Basics of Hydroxyapatitedstructure, Synthesis, Properties, and Clinical Applications

Basics of
hydroxyapatitedstructure, 4
synthesis, properties, and clinical
applications
Hamad Khalid, Aqif Anwar Chaudhry
Interdisciplinary Research Centre in Biomedical Materials (IRCBM), COMSATS University
Islamabad, Lahore Campus, Lahore, Pakistan
4.1 Biological apatite and synthetic hydroxyapatite:

differences and similarities
Hydroxyapatite (HA) is well thought out as a biomaterial and hence widely employed
in many health applications. As a source of calcium, HA is particularly used as a vital
compound to repair bones and also in toothpastes. HA exhibits a great bioactivity and
is highly compatible with the adjacent bone and teeth in living organisms because of its
appropriate chemical properties. HA is a ceramic material composed of calcium phos-
phate owning a high biocompatibility and nontoxicity, and it is an integral part of bone
and teeth tissues (Sossa et al., 2018; Raya et al., 2015). When an implant coated with
HA meets the osseous tissue, bone growth is promoted toward the implant (Zhou and
Lee, 2011; Milovac et al., 2014). The story of HA started in 1926 by Jong et al. when
the chemical formula of HA was found to be Ca10(PO4)6(OH)2 and a relation between
HA and osseous mineral was observed. Synthetic HA is similar to biological apatite (or
osseous mineral), but there are differences in chemical composition and crystallinity.
Since then, HA has been investigated widely (Sossa et al., 2018). It is important to
understand the structure of the naturally occurring product if it is to be synthesized
in a lab or on commercial scale. So, the research on HA carried on and a great advance-
ment was the identification of crystallographic structure of HA by Ponser et al.
(Posner, 1969; Posner et al., 1958; Kay et al., 1964). They used chemically precipitated
HA for structure illumination. Nowadays, intensive research focusses on development
of high-quality HA with improved biocompatibility and via ecofriendly procedures
(Huang et al., 2011; Sadat-Shojai et al., 2013). Different methods are adopted to pro-
duce HA, e.g., hydrothermal (Zhang et al., 2011; Jokic et al., 2011), chemical precip-
itation (Stipniece et al., 2014; Kim et al., 2010; Dhand et al., 2014), and use of biogenic
sources (Huang et al., 2011; Kamalanathan et al., 2014).
The chemical precipitation and synthesis from biogenic sources are cost effective,
have fewer byproducts, are easily available, and have controllable particle size
(Sadat-Shojai et al., 2013; Kamalanathan et al., 2014). Especially, the biogenic source
Handbook of Ionic Substituted Hydroxyapatites. https://doi.org/10.1016/B978-0-08-102834-6.00004-5

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86 Handbook of Ionic Substituted Hydroxyapatites
can produce HA with high crystallinity, does not have contaminations, and is friendly
with the environment. Moreover, the HA produced by biogenic source can maintain
the natural architecture of the bone tissue, which could behave as osteoconductive ma-
terial (Mucalo, 2015). There are many biogenic sources of HA, among them egg shells,
animal bones, and fish scales are important (Kamalanathan et al., 2014; Mondalet al.,
2012; Haberko et al., 2006; Janus et al., 2008; Sobczak-Kupiec and Wzorek, 2012).
HA produced form chemical precursors has many advantages such as controllable
Ca/P ratio, high crystallinity, and good purity. But there are some disadvantages of
chemical precursors methods such as lack of Fe2þ, Mg2þ, Si2þ, Naþ and F ions,
which are naturally present in bone tissues, so the biological activity could be altered
(Milovac et al., 2014; Akram et al., 2014).
Rahavi et al. synthesized and extracted HA using solegel method and calcination of
natural bones at 700 C, respectively (Rahavi et al., 2017). They used bones from hu-
man and different animals to extract HA. They concluded that X-ray diffraction (XRD)
signatures of both types of HAs were in agreement with stoichiometric ratio. Synthetic
HA, however, showed small amounts of beta-tricalcium phosphate (b-TCP) and CaO,
which showed that conversion of raw materials into products was not 100 %. More-
over, the natural HA showed higher degree of crystallinity. Scanning electron micro-
scopy (SEM) analysis of these HA powders showed aggregated, rough, and dense
particles that were denser in synthetic HA, and the author believed that this difference
could be due to the crystallinity of calcium nitrate, which was used as precursor of cal-
cium. Similarly, the TEM analysis showed that the dispersion of HA crystallite was not
good enough, one possible reason of this agglomeration could be van der Waals attrac-
tion. This phenomenon can be justified if we compare the crystallite particles size;
20e40 nm particle size was recorded for synthetic HA, and 71, 52, 97, and 28 nm
HA particle size was recorded for human, bovine, camel, and horse bone HA. Compar-
atively, synthetic HA has smaller and irregular particle size that resulted into more van
der Waals attraction as it was also observed in SEM analysis that the synthetic HA
showed denser agglomeration.
The elemental analysis of these synthesized and natural HA showed that the ele-
ments other than the calcium and phosphorus are in very little quantity in synthetic
HA (Rahavi et al., 2017). This low concentration of elements cannot alter the overall
biocompatibility of the synthetic material (Santos et al., 2004). On the other hand,
these elements have higher weight percentage in HA extracted from natural bones.
Infact, this is one of the main differences in natural and synthetic HA. Presence of these
trace elements in HA could be beneficial for bone implants (Doostmohammadi et al.,
2011). Ca/P ratio can also be calculated from elemental analysis data. The synthetic
HA showed 1.75 Ca/P, while the theoretical Ca/P ratio is 1.67. It is difficult to control
the exact stoichiometric ratio in HA because it depends on the reaction procedures and
conditions (Rajkumar et al., 2011). The 1.75 and above Ca/P ratio with presence of
CaO could be the result of heat treatment of the final product at 700 or above (Sanosh
et al., 2009). This change can also be confirmed from XRD pattern of synthetic mate-
rial as described before. The possible reason of this disturbed ratio could be the volatile
nature of the phosphorus precursor above 650 C. So, the calcium precursor, which is
not converted or incorporated into complex structure converts into CaO. The Ca/P
Basics of hydroxyapatite 87
ratio in HA derived from natural source is higher than 1.67; the scientists suggest that
this higher ratio could be due the presence of other calcium phosphates with higher Ca/
P ratio (Doostmohammadi et al., 2012). In a study, it was observed that TCP and cal-
cium oxide is present in HA derived from natural bones (Joschek et al., 2000). Here, it
should be noteworthy that the deviation of actual Ca/P ratio in HA, from the theoretical
ratio, is not necessarily due to the existence of TCP but it can also happen because of
the presence of hydrogen phosphate and carbonate instead of phosphate and hydroxide
(Landi et al., 2000).
Because the XRD data of HA can lead us to ambiguous conclusion due to presence
of a little number of carbonates in the sample, Fourier-transform infrared spectroscopy
(FTIR) was utilized. FTIR study could be helpful in diagnosis of HA and can tell what
sort of functional groups are present. FTIR studies showed that natural HA had a peak
at 879 cm1, which could be due to the presence of hydrogen phosphate. Hydrogen
phosphate could be a reason of deviated stoichiometric ration of Ca/P in natural
bone HA as we discussed before (Rahavi et al., 2017).
Another way to determine the structural and compositional details of synthetic and
natural HA is Raman spectroscopy. Khan et al. summarized the Raman studies of syn-
thetic apatite in comparison with natural bone. According to this review, synthetic HA
showed some differences from natural bone, e.g., hydroxyl stretch that was present in
synthetic HA was absent in natural bones moreover carbonate contents were greater in
natural bones (Khan et al., 2008, 2013). However, Awonusi et al., in a study, compared
the Raman spectra of bovine cortical bone and carbonated HA (see Fig. 4.1) (Awonusi
et al., 2007).
4.1.1 Wet-chemical methods

