Główna Wound Healing Biomaterials. Volume 2: Functional Biomaterials
Zgłoś problemThis book has a different problem? Report it to us
Wybierz Tak, jeśli Wybierz Tak, jeśli Wybierz Tak, jeśli Wybierz Tak, jeśli
udało ci się otworzyć plik
plik zawiera książkę (dozwolone są również komiksy)
treść książki jest akceptowalna
Tytuł, autor i język pliku odpowiadają opisowi książki. Zignoruj inne pola, ponieważ są one drugorzędne!
Wybierz Nie, jeśli Wybierz Nie, jeśli Wybierz Nie, jeśli Wybierz Nie, jeśli
- plik jest uszkodzony
- plik jest chroniony DRM
- plik nie jest książką (np. xls, html, xml)
- plik jest artykułem
- plik jest fragmentem książki
- plik jest czasopismem
- plik jest formularzem testowym
- plik jest spamem
uważasz, że treść książki jest nieodpowiednia i powinna zostać zablokowana
Tytuł, autor lub język pliku nie pasuje do opisu książki. Zignoruj inne pola.
Change your answer
Możesz być zainteresowany Powered by Rec2Me
Najbardziej popularne frazy
hai its not downloading pls check
02 June 2017 (14:06)
Related titles Nanomaterials in Tissue Engineering (ISBN 978-0-85709-596-1) Biomaterials for Cancer Therapeutics (ISBN 978-0-85709-664-7) Biomaterials and Medical Device – Associated Infections (ISBN 978-0-85709-597-8) Woodhead Publishing Series in Biomaterials: Number 115 Wound Healing Biomaterials Volume 2: Functional Biomaterials Edited by Magnus S. Ågren AMSTERDAM • BOSTON • CAMBRIDGE • HEIDELBERG LONDON • NEW YORK • OXFORD • PARIS • SAN DIEGO SAN FRANCISCO • SINGAPORE • SYDNEY • TOKYO Woodhead Publishing is an imprint of Elsevier Woodhead Publishing is an imprint of Elsevier The Officers’ Mess Business Centre, Royston Road, Duxford, CB22 4QH, UK 50 Hampshire Street, 5th Floor, Cambridge, MA 02139, USA The Boulevard, Langford Lane, Kidlington, OX5 1GB, UK Copyright © 2016 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 the; y 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. British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress ISBN: 978-1-78242-456-7 (print) ISBN: 978-0-08-100606-1 (online) For information on all Woodhead Publishing publications visit our website at https://www.elsevier.com/ Publisher: Matthew Deans Acquisition Editor: Laura Overend Editorial Project Manager: Lucy Beg Production Project Manager: Poulouse Joseph Designer: Matthew Limbert Typeset by TNQ Books and Journals List of contributors A.M. Agostinho Hunt Michigan State University, East Lansing, MI, United States C. Aguzzi University of Granada, Granada, Spain A. Ahmad University of Connecticut Health Center, Farmington, CT, United States; University of Connecticut, Farmington, CT, United States P. Aramwit Chulalongkorn University, Phatumwan, Bangkok, Thailand D.B. Barbosa University of State of São Paulo (UNESP), Araçatuba, São Paulo, Brazil A. Berretta University of São Paulo, Ribeirão Preto, São Paulo, Brazil M.C. Bonferoni University of Pavia, Pavia, Italy C. Caramella University of Pavia, Pavia, Italy M.T. Cerqueira 3B’s Research Group, University of Minho, Guimarães, Portugal V.M. Correlo 3B’s Research Group, University of Minho, Guimarães, Portugal L.J. Cowan University of Florida, Gainesville, FL, United States K. Cutting Clinical Research Consultant, Hertfordshire, United Kingdom L.P. da Silva 3B’s Research Group, University of Minho, Guimarães, Portugal B.R. Davidson Royal Free Campus University College, London, United Kingdom C. Davidson Royal Free Campus University College, London, United Kingdom A.J. Domb The Hebrew University of Jerusalem and Jerusalem College of Engineering (JCE), Jerusalem, Israel Y. Dong University College Dublin, Dublin, Ireland xiv List of contributors G.L. Fernandes University of State of São Paulo (UNESP), Araçatuba, São Paulo, Brazil R.A. Fernandes University of State of São Paulo (UNESP), Araçatuba, São Paulo, Brazil F. Ferrari University of Pavia, Pavia, Italy R. Ghadi National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, India L.F. Gorup Federal University of São Carlos, São Carlos, São Paulo, Brazil D. Grandio Santa Clara University, Santa Clara, CA, United States H.J. Haugen Department of Biomaterials, Institute for Clinical Dentistry, University of Oslo, Oslo, Norway B.B. Hsu Massachusetts Institute of Technology, Cambridge, MA, United States C.J. Jackson University of Sydney, Sydney, NSW, Australia A. Jain National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, India R. James University of Connecticut Health Center, Farmington, CT, United States R. Kelly Keraplast Research Ltd, Christchurch, New Zealand W. Khan National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, India K.R. Kirker Montana State University, Bozeman, MT, United States S.G. Kumbar University of Connecticut Health Center, Farmington, CT, United States; University of Connecticut, Farmington, CT, United States J. Kunkel Santa Clara University, Santa Clara, CA, United States D. Leaper Huddersfield University, Huddersfield, Yorkshire, United Kingdom C.H. Lee School of Pharmacy, University of Missouri-Kansas City, MO, United States Y. Lee School of Computer and Engineering, University of Missouri-Kansas City, MO, United States List of contributors xv E.G. Loboa Joint Department of Biomedical Engineering at University of North Carolina at Chapel Hill and North Carolina State University, Raleigh, NC, United States S.P. Lyngstadaas Department of Biomaterials, Institute for Clinical Dentistry, University of Oslo, Oslo, Norway L.J. Magill Royal Free Campus University College, London, United Kingdom O.S. Manoukian University of Connecticut Health Center, Farmington, CT, United States; University of Connecticut, Farmington, CT, United States C. Marin University of Connecticut Health Center, Farmington, CT, United States; University of Connecticut, Farmington, CT, United States A.P. Marques 3B’s Research Group, University of Minho, Guimarães, Portugal A.D. Mazzocca University of Connecticut Health Center, Farmington, CT, United States S.T. Meikle University of Brighton, Brighton, United Kingdom H. Mitchell Royal Free Campus University College, London, United Kingdom M. Mobed-Miremadi Santa Clara University, Santa Clara, CA, United States M. Mohiti-Asli Joint Department of Biomedical Engineering at University of North Carolina at Chapel Hill and North Carolina State University, Raleigh, NC, United States D.R. Monteiro University of State of São Paulo (UNESP), Araçatuba, São Paulo, Brazil G.A. Morris University of Huddersfield, Huddersfield, United Kingdom S. Moxon University of Huddersfield, Huddersfield, United Kingdom A. Nyström Medical Center – University of Freiburg, Freiburg, Germany K. Ousey Huddersfield University, Huddersfield, Yorkshire, United Kingdom P.L. Phillips Stills University, Kirksville, MO, United States R.L. Reis 3B’s Research Group, University of Minho, Guimarães, Portugal C. Roberts Clinical Resolutions, Hull, Yorkshire, United Kingdom xvi List of contributors F.P. Robertson Royal Free Campus University College, London, United Kingdom E. Rodrigues de Camargo Federal University of São Carlos, São Carlos, São Paulo, Brazil S. Rossi University of Pavia, Pavia, Italy K. Saleh Skåne University Hospital, Lund, Sweden M. Sambasivam Dermalink Technologies Inc., Pennington, NJ, United States G. Sandri University of Pavia, Pavia, Italy G.S. Schultz University of Florida, Gainesville, FL, United States A.M. Smith University of Huddersfield, Huddersfield, United Kingdom L.E. Smith University of South Australia, Mawson Lakes, SA, Australia H.H. Sönnergren Skåne University Hospital, Lund, Sweden C. Viseras University of Granada, Granada, Spain W. Wang University College Dublin, Dublin, Ireland R. White University of Worcester and Plymouth Wound Care Ltd, United Kingdom R.D. Wolcott Southwest Regional Wound Care Center, Lubbock, TX, United States M. Xue University of Sydney, Sydney, NSW, Australia Woodhead Publishing Series in Biomaterials 1 Sterilisation of tissues using ionising radiations Edited by J. F. Kennedy, G. O. Phillips and P. A. Williams 2 Surfaces and interfaces for biomaterials Edited by P. Vadgama 3 Molecular interfacial phenomena of polymers and biopolymers Edited by C. Chen 4 Biomaterials, artificial organs and tissue engineering Edited by L. Hench and J. Jones 5 Medical modelling R. Bibb 6 Artificial cells, cell engineering and therapy Edited by S. Prakash 7 Biomedical polymers Edited by M. Jenkins 8 Tissue engineering using ceramics and polymers Edited by A. R. Boccaccini and J. Gough 9 Bioceramics and their clinical applications Edited by T. Kokubo 10 Dental biomaterials Edited by R. V. Curtis and T. F. Watson 11 Joint replacement technology Edited by P. A. Revell 12 Natural-based polymers for biomedical applications Edited by R. L. Reiss et al 13 Degradation rate of bioresorbable materials Edited by F. J. Buchanan 14 Orthopaedic bone cements Edited by S. Deb 15 Shape memory alloys for biomedical applications Edited by T. Yoneyama and S. Miyazaki 16 Cellular response to biomaterials Edited by L. Di Silvio 17 Biomaterials for treating skin loss Edited by D. P. Orgill and C. Blanco 18 Biomaterials and tissue engineering in urology Edited by J. Denstedt and A. Atala 19 Materials science for dentistry B. W. Darvell xviii Woodhead Publishing Series in Biomaterials 20 Bone repair biomaterials Edited by J. A. Planell, S. M. Best, D. Lacroix and A. Merolli 21 Biomedical composites Edited by L. Ambrosio 22 Drug–device combination products Edited by A. Lewis 23 Biomaterials and regenerative medicine in ophthalmology Edited by T. V. Chirila 24 Regenerative medicine and biomaterials for the repair of connective tissues Edited by C. Archer and J. Ralphs 25 Metals for biomedical devices Edited by M. Niinomi 26 Biointegration of medical implant materials: Science and design Edited by C. P. Sharma 27 Biomaterials and devices for the circulatory system Edited by T. Gourlay and R. Black 28 Surface modification of biomaterials: Methods analysis and applications Edited by R. Williams 29 Biomaterials for artificial organs Edited by M. Lysaght and T. Webster 30 Injectable biomaterials: Science and applications Edited by B. Vernon 31 Biomedical hydrogels: Biochemistry, manufacture and medical applications Edited by S. Rimmer 32 Preprosthetic and maxillofacial surgery: Biomaterials, bone grafting and tissue engineering Edited by J. Ferri and E. Hunziker 33 Bioactive materials in medicine: Design and applications Edited by X. Zhao, J. M. Courtney and H. Qian 34 Advanced wound repair therapies Edited by D. Farrar 35 Electrospinning for tissue regeneration Edited by L. Bosworth and S. Downes 36 Bioactive glasses: Materials, properties and applications Edited by H. O. Ylänen 37 Coatings for biomedical applications Edited by M. Driver 38 Progenitor and stem cell technologies and therapies Edited by A. Atala 39 Biomaterials for spinal surgery Edited by L. Ambrosio and E. Tanner 40 Minimized cardiopulmonary bypass techniques and technologies Edited by T. Gourlay and S. Gunaydin 41 Wear of orthopaedic implants and artificial joints Edited by S. Affatato 42 Biomaterials in plastic surgery: Breast implants Edited by W. Peters, H. Brandon, K. L. Jerina, C. Wolf and V. L. Young 43 MEMS for biomedical applications Edited by S. Bhansali and A. Vasudev Woodhead Publishing Series in Biomaterials 44 Durability and reliability of medical polymers Edited by M. Jenkins and A. Stamboulis 45 Biosensors for medical applications Edited by S. Higson 46 Sterilisation of biomaterials and medical devices Edited by S. Lerouge and A. Simmons 47 The hip resurfacing handbook: A practical guide to the use and management of modern hip resurfacings Edited by K. De Smet, P. Campbell and C. Van Der Straeten 48 Developments in tissue engineered and regenerative medicine products J. Basu and J. W. Ludlow 49 Nanomedicine: Technologies and applications Edited by T. J. Webster 50 Biocompatibility and performance of medical devices Edited by J.-P. Boutrand 51 Medical robotics: Minimally invasive surgery Edited by P. Gomes 52 Implantable sensor systems for medical applications Edited by A. Inmann and D. Hodgins 53 Non-metallic biomaterials for tooth repair and replacement Edited by P. Vallittu 54 Joining and assembly of medical materials and devices Edited by Y. (Norman) Zhou and M. D. Breyen 55 Diamond-based materials for biomedical applications Edited by R. Narayan 56 Nanomaterials in tissue engineering: Fabrication and applications Edited by A. K. Gaharwar, S. Sant, M. J. Hancock and S. A. Hacking 57 Biomimetic biomaterials: Structure and applications Edited by A. J. Ruys 58 Standardisation in cell and tissue engineering: Methods and protocols Edited by V. Salih 59 Inhaler devices: Fundamentals, design and drug delivery Edited by P. Prokopovich 60 Bio-tribocorrosion in biomaterials and medical implants Edited by Y. Yan 61 Microfluidic devices for biomedical applications Edited by X.