Tendon regeneration

TENDON REGENERATION Understanding Tissue Physiology and Development to Engineer Functional Substitutes Edited by MANUELA E GOMES RUI L REIS MÁRCIA T RODRIGUES Amsterdam • Boston • Heidelberg • London New York • Oxford • Paris • San Diego San Francisco • Singapore • Sydney • Tokyo Academic Press is an imprint of Elsevier Academic Press is an imprint of Elsevier 125 London Wall, London EC2Y 5AS, UK 525 B Street, Suite 1800, San Diego, CA 92101-4495, USA 225 Wyman Street, Waltham, MA 02451, USA The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, UK Copyright © 2015 Elsevier Inc 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 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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 ISBN: 978-0-12-801590-2 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 For information on all Academic Press publications visit our website at http://store.elsevier.com/ Publisher: Mica Haley Acquisition Editor: Mica Haley Editorial Project Manager: Lisa Eppich Production Project Manager: Julia Haynes Designer: Inês Cruz Typeset by TNQ Books and Journals www.tnq.co.in Printed and bound in the United States of America CONTRIBUTORS Paul W Ackermann Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital, Solna, Stockholm, Sweden Giuseppe Banfi Dipartimento di Scienze Biomediche per la Salute, Università degli Studi di Milano, Milan, Italy; IRCCS Policlinico San Donato, San Donato Milanese, Milan, Italy Manus Biggs Network of Excellence for Functional Biomaterials (NFB), Biosciences Research Building, National University of Ireland Galway (NUI Galway), Galway, Ireland; Centre for Research in Medical Devices (CURAM), Biosciences Research Building, National University of Ireland Galway (NUI Galway), Galway, Ireland Helen L Birch Institute of Orthopaedics and Musculoskeletal Science, University College London, Stanmore, UK Paolo Cabitza Dipartimento di Scienze Biomediche per la Salute, Università degli Studi di Milano, Milan, Italy; IRCCS Policlinico San Donato, San Donato Milanese, Milan, Italy Yilin Cao Department of Plastic and Reconstructive Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Tissue Engineering Key Laboratory, National Tissue Engineering Center of China, Shanghai, P.R China Peter D Clegg Department of Musculoskeletal Biology, Institute of Ageing and Chronic Disease, University of Liverpool, Leahurst Campus, Neston, UK Raquel Costa-Almeida 3B’s Research Group—Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, Guimarães, Portugal; ICVS/3B’s—PT Government Associate Laboratory, Braga/Guimarães, Portugal Riccardo D’Ambrosi IRCCS Policlinico San Donato, San Donato Milanese, Milan, Italy Rui M.A Domingues 3B’s Research Group—Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, Guimarães, Portugal; ICVS/3B’s—PT Government Associate Laboratory, Braga/Guimarães, Portugal Alicia J El Haj Institute of Science and Technology in Medicine, Keele University Medical School, Guy Hilton Research Centre, University Hospital North Midlands, North Staffs, UK xi xii Contributors Brandon Engebretson School of Chemical, Biological, and Materials Engineering, University of Oklahoma, Norman, OK, USA Andrew English Regenerative, Modular & Developmental Engineering Laboratory (REMODEL), Biosciences Research Building, National University of Ireland Galway (NUI Galway), Galway, Ireland; Network of Excellence for Functional Biomaterials (NFB), Biosciences Research Building, National University of Ireland Galway (NUI Galway), Galway, Ireland; Centre for Research in Medical Devices (CURAM), Biosciences Research Building, National University of Ireland Galway (NUI Galway), Galway, Ireland Pavel Gershovich 3B’s Research Group—Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, Guimarães, Portugal; ICVS/3B’s—PT Government Associate Laboratory, Braga/ Guimarães, Portugal Manuela E Gomes 3B’s Research Group—Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, Guimarães, Portugal; ICVS/3B’s—PT Government Associate Laboratory, Braga/ Guimarães, Portugal Ana I Gonỗalves 3Bs Research GroupBiomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, Guimarães, Portugal; ICVS/3B’s—PT Government Associate Laboratory, Braga/ Guimarães, Portugal Brendan Harley Department of Chemical and Biomolecular Engineering, University of Illinois at UrbanaChampaign, Urbana, IL, USA; Carl R Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL, USA Laura A Hockaday Department of Biomedical Engineering, Tufts University, Medford, MA, USA Rebecca Hortensius Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, IL, USA Faith W Karanja Cell, Molecular and Developmental Biology Program, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, Boston, MA, USA Catherine K Kuo Department of Biomedical Engineering, Tufts University, Medford, MA, USA; Cell, Molecular