Bone repair biomaterials: regeneration and clinical applications 9780081024515, 9780081024522, 2332332332, 0081024517, 0081024525

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Bone Repair Biomaterials

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Woodhead Publishing Series in Biomaterials

Bone Repair Biomaterials Regeneration and Clinical Applications Second Edition

Edited by

Kendell M. Pawelec Josep A. Planell

Woodhead Publishing is an imprint of Elsevier The Officers’ Mess Business Centre, Royston Road, Duxford, CB22 4QH, United Kingdom 50 Hampshire Street, 5th Floor, Cambridge, MA 02139, United States The Boulevard, Langford Lane, Kidlington, OX5 1GB, United Kingdom Copyright © 2019 Elsevier Ltd. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein). Notices Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library ISBN (Print): 978-0-08-102451-5 ISBN (Online): 978-0-08-102452-2 For information on all Woodhead Publishing publications visit our website at https://www.elsevier.com/books-and-journals

Publisher: Mathew Deans Acquisition Editor: Sabrina Webber Editorial Project Manager: Charlotte Rowley Production Project Manager: Debasish Ghosh Cover Designer: Miles Hitchen Typeset by TNQ Technologies

Contents

List of contributors

xi

1 Introduction to the challenges of bone repair Kendell M. Pawelec 1.1 Introduction 1.2 Social and economic impact of bone repair 1.3 Some clinical challenges of bone repair 1.4 Role of biomaterials in bone repair 1.5 Conclusions References

1 1 2 7 8 10 10

2 Bone biology Robyn K. Fuchs, William R. Thompson and Stuart J. Warden 2.1 Introduction 2.2 Bone anatomy 2.3 Bone physiology 2.4 Bone adaptation to mechanical loading 2.5 Conclusion References

15

3 Biomechanical aspects of bone repair Damien Lacroix 3.1 Bone composition and structure 3.2 Biomechanical properties of bone 3.3 Bone damage and repair 3.4 Conclusions References Bibliography

53

4 Properties and characterization of bone repair materials Kendell M. Pawelec, Ashley A. White and Serena M. Best 4.1 Introduction 4.2 Mechanical properties 4.3 Architectural and microstructural properties 4.4 Physiological effects 4.5 Comparing material classes 4.6 Summary References

65

15 15 25 31 40 40

53 55 60 62 62 64

65 66 76 84 91 95 96

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5 Metals JL González-Carrasco, SC Cifuentes Cuellar and M Lieblich Rodríguez 5.1 Introduction 5.2 Common metallic biomaterials 5.3 Other metallic materials 5.4 Properties 5.5 Trends in the development of metallic biomaterials 5.6 Conclusions Acknowledgments References

Contents

103 103 105 111 115 122 132 133 133

6 Ceramics as bone repair materials 141 María Vallet-Regí and Antonio J. Salinas 6.1 Overview of ceramics in biomedical engineering 141 6.2 Almost bioinert ceramics: first-generation bioceramics 146 6.3 Biodegradable and bioactive ceramics: second-generation bioceramics151 6.4 Ceramics in bone regeneration: third-generation ceramics 164 6.5 Bioceramics perspectives for the future 168 Acknowledgments 168 References 168 7 Polymers for bone repair Sergi Rey-Vinolas, Elisabeth Engel and MA Mateos-Timoneda 7.1 Introduction 7.2 Ultrahigh molecular weight polyethylene 7.3 Biodegradable polymers 7.4 Conclusions References

179

8 Natural polymers for bone repair GB Ramírez Rodríguez, TMF Patrício and JM Delgado López 8.1 Introduction and overview 8.2 Natural polymers 8.3 Bone regenerative therapies with multifunctional biomaterials of natural polymers 8.4 Outlook and future perspectives: natural templates fabricated by 3D bioprinting References

199

179 179 188 193 193

199 201 213 221 223

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9 Cements as bone repair materials Maria-Pau Ginebra and Edgar B. Montufar 9.1 Definition and advantages of bone cements in orthopedic surgery 9.2 Calcium phosphate versus acrylic bone cements: historical perspective and present applications 9.3 Acrylic bone cements 9.4 Calcium phosphate bone cements References

233

10 Composite biomaterials for bone repair Roberto De Santis, Vincenzo Guarino and Luigi Ambrosio 10.1 Introduction 10.2 Basic concept of composite material 10.3 Composite biomaterials in bone repair 10.4 Nondegradable composites 10.5 Biodegradable composites 10.6 Future challenges and opportunities References Further reading

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11 Bone repair biomaterials in orthopedic surgery Antonio Merolli 11.1 Introduction 11.2 Operative techniques 11.3 Materials 11.4 Devices 11.5 Conclusions References

301

12 Glass-ceramics for dental restoration Markus Rampf and Wolfram Höland 12.1 Introduction 12.2 Glass-ceramics in prosthodontics 12.3 Bioactive rhenanite-type glass-ceramics 12.4 Conclusion Acknowledgments References

329

13 Biomaterial in spinal surgery Maurizio Genitiempo 13.1 Introduction 13.2 Brief review of spinal anatomy 13.3 Biomechanics of the spine 13.4 Pathology of the spine and application of biomaterials

341

233 233 236 245 259

273 273 276 279 283 290 291 299

301 302 304 316 324 324

329 330 334 337 338 338

341 341 342 345

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13.5 Properties of biomaterials applied to spinal surgery 13.6 Spinal implant 13.7 Future trends of biomaterials applied to spinal surgery References

347 350 356 357

14 Using bone repair materials in maxillofacial and skull surgery Shahram Ghanaati and Sarah Al-Maawi 14.1 Introduction 14.2 Characteristics of bone repairing materials 14.3 Bone regeneration, bone augmentation, and bone reconstruction 14.4 Clinical insights 14.5 Conclusion References

361

15 Long-term performance and failure of orthopedic devices Adam C. Marsh, Natalia Pajares Chamorro and Xanthippi Chatzistavrou 15.1 Introduction 15.2 Wear 15.3 Mechanical failure 15.4 Loosening 15.5 Materials approach to prevent failure 15.6 Conclusion References

379



361 364 367 369 375 376

379 381 387 391 398 400 401

16 Emerging areas of bone repair materials: nucleic acid therapy and drug delivery 411 Phil Chambers, Helen O. McCarthy and Nicholas J. Dunne 16.1 Why nucleic acids for bone repair 411 16.2 The biological barriers to nucleic acid delivery systems in the bone environment 412 16.3 MicroRNA: the future of nucleic acid therapies for bone regeneration430 16.4 Final conclusions 434 References 435 Further reading 446 17 Retrieval, sample processing, and analyses of bone-anchored implants447 Magdalena Zaborowska, Furqan A. Shah, Margarita Trobos and Anders Palmquist 17.1 Introduction 447 17.2 Need for retrieval of clinical implants 449 17.3 Collection and transport of retrieved biological material 450 17.4 Sample processing and preparation 451

Contents



ix

17.5 Examples of results 17.6 Concluding remarks 17.7 Future perspectives 17.8 Ethical considerations 17.9 Bibliography Acknowledgments References

