Recent Patents on Materials Science 2011, 4, 63-80 63

Recent Progress on Hydroxyapatite-Based Dense Biomaterials for Load

Bearing Bone Substitutes

Natasha A. Nawawi1, Asep S.F. Alqap1,2 and Iis Sopyan1,*

1
Department of Manufacturing and Materials Engineering, Faculty of Engineering, International Islamic University
Malaysia (IIUM), PO Box 10, 50728 Kuala Lumpur, Malaysia, 2 Mechanical Engineering Program, Faculty of
Engineering, University of Bengkulu, Bengkulu 38000, Indonesia

Received: November 3, 2009; Accepted: October 7, 2010; Revised: October 18, 2010

Abstract: Hydroxyapatite (HA) is the main mineral component of bone tissue, representing ca. 69 vol% in bone and up to
98 vol% in dental enamel. Its chemical composition close to the mineral phase of bone is the origin of its excellent
biocompatibility to tissue bone. Hydroxyapatite has been applied in orthopaedics as block implants, porous, granules and
coating material, either dense or porous. However, the application is restricted to non-load bearing application due to its
brittleness and low toughness and flexural strength. With this, the development of bioactive dense HA is necessary as it
has promising potential in application of load bearing bone implant. Few efforts have been made in developing many
methods to produce dense HA. Some of the methods have been combined to prepare dense HA with improved properties.
This paper will be discussing the recent progress on efforts which have been done in improving mechanical properties of
hydroxyapatite-based dense type biomaterials for load bearing bone substitutes applications. Some recent patents related
to dense calcium phosphate are also reviewed.
Keywords: Hydroxyapatite, dense, preparation, bone substitutes, review.

INTRODUCTION living hard tissues. It is biologically active and has a

For years, synthetically produced calcium hydroxyapatite
and the related calcium phosphates have been of consi-
derable interest as biocompatible materials for bone replace-
ment as they are the dominant mineral constituents of bone,
teeth and hard tissues [1-9]. Literally, hydroxyapatite (HA) is
one of the calcium phosphate compounds with a definite
composition Ca10(PO4)6(OH)2 and crystallographic structure
[10]. It is a crystalline substance essentially composed of
phosphorus and calcium [11] and constitutes ca. 69 vol% of
the mineral component of human bone [11-14]. Dejong has
first identified HA as being the mineral component of bone
[15].
HA has then been extensively studied for its potential in
variety of medical applications as HA is found to be the most
stable calcium phosphate polymorph under physiological
conditions [16, 17].
Clinically, HA was used in a variety of physical forms
such as a sintered ceramic in granular [18], block or porous
form [7, 12, 18-20], as a deposited coating on a bioinert
implant [12, 21, 22] and metal prostheses [23-28], or as a
filler phase of a polymer-ceramic composite material such as
hydroxyapatite-polyethylene implants [19]. For example, HA
powder has been used in surgery since 1920 with the aim of
promoting bony consolidation in maxillofacial surgery [11].
HA is considered to be almost fully biocompatible with
*Address correspondence to this author at the Department of Manufacturing
and Materials Engineering, Faculty of Engineering, International Islamic
University Malaysia (IIUM), PO Box 10, 50728 Kuala Lumpur, Malaysia;
Tel: +603-61964592; Fax: +603-61964477; E-mail: sopyan@iium.edu.my
significant ability to promote bone growth along its surface
and integrate in living bone structures without breaking
down or dissolving [29]. It was the first time applied for
periodontal lesion filling in 1981 [30]. Unfortunately, its
mechanical properties are insufficient for major load bearing
devices [2, 24, 28-34], limiting its medical applications to
non-stressed regions of skeletons [35]. The restriction is also
due to its low toughness (0.8-1.2MPa.m1/2) and flexural
strength (<140MPa) [32].
Nevertheless, many efforts have been made to obtain
bioactive but high strength bone implants. Improvement of
mechanical performance of dense HA and deposition of
bioactive thin film onto bio-inert implants are among the
efforts. This review will describe the current issues on the
development and application of dense HA as a bioactive
ceramics for load bearing bone substitutes.
BONE: A BRIEF OVERVIEW
Bone is a living material composed of cells and a blood
supply encased in a strong, interwoven composite structure
[10]. It consists mainly of collagen fibres and an inorganic
bone mineral in the form of small crystals [10, 32]. Bioche-
mically, the blend of three major components that defined
bone are 30-40% flexible and very tough collagen, 60-70%
bone mineral, which is the reinforcing phase of the compo-
site and the remaining 2-5% is composed of other substan-
ces, mainly proteins and inorganic salts which perform
various cellular support functions. The bone mineral consists
mainly of calcium phosphates with significant amounts of
citrate and carbonate ions and traces of fluoride, magnesium

1874-4656/11 $100.00+.00 © 2011 Bentham Science Publishers Ltd.

64 Recent Patents on Materials Science 2011, Vol. 4, No. 1 Nawawi et al.

and sodium [9]. The composition of the mineral component

can be approximated to hydroxyapatite (HA), which has the
chemical formula (Ca10 (PO4)6(OH)2) [10, 11, 32]. However,
it is not exactly HA as HA has a Ca:P ratio of 5:3 (1.67),
whereas bone mineral actually has Ca:P ratios ranging from
1.37-1.87. In addition, bone mineral has internal crystal
disorder. It has a characteristic structure with specific mecha-
nical properties such as high fracture toughness and high
flexibility.
Although the shape of bone varies in different parts of
the body, the physicochemical structure of bone for these
different shapes is basically similar. Figure 1 shows the
struc-ture of a long bone. As bone consists primarily of
organic collagen fibres and an inorganic hydroxyapatite
crystal, hence, on a simple level, it can be analyzed as a fibre
compo-site [36]. This mixture gives bone strength and
hardness. Fibre composites are commonly used in
engineering and industry where the combination of the two
materials creates a composite with properties that are
superior to those of the individual components. Table 1 lists
the mechanical proper-ties of three skeletal tissues contained
in our body: cortical bone, cancellous bone, and articular
cartilage, in comparison to hydroxyapatite.

SELECTION OF LOAD BEARING BONE IMPLANT

MATERIALS
In selecting the suitable implant materials, there are three
main criteria which must be considered. The first criterion is
biological condition of the area of implantation as the
materials need to withstand the body environment for a
prolonged period. It must be able to operate for many years
at a temperature of 37ºC in a very moist environment at pH
7.3 with dissolved gases (such as oxygen), electrolytes, cells Fig. (1). Structure of a long bone in longitudinal section.
and proteins [30]. Immersion of metals in this environment
can lead to corrosion, which is deterioration and removal of
the metal by chemical reactions. Also, bone growth can only susceptible to crevice corrosion and pitting when implanted
occur in an acidic condition as this is necessary for mineral for longer period compared to titanium and its alloys as well
deposition, so the implant must be capable of withstanding as cobalt-chromium alloys [30].
this for many years without corroding. For example, even The second criterion to be taken into account is the host’s
though stainless steel 316L implants perform satisfactorily in response. Implant materials must be designed to minimize
short-term applications, such as fracture fixation, they are the adverse reactions associated with introducing a foreign
material to the body which will lead to inflammation.

Table 1. Mechanical Properties of Skeletal Tissues [10].

Properties Cortical Bone Cancellous Bone Articular Cartilage Hydroxyapatite

Compressive Strength (MPa) 100-230 2-12 - 300-900

Flexural, Tensile Strength (MPa) 50-150 10-20 10-40 -

Strain to Failure 1-3 5-7 15-50% -

Young’s (Tensile) Modulus (GPa) 7-30 0.5-0.05 0.001-0.01 80-120

Fracture Toughness (KIC) (MPa.m1/2 ) 2-12 - - 0.6-1

-1
Compressive Stiffness (N.mm ) - - 20-60 -

Compressive Creep Modulus (MPa) - - 4-15 -

Tensile Stiffness (MPa) - - 50-225 40-300

Hydroxyapatite-Based Dense Biomaterials
Furthermore, excessive levels of particular metals in the
bloodstream can lead to various problems including cytoto-
xicity and carcinogenesis. It is therefore crucial to choose
materials that will have a minimal negative impact on the
body.
As mechanical properties of materials are of great
importance when designing load bearing orthopaedic and
dental implants, the properties of a material is the third
crucial criteria to be fulfilled. Material strength (tensile or
compressive), stiffness, fatigue endurance, wear resistance,
and dimensional stability should be considered with respect
to the end use of the prosthetic device to ensure its success.
For example, a rigid, strong material would be more suitable
for a hip implant, whereas a flexible, less strong material
would be sufficient for a vascular graft. Moreover, the
performance of materials under dynamic loading conditions
must be considered when appropriate, because many
implants are subjected to various types and magnitudes of
repeated stresses in the body.
Conventional Bone Implants for Load Bearing
To date, metals, ceramics, polymers and natural materials
have all been used for biomedical implants [37]. Among
them, metals have been used almost exclusively for load-
bearing implants, such as hip and knee prostheses and as
fracture fixation wires, pins, screws and plates. Apart from
these, it is also been used as parts of artificial heart valves as
vascular stents and as pacemaker leads. Although pure
metals are sometimes used, alloys which are metals contain-
ing two or more elements have frequently provided improve-
ment in material properties such as strength and corrosion
resistance. Hip replacement prostheses made of Ti-alloy with
ceramic (alumina or zirconia) heads have been widely used.
However, the problems of the implantation are due to
loosening of the implant because of its bioinertness and
stress concentration related to higher stiffness of the implant
than the natural bone.
Basically, the class of implantable metallic biomaterials
can be divided into four subgroups that are stainless steels,
the cobalt-based alloys, titanium and various other metals
(tantalum, gold, etc.) [37]. The first three groups dominate
biomedical metals [9, 30]. The need to avoid toxic materials
has caused aluminium or its alloys to be rarely used while
plain steel would corrode too rapidly to be used in the body.
High quality metal alloys of titanium, vanadium, and
chromium are commonly used for orthopaedic prostheses
(load bearing) or for fixing plates to correct fractures.
Besides that, engineering ceramics such as aluminium oxide
have been found to provide a hard, low friction surface that
is also suitable for orthopaedic prostheses. In many cases, the
hard aluminium oxide is paired with the much softer, but
wear resistant polymer, ultra high molecular weight
polyethylene (UHMWPE) to produce a very durable cup and
ball joint for hip joint prosthesis.
Other than metals, composite materials have attracted
interest as biomedical materials. For example, carbon fiber
weaves have been studied as reinforcing material for the
stems of orthopedic implants. Besides that, polymers are also
used in biomedical applications. They are the materials of
choice for cardiovascular devices, replacement and augmen-
Recent Patents on Materials Science 2011, Vol. 4 No. 1 65
tation of various soft tissues, drug delivery systems and as a
scaffolding material for tissue engineering applications [30].
However, they are not used in applications that bear loads
such as body weight. An exception for UHMWPE as it is
extensively used as a bearing surface in hip and knee
replacements. Meanwhile, ceramics and glasses are used as
components of hip implants, dental implants, middle ear
implants and heart valves [30]. However, they have been
used less extensively than metals or polymers. Generally,
they do not undergo corrosion but they are prone to degra-
dation in physiological environment. Taking into conside-
ration, alumina as bioinert ceramic also experiences a time
dependent decrease in strength during immersion in saline
in vitro after implantation which will end up in propagation
of crack. Bioactive ceramics and glasses are also degraded in
the body as they can undergo slow and rapid dissolution
[30]. They also may be resorbed by osteoclasts due to resem-
blance of calcium phosphates to the mineral component of
bone.
However, there is no existence implantable biomaterial
which has perfect biocompatibility with host response. This
total inertness is never achieved in above mentioned
biomaterials and some measurable host responses towards
the implantable biomaterials are expected. Hence, this
criterion must be considered in the material selection, the
device design and the implant application [38]. For example,
the function of the implants used for internal fixation req-
uires resistance to high loading and corrosion fatigue.
Generally, the prerequisite of implant materials for load
bearing applications are appropriate stiffness to maintain
reduction and stability, high load resistance to avoid failure,
fatigue resistance to withstand dynamic loading in the
physiological environment and ductility to provide a reserve
of plastic deformation under bending and torque loads. For
such characteristics in application, titanium alloy and stain-
less steel are regarded as among the nearly perfect bioma-
terials for long term implantable devices.
With a few exceptions, the high tensile and fatigue
strength of metals make them the materials of choice for
implants that carry mechanical loads compared to ceramics
and polymers. For example, the materials used in each
component of the hip implant must have suitable properties
to allow them to replace the natural tissue and continue to
perform the same functions. The mechanical property
requirement for the femoral stem is primarily to support the
loads that are applied, and therefore the modulus of the
implant material is one of the main criteria. The femoral
head and acetabular cup components are required to act as
bearing surfaces, and therefore, the coefficient of friction and
wear rates of these materials will be of great importance
[38].
The mechanical properties of the specific implants
depend not only on the type of metal but also on the
processes used to fabricate the materials and devices.
Thermal and mechanical processing conditions can change
the microstructure of materials as well as their mechanical
properties. For example, a metal which undergo cold-work-
ing process, such as rolling or forging would be stronger and
harder material due to the resulted deformation [30]. As a
consequence, the material becomes less ductile and more
chemically reactive.
66 Recent Patents on Materials Science 2011, Vol. 4, No. 1 Nawawi et al.