and Developmental Biology Program, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, Boston, MA, USA Thomas D Kwan Institute of Science and Technology in Medicine, Keele University Medical School, Guy Hilton Research Centre, University Hospital North Midlands, North Staffs, UK William N Levine Department of Orthopaedic Surgery, Columbia University, New York Presbyterian Hospital, New York, NY, USA Contributors Wei Liu Department of Plastic and Reconstructive Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Tissue Engineering Key Laboratory, National Tissue Engineering Center of China, Shanghai, P.R China Alex Lomas Regenerative, Modular & Developmental Engineering Laboratory (REMODEL), Biosciences Research Building, National University of Ireland Galway (NUI Galway), Galway, Ireland; Network of Excellence for Functional Biomaterials (NFB), Biosciences Research Building, National University of Ireland Galway (NUI Galway), Galway, Ireland; Centre for Research in Medical Devices (CURAM), Biosciences Research Building, National University of Ireland Galway (NUI Galway), Galway, Ireland Helen H Lu Biomaterials and Interface Tissue Engineering Laboratory, Department of Biomedical Engineering, Columbia University, New York, NY, USA Alessandra Menon IRCCS Policlinico San Donato, San Donato Milanese, Milan, Italy Tyler R Morris McKay Orthopaedic Research Laboratory, University of Pennsylvania, Philadelphia, PA, USA Laura Mozdzen Department of Chemical and Biomolecular Engineering, University of Illinois at Urbana-Champaign, Urbana, IL, USA Zachary Mussett School of Biomedical Engineering, University of Oklahoma, Norman, OK, USA Abhay Pandit Network of Excellence for Functional Biomaterials (NFB), Biosciences Research Building, National University of Ireland Galway (NUI Galway), Galway, Ireland; Centre for Research in Medical Devices (CURAM), Biosciences Research Building, National University of Ireland Galway (NUI Galway), Galway, Ireland Vincenza Ragone IRCCS Policlinico San Donato, San Donato Milanese, Milan, Italy Filippo Randelli IRCCS Policlinico San Donato, San Donato Milanese, Milan, Italy Pietro Randelli IRCCS Policlinico San Donato, San Donato Milanese, Milan, Italy Rui L Reis 3B’s Research Group—Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, Guimarães, Portugal; ICVS/3B’s—PT Government Associate Laboratory, Braga/ Guimarães, Portugal Corinne N Riggin McKay Orthopaedic Research Laboratory, University of Pennsylvania, Philadelphia, PA, USA Márcia T Rodrigues 3B’s Research Group—Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, Guimarães, Portugal; ICVS/3B’s—PT Government Associate Laboratory, Braga/ Guimarães, Portugal xiii xiv Contributors Benjamin B Rothrauff Center for Cellular and Molecular Engineering, Department of Orthopaedic Surgery, ­University of Pittsburgh School of Medicine, Pittsburgh, PA, USA Mitchell D Saeger Department of Chemical and Biological Engineering, Tufts University, Medford, MA, USA Sambit Sahoo Department of Biomedical Engineering, Cleveland Clinic, Cleveland, OH, USA Hazel R.C Screen Institute of Bioengineering, School of Engineering & Materials Science, Queen Mary University of London, London, UK Vassilios Sikavitsas School of Chemical, Biological, and Materials Engineering, University of Oklahoma, Norman, OK, USA; School of Biomedical Engineering, University of Oklahoma, Norman, OK, USA Aaron Simmons School of Chemical, Biological, and Materials Engineering, University of Oklahoma, Norman, OK, USA Louis J Soslowsky McKay Orthopaedic Research Laboratory, University of Pennsylvania, Philadelphia, PA, USA Chavaunne T Thorpe Institute of Bioengineering, School of Engineering & Materials Science, Queen Mary University of London, London, UK Rocky S Tuan Center for Cellular and Molecular Engineering, Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA Bin Wang Department of Plastic and Reconstructive Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Tissue Engineering Key Laboratory, National Tissue Engineering Center of China, Shanghai, P.R China Cortes Williams School of Biomedical Engineering, University of Oklahoma, Norman, OK, USA Guang Yang Center for Cellular and Molecular Engineering, Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA Dimitrios I Zeugolis Regenerative, Modular & Developmental Engineering Laboratory (REMODEL), Biosciences Research Building, National University of Ireland Galway (NUI Galway), Galway, Ireland; Network of Excellence for Functional Biomaterials (NFB), Biosciences Research Building, National University of Ireland Galway (NUI Galway), Galway, Ireland; Centre for Research in Medical Devices (CURAM), Biosciences Research Building, National University of Ireland Galway (NUI Galway), Galway, Ireland Xinzhi Zhang Biomaterials and Interface Tissue Engineering Laboratory, Department of Biomedical