HYDROXYAPATITE

HYDROXYAPATITESYNTHESIS AND APPLICATIONS

YOSHIKI OSHIDA

MOMENTUM PRESS, LLC, NEW YORK

Hydroxyapatite: Synthesis and ApplicationsCopyright © Momentum Press®, LLC, 2015.

All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means— electronic, mechanical, photocopy, recording, or any other—except for brief quotations, not to exceed 400 words, without the prior permission of the publisher.

First published by Momentum Press®, LLC222 East 46th Street, New York, NY 10017www.momentumpress.net

ISBN-13: 978-1-60650-673-8 (print)ISBN-13: 978-1-60650-674-5 (e-book)

Momentum Press Biomaterials CollectionEngineering

DOI: 10.5643/9781606506745

Cover and interior design by Exeter Premedia Services Private Ltd., Chennai, India

10 9 8 7 6 5 4 3 2 1

Printed in the United States of America

To my wife, for putting up with me, and to my parents and family members, for their love, support, and encouragement

vii

AbstrAct

This book is based on a review of about 2,000 carefully selected articles about hydroxyapatite (HA) materials from about 150 peer-review journals in both engineering and medical areas and presents itself as a typical exam-ple of evidence-based learning (EBL). Evidence-based literature reviews can provide foundation skills in research-oriented bibliographic inquiry, with an emphasis on such review and synthesis of applicable literature. Information is gathered by surveying a broad array of multidisciplinary research publications written by scholars and researchers. HA is a very unique material which has been employed equally in both engineering and medical and dental fields. In addition, the name “apatite” comes from the Greek word απατω, which means to deceive. What is actually happening inside the apatite crystal structure is based on the unique characteristics of ion exchangeability. Because of this, versatility of HA has been recog-nized in wide ranges, including bone-grafting substitutes, various ways to fabricate HAs, HA-based coating materials, HA-based biocomposites, scaffold materials, and drug-delivery systems. This book covers all these interesting areas involved in HA materials science and technology.

KEY WORDS

animal tests, biomimetic materials, biowaste-origin HA, biphasic bio-composites, bone-graft substitute materials, clinical reports, crystallinity, drug-delivery systems, elemental substitutions, hydroxyapatite coating materials, hydroxyapatite-based biocomposites, scaffolds materials and structures, synthesis

ix

contents

List of figures xiii

List of tabLes xv

acknowLedgments xvii

Preface xix

1 introduction 1 References 5

2 structure and ProPerties 7 2.1 Introduction 7 2.2 High-temperature and Low-temperature HAs 8 2.3 Dissolution and Solubility 10 2.4 Compositional Alteration of HA 11 2.5 Crystallinity and Its Effects 12 2.6 Ca–P Family Members 17 2.7 Comparison between HA and TCP 19 2.8 HA/TCP Biphasic Biocomposites 22 References 25

3 PreParation of HydroxyaPatite 33 3.1 Introduction 33 3.2 Sources for Calcium in HA 33 3.3 HA Synthesis Technologies 34 References 44

x •  COntEntS

4 eLementaL substitutions in HydroxyaPatite structure 53 4.1 Introduction 53 4.2 M Substitution in M10(XO4)6(Y)2 54 4.3 XO4 Substitution in M10(XO4)6(Y)2 74 4.4 Y Substitution in M10(XO4)6(Y)2 80 4.5 Antibiotics 83 References 85

5 HydroxyaPatite coating materiaLs 101 5.1 Introduction 101 5.2 Coating Materials 102 5.3 Coating Methods 107 5.4 Characterizations of Coated HA 119 5.5 Results on Animal Studies 129 5.6 Clinical Reports 133 References 142

6 bone-graft substitute materiaLs 159 6.1 Introduction 159 6.2 Classification 161 6.3 Calcium-Deficient HA 167 6.4 HA Bone-Graft Substitutes 169 References 195

7 HydroxyaPatite-based biocomPosites 213 7.1 Introduction 213 7.2 HA–Metal and Alloys 214 7.3 HA–Metallic Oxides 217 7.4 HA–Minerals 224 7.5 HA–Carbon, Carbides, and Nitrides 226 7.6 HA–Glass and Bioglass 227 7.7 HA–Dental Composites 230 7.8 HA–Polymers 231 7.9 HA–Protein and Collagen 242

COntEntS •  xi

7.10 HA–HA Whiskers and TCP 243 7.11 Functionally Graded HA Structure 245 References 248

8 biomimetic materiaLs and structures 263 8.1 Introduction 263 8.2 Treatments in Simulated Body Fluid 264 8.3 Treatments with Protein Groups 268 8.4 Treatments with Chitosan 280 8.5 Treatments with Other Composites 284 8.6 Mechanical Properties 289 References 290

9 scaffoLds and drug-deLivery systems 301 9.1 Introduction 301 9.2 Scaffold—Structure and Materials 301 9.3 Drug-Delivery Systems 339 References 348

10 effects of HydroxyaPatite and infLuences on HydroxyaPatite 365

10.1 Introduction 365 10.2 Effects of HA 365 10.3 Various Parameters Affecting HA 380 References 386

about tHe autHor 393

index 395

xiii

List of figures

Figure 1.1. Accumulated number of published articles on titanium biomaterials, biocompatibility, hydroxyapatite, and dental and orthopedic or both implants. 4

