Materials Synthesis Methods (Sadat-Shojai2013)

ACTBIO 2680 No.
of Pages 31, Model 5G

23 April 2013
Acta Biomaterialia xxx (2013) xxx–xxx

1
Contents lists available at SciVerse ScienceDirect
Acta Biomaterialia
journal homepage: www.elsevier.com/locate/actabiomat
2 Review
5
4 Synthesis methods for nanosized hydroxyapatite in diverse structures
6
7 Mehdi Sadat-Shojai ⇑, Mohammad-Taghi Khorasani, Ehsan Dinpanah-Khoshdargi, Ahmad Jamshidi

8 Iran Polymer and Petrochemical Institute (IPPI), P.O. Box 14965/115 Tehran, Iran
9
10
a r t i c l e i n f o a b s t r a c t
1 5
2 2
13 Article history: Hydroxyapatite (HAp) is the major mineral constituent of vertebrate bones and teeth. It has been well 26
14 Received 12 November 2012 documented that HAp nanoparticles can significantly increase the biocompatibility and bioactivity of 27
15 Received in revised form 2 April 2013 man-made biomaterials. Over the past decade, HAp nanoparticles have therefore increasingly been in 28
16 Accepted 4 April 2013
demand, and extensive efforts have been devoted to develop many synthetic routes, involving both sci- 29
17 Available online xxxx
entifically and economically new features. Several investigations have also been made to determine how 30
critical properties of HAp can be effectively controlled by varying the processing parameters. With such a 31
18 Keywords:
wide variety of methods for the preparation of HAp nanoparticles, choosing a specific procedure to syn- 32
19 Hydroxyapatite
20 Calcium phosphate
thesize a well-defined powder can be laborious; accordingly, in the present review, we have summarized 33
21 Nanoparticles all the available information on the preparation methodologies of HAp, and highlighted the inherent 34
22 Bioceramics advantages and disadvantages involved in each method. This article is focused on nanosized HAp, 35
23 Bone although recent articles on microsized particles, especially those assembled from nanoparticles and/or 36
24 nanocrystals, have also been reviewed for comparison. We have also provided several scientific figures 37
and discussed a number of critical issues and challenges which require further research and 38
development. 39
Ó 2013 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved. 40
41
42
43 1. Introduction carbonated apatite forms on its surfaces and contributes to the 66
bonding of the implant to the living bone, resulting in earlier im- 67
44 Calcium phosphate (CaP) salts are the major mineral constitu- plant stabilization and superior fixation of the implant to the sur- 68
45 ents of vertebrate bone and tooth [1–4]. As shown in Fig. 1, bone rounding tissues [15–18]. Furthermore, several studies have shown 69
46 and other calcified tissues can be considered as natural anisotropic that HAp or its derivatives can be exploited as a model compound 70
47 composites consisting of biominerals embedded in a protein ma- to study biomineralization in the human body [6,7,19–23]. Recent 71
48 trix, other organic materials and water [1,2]. The biomineral phase, studies have also shown that HAp particles inhibit the growth of 72
49 which is one or more types of calcium phosphates, comprises 65– many kinds of cancer cells [24,25]. Currently, HAp is commonly 73
50 70% of bone, water accounts for 5–8% and the organic phase, which the material of choice for various biomedical applications, e.g. as 74
51 is primarily in the form of collagen, accounts for the remaining por- a replacement for bony and periodontal defects [26,27], alveolar 75
52 tion [1–3,5]. The collagen, which gives the bone its elastic resis- ridge [28], middle ear implants [29], tissue engineering systems 76
53 tance, acts as a matrix for the deposition and growth of minerals [30,31], drug delivery agent [32], dental materials [33] and 77
54 [1,2,6,7]. Among the CaP salts, hydroxyapatite (Ca10(PO4)6(OH)2, bioactive coating on metallic osseous implants [34]. The general 78
55 HAp), as a thermodynamically most stable crystalline phase of importance of HAp and its derivatives has also led to numerous 79
56 CaP in body fluid, possesses the most similarity to the mineral part non-medical industrial and technological applications, e.g. as a cat- 80
57 of bone [2,3]. In fact, naturally occurring CaP is usually carbonated alyst for chemical reactions such as the Michael-type addition and 81
58 and calcium-deficient HAp with a Ca/P ratio of less than 1.67 [4,8]. methane oxidation [35,36], host materials for lasers [37], fluores- 82
59 For decades, synthetic HAp has been of interest owing to its excel- cence materials [38], ion conductors [39] and gas sensors [40]. Syn- 83
60 lent biocompatibility [9,10], affinity to biopolymers [11,12] and thetic HAp may also be used in column chromatography for simple 84
61 high osteogenic potential [13,14]. It has been well documented and rapid fractionation of proteins and nucleic acids [41,42]. More- 85
62 that HAp can promote new bone ingrowth through osteoconduc- over, it has been demonstrated that HAp presents very convenient 86
63 tion mechanism without causing any local or systemic toxicity, qualities for water treatment processes [43] and remediation of 87
64 inflammation or foreign body response [13,15–17]. When a HAp- heavy metal contaminated soils [44]. 88
65 based ceramic is implanted, a fibrous tissue-free layer containing Among the various HAp structures, nanosized HAp, also known 89
as HAp nanoparticles, with appropriate stoichiometry, morphology 90
and purity, have stimulated great interest in basic scientific re- 91
⇑ Corresponding author. Tel.: +98 21 44580000; fax: +98 21 44580023.
search and various biomedical applications [45]. Nanosized HAp, 92
