HYDROXYAPATITE

HYDROXYAPATITE
SYNTHESIS AND
APPLICATIONS
YOSHIKI OSHIDA

MOMENTUM PRESS, LLC, NEW YORK

Hydroxyapatite: Synthesis and Applications

Copyright 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 otherexcept for
brief quotations, not to exceed 400 words, without the prior permission
of the publisher.
First published by Momentum Press, LLC
222 East 46th Street, New York, NY 10017
www.momentumpress.net
ISBN-13: 978-1-60650-673-8 (print)
ISBN-13: 978-1-60650-674-5 (e-book)
Momentum Press Biomaterials Engineering Collection
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

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 example 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 , 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 recognized 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 biocomposites, bone-graft substitute materials, clinical reports, crystallinity,
drug-delivery systems, elemental substitutions, hydroxyapatite coating
materials, hydroxyapatite-based biocomposites, scaffolds materials and
structures, synthesis

vii

Contents
List of Figures

xiii

List of Tables

xv

Acknowledgments

xvii

Preface

xix

1Introduction

References

2Structure and Properties

2.1Introduction

2.2High-temperature and Low-temperature HAs

2.3 Dissolution and Solubility

10

2.4 Compositional Alteration of HA

11

2.5 Crystallinity and Its Effects

12

2.6 CaP 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

3.1Introduction

33

3.2 Sources for Calcium in HA

33

3.3 HA Synthesis Technologies

34

References

44

ix

xContents

4Elemental Substitutions in Hydroxyapatite Structure

53

4.1Introduction

53

4.2 M Substitution in M10(XO4)6(Y)254

4.3XO4 Substitution in M10(XO4)6(Y)274

4.4 Y Substitution in M10(XO4)6(Y)280

4.5Antibiotics

83

References

85

5 Hydroxyapatite Coating Materials

101

5.1Introduction

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

6Bone-Graft Substitute Materials

159

6.1Introduction

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

7.1Introduction

213

7.2 HAMetal and Alloys

214

7.3 HAMetallic Oxides

217

7.4HAMinerals

224

7.5 HACarbon, Carbides, and Nitrides

226

7.6 HAGlass and Bioglass

227

7.7 HADental Composites

230

7.8HAPolymers

231

242

7.9 HAProtein and Collagen

Contents xi

7.10 HAHA Whiskers and TCP

243

7.11 Functionally Graded HA Structure

245

References

248

8Biomimetic Materials and Structures

263

8.1Introduction

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

9Scaffolds and Drug-Delivery Systems

301

9.1Introduction

301

9.2 ScaffoldStructure and Materials

301

9.3 Drug-Delivery Systems

339

References

348

10Effects of Hydroxyapatite and Influences

on Hydroxyapatite

365

10.1Introduction

365

10.2 Effects of HA

365

10.3 Various Parameters Affecting HA

380

References

386

About the Author

393

Index

395

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

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

xiii

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

xv

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, JAdhes Sci Technol, J Alloys Compd,
J Am Ceram Soc, J Appl Phys, J Appl Biomater, J Assoc Ad Med Instrum,
J Arthroplasty, J Bacteriol, JBiochem Biophys Method, J Bio Sci Polym
Ed, Journal of Metals, JBiomech, 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, JChronic 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
xvii

xviiiAcknowledgments

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 appreciationfrom my teachers
who inspired me, friends and colleagues who challenged me, and most
importantly students (some of them are now my colleagues) who continue to both inspire and challenge me. To all of them, I owe my knowledge 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. Aktren,
K.Genay, Y. Gven, 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.

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
60percent of bones, 97 percent of tooth enamel, and 70 percent of tooth
dentin. The name apatite in HA originated from the Greek word ,
meaning to deceive. HA is just one type of calcium phosphate and possesses 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, adsorbent 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 remineralization 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 penetrate into sintered porous HA structure to exhibit excellent bone conductivity. 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 osteoclast 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 stabilization are demanded. Hydroxyl group, carboxyl group, and amino group are
typical functional groups to show a strong interaction with HA. HA exhibits a high absorptivity with proteins, lipids, and sugars, too. Accordingly,
HA is extensively employed as an adsorbent in chromatography to separate biomolecules or as cosmetics to remove excess lipids. HA possesses
xix

