Materials Science and Engineering C 27 (2007) 441 – 449

www.elsevier.com/locate/msec

Nanocrystalline calcium phosphate ceramics in biomedical engineering

Samar J. Kalita ⁎, Abhilasha Bhardwaj, Himesh A. Bhatt
Department of Mechanical, Materials and Aerospace Engineering, University of Central Florida, P.O. Box 162450, Orlando, FL 32816-2450, United States
Available online 22 June 2006

Abstract

Nanocrystalline calcium phosphate based bioceramics are the new rage in biomaterials research. Conventionally, calcium phosphates
based materials are preferred as bone grafts in hard tissue engineering because of their superior biocompatibility and bioactivity. However,
this group of bioceramics exhibits poor mechanical performance, which restricts their uses in load bearing applications. The recent trend in
bioceramic research is mainly concentrated on bioactive and bioresorbable ceramics, i.e. hydroxyapatite, bioactive glasses, tricalcium phosphates
and biphasic calcium phosphates as they exhibit superior biological properties over other materials. In recent times, the arena of
nanotechnology has been extensively studied by various researchers to overcome the existing limitations of calcium phosphates,
mainly hydroxyapatite, as well as to fabricate nanostructured scaffolds to mimic structural and dimensional details of natural bone.
The bone mineral consists of tiny HAp crystals in the nano- regime. It is found that nanocrystalline HAp powders improve sinterability and
densification due to greater surface area, which could improve the fracture toughness and other mechanical properties. Nano-HAp is also
expected to have better bioactivity than coarser crystals. Nanocrystalline calcium phosphate has the potential to revolutionize the field of
hard tissue engineering from bone repair and augmentation to controlled drug delivery devices. This paper reviews the current state of
knowledge and recent developments of various nanocrystalline calcium phosphate based bioceramics from synthesis to characterization.
© 2006 Elsevier B.V. All rights reserved.

Keywords: Bioceramics; Nanophase materials; Calcium phosphates; Biomaterials

1. Introduction contributed by their compositional resemblance with the

bone mineral has allowed them to be used for copious
During the past 50 years, advances in many specialty applications inside the body [1,2]. In 1920, Albee
bioceramics such as alumina, zirconia, hydroxyapatite, reported the first successful medical application of calcium
trical- cium phosphates and bioactive glasses have made phosphate biocera- mics in humans [3], and in 1975 Nery
significant contribution to the development of modern et al. reported the first dental application of these
health care industry and have improved the quality of ceramics in animals [3]. In a very short span of time,
human life. These are the ceramics, which can be used bioceramics have come a long way and have found
inside the body without rejection to augment or replace applications in numerous ways as in replacements of hips,
various diseased or damaged parts of the musculoskeletal knees, teeth, tendons and ligaments and repair for
system [1]. They are primarily used as bone substitutes in periodontal disease, maxillofacial reconstruction, augmentation
the biomedical industry due to their biocompat- ibility, low and stabilization of the jawbone and in spinal fusion.
density, chemical stability, high wear resistance, and for In all the spheres of past, present and prospected
calcium phosphates, mainly for their compositional applications of bioceramics, calcium phosphates have a
similarity with the mineral phase of bone. But the potential significant contri- bution. Today, calcium phosphates are
of any ceramic material to be used as an implant in vivo the materials of choice in both dentistry and medicine. They
depends upon its ability to withstand complex stresses have been used in the field of biomedical engineering owing
at the site of application and its compatibility with the to the range of properties that they offer, from tricalcium
biological environ- ment. The superior biocompatibility of phosphates being resorbable to hydroxyapatite being
calcium phosphates bioactive; they are undeniably the current rage for clinical
usage [4–6]. They exhibit considerably improved
⁎ Corresponding author. Tel.: +1 407 823 3159; fax: +1 407 823
biological affinity and activity compared to other
0208.
bioceramics such as alumina, zirconia, coralline, ALCAP
E-mail address: samar@mail.ucf.edu (S.J. Kalita).