4.1.1.1 Solegel methodology
Solegel is a technique in which a reactant or mixture of reactants is/are hydrolyzed and
passed through a solution state and a gel state before turning into a final product. This
technique is widely used to synthesize the metal oxides, glass, and ceramics (see
Table 4.1).
The solegel process can be explained by a series of discrete steps. In the first step,
sol is formed form the stable solution of alkoxide or metal precursor. In second step, a
gel is formed because of the oxide or alcohol-bridge network by polycondensation or
polyesterification, which increases the viscosity of the solution. The third step brings
the solidification of reactants; this step is also called aging. After aging, drying and
dehydration is carried out. In the final step, the product is treated with high temperature
(>800 C) (Cushing et al., 2004). Chemical homogeneity of starting materials is
improved by solegel method by molecular level mixing as the polycondensation or
polyesterification occurs (Hench, 1997; Hench and West, 1990; Niederberger,
2007). Solegel is also a convenient method to produce irregular surfaces in the
form of coatings on implants to mimic the natural HA. This method can be used for
dip coating, a suitable substrate such as titanium alloys and 316L stainless steel can
be dip coated repeatedly, followed by sintering (Aksakal and Hanyaloglu, 2008;
960
1071
1047
Intensity
431
1030
1003
878
450
590
852
582
610
1070
430
1047
590
449
581
609
400 500 600 700 800 900 1000 1100 1200

–1)
Raman shift (cm
Figure 4.1 Raman spectra of (a) cortical bone of bovine and (b) synthetic carbonated apatite
(Awonusi et al., 2007).
Copyright 2007. Reproduced with permission from Springer Nature.
Table 4.1 List of methods of synthesis with references.
No. Synthesis method References
1 Solegel Hench, 1997; Hench and West, 1990; Niederberger,

2007; Aksakal and Hanyaloglu, 2008; Gan and Pilliar,
2004; Liu et al., 2001; Masuda et al., 1990; Deptula
et al., 1992; Hu et al., 1993; Breme et al., 1995;
Russell et al., 1996; Kordas and Trapalis, 1997;
Jillavenkatesa and Condrate, 1998
2 Coprecipitation Donadel et al., 2005; Lopez-Macipe et al., 1998;
osarczyk et al., 1997; Tas and Aldinger, 2005;
Sl
Afshar et al., 2003; Lazic, 1995; Pang and Bao, 2003;
Phillips et al., 2003; Saeri et al., 2003; Nazir et al.,
2011; Khan et al., 2015
3 Emulsion technology Phillips et al., 2003; Koumoulidis et al., 2003; Segal,
1997; Li et al., 2008; Lim et al., 1997, 1999;
Jarudilokkul et al., 2007; Sun et al., 2007
Table 4.1 Continued

No. Synthesis method References
4 Batch hydrothermal Segal, 1997; Byrappa and Adschiri, 2007; Kaya et al.,
process 2002; Daoud et al., 2005; Takami et al., 2007; Guo
and Xiao, 2006; Arce et al., 2004; Liu et al., 1997,
2003; Riman et al., 2002; Wang et al., 2006; Yan
et al., 2001; Zhang et al., 2005
5 Continuous Chaudhry, 2008; Darr and Poliakoff, 1999; Ziegler et al.,
hydrothermal flow 2001; Chaudhry et al., 2008; Lester et al., 2013
synthesis
6 Solid-state synthesis Jia et al., 2002; Cao et al., 2005; Chen et al., 2004; Shu
et al., 2005; Core~no A et al., 2005; Silva et al., 2003;
Rhee, 2002; Suchanek et al., 2004; Fernandes et al.,
2005; Li-yun et al., 2005
Gan and Pilliar, 2004; Liu et al., 2001). HA particles can also be produced using this
method. During the solegel reaction, hydrolysis, condensation, and aggregation
happen simultaneously, which makes its chemistry very complex, therefore reproduc-
ibility and control over the particle morphology is difficult. Moreover, the heat treat-
ment of amorphous product alters the particle morphology, changes the crystallinity,
and inducea agglomeration (Niederberger, 2007).
As we already have discussed the importance of the HA in previous section, in this
section, we will discuss the different reaction conditions to synthesize HA using sole
gel technique. The morphology and other properties of HA prepared using solegel
technique is highly dependent on the temperature of reaction, precursors, time of reac-
tion, drying temperature, pH of the starting materials and solegel, and temperature and
time of heat treatment (calcination). Different scientists have explored different aspects
of this technique. Following, we will try to make a comparison of these different con-
ditions and summarize the results periodically.
Masuda et al. synthesized HA using solegel technique. They used alkoxides as the
stating material (see Table 4.1). In this study, the authors revealed that the pH of the
starting material was the most important factor that directly affected the HA synthesis.
So, they used alkaline, neutral, and acidic reaction conditions. It was observed that
only HA crystals without any additional phase were synthesized in neutral conditions.
After the successful preparation, the HA was calcined at 600 C, resulting in to plate-
like structure having 1000Å size, which resembled to HA present in living tissues. This
study was published in Japanese language; therefore, detailed information of reaction
conditions could not be acquired (Masuda et al., 1990). Deputla et al. prepared spher-
ical HA by solegel technique using calcium acetate and phosphoric acid as the starting
material. The synthesized spherical nanoparticles had diameter less than 100 mm. In
this study, the authors emulsified the freshly prepared precursor solutions using
2-ethylhexamol, and the resulted solegel was dehydrated at 50 C. The resulting
powder was calcined at 750 C (Deptula et al., 1992). Hu et al. synthesized phosphate-
rich glass powder, which was further treated with calcium hydroxide. Different condi-
tions were applied to this solegel synthesis, and it was observed that HA was produced
at 60 C and 60 min of reaction time. The authors also used ultrasonication for few mi-
nutes to accelerate the synthesis (Hu et al., 1993). Breme et al. used HA as coating
agent on titanium implants. First, the implant was coated with commercially available
HA with or without bounding agent (phosphoric acid). The implant was dip coated on
respective suspension and dried on room temperature followed by drying at 600 C and
finally sintered at 1200 C. In the second technique, Breme et al. used solegel tech-
nique to produce HA on the surface of titanium implant. The implant was dipped in
the solution of starting materials, which were CaO as calcium source and PO(OC2H5)3
or PO(OCH3)3 as phosphate source. The thin film formed on the surface of alloy was
dried at 130 C for 1 h, which resulted in the formation of gel. Finally, the implant was
annealed at 600e800 C for 5e15 min. The HA was characterized by X-ray studies
(Breme et al., 1995). Russel et al. used ion beam technology to modify HA, which
was prepared by solegel method. In this study, the HA was produced using calcium
nitrate tetrahydrate and n-butyl acid phosphate as starting materials. The reaction
mixture was spin-coated on the silicon substrate and immediately dried at 350 C fol-
lowed by annealing at 500, 600, 700, 800, 900, and 950 C in flowing nitrogen envi-
ronment (Russell et al., 1996). Kordas et al. synthesized HA by solegel method. This
time, the HA was synthesized by modification of already established method. Calcium
acetate and PO(OC2H5)3 were used as starting material, while different types of alco-
hols (methyl, ethyl, and propyl alcohol) were used as solvent. After the gel formation,
the drying was carried out at 75 C for few days and dried gel was heat treated at 930 C
(Kordas and Trapalis, 1997). Jillavenkatesa et al. synthesized solegel-based HA using
calcium acetate and triethyl phosphate, though HA with these precursors and method
was already reported, but the main purpose of this study was to produce cost-effective
and easy-to-synthesize HA. The gel prepared in this method was colloidal in nature, so
the difficulty associated with the slow dissociation of phosphate ion was resolved
(Jillavenkatesa and Condrate, 1998). Weng et al. used P2O5 to prepare HA by solegel
method. For this purpose, the P2O5 was dissolved in ethanol and refluxed for 24 h.
Ca(NO3)2$4H2O was used for calcium source. Both reactant solutions were mixed,
and resulting solution was refluxed for another 24 h. Resulting solution was dip-
coated on appropriate substrate and dried at 150 C for 15 min. The coated substrate
was calcined at 500 C for 15 min. To increase the thickness, the substrate was coated
again, and the process was repeated for 10 times. Finally, the product was calcined at
700 C.
4.1.1.2 Coprecipitation
Coprecipitation is a process in which two or more than two compounds are precipitated
simultaneously in a solvent. The coprecipitation is usually a result of supersaturation,
which involves nucleation, growth, and agglomeration of particles in a solution. Most
important part of coprecipitation is nucleation, which is the start of particle formation
after which secondary processes such as Ostwald ripening and aggregation start.
These secondary processes are responsible for determining the size morphology and
properties of particles. Particle size distribution, morphology, and particle sizes are
dependent on reaction conditions such as rate of reactant addition and stirring. Rate
of nucleation is inversely proportional to the particle size. Usually, soluble calcium
and phosphorus salts are coprecipitated by the addition of a base to result in poorly
crystalline HA, which needs proper aging to attain stoichiometric ratio (Cushing
et al., 2004).
Generally, the sources of calcium ions are calcium nitrate, calcium hydroxide, and
calcium chloride. For phosphate ions, usually diammonium hydrogen phosphate,
phosphoric acid, potassium hydrogen phosphate, and diammonium hydrogen phos-
phate are used (Donadel et al., 2005; L opez-Macipe et al., 1998; Sl osarczyk et al.,
1997; Tas and Aldinger, 2005) (see Table 4.1).
The amorphous precipitates are produced by the immediate reaction of calcium and
phosphate ions. Normally, the salts are mixed together for 2 h keeping the pH between
10 and 11. It has been often observed that the pH of the reaction system is more domi-
nant in determining the stoichiometry and thermal stability of the resulting calcium
phosphate as compared to the Ca:P molar ratio. The initial precipitate suspension is
then aged for up to a day to reach the proper stoichiometric ration of calcium and phos-
phate. The process could be sped up by increasing the temperature up to 95 C (Afshar
et al., 2003; Lazic, 1995; Pang and Bao, 2003; Phillips et al., 2003; Saeri et al., 2003).
During coprecipitation synthesis, agglomeration could be a result of local concentra-
tion due to inhomogeneity, which can be avoided by fast stirring and low addition
rate of reactants. Moreover, reaction pH plays an important role in determining the
stoichiometry of HA. A strict control of pH is important because stoichiometric HA
is only obtained at pH above then 10 (Afshar et al., 2003). Microwave assisted method
has also been used to reduce synthesis duration for synthesis of thermally stable HA
and magnesium-substituted HA (and calcium phosphates) (Nazir et al., 2011; Khan
et al., 2015).
4.1.1.3 Emulsion technology