-J. James Li and Y. Zhou 62 Decontamination in hospitals and healthcare Edited by J. T. Walker 63 Biomedical imaging: Applications and advances Edited by P. Morris 64 Characterization of biomaterials Edited by M. Jaffe, W. Hammond, P. Tolias and T. Arinzeh 65 Biomaterials and medical tribology Edited by J. Paolo Davim 66 Biomaterials for cancer therapeutics: Diagnosis, prevention and therapy Edited by K. Park 67 New functional biomaterials for medicine and healthcare E. P. Ivanova, K. Bazaka and R. J. Crawford xix xx Woodhead Publishing Series in Biomaterials 68 Porous silicon for biomedical applications Edited by H. A. Santos 69 A practical approach to spinal trauma Edited by H. N. Bajaj and S. Katoch 70 Rapid prototyping of biomaterials: Principles and applications Edited by R. Narayan 71 Cardiac regeneration and repair Volume 1: Pathology and therapies Edited by R.-K. Li and R. D. Weisel 72 Cardiac regeneration and repair Volume 2: Biomaterials and tissue engineering Edited by R.-K. Li and R. D. Weisel 73 Semiconducting silicon nanowires for biomedical applications Edited by J. L. Coffer 74 Silk biomaterials for tissue engineering and regenerative medicine Edited by S. Kundu 75 Biomaterials for bone regeneration: Novel techniques and applications Edited by P. Dubruel and S. Van Vlierberghe 76 Biomedical foams for tissue engineering applications Edited by P. Netti 77 Precious metals for biomedical applications Edited by N. Baltzer and T. Copponnex 78 Bone substitute biomaterials Edited by K. Mallick 79 Regulatory affairs for biomaterials and medical devices Edited by S. F. Amato and R. Ezzell 80 Joint replacement technology Second edition Edited by P. A. Revell 81 Computational modelling of biomechanics and biotribology in the musculoskeletal system: Biomaterials and tissues Edited by Z. Jin 82 Biophotonics for medical applications Edited by I. Meglinski 83 Modelling degradation of bioresorbable polymeric medical devices Edited by J. Pan 84 Perspectives in total hip arthroplasty: Advances in biomaterials and their tribological interactions S. Affatato 85 Tissue engineering using ceramics and polymers Second edition Edited by A. R. Boccaccini and P. X. Ma 86 Biomaterials and medical-device associated infections Edited by L. Barnes and I. R. Cooper 87 Surgical techniques in total knee arthroplasty (TKA) and alternative procedures Edited by S. Affatato 88 Lanthanide oxide nanoparticles for molecular imaging and therapeutics G. H. Lee 89 Surface modification of magnesium and its alloys for biomedical applications Volume 1: Biological interactions, mechanical properties and testing Edited by T. S. N. Sankara Narayanan, I. S. Park and M. H. Lee Woodhead Publishing Series in Biomaterials 90 Surface modification of magnesium and its alloys for biomedical applications Volume 2: Modification and coating techniques Edited by T. S. N. Sankara Narayanan, I. S. Park and M. H. Lee 91 Medical modelling: The application of advanced design and rapid prototyping techniques in medicine Second Edition Edited by R. Bibb, D. Eggbeer and A. Paterson 92 Switchable and responsive surfaces and materials for biomedical applications Edited by Z. Zhang 93 Biomedical textiles for orthopaedic and surgical applications: Fundamentals, applications and tissue engineering Edited by T. Blair 94 Surface coating and modification of metallic biomaterials Edited by C. Wen 95 Hydroxyapatite (HAP) for biomedical applications Edited by M. Mucalo 96 Implantable neuroprostheses for restoring function Edited by K. Kilgore 97 Shape memory polymers for biomedical applications Edited by L. Yahia 98 Regenerative engineering of musculoskeletal tissues and interfaces Edited by S. P. Nukavarapu, J. W. Freeman and C. T. Laurencin 99 Advanced cardiac imaging Edited by K. Nieman, O. Gaemperli, P. Lancellotti and S. Plein 100 Functional marine biomaterials: Properties and applications Edited by S. K. Kim 101 Shoulder and elbow trauma and its complications Volume 1: The shoulder Edited by R. M. Greiwe 102 Nanotechnology-enhanced orthopedic materials: Fabrications, applications and future trends Edited by L. Yang 103 Medical devices: Regulations, standards and practices Edited by S. Ramakrishna, L. Tian, C. Wang, S. L. and T. Wee Eong 104 Biomineralisation and biomaterials: Fundamentals and applications Edited by C. Aparicio and M. Ginebra 105 Shoulder and elbow trauma and its complications Volume 2: The elbow Edited by R. M. Greiwe 106 Characterisation and design of tissue scaffolds Edited by P. Tomlins 107 Biosynthetic polymers for medical applications Edited by L. Poole-Warren, P. Martens and R. Green 108 Advances in polyurethane biomaterials Edited by S. L. Cooper 109 Nanocomposites for musculoskeletal tissue regeneration Edited by H. Liu 110 Thin film coatings for biomaterials and biomedical applications Edited by H. J. Griesser 111 Laser surface modification of biomaterials Edited by R. Vilar xxi xxii Woodhead Publishing Series in Biomaterials 112 Biomaterials and regenerative medicine in ophthalmology Second edition Edited by T. V. Chirila and D. Harkin 113 Extracellular matrix-derived medical implants in clinical medicine Edited by D. Mooradian 114 Wound healing biomaterials Volume 1: Therapies and regeneration Edited by M. S. Ågren 115 Wound healing biomaterials Volume 2: Functional biomaterials Edited by M. S. Ågren Introduction to biomaterials for wound healing 1 P. Aramwit Chulalongkorn University, Phatumwan, Bangkok, Thailand 1.1 Definition of biomaterial Biomaterial by definition is “a non-drug substance suitable for inclusion in systems which augment or replace the function of bodily tissues or organs” (Nicolai and Rakhorst, 2008). These materials are capable of being in contact with bodily fluids and tissues for prolonged periods, while eliciting minimal if any adverse reactions (Heness and Ben-Nissan, 2004). In this sense, biomaterials are classified as synthetic or natural substances. Hence, in this chapter a biomaterial is defined as any substance (other than a drug) or combination of substances, synthetic or natural in origin, which can be used as a whole or as a part of a system which treats, augments, or replaces any tissue, organ, or function of the body (von Recum and LaBerge, 1995). The field of biomaterials working under biological constraints is rapidly expanding and represents 2–3% of the overall health expenses in developed countries. This field covers many different materials: cardiac artificial valves; artificial vessels; cardiac stimulators; stents; artificial hips, knees, shoulders, and elbows; materials for internal fracture fixation; scoliosis treatment; materials for urinary tract reconstruction; artificial crystalline lenses; skin; ear ossicles; and dental roots (Sedel, 2004). 1.2 Types of biomaterials Since the introduction of sutures for wound closure (Davis, 2003), the use of biomaterials has expanded intensively. Biomaterials can be divided into synthetic or natural. 1.2.1 Synthetic biomaterials The most common synthetic biomaterials used for implants are titanium, silver products, polyester, and porcelain. Synthetic biomaterials can be divided into the following four categories (Agrawal, 1998). 220.127.116.11 Metals Metals are the most widely used for load-bearing implants such as artificial joints for hips and knees. Although many metals and alloys are used for medical device Wound Healing Biomaterials - Volume 2. http://dx.doi.org/10.1016/B978-1-78242-456-7.00001-5 Copyright © 2016 Elsevier Ltd. All rights reserved. 4 Wound Healing Biomaterials applications, the most commonly used metals are stainless steel, pure titanium, and titanium alloys. 18.104.22.168 Polymers Polymers are widely used for several applications such as facial prostheses, tracheal tubes, and kidney and liver parts. They are also used for medical adhesives and sealants or for coating of other materials to modify their function. Polyester, polytetrafluoroethylene, and polyurethane are the most commonly used biomaterials for artificial devices. According to US Food and Drug Administration standards, these polymers are considered biocompatible biomaterials. The biocompatibility response of synthetic biomaterials in vivo is signified by hydrolysis via inflammatory cells and by the formation of a fibrous capsule that is the body’s response to a foreign intruder (Mathur et al., 1997; Anderson et al., 1998). In practice the biocompatibility of a material is defined by its ability to fill space and assist the body in regenerating tissue to develop permanent solutions to reconstruction and to reduce abnormal chronic wound healing (Mathur, 2009). The newer biodegradable biomaterials, including polylactic acid (PLA) and polyglycolic acid (PGA), also have a polyester chemistry, and they are degraded by hydrolysis that results in large amounts of by-products that lower the pH of the local microenvironment. This may influence wound healing (Mathur, 2009). PGA provides a biocompatible surface for the cells to proliferate and has been widely used for tissue engineering of artificial arteries. PGA does not provide a mechanically robust matrix which would enable the cells to withstand the in vivo shear and compressive loads, and it also results in dedifferentiation of cells (Higgins et al., 2003). Polyethylene glycol (PEG) lacks the chemistry for cellular interface unless ligand-presenting entities are introduced (Gobin and West, 2003). Classical tissue engineers prepared a cell-seeded biomimetic hydrogel such as ligand-modified PEG and studied the cell response by measuring proliferation and differentiation (Gobin and West, 2003). In this situation, most cells can adhere to the adhesion ligands and secrete a protease whose cleavage sequence is incorporated within the gel, which renders the hydrogel completely nonresponsive. From this case, the gel has all the characteristics of a synthetic nondegradable biomaterial and only two characteristics out of many of being a biologically responsive biomaterial. This indicates that cells need multiple signals in a tissue-engineered scaffold to mimic their in vivo behavior (Mathur, 2009). 22.214.171.124 Ceramics Ceramic is primarily used as a restorative material in dentistry. Due to its poor fracture toughness, other uses are limited. 126.96.36.199 Composites Composite materials are used extensively for prosthetic limbs wherein their low density/weight and high strength make them ideal materials for prosthetic applications. Introduction to biomaterials for wound healing Table 1.1 5 Biomaterials for medical applications Biomaterial Advantages Disadvantages Examples Metal Strong, tough, and ductile Corrodible, dense, and complicated to fabricate Polymers Resilient and easy to fabricate Fragile, deformable, and degradable Ceramics Very biocompatible, inert, and strong in compression Strong in compression Difficult to fabricate, brittle, and not resilient Difficult to fabricate Joint replacement, bone plates and screws, dental root implants, pacers, and sutures Blood vessels; sutures; tissue engineering for ear, nose, and soft tissues Dental coatings and orthopedic implants, such as femoral head of neck Joint implants, heart valves Composites The advantages and disadvantages of each biomaterial category are shown in Table 1.1. 1.2.2 Natural biomaterials Natural biomaterials are derived from animals, microbials, or plants. One advantage of natural biomaterials is that they are similar to materials familiar to the body (Davis, 2003). In this regard the field of biomimetics, or mimicking nature, is growing. There is seldom a toxicity issue with the use of natural materials in contrast to synthetic materials. Moreover, natural biomaterials may carry specific protein binding sites and other biochemical signals that may assist in tissue healing or integration. The major concerns of using these materials are immunogenicity and decomposition at temperatures below their melting points. This severely limits their fabrication into implants of different sizes and shapes (Ige et al., 2012). Natural biomaterials are typically similar to macromolecular substances which are prepared for metabolic pathways. As a result, the problems of toxicity and simulation of a chronic inflammatory reaction which is provoked by many synthetic polymers are suppressed (Ige et al., 2012). Moreover, natural biomaterials are degradable. There is also a capability for designing these biomaterials at molecular rather than macroscopic levels. Some advantages and disadvantages of natural biomaterials are presented in Table 1.2. Until now, no biomaterials were considered as “responsive” to the cell. In essence, from the initial inflammatory reaction of the body to scar formation, wound healing is controlled by cellular reactions to the biomaterial. A responsive biomaterial would have a topography, architectural assembly, biomolecular composition, and chemistry that would give a cell control of the biomaterial at the cell–material interface, which is a physical link that the cell has with the biomaterial as the cell adheres and migrates through the biomaterial. Cytokine production, growth factor release, and other chemical mediators that are released by the cell are controlled in a feedback loop at the cell–substrate interface (Miranti and Brugge, 2002). 