The Most Common Implant Materials Used
Conventional Biomedical Implants
Metals, polymers and ceramics are three main types of
materials which can be selected for load bearing appli-
cations. Table 2 is a comparative list of the physical proper-
ties of the three biomaterials.
The first implanted material was gold plate for cleft
palate in 1588. When polymer industry was developed in
1950s, the metallic materials like silver, platinum, stainless
steel and cobalt based alloys were mainly used [39]. The
materials that dominate biomedical metals are pure titanium
(Ti), titanium alloys and 316L stainless steel followed by
nearly inert bioceramics.
Titanium or any titanium rich alloy has been greatly used
in many implantation applications especially those which
involved the load bearing parts. It is not surprising as taking
into consideration its classical foundations of inertness, best
compatibility among metallic biomaterials [37, 38, 40],
corrosion resistance [30, 38, 41] and superior mechanical
properties [37, 38, 40, 42]. Among the titanium alloys, pure
titanium and Ti-6Al-4V are still the most widely used in
biomedical applications. It is well known that some titanium
ions released into tissues over a period of time give rise to a
characteristic discoloration of the tissue. In contrast, vast
majority of evidences have indicated that the titanium that is
present in the tissue, and associated with this discoloration
has very little effect. Abundant in vitro studies [11, 37]
demonstrated an absence of cytotoxic effects, or a minimal
cytotoxicity in comparison with other metallic elements.
However, the application of titanium alloy implants have
been shown to suffer fretting and without the employment of
biomedical coatings results in the production of a metallic,
cellular mash at the bone-implant interface.
In Besides titanium, stainless steel, a group of iron-based
alloys also exhibit a phenomenal resistance to rusting or
corrosion because of its chromium content. The doping of
small amount of chromium into steel has successfully
strengthened it. Moreover, stainless steel is the only implant
material which possessed superior ductile behaviour to
titanium. Stainless steels especially surgical grade type 316L
has been used as customary temporary implants. This type of
orthopaedic implants however, corrodes in the body
environment and release iron, chromium and nickel ions and
these ions are found to be powerful allergens and carcino-
gens [43]. Hence, improvement is needed in overcoming
these localized corrosion attacks and leaching of metallic
ions from implants. Besides that, AISI 316L (low carbon
content) stainless steel, is often used for temporary devices
in orthopaedic surgery. However, this alloy has a tendency to
localized corrosion, releases significant quantities of iron and
promotes the formation of fibrous tissue around implants
[44]. Moreover, the need to reduce costs in public health
services has compelled the use of stainless steel as the most
economical alternative for orthopaedic implants [10].
Alumina (Al2O3) and zirconia (ZrO2) are two nearly inert
bioceramics as they undergo little or no chemical change
during long term exposure to body fluids [31]. Al2O3 has
been used as load bearing hip prostheses and dental implants
due to its high density. It is reported that Al2O3 ball has been
used extensively for the femoral head component by 2006
for more than >106 hip prostheses [44]. However, the nature
of ceramics has hindered its application for lifetime. Increase
of loads and longer times increased the probability of failure.
It also has only moderate flexural strength and low toughness
which limits the diameter of most Al2O3 femoral head
prostheses to 32mm [31]. An aging and fatigue studies have
showed that it is necessitate that Al2O3 implants be produced

Table 2. Significant Physical Properties of Different Biomaterials [32].

Density Compressive Young’s Fracture Toughness Hardness

Material UTS (MPa)
(g/cm3) Strength (MPa) Modulus (GPa) (MPa.m1/2) (Knoop)