Emulsion is a type of liquid in which two distinct solvents (usually water and oil) or
liquids are mixed together in such a way that fine droplets of one are dispersed in
another homogenously. Mixture of water, oil, and a surfactant can result in to an emul-
sion. This emulsion looks clear because nanosized droplets do not scatter light notice-
ably. When water is dispersed in oil, it is called water-in-oil dispersion. The small
water droplets in oil work as small reactors if used in a chemical reaction. These small
droplet reactors have increased interfacial area as compared with conventional reac-
tions (Cushing et al., 2004) (see Table 4.1). Both terminologies, microemulsion or
macroemulsion, are used for emulsions. When the volume of water is very low in
oil, it is called microemulsion. Microemulsions are usually clear and transparent and
stable for a long time. But if the water is comparatively higher in volume, then it is
called macroemulsion. Macroemulsions are opaque in nature and only stable on
continuous stirring (Phillips et al., 2003).
In an emulsion, when two water droplets containing reactants are collided with each
other, chemical reaction takes place. The resulting product has small and homoge-
neous size when a reaction takes place in such a small droplet (Koumoulidis et al.,
2003; Segal, 1997). It is reported that the powders produced by emulsion techniques
have higher surface are as compared with those produced by other methods (Koumou-
lidis et al., 2003).
Keeping in view the good homogenized particles produced by emulsion method,
scientists have produces HA using this method. However, to carry out this kind of re-
action, a large volume of oil (organic solvents) is required (which makes it rather a
nonenvironment friendly method), and moreover, subsequent heat treatment is also
required for crystallinity (Phillips et al., 2003; Koumoulidis et al., 2003; Li et al.,
2008; Lim et al., 1997, 1999). Other parameters are also important for HA synthesis
using this method, e.g., Jarudilokkul et al. reported that by increasing the reaction tem-
perature (from 30 to 80 C), the surface are is decreased (from 227 to 98 m2g1) (Jar-
udilokkul et al., 2007). Similarly Sun et al. reported that using microemulsion
technique in hydrothermal conditions and neutral pH, HA with rodlike morphology
was produced, and when pH was increased, the particles morphology was converted
to spherical (Sun et al., 2007).
4.1.1.4 Batch hydrothermal synthesis

In normal chemical reactions, the temperature of reactor could be increased maximum
up to the boiling point of solvent, at which the reaction could be set on reflux. How-
ever, if the autogenous pressure is increased, the temperature of solvent can be elevated
above its boiling point in a close container just like a pressure cooker. Materials that
are insoluble in a certain solvents can be dissolved and recrystallized using this tech-
nique. The abovementioned technique is called batch hydrothermal process when wa-
ter is used as a solvent. Hydro is derived from hydra which means water and thermal
means related to heat (Cushing et al., 2004; Byrappa and Adschiri, 2007). Ceramic sols
are resulted by the chemical reaction during a batch thermal process under high pres-
sure and temperature usually in the presence of an acid or alkali. However, an acid or
alkali is not always required though they have a catalytic effect on chemical reaction
(Cushing et al., 2004; Kaya et al., 2002). Segal published a comparison of hydrother-
mal process with other processes for the synthesis of ceramic powders (Segal, 1997).
The hydrothermal synthesis of ceramic powders has number of benefits over other
methods. It is an environment friendly process (lies under green chemistry) and is a
direct route to fabricate submicron nanoparticles at comparatively lower temperature
without the need of subsequent calcination step. The hydrothermal process has been
used for the synthesis of different products such as metal oxides, phosphates, and
HA (Daoud et al., 2005; Takami et al., 2007; Guo and Xiao, 2006) (see Table 4.1).
Guo and Xiao reported the synthesis of HA using batch hydrothermal process (Guo
and Xiao, 2006). Calcium nitrate, calcium hydroxide, or calcium carbonate could be
used as calcium source, while phosphate could be acquired from phosphoric acid,
ammonium hydrogen phosphate, sodium dihydrogen phosphate, or calcium hydrogen
phosphate. Solutions of calcium and phosphate source were mixed together and put in
to closed container. Well-defined, crystalline and phase pure HA could be obtained by

hydrothermal process, but the crystallinity and morphology of HA particles is
depended on pH, pressure, temperature, and aging time during this type of synthesis.
The processing temperature is reported between 90 and 150 C, while aging time is re-
ported between few to 24 h (Guo and Xiao, 2006; Arce et al., 2004; Liu et al., 1997,
2003). Templating agents (e.g., poly(amidoamine), CTAB) can also be used in the hy-
drothermal batch processing of HA (Liu et al., 2003; Riman et al., 2002; Wang et al.,
2006; Yan et al., 2001; Zhang et al., 2005).
4.1.1.5 Continuous hydrothermal flow synthesis

