisation Inflammation, re-epithelialisation

Hemostasis

Inflammatory

Blood clot

Hair Fibroblast

Scab

Fibroblast Macrophage

Capillary bload vessels Proliferative

Remodelling Re-generated epidermis

Fibroblasts proliferating Subcutaneous fat

Re-generated dermis

Figure 18.2  Wound healing stages.

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18.3.1  Homeostasis As soon as the skin injures, vasoconstriction begins to reduce blood loss. Then blood spreads into the wounded area, platelets come into contact with and adhere to the wall of the injured blood vessels and the exposed collagen within the extracellular matrix (ECM). Following this, the platelets immediately release cytokines, growth factors and numerous pro-inflammatory mediators, resulting in triggering the coagulation. This enables fibrin clot formation, which seals the disrupted blood vessels, preventing further blood loss [7].

18.3.2  Inflammation Activation of the coagulation evokes the release of vasoactive cytokines such as prostaglandins, histamine and other amines from the granules released by mast cells, which results in increased local vasodilation and capillary permeability. The vessels become more permeable so that the migration of monocytes is allowed into the wound bed. Besides, serous fluid appears into the wound bed and surrounding tissue, creating oedema. These are strong characteristics of inflammation. During the inflammation phase, the amount of neutrophils increases within the wound area because of the chemotactic agents released from bacteria. They ingest the bacteria via phagocytosis [7].

18.3.3  Proliferation In the phase of proliferation, the wound bed is filled with highly vascular connective tissue, referred as ‘granulation tissue’. Devastated vascularity in the wound bed decreases pH in the wound environment, reduces oxygen tension and increases lactase. Therefore, neovascularisation or angiogenesis is triggered by the release of vascular endothelial growth factor (VEGF), basic fibroblast factor and transforming growth factor-β. Insufficient blood supply creates low oxygen tension, stimulating the release of hypoxia-inducible factor (HIF), which regulates the expression of VEGF [7]. As new blood vessels are formed in the wound area, the oxygen tension increases and oxygen binds onto the HIF, inhibiting its activity, which results in decreased production of VEGF. The main cells responsible for the generation of the ECM are fibroblasts, which are attracted into the wound bed by cytokines produced by macrophages and then converted into wound fibroblasts, which have decreased proliferative behaviour but incremented collagen production. During the initial step of wound healing, the fibrin clot supports the migration of cells into the wound area. This fibrous matrix is gradually replaced by the material composed of fibronectin and hyaluronic acid, both of which contribute to cell migration and proliferation. Fibroblasts bind onto the provisional fibrin matrix and begin collagen production. The early so-called ‘Type 3 collagen’ comprises approximately 30% of granulation tissue and does not play a role in contributing to the tensile strength of the wound. As collagen matures, Type 3 collagen is transformed into ‘Type 1 collagen’. In wound healing, long time is required to produce the sufficient volume of connective tissue to fill the injured part, where the granulation tissue is generated by the combined process of neovascularisation and collagen production [7].

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Because the generation of the granulation tissue is a slow process in patients with poor nutritional condition, appropriate wound management is very critical for healing. In this case, occlusive environment can be beneficial for increased rate of neovascularisation. In addition, by using absorbent dressings such as nonwoven alginate or polyurethane (PU) foams, the excess exudates can be absorbed and skin maceration can be prevented [7].

18.3.4  Maturation and re-modelling In this last stage, epithelial cells migrate from the wound edges to reconstruct the surface of the wounded area. Epithelialisation is postponed for a while to allow the granulation tissue to be filled into the wound defect. Epithelial cells can only migrate over a moist, vascular wound surface, and are hampered by a dry or necrotic wound surface [7]. Lateral migration continues until the defect is renovated, before the cells carry on upward migration and differentiation and the epidermis regains its normal thickness and stratification. The remodelling period may take a year or more, during which fibroblasts designate the process of wound matrix breakdown by matrix metalloproteinases and synthesis of new ECM. This slow process raises the tensile strength of the wound. However, scar tissue never possesses more than 80% of the tensile strength in unwounded tissue. During remodelling, an imbalance in terms of disruption of matrix degradation and synthesis may occur on occasion, creating abnormal scar formation such as hypertrophic or keloid scarring. Generally, wound healing is a well-organised process provided that the individual patient is nutritionally robust, haemodynamically well and biochemically stable [7].