HA 3.1 40-300 300-900 80-120 0.6-1.0 400-4500

Tri-calcium phosphate 3.14 40-120 450-650 90-120 1.20 -

Bioglasses 1.8-2.9 20-350 800-1200 40-140 -2 4000-5000

Apatite and Wollastonite (A- 3.07 215 1080 118 2 -

W) glass ceramic

Silica glass 2.2 70-120 - 70 0.7-0.8 7000-7500

Aluminum oxide 3.85-3.99 270-500 3000-5000 380-410 3-6 15000-20000

Partially Stabilized Zirconia 5.6-5.89 500-650 1850 195-210 5-8 17000

Polyethylene 0.9-1.0 0.5-65 - 0.1-1.0 0.4-4.0 170

Titanium (Ti) 4.52 345 250-600 117 60 1800-2600

Ti/Aluminum/Vanadium alloy 4.4 780-1050 450-1850 110 40-70 3200-3600

Ti/Aluminium/Niobium/ 4.4-4.8 840-1010 - 105 50-80 -

Tantalum alloys
Hydroxyapatite-Based Dense Biomaterials
with the highest possible standards of quality assurance for
orthopaedic prostheses [31].
In contrast, ZrO2 ceramics possessed better mechanical
properties in terms of fracture toughness, flexural strength
and elasticity than Al2O3. They have been used in
orthopaedic implant material such as knee and hip joint [45].
However, as it is exposed to bodily fluids, it will experience
a slight decrease in flexural strength and toughness [31].
Moreover, ZrO2 contains low concentration of long half-life
radioactive elements such as Th and U, which are difficult
and expensive to separate out. These emit -particles (He
nuclei), though at small activity, which can destroy both soft
and hard tissue and might lead to the long term effect of 
radiation emission. In conclusion, among these load bearing
bone substitute materials, titanium has become the metal of
choice for medical applications.
NECESSITY TO DEVELOP LOAD BEARING
BIOACTIVE BONE IMPLANTS
There is a real need for development of second gene-
ration of bioactive implants which promote regeneration of
the surrounding tissues. Such materials could be used not
only for hip-replacement prostheses but also as other artifi-
cial bones or artificial teeth roots. Appropriate hard tissue
replacement implants should be bioactive, have modulus
equal to that of bone, and be even tougher than the bone.
Several non-metallic materials have been proposed as
candidates for artificial bones but none has found wide
applications. As known, metals in elemental form are
essentially alien to the human body. When a metal implant is
inserted in tissue, most metals become encapsulated by a thin
layer, which is almost empty of human cells. Adhesion
between the metal implant and the surrounding tissue
without any biochemical bonding is comparatively weak.
From the view point of biocompatibility and bioactivity,
HA seems to be the most suitable ceramic material for
implantation purposes due to its close resemblance with the
mineral components and crystal structure to apatite in human
skeletal system of natural bone and teeth and ability to bond
to bone [34, 46]. The bone bonding capacity of HA coatings
may help cementless fixation of orthopaedic prostheses [10].
Despite of these criterions, it is also known for its simulating
effect on bone formation, termed as osseoconduction [10,
32]. However, the application of HA is offset by its lack of
strength necessary for load bearing as bulk HA is brittle [32]
and relatively low mechanical strength when compared to
common implant metals and alloys and high strength
ceramics like aluminum and zirconium oxides. The best use
of HA in load bearing implant applications would be as a
coating on one of these stronger implant materials [10].
Furthermore, HA coatings on metallic implants combine
mechanical strength of metal with excellent biocompatibility
and bioactivity of calcium phosphates.
Bioactive ceramic coatings are commonly used to modify
the surface of the implant material and to create new surfaces
with totally different properties with respect to the substrate.
Concisely, there are few reasons in applying a coating. It is
intended to protect the substrate against corrosion, make the
implant biocompatible and to turn a biopassive surface into a
bioactive one. Applying a glass or ceramic coating onto the
Recent Patents on Materials Science 2011, Vol. 4 No. 1 67
surface of a substrate allows the possession of the bulk
properties of the substrate and the surface properties of the
coating. When a bioinert metal implant is coated with
bioactive HA, bone cells adhere onto the surface of the
apatite coating without any intervening layer. The HA matrix
of the bone cells later becomes integral with the HA coating
and there is excellent adhesion of the coated implant to the
bone, resulting in shorter healing periods as well as
predictable behaviour of the implant for longer periods of
time [34, 47]. Hence, the restriction of applying HA as a load
bearing implant could be overcome by using appropriate
metallic enforcer with HA.
As a result, HA coated implants have gained prominence
because of the biocompatibility and the induced bio-activity,
which means the possibility of successful natural bone re-
growth, leading to excellent fixation of the prosthesis [32,
36]. Subsequently, the risk of release of metallic ions from
the implant into the body has been reduced via HA coatings
on titanium by extending the time before the host bone
comes into contact with the metal surface. In fact, the
deposition of HA coatings on this metallic substrate shields
the metal surface from the physiological environment [37].
The coating of titanium implants with HA to achieve bone
bonding implicitly states that this bonding does not occur so
readily or so well with uncoated titanium. For example, HA
as coatings on passive titanium oxide layer has produced a
surface which is conducive to bone formation. A specific
alloy such as Ti-6Al-4V is a common material onto which
HA is deposited in prosthesis applications because of its
inherent impact and fatigue strength, toughness, manufac-
turability and non-toxicity.
Well controlled preparation of HA coating is necessary
due to HA’s brittleness. For example if the coating on the
implant surface is too thick (>70
m), then failure of fixation
between the bone and the prosthesis may occur through
cracks which develop within the body of the coating and
Quek et al. [42] deposited HA coating on Ti-6Al-4V via
plasma spraying and it was found that an increase in the
weight percentage of HA present in the composite coatings,
the bond strength decreases. This is because the coating is
expected to have lower bond strength due to brittleness of
HA. In the research, the composition of 50wt% HA with 50
wt% Ti-6Al-4V gave higher bond strength compared to the
80wt% HA with 20 wt% Ti-6Al-4V, 21.25MPa and 19.49,
respectively at the current source of 1000A. Figure 2 shows
the SEM morphology of 50 wt% HA: 50 wt% Ti-6Al-4V as
sprayed coatings 1000 A [42].
Many efforts have been done in order to obtain the
optimum results of coating despite of all HA deficiencies or
weaknesses. Progressively, the efforts to improve the
strength of HA have also focused on the incorporation of
foreign particles into the HA matrices to form composites
that might induce energy dissipative mechanisms such as
crack deflection, thus enhancing the mechanical properties.
This was shown to yield better strength, but is often asso-
ciated with the formation of undesirable phases in the
composite due to the higher sintering temperatures em-
ployed. To date, there is a wide use of HA as coating mate-
rial on prosthetic metallic implant as HA coated implants
68 Recent Patents on Materials Science 2011, Vol. 4, No. 1
Fig. (2). SEM morphology of 50 wt% HA: 50 wt% Ti-6Al-4V as sprayed coatings 1000 Å [42].
allow natural bone re-growth to occur until close contact
between natural bone and the HA coating is achieved.
Recent Patents on Load Bearing Bone Substitutes
Due to low mechanical properties and its characteristic as
a nonbiodegradable material which inhibits new bone from
forming, hydroxyapatite is coated with degradable polymers
like poly (D, L-lactic-co-glycolic acid), poly (L-lactic acid)
and poly (glycolic acid). A biomaterial comprised of
degradable polymer and hydroxyapatite can promote bone
cell propagation and ingrowth well. Calcium phosphate
complex of sintered hydroxyapatite compact chemically
bonded to a polymer –based materials containing an isocya-
nate group and/or an alkoxysilyl is disclosed in US7473731
[48]. The invention concerns that the calcium phosphate can
be easily fixed to the surface of the polymer -based material
for a long period without losing bioactivity as calcium
phosphate is easily dissolved in a living body. The invention
also relates a modified conventional technique for manu-
facturing the calcium phosphate complex where there is no
need to perform a chemical pre-treatment with respect to the
hydroxyapatite sintered compact, thus performing it in easier
way. The hydroxyapatite sintered compact is obtained
through sintering of hydroxyapatite at a temperature ranging
from 800ºC to 1300ºC. The invention has succeeded in the
introduction of specific functional group in the calcium
phosphate complex.
US20090192628 [49] discloses the invention of a
medical material containing the bone substitute material and
process for its production. The design of the bone substitute
material comprising titanium or a titanium alloy and an
anodic oxide film of the applied titanium. The inorganic
compound microparticles of phosphorus and calcium are
firmly fixed to a surface and/or inside of the anodic oxide
film. The bone material was found to have excellent mecha-
nical strength, biological affinity and biological activity.
Meanwhile, the US20090181161 [50] issued to Jui et al.,
describes the preparation of protein mediated calcium
Nawawi et al.
hydroxyapatie coating on metal substrates, stainless steel
(316L) by biomimetic route using supersaturated simulated
body fluid. This process is designed to mimic the structural
and characteristic properties of the biological apatite to
expedite osteointegration kinetics and to further improve
biocompatibility of the metallic implant. The patent discloses
the capability of the prepared biomaterial to give rapid and
effective osteointe-gration with the host tissue following
controlled interfacial reactions. For this purpose, the
carbonated hydroxyapatite coating was developed after a
surface treatment step using aqueous solution (4-10 wt %) of
BSA at room temperature.
Ahn [51] disclosed the method of production for the
tricalcium phosphates (TCP) together with its composites
and implants incorporating them. The invention provides
method to synthesis nanoparticles of TCP. The method
employed is chemical precipitation followed by calcination.
The synthesized powder has improves the microstructural
control and design on the nanometer scale, phase uniformity
and chemical homogeneity on the molecular level, unifor-
mity of chemical and physical properties, machinability of
partially consolidated TCP, sintering behavior, mechanical
reliability and strength, net shape forming, manufacturing of
porous and dense bodies, formation of composite materials
and gene, drug and protein delivery devices.
Moreover, zirconia was incorporated into TCP to
enhance its mechanical properties is disclosed in the inven-
tion. The incorporation of trace element in calcium phos-
phate is also discussed by Ronald et al. [52]. In this
invention, silicate and trivalent cation-substituted calcium
phosphate (e.g. HA, TCP etc.) are prepared. An aqueous
precipitation method is disclosed to prepare HA and apatite
materials comprising silicon and a trivalent cation. The
calcium ion in the HA will be substituted by trivalent cation
and the phosphate ion in HA will be substituted by silicate
ion.
Besides that, silicon substitituted oxyapatite compound
for use as a synthetic bone biomaterial compound in a
Hydroxyapatite-Based Dense Biomaterials
variety of orthopedic applications such as skeletal implants
has as described by The US20090030089 [53]. It has been
used alone or in biomaterial compositions. The patent dis-
closes that this biomaterial was prepared by mixing a
calcium phosphate colloidal suspension with a finely
dispersed, fumed silica while maintaining a ratio of C/(P+Si)
at about 1.67 in said mixture followed by sintering. This
method is similar the treatment of orthopedic, maxillo-facial
and dental defects where the silicon substituted oxyapatite
compound is provided as fine or coarse powders, pellets, thin
films and coatings. The implantation of this invention has
succeeded in promoting the formation of new bone tissue at
the interfaces between the compound and the host.
Novel dental enamel inspired materials for biomedical
and dental applications are prepared from apatite-like
calcium phosphate as described by US7132015 [54]. The
patent discloses that calcium phosphate coatings are prepared
via a chemical process leading to the formation of biological
apatite. This method is similar to that found in natural bone
and teeth. The patent also discloses that the materials can be
used for dental tissue replacement, orthopedic implants for
bone repair, and coatings for improving the biocompatibility
and bone regeneration capability for implants or biomedical
devices made of metallic, polymeric, ceramic or composites
materials.
Due to the problem arises from the application of bone
grafting, a biocompatible material is sought that will act as a
filler with appropriate mechanical strength, encourage bone
healing and degrade to allow bone ingrowth without the risk
of disease transfer. The US20090048358 [55] discloses the
invention of a new composite bone-graft material. It is made
from biocompatible poly (D,L-lactic-co-glycolic acid) and
nano-sized hydroxyapatite particles exposed on its surface
using a gas foaming particle leaching method. Nano-sized
HA particles were used to reduce the total amount of HA
degrades over long periods of time in vivo while enhancing
the HA distribution on the scaffold surface. Meanwhile, the
PLGA polymer portion of the composite provides sufficient
mechanical strength to replace bone and is degradable over
time to allow new bone tissue ingrowth. Thus, a uniform
coating of mineral apatite on the surface of this novel bio-
material composite further enhances its osteogenic qualities.
Composite material comprising of a chemosynthetic
collagen and a calcium phosphate compound and a method
for its production have been disclosed by Kamitakahara et al.
[56]. This simple method comprises of soaking a polypeptide
in an aqueous solution of CaCl2 and then soaking the
polypeptide in simulated body fluid to deposit a calcium
phosphate compound on the surface of the polypeptide. The
produced composite materials is a bio-compatible hard-tissue
which having a composition analogous to a material from a
living body and suitable to be used as an artificial bone.
Further, the composite resulted in high endurance and
mechanical strength. This invention also reduced the risk as
infection of pathogens and undesired side effects of the
composite biomaterials.
Novel technology in preparing collagen with inclusions
of hydroxyapatite particles as bone repair compositions for
medical applications is described by US20090155320 [57].
The biocomposite material is designed for applications as
Recent Patents on Materials Science 2011, Vol. 4 No. 1 69
implant or growth simulator of bone tissue in bone surgery,
surgical stomatology, orthopedy, traumatology and other
fields of medicine. For this purpose, hydroxyapatite particles
are embedded in matrix at least 50% nm as it is found to be
suitable as bone implant material. The patent discloses that
this invention produces a product with a high uniformity,
provided that that ration of calcium hydroxide and phosphate
in the suspension is 1.67 ± 0.3 at the beginning of the
hydroxyapatite particle synthesis.
Recently, the US20100168798 [58] discloses the inven-
tion of bioactive composites of polymer and glass as well as
bioactive implants. The invention also describes methods of
manufacturing bioactive composites. The bioactive compo-
site finds utility in variety of load-bearing clinical appli-
cations including spine, orthopaedic and dental procedures.
Meanwhile, the US20100185297 [59] describes an
acetabular implant for use in a hip joint prosthesis. The
implant includes a body portion comprising a polycarbonate
polyurethane.The body portion includes a a substantially
semispherical inner articulating surface defining a socket
sized to receive a head portion of a femoral component of the
hip joint prosthesis and an outer engagement surface having
an annular protrusion extending outwardly therefrom. The
implant also includes a deformation control element having
an increased durometer hardness relative to the polycar-
bonate polyurethane and positioned within the body portion
between the inner articulating surface and the outer
engagement surface.
The US20100178278 [60] discloses a formable biocera-
mic including hydroxyapatite nanocrystals, gelatin, and sol-
gel-containing material. Also a process for making and using
the bioceramics. The formable bioceramic displays superior
mechanical strength, elasticity, biocompatibility and forming
capabilities and is targeted for bone repairs and template-
assisted tissue engineering applications.
The US20090118114 [61] presented invention provides a
functionally graded bioactive glass/ceramic composite
structure or bioactive glass/ceramic/bioactive glass sandwich
structure for use in such applications as damage resistant,
ceramic dental implants, immediate tooth replacement,
endodontic posts, orthopedic prostheses, orthopedic stems,
bone substitutes, bone screws, plates, and anchors, nonunion
fractures repair, alveolar ridge augmentation, missing small
bone parts (e.g. fingers, toes, etc.), maxilla facial recons-
truction, spinal fusion, and scaffolds for bone regeneration,
comprising a residual bioactive glass or glass-ceramic layer
at all accessible surfaces, followed by an underlying graded
glass-ceramic layer, and then an dense interior ceramic. The
residual bioactive glass or glass-ceramic lay can be further
transformed to a carbonate apatite (CHA) layer by
immersing in calcifying solution or simulated body fluid
(SBF) with electrolyte composition similar to that of serum.
The interior ceramic preferably contains yttria tetragonal
zirconia polycrystal (Y-TZP) or ceria stabilized tetragonal
zirconia polycrystal (Ce-TZP) or magnesia stabilized
zirconia (MG-PSZ) or calcia stabilized zirconia (Ca-PSZ) or
alumina or zirconia-alumina composites. Further, the inven-
tion provides methods for making the same functionally
graded bioactive glass/ceramic/bioactive glass sandwich
structure.
70 Recent Patents on Materials Science 2011, Vol. 4, No. 1
Dense Hydroxyapatite
Dense HA is described as HA that have porosity less than
5 volume percent [9,10] with micropores size diameter less
than 1
m and grain size bigger than 0.2
m [10]. The
microporosity is unintentionally introduced and is dependent
on the temperature and duration of sintering [9]. Table 3 lists
some of the important parameters of dense HA compared to
the two types of bone that are of most concern in the use of
bioceramic: cancellous bone and cortical bone [29]. It is
important to note that, dense HA has a compressive strength
four times that of cortical bone, but yet it shows a
significantly lower tensile strength and fracture toughness.
However, that even among studies on development of dense
HA, the values reported for mechanical properties vary
widely due to differences in sample preparation, starting HA
powders used and measurement techniques.
Table 3. Mechanical Properties of Bone and Dense HA [29].
Cortical Cancellous
Mechanical Properties
Bone Bone
Compressive Strength (MPa) 100-230 2-12
Flexural/ Tensile Strength 50-150 10-20
(MPa)
Fracture Toughness (MPa.m1/2) 2-12 N/A
There are many methods employed in producing HA
powders such as wet-chemical method in aqueous solutions
[5, 15, 18, 28, 62], sol-gel [4, 15, 63, 64], combustion syn-
thesis [65], hydrothermal [5, 14], chemical precipitation [5,
17] and solid state reaction [2, 66]. Each method has its own