Engineering, Columbia University, New York, NY, USA PREFACE In a world of scientific and technological advances, the ability to rebuild or recover tissue function at a clinically significant scale would potentially revolutionize therapeutics in biomedicine applications considering a wide spectrum of tissues prone to injury, disease, and degeneration Tissue engineering and regenerative medicine are recent scientific fields proposing alternative strategies to solve problems and limitations in clinics that are not functionally overcome by current therapies and procedures to achieve the regeneration of damaged tissues Promising tools on tissue engineering and regenerative medicine approaches in general and tendon-related strategies in particular are moving forward bringing new insights on the complex regenerative versus repair mechanisms involved In recent years, research has focused more attention to tendon tissues, unveiling aspects of tendon’s intrinsic morphology, architecture, and functionality The pivotal role of tendons in joint mechanics and movement implies well-established natural mechanisms of action under permanent and fine-tuned adjustments to balance the forces and loadings in order to adapt to changes in the environment Although walking, running, or standing may be simple and easily achieved mechanisms in daily activities, the complex dynamics involved challenges researchers to combine creativity and knowledge aiming at restoring tissue morphology, architecture, and ultimately tissue functionality Since tendons are connective tissues being mainly composed by an extracellular matrix (ECM), a supportive structure to sustain and transmit the loadings and strains of tendons, ECM analogs, or substitutes may be an interesting starting point to investigate in a regenerative strategy Although many scaffolds have been designed using different biomaterials and fabrication methodologies, there is limited success in current scaffold designs as novel approaches imply that biomaterial scaffolds should provide more than temporary architectural support to meet native tendon requirements It is widely accepted though that it is crucial to learn from native tendons, understanding the biomechanical cues and architectural phenomena so that the structural composition and organization can be replicated and to assist the design of smart and responsive biomaterials with multifunctional parameters with a new level of sophistication in order to provide the best cellular recognition with improved mechanical properties The fact that tendon architecture adapts to balance the changes in mechanical stresses and that stress forces are also dependent on the functional role, and consequently on the anatomical site, customization of strategies may be required to fulfill tendon specific requirements and restoration of local functionality xv xvi Preface Moreover, some lesions are more prone to occur in different areas within the tendon but also at the tendon interfaces, namely tendon–bone junction and muscle–tendon enthesis Thus, gradient scaffolds combining both aspects of the interface tissue may be also useful to treat these lesions Ideally, custom-made scaffold would be the preferred choice A scaffold adjusted to the defect dimensions, to the biomechanical properties, to the anatomical location, and to tissue skeletal maturity would fit all the criteria for a successful scaffold as a temporary template for promoting tendon regeneration Ultimately, tendon regeneration involves the complete restoration of morphology, biochemically and biomechanical properties of the tissue which are critically fine tuned to achieve tissue function that is often jeopardized through spontaneous healing and frequently results in the formation of scar tissue In spite of the growing understanding on the roles of the biological entities, resident or stem cells, on the actuation of bioactive molecules such as growth factors, or on the establishment of tenogenic markers, the temporal and sequential process that defines the biological cascade responsible to modulate cell behavior and guidance toward a successful mechanism of regeneration has not been discovered, and requires additional considerations for the management of tendon pathologies Despite the scientific effort in developing and validation of new strategies using the traditional pillars of tissue engineering, alone or in combination, few bioengineered products have successfully reached the market with a slow translation into clinical practice Up to date, and to editors’ knowledge, no tendon tissue engineered product has been commercialized, with the exception of biological scaffolds, often obtained from mammalian-derived tissues, and synthetic scaffolds commonly used in graft augmentation devices The major goal of this book was to update and gather all the information from