455 460 460 461 461 462 462

18 Ethical considerations in bone tissue-engineered products Whit Froehlich, Owen Brown and Christian Vercler 18.1 Introduction 18.2 Controversy and consensus 18.3 Sourcing of cells 18.4 Research: clinical trials 18.5 Therapeutic considerations 18.6 Conclusions References

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467 469 470 471 473 474 474

Index477

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List of contributors

Sarah Al-Maawi FORM, Frankfurt Oral Regenerative Medicine, Clinic for Maxillofacial and Plastic Surgery, Johann Wolfgang Goethe University, Frankfurt, Germany Luigi Ambrosio IPCB-CNR Institute for Polymers, Composites and Biomaterials National Research Council of Italy, Naples, Italy Serena M. Best University of Cambridge, Cambridge Centre for Medical Materials, Cambridge, United Kingdom Owen Brown University of Michigan Medical School, Ann Arbor, MI, United States Phil Chambers School of Pharmacy, Queen’s University of Belfast, Belfast, United Kingdom Natalia Pajares Chamorro Department of Chemical Engineering & Materials Science, Michigan State University, East Lansing, MI, United States Xanthippi Chatzistavrou Department of Chemical Engineering & Materials Science, Michigan State University, East Lansing, MI, United States SC Cifuentes Cuellar Departamento de Ciencia e Ingeniería de Materiales e Ingeniería Química, IAAB, Universidad Carlos III de Madrid, Madrid, Spain Roberto De Santis IPCB-CNR Institute for Polymers, Composites and Biomaterials National Research Council of Italy, Naples, Italy JM Delgado López Departamento de Química Inorgánica, Facultad de Ciencias, Universidad de Granada, Granada, Spain Nicholas J. Dunne School of Pharmacy, Queen’s University of Belfast, Belfast, United Kingdom; Centre for Medical Engineering Research, School of Mechanical and Manufacturing Engineering, Dublin City University, Dublin, Ireland; Trinity Centre for Bioengineering, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland; Department of Mechanical and Manufacturing Engineering, School of Engineering, Trinity College Dublin, Dublin, Ireland; School of Mechanical and Manufacturing Engineering of Ireland, Dublin City University, Dublin, Ireland

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List of contributors

Elisabeth Engel CIBER en Bioingeniería, Biomateriales y Nanomedicina (CIBERBBN), Barcelona, Spain; Biomaterials for Regenerative Therapies, Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology, Barcelona, Spain; Department of Materials Science and Metallurgical Engineering, Technical University of Catalonia (UPC), Barcelona, Spain Whit Froehlich University of Michigan Medical School, Ann Arbor, MI, United States Robyn K. Fuchs Department of Physical Therapy, School of Health and Human Sciences, Indiana University, Indianapolis, IN, United States; Indiana Center for Musculoskeletal Health, Indiana University, Indianapolis, IN, United States Maurizio Genitiempo Università Cattolica del Sacro Cuore, Spinal Unit, Gemelli Hospital of Rome, Rome, Italy Shahram Ghanaati FORM, Frankfurt Oral Regenerative Medicine, Clinic for Maxillofacial and Plastic Surgery, Johann Wolfgang Goethe University, Frankfurt, Germany Maria-Pau Ginebra Biomaterials, Biomechanics and Tissue Engineering Group, Department of Materials Science and Metallurgical Engineering, Universitat Politècnica de Catalunya, Barcelona Tech (UPC), Escola d’Enginyeria de Barcelona Est, Barcelona, Spain JL González-Carrasco Centro Nacional de Investigaciones Metalúrgicas (CENIMCSIC), Madrid, Spain Vincenzo Guarino IPCB-CNR Institute for Polymers, Composites and Biomaterials National Research Council of Italy, Naples, Italy Wolfram Höland Ivoclar Vivadent AG, Schaan, Liechtenstein Damien Lacroix Institute for Bioengineering of Catalonia (IBEC), Barcelona, Spain; Department of Mechanical Engineering, University of Sheffield, Sheffield, United Kingdom M Lieblich Rodríguez Centro Nacional de Investigaciones Metalúrgicas (CENIMCSIC), Madrid, Spain Adam C. Marsh Department of Chemical Engineering & Materials Science, Michigan State University, East Lansing, MI, United States MA Mateos-Timoneda CIBER en Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Barcelona, Spain; Biomaterials for Regenerative Therapies, Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology, Barcelona, Spain; Department of Materials Science and Metallurgical Engineering, Technical University of Catalonia (UPC), Barcelona, Spain

List of contributors

xiii

Helen O. McCarthy School of Pharmacy, Queen’s University of Belfast, Belfast, United Kingdom Antonio Merolli New Jersey Center for Biomaterials, Rutgers – The State University of New Jersey, Piscataway, NJ, United States; Orthopaedics & Trauma Surgery, The Catholic University in Rome Edgar B. Montufar Advanced Coatings Research Group, Central European Institute of Technology, Brno University of Technology, Brno, Czech Republic Anders Palmquist Department of Biomaterials, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden TMF Patrício IDI Group from Vangest, Complexo Industrial VANGEST, Marinha Grande, Portugal Kendell M. Pawelec University of Michigan, Ann Arbor, MI, United States GB Ramírez Rodríguez University of Insubria, Department of Science and High Technology (DiSAT), Como, Italy Markus Rampf Ivoclar Vivadent AG, Schaan, Liechtenstein Sergi Rey-Vinolas CIBER en Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Barcelona, Spain; Biomaterials for Regenerative Therapies, Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology, Barcelona, Spain Antonio J. Salinas Departamento de Química en Ciencias Farmacéuticas, Facultad Farmacia, Universidad Complutense, Madrid, Spain; Centro de Investigación Biomédica en Red: Bioingeniería, Biomateriales y Nanomedicina, CIBER-BBN, Madrid, Spain; Instituto de Investigación Hospital, Madrid, Spain Furqan A. Shah Department of Biomaterials, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden William R. Thompson Department of Physical Therapy, School of Health and Human Sciences, Indiana University, Indianapolis, IN, United States; Indiana Center for Musculoskeletal Health, Indiana University, Indianapolis, IN, United States Margarita Trobos Department of Biomaterials, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden María Vallet-Regí Departamento de Química en Ciencias Farmacéuticas, Facultad Farmacia, Universidad Complutense, Madrid, Spain; Centro de Investigación Biomédica en Red: Bioingeniería, Biomateriales y Nanomedicina, CIBER-BBN, Madrid, Spain; Instituto de Investigación Hospital, Madrid, Spain

xiv

List of contributors

Christian Vercler University of Michigan Medical School, Ann Arbor, MI, United States Stuart J. Warden Department of Physical Therapy, School of Health and Human Sciences, Indiana University, Indianapolis, IN, United States; Indiana Center for Musculoskeletal Health, Indiana University, Indianapolis, IN, United States Ashley A. White Lawrence Berkeley National Laboratory, Berkeley, CA, United States Magdalena Zaborowska Department of Biomaterials, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden

Introduction to the challenges of bone repair

1

Kendell M. Pawelec University of Michigan, Ann Arbor, MI, United States 

1.1   Introduction The musculoskeletal system has many key functions, from structural to metabolic. Playing a major role in the musculoskeletal system, bone is a complex tissue which is highly responsive to its environment. It is made up of around 25%–30% protein, mainly collagen type I, with a calcium phosphate ceramic, namely hydroxyapatite, making up the remaining 65%–70% of the dry mass. As a composite structure, with a remarkable hierarchical architecture, bone has unique mechanical properties allowing individuals to perform a wide range of activities [1]. To achieve these mechanics, two distinct types of bone exist within the body: cortical and trabecular bone. Cortical bone is a dense form of bone, which appears at the outer edges of long bones. Trabecular bone, on the other hand, is a very porous structure, made up of small compartments, known as trabeculae. Bone will remodel in response to mechanical cues throughout life by depositing mineral on concave surfaces of the bone and removing it from convex surfaces areas. In addition, the orientation and spacing of trabeculae is impacted by the mechanical load on the bone and adapts to changes in that loading. Factors such as the individual’s weight, physical activities, and gait play a role in determining the loading experienced by the skeletal system. This fulfills its most obvious function, as structural support for an individual, which not only aides in locomotion, but also protects sensitive tissues, such as the spinal cord and brain. Loss of bone’s structural features results in fragility of the bone and increases the risk of fractures and other trauma. In addition to structure, bone serves as a reservoir for many important metabolic ions, such as calcium and phosphates. These ions play important roles in signaling and in molecular energy storage. To regulate the level of ions systemically, bone must interact with many other organs within the body, such as muscle, kidneys, and liver [2]. This interaction is accomplished through hormones, either secreted from other organs, such as vitamin D and estrogen, or secreted from bone tissue, such as osteocalcin [3–5]. For example, osteocalcin is released in the blood, and when activated, it has a wide range of effects on muscle activity and insulin secretion [2,5]. The interconnection of many systems can manifest in chronic diseases, such as diabetes, liver disease, or kidney disease. In these cases, bone architecture is affected, reducing the structural stability of bone [2,6]. To maintain bone tissue, several cell types are active within the bone niche. Most importantly, these include osteoblasts, osteoclasts, osteocytes, and mesenchymal stem cells. Osteoblasts function primarily to deposit bone. Their activity is offset by Bone Repair Biomaterials. https://doi.org/10.1016/B978-0-08-102451-5.00001-9 Copyright © 2019 Elsevier Ltd. All rights reserved.

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Bone Repair Biomaterials

osteoclasts, large multinucleated cells, which are responsible for bone resorption [7]. Maintaining a tight balance between the two cell types is critical for the homeostasis of bone. When either resorption or deposition dominates, negative consequences result. Osteocytes, the most prevalent cell type, are found within the bone’s mineralized tissue. They form an interconnected network within the tissue and are believed to be derived from osteoblasts which become embedded in the matrix, and which undergo terminal differentiation. Given their position inside of the bone tissue, osteocytes are responsible for mechanical sensing in the bone, and can secrete factors which regulate osteoblast and osteoclast function [8]. Mesenchymal stem cells are located within the bone marrow, serving as a source for progenitor cells. It is their relative abundance and ease of proliferation which have made these stem cells interesting targets for cell therapies within the musculoskeletal system. When the delicate balance within bone tissue breaks down, whether from traumatic injury or chronic disease, the effect on quality of life can be devastating. The impact is multifaceted, requiring analysis of the direct costs of healthcare and the qualitative aspects of disease, such as pain. Given the high occurrence of musculoskeletal conditions, these disorders remain a key challenge for modern medicine. Likelihood of experiencing a musculoskeletal disease increases with age, but younger populations with high activity levels, such as athletes, also carry a higher risk of disease [9,10]. This chapter seeks to outline the social and economic impact of bone repair and highlight some of the key clinical challenges which must be met. This discussion encompasses several different areas within the musculoskeletal system: orthopedics, dentistry, maxillofacial, and spinal conditions. Finally, the role of biomaterials, and the opportunities in this field are considered, along with future trends for this area.

1.2  Social and economic impact of bone repair Diseases and trauma related to bone tissue can occur in many areas of the body. The lifetime risk for sustaining a fracture in the wrist, hip or vertebrae is estimated to be between 30% and 40% of the total population, in developed countries [11]. With the incidence of musculoskeletal trauma and disease so prevalent, the costs to society are considerable, and it has been ranked by the World Health Organization as a disease of enormous impact worldwide. The total costs vary, depending on the specific region of the world, and access to healthcare. However, in all cases, musculoskeletal disease carries a direct and indirect cost on the individual, which filters through to society, Fig. 1.1 [12]. Direct costs, those associated with the hospital, surgery, or medications, are easy to calculate. More challenging is estimating the additional indirect and intangible costs. Indirect costs are those which result from the disease, including missed work and follow on healthcare costs. In addition, the burden of disease can also be intangible: pain and loss of mobility [13,14]. These additional costs can be devastating to the individual and have a broader economic impact. These figures are only growing as the population ages, and as the prevalence of diseases such as obesity and diabetes increases.

Introduction to the challenges of bone repair

Direct costs Hospitalization Surgery Implants/hardware Medication

Indirect costs Loss of work Reduced mobility Continuing health care Physical therapy

3

Intangible costs Pain Impairment Depression

Figure 1.1  Many types of costs are associated with musculoskeletal disease, not all of which are readily quantifiable.

1.2.1   Orthopedics The burden of orthopedic ailments on society is extremely high. Falling into this general category of bone-related conditions are fractures in limbs. Under most circumstances, fractures in bone will heal naturally, with little intervention, providing both ends of the fracture are aligned and in close proximity. However, there are conditions when bone must be replaced. These include cases where fractures fail to heal, when large pieces of bone are lost during trauma, or when bone tumors are removed leaving a large gap. In addition to fractures, chronic conditions can negatively affect bone health. One such condition is osteoporosis, described as a loss of bone mass density, over 2.5 standard deviations below the average for healthy adults [11]. In addition to reduced bone density, the architecture of bone changes significantly. There is a decreased thickness in cortical bone and reduced number of trabeculae. Any alterations in bone structure will affect its ability to carry load. Reduction of the bone mass and structure increases the probability of fracture, even from very short falls. In elderly patients, especially women, osteoporosis can be associated with muscle loss (sarcopenia), as both muscle and bone are tied together through metabolic signaling [15]. When sarcopenia is present, increasing unsteadiness of mobility raises the likelihood of falls which result in a fracture [16]. Another major chronic disease, underlying many bone-related conditions which result in implants, is arthritis. Two types are known: osteoarthritis, the wearing away of bone, and rheumatoid arthritis, an autoimmune disease where cartilage is destroyed. These conditions are not limited to areas typically associated with orthopedics, but can affect any location within the body, especially the spine. Regardless, arthritis has many costs associated with it, especially due to the widespread prevalence of condition [17]. In 2003, 45 million adults (around 21% of the population) reported osteoarthritis in the United States, with over 16,500 reporting activity limitations due to the disease [18]. If current trends continue, it is estimated that up to a third of adults (age 45–64) in the United States will be diagnosed with osteoarthritis by 2030 [18]. This estimate may prove conservative, depending on how the economy fares, the average working age, and the prevalence of other diseases such as obesity [18]. In addition, arthritis has a high incremental cost over an individual’s lifetime [14]. Of the total osteoarthritis reported, a fraction is job-related, with