advantages over the others. For example, wet precipitation
technique produces only water as by-product and has low
probability of contamination during processing but it
requires high pH value to avoid the formation of a calcium
deficient HA and high sintering temperature to form
crystalline HA [63]. On the other hand, sol-gel process needs
no high pH value and not too high sintering temperature. As
described elsewhere [46], HA is confined to its poor
mechanical properties inherited by the sintered body. This
means that development of improved and ultimately bone-
like mechanical properties HA powders are desirable.
Formation of dense HA is controlled by many factors,
including Ca/P molar ratio of the powders used and sintering
temperature. Despite of having Ca/P molar ratio of pure HA
that is 1.67, dense HA varies in the Ca/P molar ratios. This
reflects variation in -TCP/HA ratios in the sintered dense
material which in turn reflect the purity of phases present
and/or composition of HA before sintering [15]. Thus, the
Ca/P molar ratio of the hydroxyapatite preparation, the
sintering temperature and conditions determine the mecha-
nical properties and microstructures of the dense HA.
Seemly, it is too premature to dismiss dense HA as useful
implant material because via a proper processing, pore free
dense HA could be prepared leading fairly good mechanical
properties to appear [10, 30]. These prepared dense bodies
could improve the mechanical properties of the bioactive HA
and enhance the applicability of HA as implant material in
Nawawi et al.
load bearing application. One of promising approaches that
have been used to improve the mechanical performance of
HA is by doping with different sintering additives such as
metal ions [17, 51, 67-72]. Besides that, HA coated metals
have been introduced as artificial bones or teeth [10]. In
order to improve the reliability of HA ceramics various
reinforcements (ceramic or polymer) have also been used
[29].
Preparation of Dense HA
Traditionally, dense HA has been made by sintering HA
powders at high temperature [24, 73]. However, in time there
are various techniques developed to prepare dense HA. In
conventional procedures, it was prepared via a uniaxial
pressing [18, 23, 25, 28, 31, 46, 67-69, 74-81] by compres-
sing apatite powder into a mould at usually at pressure of 60-
800MPa [80], where the powder was mixed with binder such
as cornstarch [15, 62], stearic acid in alcohol [11] polyvinyl
alcohol [81, 82] and Duramax [75]. The pressurized dense
Dense bodies are then subjected to sintering normally in
temperature of 900ºC to 1300ºC. Higher than this sintering
HA
temperature were not favoured as it introduced subsequent
430-920 phases of calcium phosphates such as CaO and -TCP [82].
This is unfavourable as samples with second phases are hard
17-1101
to make strong and have lower fatigue resistance. Besides
this conventional method, dense HA could also be prepared
1 via cold pressing technique [1, 15, 32, 46, 82-84] and hot
isostatic pressing (HIP) [85-87]. Forming techniques for
dense HA ceramics include in addition to common pressing,
slip casting, tape-casting, injection moulding, viscous plastic
processing, or centrifugal settling [15].
The HIP which subjects a component to elevated tempe-
ratures and pressures (generally over 98MPa (1000kgf.cm2)
to eliminate internal micro-shrinkage and it can also be used
directly to consolidate a powder or supplementary to further
densify a cold pressed, sintered, or cast part [88]. This
technique has found to be achieving densification at much
lower temperatures that is 900ºC than in the conventional
sintering process. This resulted in hindrance of possible
formation of other calcium phosphate phases such as TCP,
which usually forms at temperature higher than 900ºC.
Moreover, this method also led to save on energy costs. The
well known advantages of HIP is that it provides uniform
density very close to theoretical density, elimination of poro-
sity, improved fatigue properties, improve creep properties,
improved ductility and impact strength, decreased scatter of
properties, finer grain size structure and the ability to densify
powder which are otherwise difficult to compact [10, 88].
Meanwhile, cold isostatic pressing (CIP) is normally
consists of pressing of powders at 200MPa [32]. CIP does
not influence the crystal structure of the obtained HA powder
proven by infra red analysis and X-ray diffraction analysis
[84]. CIP also has been found to improve the limited
mechanical stability of dense bodies in uniaxial pressing due
to insufficient compaction. This improvement is based on the
overall improved mechanical stability towards manual
scratching, torsion and bending which includes the edges.
Recently, a new method was developed in preparing
dense HA, which is by direct conversion from bulk seashells
to dense HA via a hydrothermal method at the relative low
Hydroxyapatite-Based Dense Biomaterials
temperature around 200°C [12, 89]. Strombus gigas (conch)
shells and Tridacna gigas (giant clam) shells have dense,
tailored structures that impart excellent mechanical proper-
ties to these shells originally [12, 89]. This method enables
the creation of dense HA without subsequent need for com-
paction or pressing of the seashells. It involves the cutting of
these shells into small pieces to undergo autoclaving filled
with (NH4)2HPO4 solution. The derived dense HA has
average fracture stresses in the range of 137- 218MPa,
compared to the strength of compact human bone is about
170-193MPa loaded parallel to the axis, and about 133MPa
loaded normal to the bone axis. The conclusion made is the
shell samples after being partially converted to HA, have
mechanical strength values very similar to compact bone but
at the same time they have bioactivity. It also results in dense
structures and excellent mechanical properties [12].
In addition, properties of powder for the compaction also
contributed to the enhanced mechanical properties of dense
HA. Research by Gibson et al. [19] concerned to compare
the sinterability of an unannealed HA powder produced in
the laboratory (Lab HA) through an aqueous precipitation
method with that of a commercially available calcined HA
powder. In this research, these powders were subjected to
compaction at the same pressing pressure (30-200MPa). The
sintering regime at 1200ºC has resulted to some remarkable
findings where the Lab HA produced higher sintered
densities than commercial HA for all compaction pressures.
Meanwhile, the effect of sintering temperature on the
sintered densities of the compacts of the two HA powders is
illustrated in Fig. (3a). The onset of densification, indicated
by a sharp increase in the sintered density, for Lab HA was
between 800 and 900ºC, whereas commercial HA required a
higher temperature of between 1000 and 1050ºC. Moreover
as shown in Fig. (3b), it was observed that commercial HA
shows no significant change in hardness over the
temperature range 900-1100ºC, whereas Lab HA shows a
large increase in hardness from 900 to 1000-1100ºC. As in
Fig. (3a), Lab HA showed a rapid increase in density from
Fig. (3). Effect of sintering temperature (ºC) on the (a) sintered relative densities and (b) Vickers hardness; of Lab HA and commercial HA
[19].
Recent Patents on Materials Science 2011, Vol. 4 No. 1 71
58% at 900ºC to 84 and 96.5% at 1000ºC and 1100ºC,
respectively. This increase in density was reflected in the
improved hardness with the increased sintering temperature.
However, the Lab HA samples sintered at 1200-1250ºC
continued to show a small increase in hardness, whereas the
commercial HA showed a sudden increase in hardness for
samples sintered from 1100 to 1200-1250ºC. From the
results presented in Fig. (3a), the sintered density of Lab HA
increases by only 1-2% over this temperature range, whereas
the density of commercial HA increases from 70% at 1100ºC
to 91 and 97% at 1200 and 1250ºC, respectively. The
hardness tests show clearly the effect of sintered density on
the hardness of HA ceramics, and that the hardness of Lab
HA is greater than commercial HA for lower sintering
temperatures, where it achieves higher sintered densities.
These properties are ultimately depending on the charac-
teristics of the powder used to derive the dense HA.
The Properties of Dense HA
Mechanical strength of dense HA mainly depends on
grain size, grain size distribution, porosity and other
microstructural defects [90]. In general, fine powder with
greater surface area allows higher sinterability that leads to
the use of lower densification temperature. Meanwhile, the
presence of hard agglomerates tends to disrupt the densi-
fication process resulting in the formation of defects such as
porosity, grain growth and microcracks [91]. The dense HA
ceramics with greater mechanical properties is possible to
achieve if the starting HA powder is stoichiometric, i.e., has
Ca/P molar ratio of 1.67 [10]. If the Ca/P molar ratio of the
HA exceeds the value of 1.67, CaO forms during sintering.
Existence of CaO is reported to decrease strength and may
even cause structure inconsistency of the whole material due
to stresses arriving from formation of Ca(OH)2 which
subsequently transforms into CaCO3 leading to change in
volume and alteration of the rate and extent of biode-
gradation. If the Ca/P molar ratio is lower than 1.67, - or
-
tricalcium phosphate forms which increases slow crack
72 Recent Patents on Materials Science 2011, Vol. 4, No. 1
growth susceptibility and biodegradability of the HA
ceramics. Moreover, the decomposition process itself may
have a negative influence on the densification of the HA
ceramics due to formation of a new phase and evaporation of
water, decreasing in consequence the strength. However, the
Ca/P ratio was reported not to influence significantly the
grain growth of the HA ceramics [10].
Many of the HA powders can be pressurelessly sintered
up to theoretical density at moderated temperatures (1000 -
1200°C). However, processing at higher temperatures may
lead to exaggerated grain growth and/or decomposition of
HA and subsequently to strength degradation. Nevertheless,
hot pressing (HP), HIP or HIP-postsintering make it possible
to decrease the temperature of the densification process,
decrease the grain size, and achieve higher densities. This
leads to finer microstructures, higher thermal stability of HA,
and subsequently better mechanical properties of the
prepared HA ceramics.
The elastic modulus or known as Young’s Modulus (E)
was normally determined using three-point bend test of
rectangular specimens where the specimens are loaded to
failure. In one research [46], the correlation of this stiffness
measurement with sintering temperature has been studied.
The dense HA has been prepared via uniaxial pressing with
subsequent cold isostatic pressing. It was found out that the
HA attained E values
100GPa when sintered at a tempe-
rature as low as 1000ºC. This result is corresponding to the
increasing bulk density up to ~98% of the theoretical value.
This is in good agreement with the hypothesis that Young’s
Modulus of HA was controlled by the fraction of porosity in
the sintered body.
Another important properties of sintered HA dense
bodies like microhardness or hardness, can be measured by
Knoop [18] or Vickers method [1, 18, 46]. Hardness is
controlled by the bonding between the particles in the
sintered compacts. Hardness is also influenced by the
sintering temperature, as the temperature increased, so does
the hardness [1, 33, 46, 92]. A high hardness is the guarantee
for a good wear resistance, which is crucial for HA materials
which are often applied in tooth and bone implantation.
Fig. (4). The effect of grain size on the relative density of HA [32].
Nawawi et al.
Many factors may affect the hardness of HA materials, for
example, the density, Ca/P ratio, possibly the weight
percentage of the Ca2+, and so on. High Vickers hardness of
HA may be due to the high calcium weight percentage in the
HA samples [92]. In another research of commercial HA
derived dense bodies, it was found that hardness started to
decrease above a certain lower grain size limit, e.g. ca. 2m
[32]. Hence, it is revealed that the hardness of the material
was not solely dependent on the relative density.
Relative density is the ratio of the density of the prepared
HA dense bodies to the theoretical density of HA
(3.156g/cm3) [1, 46, 91]. The density of the sintered HA
compacts was usually measured by water immersion
technique. The hypothesis made is relative density is
dependent on the sintering temperature, grain size of the HA
dense bodies and also the sintering method which emphasis
on the duration taken for the grain growth. In fabrication of
HA bodies by uniaxial pressing of the precipitation
technique derived powder [75], it was found that the
densification process starts at about 1000ºC and continuously
increases with the temperature up to 1200ºC where a
maximum is reached. In terms of grain size, generally
samples with smaller average grain size exhibited lower
density whereas the highest relative density of 99.8% was
attained in samples that have larger average grain size of ca.
12.3m as shown in Fig. (4) [32]. In a similar work but via
microwave sintering, the HA compacts exhibited 90-91%
and 96% of the theoretical density when sintered at 1000ºC
and 1100ºC, respectively [6]. However, via conventional
pressureless sintering method, a relative density of 96% was
attained for dense HA at 1000ºC. Although a higher
temperature of 1100ºC is needed by microwave sintering to
achieve a similar density, this effect is offset by the very
short sintering time taken for densification [1].
Another prominent property of dense HA is its resistance
to crack propagation which is defined as fracture toughness
(KIC) [89]. This property can be measured by taking into
account the crack patterns that created by the Vickers
indentation of brittle calcium-phosphate materials and the
median crack system [18]. Besides that, hardness (H V) and
Hydroxyapatite-Based Dense Biomaterials
fracture toughness (KIC) are convenient materials parameters
for characterizing deformation and fracture phenomena in
large scale of solids ranging from metals to ceramics. The
HV/KIC ratio combining hardness (resistance to deformation)
and toughness (resistance to fracture) is used as a simple
brittleness index [18].
In the research of rapid densification of nanocrystalline
HA [1], it was observed that the maximum fracture tough-
ness value obtained by the microwave sintering method
(1.45MPa.m1/2) is higher than the one obtained via pressure-
less sintering (1.0MPa.m1/2). Hence, it can be deduced here
that the method of sintering is one of the parameter that
influence this property of dense bodies.
Nevertheless, in terms of grain size it is hypothesized that
the properties (e.g hardness, toughness and densities)
increased with grain size and reached a maximum value at a
certain grain size limit. Thereafter, both the toughness and
hardness started to decrease with increasing grain size
resulting from higher temperature sintering [1]. It is also
hypothesized that below some grain size limit (dc) the
toughness as well as hardness is governed by bulk density
(or porosity) [1]. Ramesh [32] claimed in his study of grain
size on commercial HA derived dense ceramics compacted
via uniaxial pressing and cold isostatic pressing that low
temperature sintering caused the HA exhibited a uniform
microstructure and distribution of equiaxed fine grains which
indicated the high degree of homogeneity of the starting
powder. When the sintering temperature was further
increased to 1400ºC, exaggerated grain growth accompanied
by grain coalescence was observed in the HA dense samples.
Meanwhile the grain size was found to be exponentially
increased from 1.16
m to 25.41
m as the sintering tempe-
rature increased from 1200ºC to 1450ºC. Figure 5 shows the
SEM micrographs of HA showing an equiaxed-grained
structure when sintered at 1200ºC and 1400ºC [32].
Fig. (5). SEM micrographs of HA showing an equiaxed-grained
structure when sintered at (a) 1200ºC and (b) 1400ºC. Exaggerated
grain growth is evident in (b) [32].
From the study of sintering temperatures ranging from
900 to 1300°C on the dense bodies, it was observed that HA
did not decompose to secondary phases upon sintering even
when consolidated at a temperature as high as of 1400°C
[46]. However, studies done by Slosarczyk et al. [18] proved
that the secondary phases have already appeared at 1250°C.
This difference might be correlated to the different method in
preparing the HA powder as the characteristics of the powder
precursors has great influence on the sintered dense bodies.
Recent Patents on Materials Science 2011, Vol. 4 No. 1 73
The technique used in densification of the dense bodies
could also affect their mechanical properties. The most
commonly used technique is the conventional pressureless
sintering. This method was well-known for coarse-grained
microstructure and low mechanical properties of the obtained
dense bodies [83] due to its long sintering duration, typically
about 18-24 hours [1, 32, 83, 93]. The reported rapid and
effective consolidation technique such as microwave
processing [1, 94, 95] has been reported to produce a dense
sintered HA body that possessed fine microstructure coupled
with improved mechanical characteristics [1]. This is
achieved as the heat is generated within the material instead
of being radiated from outside the body as in conventional
sintering [1]. Densification of material is resulted due to
accelerated and uniform heating, and there is no disruption
of the HA phase detected. However, sintering at higher
temperature (i.e exceeding 1150°C) has resulted in the
decreasing toughness and hardness as affected by the
increasing of dense bodies’ grain size. However, heat dried
powders are often in the forms of large agglomerates, and the
sintered HA ceramics are often weak with inhomogeneous
pores and thus can hardly meet the requirements for medical
applications. Freeze-drying has been shown to be a promi-
sing technique for preparing uniform fine-grained powders
which can be sintered to very high densities [92].
Ramesh et al. [1] produced HA discs samples via
uniaxial pressing which subsequently undergone cold isos-
tatic pressing. The green samples were the sintered in
microwave furnace. In their findings, they obtained nano HA
with maximum relative densities of 98% at 1300ºC while
maintaining fine-grained microstructure. They also found out
that microwave heating is beneficial in suppressing grain
coarsening that is unavoidable via conventional pressureless
sintering. Throughout the sintering regime of 1000ºC up to
1150ºC, the results obtained are 0.12
m, 1.45MPa.m1/2 and
6.38GPa for grain size, maximum fracture toughness and
maximum Vickers hardness, respectively. However, further
sintering the mechanical properties were not governed by
density effect but are believed to be associated with a grain
size effect [1].
Table 4 lists some of the maximum values of mechanical
properties of dense HA prepared via different methods and
conditions [13, 18, 46, 75, 76, 83, 96, 97].
Application of Dense HA
Dense HA has been used in various clinical dental and
medical applications which includes repair of bony defects in
dental and orthopaedic application [4, 20, 31, 46, 75, 94],
immediate tooth root replacement [15, 84], augmentation of
alveolar ridge [15, 20, 31], adjuvant to the placement of
metal implants [15, 71, 84], pulp-capping materials [15],
enhancement of guided tissue regeneration [15, 75], maxillo-
facial reconstruction [4, 15, 20, 56, 75], percutaneous
devices [15], middle ear reconstruction and bioreactors [15,
20, 56, 75]. However, the betterment in mechanical
performance thereby making it a desirable substitute for hard
tissues [1, 12, 45].
The applications of dense HA are divided into two forms:
block and particulate forms. For example, the block form has
74 Recent Patents on Materials Science 2011, Vol. 4, No. 1 Nawawi et al.