6 Wound Healing Biomaterials Advantages and disadvantages of natural biomaterials (Lujan, 2010) Table 1.2 Advantages Disadvantages No toxicity or foreign body response Immunological reaction, body’s immune system recognizes foreign materials for ultimate inactivation/elimination High natural variability Structurally more complex than traditional materials; technological manipulation is more complicated Function biologically at molecular level Natural degradation can occur in the body via natural enzymes; cross-linking delays this process 1.3 Wound healing Healthy skin, bone, and muscle undergo in situ self-healing that prevents the accumulation of defects from tissue aging and fatigue (Brochu et al., 2011). Healing and biomaterials are most commonly linked through the tissue response to an implant (Kindt et al., 2007). Wound healing is divided into inflammation, proliferation, and remodeling (Fig. 1.1). Various studies have aimed at modulating inflammation and proliferation. Even though inflammation is a common event in allergic diseases, autoimmune diseases, infectious diseases, and others, it is essential for proper healing (Kasuya and Tokura, 2014). The objective of wound management is to heal the wound in the shortest time to prevent infection and minimize pain, discomfort, and scarring. The successful treatment of a wound should ensure that the amount of necrotic tissue is reduced and that microbial invasion is prevented (Mayet et al., 2014). Traditional wound management used simple materials such as gauze according to the principle “to cover and conceal.” More recent developments have taken advantage of the deeper understanding of the underlying molecular and cellular mechanisms. Ensuring that the pharmacological, pharmacokinetic, and mechanical requirements of wound healing are met will provide a novel approach to remove the barriers to natural healing and enhance the effects of advanced therapies (Schultz et al., 2004). The need for effective methods or biomaterials is especially urgent for large or complicated wounds. Creative ideas will promote novel opportunities for tissue regeneration and repair (Mayet et al., 2014). To ensure maximal benefit of advanced treatments the TIME algorithm was introduced, with the main purposes being to assess and restore the biochemical environment (Schultz et al., 2004; Granick et al., 2006): T—Deficient and nonviable tissues impede the migration of keratinocytes across the wound bed and act as a focus for infection. I—Uncontrolled inflammation and infection may perpetuate a cycle of repeated injury and insult to the wound area that should be corrected for optimal cell functionalities. M—Excess moisture may result in maceration of the wound bed and surrounding tissue, whereas wound desiccation may impede the wound healing process. E—The migrating epithelial edge is a sign that healing is taking place, whereas a nonmigrating edge indicates poor healing. Introduction to biomaterials for wound healing 7 Inflammatory phase Molecules Increase of vascular permeability Damage of skin constituent cells DAMPs, PAMPs Cytokines Chemokines HMGB1 Operation of innate immunity Infiltration of neutrophils and macrophages Proliferation phase Signaling Fibroplasia, ECM formation TGF-β/Smad signaling Angiogenesis Wnt/β-catenin signaling Reepithelialization Other signaling pathways Remodeling Figure 1.1 Phases and factors involved in the wound healing process divided into inflammation, proliferation, and remodeling. Multiple factors and signaling pathways operate codependently. DAMPs, damage-associated molecular patterns; PAMPs, pathogen-associated molecular patterns; HMGB1, high-mobility group box 1; ECM, extracellular matrix; TGF-β, transforming growth factor-β. Reprinted with permission from publisher: Kasuya, A., Tokura, Y., 2014. Attempts to accelerate wound healing. J. Dermatol. Sci. 76 (3), 169–172. Modern dressings are designed to provide functional and desirable characteristics, which include debridement activity, moist wound environment, low adherence, protection from trauma, minimal dressing changes, thermal insulation, absorption of excess exudate and blood at the wound site, infection and bacterial invasion protection, adequate gaseous exchange, and cost effectiveness. In addition, dressings should be free of toxins and infectious agents, easily placed and replaced, and aid wound drainage (Brown-Etris et al., 2002). Several types of wound materials have been developed to fulfill these prerequisites and can be classified into three categories (Freyman et al., 2001): 1. traditional dressings 2. biomaterial-based dressings 3. artificial dressings 1.3.1 Traditional dressings The main functions these dressings perform are to stop bleeding and protect the wound (Sheridan and Tompkins, 1999). The best example of this group is cotton gauze (Sezer and Cevher, 2011). Gauze has several disadvantages, including damaging newly formed epithelium upon removal and causing rapid dehydration of the wound bed (Naimer and Chemla, 2000; Siritientong et al., 2014). Therefore gauze composites with a nonadherent wound contact material have been developed. Another significant 8 Wound Healing Biomaterials problem of this dressing type is the leakage of exudate, which may increase the risk of infection (Sezer and Cevher, 2011). Antibacterial agents are therefore added to minimize the infection risk. In addition, foreign body reactions to the cotton fibers are sometimes observed (Lim et al., 2000; Price et al., 2001), although this is rare (Ågren et al., 2006). The low cost is the major reason for their popularity. 1.3.2 Biomaterial-based dressings The most convenient method to achieve complete wound closure is autografting. Inadequate donor areas for large wounds have led to the search for new tissue sources (Sheridan et al., 2001). Biological dressings are typically made of collagen-type structures with elastin and lipids (Sezer and Cevher, 2011). Such dressings are categorized as allografts or xenografts (Kearney, 2001; Sheridan et al., 2001). An allograft is a graft between individuals of the same species, but of different genotypes. The most common source is fresh or freeze-dried skin fragments from cadavers or a patient’s relatives. A xenograft is a graft between animals of different species (eg, between closely related species). The most common dressing is derived from pig skin. Although this type of dressing seems to give promising outcomes, advanced technologies are necessary to provide consistent materials and simple handling. 1.3.3 Artificial dressings The use of traditional dressing materials and biomaterial-based dressings is restricted due to stability problems and the associated risk of infection (Sezer and Cevher, 2011). Several attempts have been made to overcome these disadvantages. Variations in pathophysiology make it difficult to develop an artificial dressing that meets all the criteria for optimal healing. Synthetic and natural polymers are used for artificial dressings (Table 1.3). 1.4 Biomaterials used for dermal wound healing Contemporary biomaterials used in areas of reconstruction, repair, and artificial devices are not designed to regenerate tissue, but instead to cover or fill defects, perform a mechanical function, or both (Mathur, 2009). Materials or biologics that promote tissue formation, preserve volume and shape, and shorten the time of wound healing are needed. An ideal regenerative or responsive biomaterial recruits precursor cells to form new viable tissue in vivo and stimulates wound healing (Mathur, 2009). Although the biology and chemistry of healing have significant impacts on biomaterial performance, biological healing does not address the physical repair of biomaterials that experience mechanical and chemical breakdown as they are subjected to loading and degradation effects in vivo (Brochu et al., 2011). Developing biomaterials with the intrinsic ability to autonomously repair mechanical and chemical damage would be particularly important for implants that replace tissues that are also capable of self-repair. Introduction to biomaterials for wound healing 9 Examples of wound dressing types in the world market (Sezer and Cevher, 2011) Table 1.3 Dressing material Brand name Traditional dressing Absorbent cotton pad Absorbent cotton fibers impregnated with polyhexamethylene biguanide Highly absorbent cotton wool pad Highly absorbent rayon/cellulose blend sandwiched with a layer of antishear high-density polyethylene Paraffin gauze dressing Paraffin gauze dressing containing 0.5% chlorhexidine acetate Petrolatum gauze containing 3% bismuth tribromophenate Scarlet red dressing Hydrogel dressing Telfa® “Ouchless” nonadherent dressing Telfa AMD® Gamgee® pad Exu-Dry® dressing Jelonet®, Adaptic® Bactigras® Xeroform® Scarlet Red® 2nd Skin® Biomaterial-based dressing Porcine dermis EZ Derm® Artificial dressing Polypropylene film and polyurethane foam Silicone film with peptide-coated nylon fabric Polyurethane film dressing Hydroxylated polyvinyl alcohol foam Calcium alginate Polyhydroxyethylmethacrylate and polyethylene glycol 400 spray Epigard® Biobrane® Opsite®, Tegaderm® Ivalon® Kaltostat® Hydron® 1.4.1 Synthetic biomaterials Synthetic biomaterials offer many advantages over natural biomaterials as they can be synthesized and modified in a controlled manner according to the specific requirements needed to produce constant and homogenous physical and chemical properties as well as stability (Zhong et al., 2010a). 188.8.131.52 Polyurethanes and their derivatives Polyurethanes are copolymers containing urethane groups. They are formed by conjugation of diol and diisocyanate groups (Trumble et al., 2002). Polyurethanes have been used extensively as biomaterials because of their biocompatibility, strength, and flexibility, for example, in catheters and gastric balloons. They are unstable in acidic environments (Pinchuk, 1994). An example of nontoxic polyurethanes used for treatment of burns and wounds is Pellethane® 2363-80A, which can accelerate epithelialization (Wright et al., 1998). 10 Wound Healing Biomaterials 184.108.40.206 Teflon This polymer is synthesized from tetrafluoroethylene at high temperature and pressure. Teflon is noncarcinogenic, insoluble in polar and nonpolar solvents, and easily sterilized. Furthermore, its shape is easily modified using low pressure, resulting in a comfortable fit to the injured area (Lee and Worthington, 1999; Raphael et al., 1999). 220.127.116.11 Silicone Silicone is nontoxic, nonallergenic, and highly biocompatible (O’Donovan et al., 1999; Jansson and Tengvall, 2001). Silicone is resistant to biodegradation and can be used in the preparation of implant elastomers used in soft tissue repair and in the production of hypodermic needles and syringes (Van den Kerckhove et al., 2001). Moreover, it is often used as wound support material in severe burns and wounds, for scar treatment (Whelan, 2002; Losi et al., 2004), and as a nonadherent interface material in many dressings. 1.4.2 Natural biomaterials Natural biomaterials offer a therapeutic advantage as opposed to the inert synthetic biomaterials. The natural origins of these biomaterials make them suitable substitutes of the extracellular matrix (ECM) and original cellular environment of the native skin (Mayet et al., 2014). The emollient, demulcent, astringent, antimicrobial, antiinflammatory, and antioxidant properties of natural products may be beneficial for the wound healing process (Mogosanu et al., 2012). Natural polymers such as chitosan, collagen, elastin, and fibrinogen are biocompatible substrates that are similar to macromolecules recognized by the human body (Mogosanu and Grumezescu, 2014). They are also used in regenerative medicine for human epithelial stem cell culture or in vitro– reconstituted epithelia (Guerra et al., 2009). The limitations are batch-to-batch variability, heterogeneity, and high cost (Tabata, 2009). The normally low mechanical strength of natural macromolecules can be improved by cross-linking or blending with synthetic polymers, but at the expense of biocompatibility (Mogosanu and Grumezescu, 2014). 