In early 1990s, researchers from Japanese group Arai at Tohoku University developed
continuous hydrothermal flow synthesis (CHFS), and since then, few research groups
around the globe have initiated use of this versatile technology. Researches have modi-
fied and improved CHFS and expanded its use for different materials systems. It is
important to understand the basic science of supercritical water used in this technology
(Chaudhry, 2008).
According to definition, when the temperature and vapor pressure of a fluid exceed
the critical point, it is called a supercritical fluid (SCF) (Darr and Poliakoff, 1999). The
SCFs have unique set of properties that are totally different from normal gases and
liquids. The viscosity and density of SCF can vary considerably when they are near
the critical point. When the critical point is achieved, the difference between density
of liquid and gas reduces, resulting in the disappearance of interfaces (Cansell et al.,
2003; Noyori, 1999). At 374 C and 22 MPa, water becomes supercritical, and above
that, it has variations in dielectric constant, viscosity, and ion product (Cushing et al.,
2004; Bellissent-Funel, 2001).
Water has the ability to dissolve many inorganic salts. However, when the temper-
ature of water is increased on at a constant pressure, its dielectric constant is reduced.
When water reaches its supercritical point, the inorganic salts become insoluble and
precipitate out. At this point if the salts are supersaturated, the nucleation is increased,
which results in the production of nanoparticles (Kashchiev and van Rosmalen, 2003).
At this point, metal ions are converted to crystalline metal oxides because of rapid
dehydration at high temperature in supercritical state. This could also be a possible
reason of small size particles, as rapid dehydration at high temperature does not
give enough time for crystal growth (Hakuta et al., 2003; Ziegler et al., 2001).
Chaudhry et al. used CHFS technology to produce pure and magnesium-substituted
HA for the first time. A series of magnesium substituted HAs (and calcium phosphates)
were also produced. It was observed that HA with low magnesium concentration
showed crystalline rodlike nanoparticles. Increasing concentration of magnesium up
to certain level resulted in stabilization of the magnesium whitlockite (which normally
does not precipitate directly), which appeared as a crystalline phase in addition to HA.
Further increase in magnesium content led to phase purity (of this magnesium stabi-
lized whitlockite). Generally, increasing magnesium concentration decreased crystal-
linity gradually (Chaudhry et al., 2008).
Lester et al. used CHFS technology to produce nano-HA (nHA) of three different
morphologies. These three morphologies were sheet, rod, and/or tube. It is described
that the morphology of nHA was controlled by the controlling pH and/or reaction tem-
perature. NH4OH was used to control the pH of system, which played an important
role in determining the morphology of nHA (Lester et al., 2013) (see Table 4.1).
4.1.2 Solid-state methods

Jia et al. synthesized HA powder by low temperature solid-state reaction or mechano-
chemical reaction using calcium acetate and ammonium phosphate as precursors (Jia
et al., 2002). This solid-state reaction was carried out on low temperature, though this
kind of reactions can also perform on high temperature; however, these reactions can
be accelerated significantly if treated with microwaves. Microwaves directly increase
the molecular movement, which results in rapid temperature increase. So, Cao et al.
synthesized HA from calcium nitrate and trisodium phosphate. First, they grounded
the starting material and then heated using microwave technique. When the reactants
were heated, using microwave, for half a minute, spherical morphology was obtained,
which was converted to rodlike structures when microwave heating was extended to
1 min (see Table 4.1) (Cao et al., 2005).
Solid-state reactions include mechanochemical mixing, which results into chemical
reaction. When water is involved in a mechanochemical reaction, then it is called
mechanochemicalehydrothermal reaction (Chen et al., 2004). Mechanochemicale
hydrothermal reactions could be carried out in a ball mill. The reactants in appropriate
stoichiometric ratio are mixed together and ball milled on a favorable temperature and
pressure. Chemical reaction takes place because of contact of reactants between walls
of mill and balls (and only balls also) (Shu et al., 2005). Mechanochemical reactions
usually take a long time to complete. However, mechanochemical synthesis of HA
takes few to 60 h to complete (Core~ no A et al., 2005; Silva et al., 2003), and to convert
it into phase pure HA, a heat treatment is required (Rhee, 2002). This heat treatment
can lower down the surface area as Chen et al. reported that heat treatment of HA at
900 C for 1 h reduced the surface area form 172 to 7.2 m2 g1 (Chen et al., 2004).
The mechanochemical reactions can also be used to produce ion-substituted HA
(Zhang et al., 2005; Shu et al., 2005; Core~ no A et al., 2005; Suchanek et al., 2004).
Cai et al. reported that if dicalcium phosphate dihydrate and calcium phosphate are
grinded together, carbonated HA nanofiber can be synthesized (Shu et al., 2005).
Moreover, large quantities of crystalline HA powder can be obtained by solid-state re-
actions; however, there are chances of impurities that can be added by wearing and
tearing of material used for mixing and grinding, e.g., balls of ball mill (Rhee,
2002; Fernandes et al., 2005).
4.1.3 Hydroxyapatite coatings

The metallic implants of titanium and its alloys show the greatest biocompatibility if
we compare it with other materials. Usually, these implants are grouped with bioinert
materials together with ceramics such as zirconia, titania, and alumina depending on
the applications and pattern of osteogenesis. Some applications required good bio-
interaction for tightening and compact packing, in other words a strong bonding
with natural bone. Calcium phosphateebased biomaterials such as TCP and HA
show good biocompatibility. For this kind of fixation technique, there are some
required properties such as mechanical strength, ductility, ease of fabrication, and
biocompatibility (Kasuga and Niinomi, 2010). HA-coated implants have been widely
used in dentistry and orthopedics. There are variety of methods that are used for
coating of HA such as electrophoretic deposition (EPD) (Ducheyne et al., 1986),
ion beam sputtering (Ong and Lucas, 1994), dip coating (Li et al., 1996), plasma spray-
ing (Lacefield), thermal spraying (Mardali et al., 2019), and biomimetic coating
(Kokubo, 1998) etc.
4.1.3.1 Plasma-sprayed coatings

In this technique, the HA is sprayed on the surface of implant using plasma. As the
temperature of plasma is very high, it melts the HA that is meanwhile sprayed. Coat-
ings with plasma technique have strong bonding (between metallic implant and HA)
and good dissolution in body fluids. However, there is a large difference in the thermal
expansion of metallic implant and coating, which results into residual stress at the
interface. When the crystallinity of HA is low and it is in an amorphous state, the
coating can dissolve rapidly, which could induce an inflammatory response. Tusi
et al. reported a relatively high bonding strength on titanium alloys (Tsui et al.,
1998). They optimized the conditions of coating and reported that the strength was be-
tween 20 and 40 MPa. These results were obtained because the crystallinity of HA in
these experiments was high (83%e94%). For long-term benefits of an implant, the
crystallinity of its coating is highly important. So, Ingaki et al. developed a radiofre-
quency thermal plasma spraying method to obtain strong interaction between HA
and metallic implant substrate (Inagaki et al., 2008). The authors used HA/Ti compos-
ites for this purpose. HA and Ti were plasma sprayed on the desired substrate using
two microfeeders. The coating was carried out in gradient composition, first Ti-rich
plasma was sprayed followed by the HA-rich plasma. It was also observed that the
plasma in nitrogen environment gave better strength to the coating. Moreover, a post-
heat treatment provided highly oriented HA, which showed better biocompatibility.
4.1.3.2 Electrophoretic deposition