Table 4. Maximum Values of Dense HA Mechanical Properties Obtained Via Various Processing Route.

Method and Condition Relative Density (%) Hv (GPa) KIc (MPam1/2 ) E (MPa)
F (MPa) References

Direct Conversion of Sea Shells to Hydroxyapatite N/A N/A N/A N/A 173 Zhang et al.
via Hydrothermal [13]
a) Sintering: Autoclave
Temperature: 180ºC

Uniaxial Pressing and Cold Isostatic Pressing 1st Batch 1st Batch 1st Batch 1st Batch N/A Slosarczyk
a) Starting HA powder: Wet chemical precipitation - 95.9 % 99.6% - 4.3 - 0.66 - 105 et al. [18]

b) Binder: 5wt% solution of poly(vinyl alcohol) 2nd Batch 2nd Batch 2nd Batch 2nd Batch
c) Compaction: - 98.0 % 99.9% - 4.9 - 0.97 - 112
i) 1st Batch: Uniaxial pressing
Pressure = 150 MPa
ii) 2nd Batch: Uniaxial pressing and cold
isostatic pressing
Pressure (Uniaxial Pressing) = 150 MPa
Pressure (Cold isostatic pressing) = 350 MPa
d) Sintering:
Temperature: 1250ºC
Holding time: 2 hours
Condition: Ambient

Uniaxial Pressing and Cold Isostatic Pressing 99% (1150ºC) 7.21 1.22 (1000ºC)
100 N/A Ramesh et
a) Starting HA powder: Wet chemical precipitation (1050ºC) (1000ºC) al. [46]

b) Binder: -
c) Compaction:
Pressing (Uniaxial pressing) = 1.3-2.5 MPa
Pressing (Cold isostatic pressing) = 200MPa
d) Sintering:
Temperature: 900ºC-1300 ºC
Holding time: 2 hours
Condition : Ambient

Uniaxial Pressing 96% (1200ºC) N/A N/A N/A N/A Rodriguez-

a) Starting HA powder: Precipitation technique Lorenzo
et al. [75]
b) Binder: 5% of Duramax
c) Compaction:
Pressing = 125MPa
d) Sintering:
i) Presintering
Temperature: 400ºC
Rate: 23ºC/min
Holding time: 1 hour
ii) Presintering:
Temperature: 600ºC
Rate: 10ºC/min
Holding time: 2 hours
iii) Sintering
Temperature: 600-1300º
Rate: 10ºC/min
Holding time: 2 hours
Hydroxyapatite-Based Dense Biomaterials Recent Patents on Materials Science 2011, Vol. 4 No. 1 75

(Table 4) Contd….