Figure 2.1. Unit cell of hydroxyapatite (HA) crystal. 8

xv

List of tAbLes

Table 4.1. A summary of all information on elemental substitutions and their primary influences 85

xvii

AcknowLedgments

For the preparation of this book, we studied a huge number of published valuable data resources; it is obvious that, without this valuable information, this book could not have been written. For expressing our sincere appreciation to the authors of every single peer-reviewed article that we cited in this book and the journals that release such wonderful information to the public, we would like to list those journals as follows in alphabetical order. They include Am J Orthod, Am J Dent, Angle Orthod, Advanced Material Process, American J Orthod Dentofacial Orthop, ASM Intl, Apply Sur Sci, Advances Dent Res, Amer J Orthod, Acta Biomater, Ann Biomed Eng, ACS Nano, Adv Orthop Surg, Biomaterials, Br Med J, Bone Joint Surg Br, Biomed Mater, Bioelectrochemistry, Biochemistry, Biomed Eng J, Biomed Journal, CRC Crit Rev Biocompatibility, Cell, Clin Implant Dent Relat Res, Clin Orthop, Clin Oral Implant Res, Clin Oral Invest, Clin Mater, Contact Dermatitis, Crit Rev Oral Biol Med, Cryst Eng Comm, Corr Sci, Corrosion, Colloids Surf B Biointerfaces, Dent Mater J, Digest J Nanometer and Biostructures, Electrochim Acta, Faraday Discuss, Gen Dent, Int Dental Journal, Int J Oral Maxillofac Implants, Int J Oral Surg, Int J Periodontics & Restorative Dent, Int J Nanomed, Int J Prosthodont, Implant Dent, Int Arch Allergy Apply Immunol, Int J Mol Sci, J Adhes, J Adhes Sci Technol, J Alloys Compd, J Am Ceram Soc, J Appl Phys, J Appl Biomater, J Assoc Ad Med Instrum, J Arthroplasty, J Bacteriol, J Biochem Biophys Method, J Bio Sci Polym Ed, Journal of Metals, J Biomech, J Biomed Mater Res A, J Biomed Mater Res B, J Biomed Mater Eng, J Bone Joint Surg Am, J Bone Miner Res, J Cardiovasc Technol, J Chronic Dis, J Clin Invest, J Clin Pathol, J Colloid Interface Sci, J Dent Res, J Electroceramics, J Eng Tribol, J Exp Med, J Invest Dermatol, J Jpn Soc Dental Mater Devices, J Less-Common Metals, J Mater Chem, J Mater Sci, J Mater Sci Let, J Mater Process Technol, J Mech Behave Biomed Mater, J Mater Sci Mater Med, J Nanosci Nanotechnol, J Prosthet Dent, J Electrochem Soc, J Oral Implants, J Oral Rehabil, J Orthopaedic Trauma, J Prosthodont, J Vac Sci Technol, Jpn

xviii •  ACKnOWlEDgmEntS

Inst Metals, Jpn Dent Mater, Langmuir, Metallurgical and Materials Transaction A, Metallurgical and Materials Transaction B, Materials Letters, Mater Manuf Process, Mater Science Eng A, Mater Science Eng B, Mater Perform, Mater Science Forum, Mol Biology of the Cell, Med Device Technol, Med Sci Monit, Med Prog Technol, Orthopedics, Oral Microbiol Immunol, Proc Royal Soc, Prog Organ Coat, Quint Intl, Quint Dent Technol, Soft Matter, Surf Coat Technol, Surf Technol, Surf Interface Anal, Tribology Industry, Tissue Eng, Tribol Lett, The American Society for Metals, Trans Orthop Res Soc, Trans Soc Biomater, Trans Electrochem Soc, Thin Solid Films, Toxicology, and Wear.

In closing, I admit to having a very long list of individual names to be mentioned with my memories and appreciation—from my teachers who inspired me, friends and colleagues who challenged me, and most importantly students (some of them are now my colleagues) who con-tinue to both inspire and challenge me. To all of them, I owe my knowl-edge and capability to comprehend the cited articles presented in this book. The people, who were and are valuable to me and to this book, should at least include the late T. Nakayama, V. Weiss, H. W. Liu, the late J. A. Schwartz, T. Koizumi, F. Farzin-Nia, G. K. Stookey, the late C. J. Andres, the late T. M. Barco, M. Kowolik, V. John, D. Brown, D. Burr, M. Siefert, R. Shew, M. Kingsley, J. Williams, J. Levon, A. Hashem, Z. H. Khabbaz, R. Xirouchaki, P. Agarwal, C. S. Wang, E. Matsis, R. Rani, Y.-C. Wu, K. Mirza, I. Katsilieri, C. N. Elias, E. B. Tuna, O. Aktören, K. Gençay, Y. Güven, and Japan Implant Practice (JIP) Society members and K. Tsunekawa. Special thanks should also go to M. A. Dirlam for excellent professional illustrations of the figures and table in this book, and to the editorial team at Momentum Press (J. Stein, and C. Kronstedt) and IGroup Exeter ( Jyothi). Thank you all.

xix

PrefAce

Hydroxyapatite (HA) is one of three major constituent elements of the human body (other two are water and proteins) and can be found in 60 percent of bones, 97 percent of tooth enamel, and 70 percent of tooth dentin. The name “apatite” in HA originated from the Greek word απατω, meaning to “deceive”. HA is just one type of calcium phosphate and pos-sesses variety of characteristics, depending on production processes. As a result, we can find a wide range of applications of HA; (i) in chemistry and chemical engineering, it can be used as a catalytic material, adsor-bent liquid-chromatography of proteins, (ii) in bio-medical area, it can be utilized as antimicrobial agent, artificial bone material, coating materials for dental and orthopedic implants, which promote osseointegration; and (iii) in dentistry, microsized HA can be added in tooth pastes to fill in microcrack on enamel surfaces, to easily remove plaque on tooth surfaces mainly due to a presence of Streptococcus mutans, or to promote the rem-ineralization of demineralized subsurface layers of tooth.