xxPreface

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

PO42 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 Biomedical 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. Chapter1 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 PO42 (B-site) and OH2
(A-site) for anions are discussed. Structure-related phenomena including 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, indicating that x-HA (x: substituted element) exhibits wide range of enhancement and improvement in chemical, mechanical, physical properties,
and medical performances, too. Chapter 5 discusses HA coating materials and coating technologies to improve medical function, and chemical 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 osteoconductivity, 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 collagen. Functionally graded materials can be prepared by compositing various 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 materials and structures are discussed. Various treatments on HA to make HA as
biomimetic in nature include treatments in simulated body fluid, and treatments 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. C
hapter10 identifies 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) currently 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 member of the Japan Implant Practice Society. Dr. Yutaka Ikeda (Chapter3),
PhD and DDS, is currently a member of Japan Implant Practice Society.
Dr. Katsuya Kuroki (Chapter 4) holds a PhD and a DDS, currently working at the Department of Anatomy, Osaka Dental University and a member of the Japan Implant Practice Society. Dr. Noboru Obata (Chapter5),
is PhD and DDS, is a member of the Japan Implant Practice Society.
Dr.Kyoichiro 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 University, Turkey. Dr.Guven is currently a research assistant and Dr. Aktoren is
serving as the Department Chairwoman. Dr.Mikio Fukushima (Chapter8)
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

xxiiPreface

rofessor of Manila Central University, a councilor of J apanese Society of

P
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 noncollagenous 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 28percent
is type I collagen and the other five percent is noncollagenous glycoproteins, including osteonectin, osteocalcin, bone morphogenetic proteins,
bone proteoglycan, and bone sialoprotein), and the other 67percent inorganic 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 covered 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 96percent 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 70percent inorganic materials, 20 percent organic materials, and 10percent water by weight.
Many modern implants, for example, hip or knee replacements, dental 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

2HYDROXYAPATITE

Ti-based alloys such as Ti6Al4V and Ti6Al7Nb) 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 bioinertness [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, electrophoretic deposition, solgel, ion beam assisted deposition, and sputtering [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 physiochemical 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
92.8percent, respectively, and accumulative success rates were 89.9 percent 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 influence 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, indicating 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.

Introduction3

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 nonHA-coated implants, with no significant differences observed. The reason
why there are no significant differences between HA-coated and nonHA-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 CaP 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 surfaces, 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), surface 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

4HYDROXYAPATITE

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], b iocompatibility[6], hydroxyapatite[14], and dental/orthopedic implants [6]) exhibit an ever-increasing
number of publications, (ii) the increasing trend, since 1995, appears to be

10, 000 9
8
7
6
5
4
3

The number of published articles

Titanium biomaterials
1, 000 9
8
7
6
5
4
3

Biocompatibility

100 9
8
7
6
5
4

Hydroxyapatite
Dental/Orthopedic implants

3
2

10

1965 1970 1975 1980 1985 1990 1995 2000 2005 2010 2015
Year

Figure 1.1. Accumulated number of published articles on titanium biomaterials,

biocompatibility, hydroxyapatite, and dental/orthopedic implants.

Introduction5

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 CaP family member; preparation of HA; and HA applications 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 Interpenetrating Composite Material. Acta Biomater 8, no. 3, pp.108092. 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.82335. 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 Surrounding 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.140715. doi: 10.3233/BME-130945.
[5] Mohseni, E., E. Zalnezhad, and A.R. Bushroa. 2014. Comparative Investigation on the Adhesion of Hydroxyapatite Coating on Ti6Al4V Implant:
A Review Paper. International Journal of Adhesion and Adhesives 48,
pp.23857. 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 Observation between Survival and Success Rate Outcome of Hydroxyapatite-coated
Implants in 510 Years in Function. Clinical Oral Implants Research 17,
no.1, pp.8593. 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 Predictability of Hydroxyapatite-coated Endosseous Dental Implants: A Review of
the Literature. The International Journal of Oral & Maxillofacial Implants
10, no. 6, pp.71220.

