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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


significant ability to promote bone growth along its surface
For years, synthetically produced calcium hydroxyapatite
and integrate in living bone structures without breaking
and the related calcium phosphates have been of consi-
down or dissolving [29]. It was the first time applied for
derable interest as biocompatible materials for bone replace-
periodontal lesion filling in 1981 [30]. Unfortunately, its
ment as they are the dominant mineral constituents of bone, mechanical properties are insufficient for major load bearing
teeth and hard tissues [1-9]. Literally, hydroxyapatite (HA) is
devices [2, 24, 28-34], limiting its medical applications to
one of the calcium phosphate compounds with a definite
non-stressed regions of skeletons [35]. The restriction is also
composition Ca10(PO4)6(OH)2 and crystallographic structure
due to its low toughness (0.8-1.2MPa.m1/2) and flexural
[10]. It is a crystalline substance essentially composed of
strength (<140MPa) [32].
phosphorus and calcium [11] and constitutes ca. 69 vol% of
the mineral component of human bone [11-14]. Dejong has Nevertheless, many efforts have been made to obtain
first identified HA as being the mineral component of bone bioactive but high strength bone implants. Improvement of
[15]. mechanical performance of dense HA and deposition of
bioactive thin film onto bio-inert implants are among the
HA has then been extensively studied for its potential in
efforts. This review will describe the current issues on the
variety of medical applications as HA is found to be the most
development and application of dense HA as a bioactive
stable calcium phosphate polymorph under physiological ceramics for load bearing bone substitutes.
conditions [16, 17].
Clinically, HA was used in a variety of physical forms BONE: A BRIEF OVERVIEW
such as a sintered ceramic in granular [18], block or porous
form [7, 12, 18-20], as a deposited coating on a bioinert Bone is a living material composed of cells and a blood
implant [12, 21, 22] and metal prostheses [23-28], or as a supply encased in a strong, interwoven composite structure
filler phase of a polymer-ceramic composite material such as [10]. It consists mainly of collagen fibres and an inorganic
hydroxyapatite-polyethylene implants [19]. For example, HA bone mineral in the form of small crystals [10, 32]. Bioche-
powder has been used in surgery since 1920 with the aim of mically, the blend of three major components that defined
promoting bony consolidation in maxillofacial surgery [11]. bone are 30-40% flexible and very tough collagen, 60-70%
HA is considered to be almost fully biocompatible with 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
*Address correspondence to this author at the Department of Manufacturing various cellular support functions. The bone mineral consists
and Materials Engineering, Faculty of Engineering, International Islamic mainly of calcium phosphates with significant amounts of
University Malaysia (IIUM), PO Box 10, 50728 Kuala Lumpur, Malaysia;
Tel: +603-61964592; Fax: +603-61964477; E-mail: sopyan@iium.edu.my 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 Recent Patents on Materials Science 2011, Vol. 4 No. 1 65

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

The Most Common Implant Materials Used In Besides titanium, stainless steel, a group of iron-based
Conventional Biomedical Implants alloys also exhibit a phenomenal resistance to rusting or
corrosion because of its chromium content. The doping of
Metals, polymers and ceramics are three main types of
small amount of chromium into steel has successfully
materials which can be selected for load bearing appli-
strengthened it. Moreover, stainless steel is the only implant
cations. Table 2 is a comparative list of the physical proper- material which possessed superior ductile behaviour to
ties of the three biomaterials.
titanium. Stainless steels especially surgical grade type 316L
The first implanted material was gold plate for cleft has been used as customary temporary implants. This type of
palate in 1588. When polymer industry was developed in orthopaedic implants however, corrodes in the body
1950s, the metallic materials like silver, platinum, stainless environment and release iron, chromium and nickel ions and
steel and cobalt based alloys were mainly used [39]. The these ions are found to be powerful allergens and carcino-
materials that dominate biomedical metals are pure titanium gens [43]. Hence, improvement is needed in overcoming
(Ti), titanium alloys and 316L stainless steel followed by these localized corrosion attacks and leaching of metallic
nearly inert bioceramics. ions from implants. Besides that, AISI 316L (low carbon
content) stainless steel, is often used for temporary devices
Titanium or any titanium rich alloy has been greatly used
in orthopaedic surgery. However, this alloy has a tendency to
in many implantation applications especially those which
involved the load bearing parts. It is not surprising as taking localized corrosion, releases significant quantities of iron and
promotes the formation of fibrous tissue around implants
into consideration its classical foundations of inertness, best
[44]. Moreover, the need to reduce costs in public health
compatibility among metallic biomaterials [37, 38, 40],
services has compelled the use of stainless steel as the most
corrosion resistance [30, 38, 41] and superior mechanical
economical alternative for orthopaedic implants [10].
properties [37, 38, 40, 42]. Among the titanium alloys, pure
titanium and Ti-6Al-4V are still the most widely used in Alumina (Al2O3) and zirconia (ZrO2) are two nearly inert
biomedical applications. It is well known that some titanium bioceramics as they undergo little or no chemical change
ions released into tissues over a period of time give rise to a during long term exposure to body fluids [31]. Al2O3 has
characteristic discoloration of the tissue. In contrast, vast been used as load bearing hip prostheses and dental implants
majority of evidences have indicated that the titanium that is due to its high density. It is reported that Al2O3 ball has been
present in the tissue, and associated with this discoloration used extensively for the femoral head component by 2006
has very little effect. Abundant in vitro studies [11, 37] for more than >106 hip prostheses [44]. However, the nature
demonstrated an absence of cytotoxic effects, or a minimal of ceramics has hindered its application for lifetime. Increase
cytotoxicity in comparison with other metallic elements. of loads and longer times increased the probability of failure.
However, the application of titanium alloy implants have It also has only moderate flexural strength and low toughness
been shown to suffer fretting and without the employment of which limits the diameter of most Al2O3 femoral head
biomedical coatings results in the production of a metallic, prostheses to 32mm [31]. An aging and fatigue studies have
cellular mash at the bone-implant interface. 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 Recent Patents on Materials Science 2011, Vol. 4 No. 1 67