These aforementioned versatilities of HA can be summarized with three important key words; excellent bio- and bone-compatibilities, high absorptivity, and unique ion exchangeability. Bony cells can easily pen-etrate into sintered porous HA structure to exhibit excellent bone con-ductivity. When HA artificial bone grafting material is placed into a bone-deficient area, newly born bone starts to cover the bone-deficient area and bone remodeling takes place by repeating absorption by osteo-clast cells and reproduction by osteoblast cells, resulting in substituting to autologous bone structure. Moreover, newly established bone can be stabilized by chemically-bonded HA, so that HA is a powerful agent for dental or orthopedic implants where early stage of fixation and stabiliza-tion are demanded. Hydroxyl group, carboxyl group, and amino group are typical functional groups to show a strong interaction with HA. HA exhib-its a high absorptivity with proteins, lipids, and sugars, too. Accordingly, HA is extensively employed as an adsorbent in chromatography to sepa-rate biomolecules or as cosmetics to remove excess lipids. HA possesses

xx •  PREfACE

excellent ion exchangeability. Ca+ site can be substituted by cations, and PO4

2− or OH2− sites are replaced by anions. Actually, Ca ions in natural tooth and bone are substituted by small amounts of Fe, Mg, or Sr ions, and OH ions are replaced by F ions to prevent from caries. Being parallel with currently developed and advanced tissue engineering, HA is also playing an important role in this field, which should include scaffold structures and drug-delivery system supporting elements.

Based on the aforementioned background, while we were preparing the book entitled “Surface Engineering and Technology for Biomedi-cal Implants” which was published by Momentum Press, 2014, it was found that there are valuable information on HA materials in wide ranges, which are unfortunately scattered in different disciplines. Accordingly, we have read about 2,000 published articles from about 150 peer-review journals (which are listed in the Acknowledgments) from 10- to 15-year achieve. Then, we compiled these information, analyzed, classified, and formed them into a book. Here we are now. This book has been prepared by Oshida and various coauthors for all 10 chapters. Chapter 1 provides an overview of HA in general. Chapter 2 analyzes crystalline structure and properties of HA in terms of stoichiometry and crystallinity. Ion exchangability of Ca+ (M-site) for cations, and PO4

2− (B-site) and OH2−

(A-site) for anions are discussed. Structure-related phenomena includ-ing dissolution and solubility are also described. Chapter 3 summarizes various technologies to prepare HA forms and shapes, including rodlike, flowerlike, whiskers, thin films, porosity-controlled macro-, micro-, or nanosize powder, foams, and others. Also a variety of sources for HA materials, including xenogenic biowaste and natural sea products, as well as other types of calcium phosphates which will be converted to HA structure, were identified. Chapter 4 analyzes elemental substitutions in M-, B-, and A-sites in HA structure and effects of substituted elements are identified and summarized in a table at end of the chapter, indicat-ing that x-HA (x: substituted element) exhibits wide range of enhance-ment and improvement in chemical, mechanical, physical properties, and medical performances, too. Chapter 5 discusses HA coating mate-rials and coating technologies to improve medical function, and chemi-cal and mechanical properties; in particular, biotribological properties of orthopedic implant surfaces. Chapter 6 summarizes bone-graft substitutes materials. A brief history of bone materials is reviewed. The bioactivity as the most important property in implantology including osteoconductiv-ity, osteogenicity, and osteoinductivity were described. Harvested-bone, cell-based bone, ceramic-based bone, and polymer-based bones were classified and described. Chapter 7 analyzes HA-based biocomposites.

PREfACE •  xxi

It includes HA/metallic elements, HA/metallic oxides, HA/minerals, HA/C and carbides, HA/bioglass, HA/polymers, and HA/protein and col-lagen. Functionally graded materials can be prepared by compositing vari-ous materials, and are introduced in the chapter. There are four major areas involved in the tissue engineering to which HA biomaterials are related, that is, (1) biomimetic materials, (2) biomimetic structures, (3) scaffold structures, and (4) drug-delivery system. In Chapter 8, biomimetic materi-als and structures are discussed. Various treatments on HA to make HA as biomimetic in nature include treatments in simulated body fluid, and treat-ments with protein, collagen, and chitosan. Chapter 9 analyzes remaining two areas in HA-related tissue engineering (namely, scaffold structures and drug-delivery systems). HA-based scaffold composite materials are classified and newly developed technologies to prepare scaffold structures such as 3D printing or selective laser sintering (SLS) are introduced. As regards to drug-delivery systems, HA materials used for drug-delivery systems and their medical applications are described. Chapter 10 identi-fies effects of adding or compositing with HA on mechanical, chemical, physical, and biological properties, and medical and dental performances are summarized, along with various parameters which affect structures and properties of HA are identified.