6HYDROXYAPATITE
[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.112330.
[10] Porter, A.E., N. Patel, J.N. Skepper, S.M. Best, and W. Bonfield. 2004. Effect
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at the Bone-Implant Interface. Biomaterials 25, no. 16, pp.330314. doi:
http://dx.doi.org/10.1016/j.biomaterials.2003.10.006.
[11] lsarczyk, A., J. Szymura-Oleksiak, and B. Mycek. 2000. The Kinetics
of Pentoxifylline Release from Drug-Loaded Hydroxyapatite Implants.
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[12] Kasemo, B., and J. Gold. 1999. Implant Surfaces and Interface Processes.
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1177/08959374990130011901.
[13] Wang, F., H.P. Lee, and C. Lu. 2007. ThermalMechanical Study of Functionally Graded Dental Implants with the Finite Element Method. Journal
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[14] http://academic.research.microsoft.com/Keyword/18845/hydroxyapatite?query=hydroxyapatite

Index
A
ABCA. See Anorganic bovine
carbonate apatite
Acidbase reaction, 382, 383
Air plasma spray coating, 102, 103
Allografts, 162
Anorganic bovine carbonate
apatite (ABCA), 190
Antibiotics, 8385
Apaceram-AX, 171
Aspect ratio, 39
Autogenous bone, 162
Autografts, 161, 162
B
Bioabsorbable polymers, 166
Bioceramic coating materials, 103
Biocomposites
carbon, carbides, and nitrides,
226, 227
dental composites, 230, 231
glass and bioglass, 227230
HAHA whisker composites,
243245
metallic oxides, 217224
metals and alloys, 214217
ninerals, 224226
protein and collagen, 242, 243
Biodegradable materials, 167
Biodegradable scaffolds, 304
Bioglass, 227230
Biomaterial coatings, 119
Biomimetic materials and
structures

chitosan treatments, 280284

mechanical properties, 289
other composite treatments,
284289
protein group treatments,
268280
simulated body fluid treatments,
264268
tissue engineering, 263, 264
Bioresorbable bone substitute, 74
Biphasic biocomposites, 2225
Bivalent cations (M) substitution
Al2O3, 73
barium-calcium solid solutions,
69
barium-lead solid solutions, 69
carborundum, 71
Cu ions, 57
Fe ions, 57
high-density polyethylene, 71
lanthanoids, 66, 67
magnesium, 6366
Ni3Al, 73
potassium, 71
silver, 54, 55
SiO2, 72
SiO2-Ti, 72
sodium, 70, 71
strontium, 5762
TiO2, 71, 72
titanium, 67, 68
tungsten, 68
yttrium-doped nanocrystalline,
68

396 Index

zinc ions, 56, 57

ZrO2, 73
BMP2. See Bone morphogenetic
protein-2
Bone
autogenous, 162
description, 159
grafting, 160
harvested, 161, 162
ideal resorbable, 160
resorption, 159, 160
Bone-graft extenders, 192, 193
Bone graft substitutes
animal tests, 184190
biodegradable materials, 167
cell-based, 163, 164
cement materials, 181184
ceramic-based, 164166
clinical results, 190194
growth factor-based, 163
harvested bone, 161, 162
HATCP biphase composites,
176178
newly developed materials, 194,
195
other types of HA-based
biocomposites, 178181
polymer-based, 166, 167
shape, form, and controlled
porosity, 170176
Bone metabolism, 186
Bone modeling, 186
Bone morphogenetic protein-2
(BMP2), 171, 172
Bone remodeling, 186
BoneSource, 183
Boron nitrideHA nanotube
composites, 227
Bovine bone granules, 194
C
CalciteHA composites, 225
Calcium-deficient HA-based
composites, 231233

Calcium-deficient hydroxyapatite
(CDHA), 53, 54, 167169
Calcium hydroxide salicylate
cements, 181
Calcium phosphate nanoparticles,
340
Carborundum (SiC), 71
CDHA. See Calcium-deficient
hydroxyapatite
Cell-based bone-graft substitutes,
163, 164
Cement disease, 181, 182
Cement materials, 181184
Cement pastes, 343
Ceramic-based bone-graft
substitutes
bioactive ceramics, 165, 166
bioactive glasses, 165, 166
ceramics, 164, 165
hydroxyapatite, 164
Chemical corrosion resistance,
127129
Chitosan treatments, 280284
Chlorhexidine digluconate
(CHXDG), 346
CHXDG. See Chlorhexidine
digluconate
Coated hydroxyapatite
amorphous phase, 120
animal studies, 129133
bioactivity, 120
biomaterial coatings, 119
chemical corrosion resistance,
127129
clinical reports, 133142
degree of crystallinity, 120, 121
fetal calf serum, 126
mechanical properties, 123125
residual stresses, 125, 126
sol-gel processing, 122
tribological wear behavior, 125
Coating materials
air plasma spray coating, 102,
103