E-mail address: MSadatShojai@gmail.com (M. Sadat-Shojai).
1742-7061/$ - see front matter Ó 2013 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.actbio.2013.04.012
Please cite this article in press as: Sadat-Shojai M et al. Synthesis methods for nanosized hydroxyapatite in diverse structures. Acta Biomater (2013),
ACTBIO 2680 No. of Pages 31, Model 5G
23 April 2013
2 M. Sadat-Shojai et al. / Acta Biomaterialia xxx (2013) xxx–xxx
Fig. 1. The hierarchical structure of typical bone at various length scales. The microstructure of cortical or compact bone consists of Haversian systems (circles in cross-
section and microscopic view) with osteonic canals and lamellae, and at the nanoscale, the structural framework is collagen fibers composed of bundles of mineralized
collagen fibrils.
93 which has a grain size less than 100 nm in at least one direction, figure was only 28, indicating increasing interest in HAp fabrica- 136
94 has high surface activity and an ultrafine structure, similar to the tion over the last decade. Despite this interest, the preparation of Q1 137
95 mineral found in hard tissues [8]. It is well known that bioceramics bone-like HAp or HAp having specific characteristics still remains 138
96 that mimic the bone mineral in composition and structure can an interesting challenge, especially due to the possibility of forma- 139
97 more readily promote osteointegration and subsequent bone tissue tion of intermediary products. Table 1 shows the most important 140
98 formation. Indeed, as the biological HAps found in physiological CaP salts, which usually appear as phase impurities during synthe- 141
99 hard tissues are nanoscopic plate-like or rod-like crystals that are sis of HAp particles [8,59–62]. To improve phase composition of 142
100 a few nanometers in thickness and tens of nanometers in length, HAp, it is therefore important to develop new methods possessing 143
101 it is believed that nanosized HAp paralleling natural bone minerals precise control over the crystallographic and chemical structure of 144
102 is the best material to use for bone replacement and regeneration powder. In addition to the phase impurities, preparation of nano- 145
103 [8,46]. Studies have shown that ceramic biomaterials based on sized HAp is also connected with a number of additional problems, 146
104 nanosized HAp exhibit enhanced resorbability [47,48] and much including difficulties in controlling geometry, size and size distri- 147
105 higher bioactivity [46,49] than micron-sized ceramics. Release of bution, crystallinity, stoichiometry and degree of particle agglom- 148
106 calcium ions from nanosized HAp is also similar to that from bio- eration. It is well known that in vitro and in vivo biological and 149
107 logical apatite and significantly faster than that from coarser crys- mechanical properties of HAp are strongly affected by its structural 150
108 tals. In addition, new models for nanoscale enamel and bone characteristics; hence, extensive efforts have been made to pre- 151
109 demineralization suggest that demineralization reactions may be cisely engineer the HAp crystals, in particular, by developing new 152
110 inhibited when particle sizes fall into certain critical nanoscale lev- routes or modifications of pre-existing methods. As control over 153
111 els [50]. Moreover, nanoscale HAp shows improved densification the microstructure of HAp matures, demand for a comprehensive 154
112 [51,52] and sinterability [52–54] due to its high surface energy review of reported procedures also increases: this is the main 155
113 and, therefore, problems associated with high-temperature sinter- motivation for the current paper. 156
114 ing, especially formation of microcracks, can be avoided. Some A number of authors have already reviewed the literature on 157
115 studies have also reported that nanosized HAp possesses a signifi- various aspects of HAp. For example, Doremus [63] published a re- 158
116 cant capability of decreasing apoptotic cell death and hence view on processing and mechanical properties of bioceramics. 159
117 improving cell proliferation and cellular activity related to bone Orlovskii et al. [64] published an early review of three methods 160
118 growth [46,55]. The improved cell proliferation and differentiation
119 may be due to superior surface functional properties of nanosized
120 HAp compared to its microphase counterpart; indeed nanosized
121 HAp has higher surface area and surface roughness, resulting in
122 better cell adhesion and cell–matrix interactions [46,47,56]. There-
123 fore, in recent years, bioceramics and biocomposites based on
124 nanosized HAp have been the most promising materials for a vari-
125 ety of biomedical applications [8,47,57,58].
126 Over the past decade, a number of synthetic routes for produc-
127 ing HAp powders have been developed [45]. To roughly reflect the
128 current interest in HAp synthesis and compare it with the past, we
129 searched the Scopus database for studies reporting the preparation
130 of HAp particles. Criteria for inclusion were English-language arti-
131 cles, peer-reviewed original publications addressing at least one
132 method for synthesis of HAp, and publication year between 1999
133 and 2011. Fig. 2 shows the results by year of publication. According
134 to the figure, around 67, 65 and 75 articles were published in 2009, Fig. 2. Annual number of articles on HAp preparation indexed in Scopus over the
135 2010 and 2011, respectively, whereas in 1999 the corresponding 1999–2011 period.
23 April 2013
M. Sadat-Shojai et al. / Acta Biomaterialia xxx (2013) xxx–xxx 3
Table 1
Main calcium phosphate (CaP) salts.
Name Symbol(s) Formula Ca/P