1.5 Polysaccharide-based biomaterial Polysaccharides are natural biomaterials which are inexpensive, and most of them are easily degradable. The majority (about 75%) of all organic material on earth is in the form of polysaccharides (Atala and Mooney, 1997). Polysaccharide-based biomaterials used for wound care can be classified into several categories: neutral (β-glucan, dextrans, cellulose), acidic (alginic acid, hyaluronic acid), basic (chitin, chitosan), or sulfated (heparin, heparan sulfate, chondroitin sulfate, dermatan sulfate, keratan sulfate) (Kennedy et al., 2011). Introduction to biomaterials for wound healing 11 1.5.1 Homoglycans Polysaccharides that contain molecules of one sugar are called homopolysaccharides or homoglycans. They are naturally occurring biocompatible materials used locally to modulate the cellular responses during wound healing (Lloyd et al., 1998). 18.104.22.168 Starch Starch is one of the most abundant and cheapest polysaccharide. Natural starch occurs in a granular form. Generally starch consists of amylose (linear α-(1-4) glucan) and amylopectin (dendritically branched version) (Biliaderis, 1992). The content and ratio of amylose and amylopectin in starch vary depending on the source, and they have an effect on behavior during processing and the properties of the end product. Starch is insoluble in cold water, but is very hygroscopic and binds water reversibly. It is renewable and biodegradable, and it can be used as bone replacement implants and in bone cements, drug delivery systems, and tissue scaffolds (Pereira et al., 1998). 22.214.171.124 β-Glucans Different types of β(1→3)-d-glucans isolated from yeast, fungi, and grain were investigated for their immunological and pharmacological properties because of their ability to form single- and triple-helical resilient gel structures. Highly purified yeast-derived insoluble β(1→3)-d-glucan strongly inhibited adipogenic differentiation, supported wound healing, and significantly lowered skin irritation compared to cotton gauze (Huang and Yang, 2008; Lehtovaara and Gu, 2011). 126.96.36.199 Chitin and chitosan Chitin is the structural element in the exoskeleton of crustaceans, such as crabs and shrimps, and in the cell walls of fungi. Chitin is the most abundant natural amino polysaccharide (poly-N-acetyl-glycosamine) produced annually. It is a nitrogen-containing polysaccharide and related chemically to cellulose. The native chitin molecule has strong intermolecular and intramolecular hydrogen bonds with partial N-deacetylation (Hirano and Midorikawa, 1998). One disadvantage is its insolubility in common solvents and the difficulties related to chitin processing. Chitin is hemostatic, and it may enhance immunity and wound healing. Chitin is considered a nontoxic, nonallergenic biomaterial and is not rejected by the body. The biocompatibility, biodegradability, and adsorption properties of chitin and its derivatives are considerably higher than those of synthetically substituted cellulose (Ige et al., 2012). Chitosan, a moiety of glycosaminoglycans (GAGs), is a linear polysaccharide produced by deacetylation of chitin and composed of randomly distributed β-(1-4)-linked d-glucosamine (deacetylated unit) and N-acetyl-d-glucosamine (acetylated unit) (Muzzarelli and Muzzarelli, 2002). This biomaterial is common in the biomedical field due to its biocompatibility, low toxicity, and low thrombogenicity, although it causes red blood cell agglutination (Rao and Sharma, 1997). 12 Wound Healing Biomaterials Chitosan is biodegradable and the degradation rate decreases as the degree of deacetylation increases (Tomihata and Ikada, 1997). A chitosan membrane with a deacetylation degree of 73% was degraded 7 days after application to full-thickness skin excision in rats (Nordback et al., 2015). Chitosan supports the adhesion and activation of platelets (Lord et al., 2011). Moreover, chitosan has antimicrobial (Cho et al., 1999; Mi et al., 2002) and antiinflammatory activities (Han, 2005). Chitosan elicits minimal foreign body reactions and favors both soft and hard tissue regeneration (Jin et al., 2004). Chitosan is therefore used for wound treatment (Ueno et al., 1999; Khor and Lim, 2003; Senel and McClure, 2004). Paul and Sharma (2004) found that topical chitosan accelerated fibroblast proliferation and increased early phase reactions related to healing. Chitosan also promoted granulation tissue formation and remodeling of damaged tissues in large, open wounds (Ueno et al., 2001). It has been shown that a chitosan hydrogel interacts with fibroblast growth factor-2 in open wounds of diabetic mice. This interaction resulted in increased angiogenesis, granulation tissue, and wound closure rate (Obara et al., 2005). A bilayer chitosan membrane, consisting of an upper chitosan film layer attached to an inner layer of porous membrane, served as an efficient skin-regenerating template for treating third-degree burns and cutaneous wounds (Mao et al., 2003). The three-dimensional (3D) structural organization of chitosan is essential to serve as a vehicle for delivering and retaining the cells at a specific site and to initiate appropriate cell–cell interactions (Liao et al., 2010). Chitosan is also used as an intraocular lens material due to its oxygen permeability and has been evaluated for use in the bioremediation of toxic phenolic compounds (Beran et al., 2007). 188.8.131.52 Cellulose Wound dressings of modified cellulose can incorporate active molecules such as enzymes, growth factors, antimicrobial agents, antioxidants, hormones, vitamins, and other agents (Medusheva et al., 2007; Aramwit and Bang, 2014). Bacterial cellulose is synthesized by growing Acetobacter xylinum in various media such as coconut juice, pineapple juice, or any carbohydrate substrate. Bacterial cellulose is a versatile biomaterial with a unique nanostructure (Fig. 1.2), high mechanical strength, and remarkable swelling properties. As a natural biocompatible, biodegradable, antimicrobial, hypoallergenic, and nontoxic polymer, bacterial cellulose is an innovative natural polymeric raw material for wound dressing applications (Czaja et al., 2007; Muangman et al., 2011; Park et al., 2014). One major advantage of bacterial cellulose is its absorptive capacity of wound exudate which is the reason for the many composites of bacterial cellulose sheets impregnated with several active components. Carboxymethylcellulose (CMC) is widely used in dressings. It is a cellulose derivative with carboxymethyl groups (–CH2–COOH) bound to some of the hydroxyl groups of the glucopyranose monomers that make up the cellulose backbone. In contrast to cellulose, CMC is a hydrophilic polymer and thus solubilized in water, with excellent water swelling ability. Furthermore, CMC is biocompatible and shows low toxicity and immunogenicity. These characteristics make CMC an attractive constituent in food, cosmetics, and pharmaceuticals and for tissue engineering and drug delivery systems (Bajpai and Giri, 2003; Pasqui et al., 2014). CMC can be formulated as a “solid-like solution” or hydrogel. This biomaterial can be easily mixed with other polymers Introduction to biomaterials for wound healing 13 Figure 1.2 Fiber structure of cellulose from plant (left) and bacterial cellulose (right) under a scanning electron microscope. Magnification ×500. Scale = 50 μm. such as chitosan, alginate, and polyvinyl alcohol, yielding products with favorable properties (Ågren, 1998; Bradford et al., 2009; Lee et al., 2010; Zhang et al., 2013). 1.5.2 Heteroglycans Heparin, hyaluronic acid (HA), and chondroitin sulfates are examples of heteroglycans which give sugar amine and sugar uronic acids (two different products), whereas starch gives only glucose (one product) and hence is homoglycan. Some heteroglycans exhibit important applications in biomedical areas, especially due to their biocompatibility, biodegradability, and peculiar physicochemical features (Rinaudo, 2008). 184.108.40.206 Alginic acid and its salts Alginic acid, also called algin or alginate, is an anionic polysaccharide distributed widely in the cell walls of brown algae, including Laminaria and Ascophyllum species. It is formed by linear block copolymerization of d-mannuronic acid and l-guluronic acid. Alginates are linear unbranched polysaccharides which contain different amounts of (1→4′)-linked β-d-mannuronic acid and α-l-guluronic acid residues. Alginate is biodegradable, has controllable porosity, and may be linked to other biologically active molecules. Interestingly, encapsulation of certain cell types into alginate beads may actually enhance cell survival and growth. Due to their hemostatic properties, alginate and its salts are used for wound treatment in various forms such as gel or sponge. Calcium alginate can also increase cellular activity properties such as adhesion and proliferation (Thomas, 2000a,b,c). Obtained from processed algae, calcium alginate, calcium–sodium alginate, collagen–alginate, and gelatin–alginate are highly absorbent natural fiber dressings (Qin et al., 2006; Thu et al., 2012). Alginate can absorb water and body fluids up to 20 times its weight, resulting in a hydrophilic gel. The formed gel is weak, but it maintains a moist wound healing environment. 14 Wound Healing Biomaterials 220.127.116.11 Glycosaminoglycans GAGs are important components of the ECM and are essential for skin and bone regeneration. The structure, polymer length, and degree of sulfation determine the attraction of skin and bone precursor cells (Salbach et al., 2012). Heparin-coated aligned nanofibers increase endothelial cell infiltration in 3D scaffolds and tissue remodeling in vitro and in vivo (Kurpinski et al., 2010). Heparan sulfate glycosaminoglycans (HS-GAGs) and OTR4120, a polymer engineered to mimic properties of HS-GAGs, were shown to decrease inflammation and stimulate angiogenesis and collagen maturation in wounds and burns (Tong et al., 2009). 18.104.22.168 Hyaluronic acid The extremely hydrophilic HA is a naturally occurring, nonimmunogenic, anionic, nonsulfated GAG distributed widely throughout connective tissues, epithelia, neural tissues, and synovial fluids. This biomaterial is abundant in skin, cockscomb, cartilage, and vitreous humor. HA consists of 2-acetamide-2-deoxy-α-d-glucose and β-d-gluconic acid residues linked by alternate (1,3) and (1,4) glycoside bonding, and it has a high capacity of lubrication, water sorption, and water retention and influences several cellular functions such as migration, adhesion, and proliferation (Lee et al., 2003). HA interacts with proteins, proteoglycans, growth factors, and tissue components which is of vital importance in wound healing (Park et al., 2003). HA has bacteriostatic activity (Miller et al., 2003). Due to the high density of negative charges along the polymer chain, HA adopts highly extended random coil conformations. HA is popular in the medical and bioengineering fields mainly because it degrades into simple sugars. HA has been used for wound healing (Neuman et al., 2015), tissue engineering, and ophthalmic surgery; as a component in implant materials in reconstructive plastic surgery; and for facial wrinkle and folds of the skin (Lee et al., 2003; Sparavigna et al., 2014; Zhang et al., 2015a). Moreover, HA is used for lubrication of joints in osteoarthritis. 22.214.171.124 Pectins Hydrocolloids such as pectins are used in occlusive and semiocclusive dressings for wound management. Pectin is a biocompatible and biodegradable natural polymer widely used in food industry, targeted drug delivery, wound healing materials, and tissue engineering (Mishra et al., 2012; Munarin et al., 2012). 