Index 397

bioceramic, 103
metal substrates, 104
microarc oxidation, 103
microchanneled ZrO2 bodies,
105
single-walled carbon nanotube,
105, 106
strontium-doped HA-ZnO
composites, 106, 107
surface and microstructure
characteristics, 102
Ti-6Al-4V composites, 107
Coating methods
electron-beam spraying method,
111, 112
electrophoretic deposition,
113115
gas tunnel type plasma spraying,
108, 109
high-velocity suspension flame
spraying, 109, 110
interfacial bonding, 118
laser-assisted laser ablation
method, 110, 111
physical vapor deposition, 112,
113
precipitation process, 117, 118
sol-gel coating process, 115117
Composite materials
definition, 213
properties, 214
Compositional alteration
process-related alteration, 12
resorption, 12
Crystallinity
biological performance, 1417
parameters influencing, 1214
D
Degradable synthetic polymers,
166
Degree of crystallinity, 120, 121
Dental cements, 181
Dental composites, 230, 231

Dissolution
definition, 10
in hydroxyapatite, 10, 11
Drug-delivery systems
applications, 343347
description, 339, 340
materials, 340343
E
Electron-beam spraying method,
111, 112
Electrophoretic deposition (EPD),
113115
Elemental substitutions
antibiotics, 8385
bivalent cations, 5473
description, 53, 54
monovalent anions, 8083
trivalent anions, 7480
Endobon, 188
EPD. See Electrophoretic
deposition
F
ForsteriteHA composites, 226
Functionally graded HA structure,
245247
G
Gas tunnel type plasma spraying,
108, 109
GelatinHA composite membrane,
242, 243
GICs. See Glass-ionomer cements
GlassHA composites, 227
Glass-ionomer cements (GICs),
73, 167, 181, 227
H
HA. See Hydroxyapatite
HAHA whisker composites,
243245
Harvested bone
allografts, 162
autografts, 161, 162

398 Index

HDPE. See High-density

polyethylene
High-density polyethylene
(HDPE), 71
High impact polystyrene (HIPS),
241, 242
High-temperature hydroxyapatite,
810
High-temperature processes,
3437
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, 40
Hydroxyapatite (HA)
applications of, 35
biphasic biocomposites, 2225
calcium sources, 33
Ca-P family, 1719
chemical formula, 54
compositional alteration, 11, 12
crystallinity, 1217
dissolution, 10, 11
functionally graded structure,
245247
high-temperature, 810
high-temperature processes,
3437
hydrothermal processes, 39, 40
low-crystallinity, 347
low-temperature, 810
low-temperature processes, 38,
39

new and unique techniques,

4244
parameters affecting, 381386
simulated body fluid treatment,
41, 42
sol-gel processes, 40, 41
solubility, 10, 11
stoichiometric, 7, 8
vs. tricalcium phosphate, 1922
I
Ideal resorbable bone, 160
Injectability, 174
Inorganic nanosized drug carriers,
345
Integrin-binding peptides, 276
Interfacial bonding, 118
L
Lanthanoids, 66, 67
LASAT. See Laser shock adhesion
test
Laser-assisted laser ablation
method, 110, 111
Laser shock adhesion test
(LASAT), 367, 368
Low-crystallinity hydroxyapatite,
347
Low-temperature hydroxyapatite,
810
Low-temperature processes, 38, 39
M
Magnetic field single-walled
carbon nanotubes, 282
Marrow stromal cells, 303
Medical Dictionary for the Health
Professions and Nursing, 182
Mesenchymal stem cells (MSCs),
163
Metallic oxides
HAAg2O composites, 222, 223
HAAl2O3 composites, 223
HANiO composites, 223