Monocalcium phosphate monohydrate (MCPM) and (MCPH) Ca(H2PO4)2H2O 0.5
Monocalcium phosphate anhydrous (MCPA) and (MCP) Ca(H2PO4)2 0.5
Dicalcium phosphate dehydrate (Brushite) (DCPD) CaHPO42H2O 1.0
Dicalcium phosphate anhydrous (Monetite) (DCPA) and (DCP) CaHPO4 1.0
Octacalcium phosphate (OCP) Ca8(HPO4)2(PO4)45H2O 1.33
a-Tricalcium phosphate (a-TCP) Ca3(PO4)2 1.5
b-Tricalcium phosphate (b-TCP) Ca3(PO4)2 1.5
Amorphous calcium phosphate (ACP) Cax(PO4)ynH2O 1.2–2.2
Hydroxyapatite (HA) and (HAp) Ca10(PO4)6(OH)2 1.67
161 of HAp synthesis: chemical precipitation, solid-state synthesis and such a great variety, choosing a specific route to synthesize a 211
162 the hydrothermal method. Ferraz et al. [65], Norton et al. [66], and well-defined powder for a specific application can be laborious; 212
163 Murugan and Ramakrishna [67] have separately reviewed some of accordingly, in the present review, we have classified the prepara- 213
164 the articles on HAp preparation, mainly those employing wet tion methods into five groups: dry methods (with two subgroups); 214
165 chemical procedures. Nancollas and Wang [68] discussed some wet methods (with six subgroups); high-temperature processes 215
166 important parameters related to crystal nucleation and the (with two subgroups); synthesis methods based on biogenic 216
167 growth/dissolution of various CaP phases. More recently, Dorozh- sources; and combination procedures. Table 2 summarizes this 217
168 kin [49] and also Zhou and Lee [69] reviewed the preparation of classification, together with the strong and weak points of these 218
169 HAp and its application to various biomaterials. Although all of methods. In recent years, along with the rapid development of dif- 219
170 these reviews dealt with HAp or other calcium phosphates, but ferent routes of preparing HAp, there has been a great emphasis on 220
171 they were not directed specifically to the topic of the preparation scaling up the suggested procedures; therefore, an individual col- 221
172 methodologies of HAp. Moreover, most of them concentrated more umn of Table 2 is devoted to the comparative cost of each method. 222
173 on the properties, characterization, application and/or surface By making a comparison of diverse methods, similar to that pre- 223
174 modification of HAp particles than their synthesis. In addition, sented in Table 2, one is able to choose a specific and cost-effective 224
175 we have recently written a book (in Persian), entitled Hydroxyapa- route to regulate the critical properties of the synthetic HAp. 225
176 tite: Inorganic Nanoparticles of Bone [45], which gives scientific and We also searched for the total number of indexed papers relat- 226
177 practical features of the synthesis, characterization and application ing to each method. The statistical study is presented in Fig. 3. The 227
178 of HAp nanoparticles, but still does not exclusively focus on the figure clearly indicates that around 25% of the total 650 papers in- 228
179 methods of HAp fabrication reported in the last decade. dexed over the period of 1999–2011 are solely connected to the 229
180 In view of the growing interest in the manufacture of HAp, and conventional chemical precipitation method. Following chemical 230
181 the increasing need for classification of many new preparation precipitation, combination methods and the hydrothermal process 231
182 methods, this review article is devoted to the procedures of prepar- are the next most well-known methods of preparing HAp, account- 232
183 ing HAp particles reported in recent years (1999–2011), and espe- ing for 16 and 14% of papers, respectively. The statistical survey 233
184 cially focuses on a challenging question: how does one choose a also revealed that the solid-state method has received the least 234