Method and Condition Relative Density (%) Hv (GPa) KIc (MPam1/2 ) E (MPa)
F (MPa) References

Uniaxial Pressing N/A N/A N/A 93.8 125 Akao et al.

a) Starting HA powder: Wet precipitation (1300ºC) (1300ºC) [76]

b) Binder: 1 wt% cornstarch

c) Compaction:
Pressing = 60-80 MPa
d) Sintering:
Temperature: 1150, 1200, 1250 and 1300ºC
Holding time: 3 hours
Condition: Ambient

Uniaxial Pressing and Cold Isostatic Pressing >99% (1250ºC) 6.36 N/A N/A N/A Muralitharan
a) Starting HA powder: Commercial HA (1250ºC) et al. [83]

b) Binder: -
c) Compaction:
Pressing (Uniaxial pressing) = 40 MPa
Pressing (Cold isostatic pressing) = 200MPa
d) Sintering:
Temperature: 1000ºC-1450ºC
Holding time: 2 hours
Condition: Ambient

Cold Isostatic Pressing i) 98% (1300ºC) i) 6.38 i) 1.45 N/A N/A Ramesh et
a) Starting HA powder: Wet precipitation ii) 99% (1100ºC) (1150ºC) (1050 ºC) al. [96]

b) Binder: - ii) 7.21 ii) 1.22

c) Compaction: (1050ºC) (1000 ºC)
Pressing = 200 MPa
d) Sintering:
Temperature: 1000 - 1300ºC
Condition:
i) Microwave furnace
ii) Conventional furnace

Cold Isostatic Pressing 90% N/A N/A N/A 57.7 Sopyan et al.
a) Starting HA powder: Sol-gel [97]

b) Binder: poly(vinyl alcohol)

c) Compaction:
Pressing = 100MPa
d) Sintering:
Temperature: 1250ºC
Rate: 250ºC/hour
Holding time: 1 hour
Condition: Ambient

been applied in augmentation of alveolar ridge resorption
and maintain ridge shape following tooth loss, which affects
millions of people [31]. Meanwhile, the application as filler
in bony defects [20] in dental and orthopaedic surgery
requires dense HA as particles.
Characteristics Requirements of Dense HA For Bone
Implant Application
A great number of studies have been undertaken to
improve the mechanical properties of sintered HA [4, 83,
98]. These studies concentrated on powder processing
76 Recent Patents on Materials Science 2011, Vol. 4, No. 1
techniques, composition and experimental conditions, with
the aim of obtaining the most effective synthesis method and
conditions to produce well-defined particle morphology [1].
Among the important parameters to be controlled is the
consolidation or sintering method in order to obtain a solid,
high density HA body that is characterized by having a fine
microstructure and improved mechanical properties [1, 12,
89].
However, the requirement needed depends on the role of
the dense HA played in the body. For example, the
requirement for total hip prostheses is different for a middle
ear implant. The two basic criteria are the compatibility with
the physiological environment and the mechanical properties
which should match those of the tissue being replaced. The
success of HA ceramics in biomedical applications is also
largely dependent on the availability of a high quality, sin-
tered HA that is characterized having refined microstructure
and improved mechanical properties [67].
Current & Future Developments
Generally, biological apatites are different from pure and
synthetically produced HA due to the presence of trace
elements in the apatites such as cations (Na+, K+, Mg2+,
Mn2+, Sr2+, Ba2+. Cu2+, Zn2+ or Fe2+) and anions (HCO3-,
HPO42-, Cl- and F-). These can be considered as ionic substi-
tuents in the apatite structure. In fact, in order to optimize the
bioactivity of HA implants, it is important to produce a
substituted HA that approaches the composition of bone
mineral. Inclusion of trace metal elements has a significant
role in improving the physical and/or biological properties of
bioceramics. Metals like magnesium [65, 99-101], barium
[61, 102, 103], strontium [55, 61, 104], zirconium [105],
manganese [65], and zinc [65, 92] have been doped into
hydroxyapatite and proven effective in enhancing physico-
chemical properties of hydroxyapatite. An alternative
economical technique to obtain highly dense HA body with
enhanced mechanical properties and biocompatibility is by
incorporating appropriate low temperature sintering additives
such as zirconia, magnesium, manganese, ceria and iron
[89]. It was reported that the powder produced by doping
with metal are in nanosized and resulted in better densifi-
cation due to better crystal growth with the metal ions.
Magnesium is one of the most important bivalent ions
associated with biological apatite. Magnesium-substituted
hydroxyapatite is found in cartilage as well as young bones
and it was proved to play a key role in accelerating bone
growth. It has been verified that in calcified bony tissues, the
amount of magnesium associated with the apatitic phase is
higher at the beginning of the calcinations. Also there is
growing evidence that magnesium could be an important
factor in the qualitative changes of the bone matrix that
determines bone fragility. Inclusion of magnesium can
decrease hydroxyapatite solubility, increase the size and/or
the perfection of hydroxyapatite crystals in bone, and also
increase the tensile strength of bone. This metal, when
administered to patients will encourage the growth of new
and normal bone tissue [106].
The effect of manganese (Mn) on the stability and
particle growth of HA has been also recognized [90]. The
motivation for the addition of Mn2+ ions to HA was due to
Nawawi et al.
the fact that divalent Mn2+ has influenced the activation of
integrins, a family of receptors that mediate cellular interac-
tions with extracellular matrix and cell surface ligands [75,
90]. The ligand affinity of affinity increases in the presence
of Mn, resulting in the promotion of cell adhesion. In one
study, manganese in the bone was found to cause a decrease
in bone resorption [80]. It is also reported that Mn functioned
as calcination and sintering additives of biphasic calcium
phosphate (BCP) powders without producing other secon-
dary phases like
-TCP and CaO [107]. The formation of the