Index 399

HASiO2 composites, 224

HATiO2 composites, 217, 218
HAY2O3 composites, 224
HAZrO composites, 222
HAZrO2 composites, 218222
Microarc oxidation, 103
Microchanneled ZrO2 bodies, 105
Minerals
HAcalcite composites, 225
HAFe3O4 composites, 224, 225
HAforsterite composites, 226
HAmullite composites, 225,
226
HAtobermorite composites, 225
HAwollastonite composites,
225
Monovalent anions (Y)
substitution, 8083
MSCs. See Mesenchymal stem
cells
MulliteHA composites, 225, 226
N
National Library of Medicine
of the National Institutes of
Health, 182
NEOBONE, 171
Nonmagnetic field single-walled
carbon nanotubes, 282
O
Orthopedic implants fixation, 181
Ossification, 186
OsteoBiolmp3, 188
Osteoconductivity, 160, 161
Osteogenicity, 161
Osteoinductivity, 161
Ostim, 175
P
Parameters affecting
hydroxyapatite
acidbase reaction, 382, 383
acidic protein, 384
environmental factors, 385, 386

impurities, 384
sintering parameters, 381, 382
types of chemicals, 383
Physical vapor deposition (PVD),
112, 113
Poly(etheretherketone) PEEKHA
composites, 236, 237
Polyethylene PEHAcomposites,
237, 238
PolymersHA composites
calcium-deficient HA-based
composites, 231233
high impact polystyrene, 241,
242
poly(etheretherketone)
composites, 236, 237
poly(propylene fumarate)
cross-linkable nanocomposites,
242
polyethylene composites, 237,
238
poly-lactic acid/poly(L-lactide)
composites, 233235
poly [methyl methacrylate]
composites, 238240
PVA gel composites, 240
Poly [methyl methacrylate]
PMMAHA composites,
238240
Poly(propylene fumarate) (PPF)
cross-linkable nanocomposites,
242
Poly(vinyl alcohol) gel
composites, 240
Precipitation process, 117, 118
Process-related alteration, 12
Protein group treatments, 268280
PVD. See Physical vapor
deposition
R
Residual stresses, 125, 126
Resorption
bone, 159
definition, 12

400 Index

S
SCA. See Synthetic carbonated
apatite
Scaffolds
biodegradable, 304
bone regeneration, 303, 304
CaP members, HA composites
with, 311, 312
criteria for bone tissue
engineering, 301, 302
fabrication techniques, 335339
hydroxyapatite materials,
304310
metallic oxides, HA composites
with, 313, 314
natural polymers, HA composites
with, 314324
synthetic polymers, HA
composites with, 324335
uses of, 304
Schneiderian membrane, 189
sHA. See Stoichiometric
hydroxyapatite
SiC. See Carborundum
Silicate-based glassHA
composites, 229
Silk fibroinHA nanocomposites,
243
Simulated body fluid (SBF)
treatments, 9, 41, 42, 264268
Single-walled carbon nanotube
(SWCNTs), 105, 106
magnetic field, 282
nonmagnetic field, 282
Sintering parameters, 381, 382
Sol-gel coating process, 115117
Sol-gel processes, 40, 41
Solubility
definition, 10
in hydroxyapatite, 10
Stem cells, 163
Stoichiometric hydroxyapatite
(sHA), 7, 8

Stress shielding, 138

Strontium-doped HA-ZnO
composites, 106, 107
Surface biocompatibility, 226
SWCNT. See Single-walled carbon
nanotube
Synthesis technologies
high-temperature processes,
3437
hydrothermal processes, 39, 40
low-temperature processes, 38,
39
new and unique techniques,
4244
simulated body fluid treatment,
41, 42
sol-gel processes, 40, 41
Synthetic carbonated apatite
(SCA), 190
T
TCP. See Tricalcium phosphate
Tissue engineering, 263, 264, 301
TobermoriteHA composites, 225
Tribological wear behavior, 125
Tricalcium phosphate (TCP)
biphasic biocomposites, 2225
vs. hydroxyapatite, 1922
Trivalent anions (XO4) substitution
bioresorbable bone substitute, 74
carbonate containing materials,
74
Si-substituted hydroxyapatite,
7480
V
Vanillate cements, 181
W
WollastoniteHA composites, 225
X
Xenografts, 192