0928-4931/$ - see front matter © 2006 Elsevier B.V. All rights reserved.
doi:10.1016/j.msec.2006.05.018
44 S.J. Kalita et al. / Materials Science and Engineering C 27 (2007) 441–449

(aluminum calcium phosphate ceramics), ZCAP (zinc nanostructured ceramics can be sintered at a lower
calcium phosphate oxide ceramics), ZSCAP (zinc temperature thereby problems associated with high
sulphate calcium phosphate ceramics) and FECAP (ferric temperature sintering processes are also eliminated. It is
calcium phosphate oxide ceramics). However, unlike possible to enhance both mechanical and biological
alumina and zirconia, these ceramics are mechanically performance of calcium phosphates by controlling
weak and exhibit poor crack growth resistance, which limit characteristic features of powders such as particle size and
their uses to non-load bearing applica- tions such as shape, particle distribution and agglomeration [11].
osteoconductive coatings on metallic prosthesis and as
Nanoceramics clearly represent a promising class of
nano-powders in spinal fusion. Among different forms of
orthopedic and dental implant formulations with improved
calcium phosphates, particular attention has been placed to
biological and biomechanical properties. This paper will
tricalcium phosphate (Ca3(PO4)2, TCP) and
discuss the recent developments in the field of nanoscale
hydroxyapatite (Ca10(PO4)6(OH)2, HAp) due to their
calcium phosphate based bioceramics with a brief overview
outstanding biological responses to the physiological
on classification, properties and applications of
environment. The contemporary health care industry uses
conventional forms.
calcium phosphate ceramics in various applications,
depending upon whether a resorbable or bioactive material
2. Calcium phosphates
is ideal. The recent trend in bioceramic research is
focused on overcoming the limitations of calcium
Calcium phosphates being light in weight, chemically
phosphates, precisely hydroxyapatite ceramics and in
stable and compositionally similar to the mineral phase of
improving their biological properties via exploring the
the bone are preferred as bone graft materials in hard tissue
unique advantages of nanotechnology.
engineering. They are composed of ions commonly found
The trend is shifting towards nanotechnology to improve
in physiological environment, which make them highly
the biological responses of HAp because nano-HAp is a
biocompatible. In addition, these bioceramics are also
constituent of bone, which is a natural composite of
resistant to microbial attack, pH changes and solvent
nano-HAp with collagen fibers. The main constituents of
conditions. They exist in different forms and phases
bone are collagen (20 wt.%), calcium phosphate (69 wt.
depending on temperature, partial pressure of water and
%), and water (9 wt.%). Additionally, other organic
the presence of impurities [12,13]. HAp, β-TCP, α-TCP,
materials, such as proteins, poly- saccharides, and lipids
biphasic calcium phosphate (BCP) [14], monocalcium
are also present in small quantities [7]. Collagen, which can
phosphate monohydrate (MCPM) and unsintered apatite (AP)
be considered as the matrix, is in the form of small
are different forms of commercially available calcium
microfibers. It is difficult to observe distinct collagen fibers
phosphates currently used in the biomedical industry. Table
because of its net-like mass appearance. The diameter of
1 summarizes the physical properties of various forms of
the collagen microfibers varies from 100 to 2000 nm.
calcium phosphates currently used in the biomedical
Calcium phosphate in the form of crystallized
industry. Different phases are used in different applications
hydroxyapatite (HAp) and/ or amorphous calcium
depending upon whether a resorbable or bioactive material
phosphate (ACP) provide stiffness to the bone. The HAp
is desired [15]. HAp is the ideal phase for application
crystals, present in the form of plates or needles, are about
inside human body because of its excellent stability above
40–60 nm long, 20 nm wide, and 1.5–5 nm thick. They are
pH 4.3, human blood pH
deposited parallel to the collagen fibers, such that the larger
dimension of crystals is along the long axis of the fiber. It is
worth mentioning that the mineral phase present in the bone is Table 1
not a discrete aggregation of the HAp crystals. It is rather Physical properties of various phases of calcium phosphate bioceramics
made
of a continuous phase, which is evidenced by a very Phases Chemical Ca/P Crystal structure Density
3
formulae ratio (g/cm )
good strength of the bone after a complete removal of the
organic
phase [8]. The use of nano-HAp in orthopedics is Hydroxyapatite Ca10 (PO4)6 10/6 Hexagonal, P63/m 3.16
(HAp) (OH)2 space group, cell
therefore considered to be very promising, owing to its
dimensions: a = b = 9.42
dimensional similarity with the bone crystals. Å,
and c = 6.88 Å
It has been established that nanotechnology offers a contributed size, a brittle ceramic could permit a α-
unique approach to overcome shortcomings of many by the grain- large plastic strain up to 100% [9]. Tr
conventional materials. From nanomedicine to nanofabrics, boundary Nanostructured biomaterials promote ic
al
this promising technology has encompassed almost all phase. In osteoblast adhesion and proliferation, ci
disciplines of human life. Nanostructured materials offer 1987, Karch osseointegration, and the deposition u
much improved perfor- mances than their larger particle sized et al. of calcium containing minerals on the m
counterparts due to their large surface to volume ratio and reported surface of these materials [10]. Also, p
ho
unusual chemical/electronic synergistic effects. Nanoscale that, with
sp
ceramics can exhibit significant ductility before failure nanograin ha
 S.J. Kalita et al. / Materials Science and Engineering C 27 (2007) 441– 4
te (α-TCP) Ca3(PO4)2 3/2 7.023, b = 11.986, 2.86
c = 9.473; β =
90.90°
Monoclinic, P21/
β-Tricalcium phosphate (β-TCP) a
spa
ce 3.07
gro
Tetracalcium phosphate (TTCP) up,
latt
Sources: [12,15]. ice
con
sta 3.05
nts:
a
12.
887
Å,
=
27.
280
Å,
=
15.
219
Å;
=
126
.20°
Ca3(PO4)2