1.6 Protein-based biomaterial Proteins are referred to as polypeptides which are composed of up to 20 different amino acid building blocks. Protein biomaterials are unique in that the sequence of the monomers in the polymer chain is predetermined by the template-specific reamer of the polymerization process (Ratner et al., 2013). Introduction to biomaterials for wound healing 15 1.6.1 Collagen Collagen is the most abundant protein in the human body and in the skin, and it exists mostly in fibrils. Each collagen molecule in the dermal ECM is a triple-helix structure, consisting of amino acids, mainly glycine, proline, and hydroxyproline. The collagen molecule is assembled into a super-helix procollagen molecule intracellularly and then secreted into the extracellular space (Fleck and Simman, 2010). The parallel alignment of collagen fibers gives a structure with the tensile strength of a light steel wire (Ige et al., 2012) (Fig. 1.3). Collagen is synthesized mainly by fibroblasts and is involved in all phases of the wound healing cascade (Mogosanu and Grumezescu, 2014). Bovine and fish collagens are the most well-known natural biomaterials on the market. The first medical use of collagen in humans was to provide correction of contour deformities (Knapp et al., 1977). Collagen has since been widely used in several forms and applications such as sutures, hemostatic agents, injectable materials, wound dressings, gels for periodontal reconstruction, sponges for hemostasis, and coatings of joints (Hafemann et al., 1999; Ortega et al., 2000; Gingras et al., 2003; Park et al., 2004). Collagen is usually implanted in a sponge form without significant mechanical strength or stiffness. Due to its hydrophilicity, collagen is easily blended with other polymers. Collagen and its degradation products are often used to attract fibroblasts during skin repair and fracture healing (Lee et al., 2003). Collagen-based wound dressings have distinctive practical and economic advantages compared to growth factor and cell-based therapies (Table 1.4). Collagen dressings formulated from bovine, porcine, or avian sources are recommended for the treatment of partial-thickness and full-thickness wounds with minimal-to-moderate exudation, but contraindicated for third-degree skin burns (Ruszczak, 2003). Depending on its processing, collagen can potentially alter cell growth and motility, have inappropriate mechanical properties, or shrink. Cells are able to pull and reorganize collagen fibers, causing scaffolds to lose their shape if not properly stabilized by cross-linking or incorporation of less “vulnerable” materials. Collagen fibers Collagen fibril Type I collagen α1 collagen protein chain Triple helix of 2 α1 chains 1 α2 chain Figure 1.3 Organized fiber bundles constituting collagen. Reprinted with permission from the publisher: Fleck, C.A., Simman, R., 2010. Modern collagen wound dressing: Function and purpose. J. Am. Col. Certif. Wound Spec. 2 (3), 50–54. 16 Wound Healing Biomaterials Commercial forms of collagen wound dressing (Chattopadhyay and Raines, 2014) Table 1.4 Collagen form Name Manufacturer Description Collagen composite dressing Promogran® Systagenix Fibracol® Systagenix Biobrane® Smith & Nephew Helitene® Instat® Integra LifeSciences Ethicon Avitene® Medifil® Davol BioCore (Kollagen) Helistat® Integra LifeSciences MedChem BioCore (Kollagen) Collagen-oxidized regenerated cellulose Collagen-alginate wound dressing Artificial skin substitute composed of nylon mesh, silicone, and porcine skin collagen Microfibrillar, absorbable hemostatic agent Microfibrillar collagen hemostat Microfibrillar hemostat Spherically particles of native bovine collagen Absorbable hemostatic sponge Collagen fiber Collagen powder Collagen sponge ActiFoam® SkinTemp® Hemostatic sponge Native collagen in the nonhydrolyzed form 1.6.2 Gelatin Gelatin is obtained from denatured collagen. Gelatin lacks antigenicity in comparison to its precursor and is biocompatible, biodegradable, and nonimmunogenic. Type A (GA) gelatin is derived from acid-treated material and type B (GB) from alkali-treated material. GA has an isoelectric point (pI) value of 8–9 (a positive charge at neutral pH), whereas GB has a pI value of 4.8–5.4 (a negative charge at neutral pH) (Maxey and Palmer, 1967). Gelatin is widely used as scaffold for tissue engineering and in medicine as an absorbable compressed sponge for hemostasis (Surgifoam®, Ethicon; Gelfoam®, Pfizer); wound dressings; and as an adhesive, absorbent pad for surgical use (Yao et al., 2002; Lee et al., 2003). 1.6.3 Keratin Keratin defines all intermediate filament-forming proteins found in vertebrate epithelia and corneous tissues such as horns, claws, and hooves (Bragulla and Homberger, 2009). The structural integrity and solubility of keratin as well as its natural biocompatibility, controllable biodegradability, and bioactivity make keratin an ideal medical polymer (Ige et al., 2012). Keratin extracted from hair and wool is used as platform technology to make a new family of biomaterials for biomedical applications. Animal-derived keratins seem compatible with human biological systems if carefully extracted (Mueller, 2005). Extracted proteins from human hair formulated in a hydrogel were hemostatic and had Introduction to biomaterials for wound healing 17 the ability bind cells (Aboushwareb et al., 2009). Keratin derivatives in wound dressings interact with the proteolytic wound environment of chronic wounds (Mogosanu and Grumezescu, 2014). Keratin can be used for nerve regeneration by activation of Schwann cells (Sierpinski et al., 2008). Moreover, keratin derived from human hair is neuroinductive, and the effect was comparable to autograft in a nerve injury model (Ige et al., 2012). A controlled-release profile was achieved with antibiotics and growth factors incorporated in keratin-based wound dressings (Vasconcelos and Cavaco-Paulo, 2011). 1.6.4 Fibrin Fibrin is a fibrous, nonglobular protein derived from fibrinogen by the action of the serine protease thrombin (Mogosanu and Grumezescu, 2014). Fibrin is used as a natural scaffold for wound healing and as a carrier for cells for transplantation. A fibrin–HA matrix was used for implantation of chondrocytes to symptomatic–chronic cartilage defects (Nehrer et al., 2008). Cardiomyocytes encapsulated in a fibrin hydrogel have been explored for cardiac tissue engineering (Ye et al., 2011). A dressing composed of salmon fibrinogen and thrombin with hemostatic and antiinflammatory properties was evaluated in full-thickness skin lesions in pigs (Rothwell et al., 2009). The pigs treated with the salmon fibrinogen–thrombin bandages showed a smooth recovery course in terms of both tissue healing and the immune response, without adverse effects from the exposure to the fish proteins (Rothwell et al., 2009). 1.6.5 Bovine serum albumin Bovine serum albumin (BSA) or Fraction V is widely used for pharmaceutical (Aramwit et al., 2000; Benko et al., 2015; Lomova et al., 2015) and tissue engineering applications (Kasalkova et al., 2014; Zhang et al., 2015b). BSA is relatively inexpensive since large quantities are readily purified from blood, which is a by-product of the cattle industry. Due to its stability and biochemical inertness, BSA is often included to increase the signals in enzyme-linked immunosorbent, immunoblotting, and immunohistochemical assays. BSA is also used as a nutrient in cell and microbial cultures. BSA fibers, made by electrospinning without the addition of cross-linking agents, are biocompatible and biodegradable and show favorable biomechanical properties (Dror et al., 2008). This biomaterial is therefore attractive for many wound applications (Dror et al., 2008). 1.6.6 Silk fibroin Silk is a natural fibrous protein spun by lepidopteran larvae such as silkworms; spiders; scorpions; mites; and flies (Jin et al., 2004). Silk fibroin is obtained from silk fiber (Fig. 1.4). Fibroin from the most common silkworm, Bombyx mori, is comprised of a heavy chain of 325 kDa and light chain of 25 kDa, with poor water solubility. The structural sequence consists of a crystalline domain (heavy chain) mostly composed of glycine, alanine, serine, and tyrosine amino acid repeats (GAGAGSGAAG[SG(AG)2]8Y) and a short amorphous (light chain) domain of bulkier amino acid side chain of aspartic acid. The amino acid sequence enables the silks to form an 18 Wound Healing Biomaterials Fibroin Sericin Figure 1.4 Scanning electron image (×1000) of silk fiber consisting of silk fibroin (fibrous protein) and silk sericin (globular protein). Scale = 10 μm. antiparallel β-pleated sheet secondary structure which gives silk its unique mechanical properties. Fibroin supports adhesion and growth of anchorage-dependent cells such as fibroblasts (Minoura et al., 1995). Fibroin is permeable to oxygen and water vapor, has relatively low thrombogenicity, and elicits only a minimal inflammatory response (Altman et al., 2003; Li et al., 2003; Kanokpanont et al., 2012). The presence of the RGD sequence—l-arginine, glycine, and l-aspartic acid—makes this protein suitable not only for skin regeneration, but also for bone and ligament repair (Sofia et al., 2001; Altman et al., 2003). Spiders can process silk protein into a material that is 16 times stronger and 2–3 times more elastic than nylon (Ige et al., 2012). Silks can also supercontract, especially when immersed into liquids. Silk fibroin is prepared in gels, powders, films, matrices, scaffolds, and fibers for biomedical applications. Coating silk fibroin with waxes such as carnauba wax, shellac wax, or beeswax showed improved mechanical properties compared with the noncoated fibroin fiber (Fig. 1.5). Furthermore, the coated fibroin fiber adhered less to the surface of wounds made in pig skin in vitro compared with petrolatum mesh dressing (Sofra-Tulle®), making dressing changes less painful to the patient and gentler to the wound tissue (Kanokpanont et al., 2012). Moreover, silk fibroin mixed with chitosan, gelatin, alginate, or synthetic polymers such as polyvinyl alcohol or poly(lactide-co-glycolic acid) showed improved physical properties such as tensile strength, porosity, swelling rate, and degradation and improved biological properties such as increased attachment and proliferation of L929 fibroblasts. Also, in vivo experiments indicated increased angiogenesis and improved collagen organization by using these hybrid biomaterials (Gu et al., 2013; Shahverdi et al., 2014; Shan et al., 2015). Introduction to biomaterials for wound healing 19 Figure 1.5 Image from scanning electron microscope of silk fibroin woven fabric after sericin removal ((a) 10 kV ×50 and (b) 10 kV ×2000). Scale = 500 mm (a). Scale = 10 µm (b). 1.6.7 Silk sericin Sericin is a degumming silk protein extracted from the silk cocoon. Sericin has several beneficial effects on the stratum corneum of the skin, leading to an improved skin barrier function (Padamwar et al., 2005). Other biological activities of silk sericin include promotion of fibroblast proliferation (Aramwit et al., 2009a,b) and collagen production (Aramwit and Sangcakul, 2007; Aramwit et al., 2010b). An in vitro experiment indicated that sericin at 100 μg/mL or more increased fibroblast repopulation rate of a cell-free polystyrene surface compared with a control under serum-free conditions. The stimulatory effect of sericin was similar to that of epidermal growth factor treatment (Aramwit et al., 2013a). In Fig. 1.6 the beneficial and additional effect of sericin on the healing of split-thickness skin graft donor site wounds in humans is shown (Aramwit et al., 2013a). Sericin in the presence of fibroin, as in native fibers, can activate the immune system (Zaoming et al., 1996). In contrast, pure soluble sericin proteins extracted from native silk fibers did not activate macrophages significantly, indicated by proinflammatory cytokine secretion (Panilaitis et al., 2003; Aramwit et al., 2009a,b). Accordingly, implantation of sericin scaffolds subcutaneously showed no signs of inflammation in standardized ISO 10993-6 test in rats. Furthermore, no excessive inflammatory reaction was observed around the implantation sites. At each time point during the 21-day implantation period, the number of inflammatory cells that infiltrated the silk sericin–releasing wound dressing was comparable to that of a commercial dressing (Bactigras®). Sericin also possesses antiinflammatory activity (Aramwit et al., 2013c). The silk sericin–releasing wound dressing was judged as being nonirritating throughout the implantation period compared to a control in rats (Siritientong et al., 2014). Sericin is water soluble and be can mixed with other polymers into films (Teramoto et al., 2008; Siritientong and Aramwit, 2012), hydrogels (Kundu and Kundu, 2012; Wang et al., 2014), and scaffolds (Aramwit et al., 2010c, 2015). The physical appearances of 20 Wound Healing Biomaterials Figure 1.6 Effect of the addition of sericin to an experimental petrolatum dressing containing 1% (w/v) silver sulfadiazine and 1% zinc oxide (control) on the healing of donor sites in burn patients (Aramwit et al., 2013a). Treatments were changed daily. Mean ± SD. n = number of wounds. ***p < 0.001. sericin film cross-linked with genipin and scaffold composed of sericin, polyvinyl alcohol, and glycerin fabricated using a freeze-drying technique are shown in Fig. 1.7. The mechanical properties of sericin are improved when combined with other biomaterials such as poly(γ-glutamic acid) (Shi et al., 2015), polyvinyl alcohol (Aramwit et al., 2015), CMC (Nayak and Kundu, 2014), or gelatin (Hasatsri et al., 2015). Sericin scaffolds fabricated with different polymers and cross-linkers promote cell proliferation and differentiation. Moreover, they accelerate wound healing in vivo (Aramwit, 2011,2012; Kanokpanont et al., 2012; Siritienthong et al., 2012; Aramwit et al., 2013b). Full-thickness skin wounds in rats treated with sericin/polyvinyl alcohol scaffold showed faster wound area reduction (p < 0.05) compared to the wounds treated with the sericin-free scaffold (Siritienthong et al., 2012). In a clinical study on split-thickness skin graft donor site wounds, the sericin scaffold reduced the time to healing and the pain significantly compared to Bactigras® (Siritientong et al., 2014). Hyperpigmentation is common sequelae of inflammatory conditions that seems to be more common and severe in dark-skinned patients. The treatment results with hydroquinone or retinoic acid are mediocre. Wound treatment with sericin seems to reduce the postoperative hyperpigmentation of scars (Siritientong et al., 2014), perhaps due to the antityrosinase activity of sericin (Aramwit et al., 2010b). 