EPD is a method of particles coating on a surface using electrochemistry. In this
method, the particles, e.g., bioceramics, are suspended in a solvent that is transferred
in an electrochemical cell, where one electrode is the surface that is to be coated and
other is counter electrode. Because of the potential difference of electrodes, the sus-
pended particles are polarized and attracted by the substrate where they deposited in
the form of lose coating. To increase the bonding and crystallinity of ceramic particles,
a postheat treatment is usually recommended (Augello et al., 2015; Ducheyne et al.,
1990).
Ducheyne and Radin coated the metallic implants with HA using EPD and heat-
treated the coatings at 900 C for 1 h (Ducheyne et al., 1990). They obtained uniform
thicknesses, which were controlled by changing the electrical field strength and depo-
sition time. The deposited ceramic coatings were hampered by the absorbed water, and
a vacuum sintering led to phase transformation that, the author suggested, could pro-
voke the considerable changes in the in vitro dissolution experiments. Mehboob et al.
used polymer-assisted EPD of HA on medical-grade stainless steel. Polyethylene
glycolemodified HA was used for EPD. The purpose of using polymer was to avoid
postdeposition heat treatment (Mehboob et al., 2014). Similarly, Iqbal et al. used poly-
vinyl alcohol (PVA)ecoated HA to deposit on 361L stainless steel substrate using
EPD technique. The addition of PVA improved the adhesion of the powder on sub-
strate, which eliminated the heat treatment process (Iqbal et al., 2012).
4.1.3.3 Thin film coatings

Thin, uniform, and dense coatings of HA on metallic substrates can be obtained by
physical vapor deposition, which is one of the most promising methods for coating.
Calcium phosphate thin films were coated on titanium substrate using radiofrequency
(RF) magnetron sputtering. This technique has been widely used for coatings of thin
films with excellent bonding of coating materials with substrate (Yoshinari et al., 1997;
Wolke et al., 2003). The RF technique was also used for titanium alloys substrate (van
Dijk et al., 1995). This method has advantages over the other high-temperature tech-
niques as it can be executed at relatively low temperature that does not alter the prop-
erties of substrate.
4.1.3.4 Biomimetic apatite coatings

Formation of a bioactive coating on the surface of any implant by soaking it in a simu-
lated body fluid (SBF) with ion concentrations equal to those of human blood plasma
(Kokubo, 1998) is called biomimetic method. Using this method, HA can be deposited
on a surface, which is also called bone-like apatite. This method has advantages over
conventional methods as materials can be homogenously coated on an implant without
the need of heat treatmentdmaking this technique applicable to polymer surfaces as
well. Although heat treatment is not applied in this technique, even then a good crys-
talline nanosized apatite layer was obtained. Formation of biomimetic HA (BHA) us-
ing SBF requires two conditions: (1) the surface must have such functional group that
can induce nucleation of apatite, e.g., hydroxyl, carboxylic, and phosphate and (2)
increased concentration of apatite (Kokubo, 1998; Kokubo et al., 1990). Metallic im-
plants are usually covered with passive oxide layer, e.g., titanium is covered with tita-
nium oxide. Because the surface of passive layer also has titanium hydroxide,
therefore, there are great chances of HA nucleation on metallic implants. A large
amount of calcium ions should also be dissolved in the SBF to increase the possibility
of BHA formation.
4.2 Properties of hydroxyapatite

4.2.1 Structural insights
The chemical formula of HA is represented by Ca10(PO4)6(OH)2. A stoichiometric HA
has monoclinic geometry with P21/b space group (Morgan et al., 2000), and HA hav-
ing hexagonal system with P63/m space group has little deviation from stoichiometry
(Hench). Most of the synthetic methods produce a slight nonstoichiometry and hence a
hexagonal structure. Fig. 4.2 represents the sketch of a unit cell of hexagonal HA.
Two different positions of calcium ions are mentioned (these refer to Ca(I) and
Ca(II) positions). Phosphorus atoms are not shown in the figure because they are hid-
den by the space occupied by oxygen atoms. Overall, 18 ions are closely packed to
make the hexagonal structure. At each hexagonal corner, a calcium ion is surrounded
by 3 hexagons (i.e., 12 calcium ions shared by 3 hexagons ¼ 4 calcium ions per hexa-
gon). There is a hydroxyl ion in the center of each unit cell (which makes two hy-
droxyls per unit cell). Hydroxyl group in center is surrounded by three calcium ion
per hexagon forming a ring (i.e., six calcium ions). A “chord” is formed throughout
the structure because of these rings that are responsible for many properties of HA.
Void spaces between two hexagons are filled with three phosphate tetrahedra per
unit cell. Ions in HA can be substituted (also referred to as doping interchangeably
in literature) by biologically beneficial ions due to the inherent versatility of this crystal
structure. Substitutions can be both cationic and anionic referring to substitutions of
the calcium, phosphate, and/or hydroxyl ions.
Calcium
Oxygen
Hydrogen
Figure 4.2 Schematic representation of hydroxyapatite unit cell. The doted lines are
representing the lower level (Sarig, 2004).
Copyright 2004. Reproduced with permission from Elsevier Ltd.
4.2.2 Physical and thermal properties

The physical properties of HA highly depend on the source of method from which HA
is obtained or synthesized, as we have already discussed in first section. The HA syn-
thesized in lab shows low crystallinity and high surface area and can have high
porosity depending on the processing method used. On the other hand, natural HA
is usually derived by heat treatment of bones at higher temperature (usually 800 C),
which results in highly crystalline HA (Sobczak-Kupiec et al., 2012). Sintered HA
derived from bovine bone has porosity and pore structure that matches the natural
bone. This porosity and wettability of HA makes it useful for drug loading. The
most stable calcium phosphate salt has a Ca:P molar ratio of 1.67 and normally pre-
cipitates at or above pH 10. However, the biological and synthetic apatite differs
from the ideal stoichiometric ratio due to substitutions.
4.2.3 Mechanical properties

HA is usually implanted in the form of granules or porous scaffolds. However, it is not
used as a load-bearing implant because of its mechanical properties, which limits its
use (Lin et al., 2012). To improve the mechanical properties of HA is a great challenge
of scientists so far. Usage of carbon nanotubes and different metal oxides such as
alumina, zirconia, and titania as reinforcing agent is very common (Mukherjee
et al., 2014; Mobasherpour et al., 2009). However, these reinforcing materials may
compromise the biocompatibility of HA because usually they are bioinert or nonbio-
compatible. On the other hand, HA whiskers or fibers are considered to have better me-
chanical properties without compromising the biocompatibility (Bose et al., 2009;
Suchanek et al., 1997), but HA whiskers do not have thermal stability as they disap-
pear after sintering (Lin et al., 2012). There is another effective way to enhance the
mechanical properties of HA, which is the fabrication of nanosized HA. Nanosized
ceramics have apparently higher mechanical properties as compared with microsized
ceramics (Wang and Shaw, 2009). Another way to improve the mechanical properties
of HA is to make composites with polymer and crosslinking agents. Iqbal et al. fabri-
cated chitosan/HA sponge-like scaffolds using freeze-drying technique, and hydroxy
propyl methyl cellulose was used as crosslinking agent (Iqbal et al., 2017). The fabri-
cated sponges showed better compression strength and elasticity including good cell
support and favorable degradability. Architecture of porous scaffolds also plays an
important role in determining its strength (Bignon et al., 2003; Kalita et al., 2003).
As the strength is a very important property especially for those scaffolds that are
used for the replacement of load-bearing bone. Therefore, it is important to design
scaffolds carefully (Hollister et al., 2002; Lin et al., 2004).
4.2.4 Biological performance