recent years in the field of tendon tissue regeneration so as to provide a state-of-the-art scientific document covering fundamental aspects of the tendon tissue that must be considered when designing regenerative strategies Hot topics on recent findings from a developmental biology perspective to current pathologies and treatments have been identified in this volume and could act as a holistic platform for guidance into innovative strategies aiming at tendon regenerative medicine With this book, the editors of Tendon Regeneration intend to leave a door open to the continuity of innovative strategies and challenges while sharing ideas from a biologic to a clinical point of view to be developed, designed, updated, or rethought in forthcoming studies under the tendon regeneration thematic, combining perspectives reunited in this publication and beyond Manuela E Gomes Rui L Reis Márcia T Rodrigues CHAPTER Tendon Physiology and Mechanical Behavior: Structure–Function Relationships Chavaunne T Thorpe1, Helen L Birch2, Peter D Clegg3, Hazel R.C Screen1 1Institute of Bioengineering, School of Engineering & Materials Science, Queen Mary University of London, London, UK; of Orthopaedics and Musculoskeletal Science, University College London, Stanmore, UK; 3Department of Musculoskeletal Biology, Institute of Ageing and Chronic Disease, University of Liverpool, Leahurst Campus, Neston, UK 2Institute Contents Tendon Structure and Composition 1.1 Collagens 1.2 Proteoglycans 1.3 Glycoproteins and Other Molecules 1.4 Cells 1.5 Bone Insertion 1.6 Myotendinous Junction Tendon Mechanics 2.1 In Vitro Mechanical Testing 2.2 In Vivo Mechanical Testing 2.3 Viscoelasticity Multiscale Mechanics and Structure–Function Characterization 3.1 Macroscale Mechanics 3.2 Microscale Mechanics 3.3 Nanoscale Mechanics 3.4 Multiscale Structure–Function Mechanistic Studies 3.5 Enzymatic Depletion Studies 3.6 Mouse Knockout Studies Mechanical and Compositional Variations in Tendons with Different Functions 4.1 Variations in Tendon Mechanical Properties According to Tendon Function 4.2 Whole Tendon Properties 4.3 Variations in Fascicle-Level Mechanical Properties 4.4 Variations in Mechanical Properties at the Fiber (Microscale) Level 4.5 Variations in Mechanical Properties at the Fibril (Nanoscale) Level 4.6 Variations in Tendon Composition According to Tendon Function 4.7 Variation in Tendon Collagen 4.8 Variation in Collagen Cross-Links 4.9 Variation in Collagen Aggregates 4.10 Variation in Noncollagenous Components 4.11 Variation in Muscle–Tendon Relationship Tendon Regeneration http://dx.doi.org/10.1016/B978-0-12-801590-2.00001-6 6 8 10 10 11 13 15 17 18 19 21 22 23 23 24 24 24 25 26 27 28 28 29 30 31 32 Copyright © 2015 Elsevier Inc All rights reserved Tendon Regeneration 4.12 Variation in Cell Density 33 4.13 Differences in Gene Expression 33 4.14 Differences in Matrix Turnover 34 4.15 Adaptability and Cell-Mediated Behavior 34 List of Abbreviations 35 Glossary35 References35 1. TENDON STRUCTURE AND COMPOSITION Tendons are fibrous soft tissue structures that connect muscle to bone Their primary function is to act as passive, relatively inelastic structures, to allow force from muscle to be applied to bone However, specific tendons, for example, the equine superficial digital flexor tendon (SDFT) and the human Achilles tendon, have additional functional specializations to allow energy storage [1] They act like highly adapted elastic springs that stretch and store energy, which they can then return to the system through elastic recoil, to improve locomotory efficiency This variability in tendon function requires differences in tendon structure The main component of tendon is water, which makes up 55–70% of the wet weight of a tendon The major molecular components of the tendon extracellular matrix are collagens, which make up 60–85% of the tendon dry weight [2] Tendons have a hierarchical organization, with the highly aligned collagen fibers arranged in a longitudinal manner, parallel to the mechanical axis, to develop a structure that has a high tensile strength (Figure 1) Each level of this collagen-rich hierarchy is interspersed with varying amounts of noncollagenous extracellular matrix [3,4] Figure 1 Schematic showing the hierarchical structure of tendon, in which collagen molecules assemble to form subunits of increasing diameter 430 Tendon Regeneration [36] Oh JH, Kim SH, Ji HM, Jo KH, Bin SW, Gong HS Prognostic factors affecting anatomic outcome of rotator cuff repair and 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2008 [Ref Type: Abstract] 437 INDEX Note: Page numbers followed by “f ” and “t” indicate figures and tables respectively A A disintegrin and metalloproteinases (ADAMs), 160–161 Abnormal loading, 161–163, 165 Acellularized tissue-based scaffold, 391–392 Achilles tendinopathy, 215–216 See