-TCP phase during the sintering process is not preferable as
it induces micro-cracks, which eventually reduces the
mechanical properties of the sintered specimens.
By forming HA composite, the toughness of the ceramics
has been improved while decreasing its modulus of elasticity
[37]. Small changes in particle size and morphology of the
HA powders used was proven to have significant effects on
the mechanical properties of the final composite [78]. The
composite can be formed by using the ceramic as the
reinforcement phase, the matrix or both. For example, a
polymer-matrix composite (PMC) reinforced with a biocera-
mic; polyethylene (PE) is reinforced with HA particles. The
incorporation of foreign particles into the HA matrices to
form composites that might induce energy dissipative
mechanisms such as crack deflection, thus enhancing the
mechanical properties. This has shown to yield better
strength, but is often associated with the formation of
undesirable phases in the composite due to higher sintering
temperatures employed [83]. In addition, the formation of
composite needs large amount of reinforcing phases to
achieve desired properties, and as these phases are either
bioinert, significantly less bioactive than HA, or bioresorb-
able, then the ability of the composite to form a stable
interface with bone is poor compared with HA alone [72].
ZrO2-HA composites have also been studied before [8, 108,
109]. However, these composites do not have high strength
and fracture toughness, because the added ZrO2 prevented
densification of the HA. Hence, yttria stabilized zirconia
ceramics are doped with HA and they were found to be
better in bioactivity and having sufficient mechanical
strength and fracture toughness for a heavy load [8, 110].
HA has also been reinforced with carbon fiber [95] to
improve the mechanical properties for load bearing appli-
cations.
Ashley et al. proposed that incorporation of carbon
nanotubes (CNTs) into HA would be beneficial in improving
the mechanical properties at low loadings without
diminishing its bioactivity [29]. This material has only been
first developed a couple of years ago, thus creating a
synthetic bone graft material that can be used in major load
bearing situations. CNTs with their small dimensions, high
aspect ratio (length to diameter), and high strength and
stiffness, have excellent potential to accomplish this [29].
However, a way to densify the HA while preserving its
structure and retaining the CNTs must be found for these
composites to be viable in major load bearing clinical
devices. As this area has newly been sought, the bioactivity
and toxicity of these composites are yet to be determined. At
this early stage, an HA-CNT composite would ideally be
used in load bearing situation that have mechanical
properties similar to those of bone, with a tensile strength of
Hydroxyapatite-Based Dense Biomaterials
at least 50MPa and a fracture toughness of at least
2MPa.m1/2.
In addition, reactions by which HA can be formed at low
temperatures by cement-type reaction involving dissolution
and precipitation have been identified [23, 111, 112].
Currently, this type of materials is known as calcium
phosphate cements (CPC). Due to its high biocompatibility
[9], bioactivity [9] and good resorbability [9, 97], CPC
belongs to the second generation of bone substituting
biomaterials [97]. These cements are blends of amorphous
and/or crystalline calcium orthophosphate powder with an
aqueous solution [9]. When the powder and the solution are
mixed together, a viscous and mouldable paste is formed that
sets to a firm mass within a few minutes when the paste
becomes sufficiently stiff. It can be placed into a defect as a
substitute for the damaged part of bone, when it hardens
in situ within the operating theatre. As the paste is set and
hardened at room or body temperature, direct application, in
healing bone defects became a new and innovative treatment
modality in the end of the twentieth century. Moreover,
calcium orthophosphate cements can be injected directly into
fractures and bone defects, where they intimately adapt to
the bone cavity regardless of its shape [9, 23, 97]. This
enables them to fill the bone defects much better than HA
solid block, powder or granules, which are difficult to shape
and keep in place. Besides, they were found to promote
development of osteoconductive pathways, possess sufficient
compressive strengths, be noncytotoxic, create chemical
bonds to the host bones, restore contour and have both the
chemical composition and X-ray diffraction patterns similar
to those of bone. Finally, but yet importantly, they are osteo-
transductive [97], i.e., after implantation calcium orthophos-
phate cements are replaced by a new bone tissue. Verheggen
et al. have found out that HA cement has an excellent
biocompatibility as it is non-immunogenic and non-toxic
[113].
In recent years, interest in biphasic mixture of
hydroxyapatite and tetracalcium phosphate thin coatings for
biomedical applications has arisen progressively. This is due
to its enhanced bioactivity and mechanical stability that is
difficult to achieve in single-phase materials. This feature
has made these biphasic bioceramics promising substrate
materials for applications in bone tissue regeneration and
repair [21]. An important thrust of current research
associated with calcium phosphate bioceramics is focused on
biphasic coatings composed of nonresorbable HA and
resorbable TCP. The partial dissolution of the bioresorbable
phase in biphasic calcium phosphate coatings is considered
beneficial because it may stimulate bone apatite formation at
the interface between implant and tissue bone [21]. How-
ever, if the dissolution of the bioresorbable phase is too rapid
it can deteriorate the coatings. Hence, it is very important to
find the optimum amount of the highly resorbable phases in
the coatings so that they can enhance bioactivity at the bone-
implant interface. The main limiting factor in the exploration
of other biphasic configurations is the difficulty in
identifying coating deposition methods capable of generating
high quality biphasic coatings with good reproducibility.
Mechanical properties that are fracture toughness and
Young’s Modulus of the presently available biomaterials for
Recent Patents on Materials Science 2011, Vol. 4 No. 1 77
bone replacements has been reported [114]. The HA and the
HA/bioactive glass composites are the most biocompatible
among the presented biomaterials. However, KIc values of
both the HA ceramics and the HA/bioactive glass composites
are below or on the lower KIc limit of the bone, thus these
materials cannot be used as heavy-load-bearing implants.
The HA-based ceramic composites are in the KIc range of the
bone, and KIc of the HA-coated titanium alloys exceed
several times the upper KIc limit of the bone. However, both
the HA-based ceramic composites and the HA-coated Ti
suffer first of all too high a Young’s modulus; second, there
are problems related to their processing; third, their biolo-
gical features are insufficient. The HA/polymer composites
have Young’s modulus close to the Young’s modulus of the
bone and exhibit quite good mechanical reliability [100].
Thus, many efforts have been shown worldwide to get
reliable load bearing bone substitute devices close to the
properties of living bone. In the upcoming future, efforts
should be emphasized on development of biocompatible HA-
biopolymer composites to obtain long-term stable, bioactive
but mechanically and biologically compatible cortical bone
substitutes.
ACKNOWLEDGEMENTS
The authors are grateful to Research Management Centre,
IIUM for the partial support provided through the
Endowment Fund Research Grant.
CONFLICT OF INTEREST
No.
REFERENCES
[1] Ramesh S, Tan CY, Baiduri SB, Teng WD. Rapid densification of
nanocrystalline hydroxyapatite for biomedical applications. Ceram
Int 2007; 33: 1363-7.
[2] Pramanik S, Agarwal AK, Rai KN. Development of high strength
hydroxyapatite for hard tissue replacement. Trends Biomater Artif
Organs 2005; 19: 46-51.
[3] Liu DM. Fabrication of hydroxyapatite ceramic with controlled
porosity. J Mater Sci Mater Med 1997; 8: 227-32.
[4] Jillavenkatesa A, Hoelzer DT, Condrate RA. An electron
microscopy study of the formation of hydroxyapatite through sol-
gel processing. J Mater Sci 1999; 34: 4821-30.
[5] Loo SCJ, Siew YE, Ho S, Freddy YCB. Synthesis and
hydrothermal treatment of nanostructured hydroxyapatite of
controllable sizes. J Mater Sci Mater Med 2008; 19: 1389-97.
[6] Siddharthan A, Seshadri SK, Kumar STS. Rapid synthesis of
calcium deficient hydroxyapatite nanoparticles by microwave
irradiation. Trends Biomater Artif Organs 2005; 18: 110-13.
[7] Nakano T, Tokumura A, Umakoshi Y. Variation in crystallinity of
hydroxyapatite and the related calcium phosphates by mechanical
grinding and subsequent heat treatment. Metall Mater Trans A
2002; 33A: 521-8.
[8] Prabakaran S, Kannan S, Rajeswari S. Development and
characterisation of zirconia and hydroxyapatite composites for
orthopaedic applications. Trends Biomater Artif Organs 2005; 18:
114-6.
[9] Yuan H, Groot KD. Calcium Phosphate Biomaterials: An
Overview, in Learning from Nature how to Design New
Implantable Biomaterialsis: From Biomineralization Fundamentals
to Biomimetic Materials and Processing Routes. In: Reis RL,
Weiner S, Eds. Springer: Netherlands 2005; 37-57.
[10] LeGeros RZ, LeGeros JP. Dense Hydroxyapaite, in an Introduction
to Bioceramics. In: Hench LL, Wilson J, Eds. World Scientific
Publishing Co: USA 1993; 139-79.
78 Recent Patents on Materials Science 2011, Vol. 4, No. 1
[11] Petit R. The use of hydroxyapatite in orthopaedic surgery: A ten
year review. Eur J Orthop Surg Traumatol 1999; 9: 71-4.
[12] Zhang X, Vecchio KS. Creation of dense hydroxyapatite (synthetic
bone) by hydrothermal conversion of seashells. Mater Sci Eng C
2006; 26: 1445-50.
[13] Barinov SM, Tumanov SV, Fadeeva IV, Bibikov VY. Environment
effect on the strength of hydroxyapatite and fluorohydroxyapatite
ceramics. Inorg Mater 2003; 39: 877-80.
[14] Silva CC, Thomazini D, Pinheiro AG, Lanciotti Jr. F, Sasaki JM,
Goes JC, et al. Optical properties of hydroxyapatite obtained by
mechanical alloying. J Phys Chem Solids 2002; 63: 1745-57.
[15] Dejong WF. The mineral components of bones. Recueil Travaux
Chimiques Pays-Bas 1926; 45: 415-48.
[16] Sinha A, Mishra T, Ravishankar N. Polymer assisted
hydroxyapatite microspheres suitable for biomedical application. J
Mater Sci Mater Med 2008; 19: 2009-13.
[17] Correia RN, Magalh MCF, Marques PAAP, Senos AMR. Wet
synthesis and characterization of modified hydroxyapatite powders.
J Mater Sci Mater Med 1996; 7: 501-5.
[18] Slosarczyk A, Bialoskorski J. Hardness and fracture toughness of
dense calcium-phosphate-based materials. J Mater Sci Mater Med
1998; 9: 103-8.
[19] Gibson IR, Ke S, Best SM, Bonfield W. Effect of powder
characteristics on the sinterability of hydroxyapatite powders. J
Mater Sci Mater Med 200; 12: 1163-71.
[20] Tadic D, Epple M. A thorough physicochemical characterisation of
14 calcium phosphate-based bone substitution materials in
comparison to natural bone. Biomaterials 2004; 25: 987-94.
[21] Kim H, Camata RP, Vohra YK, Lacefield WR. Control of phase
composition in hydroxyapatite/tetracalcium phosphate biphasic thin
coatings for biomedical applications. J Mater Sci Mater Med 2005;
16: 961-6.
[22] Suzuki O, Kamakura S, Katagiri T, Nakamura M, Zhao B, Honda
Y, et al. Bone formation enhanced by implanted octacalcium
phosphate involving conversion into Ca-deficient hydroxyapatite.
Biomaterials 2006; 27: 2671-81.
[23] Durucan C, Brown PW.
-Tricalcium phosphate hydrolysis to
hydroxyapatite at and near physiological temperature. J Mater Sci
Mater Med 2000; 11: 365-71.
[24] Popescu ML, Piticescu RM, Petresc S, Zdrentu L, Mihailescu I,
Socol G, et al. Biocompatibility of hydroxyl-apatite thin films
obtained by pulsed laser deposition. Rev Adv Mater Sci 2004; 8:
164 -9.
[25] Ryu HS, Hong KS, Lee JK, Kim DJ. Variations of structure and
composition in magnesium incorporated hydroxyapatite/ -
tricalcium phosphate. J Mater Res 2006; 21: 428- 36.
[26] Nein RWN, Richter PW. The thermal stability of hydroxyapatite in
biphasic calcium phosphate ceramics. J Mater Sci Mater Med 2008;
19: 1693-702.
[27] Trommer RM, Santos LA, Bergmann CP. Alternative technique for
hydroxyapatite coatings. Surf Coat Technol 2007; 201: 9587- 93.
[28] Pattanayak DK, Divya P, Upadhyay S, Prasad RC, Rao BT, Mohan
TRR. Synthesis and evaluation of hydroxyapatite ceramics. Trends
Biomater Artif Organs 2005; 18: 87-92.
[29] Ashley AW, Serena MB, Ian AK. Hydroxyapatite-carbon nanotube
for biomedical applications: A review. Int J Appl Ceram Technol
2007; 4: 1-13.
[30] Dee KC, Puleo DA, Bizios R. Biocompatibility, in an Introduction
to Tissue-Biomaterial Interactions. In: Dee KC, Puleo DA, Bizios
R, Eds. Wiley-Liss Inc: USA 2003; 173-84.
[31] Carter CB, Norton MG. Ceramics in Biology and Medicine, in
Ceramic Materials: Science and Engineering. In: Carter CB, Norton
MG, Eds. Springer-Verlag: USA 2007; 635-51.