At last but not least important, let me introduce my coauthors for each chapter. Dr. Che-Shun Wang and Dr. Keng-Liang Ou (Chapter 1) are at Taipei Medical University. Dr. Wang (PhD, MDS, and DDS) cur-rently serving as Chairman, Decent Care Dental Group, and Dr. Ou, PhD, is serving as Dean, College of Oral Medicine. Dr. Katsumasa Tsushima (Chapter 2) holds a PhD and a DDS. Dr. Tsushima is currently a member of International Society of Internal Medicine in Periodontics and a mem-ber of the Japan Implant Practice Society. Dr. Yutaka Ikeda ( Chapter 3), PhD and DDS, is currently a member of Japan Implant Practice Society. Dr. Katsuya Kuroki (Chapter 4) holds a PhD and a DDS, currently work-ing at the Department of Anatomy, Osaka Dental University and a mem-ber of the Japan Implant Practice Society. Dr. Noboru Obata ( Chapter 5), is PhD and DDS, is a member of the Japan Implant Practice Society. Dr. Kyo’ichiro Imai (Chapter 6) holds a PhD and a DDS and is currently a member of the Japan Implant Practice Society. Dr. Yeliz Guven and Dr. Oya Aktoren (Chapter 7) both hold a PhD and a DDS, working at the Department of Pediatric Dentistry, Faculty of Dentistry Istanbul Univer-sity, Turkey. Dr. Guven is currently a research assistant and Dr. Aktoren is serving as the Department Chairwoman. Dr. Mikio Fukushima (Chapter 8) holds a PhD and a DDS and is a member of the Japan Implant Practice Society. Dr. Masaki Fukai (Chapter 9) is PhD and a DDS and is a visiting

xxii •  PREfACE

Professor of Manila Central University, a councilor of Japanese Society of Oral Implantology, and president of the Asia Oral Implant Academy. He is also a member of the Japan Implant Practice Society. Dr. Takeaki Maeta (Chapter 10) holds a PhD and a DDS. He is currently a member of the International Society of Internal Medicine in Periodontics and a member of the Japan Implant Practice Society.

Yoshiki Oshida

CHAPtER 1

introduction

Yoshiki Oshida, Che-Shun Wang, and Keng-Liang Ou

Hydroxyapatite (HA) can be found in teeth and bones of the human body. Bone is the structural component of our body and can be considered as a natural biocomposite comprising of biopolymers (collagen and noncollag-enous proteins) and minerals (HA), together with void spaces (porosity); more precisely, bone is a specialized form of mineralized connective tissue consisting, by weight, of 33 percent organic matrix (of which 28 percent is type I collagen and the other five percent is noncollagenous glycopro-teins, including osteonectin, osteocalcin, bone morphogenetic proteins, bone proteoglycan, and bone sialoprotein), and the other 67 percent inor-ganic portion of the bone is made up of HA, which permeates the organic matrix [1]. The tooth has two anatomical parts: (1) the crown which is cov-ered with enamel and is the part usually visible in the mouth and supported by underlying dentin and (2) the root is embedded in the jaw to anchor the tooth in its bony socket and is normally not visible. About 96 percent of enamel consists of mineral HA, which is crystalline calcium phosphate, and water and organic material. The enamel is the hardest substance in the body. Underlying dentin is not as hard as enamel, forms the bulk of the tooth, and can be sensitive if the protection of the enamel is lost. Dentin is the porous yellow-hued material made up of 70 percent inorganic materi-als, 20 percent organic materials, and 10 percent water by weight.

Many modern implants, for example, hip or knee replacements, den-tal implants, and bone conduction implants, are coated with HA, due to the fact that (i) HA possesses similarities with the mineral part of the bone and (ii) HA promotes osseointegration, which can be defined as the direct structural and functional connection between ordered, living bone and the surface of a load-carrying implant [2]. It has been well documented that Ti biomaterials (including both commercially pure titanium or CpTi and

2 •  HYDROXYAPAtItE

Ti-based alloys such as Ti–6Al–4V and Ti–6Al–7Nb) are considered as the best material choice for both orthopedic and dental implant materials, and mechanical retention basically refers to the metallic substrate systems such as titanium or titanium alloy due to bioinertness. The retention is based on undercut forms such as vents, slots, dimples, screws, and so forth and involved direct contact between the dioxide (TiO2) layer on the base metal and bone with no chemical bonding [3]. However, due to this bioin-ertness [3] and potential allergic reaction [4], osseointegration cannot be achieved well, so that bioactive HA has been coated onto Ti biomaterials, by various techniques including plasma-sprayed deposition, hot isostatic pressing (HIP), thermal spray, dip coating, pulsed laser deposition, elec-trophoretic deposition, sol–gel, ion beam assisted deposition, and sput-tering [5, 6]. HA displays osteoconductivity, a property that encourages bone already formed to lie closely to, or adhere to its own surface, and the bioactive retention is achieved with bioactive materials such as HA, which bond directly to bone, similar to the ankylosis of natural teeth. Bone matrix is deposited on the HA layer as a result of some type of phys-iochemical interaction between the collagen of bone and the HA crystals of the implant [3].