185 specific and cost-effective route from the huge number of methods attention in the literature, probably because of its inherent limita- 235
186 available to regulate the critical characteristics of HAp? To address tions in synthesizing nanosized particles and its lack of clear con- 236
187 this question, the article collates all the available information on trol over the microstructural characteristics of the powder. 237
188 the preparation methodologies of HAp particles and shows how As previously mentioned, the critical characteristics of HAp par- 238
189 the wide variety of new preparation methods can be effectively ticles, such as strength, toxicity to cells, osseointegrativity and 239
190 classified into a few groups. The emphasis of this article will be bioresorbability, depend strongly upon their microstructure – 240
191 on nanosized particles, although recent articles on microsized par- mainly their morphology, stoichiometry, crystallographic structure 241
192 ticles, especially those assembled from nanoparticles and/or nano- and phase purity. However, when one considers the nano- or 242
193 crystals, are also reviewed for comparison. HAp particles are very micropowder, the morphology and dimensions of particles seem 243
194 prone to various ion substitutions; thus a large number of articles to be highlighted more than other characteristics [46,55,70]. In- 244
195 on the preparation of partially ion-substituted HAp, especially car- deed, a major challenge in the synthesis of crystalline powders is 245
196 bonated HAp and fluoridated HAp, are included in this review. always the precise control of crystal growth, which directly relates 246
197 However, those techniques creating highly chemically modified to the size and geometric shape of the final particles. In particular, 247
198 apatites – especially biomimetic methods based on simulated body for HAp crystals, it has been demonstrated that their microscopic 248
199 fluid – are not the focus of this paper. As mentioned before, this is shape, size and size distribution can significantly affect their 249
200 not the first literature review on HAp, but to the best of our knowl- mechanical properties, processing conditions, surface chemistry, 250
201 edge, it is the first critical review which focuses on the many new biocompatibility and bioactivity [46,55,70–73]. So, by controlling 251
202 methods of preparing HAp, provides several figures for these prep- the crystal and/or particle shape, the potential applications of 252
203 aration methods, and systematically compares the inherent advan- nanoparticles can be expanded. For example, due to poor mechan- 253
204 tages and disadvantages of the synthesis procedures. ical reliability, HAp bioceramics having the conventional micro- 254
structure cannot be used for load-bearing orthopedic and dental 255
applications [66,74,75]. It has been demonstrated that the mechan- 256
205 2. Preparation methods of HAp ical properties can be significantly improved by fabricating HAp 257
particles of complex shapes [8,69,76]. Therefore, it is of great 258
206 During the past decade, many diverse methods have claimed to importance to develop new synthesis procedures having precise 259
207 prepare HAp nanoparticles with precise control over its micro- control over the crystal geometry. According to the literature, 260
208 structure. These methods involve various types of known chemical shape-tailored HAp can be synthesized through the anisotropic 261
209 synthesis routes. In each method, processing conditions can be var- growth of crystal faces induced by organic additives and/or selec- 262
210 ied across a wide range, resulting in several submethods. With tive operating conditions. In this strategy, initial nucleation first 263
23 April 2013
occurs upon mixing the reactants, and anisotropic growth is 264