[32] Ramesh S. Grain size - Properties correlation in polycrystalline
hydroxypatite bioceramic Malaysian J Chem 2001; 3: 35-40.
[33] Nakahira A, Eguchi K. Evaluation of microstructure and some
properties of hydroxyapatite/Ti composites. J Ceream Process Res
2001; 2: 108-12.
[34] Guo L, Li H. Fabrication and characterization of thin nano-
hydroxyapatite coatings on titanium. Surf Coat Technol 2004; 185:
268-74.
Nawawi et al.
[35] With GD, Van Djik HJA, Hattu N, Prijs K. Preparation,
microstructure and mechanical properties of dense polycrystalline
hydroxyapatite. J Mater Sci 1981; 16: 1592-8.
[36] Batchelor AW, Chandrasakeran M. Introduction, in Service
Characteristics of Biomedical Materials and Implant. In: Batchelor
AW, Chandrasakeran M, Eds. Imperial College Press: USA 2004;
1-13.
[37] Williams DF. Titanium for Medical Applications, in Titanium in
Medicine: Material Science, Surface Science, Engineering,
Biological Responses and Medical Applications. In: Brunette DM,
Tengvall P, Textor M, Thomsen P, Eds. Springer-Verlag: Berlin
2001; 13-24.
[38] Sivakumar R. On the relevance of biomaterial. Bull Mater Sci
1999; 22: 647-55.
[39] Niinomi M. Recent research and development in titanium alloys for
biomedical applications and healthcare goods. Sci Technol Adv
Mater 2003; 4: 445-54.
[40] Aves EP, Sader MS, Jeronimo FAR, de Sena LA, Sierra JCG,
Soares GDA. Comparative study of hydroxyapatite coatings
obtained by sol-gel and electrophoresis on titanium sheets. Rev
Mater 2007; 12: 156-63.
[41] Dorozkhin SV. Calcium orthophosphates cements for biomedical
applications. J Mater Sci 2008; 43: 3028-57.
[42] Quek CH, Khor KA, Cheang P. Influence of processing parameters
in the plasma spraying of hydroxyapatite/Ti-6Al-4V composite
coatings. J Mater Process Technol 1999; 89: 550-5.
[43] Gallardo J, Galliano P. Bioactive sol-gel coatings for orthopaedic
prosthesis. J Sol-Gel Sci Technol 2000; 19: 107-11.
[44] Singha RR, Mitra M, Basu D. Characterization of mechanical
properties of alumina based hip joint prostheses. Trends Biomater
Artif Organs 2005; 18: 166-73.
[45] Inuzuka M, Nakamura S, Kishia S, Yoshida K, Hashimoto K, Toda
Y, et al. Hydroxyapatite-doped zirconia for preparation of
biomedical composites ceramics. Solid State Ionics 2004; 172:
509-13.
[46] Ramesh S, Tan CY, Sopyan I, Hamdi M, Teng WD. Consolidation
of nanocrystalline hydroxyapatite powder. Sci Technol Adv Mater
2007; 8: 124-30.
[47] Simon V, Muresan D, Popaa C, Simon S. Microscopic analysis of
sintered titanium-hydroxyapatite implant materials. J Optoelectron
Adv Mater 2005; 7: 2823-6.
[48] Furuzano, T., Kisida, A., Tanaka, J., Matsuda, A. Hydroxyapatite
composite and manufacturing method thereof, medical material
using hydroxyapatite complex. US7473731 (2009).
[49] Ito, S., Iwasaki, M. Bone substitute material, medical material
comprising the bone substitute material and method for
manufacturing the bone substitute material. US20090192628
(2009).
[50] Jui, C., Sanghamitra, B., Kumar, S. M., Debabrata, B. Process for
the preparation of protein mediated calcium hydroxyapatite (hap)
coating on metal substrate. US20090181161 (2009).
[51] Ahn, E. S. Tricalcium phosphates, their composites, implants
incorporating them, and method for their production.
US20050031704 (2005).
[52] Ronald, G. I., Skakle, J. M. S., Stephen, J. A., Buckland, T.
Biomedical materials. WO2007000608 (2007).
[53] Sayer, M., Reid, J., Smith, J. N., Hendry, J. Silicon substituted
oxyapatite. US20090030089 (2009).
[54] Wen, H. B., Moradian-Oldak, J. Materials for dental and
biomedical application. US7132015 (2006).
[55] Kim, B. S. PLGA/Hydroxyapatite Composite Biomaterial and
Method of Making the Same. US20090048358 (2009).
[56] Kamitakahara, M., Tanihara, M., Ohtsuki, C., Ogata, S. Composite
material useful as biomaterial and its preparation. US20090005881
(2009).
[57] Rudin, V. N., Melikhov, I. V., Minaev, V. V., Orlov, A. Y.,
Bozhevolnov, V. E. Method for producing hydroxyapatite particles.
US20090155320 (2009).
[58] Clineff, T. D., Darmoc, M. M., Havener, M. B., Murphy, J. P.,
Szczerbinski, Z. S.E. Bioactive composite of polymer and glass and
method for making same. US20100168798 (2010).
[59] Steinberg, A. Cushion bearing implants for load bearing
applications. US20100185297 (2010).
Hydroxyapatite-Based Dense Biomaterials
[60] Luo, T.-J. M., Ko, C.-C., Tulloch, C. Formable bioceramics.
US20100178278 (2010).
[61] Zhang, Y., Regeros, R., Kim, J-W. Bioactive graded zirconia based
structure. US20090118114 (2009).
[62] Kweh SWK, Khor KA, Cheang P. The production and
characterization of Hydroxyapatite (HA) powders. J Mater Process
Technol 1999; 89: 373-7.
[63] Feng W, Mu-sen L, Yu-peng L, Yong-xin Q. A simple sol-gel
technique for preparing hydroxyapatite nanopowders. Mater Lett
2005; 59: 916-9.
[64] Hsieh MF, Perng LH, Chin TS, Perng HG. Phase purity of sol-gel
derived hydroxyapatite ceramic. Biomaterials 2001; 22: 2601-7.
[65] Xiu Z, Lu M, Liu S, Zhou G, Su B, Zhang H. Barium
hydroxyapatite nanoparticles synthesized by citric acid sol-gel
combustion method. Mater Res Bull 2005; 40: 1617-22.
[66] Ramachandra RR, Roopa HN, Kannan T. Solid state synthesis and
thermal stability of HAP and HAP – -TCP composite ceramic
powders. J Mater Sci Mater Med 1997; 8: 511-8.
[67] Zyman Z, Tkachenko M, Epple M, Polyakov M, Naboka M.
Magnesium-substituted hydroxyapatite ceramics. Biomaterials
2006; 37: 474 -7.
[68] Kalitha SJ, Bhatt HA. Nanocrystalline hydroxyapatite doped with
magnesium and zinc: Synthesis and characterization. Mater Sci
Eng C 2007; 27: 837-48.
[69] Gibson IR, Bonfield W. Preparation and characterization of
magnesium/carbonate co-substituted hydroxyapatites. J Mater Sci
Mater Med 2002; 13, 685-93.
[70] Reid JW, Tuck L, Sayer M, Fargo K, Hendry JA. Synthesis and
characterization of single-phase silicon-substituted
-tricalcium
phosphate. Biomaterials 2006; 27: 2916-25.
[71] Lilley KJ, Gbureck U, Knowles JC, Farrar DF, Barralet JE. Cement
from magnesium substituted hydroxyapatite. J Mater Sci Mater
Med 2005; 16: 455-60.
[72] Pietak AM, Reid JW, Stott MJ, Sayer M. Silicon substitution in the
calcium phosphate bioceramics. Biomaterials 2007; 28: 4023-32.
[73] Tas AC. Combustion synthesis of calcium phosphate bioceramic
powder. J Eur Ceram Soc 2000; 20: 2389-94.
[74] Yeong KCB, Wang J, Ng SC. Fabricating densified hydroxyapatite
ceramics from a precipitated precursor. Mater Lett 1999; 38: 208-
13.
[75] Rodriguez-Lorenzo LM, Vallet-Regi M, Ferreira JMF. Fabrication
of hydroxyapatite bodies by uniaxial pressing from a precipitated
powder. Biomaterials 2001; 22: 583-8.
[76] Akao M, Aoki H, Kato K. Mechanical properties of sintered
hydroxyapatite for prosthetic applications. J Mater Sci 1981; 16:
809-12.
[77] Acchar W, Ramalho EG. Effect of MnO 2 addition on sintering
behavior of tricalcium phosphate: Preliminary results. Mater Sci
Eng C 2008; 28: 248-52.
[78] Patel N, Gibson IR, Ke S, Best SM, Bonfield W. Calcining
influence on the powder properties of hydroxyapatite. J Mater Sci
Mater Med 2001; 12: 181-8.
[79] Nakamura S, Nakahira A. Synthesis and evaluation of porous
hydroxyapatite prepared by hydrothermal treatment and subsequent
sintering method. J Ceram Soc Jpn 2008; 116: 42-5.
[80] Li XW, Yasuda HY, Umakoshi Y. Bioactive ceramic composites
sintered from hydroxyapatite and silica at 1200ºC: Preparation,
microstructures and in vitro bone-like layer growth. J Mater Sci
Mater Med 2006; 17: 573-81.
[81] Jinawath S, Sujaridworakun P. Fabrication of porous calcium
phosphate. Mater Sci Eng C 2002; 22: 41-6.
[82] Tadic D, Beckmann F, Schwarz K, Epple M. A novel method to
produce hydroxyapatite objects with interconnecting porosity that
avoids sintering. Biomaterials 2004; 25: 3335-40.
[83] Muralitharan G, Ramesh S. The effects of sintering temperature on
the properties of hydroxyapatite. Ceram Int 2000; 26: 221-30.
[84] Tadic D, Epple M. Mechanically stable implants of synthetic bone
mineral by cold isostatic pressing. Biomaterials 2003; 24: 4565-71.
[85] Rapacz-Kmita A, Paluszkiewicz C, Slosarczyk A, Paszkiewicz Z.
FTIR and XRD investigations on the thermal stability of
hydroxyapatite during hot pressing and pressureless sintering
processes. J Mol Struct 2005; 744: 653-6.
Recent Patents on Materials Science 2011, Vol. 4 No. 1 79
[86] Fang L, Leng Y, Gaob P. Processing and mechanical properties of
HA/UHMWPE nanocomposites. Biomaterials 2006; 27: 3701-7.
[87] Chang S, Doremus RH, Schadler LS, Siegel RW. Hot pressing of
nano-size alumina powder and the resulting mechanical properties.
Int J Appl Ceram Technol 2004; 11:72-9.
[88] Bocanegra BMH. Review Hot Isostatic Pressing (HIP) technology
and its applications to metals and ceramics. J Mater Sci Mater Med
2004; 39: 6399-420.
[89] Vecchio KS, Zhang X, Massie JB, Wang M, Kim CW. Conversion
of bulk seashells to biocompatible hydroxyapatite for bone
implants. Acta Biomater 2007; 3: 910-18.
[90] Sinha A, Ingle A, Munim KR, Vaidya SN, Sharma BP, Bhisey AN.
Development of calcium phosphate based bioceramics. Bull Mater
Sci 2001; 24: 653-7.
[91] Tan CY, Ramesh S, Hamdi M, Sopyan I. Sinterability of
Hydroxyapatite Compacts Prepared by Cold Isostatic Pressing for
Clinical Applications. IFMBE Proceedings. Berlin: Springer 2006;
15: 137-40.
[92] Lu H, Qu Z, Zhou Y. Preparation and mechanical properties of
dense polycrystalline hydroxyapatite through freeze-drying. J
Mater Sci Mater Med 1998; 9: 583-7.
[93] Jolata S, Tas AC, Bhaduri S. Microwave assisted synthesis of
calcium phosphate nanowhiskers. J Mater Res 2004; 19: 1876-81.
[94] Hench LL. Bioceramics. J Am Ceram Soc 1998; 81: 1705-28.
[95] Slosarczyk A, Klisch M, Blazewicz M, Piekarczyk J, Stobierski L,
Rapacz-Kmita A. Hot pressed hydroxyapatite-carbon fibre
composites. J Eur Ceram Soc 2000; 20: 1397-402.
[96] Ramesh S, Tan CY, Bhaduri SB, Teng WD, Sopyan I.
Densification behaviour of nanocrystalline hydroxyapatite
bioceramics. J Mater Process Technol 2008; 206: 221-30.
[97] Sopyan I, Ramesh S, Hamdi M. Synthesis of nanosized
hydroxyapatite powder using sol-gel technique and its conversion
to dense and porous bodies. Ind J Chem 2008; 47A: 1626-31.
[98] Monthien C, Silikulrat K, Rujijanagul G, Tunkasiri T, Punyanitya
S, Raksujarit A. Sintering and mechanical properties of dense
hydroxyapatite nanocomposites. Adv Mater Res 2010; 123-5: 771-
4.
[99] Martin RI, Brown PW. The effects of magnesium on
hydroxyapatite formation in vitro from CaHPO4 and Ca4(PO4)2O at
37.4°C. Calcified Tissue Int 1998; 60: 538-46.
[100] Lilley KJ, Gbureck U, Knowles JC, Farrar DF, Barralet JE. Cement
from magnesium substituted hydroxyapatite. J Mater Sci Mater
Med 2005; 16: 455-60.
[101] Fadeev V, Shvorneva LI, Barinov SM, Orlovskii VP. Synthesis and
structure of magnesium-substituted hydroxyapatite. Inorg Mater
2003; 39: 947-50.
[102] Yang Z, Jiang Y , Yu L, Wen B, Li F, Sun S, et al. Preparation and
characterization of magnesium doped hydroxyapatite-gelatin
nanocomposite. J Mater Chem 2005; 15: 1807-11.
[103] Patel N, Best SM, Bonfield W, Gibson IR, Hing KA, Damien E, et
al. A comparative study on the in vivo behavior of hydroxyapatite
and silicon substituted hydroxyapatite granules. J Mater Sci Mater
Med 2002; 13: 1199-206.
[104] Brunski JB. Metals, in Biomaterials Science: An Introduction to
Materials in Medicine. In: Ratner BD, Hoffman AS, Schoen FJ,
Lemons JE, Eds. Elsevier Academic Press: USA 2004; 137-52.
[105] Miao S, Weng W, Cheng K, Du P, Shen G, Han G, et al. Sol gel
preparation of Zn-doped fluoridated hydroxyapatite films. Surf
Coat Technol 2005; 198: 223-6.
[106] Mayer I, Diab H, Reinen D, Albrecht Ch. Manganese in apatites,
chemical, ligand-field and electron paramagnetic resonance
spectroscopy studies. J Mater Sci 1993; 28: 2428-32.
[107] Ramesh S, Tan CY, Peralta CL, Teng WD. The effect of
manganese oxide on the sinterability of hydroxyapatite. Sci
Technol Adv Mater 2007; 8: 257-63.
[108] Narulkar VV, Prakash S, Chandra K. Characteristics of porous
zirconia coated with hydroxyapatite as human bones. Bull Mater
Sci 2007; 30: 309-14.
[109] Nayak Y, Rana RP, Pratihar SK, Bhattacharyya S. Pressureless
sintering of dense hydroxyapatite-zirconia composites. J Mater Sci
Mater Med 2008; 19: 2437-44.
[110] Othman SZ, Ramesh S, Teng WD. Sintering of commercial yttria-
stabilized zirconia. Eng Trans 2006; 1: 14-8.
80 Recent Patents on Materials Science 2011, Vol. 4, No. 1
[111] Calafiori RA, Marco GD, Martino G, Marotta M. Preparation and
characterization of calcium phosphate biomaterials. J Mater Sci
Mater Med 2007; 18: 2331-8.
[112] Lu J, Descamps D, Dejou J, Koubi G, Hardouin P, Lemaitre J,
et al. The biodegradation mechanism of calcium phosphate
biomaterials in bone. J Biomed Mater Res (Appl Biomater) 2002;
63(4): 408-12.
Nawawi et al.
[113] Verheggen R, Merten HA. Correction of skull defects using
hydroxyapatite cement (HAC)--evidence derived from animal
experiments and clinical experience. Acta Neurochir 2001; 143:
919-26.
[114] Suchanek W, Yoshimura M. Processing and properties of
hydroxyapatite-based biomaterials for use as hard tissue
replacement implants. J Mater Res 1998; 13: 94-117.