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estimates reaching up to 15% [19]. Lost productivity in the workplace is believed to represent 49% of the total cost of job-related arthritis in the United States, between 3.4 and 13.2 billion US dollars (adjusted to 1994) [19]. Because of arthritis, strategies are required to both manage pain and help restore mobility to those affected. While nonsurgical treatments are sometimes available, in severe cases, the replacement of joints, including hips and knees, is advocated. Joint replacements carry high costs, both direct and indirect [12]. Costs arise, not only due to the initial surgery and lost productivity, but should implants fail, there are additional costs associated with replacement and repair. There are many reasons that implants may fail, related to the site of the joint, physical activity of the patients, and interactions between the host and the implant. Studies have found that the most common reason for the failure of hips was dislocation, followed by aseptic loosening [20,21]. Aseptic loosening refers to a process where the implant becomes loose over time, often due to a resorption of bone around it. In addition, infection, misalignment, and periprosthetic fractures can also cause hip implant failure [20,21]. Knee replacements, on the other hand, were found to fail most often due to infections and mechanical loosening [22]. Carrying an average total direct cost of over 75,000 per procedure (US dollars), the burden of failure becomes apparent [22]. Another potential complication involves fractures around the implant. These fractures are very difficult to manage, especially in the elderly, and can require additional surgeries, hospital time, and prolonged loss of mobility [23,24]. While hip and knee joint replacements are the most common, other joints, such as elbow, wrist, and ankle, also can be replaced. In all cases, there are many costs which must be weighed when choosing treatment options, related to both the type of implant and surgical technique used, and the overall quality of life regained for patients. It is necessary to consider both aspects when weighing the costs of patient treatment and determining the best option.

1.2.2  Dentistry Within the field of dentistry, there are several conditions which can negatively impact quality of life. Worldwide, there are over 3.9 billion people affected by oral conditions such as untreated carries (cavities) and severe periodontitis, an infection or inflammation of soft tissue around teeth [25]. Overall, from 1990 to 2010, the incidence has risen to 20.8%, worldwide [25]. This can impact an individual’s ability to chew, and lead to poor nutrition and further health issues. Despite an increase in poor oral health, the worldwide rate of tooth loss is decreasing [26]. Between the years of 1990 and 2010, the rate has dropped 45%, to a mean of 2.3% of the worldwide population with severe tooth loss. This still amounts to over 150 million people affected, and this drop is not consistent across all regions of the world [26]. The incidence of tooth loss, and how it is dealt with, varies by country [27]. However, the use of dental implants has become ever more common worldwide. There are over 1300 types of implants for dentistry, with investigation ongoing into the properties which ensure superior performance [28]. Implants are designed to be placed into the bone of the jaw and integrate with the host tissue, providing a stable anchor for a false tooth to be applied over the top. One of the most important

Introduction to the challenges of bone repair

5

design considerations with dental implants is that they must deal with a unique set of microbiology and loading in comparison to other musculoskeletal sites [29]. Like all mineralized tissue, the hard tissues in teeth (dentin and enamel) are adapted to withstand repeated loading without fracture [6]. Despite widespread use of dental implants, problems can arise after implantation. For example, peri-implantitis can occur, a condition driven by inflammation, resulting in the loss of supporting bone around implants [30]. Peri-implant mucositis is another condition where the soft tissue of the gums recedes around the implants. Smoking and radiotherapy give patients an increased risk of implant failure [31].

1.2.3   Maxillofacial conditions Maxillofacial conditions are those associated with the face and head. While this covers a wide range of issues, those related to bone are generally the correction of bone defects/malformations and fracture repair. One of the most pronounced bone malformations are orofacial clefts, such as the cleft palate. As a birth malformation, it is associated with both genetic and environmental factors, such as smoking or alcohol consumption [32]. While rare, striking an average of 10.2 per 1000 live births in the United States, this number can rise to over 20 per 1000 births in areas such as Japan [32]. Orofacial malformations carry not only the direct costs of surgery and follow on dental care, but also speech impediments, which can affect an individual over their entire lifetime. In the adult population, fractures are the most prevalent form of maxillofacial condition, affecting either the nasal bones or the mandible (lower jaw bone) [33]. In many cases, this type of injury is associated with severe trauma, amounting to over 400,000 cases in the United States (in 2007) [34]. The leading causes reported for facial fractures are assault, falls, and motor vehicle accidents [33,34]. The cause determines the location of the fracture, although the percentage of fractures due to each varies depending on the demographics of the population. For example, there is evidence that in areas where the mean age for individuals with maxillofacial fractures has increased, the percentage of fractures due to falls also increases significantly [35]. Regardless, men are more likely than women to experience maxillofacial fractures, with estimates from 2 to 4 fold higher [33,36]. Given the causes of maxillofacial trauma, especially in the case of motor vehicle accidents, there are often many other injuries associated with facial fracture [34]. Multiple injuries sustained at the same time makes it difficult to determine the burden of maxillofacial conditions alone. However, estimates of the direct hospital costs for those with facial trauma is over 60,000 per individual (total of over 5 billion) in the United States. As with other bone conditions, those with osteoporosis were more likely to sustain multiple fractures [37]. In general, the treatment of fractures requires fixation of the bones to allow healing. Implants can be used to stabilize the region, and their design can affect the overall cost of the treatment. For example, in the fixation of mandible fractures, it is possible to use either large titanium plates (rigid) or small titanium plates (semirigid), both utilizing screws to ensure fixation of the bone. A study has shown an 8% cost reduction (from 16,500 to 15,300 US dollars) when switching from a rigid plate to a semirigid implant.

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Bone Repair Biomaterials

With no statistical differences in hospital time recorded, the reduced costs are believed to be due to reduced surgical time and hardware charges [38]. This example highlights how implant design and materials can reduce the overall socioeconomic burden of maxillofacial trauma.