then gained by either the face-selective adsorption of additives 265
or a change in the crystallization pathway to, for example, in- 266
duce Ostwald ripening. Over the past decade, many researchers 267
[239–289]
[315–324]
[325–337]
[338–345]
[346–387]
[388–454]
[194–209]
[210–238]
[290–314]
[98–193]
[78–82]
[83–97]
have tried to fabricate nanometer HAp with one-, two- or three- 268
dimensional geometric shapes. In Table 3, the literature was 269
Ref.
scanned for HAp particles having different shapes and dimen- 270
sions. According to the table, the variety of methods by which
distribution
271
irregular, rod-like or spherical morphologies can be synthesized 272
variable
variable
variable
variable
variable
narrow
narrow
narrow
usually
usually
usually
is much greater than for others. However, as indicated in the
wide
wide
wide
wide
273
Size
third column of the table, complex shapes are normally con- 274
structed from nanoparticles of a simple shape. Furthermore, in 275
almost all cases the dimensions of particles can vary across a 276
nano particles embedded in

very wide range. 277
From Table 3, it can also be seen that there is a discrepancy 278
in the nomenclature of geometric shapes in the literature. The 279
micron aggregates
ambiguity in nomenclature becomes especially serious when 280
nano or micron
usually micron
one synthesizes an elongated shape (i.e. the geometry indicated 281

usually nano
usually nano
usually nano
in the fourth row of the table). Some authors have suggested 282
variable
variable
that elongated shapes should be named according to their axial 283

nano
nano
nano
nano
Size
dimensions, i.e. their aspect ratio [77]. For example, a fiber has a 284
higher aspect ratio than a needle and a much greater ratio than 285
non-stoichiometric
non-stoichiometric
a rod. Although this nomenclature scheme is somewhat arbi- 286

trary, it is important that authors clearly define the meaning 287
stoichiometric
stoichiometric
stoichiometric
stoichiometric
stoichiometric
stoichiometric
usually non-
of the terms used in any morphological descriptions. 288

Ca/P ratio
variable
variable
variable
variable
usually
usually
2.1. Dry methods 289
Dry methods do not use a solvent, unlike wet methods. 290

variable
variable
variable
variable
usually
usually
usually
usually
usually
usually
usually
According to the literature, the characteristics of a powder syn-

purity
291
Phase
high
high
high
high
high
high
low
low
thesized by a dry method are not strongly influenced by the 292

processing parameters, hence most dry methods do not require 293
frequently high
frequently low
frequently low
precisely controlled conditions, making them suitable for mass 294

(usually low)
Crystallinity
production of powders. A number of researchers have therefore 295

very high
very high
very high
variable
variable
variable
variable
variable
adapted well-known dry methods, including solid-state synthe- 296

degree
high
sis and the mechanochemical process, for the preparation of 297

HAp particles.
Characteristics of powder
298
frequently needle-like
frequently needle-like
diverse (frequently
2.1.1. Solid-state synthesis 299

diverse (usually
diverse (usually
Solid-state reaction, as a relatively simple procedure, can be 300

Morphology
employed in the mass production of HAp powder [78–81]. Sup-

needle-like)
needle-like)
301
irregular)
plementary Table S1 shows recent progress in the synthesis of 302

diverse
diverse
diverse
diverse
diverse
diverse
diverse
HAp powder using the solid-state method. In a typical proce- 303

dure, precursors are first milled and then calcined at a very high 304
temperature (e.g. 1000 °C) [78]. The precursors can be calcium- 305
Comparison of different methods for the preparation of HAp nanoparticles.
variable
variable
usually
usually
usually
usually
usually
usually
and phosphate-containing chemicals of various types or simply 306

high
high
high
Cost
low
low
low
low
low
low
low
a previously prepared CaP salt. The high temperature of calcina- 307

Processing aspects
tion leads to the formation of a well-crystallized structure. The 308

frequently few
general process is shown in Fig. 4. As a disadvantage, the pow- 309

Number of
der synthesized by a solid-state reaction often exhibits hetero- 310

chemicals
variable
variable
variable
variable
geneity in its phase composition, owing to the small diffusion 311

many
coefficients of ions within the solid phase [79,80]. Recently, Pra-

few
few
few
few
few
few
312
manik et al. [78] claimed to have synthesized HAp particles 313
Chemical precipitation
with a single phase, using powder mixing and cold pressing.