Artzi, Carmeli, and Kozlovsky [7] differentiated between the survival and success definitions of functional HA-coated implant prosthesis, using 248 implants (62 patients) for 5 and 10 years in function. They adapted the following criteria: (i) only implants that fulfilled the success rate criteria were considered as successful, (ii) all other functional implants were assigned to the nonsuccessful group, and (iii) all functional implant prostheses were defined as survival ones. Based on their findings that the accumulative survival rates after 5 and 10 years were 94.4 percent and 92.8 percent, respectively, and accumulative success rates were 89.9 per-cent and 54 percent, respectively, it was concluded that a distinguishable observation between survival and success rates was noted particularly in long-term observations. Implant length and diameter also have an influ-ence on the survival rate [7].

On the other hand, there are some nonencouraging reports toward HA-coated implants [8, 9]. Biesbrock and Edgerton [8] studied the clinical predictability and indications for use of HA-coated endosseous implants. It was reported that clinical studies suggested that HA-coated implants have short-term survival rates (ranging from six months to six years) that are comparable to short-term survival rates of titanium implants, indicat-ing no significant advantages of HA-coating. Alsabeeha, Ma, and Atieh [9] evaluated clinical outcomes of HA-coated implants in comparison to non-HA-coated implants for an observation period of at least five years.

IntRODuCtIOn •  3

It was reported that the survival rates ranged from 77.8 to 98.1 percent for the HA-coated implants and from 77.1 to 95.2 percent for the non-HA-coated implants, with no significant differences observed. The reason why there are no significant differences between HA-coated and non-HA-coated Ti implants can be speculated as follows: Ti surface is prone to develop a stable passive oxide film within a very short time period, immediately followed by precipitation of a Ca–P layer, which might be substituted to calcium phosphate (being similar to HA) later on. Once the HA layer was produced inside the biological environment, this cannot be differentiated with synthetic HA.

The application of HA materials is not limited as coating materials; they are also used as bone graft substitutes. Among many types of bone graft substitute materials, a continued interest in avoiding donor sites and utilizing the convenience of off-the-shelf bone-substitute products has stimulated the development of several synthetic, yet biocompatible, bone substitutes. To date, the calcium phosphate apatites including HA cements have been the most useful synthetic bone graft substitutes. Synthetic HA cement has excellent biocompatibility when used to repair bone defects and is capable of osseointegration and substitution by bone when placed in direct contact with viable host bone due to a well-operated balance between osteoclast and osteoblast cells to control amounts of Ca and P in blood, during the bone remodeling process.

One of the most interesting and unique properties of apatites is their ability to accept ionic substitutes and vacancies. Although living creatures fully used these abilities to adapt mineralized tissues to their physiology and functional needs, substituted apatites are only at the beginning of their development in elaborated tailored biomaterials and some of them have been shown to exhibit improved biological properties compared to stoichiometric HA [10]. Excellent ion exchangeability of HA is applied not only in the medical or dental area, but also to control environmental parameters such as F in water, or As or Pb in polluted air. This uniqueness associated with HA has led to further development of scaffold structures for bone tissue engineering and drug-delivery systems [11].

One major trend in the biomedical materials and science field is an increased degree of putting more biofunctional features on material sur-faces, resulting to meet the demands of the biological host system. This can be achieved by optimizing three-dimensional physical micro- and nanoarchitecture of the surface (pore size distributions or roughness), sur-face coatings and impregnations (ion release, multilayer coatings, coatings with biomolecules, controlled drug release, and so on), and the viscoelastic properties (or more generally, the micromechanical properties) of material

4 •  HYDROXYAPAtItE

surfaces [12]. Also these surface modifications are not necessitated on the extreme outer layer of the materials, but rather conducted by building the functionally graded structure and materials from core structures to case layers [13].

Reflecting the aforementioned versatile medical applications of HA, its importance can be demonstrated by showing the ever-increasing research popularity in terms of peer-reviewed publications. Figure 1.1 shows the number of published articles versus annual total or five-year span. For selecting articles, there was only one criterion: if the article has the term, for example, “hydroxyapatite” in either the title or list of key words, the article should count for one. Some interesting things can be found: (i) all categories (titanium biomaterials [6], biocompatibility [6], hydroxyapa-tite [14], and dental/orthopedic implants [6]) exhibit an ever-increasing number of publications, (ii) the increasing trend, since 1995, appears to be

Figure 1.1. Accumulated number of published articles on titanium biomaterials, biocompatibility, hydroxyapatite, and dental/orthopedic implants.

Titanium biomaterials

9876543

2

9876543

2

9876543

2

2

10, 000

1, 000

100

101965 1970 1975 1980 1985 1990 1995 2000 2005 2010 2015

Biocompatibility

Hydroxyapatite

Dental/Orthopedic implants

Year

The

num

ber

of p

ublis

hed

artic

les

IntRODuCtIOn •  5

parallel among four categories, and (iii) particularly, it is implicated that HA proves its biocompatibility.

In subsequent chapters, we will discuss structures and properties of HA; HA as a Ca–P family member; preparation of HA; and HA applica-tions as coating materials, bone graft substitute materials, biocomposite materials, biomimetic materials, and scaffold and drug-delivery materials. It follows a diversity of ion-substituted HA, and effects and influences of HA in medical and dental applications.

REfEREnCES

[1] Hamed, E., E. Novitskaya, J. Li, P.-Y. Chen, I. Jasiuk, and J. McKittrick. 2012. “Elastic Moduli of Untreated, Demineralized and Deproteinized Cortical Bone: Validation of a Theoretical Model of Bone as an Interpen-etrating Composite Material.” Acta Biomater 8, no. 3, pp. 1080–92. doi: http://dx.doi.org/10.1016/j.actbio.2011.11.010.http://dx.doi.org/10.1016/j .actbio.2011.11.010.