with the highest possible standards of quality assurance for surface of a substrate allows the possession of the bulk
orthopaedic prostheses [31]. properties of the substrate and the surface properties of the
coating. When a bioinert metal implant is coated with
In contrast, ZrO2 ceramics possessed better mechanical
bioactive HA, bone cells adhere onto the surface of the
properties in terms of fracture toughness, flexural strength
and elasticity than Al2O3. They have been used in apatite coating without any intervening layer. The HA matrix
of the bone cells later becomes integral with the HA coating
orthopaedic implant material such as knee and hip joint [45].
and there is excellent adhesion of the coated implant to the
However, as it is exposed to bodily fluids, it will experience
bone, resulting in shorter healing periods as well as
a slight decrease in flexural strength and toughness [31].
predictable behaviour of the implant for longer periods of
Moreover, ZrO2 contains low concentration of long half-life
time [34, 47]. Hence, the restriction of applying HA as a load
radioactive elements such as Th and U, which are difficult
and expensive to separate out. These emit -particles (He bearing implant could be overcome by using appropriate
metallic enforcer with HA.
nuclei), though at small activity, which can destroy both soft
and hard tissue and might lead to the long term effect of  As a result, HA coated implants have gained prominence
radiation emission. In conclusion, among these load bearing because of the biocompatibility and the induced bio-activity,
bone substitute materials, titanium has become the metal of which means the possibility of successful natural bone re-
choice for medical applications. growth, leading to excellent fixation of the prosthesis [32,
36]. Subsequently, the risk of release of metallic ions from
NECESSITY TO DEVELOP LOAD BEARING the implant into the body has been reduced via HA coatings
BIOACTIVE BONE IMPLANTS on titanium by extending the time before the host bone
comes into contact with the metal surface. In fact, the
There is a real need for development of second gene- deposition of HA coatings on this metallic substrate shields
ration of bioactive implants which promote regeneration of the metal surface from the physiological environment [37].
the surrounding tissues. Such materials could be used not The coating of titanium implants with HA to achieve bone
only for hip-replacement prostheses but also as other artifi- bonding implicitly states that this bonding does not occur so
cial bones or artificial teeth roots. Appropriate hard tissue readily or so well with uncoated titanium. For example, HA
replacement implants should be bioactive, have modulus as coatings on passive titanium oxide layer has produced a
equal to that of bone, and be even tougher than the bone. surface which is conducive to bone formation. A specific
Several non-metallic materials have been proposed as alloy such as Ti-6Al-4V is a common material onto which
candidates for artificial bones but none has found wide HA is deposited in prosthesis applications because of its
applications. As known, metals in elemental form are inherent impact and fatigue strength, toughness, manufac-
essentially alien to the human body. When a metal implant is turability and non-toxicity.
inserted in tissue, most metals become encapsulated by a thin
layer, which is almost empty of human cells. Adhesion Well controlled preparation of HA coating is necessary
between the metal implant and the surrounding tissue due to HA’s brittleness. For example if the coating on the
without any biochemical bonding is comparatively weak. implant surface is too thick (>70m), then failure of fixation
between the bone and the prosthesis may occur through
From the view point of biocompatibility and bioactivity, cracks which develop within the body of the coating and
HA seems to be the most suitable ceramic material for Quek et al. [42] deposited HA coating on Ti-6Al-4V via
implantation purposes due to its close resemblance with the plasma spraying and it was found that an increase in the
mineral components and crystal structure to apatite in human weight percentage of HA present in the composite coatings,
skeletal system of natural bone and teeth and ability to bond the bond strength decreases. This is because the coating is
to bone [34, 46]. The bone bonding capacity of HA coatings expected to have lower bond strength due to brittleness of
may help cementless fixation of orthopaedic prostheses [10]. HA. In the research, the composition of 50wt% HA with 50
Despite of these criterions, it is also known for its simulating wt% Ti-6Al-4V gave higher bond strength compared to the
effect on bone formation, termed as osseoconduction [10, 80wt% HA with 20 wt% Ti-6Al-4V, 21.25MPa and 19.49,
32]. However, the application of HA is offset by its lack of respectively at the current source of 1000A. Figure 2 shows
strength necessary for load bearing as bulk HA is brittle [32] the SEM morphology of 50 wt% HA: 50 wt% Ti-6Al-4V as
and relatively low mechanical strength when compared to sprayed coatings 1000 A [42].
common implant metals and alloys and high strength
ceramics like aluminum and zirconium oxides. The best use Many efforts have been done in order to obtain the
of HA in load bearing implant applications would be as a optimum results of coating despite of all HA deficiencies or
coating on one of these stronger implant materials [10]. weaknesses. Progressively, the efforts to improve the
Furthermore, HA coatings on metallic implants combine strength of HA have also focused on the incorporation of
mechanical strength of metal with excellent biocompatibility foreign particles into the HA matrices to form composites
and bioactivity of calcium phosphates. that might induce energy dissipative mechanisms such as
crack deflection, thus enhancing the mechanical properties.
Bioactive ceramic coatings are commonly used to modify This was shown to yield better strength, but is often asso-
the surface of the implant material and to create new surfaces ciated with the formation of undesirable phases in the
with totally different properties with respect to the substrate. composite due to the higher sintering temperatures em-
Concisely, there are few reasons in applying a coating. It is ployed. To date, there is a wide use of HA as coating mate-
intended to protect the substrate against corrosion, make the rial on prosthetic metallic implant as HA coated implants
implant biocompatible and to turn a biopassive surface into a
bioactive one. Applying a glass or ceramic coating onto the
68 Recent Patents on Materials Science 2011, Vol. 4, No. 1 Nawawi et al.