Hydrothermal method
314
Sonochemical Method
Combustion method
For this, samples were prepared by mixing the ingredients, fol-

Solid-state method
Hydrolysis method
315
Mechanochemical
Pyrolysis method
biogenic sources
lowed by sintering the cold-compacted pellets at various tem-

Sol–gel method
316
Synthesis from
Combination
peratures up to 1250 °C. However, this powder was irregular 317

procedures
Emulsion
in shape, with micron-sized grains. Some attempts have also 318

method
been made to achieve a powder with a regular shape or a nano- 319

sized structure, or both. For example, Tas [81] used a modified 320
solid-state reaction called ‘‘molten salt synthesis’’ (MSS) to pre- 321
Wet methods
pare one-dimensional (1-D) HAp. The MSS technique is based 322

Dry methods
processes
High Temp.
on the use of low-melting fluxing agents, e.g. alkali chlorides, 323

Method
sulfates, carbonates or hydroxides, as the medium for the reac- 324

Table 2
tion. In this study, a previously synthesized submicron HAp 325

powder was exploited as the starting material and the effects 326
23 April 2013
the solid-state process unattractive, both scientifically and techno- 374

logically, for the fabrication of HAp particles. 375
2.1.2. The mechanochemical method 376

The mechanochemical process, sometimes known as mechani- 377
cal alloying, is a simple dry method for fabrication various advanced 378
materials, such as nanocrystalline alloys and ceramics [83,84]. Con- 379
trary to the solid-state method by which heterogeneous particles 380
with irregular shape are usually produced, powder synthesized 381
using a mechanochemical route usually possesses a well-defined 382
structure. This is due to the perturbation of surface-bonded species 383
as a result of pressure, enhancing the thermodynamic and kinetic 384
reactions between solids [85–89]. Indeed, the mechanochemical 385
process has the advantages of simplicity and reproducibility of a so- 386
lid-state procedure to perform mass production and the basic char- 387
acteristics of an ordinary wet reaction to generate a powder with an 388
Fig. 3. Total number of articles indexed in Scopus over 1999–2011 by the method
of preparation.
acceptable microstructure. As shown in Fig. 5, in a typical process, 389
the materials are ground on a planetary mill while the molar ratio 390
between the reagents is kept at the stoichiometric ratio [90,91]. 391
327 of a specifically chosen alkali salt on the particles’ morphology, The main processing variables include the type of reagents, the type 392
328 temperature/time of synthesis and salt to HAp ratio were investi- of milling medium, the type and diameter of the milling balls, the 393
329 gated. Tas’s results showed that MSS with K2SO4 flux is a simple type of atmosphere, the duration of the milling steps and interval 394
330 and sturdy technique to fabricate short HAp whiskers in the tem- pauses, the powder-to-ball mass ratio and the rotational speed 395
331 perature range of 1080–1200 °C. The study also revealed that other [88,90,92–96]. Supplementary Table S2 presents recent progress 396
332 fluxing agents, such as KCl and KBr, produced large single crystals in the mechanochemical synthesis of HAp powder. Some of relevant 397
333 of HAp, rather than whiskers. However, all the samples were re- (simplified) reactions involved are as follows: 398
399
334 ported to have a grain size much larger than 1 lm. Recently, Tseng
6CaHPO4 2H2 O þ 4CaO ! Ca10 ðPO4 Þ6 ðOHÞ2 þ 14H2 O ð1Þ
335 et al. [82] synthesized HAp nanoparticles through a polyethylene
336 glycol (PEG)-assisted reaction, using calcination of calcium dihy- 10CaCO3 þ 6ðNH4 ÞH2 PO4 ! Ca10 ðPO4 Þ6 ðOHÞ2 þ 8H2 O þ 10CO2 þ 6NH3 ð2Þ
337 drogenphosphate (MCPM; see Table 1) and calcium hydroxide 3Ca3 ðPO4 Þ2 xH2 O þ CaðOHÞ2 ! Ca10 ðPO4 Þ6 ðOHÞ2 þ xH2 O ð3Þ