There is a clinical need of synthetic bone graft that has ability to stimulate the bone
growth and act as temporary bone scaffold. Physiological tissues interact with
implanted materials that determine the fate of implant in living system. An implant
could be a failure if the boneeimplant interface is loosened. On contrary, the intimate
contact of bone and implant and chemical interaction of implant with surrounding bone
are considered as promising successful implantation. Therefore, the evaluation of any

biomaterial for its performance in living organism or tissue culture is important so that
in future any misbehavior of biomaterial could be preempted (Bizios, 1994). HA is
considered as a well-tolerated material in both in vitro and in vivo studies.
4.2.4.1 In vitro
The HA is considered as a good biomaterial and harmless to cell environment. How-
ever, very fine particles of HA may damage the fibroblast cell, whereas large particle
HA does not damage (Evans et al., 1992). This damage could be due to the direct con-
tact of the cells with HA particles. Sautier et al. carried out in vitro study of isolated
mouse calvaria cells on synthetic HA (Sautier et al., 1991). Initially an electron dense
layer at the periphery of the material was observed, which was granular and collagen
free. With the passage of time, this dense layer was converted to an amorphous gran-
ular form in between the HA aggregates. An osteoid matrix was observed, which was
mineralized on the previously prepared layer. In vitro studies of HA/collagen bone-like
composites showed excellent biocompatibility and biointegrative activities, which
were equal to autogenous bone and much better than other materials. On the bases
of in vitro studies, it was concluded that this composite was a potential material in
medical and dental field (Kikuchi et al., 2004). Sonocoated scaffolds with nHA also
showed increased proliferation of osteoblast cells (Rogowska-Tylman et al., 2019).
4.2.4.2 In vivo (animal model)

Rogowaska et al. prepared scaffolds that were coated with biological HA using sono-
coating technique. HA-coated scaffolds were tested in vitro using rabbit model. The
animal studies showed that HA-coated scaffolds showed new bone formation. Up to
68% volume of porous scaffolds was filled with new bone formed during in vitro
experiment (Rogowska-Tylman et al., 2019). Cardoso et al. (2019) prepared porous
scaffolds of calcium deficient HA with PCL using NaCl as leaching salt for porosity.
HA was used in the form of needle-shaped whiskers. In vivo studies showed good
biocompatibility. Rat model was used for in vivo studies. The in vivo studies
confirmed the potential of osteogenesis. Oversall, up to 31% improvement in osteo-
genic properties was observed as compared with the control. Fang et al. prepared poly-
meric hydrogel and incorporated nHA by in situ synthesis (Fang et al., 2019). The
rabbit animal model was used for in vivo testing. Regeneration of a highly mineralized
bone tissue and direct bonding to the nHA containing hydrogel was observed in
femoral condyle defect rabbit model. Ripamonti et al. (1992) used baboon model to
study in vivo application of HA in combination with osteogenin. Osteogenin is a pro-
tein that plays an important role in osteogenesis. Porous HA replicas were obtained
from the heat treatment of calcium phosphate from exoskeleton of coral. Osteogenin
was obtained from bovine and delivered to bioresorbable and nonbioresorbable HA
rods. For assessment of osteogenic activity, a total of 48 rods were bioassayed into
eight baboons. Osteogenin fractions were reconstructed with baboon-insoluble collag-
enous bone matrix, which was implanted in additional four baboons. The results
demonstrated that differentiation of bone was observed in nonbioresorbable rods
with or without ostegenin. However, bioresorbable HA did not support any bone
formation even in the presence of osteogenin. Thus, nonresorbable HA replicas and

reconstituted insoluble baboon collagenous bone matrix with bovine osteogenin devel-
oped the potential therapeutic possibility of bone induction in different areas such as
craniofacial, periodontal, and surgery for orthopedic reconstruction.
4.2.4.3 Clinical trials

To evaluate medical, surgical, or behavioral intervention in human, clinical trials are
an essential step. A biomaterial that has passed in vitro and in vivo studies successfully
can be considered for clinical or human trials in confluence with regional ethical and
regulatory permissions. Clinical or human trials of HA have been studied extensively
for use in different areas of the human body. These include (but are not limited to)
dentine pulp regeneration (Nakashima et al., 2019), impact of implant length on mar-
ginal bone lose in atrophied arches (Amine et al., 2019), bone grafting in orthognathic
surgery (Alyahya and Swennen, 2019), alveolar ridge preservation, sinus augmenta-
tion, periodontal bone defect (Dewi and Ana, 2018; Zhou et al., 2018a), total knee
arthroplasty (Zhou et al., 2018b), and anterior cervical discectomy and fusion
(Zadegan et al., 2017). Some key reports are further discussed below for elucidation.
Pines et al. (1984) carried out clinical trials on 40 patients at risk of osteoporosis
because of long-term treatment with prednisolone to determine the efficacy and toler-
ance of crystalline micro-HA to avoid the appearance or progression of osteoporosis. A
total of 32 patients were administrated with 6e8 g HA for 12 months, and 8 patients
were served untreated as control group. The results confirmed the tolerance of HA and
the superior acceptability of HA as tablet form. Moreover, it was observed that skeletal
pain in patients developing osteoporosis was dramatically reduced. Livesley et al. con-
ducted clinical trials to compare the use of HA-coated and uncemented bipolar hemi-
arthroplasty for the treatment of a displaced subcapital fracture of the femur (Livesley
et al., 1993). A total of 82 patients suffering from subcapital fractures of the femur
were included in trials. The results were superior significantly in HA-coated group af-
ter 1 year postoperative follow-up. Jones et al. (1997) preformed the clinical trial of
cylinder implants in different region of mouth. Comparison of plasma-sprayed Ti
and HA-coated plasma spray Ti implants was studied in these trials. A total of 65 sub-
jects were included in this study. A total of 352 implants (equally distributed between
with and without HA-coated, plasma-sprayed Ti) were implanted in four different
sites. The results suggested that HA-coated, plasma-sprayed Ti implants showed supe-
rior integration in the beginning. Similarly, Nilsson et al. preformed clinical trials on
57 subjects (Nilsson et al., 1999). It was a randomized study to compare the fixation of
HA coated with cemented tibia components in the Tricon II total knee arthroplasty.
Radiostereometric analysis was adopted to evaluate the quality of fixation for 5 years
after surgery. There was one early delamination of the coating and clinical lessening
and two implants got infection. Eight patients (a total of nine knees) died, one patient
sustained a stroke, and one patient refused to be investigated after 1 year. In remaining
patients, the magnitude of the micromotion between the HA-coated and cemented
groups did not differ. Most of the migration was shown within 3 months, in HA-
coated implants, and then stabilized, and on the other hand, cemented implants showed
initially lower but over the time continuously increasing migration.
4.2.5 Applications of hydroxyapatite

In previous sections, we have discussed the HA-based tissue engineering applications.
Following are some other applications of HA.
4.2.5.1 Hydroxyapatite as a drug carrier