[2] Sicilia, A., S. Cuesta, G. Coma, I. Arregui, C. Guisasola, E. Ruiz, and A. Maestro. 2008. “Titanium Allergy in Dental Implant Patients: A Clinical Study on 1500 Consecutive Patients.” Clinical Oral Implants Research 19, no. 8, pp. 823–35. doi: http://dx.doi.org/10.1111/j.1600-0501.2008.01544.x.

[3] James, R.A., R.V. McKinney Jr, and R.M. Meffert. 1999. “Tissues Surround-ing Dental Implants.” In Contemporary Implant Dentistry, ed. C.E. Misch, 2nd ed. St. Louis, MO: Mosby.

[4] Huang, Y.-M., I.-C. Chou, C.-P. Jiang, Y.-S. Wu, and S.-Y. Lee. 2014. “Finite Element Analysis of Dental Implant Neck Effects on Primary Stability and Osseointegration in a Type IV Bone Mandible.” Bio-Medical Materials and Engineering 24, no. 1, pp. 1407–15. doi: 10.3233/BME-130945.

[5] Mohseni, E., E. Zalnezhad, and A.R. Bushroa. 2014. “Comparative Investi-gation on the Adhesion of Hydroxyapatite Coating on Ti–6Al–4V Implant: A Review Paper.” International Journal of Adhesion and Adhesives 48, pp. 238–57. doi: http://dx.doi.org/10.1016/j.ijadhadh.2013.09.030.

[6] Oshida, Y. 2014. Surface Engineering and Technology for Biomedical Implants. New York, NY: Momentum Press.

[7] Artzi, Z., G. Carmeli, and A. Kozlovsky. 2006. “A Distinguishable Observa-tion between Survival and Success Rate Outcome of Hydroxyapatite-coated Implants in 5–10 Years in Function.” Clinical Oral Implants Research 17, no. 1, pp. 85–93. doi: http://dx.doi.org/10.1111/j.1600-0501.2005.01178.x.

[8] A.R. Biesbrock, and M. Edgerton. 1995. “Evaluation of the Clinical Predict-ability of Hydroxyapatite-coated Endosseous Dental Implants: A Review of the Literature.” The International Journal of Oral & Maxillofacial Implants 10, no. 6, pp. 712–20.

6 •  HYDROXYAPAtItE

[9] Alsabeeha, N.H.M., S. Ma, and M.A. Atieh. 2012. “Hydroxyapatite-Coated Oral Implants: A Systematic Review and Meta-Analysis.” The International Journal of Oral & Maxillofacial Implants 27, no. 5, pp. 1123–30.

[10] Porter, A.E., N. Patel, J.N. Skepper, S.M. Best, and W. Bonfield. 2004. “Effect of Sintered Silicate-Substituted Hydroxyapatite on Remodelling Processes at the Bone-Implant Interface.” Biomaterials 25, no. 16, pp. 3303–14. doi: http://dx.doi.org/10.1016/j.biomaterials.2003.10.006.

[11] Ślósarczyk, A., J. Szymura-Oleksiak, and B. Mycek. 2000. “The Kinetics of Pentoxifylline Release from Drug-Loaded Hydroxyapatite Implants.” Biomaterials 21, no. 12, pp. 1215–21. doi: http://dx.doi.org/10.1016/s0142-9612(99)00269-0

[12] Kasemo, B., and J. Gold. 1999. “Implant Surfaces and Interface Processes.” Advances in Dental Research 13, no. 1, pp. 18–20. doi: http://dx.doi.org/10.1177/08959374990130011901.

[13] Wang, F., H.P. Lee, and C. Lu. 2007. “Thermal–Mechanical Study of Func-tionally Graded Dental Implants with the Finite Element Method.” Journal of Biomedical Materials Research Part A 80A, no. 1, pp. 146–58. doi: http://dx.doi.org/10.1002/jbm.a.30855.

[14] http://academic.research.microsoft.com/Keyword/18845/hydroxyapa-tite?query=hydroxyapatite

index

AABCA. See Anorganic bovine

carbonate apatiteAcid−base reaction, 382, 383Air plasma spray coating, 102, 103Allografts, 162Anorganic bovine carbonate

apatite (ABCA), 190Antibiotics, 83–85Apaceram-AX®, 171Aspect ratio, 39Autogenous bone, 162Autografts, 161, 162

BBioabsorbable polymers, 166Bioceramic coating materials, 103Biocomposites

carbon, carbides, and nitrides, 226, 227

dental composites, 230, 231glass and bioglass, 227–230HA−HA whisker composites,

243–245metallic oxides, 217–224metals and alloys, 214–217ninerals, 224–226protein and collagen, 242, 243

Biodegradable materials, 167Biodegradable scaffolds, 304Bioglass, 227–230Biomaterial coatings, 119Biomimetic materials and

structures

chitosan treatments, 280–284mechanical properties, 289other composite treatments,

284–289protein group treatments,

268–280simulated body fluid treatments,

264–268tissue engineering, 263, 264

Bioresorbable bone substitute, 74Biphasic biocomposites, 22–25Bivalent cations (M) substitution