1.2.4  Spinal conditions Maladies of the spine include back pain, heterotopic ossification (formation of bone in soft tissue, where bone should not normally exist), fractures, and instability. These are widespread, and it has been suggested that back pain affects around 10% of US population [10]. In the workforce, chronic back pain can reduce productivity. Estimates predict that around 14%, of the workforce, missed an average of 7 days per year, due to back pain [10]. While many may respond to conservative treatment options, surgery must be considered, in some cases, to halt degeneration. Patient populations have grown significantly older in the United States, between 2002 and 2009, raising the chances of comorbidity and lowering the healing quality [39]. In a longer term study, from 1993 to 2012, it was found that the percentage of population which experience spinal cord injuries is the same, but the total number has increased with population growth in the United States [40]. Like all conditions, with increasing age, there is a far greater likelihood of experiencing problems. Older individuals are prone to falls, which can result in trauma, and osteoarthritis, causing pain and disability [40]. With age, individuals carry a greatly increased risk of vertebral fractures, which lead to pain and reduced mobility [41]. In general, this is linked to low bone mass. The incidence of fracture correlates with reduced cortical and trabecular bone structure, hallmarks of osteoporosis [41]. While the likelihood of vertebral fracture rises with age for both sexes, the incidence is much higher in older women [42]. The costs can be considerable, due to both hospitalization, which is estimated at over 10,000 per visit (US dollars), and to follow-on costs. It has been estimated that 50% of those discharged with vertebral fractures require some form of continuing care [42]. The vertebrae in the spine serve a dual role. They are a structural component for the body and protect the delicate spinal cord which carries signals throughout the body. The spine also functions as a hinge allowing movement incorporating facet joints and spacers, known as disks. However, individuals with osteoarthritis, in the spine, may experience a narrowing of the disks, the formation of osteophytes (bony projections along bone joints), and the wearing of facet joints. These symptoms can eventually lead to conditions such as degenerative cervical myelopathy, where the spinal cord is impinged, causing nerve damage. Surgical procedures, such as fusing vertebrae together, are necessary to correct for degenerative cervical myelopathy. These surgeries often utilize bone grafts and implants to encourage bone fusion between vertebrae, to increase the stability of the spine and reduce pressure on the spinal cord when disks fail. Over 180,000 procedures are performed each year in the United States, and studies in the United States and Canada have shown the average cost per operation is about 15,000 US dollars (12–19,000 Canadian dollars) in direct costs [39,43]. That equates to over 2.7 billion US dollars per year and does not include any of the indirect costs associated with the disease.

Introduction to the challenges of bone repair

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1.3  Some clinical challenges of bone repair Bone-related conditions can become a huge burden to society, due to the prevalence of the diseases. This burden includes the cost of healthcare and lost productivity, as well as the intangible cost of pain and reduced mobility for an individual. With an aging population, there is increasing pressure to alleviate some of the burden by reducing costs and increasing the quality of life after treatment. One of the key challenges for driving bone repair forward is the translation of new technologies to the clinic. The unmet needs identified by clinical doctors and by researchers are not the same. Clinicians often raise issues with infection around the implant, the ability to provide adequate fixation, and the overall cost of the device [44]. On the other hand, researchers are more concerned with the interaction of the implant with native bone and its integration at the site [44]. These points are valid and worthy of further study to achieve the goal of better patient care and improved quality of life. The demands on implants in the musculoskeletal system are extreme. Implants must often survive cyclical load bearing, a condition of everyday activities such as walking or chewing, for many repetitions without wearing. The types of mechanical loading are very dependent on location within the body, varying between individuals due to differences in height, weight, and physical activities. The differences in mechanics, can, in turn, translate to clinical outcomes. In the normal course of events, cells will migrate into the damaged area, forming a cartilaginous callous before replacing this with bony tissue. If there is movement at the site of injury, or if the bones are too far apart, this delicate process is disrupted, and the fracture may not heal. These nonunions have real implications on the outcome of the implant. Thus, bone implants are often designed to encourage integration with native bone to create a stable system. However, integration with bone can be problematic in areas where there is a low bone density, even in otherwise healthy bone. An example from dentistry shows that the time required for implants to integrate with the underlying bone depends on the implant’s location in the jaw. Implants placed at certain positions have a slower rate of integration, and a statistically higher rate of failure long term [45]. In addition to the requirements for mechanics, function, and stability, implants must be able to perform within a diverse range of physiological environments. Depending on the overall health of the individual, and the extent of the trauma suffered, healing can be delayed or even suppressed. For example, diabetes is known to contribute to slow wound healing. Smoking and high alcohol consumption may also act negatively on bone healing [31]. Patient demographics also play a role on the physiological environment. Elderly patients, which represent a growing portion of the population, do not have a robust healing capacity. This, along with tendencies toward osteoporosis and osteosarcopenia, raise special concerns for bone repair in the clinic. With reduced bone mineral of osteoporosis, there is very little native tissue to anchor fixation devices or artificial joint replacements. Other key problems with any implant technology are inflammation and infection around the implant. Should these occur, they can play a large role in the failure of many implants [20,46]. Inflammation can cause chronic conditions which adversely affect the implant, such as lowering the pH at the implant site and allowing adverse

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chemical reactions at the implant surface, degradation of the material, or a reduction of the implant’s mechanical properties [47]. Inflammatory responses can also cause conditions such as peri-implantitis, resulting in a loss of supporting bone around oral implants and ultimate failure [30]. While infection is a relatively rare complication, only occurring in 1%–2% of joint replacements, it can be very difficult to correct, especially in the elderly [47]. Additional surgeries are often needed, and with a reduced healing capacity, this compounds the trauma. The long hospitalization times necessary for correction can also lead to the acquisition of antibody resistant strains of bacteria [47].

1.4  Role of biomaterials in bone repair Autografts remain a gold standard for bone reconstruction in many applications [48]. However, donor site morbidity and complications from additional surgeries are limiting factors on their use. There is a good case for the rise of man-made materials to replace autografts in the clinic. In terms of the socioeconomic impact, studies have shown that the indirect costs of autografts make repair materials more cost effective for trabecular bone fixation [49]. In addition, it has been demonstrated that reconstruction of severe trauma can be more cost effective, in the long term, than amputation [50]. Further, the relatively low availability of autograft material, especially in cases of severe trauma, necessitate other options. Within the last decades, biomaterials have emerged to direct the repair of tissue after disease or trauma by directing the regeneration of healthy native tissue at the site [51]. Materials which function in this way are not merely fulfilling a mechanical or engineering requirement but are interacting with various cell types in the bone space. Cellular response can be directed by many different cues inherent in the material and its structure. Thus, it is important to consider all aspects of implant and material design when considering bone repair. Developments over the past 10 years have included novel manufacturing technologies and a growth in novel materials and drug delivery. Technologies like 3D printing have increased the possible range of material shapes and properties. It is now possible to tailor bone implants to the individual trauma site. This is a huge advance in the field of personalized medicine and it can make a big impact in areas like reconstructive surgery, where physical appearance is a very important factor in the treatment success. Additive manufacturing can also help to alleviate some of the problems with traditional load bearing implants. Namely, these implants have such high mechanical properties when compared to native bone, that they tend to carry most of the load placed on the skeletal system at that point. With very little load being transmitted to the bone, it tends to resorb, which can lead to fracture or loosening of the implant. Indeed, aseptic loosening has been reported as a major failure mechanism of hip and knee replacements [20,21]. With precise 3D control, and ability to create porous structures, 3D printed matrices can allow specific mechanical characteristics to be achieved which more closely match native bone material [52].