HA has been explored in research as viable delivery platforms for clinical applications.
HA is a material of particular interest due to its alluring features: interconnecting
porosity of bulk material, good biocompatibility, resistance to mechanical force, and
sustained release capacity Researchers have been investigating HA nanoparticles for
different clinical applications such as immunoadjuvant therapy, drug delivery, and
gene/siRNA transportation. Using HA as therapeutic drug/antigens/protein carrier pro-
vides slow rate of release and protection from degradation (Shinto et al., 1992; Netz
et al., 2001; Komlev et al., 2002; Bhattarai et al., 2008; Barroug and Glimcher,
2002). Barroug and Glimcher reported the adsorption and desorption kinetics of
cisplatin in vitro. They prepared plate-like nHA particles having dimension of
93 nm 23 nm. These particles were loaded with the drug for 40 h in ambient condi-
tions. The release profile of the drug showed that after 102 h, only 33% of total
absorbed drug was released. The extended studies showed that after 14 days, a total
of 58% drug were released (Barroug and Glimcher, 2002).
Similarly, Palazzo et al. reported the viability of HA as a drug delivery vector by
investigating the adsorption and desorption kinetics of anticancer drugs cisplatin
(CDDP), di(ethylenediamineplatinum) medronate, and bisphosphonate alendronate
on nHA. The investigators prepared needle-like and plate-like nanoparticles of HA us-
ing modified wet-chemical precipitation method. The drug release mechanism of these
nHA particles was controlled by morphology and by tuning the surface charges. Posi-
tively charged cisplatin was electrostatically bound to plate-like nHA, and counterrally
negatively charged alendronate was attached to needle-like nHA through ligand
exchangeeinduced binding mechanism. Approximately, 90% of initial drug concen-
tration of alendronate and CDDP was loaded on needle-like nHA with regard to sur-
face area. As the needle-shaped nHA has more negative surface charge, which resulted
in more electrostatic interaction between nHA and drug therefore, it was able to load
more CDDP (Barroug and Glimcher, 2002; Palazzo et al., 2007).
Plasmid DNA and siRNA are degraded in living tissues, therefore their delivery to
specific area could be a challenge. Zhe et al. demonstrated that nHA can be used to
deliver plasmid DNA (pDNA) in vitro and in vivo. So, rod-shaped nHA
(40e60 nm) was synthesized, which was able to carry 1 mg of plasmid DNA per
36 mg. These nanoparticles were used to carry EGFP-N1 pDNA to the required site
of gastric cancer cells (SGC-7901). It was observed that the cancer cells were trans-
fected in comparis on to free pDNA, which was used as control. Fluorescent proteins
were also successfully expressed on the required side in vitro (in mice model), which
also indicates the flexibility of nHA in gene delivery (Zhu et al., 2004).
nHA was also used as a nonviral vector in gene delivery. Bisht et al. investigated
that 100e120 nm HA particles were able to make complex with pDNA, and this com-
plex showed that expression of green fluorescent protein was increased over a period
of 24 h in HeLa cells, which is an evidence of sustain release. The possible reason
behind this phenomena is that the HA was able to encapsulate the pDNA and protected
it from cellular environment and successfully transferred it to nuclear space (Bisht
et al., 2005). Small interfering ribose nucleic acid or simply siRNA is important in
blocking the impression of different receptors. However, siRNA could be disintegrated
in the cell medium, so Yand et al. investigated the ability of nHA to carry siRNA to
block NR2B expression, a receptor important in chronic pain. He loaded one of
anti-NR2B-siRNA to 35 mg of rod-shaped nHA (40e50 nm). Mice model was used
to evaluate the in vivo studies. It was observed that the nociceptive behavior was pre-
sent even after 7 days of injection, which confirms the sustained release of NR2B-
siRNA (Yang et al., 2008).
To induce the immune response in the body, antigens are used, e.g., for vaccination
purposes. Hepatitis B is a big concern nowadays especially in developing countries.
Transportation of hepatitis B surface antigen (HBsAg) was done using cellobiose-
coated nHA ranging from 50 to 150 nm by Goyal et al. It was observed that
cellobiose-coated nHA was able to load approximately 20% HBsAg, while up to
50% HBsAg was loaded on noncoated nHA. For in vivo studies, HBsAg (10 mg)
loaded on coated and noncoated nHA and free HBsAg was administrated subcutane-
ously in mice. Cellobiose-coated nHA proved to be a more effective adjuvant, and it
induced rapid antibody response, which showed that cellobiose-coated nHA can act as
an efficient antigen delivery vehicle (Goyal et al., 2006). It is believed that cellobiose
coating protected the conformation of specific protein, therefore bioactivity of HBsAg
was maintained (Goyal et al., 2006; Kossovsky et al., 1996).
4.2.5.2 Bioimaging
Bioimaging is a process in which the biological systems are noninvasively monitored
by visualization in real time. Florescent dyes and other organic compounds are used for
bioimaging. For a better performance, it is important to encapsulate the bioimaging
material, e.g., a dye in nanoparticulate system (Morgan et al., 2008). The nanoparticu-
late system can protect the dye in vitro until it reaches its destination. Besides the abil-
ity of HA to carry drugs, it also has been used to carry bioimaging molecules. Because
the formulation of HA involves a simple chemical reaction, encasement of bioimaging
molecules can be achieved by only mixing that molecule during the formation of nHA.
Moreover, formation of amorphous HA under the typical synthesis conditions allows
the inclusion of a broad range of molecules such as organic fluorophores or other low
molecular weight molecules (Panyam and Labhasetwar, 2003; Tung and Amjad,
1998). Morgan et al. reported that nHA (20e30 nm) can be synthesized and loaded
with a number of fluorescent dyes. Specifically, he used Cascade Blue, Cy3 Amidite,
Rhodamine WT, fluorescein sodium salt, and 10-(3-sulfopropyl) acridinium betaine
(SAB) to encapsulate in nHA. For free and encapsulated dye, nearly a fourfold increase
in fluorescence quantum efficiency from 0.045 to 0.202 was observed, respectively
(Morgan et al., 2008). Another important way to exploit nHA for bioimaging is conju-
gation of radioisotopes to nHA. Ethylene diamine tetramethylene phosphate has
shown high attraction to 153Sm and bone and/or HA and therefore offers a potential
avenue to develop nHA conjugated with radioisotopes with Ethylene-diamine-
tetramethylene-phosphonate (EDTMP) ligands for both bioimaging and radiotherapy
functions (Loo et al., 2010).
4.2.5.3 Commercial products

A great number of bioceramics and calcium phosphateebased biomaterials are either
available or under consideration under different trade names (see Table 4.2) for ortho-
pedic and dentistry applications (Dorozhkin, 2013a). For example, for augmentation,
tooth replacement, alveolar ridge augmentation, and maxillofacial reconstruction, bulk
materials in dense and porous form are available (Dorozhkin, 2013b). Other applica-
tions include bone defects repair (Silva et al., 2005; Damron, 2007), buttons for burr
hole (Easwer et al., 2007; Kashimura et al., 2010), spine fusion (Thalgott et al., 1999;
Mashoof et al., 2002; Minamide et al., 2005), orbital implants (including Bio-Eye)
(Jordan et al., 2004; Yoon et al., 2008; Tabatabaee et al., 2011; Kundu et al., 2013),
and hearing ossicles increment (Wehrs, 1991; Smith et al., 2002; Doi et al., 2007).
The trade names and producer of commercial orthophosphates are given below in
Table 4.2.
Table 4.2 Trade names and producers of calcium phosphate products (Dorozhkin, 2013a).
Calcium phosphate Trade name and producer (when available)
Hydroxyapatite (HA) BoneSource (Stryker Orthopedics, NJ, USA)

Calcitite (Zimmer, IN, USA)
Cerapatite (Ceraver, France)
Durapatite (unknown producer)
HA BIOCER (CHEMAeELEKTROMET, Poland)
HAnano Surface (Promimic, Sweden)
nanoXIM (Fluidinova, Portugal)
NEOBONE (Covalent Materials, Japan)
OssaBase-HA (Lasak, Czech Republic)
Ostegraf (Ceramed, CO, USA)
Ostim (Heraeus Kulzer, Germany)
Periograf (Cooke-Waite Laboratories, USA)
PermaOS (Mathys, Switzerland)
PurAtite (PremierBiomaterials, Ireland)
Synatite (SBM, France)
Synthacer (KARL STORZ Recon, Germany)
Without trade name (Cam Bioceramics, Netherlands)
Without trade name (CaP Biomaterials, WI, USA)
HA embedded in NanoBone (Artoss, Germany)
silica gel
Continued
Table 4.2 Continued

HA/collagen Bioimplant (Connectbiopharm, Russia)