1.7 Nanofiber-based biomaterial Nanofibrous membranes are highly soft materials with high surface-to-volume ratios, and they are excellent carriers for therapeutics such as antimicrobial agents and wound healing enhancers (Zhong et al., 2010b). In nature, very few biomaterials Introduction to biomaterials for wound healing 21 Figure 1.7 Physical appearance of sericin film cross-linked with genipin (left; the dark color of the film is due to genipin) and sericin scaffold–stabilized polyvinyl alcohol and glycerin at weight ratio of 3:2:1 (right). Adapted from Aramwit, P., Palapinyo, S., Srichana, T., Chottanapund, S., Muangman, P., 2013a. Silk sericin ameliorates wound healing and its clinical efficacy in burn wounds. Arch. Dermatol. Res. 305, 585–594. are presented in the form of fibers. One exception is cellulose which is a natural fiber material. Other carbohydrate and protein materials can be formed as nanofibers by using various techniques such as self-assembly, phase separation, and electrospinning (Vasita and Katti, 2006). Electrospinning is a technique for producing ultrafine fibers as a result of charging and ejecting a biomaterial melt or solution through a spinneret under a high-voltage electric field (up to 30 kV) and solidifying it to form a filament. This technique can be used for natural biomaterials such as collagen, silk fibroin, and chitosan and for the synthetic biomaterials (Zhong et al., 2010b) polyvinyl alcohol and PLA. A nonwoven silk fibroin nanofiber coated with type I collagen by electrospinning for skin tissue engineering has been developed (Min et al., 2004). The material promoted keratinocyte–fibroblast adhesion and spreading due to its high porosity and high surface-to-volume ratio (Min et al., 2004). Other examples are electrospun polyurethane nanofiber membranes which provide optimal oxygen permeability and preventing dehydration of the wound (Khil et al., 2003). Moreover, the ultrafine porosity of the polyurethane nanofiber membranes was an effective barrier against microorganisms. 1.8 Marine biomaterial Marine biomaterials for tissue engineering and wound healing are normally sulfated polysaccharides which have diverse functions in the tissues. They bind proteins at several levels of specificity and are mainly involved in the development, cell proliferation, cell adhesion, cell signaling, and cell–matrix interactions (Senni et al., 2011). Marine 22 Wound Healing Biomaterials polysaccharides present an enormous variety of structures. Sulfated polysaccharides, possessing GAG-like biological properties, can be found either in marine eukaryotes or in marine prokaryotes. 1.8.1 Sulfated polysaccharides from red algae Carrageenans are sulfated polysaccharides that occur as matrix material in several species of red seaweeds. The sulfate content largely determines the biological activities of carrageenans (Opoku et al., 2006). κ-Carrageenan possesses antioxidant, antitumor, and immunomodulation activities (Zhou et al., 2004; Yuan et al., 2006). Anticoagulant and growth factor activities have also been reported for carrageenan (Hoffman, 1993; Farias et al., 2000). Nevertheless, carrageenan biocompatibility has been questioned in the literature, with examples of inflammatory responses being presented (Morris, 2003; Aramwit et al., 2013c). It should be emphasized that food-grade carrageenan and degraded carrageenan (low molecular weight) have completely different toxicological properties (Cicala et al., 2007). For tissue engineering and wound healing, carrageenan has been considered for growth factor/ drug delivery systems (Santo et al., 2009), immobilization of enzymes (Desai et al., 2004), and encapsulation of cells for in vivo delivery (Rocha et al., 2011; Popa et al., 2012). 1.8.2 Sulfated polysaccharides from green algae Sulfated polysaccharides found in green algae are more complex and diverse chemistries compared to sulfated polysaccharides found in marine invertebrates (Pomin and Mourao, 2008). These polysaccharides are antioxidative, scavenging radical oxygen species, chelating metals (Costa et al., 2010), antiproliferative, immunostimulating, and antitumorgenic (Kim et al. 2011). Nanofibers (Toskas et al., 2011), membranes (Alves et al., 2012), 3D porous structures (Alves et al., 2013), and hydrogels (Morelli and Chiellini, 2010) have been developed from native, modified, or processed forms of these polysaccharides that may be used for drug delivery, wound dressings, and bone tissue engineering (Morelli and Chiellini, 2010; Alves et al., 2012, 2013). 1.8.3 Sulfated polysaccharides from brown algae Brown macroalgae are rich in polysaccharides such as alginic acids (alginate) or laminarins (laminarans) and sulfated fucans which are potential therapeutic agents. Fucoidan is found in the cell wall of these algae, amounting to 5–20% of the algae dry weight (Vera et al., 2011). For tissue engineering and wound healing application, fucoidan is normally combined with different polymers such as chitosan, alginate, or polycaprolactone processed into nanofibers, films, scaffolds, and hydrogels (Sezer et al., 2007; Murakami et al., 2010). Fucoidan-chitosan hydrogel has been applied as burn injury healing accelerator in rabbits (Sezer et al., 2008). Hydrogel sheets composed of alginate, chitosan, and fucoidan stimulated wound healing in rats (Murakami Introduction to biomaterials for wound healing 23 et al., 2010). These materials showed advantages over chitosan due to the hydrogel-forming properties and anticoagulant activity of fucoidan (Silva et al., 2012). 1.9 Biomaterials with antimicrobial activity Wound infection is a manifestation of disturbed host–bacteria equilibrium in a traumatized tissue environment in favor of bacterial proliferation. A wound infection can elicit a systemic response such as sepsis, but also inhibit any process of the wound healing cascade (Robson 1997; Dai et al., 2011). Antimicrobial biomaterials used for fabrication are especially interesting. 1.9.1 Honey The antimicrobial activity of honey is well established, and many modern wound care products contain medical-grade honey. It has been documented that honey is bactericidal against at least 70 Gram-positive and Gram-negative bacterial strains and some yeasts (Cooper, 2008). Like sugar pastes, honey is hypertonic and inhibits bacterial growth through osmosis (Cooper, 2008). Therefore honey is often used to inhibit the growth of bacterial strains resistant to conventional antibiotics. Honey also facilitates autolytic debridement and maintains a moist wound environment. Despite these beneficial effects, research trends are controversial with respect to the overall clinical efficacy of honey (Henriques et al., 2006; Molan, 2006). 1.9.2 Iodine Iodine, a natural halogen, is an antiseptic and targets a broad spectrum of bacteria and other pathogens such as fungi, viruses, protozoa, and prions through a nonspecific action (Cooper, 2007). The use of iodine has declined due to the increase in resistant bacterial strains and the cytotoxicity of elemental iodine against fibroblasts, keratinocytes, and leukocytes, which may impede wound healing. Modern preparations of iodine were therefore developed to complex elemental iodine to a surfactant to improve solubility and reduce the cytotoxic effects (Daunton et al., 2012). The use of iodophors in wound dressings ensures release of lower concentrations of free iodine into the wound (Jones and San Miguel, 2006). The most widely used formulations are povidone-iodine and cadexomer-iodine. Even these formulations at concentrations as low as 1% are cytotoxic to granulocytes and monocytes in vitro (Jones and San Miguel, 2006). Systemic iodine toxicity has been reported after the use povidone-iodine dressings containing 7.5% iodine on large wounds (Jones and San Miguel, 2006). The cadexomer-iodine formulation seems to be effective in controlling the bacterial burden and is also able to accelerate epithelialization through up-regulation of cytokines and growth factors (Lamme et al., 1998; Ohtani et al., 2007). In addition, cadexomer-iodine may improve the healing of chronic wounds by inhibiting excessive protease activities (Eming et al., 2006). 24 Wound Healing Biomaterials 1.9.3 Silver Silver dressings are used in a wide range of infected wounds, although their potential cytotoxicity remains an issue (Wei et al., 2010; Zou et al., 2013). Ionic, metallic, and nanocrystalline forms of silver have been used as foams, alginates, hydrofibers, and hydrocolloids. The amount of bioavailable free silver varies, which impacts the effectiveness of the dressings on wound healing. Silver ions act upon bacteria by binding and disrupting proteins and nucleic acids through interaction with their negatively charged groups such as thiols, carboxylates, phosphates, hydroxyls, imidazoles, indoles, and amines as well as by stimulating the generation of reactive oxygen species (Kim et al., 2012). As a result, cellular changes rapidly occur through several mechanisms, resulting in loss of viability (Cooper, 2004). Silver nanoparticles penetrated into mitochondria and nuclei and interrupted ATP synthesis and damaged DNA of human glioblastoma cells and lung fibroblasts in vitro (Asharani et al., 2009). Other studies indicated that silver nanoparticles were cytotoxic to keratinocytes in vitro (Sibbald et al., 2011; Zanette et al., 2011). 1.9.4 Chitosan Many factors present in the chitosan molecule or its environment can influence the antimicrobial properties such as molecular weight, ionic strength, pH of the dissolving medium, and the physical state of the chitosan itself (Dai et al., 2011). The exact mechanisms of the antimicrobial actions of chitosan are still uncertain, but it has been proposed that interaction between positively charged chitosan molecules and negatively charged microbial cell membranes leads to the disruption of microbial membrane, and subsequently the leakage of protein as well as other intracellular constituents (Rabea et al., 2003; Raafat et al., 2008; Kong et al., 2010). Use of fluorescent probes and field emission scanning electron microscopy indicated that chitosan-arginine increases membrane permeability, which could partly explain its antibacterial activity (Tang et al., 2010). Chitosan is essentially water insoluble at physiological pH, but the solubility is increased when functionalized with arginine. Furthermore, at low concentrations (<0.2 mg/mL), the polycationic chitosan binds to the negatively charged bacterial surface causing agglutination, whereas at higher concentrations, the larger number of positive charges have imparted a net positive charge to the bacterial surfaces to keep them in suspension (Rabea et al., 2003). Many studies showed that chitosan prevents fatal systemic sepsis by controlling the growth of Pseudomonas aeruginosa and Pseudomonas mirabilis in wounds (Dai et al., 2009; Dutta et al., 2012). A chitosan acetate dressing was even superior to nanocrystalline silver with respect to survival from P. aerugnosa-infected burn wounds (Dai et al., 2009). 