3/2

Pure hexagonal,
rho
mbo
hed
ral,
spa
ce
grou
p
R3c
H,
unit
cell
dim
ensi
ons:
a
b
10.
439
Å,
c
37.
375
Å,
and
α
β
90°,
γ
120
°
Ca4P2O9

2/1

Monoclinic, space
group
P2
,
=
44 S.J. Kalita et al. / Materials Science and Engineering C 27 (2007) 441–449

being 7.3. Table 2 presents solubility and pH stability 2

area (typical 2–5 m /g). In addition, it has been also recorded
of different forms of calcium phosphates in aqueous
that the resorption process of synthetic calcium phosphates
solution.
(conventional forms) is quite different from that of bone
One of the major shortcomings of calcium phosphate
mineral. Bone mineral crystals are in nano-size with a very
bioceramics is their poor mechanical strength under
large surface area. They are grown in an organic matrix and
complex stress states. Further, it has been proved that the
have very loose crystal-to-crystal bonds; therefore the
bioactivity of synthetic calcium phosphates (micron size
resorption by osteoclasts is quite homogeneous. Calcium
powder) is inferior to natural apatite, the bone mineral
phosphates (micron size), on the contrary, present a low
[16,17]. Like other ceramic materials, the tensile and
surface area and have strong crystal-to- crystal bond.
compressive strengths of calcium phosphates are governed
Resorption takes place in two steps: (i) disintegration
by the presence of voids, pores or interstices, which
of particles and (ii) dissolution of the crystals [19].
results during the process of densification while sintering.
Nanoscale bioceramics is one of the emerging approaches
However, unlike most advanced ceramics, calcium
that have been extensively studied recently by various
phosphates are difficult to sinter and thus are
researchers to find a solution to these long standing
mechanically weak. The resistance to fatigue is another
problems associated with calcium phosphates. In a recent
essential factor for (tensile) load-bearing implants. In terms
publication, Kim et al. reported that biomineralization of
of Weibull factor, n, values of n = 50 to 100 usually
calcium phosphate nanocrystals on ceramics with
signify good resistance but values of n = 10 to 20 are
specific compositions and structures is a core
insufficient and may fail in several months of usage [18].
mechanism of bioactivity, that inspires acellular and
For conventional HAp, n = 50 in dry environment and n =
protein free biomimetic strategies for bio- interactive
12 in a wet physiological implant bed [5], which is below
materials with new physical, chemical and biological
the satisfactory limit as repotted by Putter et al.
functions, e.g., bioactive surface functionalizations on tough
Nanotechnology is one of the approaches, which has been
metallic and ceramic materials, sol–gel derivation of bioactive
explored recently to improve both the strength and
ceramic-polymer nano-hybrids and textured biomimetic deposi-
toughness of this novel group of bioceramics to make
tions of nano-calcium phosphate on polymer templates [20].
them useful in load-bearing applications.
Crystallization of various salts of calcium phosphates
Conventional calcium phosphate based ceramic powders
suffer from poor sinterability possibly due to their low like hydroxyapatite (HAp) and β-TCP depends on Ca/P
surface ratio, presence of water and impurities, and temperature. For
instance, in a wet environment and at a lower temperature
(< 900 °C), the formation of hydroxyapatite is most likely to
Table 2 happen, but in a
Solubility and pH stability of different phases of calcium phosphates dry atmosphere and at a higher temperature, β-TCP is
more
Phases Solubility at 25 pH stability range
°C, likely to form.
in aqueous solution
− log(Ksp) at 25 °C
2.1. Hydroxyapatite
Hydroxyapatite 116.8 9.5–12
(HAp)
β-Tricalcium 28.9 Cannot be precipitated Hydroxyapatite ((Ca10(PO4)6(OH)2), HAp) is a bioactive
phosphate from aqueous ceramics widely used as powders or in particulate forms
(β-TCP) solutions in various bone repairs and as coatings for metallic
α-Tricalcium prostheses to improve their biological properties [21]. HAp is
phosphate 25.5 Cannot be precipitated
(α-TCP) from aqueous thermodynam- ically the most stable calcium phosphate
Tetracalcium solutions ceramic compound at the pH, temperature and composition
phosphate of the physiological fluid [22]. Recently, HAp has been
(TTCP) 38–44 Cannot be precipitated used for a variety of biomedical applications, including
Dicalcium from aqueous matrices for drug release control [23]. Due to the chemical
phosphate solutions
dihydrate
similarity between HA and mineralized bone of human
(DCPD) 6.59 2.0–6.0 tissue, synthetic HAp exhibits strong affinity to host hard
Dicalcium tissues. Formation of chemical bond with the host tissue
phosphate offers HAp a greater advantage in clinical applications over
anhydrate most other bone substitutes, such as allografts or metallic
(DCPA) 6.90 Stable at
implants [24]. Some of the present and proposed applications
temperatures above
100 °C of nanocrystalline
hydroxyapatite bioceramics are presented in Table 3.
Amorphous Cannot be measured (pH 5.28). Always metastable. The composition of a precipitate depends on the
calcium precisely. However, solution pH
phosphate the following values value and composition.
(ACP) were reported: 25.7 ±
0.1
(pH 7.40), 29.9 ± 0.1
(pH 6.00), 32.7 ± 0.1
 S.J. Kalita et al. / Materials Science and Engineering C 27 (2007) 441– 4
HAp nal structure dimensions a = refers to a space group with a six-fold symmetry axis
possess with a P63/m b = 9.42 Å, and with a three-fold helix and a microplane [12]. It has an
es a space group c = 6.88 Å, exact stoichiometric Ca/P ratio of 1.67 and is chemically
hexago and cell where P63/m very similar
Calcium-deficient ∼85.1 6.5–9.5 to the mineralized human bone [25]. However, in spite of
hydroxyapatite chemical similarities, mechanical performance of synthetic
(CDHA)
HAp is very poor compared to bone. In addition, the
Sources: [86,87,91]. bone mineral present a higher bioactivity compared to
synthetic HAp.
44 S.J. Kalita et al. / Materials Science and Engineering C 27 (2007) 441–449