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 hydroxyapatie coating on metal substrates, stainless steel
between natural bone and the HA coating is achieved. (316L) by biomimetic route using supersaturated simulated
body fluid. This process is designed to mimic the structural
Recent Patents on Load Bearing Bone Substitutes and characteristic properties of the biological apatite to
expedite osteointegration kinetics and to further improve
Due to low mechanical properties and its characteristic as biocompatibility of the metallic implant. The patent discloses
a nonbiodegradable material which inhibits new bone from the capability of the prepared biomaterial to give rapid and
forming, hydroxyapatite is coated with degradable polymers effective osteointe-gration with the host tissue following
like poly (D, L-lactic-co-glycolic acid), poly (L-lactic acid) controlled interfacial reactions. For this purpose, the
and poly (glycolic acid). A biomaterial comprised of carbonated hydroxyapatite coating was developed after a
degradable polymer and hydroxyapatite can promote bone surface treatment step using aqueous solution (4-10 wt %) of
cell propagation and ingrowth well. Calcium phosphate BSA at room temperature.
complex of sintered hydroxyapatite compact chemically
bonded to a polymer –based materials containing an isocya- Ahn [51] disclosed the method of production for the
nate group and/or an alkoxysilyl is disclosed in US7473731 tricalcium phosphates (TCP) together with its composites
[48]. The invention concerns that the calcium phosphate can and implants incorporating them. The invention provides
be easily fixed to the surface of the polymer -based material method to synthesis nanoparticles of TCP. The method
for a long period without losing bioactivity as calcium employed is chemical precipitation followed by calcination.
phosphate is easily dissolved in a living body. The invention The synthesized powder has improves the microstructural
also relates a modified conventional technique for manu- control and design on the nanometer scale, phase uniformity
facturing the calcium phosphate complex where there is no and chemical homogeneity on the molecular level, unifor-
need to perform a chemical pre-treatment with respect to the mity of chemical and physical properties, machinability of
hydroxyapatite sintered compact, thus performing it in easier partially consolidated TCP, sintering behavior, mechanical
way. The hydroxyapatite sintered compact is obtained reliability and strength, net shape forming, manufacturing of
through sintering of hydroxyapatite at a temperature ranging porous and dense bodies, formation of composite materials
from 800ºC to 1300ºC. The invention has succeeded in the and gene, drug and protein delivery devices.
introduction of specific functional group in the calcium Moreover, zirconia was incorporated into TCP to
phosphate complex. enhance its mechanical properties is disclosed in the inven-
US20090192628 [49] discloses the invention of a tion. The incorporation of trace element in calcium phos-
medical material containing the bone substitute material and phate is also discussed by Ronald et al. [52]. In this
process for its production. The design of the bone substitute invention, silicate and trivalent cation-substituted calcium
material comprising titanium or a titanium alloy and an phosphate (e.g. HA, TCP etc.) are prepared. An aqueous
anodic oxide film of the applied titanium. The inorganic precipitation method is disclosed to prepare HA and apatite
compound microparticles of phosphorus and calcium are materials comprising silicon and a trivalent cation. The
firmly fixed to a surface and/or inside of the anodic oxide calcium ion in the HA will be substituted by trivalent cation
film. The bone material was found to have excellent mecha- and the phosphate ion in HA will be substituted by silicate
nical strength, biological affinity and biological activity. ion.
Meanwhile, the US20090181161 [50] issued to Jui et al., Besides that, silicon substitituted oxyapatite compound
describes the preparation of protein mediated calcium for use as a synthetic bone biomaterial compound in a
Hydroxyapatite-Based Dense Biomaterials Recent Patents on Materials Science 2011, Vol. 4 No. 1 69