1.10 Biomaterials used for corneal wound healing Skin and cornea share a similar tissue structure: dermis and stroma are connective tissues, and epidermis and cornea are stratified epithelia (Parenteau-Bareil et al., 2010). The cornea is the most vital refractive medium in the anterior part of the eye, and it Introduction to biomaterials for wound healing 25 is responsible for two-thirds of the total ocular refractive power. Disease affecting the cornea is a common cause of blindness worldwide. To date, the amniotic membrane is the most widely used clinical method for cornea regeneration (Tsai et al., 2015). Donor-dependent differences in the amniotic membrane may result in variable clinical outcomes. Thus other biomaterials are currently under investigation for corneal regeneration. 1.10.1 Collagen/gelatin Collagen is the most abundant protein in the human cornea (Michelacci, 2003). Advances in collagen-based corneal scaffolds also include recombinant human collagen (Liu et al., 2006; Lagali et al., 2008), the secretion of collagen by the fibroblasts themselves (self-assembled fibroblasts sheets) (Carrier et al., 2008), and surface modification to reduce endothelialization (Rafat et al., 2009). In the last decade, collagen scaffolds have been intensively studied for the delivery of limbal epithelial stem cells to damaged cornea (Schwab, 1999; Grueterich et al., 2003). Collagen hydrogels are biocompatible, biodegradable, and maintain the proliferation and differentiation of limbal epithelial cells. In clinical studies corneal reepithelialization occurred in all patients who had significant vision loss after treatment with a cross-linked collagen hydrogel (Fagerholm et al., 2010, 2014). Gelatin hydrogels have been used as cell carriers, including corneal endothelial and stromal cells, and for sustained ocular drug release for corneal regeneration (Hori et al., 2007; Watanabe et al., 2011). An animal study showed that transplantation of fibroblast precursors into the corneal stroma from a gelatin hydrogel promoted wound healing of the cornea (Mimura et al., 2008). 1.10.2 Fibrin Fibrin hydrogels increase the survival rate of limbal stem cells, while maintaining their phenotype during culturing (Meyer-Blazejewska et al., 2010; Rama et al., 2010). Moreover, fibrin hydrogels are degraded within 24 h after transplantation, which is ideal for a cell carrier biomaterial (Meyer-Blazejewska et al., 2010). In a clinical study, patients with corneal damage regained useful vision after treatment with autologous limbal stem cells that had been cultured on autologous fibrin hydrogel (Rama et al., 2010). Mesenchymal stem cells are also widely investigated for their use in corneal regeneration. Mesenchymal stem cells can differentiate into corneal epithelial-like cells in vivo and ex vivo (Tsai et al., 2015). The studies showed that injured cornea in rabbits could be successfully reconstructed by delivery of mesenchymal stem cells that had been cultured on fibrin hydrogels (Ye et al., 2006; Gu et al., 2009). 1.10.3 Alginate There are few studies on alginates in ophthalmology (Lee and Mooney, 2012; Pawar and Edgar, 2012). Nonetheless, these studies indicate that alginate-based hydrogels are promising carriers for limbal epithelial cells and thus for corneal regeneration applications (Liang et al., 2011; Wright et al., 2012). 26 Wound Healing Biomaterials 1.10.4 Chitosan Chitosan-based biomaterials have been investigated for ocular drug and cell delivery (Cao et al., 2007; Yeh et al., 2009). A chitosan membrane promoted wound healing and decreased scar tissue formation in a rabbit corneal alkali burn model (Du et al., 2008). Chitosan-based hydrogels combined with induced pluripotent stem cells were reported effective in the treatment of surgical abrasion–injured corneas in rats (Chien et al., 2012). 1.11 Trends of biomaterials used for wound healing The search for the ideal wound dressing is ongoing. With the application of modern biotechnologies and tissue engineering skills combined with conventional materials, advanced wound treatments are steadily being improved. 1.11.1 Extracellular matrix-derived biomaterials Biologics describe ECM-based products of human or animal sources (Mathur et al., 1997; Badylak et al., 2002; Badylak, 2002). The rationale behind the use of these biomaterials/bioscaffolds is replicating the biological and mechanical function of the native ECMs that ascertain optimal conditions not only for repair but also for regeneration of new tissue (Bellows et al., 2007). Different mechanisms have been proposed, including promotion of angiogenesis, recruitment of circulating progenitor cells, rapid scaffold degradation and generation of active peptides, and antibacterial activity (Badylak, 2002). One challenge when producing these biomaterials is to completely remove cells and antigens of the native materials without altering their 3D structure and their biological and mechanical properties. Human acellular dermal matrices derived from cadavers include Alloderm® (LifeCell, Branchburg, NJ, USA) and GraftJacket® (KCI, San Antonio, TX, USA). These allografts are thought to support the body’s own healing capacity. Small intestine submucosa (SIS) is derived from the thin, translucent tunica submucosa layer of the small intestine of pigs which remains after removing the mucosal and muscular layers. SIS consists primarily of a collagen-based extracellular matrix which provides strength, structural support, and stability and signals to the constantly regenerating mucosal cell layer (Ko et al., 2006; Chang et al., 2013). SIS also contains many growth factors. In vitro studies indicate that SIS provides an environment that ensures fibroblast and keratinocyte attachment, proliferation, and migration (Voytik-Harbin et al., 1998). Commercially, sterile single-use monolayer and trilayer SIS are available (Smith & Nephew, London, UK). The trilayer product is stronger than the monolayer and therefore supports more suture tension. Using tissue engineering techniques, many physical and chemical properties such as the composition and structure of the matrix, molecular composition, flexibility, thickness, tensile strength, elasticity, degradation rate, and the remodeling behavior can be recapitulated to the need of the specific repair site (Gobin et al., 2006). Several Introduction to biomaterials for wound healing 27 natural biomaterials, such as silk protein, chitosan, and collagen, are promising starting materials in engineered products with reparative and regenerative capacity. One example is Biobrane® (Smith & Nephew), which is a biocomposite dressing composed of a silicone–nylon matrix in which collagenous peptides from porcine skin have been covalently bonded. 1.12 Limitations of biomaterials for wound healing applications The main limitation of synthetic biomaterials is biocompatibility with human tissues which may cause problems after their use for extended times. Moreover, the impurity from precursors or byproducts may affect the physical and biological properties of these biomaterials. Although biocompatibility is not a significant concern with natural biomaterials, there are other limitations associated with their use: 1. Productivity: Due to the natural sources of these biomaterials which are difficult to control, the amount of some natural biomaterials may not be sufficient for practical use. 2. Consistency: The origin of natural materials may affect their properties. The same animal species found in different areas may produce biomaterials with slightly different physical and biological activities. Moreover, the extraction methods need to be verified to provide good-quality materials. 3. Degradation: Most natural biomaterials are susceptible for degradation, especially after extraction and exposure to heat and light. Some natural products are recommended to be used immediately after extraction to avoid the nonuniformity. 4. Contamination: Some natural biomaterials such as proteins are excellent growth media for microorganisms. Sterilization may have adverse effects on the structure or properties of the materials. Despite these limitations, natural biomaterials have advantages over synthetic biomaterials via their versatility, biocompatibility, sustainability, green chemistry issues, and various biological properties from single material. These features may explain the growing interest of natural biomaterials in all biomedical areas. 1.13 Conclusions According to the variation in the rate of production of wound exudate and the appearance of the wound bed, no single wound dressing, either from synthetic or natural biomaterials, is beneficial for all wound types. The main challenge is to develop novel wound healing drug delivery or cell delivery formulations that have the capacity to positively influence the majority of wounds. Novel biomaterials and other active ingredients such as growth factors, pharmaceuticals, or cells can stimulate the healing cascade. These materials combined with tissue engineering techniques provide a better chance for optimal treatment and management resulting in positive clinical outcomes. 28 Wound Healing Biomaterials References Aboushwareb, T., Eberli, D., et al., 2009. A keratin biomaterial gel hemostat derived from human hair: evaluation in a rabbit model of lethal liver injury. J. Biomed. Mater. Res. B Appl. Biomater. 90 (1), 45–54. Agrawal, C.M., 1998. Reconstructing the human body using biomaterials. JOM 50 (1), 31–35. Ågren, M.S., 1998. An amorphous hydrogel enhances epithelialisation of wounds. Acta Derm. Venereol. 78 (2), 119–122. Ågren, M.S., Ostenfeld, U., et al., 2006. A randomized, double-blind, placebo-controlled multicenter trial evaluating topical zinc oxide for acute open wounds following pilonidal disease excision. Wound Repair Regen. 14 (5), 526–535. Altman, G.H., Diaz, F., et al., 2003. Silk-based biomaterials. Biomaterials 24 (3), 401–416. Alves, A., Pinho, E.D., et al., 2012. Processing ulvan into 2D structures: cross-linked ulvan membranes as new biomaterials for drug delivery applications. Int. J. Pharm. 426 (1–2), 76–81. Alves, A., Sousa, R.A., et al., 2013. Processing of degradable ulvan 3D porous structures for biomedical applications. J. Biomed. Mater. Res. A 101 (4), 998–1006. Anderson, J.M., Hiltner, A., et al., 1998. Recent advances in biomedical polyurethane biostability and biodegradation. Polym. Int. 46 (3), 163–171. Aramwit, P., 2011. Method for preparing silk sericin-PVA scaffold using Genipin as crosslinking agent. I. A. N. PCT/TH2011/000013. Aramwit, P., 2012. Method for preparing porous silk sericin scaffold by cross-linking process and products from the same. T. p. g. n. 9423. Aramwit, P., Bang, N., 2014. The characteristics of bacterial nanocellulose gel releasing silk sericin for facial treatment. BMC Biotechnol. 14, 104. Aramwit, P., Damrongsakkul, S., et al., 2010a. Properties and antityrosinase activity of sericin from various extraction methods. Biotechnol. Appl. Biochem. 55 (2), 91–98. Aramwit, P., Kanokpanont, S., et al., 2009a. The effect of sericin with variable amino-acid content from different silk strains on the production of collagen and nitric oxide. J. Biomater. Sci. Polym. Ed. 20 (9), 1295–1306. Aramwit, P., Kanokpanont, S., et al., 2009b. Monitoring of inflammatory mediators induced by silk sericin. J. Biosci. Bioeng. 107 (5), 556–561. Aramwit, P., Kanokpanont, S., et al., 2010b. The effect of sericin from various extraction methods on cell viability and collagen production. Int. J. Mol. Sci. 11 (5), 2200–2211. Aramwit, P., Palapinyo, S., et al., 2013a. Silk sericin ameliorates wound healing and its clinical efficacy in burn wounds. Arch. Dermatol. Res. 305 (7), 585–594. Aramwit, P., Ratanavaraporn, J., et al., 2015. A green salt-leaching technique to produce sericin/ PVA/glycerin scaffolds with distinguished characteristics for wound-dressing applications. J. Biomed. Mater. Res. B Appl. Biomater. 103 (4), 915–924. Aramwit, P., Sangcakul, A., 2007. The effects of sericin cream on wound healing in rats. Biosci. Biotechnol. Biochem. 71 (10), 2473–2477. Aramwit, P., Siritienthong, T., et al., 2013b. Accelerated healing of full-thickness wounds by genipin-crosslinked silk sericin/PVA scaffolds. Cells Tissues Organs 197 (3), 224–238. Aramwit, P., Siritientong, T., et al., 2010c. Formulation and characterization of silk sericin-PVA scaffold crosslinked with genipin. Int. J. Biol. Macromol. 