Table 3
Present and proposed applications of nanocrystalline hydroxyapatite and hydrothermal reaction [44], microemulsion syntheses [45]
its composites and mechanochemical synthesis [46,47]. Table 4
Year Present and proposed applications Reference presents the chronological development of synthesis of
nano-HAp ceramics during the last 10 years. Recently, the
use of sol–gel method for
2002 HAp/chitosan (CTS) nano-composites of [66] synthesis of calcium phosphates has gained interest
homogeneous microstructure were formed. because of its unique advantages. The sol–gel method offers
They were proposed to be helpful for
producing uniform nanomaterials with best a molecular- level mixing of the calcium and phosphorus
properties for biomedical applications. precursors, which is capable of improving chemical
2004 Bioresorbable nano-HAp composite bone paste [65] homogeneity and reducing synthesis temperature in
with natural polysaccharide and chitosan comparison with conventional meth- ods. Many variations
anticipated to act as a bioresorbable bone of the sol–gel process have been developed and used to
substitute with superior bioactivity and
osteoconductivity in vivo. produce powders with different Ca/P ratios by altering the
[48]
2004 HAp/polyanhydride nano-composite was formed. quantity and the composition of precursors and processing
If the HAp content in the polyanhydrides was variables.
appropriate and compositions in the crosslinking Liu et al. and Yingchao et al. synthesized nano-HAp of 8–
network are suitable, it meets the rehabilitation 10 nm sizes via template mediated and non-template
need of different fracture bones in human body,
both in mechanical properties and in the mediated sol–gel techniques, respectively [48,49]. In most
biodegradable rate. [67]
literature on synthesis of HAp by sol–gel process,
2004 Nanocrystalline hydroxyapatite and calcium phosphorous alkoxide has been used as precursor for P.
sulphate as biodegradable composite carrier material Liu et al. [21] used triethyl phosphate and calcium nitrate
for local delivery of antibiotics in bone as the precursors respectively for P and Ca for HAp
infections offers a new treatment option in [90]
osteomyelitis. synthesis. Kuriakose et al. suggested that agars can
2004 Nano-HAp coatings on surfaces of titanium also be used to synthesize HAp using similar
prosthesis to get improved biocompatibility precursors at low temperatures [38]. These processes
and mechanical performance of the prosthesis. require high temperature operation and produces multi-phase
powder. A relatively simpler sol–gel process using ethanol
and/or water as solvent has also been reported to obtain
stoichiometric,
Many researchers have observed that the mechanical nanocrystalline single phase HAp.
strength and fracture toughness of HAp ceramics can be
improved by the use of different sintering techniques Table 4
which include addition of a low melting secondary phase to Synthesis of nano-hydroxyapatite—chronological development
achieve liquid phase sintering for better densification
Year Process Reference
[26–28],
incorporation of sintering additives to enhance densification
through grain boundary strengthening [29–31], and use A number of powder processing techniques 1995
Synthesis
of nanoscale ceramic powders for better densification have been developed and used to synthesize of
nanocryst
contributed by large surface area to volume ratios of nano- calcium phosphate based ceramic powders, mainly alline
hydroxyap
size powders. It is believed that nanoscale HAp has the HAp, which include sol–gel synthesis [37–41], atite
potential to revolutionize the field of biomedical science solid state reactions [42], co-precipitation [43], (particle
size
from bone regeneration to drug delivery. During the past ∼
10 years, much attention has been given to nanostructured 20
HAp calcium phosphate ceramic, with major research
nm
emphases of produc- tion of nanoscale powders to improve
)
the mechanical as well as biological properties.
for
Importance and advantages of nanocrystalline HAp
the
were highlighted by Sarig and Kahana in a 2002 issue of
firs
the Journal Crystal Growth 237. In their work, Sarig and
t
Kahana could synthesize HAp with 300 nm edges, which
tim
were loosely aggregated into spherulites of 2– 4 mm
e
dimensions [32]. Nanocrystalline HAp powders exhibit
usi
improved sinterability and enhanced densification due to
ng
greater surface area [33], which could improve the
fracture toughness as well as other mechanical cal
properties [34]. Moreover, nano-HAp is also expected to ciu
have better bioactivity than coarser crystals [35,36]. m
nitr
2.1.1. Synthesis of nano-hydroxyapatite powders ate
 S.J. Kalita et al. / Materials Science and Engineering C 27 (2007) 441– 4
and [88]
ammonium hydrophosphate as precursors by solution spray dry
method.
2000 Synthesis of biomimetic nano-sized Ca-hydroxyapatite powders
(∼50 nm) at 373 °C and pH of 7.4 from calcium [89]
nitrate tetrahydrate and diammonium hydrogen phosphate salts in
synthetic body fluid (SBF) using novel chemical precipitation
technique.
2002 Preparation of nano-sized hydroxyapatite particles and
hydroxyapatite/chitosan nano-composite. [66]
2002 Direct precipitation from dilute calcium chloride and sodium
phosphate solutions. [32]
2003 Radio frequency (rf) plasma spray process employing fine spray
dried (SD) HAp powders (average size ∼15 μm) as
feedstock. [10]
2003 Sol–gel process using equimolar solutions of Ca (NO3)2·4H2O and
(NH4)2HPO4 dissolved in ethanol solvent.
2003 Chemical precipitation through aqueous solutions of calcium [38]
chloride and ammonium hydrogen phosphate.
2003 Mechanochemical synthesis of nano-HAp and TCP powders using [61]
calcium hydrogen phosphate (CaHPO4·2H2O) and calcium oxide
(CaO) as starting materials. [47]
2003 Synthesis of HAp nano-powders via sucrose-templated sol– gel
method using calcium nitrate and ammonium hydrogen phosphate
as precursor chemicals. [40]
2004 Hydrolysis method by hydrolysis of dicalcium phosphate
dihydrate (CaHPO4·2H2O, DCPD) and CaCO3 with 2.5 M
NaOH(aq). [37]
2004 Citric acid sol–gel combustion process using calcium nitrate,
diammonium hydrogen phosphate and citric acid.
[49]
44 S.J. Kalita et al. / Materials Science and Engineering C 27 (2007) 441–449