Al2O3, 73barium-calcium solid solutions,

69barium-lead solid solutions, 69carborundum, 71Cu ions, 57Fe ions, 57high-density polyethylene, 71lanthanoids, 66, 67magnesium, 63–66Ni3Al, 73potassium, 71silver, 54, 55SiO2, 72SiO2-Ti, 72sodium, 70, 71strontium, 57–62TiO2, 71, 72titanium, 67, 68tungsten, 68yttrium-doped nanocrystalline,

68

396 • InDEX

zinc ions, 56, 57ZrO2, 73

BMP2. See Bone morphogenetic protein-2

Boneautogenous, 162description, 159grafting, 160harvested, 161, 162ideal resorbable, 160resorption, 159, 160

Bone-graft extenders, 192, 193Bone graft substitutes

animal tests, 184–190biodegradable materials, 167cell-based, 163, 164cement materials, 181–184ceramic-based, 164–166clinical results, 190–194growth factor-based, 163harvested bone, 161, 162HA−TCP biphase composites,

176–178newly developed materials, 194,

195other types of HA-based

biocomposites, 178–181polymer-based, 166, 167shape, form, and controlled

porosity, 170–176Bone metabolism, 186Bone modeling, 186Bone morphogenetic protein-2

(BMP2), 171, 172Bone remodeling, 186BoneSource™, 183Boron nitride−HA nanotube

composites, 227Bovine bone granules, 194

CCalcite−HA composites, 225Calcium-deficient HA-based

composites, 231–233

Calcium-deficient hydroxyapatite (CDHA), 53, 54, 167–169

Calcium hydroxide salicylate cements, 181

Calcium phosphate nanoparticles, 340

Carborundum (SiC), 71CDHA. See Calcium-deficient

hydroxyapatiteCell-based bone-graft substitutes,

163, 164Cement disease, 181, 182Cement materials, 181–184Cement pastes, 343Ceramic-based bone-graft

substitutesbioactive ceramics, 165, 166bioactive glasses, 165, 166ceramics, 164, 165hydroxyapatite, 164

Chemical corrosion resistance, 127–129

Chitosan treatments, 280–284Chlorhexidine digluconate

(CHXDG), 346CHXDG. See Chlorhexidine

digluconateCoated hydroxyapatite

amorphous phase, 120animal studies, 129–133bioactivity, 120biomaterial coatings, 119chemical corrosion resistance,

127–129clinical reports, 133–142degree of crystallinity, 120, 121fetal calf serum, 126mechanical properties, 123–125residual stresses, 125, 126sol-gel processing, 122tribological wear behavior, 125

Coating materialsair plasma spray coating, 102,

103

InDEX • 397

bioceramic, 103metal substrates, 104microarc oxidation, 103microchanneled ZrO2 bodies,

105single-walled carbon nanotube,

105, 106strontium-doped HA-ZnO

composites, 106, 107surface and microstructure

characteristics, 102Ti-6Al-4V composites, 107

Coating methodselectron-beam spraying method,

111, 112electrophoretic deposition,

113–115gas tunnel type plasma spraying,

108, 109high-velocity suspension flame

spraying, 109, 110interfacial bonding, 118laser-assisted laser ablation

method, 110, 111physical vapor deposition, 112,

113precipitation process, 117, 118sol-gel coating process, 115–117

Composite materialsdefinition, 213properties, 214

Compositional alterationprocess-related alteration, 12resorption, 12

Crystallinitybiological performance, 14–17parameters influencing, 12–14

DDegradable synthetic polymers,

166Degree of crystallinity, 120, 121Dental cements, 181Dental composites, 230, 231

Dissolutiondefinition, 10in hydroxyapatite, 10, 11

Drug-delivery systemsapplications, 343–347description, 339, 340materials, 340–343

EElectron-beam spraying method,

111, 112Electrophoretic deposition (EPD),

113–115Elemental substitutions

antibiotics, 83–85bivalent cations, 54–73description, 53, 54monovalent anions, 80–83trivalent anions, 74–80

Endobon®, 188EPD. See Electrophoretic

deposition

FForsterite−HA composites, 226Functionally graded HA structure,

245–247

GGas tunnel type plasma spraying,

108, 109Gelatin−HA composite membrane,

242, 243GICs. See Glass-ionomer cementsGlass−HA composites, 227Glass-ionomer cements (GICs),

73, 167, 181, 227

HHA. See HydroxyapatiteHA−HA whisker composites,

243–245Harvested bone

allografts, 162autografts, 161, 162

398 • InDEX

HDPE. See High-density polyethylene

High-density polyethylene (HDPE), 71

High impact polystyrene (HIPS), 241, 242

High-temperature hydroxyapatite, 8–10

High-temperature processes, 34–37

High-velocity suspension flame spraying (HVSFS), 109, 110

HIPS. See High impact polystyrene

hMSCs. See Human mesenchymal stem cells

HOB. See Human osteoblastlike cells

Human mesenchymal stem cells (hMSCs), 283

Human osteoblastlike cells (HOB), 179

HVSFS. See High-velocity suspension flame spraying

Hydrothermal processes, 39, 40Hydroxyapatite (HA)

applications of, 3–5biphasic biocomposites, 22–25calcium sources, 33Ca-P family, 17–19chemical formula, 54compositional alteration, 11, 12crystallinity, 12–17dissolution, 10, 11functionally graded structure,