47 (5), 668–675. Aramwit, P., Towiwat, P., et al., 2013c. Anti-inflammatory potential of silk sericin. Nat. Prod. Commun. 8 (4), 501–504. Aramwit, P., Yu, B.G., et al., 2000. The effect of serum albumin on the aggregation state and toxicity of amphotericin B. J. Pharm. Sci. 89 (12), 1589–1593. Asharani, P.V., Hande, M.P., et al., 2009. Anti-proliferative activity of silver nanoparticles. BMC Cell Biol. 10, 65. Introduction to biomaterials for wound healing 29 Atala, A., Mooney, D., 1997. Synthetic Biodegradable Polymer Scaffolds. Birkhauser BioSciences, New York, USA. Badylak, S., Kokini, K., et al., 2002. Morphologic study of small intestinal submucosa as a body wall repair device. J. Surg. Res. 103 (2), 190–202. Badylak, S.F., 2002. The extracellular matrix as a scaffold for tissue reconstruction. Semin. Cell Dev. Biol. 13 (5), 377–383. Bajpai, A.K., Giri, A., 2003. Water sorption behaviour of highly swelling (carboxy methylcellulose-g-polyacrylamide) hydrogels and release of potassium nitrate as agrochemical. Carbohydr. Polym. 53 (3), 271–279. Bellows, C.F., Albo, D., et al., 2007. Abdominal wall repair using human acellular dermis. Am. J. Surg. 194 (2), 192–198. Benko, M., Varga, N., et al., 2015. Bovine serum albumin-sodium alkyl sulfates bioconjugates as drug delivery systems. Colloids Surf. B Biointerfaces 130, 126–132. Beran, M., Urban, M., et al., 2007. Applications of Mushroom Chitosans in Medical Biomaterials. From: http://www.vupp.cz/czvupp/publik/07poster/MBposter4-2007-1.pdf. Biliaderis, C., 1992. Structure and phase transition of starch in food systems. Food Technol. 46 (6), 98–109. Bradford, C., Freeman, R., et al., 2009. In vitro study of sustained antimicrobial activity of a new silver alginate dressing. J. Am. Col. Certif. Wound Spec. 1 (4), 117–120. Bragulla, H.H., Homberger, D.G., 2009. Structure and functions of keratin proteins in simple, stratified, keratinized and cornified epithelia. J. Anat. 214 (4), 516–559. Brochu, A.B., Craig, S.L., et al., 2011. Self-healing biomaterials. J. Biomed. Mater. Res. A 96 (2), 492–506. Brown-Etris, M., Cutshall, W., et al., 2002. A new biomaterial derived from small intestine submucosa and developed into a wound matrix device. Wounds 14 (4), 150–166. Cao, Y., Zhang, C., et al., 2007. Poly(N-isopropylacrylamide)-chitosan as thermosensitive in situ gel-forming system for ocular drug delivery. J. Control. Release 120 (3), 186–194. Carrier, P., Deschambeault, A., et al., 2008. Characterization of wound reepithelialization using a new human tissue-engineered corneal wound healing model. Invest. Ophthalmol. Vis. Sci. 49 (4), 1376–1385. Chang, J., DeLillo Jr., N., et al., 2013. Review of small intestine submucosa extracellular matrix technology in multiple difficult-to-treat wound types. Wounds 25 (5), 113–120. Chattopadhyay, S., Raines, R.T., 2014. Review collagen-based biomaterials for wound healing. Biopolymers 101 (8), 821–833. Chien, Y., Liao, Y.W., et al., 2012. Corneal repair by human corneal keratocyte-reprogrammed iPSCs and amphiphatic carboxymethyl-hexanoyl chitosan hydrogel. Biomaterials 33 (32), 8003–8016. Cho, Y.W., Cho, Y.N., et al., 1999. Water-soluble chitin as a wound healing accelerator. Biomaterials 20 (22), 2139–2145. Cicala, C., Morello, S., et al., 2007. Haemostatic imbalance following carrageenan-induced rat paw oedema. Eur. J. Pharmacol. 577 (1–3), 156–161. Cooper, R., 2004. A Review of the Evidence of the Use of Topical Antimicrobial Agents in Wound Care. From: http://www.worldwidewounds.com/2004/february/Cooper/ Topical-Antimicrobial-Agents.html. Cooper, R., 2008. Using honey to inhibit wound pathogens. Nurs. Times 104 (3), 46 48–49. Cooper, R.A., 2007. Iodine revisited. Int. Wound J. 4 (2), 124–137. Costa, L.S., Fidelis, G.P., et al., 2010. Biological activities of sulfated polysaccharides from tropical seaweeds. Biomed. Pharmacother. 64 (1), 21–28. Czaja, W.K., Young, D.J., et al., 2007. The future prospects of microbial cellulose in biomedical applications. Biomacromolecules 8 (1), 1–12. 30 Wound Healing Biomaterials Dai, T., Tanaka, M., et al., 2011. Chitosan preparations for wounds and burns: antimicrobial and wound-healing effects. Expert Rev. Anti Infect. Ther. 9 (7), 857–879. Dai, T., Tegos, G.P., et al., 2009. Chitosan acetate bandage as a topical antimicrobial dressing for infected burns. Antimicrob. Agents Chemother. 53 (2), 393–400. Daunton, C., Kothari, S., et al., 2012. A history of materials and practices for wound management. Wound Pract. Res. 20 (4), 174–186. Davis, J., 2003. Overview of biomaterials and their use in medical devices. In: Davis, J. (Ed.), Handbook of Materials for Medical Devices. Knovel, Pensylvania, USA. Desai, P.D., Dave, A.M., et al., 2004. Entrapment of lipase into K-carrageenan beads and its use in hydrolysis of olive oil in biphasic system. J. Mol. Catal. B Enzym. 31 (4–6), 143–150. Dror, Y., Ziv, T., et al., 2008. Nanofibers made of globular proteins. Biomacromolecules 9 (10), 2749–2754. Du, L.Q., Wu, X.Y., et al., 2008. Effect of different biomedical membranes on alkali-burned cornea. Ophthalmic Res. 40 (6), 282–290. Dutta, J., Tripathi, S., et al., 2012. Progress in antimicrobial activities of chitin, chitosan and its oligosaccharides: a systematic study needs for food applications. Food Sci. Technol. Int. 18 (1), 3–34. Eming, S.A., Smola-Hess, S., et al., 2006. A novel property of povidon-iodine: inhibition of excessive protease levels in chronic non-healing wounds. J. Invest. Dermatol. 126 (12), 2731–2733. Fagerholm, P., Lagali, N.S., et al., 2010. A biosynthetic alternative to human donor tissue for inducing corneal regeneration: 24-month follow-up of a phase 1 clinical study. Sci. Transl. Med. 2 (46), 46ra61. Fagerholm, P., Lagali, N.S., et al., 2014. Stable corneal regeneration four years after implantation of a cell-free recombinant human collagen scaffold. Biomaterials 35 (8), 2420–2427. Farias, W.R., Valente, A.P., et al., 2000. Structure and anticoagulant activity of sulfated galactans. Isolation of a unique sulfated galactan from the red algae Botryocladia occidentalis and comparison of its anticoagulant action with that of sulfated galactans from invertebrates. J. Biol. Chem. 275 (38), 29299–29307. Fleck, C.A., Simman, R., 2010. Modern collagen wound dressings: function and purpose. J. Am. Col. Certif. Wound Spec. 2 (3), 50–54. Freyman, T.M., Yannas, I.V., et al., 2001. Cellular materials as porous scaffolds for tissue engineering. Prog. Mater. Sci. 46 (3–4), 273–282. Gingras, M., Paradis, I., et al., 2003. Nerve regeneration in a collagen-chitosan tissue-engineered skin transplanted on nude mice. Biomaterials 24 (9), 1653–1661. Gobin, A.S., Butler, C.E., et al., 2006. Repair and regeneration of the abdominal wall musculofascial defect using silk fibroin-chitosan blend. Tissue Eng. 12 (12), 3383–3394. Gobin, A.S., West, J.L., 2003. Effects of epidermal growth factor on fibroblast migration through biomimetic hydrogels. Biotechnol. Prog. 19 (6), 1781–1785. Granick, M., Boykin, J., et al., 2006. Toward a common language: surgical wound bed preparation and debridement. Wound Repair Regen. 14 (Suppl. 1), S1–10. Grueterich, M., Espana, E.M., et al., 2003. Ex vivo expansion of limbal epithelial stem cells: amniotic membrane serving as a stem cell niche. Surv. Ophthalmol. 48 (6), 631–646. Gu, S., Xing, C., et al., 2009. Differentiation of rabbit bone marrow mesenchymal stem cells into corneal epithelial cells in vivo and ex vivo. Mol. Vis. 15, 99–107. Gu, Z., Xie, H., et al., 2013. Preparation of chitosan/silk fibroin blending membrane fixed with alginate dialdehyde for wound dressing. Int. J. Biol. Macromol. 58, 121–126. Guerra, L., Dellambra, E., et al., 2009. Tissue engineering for damaged surface and lining epithelia: stem cells, current clinical applications, and available engineered tissues. Tissue Eng. Part B Rev. 15 (2), 91–112. Introduction to biomaterials for wound healing 31 Hafemann, B., Ensslen, S., et al., 1999. Use of a collagen/elastin-membrane for the tissue engineering of dermis. Burns 25 (5), 373–384. Han, S., 2005. Topical formulations of water-soluble chitin as a wound healing assistant. Fibers and Polym. 6 (3), 219–223. Hasatsri, S., Aungsapat, A., et al., 2015. Randomized clinical trial of the innovative bilayered wound dressing made of silk and gelatin: safety and efficacy tests using a split-thickness skin graft model. Evid. Based Complement Alternat. Med. 2015:Article ID 206871. Heness, G., Ben-Nissan, B., 2004. Innovative bioceramics. Mater. Forum 27, 104–114. Henriques, A., Jackson, S., et al., 2006. Free radical production and quenching in honeys with wound healing potential. J. Antimicrob. Chemother. 58 (4), 773–777. Higgins, S.P., Solan, A.K., et al., 2003. Effects of polyglycolic acid on porcine smooth muscle cell growth and differentiation. J. Biomed. Mater. Res. Part A 67A (1), 295–302. Hirano, S., Midorikawa, T., 1998. Novel method for the preparation of N-acylchitosan fiber and N-acylchitosan-cellulose fiber. Biomaterials 19 (1–3), 293–297. Hoffman, R., 1993. Carrageenans inhibit growth-factor binding. Biochem. J. 289 (Pt 2), 331–334. Hori, K., Sotozono, C., et al., 2007. Controlled-release of epidermal growth factor from cationized gelatin hydrogel enhances corneal epithelial wound healing. J. Control. Release 118 (2), 169–176. Huang, M., Yang, M., 2008. Evaluation of glucan/poly(vinyl alcohol) blend wound dressing using rat models. Int. J. Pharm. 346 (1–2), 38–46. Ige, O.O., Umoru, L.E., et al., 2012. Natural products: a minefield of biomaterials. ISRN Mater. Sci. 2012, 20. Jansson, E., Tengvall, P., 2001. In vitro preparation and ellipsometric characterization of thin blood plasma clot films on silicon. Biomaterials 22 (13), 1803–1808. Jin, H.J., Park, J., et al., 2004. Biomaterial films of Bombyx mori silk fibroin with poly(ethylene oxide). Biomacromolecules 5 (3), 711–717. Jones, A.M., San Miguel, L., 2006. Are modern wound dressings a clinical and cost-effective alternative to the use of gauze? J. Wound Care 15 (2), 65–69. Kanokpanont, S., Damrongsakkul, S., et al., 2012. An innovative bi-layered wound dressing made of silk and gelatin for accelerated wound healing. Int. J. Pharm. 436 (1–2), 141–153. Kasalkova, N.S., Slepicka, P., et al., 2014. Grafting of bovine serum albumin proteins on plasma-modified polymers for potential application in tissue engineering. Nanoscale Res. Lett. 9 (1), 161. Kasuya, A., Tokura, Y., 2014. Attempts to accelerate wound healing. J. Dermatol. Sci. 76 (3), 169–172. Kearney, J.N., 2001. Clinical evaluation of skin substitutes. Burns 27 (5), 545–551. Kennedy, J., Knill, C., et al., 2011. Natural polymers for healing wounds. In: Kennedy, J., Philips, G., Williams, P., Hatakeyama, H. (Eds.), Recent Advances in Environmentally Compatible Polymers. Woodhead Publishing, Cambridge, England. Khil, M.S., Cha, D.I., et al., 2003. Electrospun nanofibrous polyurethane membrane as wound dressing. J. Biomed. Mater. Res. B Appl. Biomater. 67 (2), 675–679. Khor, E., Lim, L.Y., 2003. Implantable applications of chitin and chitosan. Biomaterials 24 (13), 2339–2349. Kim, J.K., Cho, M.L., et al., 2011. In vitro and in vivo immunomodulatory activity of sulfated polysaccharides from Enteromorpha prolifera. Int. J. Biol. Macromol. 49 (5), 1051–1058. Kim, T.H., Kim, M., et al., 2012. Size-dependent cellular toxicity of silver nanoparticles. J. Biomed. Mater. Res. A 100 (4), 1033–1043. Kindt, T., Goldsby, R., et al., 2007. Kuby Immunology. Freemand and Company, New York, USA. 32 Wound Healing Biomaterials Knapp, T.R., Kaplan, E.N., et al., 1977. Injectable collagen for soft tissue augmentation. Plast. Reconstr. Surg. 60 (3), 398–405. Ko, R., Kazacos, E.A., et al., 2006. Tensile strength comparison of small intestinal submucosa body wall repair. J. Surg. Res. 135 (1), 9–17. Kong, M., Chen, X.G., et al., 2010. Antimicrobial properties of chitosan and mode of action: a state of the art review. Int. J. Food Microbiol. 144 (1), 51–63. Kundu, B., Kundu, S.C., 2012. Silk sericin/polyacrylamide in situ forming hydrogels for dermal reconstruction. Biomaterials 33 (30), 7456–7467. Kurpinski, K.T., Stephenson, J.T., et al., 2010. The effect of fiber alignment and heparin coating on cell infiltration into nanofibrous PLLA scaffolds. Biomaterials 31 (13), 3536–3542. Lagali, N., Griffith, M., et al., 2008. Innervation of tissue-engineered recombinant human collagen-based corneal substitutes: a comparative in vivo confocal microscopy study. Invest. Ophthalmol. Vis. Sci. 49 (9), 3895–3902. Lamme, E.N., Gustafsson, T.O., et al., 1998.