Suchanek et al. synthesized nanocrystalline hydroxyapatite Calcination was carried out at 250–600 °C. Transmission
powder by the citric acid sol–gel combustion method [50– electron microscopy (HRTEM) was used to determine
56]. The attractive features of this method were to particle size of powders produced via both of
synthesize materials with high purity, better homogeneity
and high surface area in a single step [49,57–59]. Varma et
al. synthesized the nano-HAp by polymeric combustion
method and self-propa- gating combustion synthesis using
novel body fluid solutions [60].
Shih et al. synthesized nano-hydroxyapatite powder (Ca/
P = 1.67) of 20 nm particle size by the hydrolysis method.
They also observed that the HAp particle size increases
with the annealing temperature. An annealing temperature
of 1000 °C resulted in an average increase in particle
diameter to 50 nm after soaking for 4 h [37]. Xu et al.
used radio frequency (rf) plasma spray process to
synthesize nano-sized HAp powder with particle size in the
range of 10–100 nm [10].
Synthesis of stoichiometric nano-HAp powders by sol–gel
method is relatively easy. It gives higher product purity,
more homogeneous composition and comparatively low
synthesis temperatures than other methods. Sol–gel
derived HAp is always accompanied by secondary phase
of calcium oxide. Phosphorous, alkoxides, gels and
ethanol can be used as solvents in this method. Kuriakose
et al. synthesized nanocrys- talline HAp of size 1.3 nm
radius that is stable till 1200 °C without any by-products
in the samples synthesized with pores in the crystal planes,
using the later as solvent. Synthesis of pure HAp crystals of
8–10 nm size can also be done by a novel sol– gel
technique using agars [38]. Han et al. synthesized
nanocrystalline HAp powder at low calcination temperature
of 750 °C by citric acid sol–gel combustion method. The
grain size of the resulting powder was found to be between
80 and 150 nm and the open porosity to be 19% [49].
Sarig et al. synthesized nanocrystalline plate-shaped
particles of HAp, directly precip- itated from dilute calcium
chloride and sodium phosphate solutions at ambient
temperature. The solution was introduced to microwave
irradiation immediately after mixing. The pH of the solution
was kept 7.4 to make HAp suitable for medical
applications. This method is a relatively fast method
to synthesize nano-HAp.
In our research, we have synthesized nanocrystalline
hydro- xyapatite (Ca10(PO4)6(OH)2, HAp) powders using
ethanol- based and water-based sol–gel techniques, and
compared them. Calcium nitrate and triethyl phosphite
were used as precursors for calcium and phosphorous,
respectively. In the ethanol-based method, triethyl
phosphite sol was diluted in anhydrous ethanol with a
small amount of distilled water. A stoichiometric amount
of calcium nitrate, dissolved in anhydrous ethanol, was
subsequently added dropwise into the hydrolyzed
phosphite sol. As-formed gel was aged for
16 h, then dried, and calcined at 300–800 °C to
produce nano-HAp. In the water-based method,
phosphorous and calcium precursors were hydrolyzed in
distilled water, separately, under vigorous stirring.
Calcium nitrate sol was added dropwise into the
hydrolyzed phosphite sol and then aged and dried.
 S.J. Kalita et al. / Materials Science and Engineering C 27 (2007) 441– 4
these techniques. TEM analyses revealed that particle
size diameter of powders synthesized via ethanol-based
(Fig. 1A) and water-based (Fig. 1B) methods were 20–50
nm and 5–
10 nm in diameter, respectively. Powder X-ray
diffraction technique was used to analyze the phases. X-
ray diffraction results (Fig. 2) showed that the apatite
phase first appeared at 400 °C and the HAp content
increased with increase in calcination temperatures.
Nano-sized HAp particles can also be prepared by
chemical precipitation through aqueous solutions of calcium
chloride and ammonium hydrogen phosphate. Pang et al.
observed that the crystallinity and crystallite size of HAp
increases with the