variety of orthopedic applications such as skeletal implants implant or growth simulator of bone tissue in bone surgery,
has as described by The US20090030089 [53]. It has been surgical stomatology, orthopedy, traumatology and other
used alone or in biomaterial compositions. The patent dis- fields of medicine. For this purpose, hydroxyapatite particles
closes that this biomaterial was prepared by mixing a are embedded in matrix at least 50% nm as it is found to be
calcium phosphate colloidal suspension with a finely suitable as bone implant material. The patent discloses that
dispersed, fumed silica while maintaining a ratio of C/(P+Si) this invention produces a product with a high uniformity,
at about 1.67 in said mixture followed by sintering. This provided that that ration of calcium hydroxide and phosphate
method is similar the treatment of orthopedic, maxillo-facial in the suspension is 1.67 ± 0.3 at the beginning of the
and dental defects where the silicon substituted oxyapatite hydroxyapatite particle synthesis.
compound is provided as fine or coarse powders, pellets, thin
Recently, the US20100168798 [58] discloses the inven-
films and coatings. The implantation of this invention has tion of bioactive composites of polymer and glass as well as
succeeded in promoting the formation of new bone tissue at
bioactive implants. The invention also describes methods of
the interfaces between the compound and the host.
manufacturing bioactive composites. The bioactive compo-
Novel dental enamel inspired materials for biomedical site finds utility in variety of load-bearing clinical appli-
and dental applications are prepared from apatite-like cations including spine, orthopaedic and dental procedures.
calcium phosphate as described by US7132015 [54]. The Meanwhile, the US20100185297 [59] describes an
patent discloses that calcium phosphate coatings are prepared
acetabular implant for use in a hip joint prosthesis. The
via a chemical process leading to the formation of biological
implant includes a body portion comprising a polycarbonate
apatite. This method is similar to that found in natural bone
polyurethane.The body portion includes a a substantially
and teeth. The patent also discloses that the materials can be
semispherical inner articulating surface defining a socket
used for dental tissue replacement, orthopedic implants for
sized to receive a head portion of a femoral component of the
bone repair, and coatings for improving the biocompatibility hip joint prosthesis and an outer engagement surface having
and bone regeneration capability for implants or biomedical
an annular protrusion extending outwardly therefrom. The
devices made of metallic, polymeric, ceramic or composites
implant also includes a deformation control element having
materials.
an increased durometer hardness relative to the polycar-
Due to the problem arises from the application of bone bonate polyurethane and positioned within the body portion
grafting, a biocompatible material is sought that will act as a between the inner articulating surface and the outer
filler with appropriate mechanical strength, encourage bone engagement surface.
healing and degrade to allow bone ingrowth without the risk
The US20100178278 [60] discloses a formable biocera-
of disease transfer. The US20090048358 [55] discloses the
mic including hydroxyapatite nanocrystals, gelatin, and sol-
invention of a new composite bone-graft material. It is made
gel-containing material. Also a process for making and using
from biocompatible poly (D,L-lactic-co-glycolic acid) and
the bioceramics. The formable bioceramic displays superior
nano-sized hydroxyapatite particles exposed on its surface mechanical strength, elasticity, biocompatibility and forming
using a gas foaming particle leaching method. Nano-sized
capabilities and is targeted for bone repairs and template-
HA particles were used to reduce the total amount of HA
assisted tissue engineering applications.
degrades over long periods of time in vivo while enhancing
the HA distribution on the scaffold surface. Meanwhile, the The US20090118114 [61] presented invention provides a
PLGA polymer portion of the composite provides sufficient functionally graded bioactive glass/ceramic composite
mechanical strength to replace bone and is degradable over structure or bioactive glass/ceramic/bioactive glass sandwich
time to allow new bone tissue ingrowth. Thus, a uniform structure for use in such applications as damage resistant,
coating of mineral apatite on the surface of this novel bio- ceramic dental implants, immediate tooth replacement,
material composite further enhances its osteogenic qualities. endodontic posts, orthopedic prostheses, orthopedic stems,
bone substitutes, bone screws, plates, and anchors, nonunion
Composite material comprising of a chemosynthetic
fractures repair, alveolar ridge augmentation, missing small
collagen and a calcium phosphate compound and a method bone parts (e.g. fingers, toes, etc.), maxilla facial recons-
for its production have been disclosed by Kamitakahara et al.
truction, spinal fusion, and scaffolds for bone regeneration,
[56]. This simple method comprises of soaking a polypeptide
comprising a residual bioactive glass or glass-ceramic layer
in an aqueous solution of CaCl2 and then soaking the
at all accessible surfaces, followed by an underlying graded
polypeptide in simulated body fluid to deposit a calcium
glass-ceramic layer, and then an dense interior ceramic. The
phosphate compound on the surface of the polypeptide. The
residual bioactive glass or glass-ceramic lay can be further
produced composite materials is a bio-compatible hard-tissue transformed to a carbonate apatite (CHA) layer by
which having a composition analogous to a material from a
immersing in calcifying solution or simulated body fluid
living body and suitable to be used as an artificial bone.
(SBF) with electrolyte composition similar to that of serum.
Further, the composite resulted in high endurance and
The interior ceramic preferably contains yttria tetragonal
mechanical strength. This invention also reduced the risk as
zirconia polycrystal (Y-TZP) or ceria stabilized tetragonal
infection of pathogens and undesired side effects of the
zirconia polycrystal (Ce-TZP) or magnesia stabilized
composite biomaterials. zirconia (MG-PSZ) or calcia stabilized zirconia (Ca-PSZ) or
Novel technology in preparing collagen with inclusions alumina or zirconia-alumina composites. Further, the inven-
of hydroxyapatite particles as bone repair compositions for tion provides methods for making the same functionally
medical applications is described by US20090155320 [57]. graded bioactive glass/ceramic/bioactive glass sandwich
The biocomposite material is designed for applications as structure.
70 Recent Patents on Materials Science 2011, Vol. 4, No. 1 Nawawi et al.