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Metals and calcium phosphate ceramics and glasses, materials which mimic the natural mineral of bone, have had a long history as bone repair materials. With the advancement of imaging and surgical techniques, new forms of implants are being devised, based on the refinement and the synthesis of various materials. This has been an active field of research for some time, to match materials to the stringent requirements of medical devices. To use biomaterials effectively, it is necessary to understand how the body interacts, not only with the bulk material, but with the surface and any resulting degradation products, as well [53]. A key example from orthopedics, is the use of ultrahigh molecular weight polyethylene (UHWPE), which is biocompatible in bulk, but prone to degradation products (small particles) which can induce inflammation and tissue loss [54]. For load-bearing applications, metals and ceramics continue to account for a large part as bone biomaterials. However, polymeric materials are now playing an even larger role in bone repair. In a move toward mimicking the natural environment, there has been a growth of natural polymers and hydrogels, and the mineralization of these networks. With the advancement of molecular biology, novel recombinant proteins are also being investigated as substrates for bone repair [55,56]. While not load bearing, these materials can mimic the properties of the collagenous material which forms as an intermediate in the bone healing process, potentially shortening the healing time. They also have an advantage of increasing integration with native bone tissue, by allowing the migration of bone cells into the porous structure. By encouraging integration, porous polymeric materials could potentially help anchor implants into diseased bone. The ability to deliver growth factors or drugs to the local site of trauma is also attracting attention within the field of biomaterials. Overuse of certain growth factors, or systemic administration, can lead to complications, such as bone formation in soft tissue, where it is not advantageous [57]. However, through surface and bulk modifications to materials, biological cues can be incorporated to act at local levels. This may be used to improve the quality of regenerated tissue and lower the likelihood of infections around implants, both extremely important for elderly patients. This field is in the beginning stages, as it is necessary to understand all aspects of therapeutic release at the site of trauma and the systemic effect on the entire organism, before attempting to translate this to the clinic. With the development of model systems and local delivery, it is hoped that the dangers of nonspecific dosages can be alleviated. By limiting the ability of bacteria to adhere or thrive at the implant site, the risk of infection may be dramatically lowered. A key challenge with all implant technology is allowing concurrent growth of not only bone, but vascularization as well [58]. Blood vessels are responsible for supplying cells with nutrients and removing waste. When these vessels are damaged during trauma, the only way in which nutrients can reach regenerating tissues is via diffusion, a process which is extremely inefficient past a few hundred microns. Therefore, increasing attention is being given to implants which can regenerate blood vessels. This becomes especially important with the scaling-up of implants over 1–2 cm, which is relevant for many clinical applications. Implants which develop a necrotic, or dead, center, where cells cannot survive due to limitations on nutrients, impair the healing process. This center is gradually reduced over time, but eliminating it could be the key to improved integration in much shorter time scales.

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1.5  Conclusions Disease conditions in bone are extremely prevalent in society and appear to be growing as the worldwide population ages. Altogether they account for a large portion of overall healthcare spending. Causing pain and reduced mobility, bone trauma, and disease places a large burden on society, especially in lost productivity. Osteoarthritis is one of the most devastating chronic conditions, affecting a large proportion of the population. It can necessitate many interventions, including the need for total joint replacements or the fusing of vertebrae. Thus, it is a leading contributor to the high costs of healthcare, both due to surgical intervention and follow on care. Oral diseases are also not uncommon, afflicting over 20% of the worldwide population. Added to this, maxillofacial fractures account for over 400,000 cases a year, in the United States alone. Surgeons and researchers have identified key clinical challenges for bone repair including: infection at the implant, poor fixation to the bone, implant integration, and overall costs. Looking to the future, biomaterials design can play a large role in the creation of a new generation of clinical alternatives. This will require interdisciplinary cooperation between clinicians, biologists, engineers, chemists, and materials scientists to gain a more comprehensive understanding of the in vivo environment and how materials interact with it. Porous materials, and those mimicking the natural environment, can help address problems with inflammation and nonintegration with bone tissue. Incorporation of therapeutic molecules, such as drugs or growth factors, will potentially decrease the risk of infection while locally promoting the growth of bone. An important milestone for many porous structures will be the scale up of implants to encourage the even distribution of nutrients, in implants exceeding 1–2 cm, and encouraging the concurrent growth of vascularization along with new bone. There remains a large unmet need for bone repair materials, prompting research to both benefit individuals and society.

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[26] Kassebaum NJ, Bernabe E, Dahiya M, Bhandari B, Murray CJL, Marcenes W. Global burden of severe tooth loss: a systematic review and meta-analysis. J Dent Res 2014;93(Suppl. 7):20S–8S. https://doi.org/10.1177/0022034514537828. [27] Stock C, Juerges H, Shen J, Bozorgmehr K, Listl S. A comparison of tooth retention and replacement across 15 countries in the over-50s. Community Dent Oral Epidemiol 2016;44:223–31. https://doi.org/10.1111/cdoe.12209. [28] Esposito M, Ardebili Y, Worthington HV. Interventions for replacing missing teeth: different types of dental implants. Cochrane Database Syst Rev 2014;7:CD003815. https://doi. org/10.1002/14651858.CD003815.pub4. [29] Marsh PD, Martin MV, Lewis MAO, Williams D. Oral microbiology. 5th ed. Elsevier Health Sciences; 2009. [30] Mombelli A. Microbiology and antimicrobial therapy of peri-implantitis. Periodontology 2002;28:177–89. [31] Chen H, Liu N, Xu X, Qu X, Lu E. Smoking, radiotherapy, diabetes and osteoporosis as risk factors for dental implant failure: a meta-analysis. PLoS One 2013;8:e71955. [32] Watkins SE, Mayer RE, Strauss RP, Aylsworth AS. Classification, epidemiology, and genetics of orofacial clefts. Clin Plast Surg 2014;41:149–63. https://doi.org/10.1016/j.cps.2013.12.003. [33] Afrooz PN, Bykowski MR, James IB, Daniali LN, Clavijo-Alvarez JA. The epidemiology of mandibular fractures in the United States, part i: a review of 13,142 cases from the US national trauma data bank. J Oral Maxillofac Surg 2015;73:2361–6. https://doi. org/10.1016/j.joms.2015.04.032. [34] Allareddy V, Allareddy V, Nalliah RP. Epidemiology of facial fracture injuries. J Oral Maxillofac Surg 2011;69:2613–8. https://doi.org/10.1016/j.joms.2011.02.057. [35] Martinez AY, Como JJ, Vacca M, Nowak MJ, Thomas CL, Claridge JA. Trends in maxillofacial trauma: a comparison of two cohorts of patients at a single institution 20 years apart. J Oral Maxillofac Surg 2014;72:750–4. https://doi.org/10.1016/j.joms.2013.11.018. [36] Bormann K-H, Wild S, Gellrich N-C, Kokemueller H, Stuehmer C, Schmelzeisen R, Schoen R. Five-year retrospective study of mandibular fractures in Freiburg, Germany: incidence, etiology, treatment, and complications. J Oral Maxillofac Surg 2009;67:1251– 5. https://doi.org/10.1016/j.joms.2008.09.022. [37] Werning JW, Downey NM, Brinker RA, Khuder SA, Davis WJ, Rubin AM, Elsamaloty HM. The impact of osteoporosis on patients with maxillofacial trauma. Arch Otolaryngol Head Neck Surg 2004;130:353–6. [38] Bouloux GF, Demo M, Moe J, Easley KA. Mandibular fractures treated with small plates and screws reduce treatment cost. J Oral Maxillofac Surg 2014;72:362–9. https://doi. org/10.1016/j.joms.2013.08.005. [39] Oglesby M, Fineberg SJ, Patel AA, Pelton MA, Singh K. Epidemiological trends in cervical spine surgery for degenerative diseases between 2002 and 2009. Spine 2013;38(14):1226– 32. https://doi.org/10.1097/BRS.0b013e31828be75d. [40] Jain NB, Ayers GD, Peterson EN, Harris MB, Morse L, O’Connor KC, Garshick E. Traumatic spinal cord injury in the United States, 1993-2012. JAMA 2015;313(22):2236– 43. https://doi.org/10.1001/jama.2015.6250. [41] Schousboe JT. Epidemiology of vertebral fractures. J Clin Densitom 2016;19(1):8–22. https://doi.org/10.1016/j.jocd.2015.08.004. [42] Gehlbach SH, Burge RT, Puleo E, Klar J. Hospital care of osteoporosis-related vertebral fractures. Osteoporos Int 2003;14:53–60. [43] Witiw CD, Tetreault LA, Smieliauskas F, Kopjar B, Massicotte EM, Fehlings MG. Surgery for degenerative cervical myelopathy: a patient-centered quality of life and health economic evaluation. Spine J 2017;17:15–25. https://doi.org/10.1016/j.spinee.2016.10.015.