also Elbow tendinopathy Achilles tendon, 153, 153f, 282, 303–304 mechanics, 14 in rabbit model, 393 ACL See Anterior cruciate ligament (ACL) Acromion morphology, 155, 156f Actin, 101–102 Activin receptor-like kinases (ALKs), 68–69 ADAMs See A disintegrin and metalloproteinases (ADAMs) ADAMs with thrombospondin motifs (ADAMTSs), 160–161 Adaptability, 34 Adipose stem cells (ASCs), 194, 286–287 Adipose-derived stem cells (ADSCs), 331, 382 Adult tendon, 78–79 See also Embryonic tendon; Flexor tendon regenerative approach compressive and shear loads, 89–90 exercise studies, 94 biochemical changes, 95–96 exercise-induced mechanical loading of tendons, 95 immature collagen, 96 mechanical loading, 96 mechanical properties, 94–95 motion-induced loading, 97 muscle-induced loading, 97–98 tendon degradation, 97 structure, 84 tensile loads, 89 in vitro studies compressive loads, 99–100 elastic modulus, 101 shear stress, 100–101 tensile loads, 98–99 AFM See Atomic force microscopy (AFM) Age, 154–155 ALKs See Activin receptor-like kinases (ALKs) Allograft scaffolds, 245–247 αSMA, 65–66 Angiogenesis, 165 Angiopoietin-like (ANGPTL4), 165 Animal model, 390, 393–395 Animal studies, 367–369 Anisotropic electrospun fibers, 228–229 mechanical properties of electrospun scaffolds, 230t multihierarchical scaffolds, 230–231 non-cross-linked fibers, 229f tendon repair, 229–230 Anisotropic imprinted substrates, 231–233 Anisotropic self-assembled fibers, 227–228 Anisotropic sponges, 226–227 Anterior cruciate ligament (ACL), 157, 247, 265 Arginine-glycine-aspartic acid (RGD), 361–362 ASCs See Adipose stem cells (ASCs) Atomic force microscopy (AFM), 21, 21f Autologous cells, 193 B BAPN See β-aminopropionitrile (BAPN) Basic fibroblastic growth factor (bFGF), 284 β-aminopropionitrile (BAPN), 86–87 bFGF See Basic fibroblastic growth factor (bFGF) Biglycan (Bgn), 53 Bioactive scaffolds, 251 Biologic-derived scaffolds, 245–247 See also Extracellular matrix (ECM) Biological grafts, 416–417 Biological tissues, 272 Biomaterial(s) cellular response to, 365–366 composition, 354–356 mechanics, 358–359 structural properties, 356–358 for tissue regeneration, 355f Biomolecules presentation, 361–362 bioprinting, 365 growth factors and, 362 photolithography-based methods, 363 proteoglycan–protein interactions, 364 439 440 Index Biophysical treatments, 138 ESWT, 138–139 laser therapy, 139 LIPUS, 139 Bioplotting See 3D deposition process Bioprinting, 365 Bioreactor(s) system, 382 in tendon regeneration models, 401 engineered tendons after in vivo implantation, 407f extensor tendon complex scaffold, 404f gross view of in vitro engineered tendons, 402f H&E staining, 405f histology of in vivo engineered tendons with H&E staining, 408f for mechanical stimulation, 403–405 scaffolds, 406–407 for tendon tissue engineering, 327f, 337 Blood injections, PRP vs., 214 Blood products, 140 Blood supply, 118 BMP See Bone morphogenetic protein (BMP) BMSCs See Bone marrow stem cells (BMSCs) Body habitus, 155 Bone insertion, 9–10 Bone marrow stem cells (BMSCs), 194, 286–287, 382, 384–387 Bone marrow-derived stem cells See Bone marrow stem cells (BMSCs) Bone morphogenetic protein (BMP), 44, 127–128, 287, 333 BMP-2, 167, 251 BMP-12, 335–336, 387 BMP-13, 335–336, 421–422 Botox See Botulinum toxin A (Botox) Botulinum toxin A (Botox), 173 Braided scaffolds, 249–250 Braided submicron fibrous scaffolds (BSMFSs), 390 Braiding techniques, 273, 275f BSMFSs See Braided submicron fibrous scaffolds (BSMFSs) Bupivacaine, PRP vs., 213 Bursitis, 153 C C cysteine-rich protein, 93 C-PCL nanofibers See Chitosan-poly-caprolactone nanofibers (C-PCL nanofibers) Ca-P matrix See Calcium-phosphate matrix (Ca-P matrix) Calcific tendonitis, 157 Calcified insertional Tendinopathy, 115–116 Calcitonin gene-related peptide (CGRP), 130 Calcium-phosphate matrix (Ca-P matrix), 207–208 Callus formation orchestration, 129 neoinnervation and neovascularization, 130–132 sensory neuropeptide localization in healing, 132f tendon healing emergence of neuropeptides, 131f neuronal plasticity, 131f neuroanatomy, 130f Callus production, 127–129 BMP, 128 insulin-like growth factor, 128 neuropeptides, 128 stem cells and gene therapy, 129 tendon response to exercise, 127f to neuropeptide supplement, 129f TGF-β, 128 Cartilage oligomeric matrix protein (COMP), Cartilage tissue, 163–165 Cartilage-derived morphogenic protein-2 See Growth differentiation factor-6 (GDF-6) Cartilaginous markers, 160 CD80 See Cluster of differentiation 80 (CD80) CDET See Common digital extensor tendon (CDET) Cell-based tendon tissue engineering See also Tendon endogenous regeneration alternative stem cells sources, 193 ESCs, 193–194 Fetal fibroblasts, 193–194 iPSCs, 193–194 MSCs, 194–196 Cell-mediated behavior, 34 Cell-mediated strategies, 188 Cell(s), 8–9, 283 BMP, 333 cell-based therapies, 187 donor site morbidity, 