Dense Hydroxyapatite load bearing application. One of promising approaches that


have been used to improve the mechanical performance of
Dense HA is described as HA that have porosity less than
HA is by doping with different sintering additives such as
5 volume percent [9,10] with micropores size diameter less
metal ions [17, 51, 67-72]. Besides that, HA coated metals
than 1m and grain size bigger than 0.2m [10]. The
have been introduced as artificial bones or teeth [10]. In
microporosity is unintentionally introduced and is dependent order to improve the reliability of HA ceramics various
on the temperature and duration of sintering [9]. Table 3 lists
reinforcements (ceramic or polymer) have also been used
some of the important parameters of dense HA compared to
[29].
the two types of bone that are of most concern in the use of
bioceramic: cancellous bone and cortical bone [29]. It is Preparation of Dense HA
important to note that, dense HA has a compressive strength
Traditionally, dense HA has been made by sintering HA
four times that of cortical bone, but yet it shows a
significantly lower tensile strength and fracture toughness. powders at high temperature [24, 73]. However, in time there
are various techniques developed to prepare dense HA. In
However, that even among studies on development of dense
conventional procedures, it was prepared via a uniaxial
HA, the values reported for mechanical properties vary
pressing [18, 23, 25, 28, 31, 46, 67-69, 74-81] by compres-
widely due to differences in sample preparation, starting HA
sing apatite powder into a mould at usually at pressure of 60-
powders used and measurement techniques.
800MPa [80], where the powder was mixed with binder such
Table 3. Mechanical Properties of Bone and Dense HA [29]. as cornstarch [15, 62], stearic acid in alcohol [11] polyvinyl
alcohol [81, 82] and Duramax [75]. The pressurized dense
Cortical Cancellous Dense bodies are then subjected to sintering normally in
Mechanical Properties temperature of 900ºC to 1300ºC. Higher than this sintering
Bone Bone HA
temperature were not favoured as it introduced subsequent
Compressive Strength (MPa) 100-230 2-12 430-920 phases of calcium phosphates such as CaO and -TCP [82].
This is unfavourable as samples with second phases are hard
Flexural/ Tensile Strength 50-150 10-20 17-1101
to make strong and have lower fatigue resistance. Besides
(MPa)
this conventional method, dense HA could also be prepared
Fracture Toughness (MPa.m1/2) 2-12 N/A 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,
There are many methods employed in producing HA slip casting, tape-casting, injection moulding, viscous plastic
powders such as wet-chemical method in aqueous solutions processing, or centrifugal settling [15].
[5, 15, 18, 28, 62], sol-gel [4, 15, 63, 64], combustion syn- The HIP which subjects a component to elevated tempe-
thesis [65], hydrothermal [5, 14], chemical precipitation [5,
ratures and pressures (generally over 98MPa (1000kgf.cm2)
17] and solid state reaction [2, 66]. Each method has its own
to eliminate internal micro-shrinkage and it can also be used
advantages over the others. For example, wet precipitation
directly to consolidate a powder or supplementary to further
technique produces only water as by-product and has low densify a cold pressed, sintered, or cast part [88]. This
probability of contamination during processing but it technique has found to be achieving densification at much
requires high pH value to avoid the formation of a calcium lower temperatures that is 900ºC than in the conventional
deficient HA and high sintering temperature to form
sintering process. This resulted in hindrance of possible
crystalline HA [63]. On the other hand, sol-gel process needs
formation of other calcium phosphate phases such as TCP,
no high pH value and not too high sintering temperature. As
which usually forms at temperature higher than 900ºC.
described elsewhere [46], HA is confined to its poor Moreover, this method also led to save on energy costs. The
mechanical properties inherited by the sintered body. This well known advantages of HIP is that it provides uniform
means that development of improved and ultimately bone- density very close to theoretical density, elimination of poro-
like mechanical properties HA powders are desirable.
sity, improved fatigue properties, improve creep properties,
Formation of dense HA is controlled by many factors, improved ductility and impact strength, decreased scatter of
including Ca/P molar ratio of the powders used and sintering properties, finer grain size structure and the ability to densify
temperature. Despite of having Ca/P molar ratio of pure HA powder which are otherwise difficult to compact [10, 88].
that is 1.67, dense HA varies in the Ca/P molar ratios. This Meanwhile, cold isostatic pressing (CIP) is normally
reflects variation in -TCP/HA ratios in the sintered dense
consists of pressing of powders at 200MPa [32]. CIP does
material which in turn reflect the purity of phases present
not influence the crystal structure of the obtained HA powder
and/or composition of HA before sintering [15]. Thus, the
proven by infra red analysis and X-ray diffraction analysis
Ca/P molar ratio of the hydroxyapatite preparation, the [84]. CIP also has been found to improve the limited
sintering temperature and conditions determine the mecha- mechanical stability of dense bodies in uniaxial pressing due
nical properties and microstructures of the dense HA. to insufficient compaction. This improvement is based on the
Seemly, it is too premature to dismiss dense HA as useful overall improved mechanical stability towards manual
implant material because via a proper processing, pore free scratching, torsion and bending which includes the edges.
dense HA could be prepared leading fairly good mechanical Recently, a new method was developed in preparing
properties to appear [10, 30]. These prepared dense bodies dense HA, which is by direct conversion from bulk seashells
could improve the mechanical properties of the bioactive HA to dense HA via a hydrothermal method at the relative low
and enhance the applicability of HA as implant material in
Hydroxyapatite-Based Dense Biomaterials Recent Patents on Materials Science 2011, Vol. 4 No. 1 71

temperature around 200°C [12, 89]. Strombus gigas (conch) 58% at 900ºC to 84 and 96.5% at 1000ºC and 1100ºC,
shells and Tridacna gigas (giant clam) shells have dense, respectively. This increase in density was reflected in the
tailored structures that impart excellent mechanical proper- improved hardness with the increased sintering temperature.
ties to these shells originally [12, 89]. This method enables However, the Lab HA samples sintered at 1200-1250ºC
the creation of dense HA without subsequent need for com- continued to show a small increase in hardness, whereas the
paction or pressing of the seashells. It involves the cutting of commercial HA showed a sudden increase in hardness for
these shells into small pieces to undergo autoclaving filled samples sintered from 1100 to 1200-1250ºC. From the
with (NH4)2HPO4 solution. The derived dense HA has results presented in Fig. (3a), the sintered density of Lab HA
average fracture stresses in the range of 137- 218MPa, increases by only 1-2% over this temperature range, whereas
compared to the strength of compact human bone is about the density of commercial HA increases from 70% at 1100ºC
170-193MPa loaded parallel to the axis, and about 133MPa to 91 and 97% at 1200 and 1250ºC, respectively. The
loaded normal to the bone axis. The conclusion made is the hardness tests show clearly the effect of sintered density on
shell samples after being partially converted to HA, have the hardness of HA ceramics, and that the hardness of Lab
mechanical strength values very similar to compact bone but HA is greater than commercial HA for lower sintering
at the same time they have bioactivity. It also results in dense temperatures, where it achieves higher sintered densities.
structures and excellent mechanical properties [12]. These properties are ultimately depending on the charac-
In addition, properties of powder for the compaction also teristics of the powder used to derive the dense HA.
contributed to the enhanced mechanical properties of dense
HA. Research by Gibson et al. [19] concerned to compare The Properties of Dense HA
the sinterability of an unannealed HA powder produced in Mechanical strength of dense HA mainly depends on
the laboratory (Lab HA) through an aqueous precipitation grain size, grain size distribution, porosity and other
method with that of a commercially available calcined HA microstructural defects [90]. In general, fine powder with
powder. In this research, these powders were subjected to greater surface area allows higher sinterability that leads to
compaction at the same pressing pressure (30-200MPa). The the use of lower densification temperature. Meanwhile, the
sintering regime at 1200ºC has resulted to some remarkable presence of hard agglomerates tends to disrupt the densi-
findings where the Lab HA produced higher sintered fication process resulting in the formation of defects such as
densities than commercial HA for all compaction pressures. porosity, grain growth and microcracks [91]. The dense HA
Meanwhile, the effect of sintering temperature on the ceramics with greater mechanical properties is possible to
sintered densities of the compacts of the two HA powders is achieve if the starting HA powder is stoichiometric, i.e., has
illustrated in Fig. (3a). The onset of densification, indicated Ca/P molar ratio of 1.67 [10]. If the Ca/P molar ratio of the
by a sharp increase in the sintered density, for Lab HA was HA exceeds the value of 1.67, CaO forms during sintering.
between 800 and 900ºC, whereas commercial HA required a Existence of CaO is reported to decrease strength and may
higher temperature of between 1000 and 1050ºC. Moreover even cause structure inconsistency of the whole material due
as shown in Fig. (3b), it was observed that commercial HA to stresses arriving from formation of Ca(OH)2 which
shows no significant change in hardness over the subsequently transforms into CaCO3 leading to change in
temperature range 900-1100ºC, whereas Lab HA shows a volume and alteration of the rate and extent of biode-
large increase in hardness from 900 to 1000-1100ºC. As in gradation. If the Ca/P molar ratio is lower than 1.67, - or -
Fig. (3a), Lab HA showed a rapid increase in density from tricalcium phosphate forms which increases slow crack