18.4  Fabric-manufacturing techniques and related wound dressing structures The word ‘textile’ is described as any material made of interlacing fibres, while the word ‘fabric’ is defined as any material fabricated by weaving, knitting, crocheting or bonding yarns or fibres. Traditionally, fibres are transformed into yarn or thread by spinning process before they are used into the fabric. However, nonwoven textiles are produced directly from the bonded fibres. Bonding can be realised thermally, mechanically or by using adhesives. To add the required properties, various chemical, physical and biological processes can be applied to fibres, yarns and textile fabrics. In the case of medical textiles, the end products also need to be packaged and sterilised to meet the functional and safety requirements [7].

18.4.1  Weaving In this process, two sets of yarns, named as warp and weft, are interlaced with each other systematically to form a woven fabric. Woven fabrics are comparatively inextensible and

Advances in fabric structures for wound care

(a)

Warp

(b)

515

(c)

Weft

y

y1

Figure 18.3  (a) Classical weaving, (b) Leno weaving, (c) Leno-woven gauze fabric.

dimensionally very stable structures. The prominent characteristics of woven fabrics are high permeability, minimal blinding and straight flow path. If smaller pore sizes or openings are required, the weave construction can be changed accordingly. A closed-weave construction generates small openings while keeping fibre strength and integrity the same. Woven textile materials are non-shedding, pliable and can be customised to gain wicking and absorption properties [7]. Major drawback of the traditionally woven fabric is the tendency of threads to unravel at selvedge. This may cause a big problem in terms of fabricating wound dressing. To avoid this drawback, a special weave known as ‘Leno’ has been reported. In leno weaves, warp ends are not placed parallel with other ends, instead they are partly twisted around. As illustrated in Fig. 18.3 the end y, which is stated as the doup end, is raised over the first pick on the left side of the end y1, which is named as the ground end; however, on the second pick, y is raised on the right side of y1 [16]. Because of the properties such as inexpensive, readily available, having much absorbent capacity and some sort of protection against bacterial infection and being suitable for a large number of wounds, plain gauzes made of cotton or rayon-woven fabrics are still extensively preferred in wound management. However, gauze fabrics without any treatments cause some serious problems during healing, for instance, fast dehydration, promoting bacterial growth and contamination, bleeding and damage in renewed epithelial flora at the stage of dressing removal. Also, these dressings require frequent changing to protect healthy tissues from maceration. Thus, many attempts have been exerted to compensate these disadvantages. It is stated that impregnation of the gauze dressings with zinc, iodine or petrolatum helps to minimise desiccation and provides non-adherent coverage [17]. Advanced cotton gauze composite has been recently reported, coated with chitosan–Ag–ZnO nanocomplex. Experimental results presented that the treatment increased swelling capacity and improved antibacterial activity versus Escherichia coli and Staphylococcus aureus [18]. Xeroform (non-occlusive dressing) is petrolatum gauze, impregnated with 3% of Bismuth tribromophenate and is suitable for non-exudating to slightly exudating wounds. There are also reputative paraffin-impregnated commercial tulle dressings such as Bactigras, Jelonet and Paratulle that are proper for superficial cleaning of wounds. Some of the

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commercially used gauze dressings are briefly explained in Table 18.2. In general, traditional gauze dressings are preferred for the clean and dry wounds with mild exudate levels, or utilised as secondary dressings. Because these dressings do not perform well on providing moist environment in wounded area, modern dressings, with more advanced formulations, have been started to be used in more complex wounds [19].

Table 18.2 

Commercially used woven gauze fabrics

Product

Company

Description

Meditull Jelonet Dressing

Fleming Medical

Euronet Paraffin

Pharmacy Line

Paranet

Synergy Health

Bactigras

Smith & Nephew

Pharmatull plus

Biologica pharmaceutical

UniTulle

ZENTA

JELONET

Smith & Nephew

Sofra-tulle

Hoechst Marion Roussel Ltd.