Fig. 1. (A) HRTEM micrograph of the nano-HAp powder synthesized

via ethanol-based sol–gel route. (B) TEM micrograph of the nano-HAp
powder synthesized via water-based technique calcined at 500 °C for 15
min.
45 S.J. Kalita et al. / Materials Science and Engineering C 27 (2007) 441–449

Fig. 2. XRD patterns of nanocrystalline hydroxyapatite powders synthesized via ethanol-based and water-based sol–gel routes.

increase of synthetic temperature and ripening time when combination with some polymers and other compounds
the solution is prepared by this method. Also, the as composites.
morphology change of HAp nanoparticles is related to their To augment its usage in this area, Murugan et al.
crystallinity. Regular shape and smooth surface of the prepared and characterized HA composite bone paste
nanoparticles can be obtained by higher crystallinity of with a natural polysaccharide, chitosan, using wet
HAp. They observed needle- like shape of nanoparticles chemical method at low temperature. Their findings
with rough surface and blurred contour and higher suggest that the HA/chitosan composite paste would be
combined water content for lesser crystalline HAp whereas highly beneficial for the particle immobilization upon
bar-like shape with smooth surface, clear contour and lower implantation and may be a candidate bioresorbable
water content was observed for nanoparticles with higher material as bone substitute [65].
crystallinity [61]. Chen et al. from Xiamen University, China, prepared and
Mechanochemical processing (MCP) is another characterized nano-sized hydroxyapatite particles and hydroxy-
compelling method to produce nanostructured HAp in solid apatite/chitosan nano-composite for use in biomedical materi-
state. Yeong et al. used appropriate amounts of calcium als. They were able to produce nano-HAp particles of 20–30
hydrogen phosphate (CaHPO4·2H2O) and calcium oxide nm width and 50–60 nm length and particles of almost
(CaO) [62]. Yang et al. reported the nano-sized HAp homoge- neous microstructure so that they can be useful in
powders nano-size using the MCP technique [48]. producing uniform nanomaterials. The nanostructured
HAp/chitosan composite promises to have excellent
2.1.2. Nano-hydroxyapatite based composites in tissue biomedical properties for use in the clinics [66].
engineering Recently, in 2004, Rauschmann et al. assessed the
HAp has been widely used for biomedical implants material properties of a calcium sulphate nanoparticulate HAp
and bone regeneration applications [4,63,64]. However, its composite material and analyzed its in vitro uptake and
appli- cations in periodontal and alveolar ridge release of vancomycin (antibacterial used for treating
augmentation are limited due to its particle mobilization infections in different parts of the body, usually given in
and slow resorbable nature. To overcome these combination with other antibiotics) and gentamicin
limitations, HAp is widely used in (antibacterial used for treating
 S.J. Kalita et al. / Materials Science and Engineering C 27 (2007) 441– 4
infections of the skin) antibiotics [67]. Their results suggest
this composite to be a new treatment option in osteomyelitis Ca9ðHPO4ÞðPO4Þ5ðOHÞ→3Ca3ðPO4Þ2 þ H2O
(acute or chronic bone infection usually caused by bacteria)
owing to its good biocompatibility and sufficient antibiotic Synthesis of nano-β-TCP has been formulated by many
release. researchers using starting materials as (CH3COO)2Ca·xH2O as
Zhang et al. of Tsinghua University (Beijing) described
their use of conventional and high-resolution transmission
electron spectroscopy (HRTEM) to study nanofibrils of
mineralized collagen. They have found a key mechanism
behind how these fibrils self-assemble. They have also
demonstrated for the first time that HAp crystals associate
specifically with the surfaces of collagen fibrils. They
observed that the HAp crystals align themselves with the
long axis of the collagen fibrils. Previously, other
researchers had found that anions on the collagen
molecules act as nucleation sites for HAp crystals and that
the positions of the hydroxyl groups in HAp crystals lie
along the same axis as the carbonyl groups in collagen
[68].