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[44] Schwartz AM, Shenker ML, Ahn J, Willett NJ. Building better bone: the weaving of biologic and engineering strategies for managing bone loss. J Orthop Res Soc 2017;35:1855– 64. https://doi.org/10.1002/jor.23592. [45] Choi YG, Eckert SE, Kang KL, Shin SW, Kim YK. Epidemiology of implant mortality disparity among intraoral positions and prosthesis types. Int J Oral Maxillofac Implants 2017;32:525–32. https://doi.org/10.11607/jomi.5044. [46] Da Silva JD, Kazimiroff J, Papas A, Curro FA, Thompson VP, Vena DA, Collie D, Craig RG. Outcomes of implants and restorations placed in general dental practices: a retrospective study by the practitioners engaged in applied research and learning (PEARL) network. JADA 2014;145:704–13. https://doi.org/10.14219/jada.2014.27. [47] Rao N, Soxman GL. Prosthetic joint infections in the elderly. Operat Tech Orthop 2002;12(2):131–8. https://doi.org/10.1053/otor.2002.36175. [48] Sakkas A, Wilde F, Heufelder M, Winter K, Schramm A. Autogenous bone grafts in oral implantology - is it still a “gold standard”? A consecutive review of 279 patients with 456 clinical procedures. Int J Implant Dent 2017;3:23. https://doi.org/10.1186/ s40729-017-0084-4. [49] Lohmann H, Grass G, Rangger C, Mathiak G. Economic impact of cancellous bone grafting in trauma surgery. Arch Orthop Trauma Surg 2007;127:345–8. https://doi.org/10.1007/ s00402-006-0277-4. [50] MacKenzie EJ, Jones AS, Bosse MJ, Castillo RC, Pollak AN, Webb LX, Swiontkowski MF, Kellam JF, Smith DG, Sanders RW, Jones AL, Starr AJ, McAndrew MP, Patterson BM, Burgess AR. Health-care costs associated with amputation or reconstruction of a limb-threatening injury. Am J Bone Jt Surg 2007;89:1685–92. https://doi.org/10.2106/ JBJS.F.01350. [51] Hench LL, Polak JM. Third-generation biomedical materials. Science 2002;295: 1014–7. [52] Wang Z, Wang C, Li C, Qin Y, Zhong L, Chen B, Li Z, Liu H, Chang F, Wang J. Analysis of factors influencing bone ingrowth into three-dimensional printed porous metal scaffolds: a review. J Alloy Compd 2017;717:271–85. https://doi.org/10.1016/ j.jallcom.2017.05.079. [53] Ghaffar A, Schoenmakers PJ, van der Wal SJ. Methods for the chemical analysis of degradable synthetic polymeric biomaterials. Crit Rev Anal Chem 2014;44(1):23–40. https://doi. org/10.1080/10408347.2013.831729. [54] Bracco P, Bellare A, Bistolfi A, Affatato S. Ultra-high molecular weight polyethylene: influence of the chemical, physical and mechanical properties on the wear behavior. a review. Materials 2017;10:791. [55] Pawelec KM, Confalonieri D, Ehlicke F, van Boxtel H, Walles H, Kluijtmans SGJM. Osteogenesis and mineralization of mesenchymal stem cells in collagen type i based recombinant peptide scaffolds. J Biomed Mater Res Part A 2017;105A:1856–66. https:// doi.org/10.1002/jbm.a.36049. [56] Pawelec KM, Kluijtmans SGJM. Biomineralization of recombinant peptide scaffolds: interplay among chemistry, architecture, and mechanics. ACS Biomater Sci Eng 2017;3:1100–8. https://doi.org/10.1021/acsbiomaterials.7b00175. [57] Goode AP, Richardson WJ, Schectman RM, Carey TS. Complications, revision fusions, readmissions, and utilization over a 1-year period after bone morphogenetic protein use during primary cervical spine fusions. Spine J 2014;14:2051–9. https://doi.org/10.1016/j. spinee.2013.11.042. [58] Stegen S, Carmeliet G. The skeletal vascular system - breathing life into bone tissue. Bone 2017. https://doi.org/10.1016/j.bone.2017.08.022.

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Bone biology Robyn K. Fuchs1,2, William R. Thompson1,2, Stuart J. Warden1,2 1Department of Physical Therapy, School of Health and Human Sciences, Indiana University, Indianapolis, IN, United States; 2Indiana Center for Musculoskeletal Health, Indiana University, Indianapolis, IN, United States 

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2.1   Introduction Bone is a specialized connective tissue consisting of cells, fibers, and ground substance. Unlike other connective tissues, its extracellular components are mineralized, giving it substantial strength and rigidity. This makes bone ideally suited to fulfilling its most recognized role within the body, that of mechanical support. Bone provides internal support countering the force of gravity, forms specific cavities which serve to protect vital internal organs, and provides attachment sites for muscles allowing motion to occur at specialized bone-to-bone linkages. To fulfill these mechanical roles bone needs to be stiff to resist deformation, yet flexible to absorb energy. In addition, to meeting these contrasting mechanical demands, bone also needs to be able to meet important auxiliary functions of maintaining calcium homeostasis and hematopoiesis. This chapter provides an overview of the anatomy and physiology of bone in relation to these functions, with reference to the mechanical role of bone and its response to mechanical stimuli.

2.2   Bone anatomy The anatomy or morphology of bone can be viewed hierarchically, starting at the gross, macroscopic level, and progressing microscopically down to the nanoscale level (Fig. 2.1).