A leno weave fabric of 100% absorbent cotton thread, impregnated with white soft paraffin. It is used as a primary contact layer for especially granulating wounds. Absorbent cotton thread gauze, impregnated with white soft paraffin ointment. Non-adherent and non-allergenic dressing. Used as a primary wound contact layer in the treatment of burns, ulcers, skin grafts and a variety of traumatic injuries. Sterile gauze dressing is made from 100% cotton open-mesh leno weave, impregnated with yellow soft paraffin. Used on superficial wounds, burns, skin grafts and traumatic injuries. Leno weave–impregnated with white soft paraffin BP containing 0.5% Chlorhexidine. Protects the wound and allows free passage of viscous exudate. Maintains the shape and resists fraying. Used for minor burns and scalds – lacerations, abrasions and other skin-loss wounds. Leno gauze of 100% absorbent cotton thread impregnated with white soft paraffin jelly which makes it non-adherent and non-allergenic dressing. Contains chlorhexidine digluconate B.P. 0.5% (w/w) which has antimicrobial effect. Leno weave evenly impregnated with soft paraffin BP. Low adherent, non-allergic, protecting and healing the wound allowing easy drainage and easily removable without damage of wound surface and newly formed epithelium. Paraffin-impregnated tulle gras dressing made from open leno weave. Used for minor burns, lacerations, abrasions and leg ulcers. Leno weave cotton fabric impregnated with white soft paraffin, anhydrous lanolin and 1% (w/w) framycetin sulphate. Used as a primary wound-contact layer in the management of infected wounds.

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18.4.2  Knitting Knitting can be classified as ‘weft’ and ‘warp’ constructed. In weft knitting, loops are generated principally in the transverse direction of the fabric, whilst in warp knitting loops are formed across the length direction of the fabric, as illustrated in Fig. 18.4. Knitting is a very economical technique where a single package of yarn is utilised to produce fabric; however, in the case of warp knitting a warp beam is needed to manage the warp yarns during the process similar to weaving. Compared with woven and leno fabric structures, knitting structures are more flexible, compliant and conformable. In addition, unlike woven structure, the knitted structure does not fray at the cut edge. There are various types of knitting structures available with different properties. Plain weft knits, for instance, are more extensible and dimensionally unstable compared with the warp knitting. This is because more interlocked loops are constructed in the warp knitting. Drapeability of the knitted fabrics is a big advantage in medical field when the 3D conformability is demanded. On the other hand, porosity is a major limitation because of the loop formation [16]. Court et al. patented a novel wound dressing structure made by warp-knitted technique (Fig. 18.5). The dressing is composed of support yarns and in-laid yarns. It has been stated that the support yarn can be a continuous-filament viscose, polypropylene, polyester, polyamide or polyethylene yarn or mixture thereof. The in-laid yarn is composed of gel-forming fibres that are preferably sodium carboxymethyl cellulose fibres, chemically modified cellulosic fibres, pectin fibres, alginate fibres, polysaccharide fibres, hyaluronic acid fibre or fibres derived from gums. With this invention, it has been possible to knit wound dressings from a mixture of gel-forming fibres and textile fibres. Also, fast-knitting production speeds can be achieved. In addition, preservatives or pharmacological ingredients can be included in the final composition of the dressing material such as metronidazole, silver sulphadiazine, neomycin or penicillin and antiseptic agents such as povidone iodine and anti-inflammatory agents such as hydrocortisone or triamcinolone acetonide [20]. In another recent patent, it is described that a yarn consisting of a blend of gelling fibres and non-gelling fibres, in which at least 50% w/w gelling fibres are present, exists. A knitted structure was developed by using these yarns [21]. Preferably, the gelling fibres are chosen from pectin, alginate, chitosan, hyaluronic acid and Face wale

Back wale

1x1 ribana

Weft knitted structure

Figure 18.4  Schematic illustration of weft (ribana) (left) and warp (right) knittings.