Fig. (3). Effect of sintering temperature (ºC) on the (a) sintered relative densities and (b) Vickers hardness; of Lab HA and commercial HA
[19].
72 Recent Patents on Materials Science 2011, Vol. 4, No. 1 Nawawi et al.

growth susceptibility and biodegradability of the HA Many factors may affect the hardness of HA materials, for
ceramics. Moreover, the decomposition process itself may example, the density, Ca/P ratio, possibly the weight
have a negative influence on the densification of the HA percentage of the Ca2+, and so on. High Vickers hardness of
ceramics due to formation of a new phase and evaporation of HA may be due to the high calcium weight percentage in the
water, decreasing in consequence the strength. However, the HA samples [92]. In another research of commercial HA
Ca/P ratio was reported not to influence significantly the derived dense bodies, it was found that hardness started to
grain growth of the HA ceramics [10]. decrease above a certain lower grain size limit, e.g. ca. 2m
[32]. Hence, it is revealed that the hardness of the material
Many of the HA powders can be pressurelessly sintered
was not solely dependent on the relative density.
up to theoretical density at moderated temperatures (1000 -
1200°C). However, processing at higher temperatures may Relative density is the ratio of the density of the prepared
lead to exaggerated grain growth and/or decomposition of HA dense bodies to the theoretical density of HA
HA and subsequently to strength degradation. Nevertheless, (3.156g/cm3) [1, 46, 91]. The density of the sintered HA
hot pressing (HP), HIP or HIP-postsintering make it possible compacts was usually measured by water immersion
to decrease the temperature of the densification process, technique. The hypothesis made is relative density is
decrease the grain size, and achieve higher densities. This dependent on the sintering temperature, grain size of the HA
leads to finer microstructures, higher thermal stability of HA, dense bodies and also the sintering method which emphasis
and subsequently better mechanical properties of the on the duration taken for the grain growth. In fabrication of
prepared HA ceramics. HA bodies by uniaxial pressing of the precipitation
technique derived powder [75], it was found that the
The elastic modulus or known as Young’s Modulus (E)
densification process starts at about 1000ºC and continuously
was normally determined using three-point bend test of
increases with the temperature up to 1200ºC where a
rectangular specimens where the specimens are loaded to
failure. In one research [46], the correlation of this stiffness maximum is reached. In terms of grain size, generally
samples with smaller average grain size exhibited lower
measurement with sintering temperature has been studied.
density whereas the highest relative density of 99.8% was
The dense HA has been prepared via uniaxial pressing with
attained in samples that have larger average grain size of ca.
subsequent cold isostatic pressing. It was found out that the
12.3m as shown in Fig. (4) [32]. In a similar work but via
HA attained E values  100GPa when sintered at a tempe-
microwave sintering, the HA compacts exhibited 90-91%
rature as low as 1000ºC. This result is corresponding to the
increasing bulk density up to ~98% of the theoretical value. and 96% of the theoretical density when sintered at 1000ºC
and 1100ºC, respectively [6]. However, via conventional
This is in good agreement with the hypothesis that Young’s
pressureless sintering method, a relative density of 96% was
Modulus of HA was controlled by the fraction of porosity in
attained for dense HA at 1000ºC. Although a higher
the sintered body.
temperature of 1100ºC is needed by microwave sintering to
Another important properties of sintered HA dense achieve a similar density, this effect is offset by the very
bodies like microhardness or hardness, can be measured by short sintering time taken for densification [1].
Knoop [18] or Vickers method [1, 18, 46]. Hardness is
Another prominent property of dense HA is its resistance
controlled by the bonding between the particles in the
to crack propagation which is defined as fracture toughness
sintered compacts. Hardness is also influenced by the
(KIC) [89]. This property can be measured by taking into
sintering temperature, as the temperature increased, so does
account the crack patterns that created by the Vickers
the hardness [1, 33, 46, 92]. A high hardness is the guarantee
for a good wear resistance, which is crucial for HA materials indentation of brittle calcium-phosphate materials and the
median crack system [18]. Besides that, hardness (H V) and
which are often applied in tooth and bone implantation.

Fig. (4). The effect of grain size on the relative density of HA [32].
Hydroxyapatite-Based Dense Biomaterials Recent Patents on Materials Science 2011, Vol. 4 No. 1 73