2.2.1   Macroscopic anatomy The human skeletal system contains over 200 unique bones, each of which have a different macroscopic appearance. To assist in simplifying the system, several classification methods have been used to categorize bones into groups. This has included grouping bones according to their type (long, short, flat, or irregular), location (axial or appendicular), or predominant tissue composition (cortical or trabecular). The categorization of bones according to their type or location is convenient; however, greater information regarding bone function can be derived by identifying the predominant bone tissue type present within a specific bone or bone region. The skeleton can be divided macroscopically into two distinct types of bone tissue—cortical and trabecular (Fig. 2.2). These two tissue types have the same matrix composition; however, they differ in terms of their structure and function, and relative distribution both between and within bones. Bone Repair Biomaterials. https://doi.org/10.1016/B978-0-08-102451-5.00002-0 Copyright © 2019 Elsevier Ltd. All rights reserved.

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Collagen molecule

Collagen fibers

Haversian canal

2.86 nm

64 nm

Haversian osteon

Collagen fibril Hydroxyapatite crystal 1 nm

100 nm

1 µm

Osteocyte lacuna Canaliculi 10 µm

200 µm

Size scale

Figure 2.1  Hierarchical structure of cortical bone. Reproduced with permission of John Wiley and Sons, Inc. from Ritchie RO, Nalla RK, Kruzic JJ, Ager JW, Balooch G, et al. Fracture and ageing in bone: toughness and structural characterization. Strain 2006;42:225–32.

Epiphysis

Cortical bone Diaphysis Trabecular bone

Epiphysis

Figure 2.2  Macroscopic anatomy of a long bone. The cylindrical shaft or diaphysis consists of cortical bone, whereas the expanded epiphyses have a greater proportion of trabecular bone enclosed within a thinner cortical shell. The narrow intervening metaphysis contains the growth plate which allows longitudinal growth when young. Images are of a mouse femur acquired using microcomputed tomography.

Bone biology

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2.2.1.1   Cortical bone Cortical (or compact) bone makes up approximately 80% of total skeletal tissue mass. It has a high matrix mass per unit volume and low porosity. These features endow cortical bone with great compressive strength enabling it to prominently contribute to the mechanical role of bone. This is reflected in its distribution primarily within the long bones of the appendicular skeleton. The appendicular or peripheral skeleton is made up of long and short bones, including all the bones of the upper and lower limbs. Long bones can be divided into three general regions—a relatively cylindrical shaft (diaphysis), two expanded ends (epiphyses), and a developing region in between (metaphysis) (Fig. 2.2). Cortical bone is particularly prominent within the diaphyses where it forms a thick cortical shell (cortex) that surrounds a medullary canal filled with bone marrow. This tube-like structural design distributes bone mineral away from bending axes, resulting in a substantial increase in bending resistance without a concomitant increase in bone weight. This endows long bones the strength and rigidity required for muscle action and weight bearing, yet lightness required for energy-efficient locomotion. Cortical bone thins toward the metaphyses and epiphyses of long bones where it plays a lesser, yet clinically significant mechanical role. The best example of this is at the femoral neck where cortical bone thickness and distribution are important variables influencing osteoporotic fracture risk [1–3]. While cortical bone is solid, it does contain microscopic pores (constituting approximately 10% of total cortical bone volume) which permit vascular and neural supply [4], and the delivery of nutrients. The porosity increases with age [5,6], disuse [7], overuse [8,9], disease states [10,11], and may increase [12,13] or decrease [14,15] with pharmacological intervention. The degree of porosity of cortical bone is important from a fracture standpoint as an increase in intracortical porosity can result in reduced bone strength and a concomitant increase in fracture risk [16]. Cortical bone does not appear to have a major role in hematopoiesis beyond skeletal maturity. The diaphyses of long bones have a medullary canal filled with bone marrow. However, the content of the marrow transforms after birth from red (hematopoietic, metabolically active) into yellow (fatty tissue that is not metabolically active) marrow during skeletal maturation [17–19].

2.2.1.2   Trabecular bone In contrast to the low porosity of cortical bone, trabecular (or cancellous) bone has high porosity with pores making up 50%–90% of total trabecular bone volume. These pores are interspersed among an orderly arranged network of vertical and horizontal plate- and rod-like structural elements called trabeculae, which give trabecular bone a sponge-like appearance. The reduced matrix mass per unit volume and high porosity of trabecular bone reduces its compressive strength to approximately one-tenth that of cortical bone [20]; however, it has the function of providing increased surface area for red bone marrow, blood vessels and connective tissues to be in contact with bone. This facilitates the role of bone in hematopoiesis and mineral homeostasis.

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Bone Repair Biomaterials

Trabecular bone does not have the strength of cortical bone; however, it contributes to the mechanical role of bone by providing internal support. This supportive role facilitates the ability of bone to evenly distribute load and absorb energy, particularly near joints. It is also important during aging as trabecular bone is lost earlier and at a greater rate than cortical bone [21]. This contributes to osteoporosis at skeletal sites rich in trabecular bone, such as the femoral neck and vertebral bodies. Bone strength at these sites is determined by the number, thickness, spacing, distribution, and connectivity of trabeculae, with the latter being particularly important [22]. For a given trabecular density, loss of connectivity has more deleterious effect on bone strength than the presence of thin but well-connected trabeculae [23–25]. This is supported by the finding that women with low bone mass and vertebral fractures have four times as many unconnected trabeculae as women without fractures, despite a similar bone mineral density [26].

2.2.2  Microscopic anatomy 2.2.2.1  Bone coverings The microscopic anatomy of bone is demonstrated in Fig. 2.3. The outer and inner surfaces of bone are covered by specialized connective tissues called the periosteum and endosteum, respectively. The periosteum serves as a transitional fibrous layer between cortical bone and the overlying soft tissue or musculature. It covers the external surfaces of most bones, except at articular surfaces, tendon insertions, and the surfaces of sesamoid bones [27]. The periosteum can be divided into two distinct layers (Fig. 2.3(f)). The outer most “fibrous” layer is composed of fibroblasts, collagen, and elastin fibers [28], along with a distinctive nerve and microvascular network [29]. The inner “cambium” or “cellular” layer is positioned in direct contact with the bone surface. It contains mesenchymal stem cells (MSCs) which have the potential to differentiate into osteoblasts and chondrocytes [30–32], and differentiated osteogenic progenitor cells, fibroblasts, microvessels, and sympathetic nerves [33]. The localization of MSCs and osteoprogenitor cells within the cambium layer has made the periosteum a target for drug therapies and cell harvesting for tissue engineering purposes. The endocortical or inner surface of a bone faces the medullary canal and is lined by a membranous sheath called the endosteum (Fig. 2.3(g)). The endosteum is lined by a single thin layer of bone-lining cells (mature osteoblasts) and osteoblasts which form a membrane over endocortical and trabecular bone surfaces to enclose the bone marrow [34]. Osteoclasts can also be present in the endosteum in regions of active bone resorption. The endosteum contains osteoprogenitor cells but does not appear to contain either MSCs or hematopoietic stem cells (HSCs). However, a portion of HSCs (