Bonject (Koken, Japan)
Collagraft (Zimmer and Collagen Corporation, USA)
CollapAn (Intermedapatite, Russia)
HAPCOL (Polystom, Russia)
LitAr (LitAr, Russia)
HA/sodium alginate Bialgin (Biomed, Russia)
HA/poly-L-Lactic acid SuperFIXSORB30 (Takiron, Japan)
HA/polyethylene HAPEX (Gyrus, TN, USA)
HA/CaSO4 Hapset (LifeCore, MIN, USA)
PerOssal (aap Implantate, Germany)
Coralline HA Interpore (Interpore, CA, USA)
ProOsteon (Interpore, CA, USA)
Algae-derived HA Algipore (Dentsply Friadent, Germany)
Bovine bone apatite Bio-Oss (Geitslich, Switzerland)
(unsintered)
Laddec (Ost-Developpement, France)
Lubboc (Ost-Developpement, France)
Oxbone (Bioland biomateriaux, France)
Tutoplast (Tutogen Medical, Germany)
Bovine bone apatite BonAP (unknown producer)
(sintered)
Cerabone (aap Implantate, Germany)
Endobon (Merck, Germany)
Navigraft (Zimmer Dental, USA)
Osteograf (Ceramed, CO, USA)
PepGen P-15 (Dentsply Friadent, Germany)
Pyrost (Osteo AG, Germany)
Hyman bone allograft maxgraft (botiss, Germany)
Osnatal (aap Implantate, Germany)
Equine BioGen (unknown producer)
Table 4.2 Continued

a-tricalcium phosphate BioBase (Zimmer, IN, USA)

(TCP)
Without trade name (PremierBiomaterials, Ireland)
b-TCP adboneTCP (Medbone Medical Devices, Portugal)
Antartik TCP (MedicalBiomat, France)
Augment Bone Graft (BioMimetic Therapeutics, TN, USA)
BioGraft (IFGL BIO CERAMICS, India)
Bioresorb (Sybron Implant Solutions, Germany)
Biosorb (SBM S.A., France)
Bi-Ostetic (Berkeley Advanced Biomaterials, CA, USA)
Calc-i-oss classic (Degradable Solutions, Switzerland)
Calciresorb (Ceraver, France)
CELLPLEX (Wright Medical Technology, TN, USA)
Cerasorb (Curasan, Germany)
Ceros (Thommen Medical, Switzerland)
ChronOS (Synthes, PA, USA)
Conduit (DePuy Spine, USA)
GenerOs (Berkeley Advanced Biomaterials, CA, USA)
HT BIOCER (CHEMAeELEKTROMET, Poland)
JAX (Smith and Nephew Orthopedics, USA)
Osferion (Olympus Terumo Biomaterials, Japan)
OsSatura TCP (Integra Orthobiologics, CA, USA)
PORESORB-TCP (Lasak, Czech Republic)
SynthoGraft (Bicon, MA, USA)
Synthos (unknown producer)
Syntricer (KARL STORZ Recon, Germany)
Vitoss (Orthovita, PA, USA)
Without trade name (Shanghai Bio-lu Biomaterials, China)
b-TCP/collagen Integra Mozaik (Integra Orthobiologics, CA, USA)
Continued
Table 4.2 Continued

Biphasic Calcium 4Bone (MIS, Israel)

Phosphate (BCP)
adboneBCP (Medbone Medical Devices, Portugal)
(HA þ b-TCP)
Antartik Genta (MedicalBiomat, France)
Artosal (aap Implantate, Germany)
BCP BiCalPhos (Medtronic, MN, USA)
BioGraft (IFGL BIO CERAMICS, India)
Biosel (Depuy Bioland, France)
BonaGraft (Biotech One, Taiwan)
BoneCeramic (Straumann, Switzerland)
BoneSave (Stryker Orthopedics, NJ, USA)
Calcicoat (Zimmer, IN, USA)
Calciresorb (Ceraver, France)
Calc-i-oss crystal (Degradable Solutions, Switzerland)
CellCeram (Scaffdex, Finland)
Ceraform (Teknimed, France)
Ceratite (NGK Spark Plug, Japan)
CuriOs (Progentix Orthobiology BV, Netherlands)
Eurocer (FH Orthopedics, France)
GenPhos HA TCP (Baumer, Brazil)
Graftys BCP (Graftys, France)
Hatric (Arthrex, Naples, FL, USA)
Hydros (Biomatlante, France)
Indost (Polystom, Russia)
Kainos (Signus, Germany)
MasterGraft Granules (Medtronic Sofamor Danek, TN, USA)
MBCP (Biomatlante, France)
OrthoCer HA TCP (Baumer, Brazil)
OpteMX (Exactech, FL, USA)
OsSatura BCP (Integra Orthobiologics, CA, USA)
ossceram nano (bredent medical, Germany)
Osteosynt (Einco, Brazil)
Table 4.2 Continued

Ostilit (Stryker Orthopedics, NJ, USA)

ReproBone (Ceramisys, UK)
SBS (Expanscience, France)
Scaffdex (Scaffdex Oy, Finland)
TCH (Kasios, France)
Triosite (Zimmer, IN, USA)
Tribone (Stryker, Europe)
BCP (HA þ a-TCP) Skelite (Millennium Biologix, ON, Canada)
BCP (HA þ b-TCP)/ Allograft (Zimmer, IN, USA)
collagen
Collagraft (Zimmer, IN, USA)
BCP/fibrin TricOS (Baxter BioScience, France)
BCP/silicon FlexHA (Xomed, FL, USA)
Fluorapatite (FA) Without trade name (CaP Biomaterials, WI, USA)
FA þ BCP FtAP (Polystom, Russia)
(HA þ b-TCP)
Carbonate apatite Healos (Orquest, CA, USA)
SRS (Norian, CA, USA)
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Basics of Hydroxyapatitedstructure, Synthesis, Properties, and Clinical Applications

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Basics of Hydroxyapatitedstructure, Synthesis, Properties, and Clinical Applications

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Basics of

4.1 Biological apatite and synthetic hydroxyapatite:

Handbook of Ionic Substituted Hydroxyapatites. https://doi.org/10.1016/B978-0-08-102834-6.00004-5

4.1.1 Wet-chemical methods

400 500 600 700 800 900 1000 1100 1200

Table 4.1 List of methods of synthesis with references.

No. Synthesis method References

1 Solegel Hench, 1997; Hench and West, 1990; Niederberger,

Table 4.1 Continued

4.1.1.3 Emulsion technology

4.1.1.4 Batch hydrothermal synthesis

to closed container. Well-deﬁned, crystalline and phase pure HA could be obtained by

4.1.1.5 Continuous hydrothermal ﬂow synthesis

4.1.2 Solid-state methods

4.1.3 Hydroxyapatite coatings

4.1.3.1 Plasma-sprayed coatings

4.1.3.2 Electrophoretic deposition

4.1.3.3 Thin ﬁlm coatings

4.1.3.4 Biomimetic apatite coatings

4.2 Properties of hydroxyapatite

4.2.2 Physical and thermal properties

4.2.3 Mechanical properties

4.2.4 Biological performance

are considered as promising successful implantation. Therefore, the evaluation of any

4.2.4.2 In vivo (animal model)

formation even in the presence of osteogenin. Thus, nonresorbable HA replicas and

4.2.4.3 Clinical trials

4.2.5 Applications of hydroxyapatite

4.2.5.1 Hydroxyapatite as a drug carrier

4.2.5.3 Commercial products

Calcium phosphate Trade name and producer (when available)

Hydroxyapatite (HA) BoneSource (Stryker Orthopedics, NJ, USA)

Table 4.2 Continued

HA/collagen Bioimplant (Connectbiopharm, Russia)

Table 4.2 Continued

a-tricalcium phosphate BioBase (Zimmer, IN, USA)

Table 4.2 Continued

Biphasic Calcium 4Bone (MIS, Israel)

Table 4.2 Continued

Ostilit (Stryker Orthopedics, NJ, USA)

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