2.2. Tricalcium phosphate

Tricalcium phosphate is thermodynamically stable only

at elevated temperatures [1000–1500 °C]. It has been proved
to be resorbable in vivo with new bone growth replacing
the implanted TCP [69]. β-TCP and α-TCP are the two
forms of TCP that are known to exist. β-TCP transforms
to α-TCP at around 1200 °C. The later phase is stable in the
range of 700– 1200 °C [70]. α-TCP, however, has received
very little interest in the biomedical field. The disadvantage
for using α-TCP is its quick resorption rate, which limits its
usage in this area [71]. On the other hand β-TCP, also
known as β-whitlockite, is essentially a slowly degrading
bioresorbable calcium phosphate ceramic (CPC) [16] and is
a promising material in the field of biomedical
applications such as orthopedics. It has also been observed
to have significant biological affinity and activity and
responds very well to the physiological environments
[72]. Because of its slow degradation characteristic, the
porous β- TCP is regarded as an ideal material for bone
substitutes that should degrade by advancing bone growth
[73]. These factors give β-TCP an edge over other
biomedical materials when it comes to resorbability and
replacement of the implanted TCP in vivo by the new bone
tissue [69]. Its excellent biocompatibility makes it a possible
material to act as a scaffold allowing bone regeneration and
growth [74]. X-ray patterns reveal that β-TCP has a pure
hexagonal crystal structure. It is reported that the
resorbability of β-TCP in vivo might be strongly related to
the characterization and stability of the β-TCP structure
[75].
A number of synthesis methods have been used to
produce β-TCP powders. The conventional methods include
solid-state process [76] and wet-chemical method [77]. The
wet-chemical method gives Ca-deficient apatite
(Ca9(HPO4)(PO4)5(OH), CDHA) with the same molar ratio
of Ca/P as that of TCP. It needs to be calcined above 700–
800 °C to transform into β- TCP as shown by the
following reaction:
45the Ca sources and H3PO4 S.J. Kalita et al. / Materials Science and Engineering C 27 (2007)
as thepowder
P sources. Bownm et
441–449
al. synthesized nano-sized β-TCP of ∼50
particle
diameter at room temperature in methanol solvent.
They found that phase transformation was taking place
from CaHPO4, intermediate amorphous calcium
phosphate (ACP) phases (including ACP1 and ACP2 with
different structures) to final β-TCP with increase in
aging time. They observed that the incorporation of
carbonate helps in suppressing the transformation of
ACP1 phase with HAp-like structure into poorly
crystalline CDHA and favors the formation of β-TCP
phase. It was observed that the presence of micropores in
the sintered material affect the bioresorption of TCP-
based ceramic implants, therefore, the size and
amount of macro- and microporosity must be controlled
closely during manu- facturing processes [78]. SEM
studies revealed that the appearance of needles or petal-
like plates is characteristic of nano-β-TCP-based calcium
phosphate cements [79]. The nano-TCP powders can be
compacted into cylindrical pallets and then sintered for
mechanical and biodegradation studies to achieve
appropriate mechanical strength to be used as drug
delivery devices [80–82]. Metsger et al. reported a 21