fracture toughness (KIC) are convenient materials parameters The technique used in densification of the dense bodies
for characterizing deformation and fracture phenomena in could also affect their mechanical properties. The most
large scale of solids ranging from metals to ceramics. The commonly used technique is the conventional pressureless
HV/KIC ratio combining hardness (resistance to deformation) sintering. This method was well-known for coarse-grained
and toughness (resistance to fracture) is used as a simple microstructure and low mechanical properties of the obtained
brittleness index [18]. dense bodies [83] due to its long sintering duration, typically
about 18-24 hours [1, 32, 83, 93]. The reported rapid and
In the research of rapid densification of nanocrystalline
effective consolidation technique such as microwave
HA [1], it was observed that the maximum fracture tough-
processing [1, 94, 95] has been reported to produce a dense
ness value obtained by the microwave sintering method
sintered HA body that possessed fine microstructure coupled
(1.45MPa.m1/2) is higher than the one obtained via pressure-
less sintering (1.0MPa.m1/2). Hence, it can be deduced here with improved mechanical characteristics [1]. This is
achieved as the heat is generated within the material instead
that the method of sintering is one of the parameter that
of being radiated from outside the body as in conventional
influence this property of dense bodies.
sintering [1]. Densification of material is resulted due to
Nevertheless, in terms of grain size it is hypothesized that accelerated and uniform heating, and there is no disruption
the properties (e.g hardness, toughness and densities) of the HA phase detected. However, sintering at higher
increased with grain size and reached a maximum value at a temperature (i.e exceeding 1150°C) has resulted in the
certain grain size limit. Thereafter, both the toughness and decreasing toughness and hardness as affected by the
hardness started to decrease with increasing grain size increasing of dense bodies’ grain size. However, heat dried
resulting from higher temperature sintering [1]. It is also powders are often in the forms of large agglomerates, and the
hypothesized that below some grain size limit (dc) the sintered HA ceramics are often weak with inhomogeneous
toughness as well as hardness is governed by bulk density pores and thus can hardly meet the requirements for medical
(or porosity) [1]. Ramesh [32] claimed in his study of grain applications. Freeze-drying has been shown to be a promi-
size on commercial HA derived dense ceramics compacted sing technique for preparing uniform fine-grained powders
via uniaxial pressing and cold isostatic pressing that low which can be sintered to very high densities [92].
temperature sintering caused the HA exhibited a uniform
Ramesh et al. [1] produced HA discs samples via
microstructure and distribution of equiaxed fine grains which
uniaxial pressing which subsequently undergone cold isos-
indicated the high degree of homogeneity of the starting
powder. When the sintering temperature was further tatic pressing. The green samples were the sintered in
microwave furnace. In their findings, they obtained nano HA
increased to 1400ºC, exaggerated grain growth accompanied
with maximum relative densities of 98% at 1300ºC while
by grain coalescence was observed in the HA dense samples.
maintaining fine-grained microstructure. They also found out
Meanwhile the grain size was found to be exponentially
that microwave heating is beneficial in suppressing grain
increased from 1.16m to 25.41m as the sintering tempe-
coarsening that is unavoidable via conventional pressureless
rature increased from 1200ºC to 1450ºC. Figure 5 shows the
SEM micrographs of HA showing an equiaxed-grained sintering. Throughout the sintering regime of 1000ºC up to
1150ºC, the results obtained are 0.12m, 1.45MPa.m1/2 and
structure when sintered at 1200ºC and 1400ºC [32].
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
Fig. (5). SEM micrographs of HA showing an equiaxed-grained Dense HA has been used in various clinical dental and
structure when sintered at (a) 1200ºC and (b) 1400ºC. Exaggerated medical applications which includes repair of bony defects in
grain growth is evident in (b) [32]. 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
From the study of sintering temperatures ranging from metal implants [15, 71, 84], pulp-capping materials [15],
900 to 1300°C on the dense bodies, it was observed that HA enhancement of guided tissue regeneration [15, 75], maxillo-
did not decompose to secondary phases upon sintering even facial reconstruction [4, 15, 20, 56, 75], percutaneous
when consolidated at a temperature as high as of 1400°C devices [15], middle ear reconstruction and bioreactors [15,
[46]. However, studies done by Slosarczyk et al. [18] proved 20, 56, 75]. However, the betterment in mechanical
that the secondary phases have already appeared at 1250°C. performance thereby making it a desirable substitute for hard
This difference might be correlated to the different method in tissues [1, 12, 45].
preparing the HA powder as the characteristics of the powder
The applications of dense HA are divided into two forms:
precursors has great influence on the sintered dense bodies.
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 Characteristics Requirements of Dense HA For Bone
and maintain ridge shape following tooth loss, which affects Implant Application
millions of people [31]. Meanwhile, the application as filler
in bony defects [20] in dental and orthopaedic surgery A great number of studies have been undertaken to
requires dense HA as particles. 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 Nawawi et al.