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4

4 2

6

Figure 18.5  Warp-knitted dressing composed of support yarn (2), in-laid yarn (4). Each warp yarn (6) is almost in line with the direction in which the fabric was fabricated. The warp yarn (6) is in the form of pillars or chains of stitches held together by the in-laid yarn (4) [20].

chemically modified cellulosic fibres, or combinations thereof. The non-gelling fibres can be cellulosic fibres, such as lyocell or viscose. One or more additional finishing such as antimicrobial, antiseptic, antifungal and/or anti-inflammatory agents may also be applied to the knitted structure [21]. Zhao et al. prepared carboxymethyl cotton knitted fabrics (CM-CKFs) as wound dressings by using different solvents: water, ethanol–water and isopropanol–water. Knitted fabric structures were selected for this novel study because of the high absorption capacity. However, the reaction efficiency could be low because of the high density of knitted fabrics, which is not suitable for the reagents to penetrate. The weight of the CKFs was approximately 190 g/m2. Two reaction steps were performed for the preparation of CM-CKFs, alkalisation and etherification. Seven different solvents with various ratios were used. The obtained results exhibited that CM-CKFs treated in isopropanol–water solution exhibited excellent mechanical characteristics, water vapour permeability and barrier properties and was considered a potential candidate for industrial production for wound therapy applications [22]. In the commercial side, Advancis Medical announced Activon Tulle which is a knitted viscose mesh primary dressing impregnated with Manuka honey (MH). It is ideally designed for granulating or shallow wounds. It can also be a proper option if there exist debriding or de-sloughing small areas in necrotic or sloughy tissue [23].

18.4.3  Spacer fabrics Spacer fabrics are a kind of 3D manufactured textile structures in which two outer fabric layers are connected by a layer of pile threads. Because of the layer of these spacer yarns, a defined distance can be established between the outer layers, which generally varies from 1.5 to 10 mm. The design of construction affects the functionality of the 3D structure in terms of thermoregulation, breathability, pressure stability and pressure elasticity. Both the outer layers can be constructed differently. Material types and

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the surface characteristics of the layers influence the elastic and comfort properties of the whole structure and the moisture transport and air circulation level between the layers. Because of the latter two functionalities, heat congestion and maceration of the skin can be avoided [24]. Spacer fabrics may offer new opportunities to design novel wound dressings by providing moist, absorbent, interactive and nontoxic environments for wound healing. Spacer fabrics are breathable with high air permeability, which is crucial for odour removal. Spacer fabrics are also soft and possess good resilience that can create a good cushioning effect to the body. Because the pressure is very well distributed within the 3D structure of spacer fabrics, wounds can be protected from the negative impacts of physical and mechanical movements [24,25]. Knitted spacer fabricating technique enables the product developers to adjust absorbency and water vapour permeability level of the fabric; therefore, the requirements of different types and stages of exuding wounds can be met. These structural changes can easily and cost-effectively be set by controlling spacer yarn connecting distance, determining the number of elastic yarns to be used and selecting the suitable type of spacer yarns and the process parameters. In addition, spacer fabrics can effectively be used to obtain thermal comfort and regulate human body temperature when produced with different types of yarns on different layers [26]. Davies and Williams [27] explored the possible use of spacer fabrics for absorbent medical applications. They measured the absorbency and liquid spreading inside spacer fabrics and figured out that spacer fabric containing roving in the central spacer zone exhibited the greatest absorbency and control over the area of spreading. Tong et al. [28] recently claimed that warp-knitted spacer fabrics could be preferred as a substitute for the absorbent layer for advanced wound dressings. Their study ensured the good air and water vapour permeability of spacer fabrics. Commercial dressings that are currently used for heavily exuding wounds still face some drawbacks, for example, insufficient integrity, poor air permeability, low water vapour transmission and the need for a secondary dressing as a cover. To eliminate these challenges, a new type of wound dressing based on the three-layer spacer fabric structure has been announced. As illustrated in Fig. 18.6, the spacer fabric was the base material of the newly designed dressing structure. Top and bottom layers were formed with elastic synthetic fibres to make them hydrophobic, extensible and conformable. Hence, the wound contact layers of the dressing had hydrophobic character. After the knitting of spacer fabric, a permeable nanofibrous membrane was also deposited on the outer layer of the spacer fabric to improve water-proof property while not losing its permeability. Electrospinning process was utilised for the deposition of the nanofibrous membrane. In this construction, spacer layer was formed as the absorbent layer by knitting the yarns that possessed good absorbency and moisture conductivity. With the selection of different types of absorbent yarns, wetting speed and the absorption capacity could be varied. The appropriate thickness and areal mass of the dressing could be gained through controlling the spacer yarn length and size of the surface yarns. In this example, outer layers were generated via single-jersey knitting by using single- or double-polyester/ spandex (100D/40D) yarns. The spacer layer was knitted with 32S/2 bleached cotton or Tencel yarns. When knitting was completed, all spacer fabrics were exposed to a