GPa value for the Young's modulus of nano-β-TCP
ceramic. The mechanical strength of the cement was
enhanced when the nanostructures were immersed for
24 h and 7 days in SBF [71].
Nano-β-tricalcium phosphate cements can serve as
drug delivery systems for a variety of remedies such as
antibiotics, anti-tumor and anti-inflammatory drugs, etc.,
that can easily be added to them [83]. Also, β-TCP
prepared by wet precipitation procedure from an aqueous
solution of Ca(NO3)2 and NaH2PO4 and calcined at 1150
°C can be used as bone substitutes after grinding and
sieving to obtain the desired particle size [84,85]. A
subsidiary of Tredegar Corporation has recently
received FDA clearance to market a new resorbable β-
tricalcium phosphate bone void filler device used to
treat osseous defects of the skeletal system. Future
directions are aimed at creating a therapeutic nano-
TCP coating that has a dual beneficial effect:
osteoconductive properties combined with the ability to
deliver therapeutic agents, proteins, and growth factors
directly into the coating. These new coatings may offer
the ability to stimulate bone growth, combat infection,
and, ultimately, increase implant lifetime.

2.3. Tetracalcium phosphate

Tetracalcium phosphate ((Ca4(PO4)2O), TTCP) is the

most basic calcium orthophosphate ceramic. However, its
solubility in water is higher than that of HAp. TTCP cannot
be precipitated from aqueous solutions, and thus can
only be prepared by a solid-state reaction above 1300
°C. TTCP is not very stable in aqueous solutions, it
slowly hydrolyzes to HA and calcium hydroxide.
Consequently, TTCP is never found in biological
calcifications. In medicine, TTCP is widely used for
the preparation of various self-setting cements.
However, not much has been reported for the synthesis
and applications of nano-TTCP.
 S.J. Kalita et al. / Materials Science and Engineering C 27 (2007) 441– 4
3. Conclusion [22] R.N. Correia, M.C.F. Magalhaes, P.A.A.P. Marques, A.M.R. Senos, J.
Mater. Sci., Mater. Med. 7 (1996) 501.
Nanophase calcium phosphate bioceramics have gained
regard in the biomedical field due to their superior
biological and biomechanical properties. HAp and β-TCP are
essentially the main calcium phosphates used in the clinics
at present. Several ways of synthesis of both these forms
of CPCs on the nanoscale have evolved in the past few
decades. Due to the chemical similarity between HAp
and mineralized bone of human tissue, synthetic HAp
exhibits strong affinity to host hard tissues. Nano-HAp is
used primarily as bioactive coatings on metallic prosthesis
of bioinert materials like titanium and its alloys, in bone
tissue repairs and implants and also for drug delivery.
Nanoscale β-TCP exhibits significant biological affinity
and activity and responds very well to the physiological
environments. Also owing to its slow degradation characteristic,
the porous β-TCP is regarded as an ideal material for
bone substitutes that should degrade by advancing bone
growth. It also finds applications in drug delivery systems
and as bone substitutes. A lot of research in this area is
expected in the nano- zone for much enhanced applications
in drug delivery systems and as resorbable scaffolds that
can be replaced by the endogenous hard tissues with the
passage of time.

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