245–247high-temperature, 8–10high-temperature processes,

34–37hydrothermal processes, 39, 40low-crystallinity, 347low-temperature, 8–10low-temperature processes, 38,

39

new and unique techniques, 42–44

parameters affecting, 381–386simulated body fluid treatment,

41, 42sol-gel processes, 40, 41solubility, 10, 11stoichiometric, 7, 8vs. tricalcium phosphate, 19–22

IIdeal resorbable bone, 160Injectability, 174Inorganic nanosized drug carriers,

345Integrin-binding peptides, 276Interfacial bonding, 118

LLanthanoids, 66, 67LASAT. See Laser shock adhesion

testLaser-assisted laser ablation

method, 110, 111Laser shock adhesion test

(LASAT), 367, 368Low-crystallinity hydroxyapatite,

347Low-temperature hydroxyapatite,

8–10Low-temperature processes, 38, 39

MMagnetic field single-walled

carbon nanotubes, 282Marrow stromal cells, 303Medical Dictionary for the Health

Professions and Nursing, 182Mesenchymal stem cells (MSCs),

163Metallic oxides

HA–Ag2O composites, 222, 223HA–Al2O3 composites, 223HA–NiO composites, 223

InDEX • 399

HA–SiO2 composites, 224HA–TiO2 composites, 217, 218HA–Y2O3 composites, 224HA–ZrO composites, 222HA–ZrO2 composites, 218–222

Microarc oxidation, 103Microchanneled ZrO2 bodies, 105Minerals

HA−calcite composites, 225HA−Fe3O4 composites, 224, 225HA−forsterite composites, 226HA−mullite composites, 225,

226HA−tobermorite composites, 225HA−wollastonite composites,

225Monovalent anions (Y)

substitution, 80–83MSCs. See Mesenchymal stem

cellsMullite−HA composites, 225, 226

NNational Library of Medicine

of the National Institutes of Health, 182

NEOBONE®, 171Nonmagnetic field single-walled

carbon nanotubes, 282

OOrthopedic implants fixation, 181Ossification, 186OsteoBiol®mp3, 188Osteoconductivity, 160, 161Osteogenicity, 161Osteoinductivity, 161Ostim®, 175

PParameters affecting

hydroxyapatiteacid−base reaction, 382, 383acidic protein, 384environmental factors, 385, 386

impurities, 384sintering parameters, 381, 382types of chemicals, 383

Physical vapor deposition (PVD), 112, 113

Poly(etheretherketone) PEEK−HA composites, 236, 237

Polyethylene PE−HAcomposites, 237, 238

Polymers−HA compositescalcium-deficient HA-based

composites, 231–233high impact polystyrene, 241,

242poly(etheretherketone)

composites, 236, 237poly(propylene fumarate)

cross-linkable nanocomposites, 242

polyethylene composites, 237, 238

poly-lactic acid/poly(l-lactide) composites, 233–235

poly [methyl methacrylate] composites, 238–240

PVA gel composites, 240Poly [methyl methacrylate]

PMMA−HA composites, 238–240

Poly(propylene fumarate) (PPF) cross-linkable nanocomposites, 242

Poly(vinyl alcohol) gel composites, 240

Precipitation process, 117, 118Process-related alteration, 12Protein group treatments, 268–280PVD. See Physical vapor

deposition

RResidual stresses, 125, 126Resorption

bone, 159definition, 12

400 • InDEX

SSCA. See Synthetic carbonated

apatiteScaffolds

biodegradable, 304bone regeneration, 303, 304Ca–P members, HA composites

with, 311, 312criteria for bone tissue

engineering, 301, 302fabrication techniques, 335–339hydroxyapatite materials,

304–310metallic oxides, HA composites

with, 313, 314natural polymers, HA composites

with, 314–324synthetic polymers, HA

composites with, 324–335uses of, 304

Schneiderian membrane, 189sHA. See Stoichiometric

hydroxyapatiteSiC. See CarborundumSilicate-based glass−HA

composites, 229Silk fibroin−HA nanocomposites,

243Simulated body fluid (SBF)

treatments, 9, 41, 42, 264–268Single-walled carbon nanotube

(SWCNTs), 105, 106magnetic field, 282nonmagnetic field, 282

Sintering parameters, 381, 382Sol-gel coating process, 115–117Sol-gel processes, 40, 41Solubility

definition, 10in hydroxyapatite, 10

Stem cells, 163Stoichiometric hydroxyapatite

(sHA), 7, 8

Stress shielding, 138Strontium-doped HA-ZnO

composites, 106, 107Surface biocompatibility, 226SWCNT. See Single-walled carbon

nanotubeSynthesis technologies

high-temperature processes, 34–37

hydrothermal processes, 39, 40low-temperature processes, 38,

39new and unique techniques,

42–44simulated body fluid treatment,

41, 42sol-gel processes, 40, 41

Synthetic carbonated apatite (SCA), 190

TTCP. See Tricalcium phosphateTissue engineering, 263, 264, 301Tobermorite−HA composites, 225Tribological wear behavior, 125Tricalcium phosphate (TCP)

biphasic biocomposites, 22–25vs. hydroxyapatite, 19–22

Trivalent anions (XO4) substitutionbioresorbable bone substitute, 74carbonate containing materials,

74Si-substituted hydroxyapatite,

74–80

VVanillate cements, 181

WWollastonite−HA composites, 225

XXenografts, 192