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Advanced Textiles for Wound Care Top layer: Electrospun waterproof film with air permeability Hydrophobic surface of spacer fabric knitted with synthetic and elastic yarns Highly absorbent spacer layer with good liquid retention, composed of absorbent yarns

Water vapor and air permeable

Hydrophobic wound contact layer with rapid liquid transportation and good permeability, composed of synthetic and elastic yarns

Figure 18.6  Spacer fabric wound dressing with electrospun membranes covered on outer surfaces.

steaming process to allow shrinkage of the surface layers without causing any damage to the spandex yarn. PU and polystyrene (PS) polymers were chosen to be electrospun to cover outer layer surfaces with nanofibrous membranes, respectively. Results proved that spacer fabric dressings presented better water resistance compared with the commercial dressings. It was also observed that their air permeability was much higher than that of the foam dressings. There were also comparisons conducted among the spacer fabrics. According to findings, PS membrane had better water resistance and lower air resistance than the PU membrane. It was finally concluded that the spacer fabric–based dressings could absorb a high amount of fluid in a very short period of time, and they were permeable for air and water vapour, while maintaining a moist environment with low evaporation rate after absorbing [25].

18.4.4  Embroidery technique In embroidery technique, stitch type and machine specifications are very crucial to design novel structures that are compatible with various industrial applications. For fabrication of medical textiles, basic lock stitch of shuttle embroidery machines can be used. The lock stitch includes a two-thread loop between the needle and the bobbin threads. In this situation, yarns have almost adequate stiffness and tension. A modified lock stitch is formed by either increasing the tension of the bobbin thread or decreasing the tension in the needle thread, which leads the needle thread to travel on the surface of the fabric (Fig. 18.7) [29]. It is very well perceived that embroidery is realised upon a substrate which can be any textile structure. For specific applications, especially the medical ones, stitching is carried out on a degradable substrate, which is washed out later on, leaving behind only the stitched threads [29]. Although the use of embroidery method is very limited in wound dressing applications, it is occasionally preferred for other biomedical applications. In his patents, Ellis [30–32] pointed out the possible use of embroidery technique for various medical textile applications such as hernia patches and ligament prostheses. McLeod and

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f s

sy n

Lock stitch

by s

f

by

sy f

Modified lock stitch

by

n

sy

Figure 18.7  Lock stitch generation in shuttle embroidery machines. The stitching yarn (sy) is penetrated through the fabric (f) by the needle (n) and generates a loop through which the shuttle (s) carries the bobbin yarn (by) [29].