techniques, composition and experimental conditions, with the fact that divalent Mn2+ has influenced the activation of
the aim of obtaining the most effective synthesis method and integrins, a family of receptors that mediate cellular interac-
conditions to produce well-defined particle morphology [1]. tions with extracellular matrix and cell surface ligands [75,
Among the important parameters to be controlled is the 90]. The ligand affinity of affinity increases in the presence
consolidation or sintering method in order to obtain a solid, of Mn, resulting in the promotion of cell adhesion. In one
high density HA body that is characterized by having a fine study, manganese in the bone was found to cause a decrease
microstructure and improved mechanical properties [1, 12, in bone resorption [80]. It is also reported that Mn functioned
89]. as calcination and sintering additives of biphasic calcium
phosphate (BCP) powders without producing other secon-
However, the requirement needed depends on the role of
dary phases like -TCP and CaO [107]. The formation of the
the dense HA played in the body. For example, the
requirement for total hip prostheses is different for a middle -TCP phase during the sintering process is not preferable as
it induces micro-cracks, which eventually reduces the
ear implant. The two basic criteria are the compatibility with
mechanical properties of the sintered specimens.
the physiological environment and the mechanical properties
which should match those of the tissue being replaced. The By forming HA composite, the toughness of the ceramics
success of HA ceramics in biomedical applications is also has been improved while decreasing its modulus of elasticity
largely dependent on the availability of a high quality, sin- [37]. Small changes in particle size and morphology of the
tered HA that is characterized having refined microstructure HA powders used was proven to have significant effects on
and improved mechanical properties [67]. the mechanical properties of the final composite [78]. The
composite can be formed by using the ceramic as the
Current & Future Developments reinforcement phase, the matrix or both. For example, a
polymer-matrix composite (PMC) reinforced with a biocera-
Generally, biological apatites are different from pure and mic; polyethylene (PE) is reinforced with HA particles. The
synthetically produced HA due to the presence of trace incorporation of foreign particles into the HA matrices to
elements in the apatites such as cations (Na+, K+, Mg2+, form composites that might induce energy dissipative
Mn2+, Sr2+, Ba2+. Cu2+, Zn2+ or Fe2+) and anions (HCO3-, mechanisms such as crack deflection, thus enhancing the
HPO42-, Cl- and F-). These can be considered as ionic substi- mechanical properties. This has shown to yield better
tuents in the apatite structure. In fact, in order to optimize the strength, but is often associated with the formation of
bioactivity of HA implants, it is important to produce a undesirable phases in the composite due to higher sintering
substituted HA that approaches the composition of bone temperatures employed [83]. In addition, the formation of
mineral. Inclusion of trace metal elements has a significant composite needs large amount of reinforcing phases to
role in improving the physical and/or biological properties of achieve desired properties, and as these phases are either
bioceramics. Metals like magnesium [65, 99-101], barium bioinert, significantly less bioactive than HA, or bioresorb-
[61, 102, 103], strontium [55, 61, 104], zirconium [105], able, then the ability of the composite to form a stable
manganese [65], and zinc [65, 92] have been doped into interface with bone is poor compared with HA alone [72].
hydroxyapatite and proven effective in enhancing physico- ZrO2-HA composites have also been studied before [8, 108,
chemical properties of hydroxyapatite. An alternative 109]. However, these composites do not have high strength
economical technique to obtain highly dense HA body with and fracture toughness, because the added ZrO2 prevented
enhanced mechanical properties and biocompatibility is by densification of the HA. Hence, yttria stabilized zirconia
incorporating appropriate low temperature sintering additives ceramics are doped with HA and they were found to be
such as zirconia, magnesium, manganese, ceria and iron better in bioactivity and having sufficient mechanical
[89]. It was reported that the powder produced by doping strength and fracture toughness for a heavy load [8, 110].
with metal are in nanosized and resulted in better densifi- HA has also been reinforced with carbon fiber [95] to
cation due to better crystal growth with the metal ions. improve the mechanical properties for load bearing appli-
Magnesium is one of the most important bivalent ions cations.
associated with biological apatite. Magnesium-substituted Ashley et al. proposed that incorporation of carbon
hydroxyapatite is found in cartilage as well as young bones nanotubes (CNTs) into HA would be beneficial in improving
and it was proved to play a key role in accelerating bone the mechanical properties at low loadings without
growth. It has been verified that in calcified bony tissues, the diminishing its bioactivity [29]. This material has only been
amount of magnesium associated with the apatitic phase is first developed a couple of years ago, thus creating a
higher at the beginning of the calcinations. Also there is synthetic bone graft material that can be used in major load
growing evidence that magnesium could be an important bearing situations. CNTs with their small dimensions, high
factor in the qualitative changes of the bone matrix that aspect ratio (length to diameter), and high strength and
determines bone fragility. Inclusion of magnesium can stiffness, have excellent potential to accomplish this [29].
decrease hydroxyapatite solubility, increase the size and/or However, a way to densify the HA while preserving its
the perfection of hydroxyapatite crystals in bone, and also structure and retaining the CNTs must be found for these
increase the tensile strength of bone. This metal, when composites to be viable in major load bearing clinical
administered to patients will encourage the growth of new devices. As this area has newly been sought, the bioactivity
and normal bone tissue [106]. and toxicity of these composites are yet to be determined. At
The effect of manganese (Mn) on the stability and this early stage, an HA-CNT composite would ideally be
particle growth of HA has been also recognized [90]. The used in load bearing situation that have mechanical
motivation for the addition of Mn2+ ions to HA was due to properties similar to those of bone, with a tensile strength of
Hydroxyapatite-Based Dense Biomaterials Recent Patents on Materials Science 2011, Vol. 4 No. 1 77

at least 50MPa and a fracture toughness of at least bone replacements has been reported [114]. The HA and the
2MPa.m1/2. HA/bioactive glass composites are the most biocompatible
among the presented biomaterials. However, KIc values of
In addition, reactions by which HA can be formed at low
both the HA ceramics and the HA/bioactive glass composites
temperatures by cement-type reaction involving dissolution
and precipitation have been identified [23, 111, 112]. are below or on the lower KIc limit of the bone, thus these
materials cannot be used as heavy-load-bearing implants.
Currently, this type of materials is known as calcium
The HA-based ceramic composites are in the KIc range of the
phosphate cements (CPC). Due to its high biocompatibility
bone, and KIc of the HA-coated titanium alloys exceed
[9], bioactivity [9] and good resorbability [9, 97], CPC
several times the upper KIc limit of the bone. However, both
belongs to the second generation of bone substituting
the HA-based ceramic composites and the HA-coated Ti
biomaterials [97]. These cements are blends of amorphous
and/or crystalline calcium orthophosphate powder with an suffer first of all too high a Young’s modulus; second, there
are problems related to their processing; third, their biolo-
aqueous solution [9]. When the powder and the solution are
gical features are insufficient. The HA/polymer composites
mixed together, a viscous and mouldable paste is formed that
have Young’s modulus close to the Young’s modulus of the
sets to a firm mass within a few minutes when the paste
bone and exhibit quite good mechanical reliability [100].
becomes sufficiently stiff. It can be placed into a defect as a
Thus, many efforts have been shown worldwide to get
substitute for the damaged part of bone, when it hardens
in situ within the operating theatre. As the paste is set and reliable load bearing bone substitute devices close to the
properties of living bone. In the upcoming future, efforts
hardened at room or body temperature, direct application, in
should be emphasized on development of biocompatible HA-
healing bone defects became a new and innovative treatment
biopolymer composites to obtain long-term stable, bioactive
modality in the end of the twentieth century. Moreover,
but mechanically and biologically compatible cortical bone
calcium orthophosphate cements can be injected directly into
substitutes.
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 ACKNOWLEDGEMENTS
solid block, powder or granules, which are difficult to shape The authors are grateful to Research Management Centre,
and keep in place. Besides, they were found to promote IIUM for the partial support provided through the
development of osteoconductive pathways, possess sufficient Endowment Fund Research Grant.
compressive strengths, be noncytotoxic, create chemical
bonds to the host bones, restore contour and have both the CONFLICT OF INTEREST
chemical composition and X-ray diffraction patterns similar
to those of bone. Finally, but yet importantly, they are osteo- No.
transductive [97], i.e., after implantation calcium orthophos-
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