285 low oxygen tension culture, 284 niches, 187–188 phenotypic drift of tenocytes in culture, 285f tendon stem/progenitor cells, 286 tendon tissue engineering strategies with MSCs, 332 tendon-centric developments, 287 Index tenocytes isolation, 284 for tissue-engineered construct, 331 variation in density, 33 in vitro MSCs, 287 Cell–biomaterial interactions biomolecules presentation, 361–365 cellular response to biomaterials, 365–366 mechanical stimulation, 366–367 tendon-inspired materials creation techniques, 359–361 Cellular manifestations, 118 CG scaffolds See Collagen-GAG scaffolds (CG scaffolds) CGRP See Calcitonin gene-related peptide (CGRP) Chemical modulators, 169 BMP family, 171 FGF, 170 IGF-1, 169–170 IL-1β, 170 MMP family, 169 NO, 171 PDGF, 170 PGE2, 171 Substance P, 171 TGF, 170 TNF-α, 171 VEGF, 170 Chemical stimulation, 335–336, 340–341 Chitosan, 294 Chitosan-poly-caprolactone nanofibers (C-PCL nanofibers), 57–58 Chondrocytes, 55–56 Chondroitinase, 23 Chronic paratendinopathy, 115, 153 Clinics, moving cell therapies into, 197–198 Clostridial collagenase, 192 Clostridiopeptidase A, 192 Clostridium histolyticum(C histolyticum), 192 Cluster of differentiation 80 (CD80), 190 Col1A1 See Collagen type I (COLI) Col5A1, 157 COLI See Collagen type I (COLI) Collagen aggregates, variation in, 30–31 Collagen cross-links, variation in, 29–30 Collagen oligomeric matrix protein (COMP), 53–54 Collagen type I (COLI), 49–52, 78–79, 190 fibrils, 225–226 Collagen-GAG scaffolds (CG scaffolds), 356 Collagen(s), 6, 7f, 355–356 collagen-based scaffold, 391 collagen-III, collagen-V, electrochemically aligned, 269–270 fibers hierarchical structure, 51f number and diameter, 51–52 fibrils, 5, 10 gels, 293 microfibers, 227 properties of self-assembled collagen fibers, 228t sponges, 297–298 Collagenase-induced tendinosis models, 167 Common digital extensor tendon (CDET), 24 COMP See Cartilage oligomeric matrix protein (COMP); Collagen oligomeric matrix protein (COMP) Complex scaffold design for insertion regeneration, 424 biphasic scaffold, 426f for integrative tendon–bone repair, 424t rotator cuff tendon–bone repair, 426–427 tendon–bone insertion, 425–426 Compressive loads, 89–90, 92–93, 99–100 Conduction of ingrowth, 132–133 Corticosteroids, 139–140 PRP vs, 214 COX-2 See Cyclooxygenase-2 (COX-2) Crimp, 82 Custom bioreactors design, 309–311 Cyclooxygenase-2 (COX-2), 165 Cytochalasin B, 99–100 D d-tubocurarine, 91 DASH See Disabilities of the Arm, Shoulder and Hand (DASH) DCN See Decorin (DCN) Decellularization, 330 Decorin (DCN), 7, 7f, 53, 190 Dehydro-hydroxylysinonorleucine (Dehydro-HLNL), 29 Dermal fibroblasts, 383 Diabetes, 156 Direct mechanical injury, 159–160 Disabilities of the Arm, Shoulder and Hand (DASH), 214 Distal autopodial tendons, 43f Doppler ultrasound, 151–152, 152f Dyxin, 93 441 442 Index E Early postnatal tendon development, 83 density and expression of gap junctions, 83 fibrocartilage regions of tendon, 84 Eccentric exercises, 134 collagen synthesis and collagen fiber cross-linking, 137–138 concentric training, 136 eccentric squats exercises for patellar tendon, 137f intention-to-treat analysis, 138 nerve fibers, 138 tendinopathic locations, 136 ECM See Extracellular matrix (ECM) Economic cost, 150 EDC See 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC); N-(3-dimethylaminopropyl)-N’ethylcarbodiimide hydrochloride (EDC) EGDE See Ethylene-glycol-diglycidyl-ether (EGDE) EGF See Epidermal growth factor (EGF) Ehlers–Danlos syndrome, 157 ELAC See Electrochemically aligned collagen (ELAC) Elastic fibers, Elastic modulus, 93–94, 101 Elastin, 8, 53–54 Elbow tendinopathy See also Achilles tendinopathy PRP injections, 213 vs Blood Injections, 214 vs Bupivacaine, 213 vs Corticosteroids, 214 Electrochemically aligned collagen (ELAC), 57–58, 261 Electrospinning, 228–229, 263–264, 360 See also Anisotropic electrospun fibers crimped scaffolds, 265–266 hTDCs, 264, 264f 3D nanoyarn networks, 266–268 Embryonic paralysis studies, 78 Embryonic stem cells (ESCs), 193–194, 286, 382 Embryonic tendon See also Adult tendon ECM composition, 79 growth factors and fibrillogenesis, 82 mechanical properties and contributors, 84 collagen cross-linking, 86–87 ECM, 87–89 FV-AFM, 85–86 mechanical testing, 87 tendon elastic modulus for, 88t parallel fibril and fiber formation, 80 crimp, 82 GPC, 81 tendon extracellular matrix and cells, 80f studies in embryo suggest mechanical factors influencing, 90–91 tensile loads, 89 in vitro studies suggesting mechanical factors compressive loads, 92–93 elastic modulus, 93–94 shear stresses, 93 tensile loads, 91–92 Endotendon, 5, 51–52, 322 Energy storing, 24–26, 28, 30–31 Enthesis, 9–10 Enthesopathy See Insertional tendinopathy Enzymatic depletion studies, 23 Eph-A4 transcripts, 42–44 Epidermal growth factor (EGF), 196 Epitenon, ERK pathway See Extracellular