Jackowsky [33] mentioned an implant design for intervertebral disc where an elastomeric block was reinforced by an embroidered textile. Philips et al. [34] reported a graft stent for the repair of abdominal aortic aneurysm. Karamuk [29] has recently developed an embroidery-based wound dressing for the treatment of large skin defects such as chronically non-healing wounds (Fig. 18.8). In this unique multilayered system, first layer has been designed as the contact layer that directly touched the wound surface. Its structure has various sizes of pores including macropores (500–3000 μm), mesopores (100–500 μm) and micropores (10–100 μm). These pores were formed by stitching interconnected loops. Onto this porous structure, cross-stitches were made by using polyamide monofilament yarn. The aim of the preparation of this first layer was to apply local mechanical stress, to adsorb coagulated blood without stiffening and to provide space for cellular in-growth. The second layer was a PET-based knitted spacer fabric. The function of this layer was defined as providing a dense capillary structure for transport of wound exudates and distribution of the pressure coming from outer bandages to the wound surface. The third layer was a commercial superabsorber made of poly(hydroxy-acrylate), and it is covered with warp-knitted polyester fabric for mechanical protection. In vitro assays proved that no cytotoxic affect was observed and a satisfactory healing performance was obtained.

18.4.5  Nonwoven Nonwoven structures are widely used in wound dressing applications because of its ability of providing a soft and resilient hand, absorbing and retaining exudates and being a protective covering. Such structures have been preferred as the facing and the entire absorbent pad of a wide variety of dressings. These fabrics are more homogenous, softer and more resilient compared with woven and knitted structures. Properties of the nonwoven fabrics (NWFs) are mainly influenced by the choice of the fibres, the technology used (how the fibres are to be arranged), the bonding process and the bonding agent. Because nonwovens are fabricated from the fibres directly, eliminating the intermediate yarn preparation steps, the process is fast and economic. Wide variety of processes can be applied for manufacturing of nonwovens used in wound care

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B A B

A

D

5000 µm

5000 µm

C D B 2000 µm

Figure 18.8  SEM images of the designed embroidery wound dressing [29]. A: Macroscopic pores 500–3000 μm. B: Mesoscopic pores 100–500 μm. C: Microscopic pores 10–100 μm. D: Integrated stiff elements for mechanical stimulation.

products. Hence, it is possible to obtain different structures and properties in terms of developing new functional dressing materials [16]. The first stage in the production of nonwovens is ‘forming the web by assembling or laying the fibres’ and second step is ‘bonding the web’ by using several methods such as needle-punching, adhesive bonding, thermal bonding, stitch bonding, felting, hydroentanglement and spin laying [35]. NWFs can also be functionalised by final treatments, for example, chemical repellents, wetting, antimicrobial, mechanical embossing, aperturing or glazing treatments [16]. Some of the formation and bonding techniques are briefly explained under the following subtitles.

18.4.5.1  Parallel-laid web forming In this system, number of carding machines are aligned in a way one after another. Carded fibres are deposited layer by layer on the moving conveyor belt underneath (Fig. 18.9). The process continues until a fleece of the correct mass per unit area is achieved. Parallel-laid system is widely preferred for the production of fleeces for relative light-weight adhesive-bonded nonwovens. Of course, the webs fabricated from this system are much stronger in the machine direction comparing with the width direction. There is an economical limitation with this system, because it is claimed that using more than 12 cards is not feasible [36].

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Figure 18.9  Parallel-laid web forming process. Combed fibrous web

Feed conveyor

First transverse Web Second transverse Delivery conveyor

Figure 18.10  Cross-lapping process.

18.4.5.2  Cross-laid web forming During carding process, fibres are teased, combed and oriented by wires and formed into a web. Fibres placed in the web are usually parallel to each other in the longitudinal direction. Therefore, prepared webs exhibit better tensile strength in the machine direction compared with the transverse direction. Cross-lapping of the web is utilised to cope with this deficiency and also to regulate either weight or thickness of the web (Fig. 18.10). This cross-laying action is realised in a continuous manner, creating an unidirectional orientation in the machine direction, so that, in this way it is possible to control the fibre orientation and the isotropy of the final web [16,35].

18.4.5.3  Random-laid or air-laid process This process specifically depends on the aerodynamic feed of the fibres. Individualised fibres coming from a carding cylinder are suspended into an airstream and deposited onto a condenser cage (hollow perforated cylinder) or moving perforated belt (Fig. 18.11). The air passes through the holes and fibres and gets collected randomly. In this technique, length of the fibres can be in the range between 0.9 and 2 inch approximately. Besides, very short wood pulp fibres (