signal-regulated kinase pathway (ERK pathway) Erm See Ets-related molecule (Erm) ESCs See Embryonic stem cells (ESCs) ESWT See Extracorporeal shock wave treatment (ESWT) 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), 262 Ethylene-glycol-diglycidyl-ether (EGDE), 262 Ets-related molecule (Erm), 46–47 Ex vivo approach of tendon engineering, 391 Excess loading, 158 Exercise-induced mechanical loading of tendons, 95 External tendon activation, 134 Extracellular matrix (ECM), 4, 8–9, 116, 118, 151, 187, 206, 245, 259–260, 284, 323, 349, 382, 416 ECM-derived scaffolds, 245 allograft scaffolds, 245–247 xenograft scaffolds, 247 proteins, 42, 78–79 Extracellular signal-regulated kinase pathway (ERK pathway), 46–47 Extracorporeal shock wave treatment (ESWT), 138–139 Index Extrinsic causes, 157 See also Intrinsic causes compression, 159 disuse, 159 excess loading, 158 exogenous damage, 159–160 fatigue loading, 158 improper loading, 158–159 Extrinsic healing, 171–172 Extrinsic injuries, 413–415 Extruded collagen fibers, 227 Eyes absent gene (Eya gene), 42–44 F Fabrication, 261–262, 267 FACIT helices See Fibril-associated collagens with interrupted triple helices (FACIT helices) FAK pathway See Focal adhesion kinase pathway (FAK pathway) Familiar hypercholesterolemia, 120 Fascicles, 5, 322 Fatigue loading, 158 FDA See US Food and Drug Administration (FDA) FDS See Flexor digitorum superficialis (FDS) Fetal fibroblasts, 193–194 FGF See Fibroblast growth factor (FGF) Fiber-based scaffolds braided scaffolds, 249–250 knitted scaffolds, 250 woven scaffolds, 249–250 Fibers, 322 Fibril-associated collagens with interrupted triple helices (FACIT helices), 51–52 Fibrillar crimp, 30–31 Fibripositors, 62–63 Fibroblast growth factor (FGF), 46–47, 91–92, 126–127, 170 FGF-1, 170 FGF-2, 170, 330–331 Fibrocartilaginous enthesis, 9–10 Fibromodulin (Fmod), 53 Fibronectin, 53–54 Fibrous biomaterials assembly, 273–274 Fibrous enthesis, 9–10 Five-lipoxygenase activating protein (FLAP), 165 Flatfoot See Pes planus Flexor digitorum superficialis (FDS), 301 Flexor tendon regenerative approach See also Adult tendon; Embryonic tendon; Multifactoral tendon tissue engineering strategies engineered sheath, 399f repair, 398–401 engineered tendons gross views and histology, 396f repair in porcine model, 397f H&E staining of scar-repaired surrounding tissues, 400f in hen and porcine models, 393–395 tendon sheath, 395–398 WOF ratio, 401f Flexor tendons, 301–303 Fluoroquinolones, 159 Fmod See Fibromodulin (Fmod) Focal adhesion kinase pathway (FAK pathway), 67–68, 296, 366–367 Follistatin, 42–44 Force volume-atomic force microscopy (FV-AFM), 85–86 Freeze-drying, 226–227, 360–361 Functional scaffolds, 251 Functional specialization, Functional tendon tissue engineering, 325 cells, 331–333 chemical stimulation, 335–336 mechanical stimulation, 333–335 scaffolds, 325–331 FV-AFM See Force volume-atomic force microscopy (FV-AFM) G GAG See Glycosaminoglycan (GAG) GDF See Growth differentiation factor (GDF) Gene expression differences in, 33 and markers, 324–325 Gene therapy, 129 Gene transfer-based techniques, 251 Genetics, 157 GF See Growth factors (GF) Glycoproteins, 8, 53–54 Glycosaminoglycan (GAG), 6–7, 52–53, 84, 151, 225–226, 350–351, 419–420 Golgi-to-plasma membrane carriers (GPCs), 81 Gore-Tex graft, 418 GPCs See Golgi-to-plasma membrane carriers (GPCs) Grafts, rotator cuff tendon augmentation, 415–416 biological grafts, 416–417 synthetic grafts, 417–419 443 444 Index Growth differentiation factor (GDF), 171, 383 GDF-5, 332–333, 361 GDF-6, 287, 335–336 GDF-7, 287, 335–336 Growth factors (GF), 126, 206, 362, 422–423 IGF-I, 209 PDGF, 208–209 TGF-β, 206–208 VEGF, 208 H HA See Hyaluronic acid (HA); Hydroxyapatite (HA) hAFSCs See Human amniotic fluid stem cells (hAFSCs) Hamburger–Hamilton stages (HH stages), 42–44, 81 HARP See Heparin affine regulatory peptide (HARP) Healing callus modification external tendon activation, 134 immobilization, 133, 134f–135f mobilization, 133, 134f–135f Healing response, 168–169 Hen and porcine models engineered sheath, 399f repair, 398–401 engineered tendons gross views and histology, 396f repair in porcine model, 397f flexor tendon regenerative approach in, 393–395 H&E staining of scar-repaired surrounding tissues, 400f tendon sheath, 395–398 WOF ratio, 401f Heparin affine regulatory peptide (HARP), 163–165 Hepatocyte growth factor (HGF), 188–189 hESC-derived MSCs (hESC-MSCs), 193–194 hESCs See Human ESCs (hESCs) HGF See Hepatocyte growth factor (HGF) HH stages See Hamburger–Hamilton stages (HH stages) HHL See Histidino-hydroxylysinonorleucine (HHL) HHMD See Histidinohydroxymesodesmosine (HHMD) Hierarchical structure, tendon, 269 hiPSC-MSCs See Human-induced pluripotent stem cell-derived mesenchymal stem cells (hiPSC-MSCs) Histidino-hydroxylysinonorleucine (HHL), 29 Histidinohydroxymesodesmosine (HHMD), 29 HL-Pyr See Hydroxylysyl-pyridinoline (HL-Pyr) Homeostasis, 78 hTDCs See Human tenocytes (hTDCs) Human amniotic fluid stem cells (hAFSCs), 196 Human ESCs (hESCs), 388 Human patellar tendon cells, 99 Human soleus muscle, 32–33, 32f Human tenocytes (hTDCs), 264, 264f Human umbilical vein (HUV), 326, 326f Human-induced pluripotent stem cell-derived mesenchymal stem cells (hiPSC-MSCs), 194, 273–274 HUV See Human umbilical vein (HUV) Hyaluronic acid (HA), 261–262 Hybrid/composite scaffolds, 250 Hydrogels, microengineered, 270 See also Tendons interfacial polyelectrolyte complexation, 272 microfabrication with chemical interactions, 273f microfluidics, 271–272 microfluidic spinning, 271–272 Hydroxyapatite (HA), 419–420 Hydroxylysine residues, 50–51 Hydroxylysyl-pyridinoline (HL-Pyr), 29 Hypoxia, 118, 122–123 Hysteresis, 15–16 I IGF See Insulin-like growth factor (IGF) IL-1 See Interleukin-1 (IL-1) IL-6 See interleukin-6 (IL-6) Immature collagen, 96 Immobilization, 133, 173–174 Immunocompromised models, 393 Improper loading, 158–159 In vitro mechanical testing, 11 quasi-static mechanical properties of tendons, 13 single value of modulus calculation, 12–13 stress–strain curve for tendon, 11–12, 12f–13f In vitro tendon engineering, 382–383, 390–391, 401 In vivo mechanical testing, 13, 14f Achilles tendon mechanics, 14 automated tracking of MTJ, 15 functional movements, 15 moment arm, 15 relationships between applied force and material extension, 14 Index In vivo tendon engineering, 394f gross views and histology, 396f hen and porcine models, 393–401 immunocompromised models, 393 rabbit model, 393 induced pluripotent stem cells (iPSCs), 193–194, 388 Induced-paralysis studies of neonatal mice, 78 Induction of healing, 126 platelets, 126–127 Inflammatory arthropathies, 157 Inflammatory molecules, 124 Injection therapies, 139 blood products, 140 corticosteroids, 139–140 sclerotherapy, 140 Insertional tendinopathy, 115–116 Instructive biomaterials, passive biomaterials vs., 354 Insulin-like growth factor (IGF), 128 IGF-1, 126–127, 169–170, 188–189, 206, 209, 284, 336 Intact tendons, 116 Integrative rotator cuff tendon–bone repair, 419 tendon–bone insertion characterization, development, and healing, 419–421 tissue engineering strategies, 421 complex scaffold design for insertion regeneration, 424–427 nonscaffold-based approach, 421–424 Intention-to-treat analysis, 138 Interfacial polyelectrolyte complexation, 272 Interfascicular matrix (IFM) See Endotendon Interleukin-1 (IL-1), 351 IL-1β, 165 interleukin-6 (IL-6), 188–189 Intermittent pneumatic compression (IPC), 134, 136f Intrinsic causes, 154 See also Extrinsic causes age, 154–155 body habitus, 155 genetics, 157 metabolic diseases, 156–157 nutrition, 156 Intrinsic healing, 171–172 Intrinsic injuries, 413–415 IPC See Intermittent pneumatic compression (IPC) iPSCs See induced pluripotent stem cells (iPSCs) K Knitted scaffolds, 250 L L-PRP See leukocyte-rich PRP (L-PRP) L-Pyr See Lysyl-pyridinoline (L-Pyr) Laser therapy, 139 leukocyte-rich PRP (L-PRP), 209–210 LIPUS See Low-intensity pulsed ultrasound (LIPUS) Lithography, 231 advantages and disadvantages, 232t LLLT See Low-level laser therapy (LLLT) Local steroid injection, 159 Low-intensity pulsed ultrasound (LIPUS), 139 Low-level laser therapy (LLLT), 139 LOX See Lysyl oxidase (LOX) Lubricin, Lumican, 53, 93 Lyophilization, 360–361 Lysyl oxidase (LOX), 86–87 Lysyl-pyridinoline (L-Pyr), 30 M Macroscale mechanics, 18–19 Magnetic resonance imaging (MRI), 151–152, 214–215 MAPK See Mitogen-activated protein kinase (MAPK) MAPK phosphatase (Mkp3), 46–47 Material fabrication techniques, 57 Matrix metalloproteinases (MMPs), 33, 96, 154–155, 207, 351 MMP-3, 120 MMP-13, 289 Matrix turnover, differences in, 34 Mature collagen protein synthesis, 50–51 MDCs See Muscle-derived cells (MDCs) Mechanical stimulation, 295, 333, 366–367 cell–cell and cell–matrix adhesions, 296 collagen sponges, 297–298 creation of extensor tendon complexes, 300f cyclical stimulation of rabbit MSCs, 297 cytoskeletal organization, 296–297 dynamic strain, 338 high-intensity stretching, 339 mechanical force, 295 mechanotransduction, 333–334 MSCs, 334–335 OPF, 339 PGA fibers, 299 TDSCs, 335 for tendon tissue engineering, 337 445 ... in tendon function requires differences in tendon structure The main component of tendon is water, which makes up 55–70% of the wet weight of a tendon The major molecular components of the tendon. .. time-dependent element to tendon behavior However, regions of tendon require different properties, and tendon structure and composition often varies longitudinally within a tendon Regions of tendons that... decorin in tendon time-dependent behavior, but provide little evidence for a role of decorin in contributing to tendon tensile strength 23 24 Tendon Regeneration The role of other PGs in tendon has