338 (Ca(OH)2) at 900 °C in an oxygen atmosphere. They claimed that 10CaðOHÞ2 þ 3P2 O5 ! Ca10 ðPO4 Þ6 ðOHÞ2 þ 9H2 O ð4Þ
339 the process yields a well-crystallized and non-aggregated powder 9CaO þ CaðOHÞ2 þ 3P2 O5 ! Ca10 ðPO4 Þ6 ðOHÞ2 ð5Þ
340 with a nanometer particle size. According to their results, PEG 6CaHPO4 2H2 O þ 3CaO ! Ca9 ðHPO4 ÞðPO4 Þ5 OH þ 14H2 O ð6Þ 401
341 can control the particle size, crystal phase and degree of aggrega-
Recently, Nasiri-Tabrizi et al. [86] synthesized single-crystal 402
342 tion, and also decrease the particle size distribution from 80–
HAp nanorods and nanogranules via a mechanochemical process 403
343 150 nm to 50–80 nm (as determined by scanning electron micros-
in polyamide 6 milling medium. They used two distinct experi- 404
344 copy (SEM)). Indeed, HAp(PEG) was well dispersed, while the
mental procedures, according to the following reactions: 405
345 HAp(non) was seriously aggregated into a single flat piece. Analysis 406
346 of secondary particle sizes using dynamic light scattering (DLS) 6CaHPO4 þ 4CaðOHÞ2 ! Ca10 ðPO4 Þ6 ðOHÞ2 þ 6H2 O ð7Þ
347 showed that the diameter of HAp(PEG) secondary particles ranges 4CaCO3 þ 6CaHPO4 ! Ca10 ðPO4 Þ6 ðOHÞ2 þ 2H2 O þ 4CO2 ð8Þ 408
348 from 150 to 600 nm and that of HAp(non) ranges from 35 to
349 36 lm, indicating that HAp(PEG) was much less aggregated than They reported that the average size of particles determined 409
350 HAp(non). The results also suggested that the energy required for from transmission electron microscopy (TEM) observations was 410
351 formation of HAp nanoparticles in the HAp(PEG) system should about 13 ± 7 and 15 ± 8 nm for reactions (7) and (8), respectively. 411
352 be greater than that required for HAp(non), because the crystalliza- Their results indicated that increasing the milling time leads to 412
353 tion of HAp will proceed after the decomposition of PEG–Ca–P an increase in lattice strain and a decrease in crystallite size. 413
354 complex in the former system. This effectively delays the phase According to the results, the degree of crystallinity of the product 414
355 transition from pure HAp to tricalcium phosphate (TCP). in reaction (7) is higher than that in reaction (8). Moreover, the 415
356 Regardless of these efforts, and as mentioned before, a solid- trend of decreasing crystallinity was found to be related to increas- 416
357 state method usually suffers from the small diffusion of ions during ing milling time. Finally, they concluded that the use of polymeric 417
358 the reaction; this is an inherent characteristic, and is why very lit- milling medium in the mechanochemical process is an effective 418
359 tle work is available on solid-state processing of HAp. To improve way to prepare nanosized HAp particles. In another study, Fathi 419
360 the kinetic performance, some researchers have used an alterna- and Zahrani [97] synthesized fluoridated hydroxyapatite (FHAp) 420
361 tive approach, known as the mechanochemical method, for the nanopowder with different degrees of fluoridation via mechanical 421
362 preparation of HAp powder in a dry manner (see the following sec- alloying. For this, they mechanically milled a mixture of calcium 422
363 tion). Although the solid-state process, due to its simplicity and hydroxide, phosphorous pentoxide and calcium fluoride powders 423
364 low cost, is commonly the method of choice for commercial pro- for 6 h at 300 rpm using eight balls of 20 mm diameter and a pow- 424
365 duction of various powders, if one considers the mass production der-to-ball mass ratio of 1:35. According to their results, a single- 425
366 of a biomedical material, such as HAp, for use in drug delivery phase FHAp having some carbonated groups and a particle size dis- 426
367 and cell scaffolds for tissue engineering, a precise control over tribution of 35–65 nm (as determined by TEM) could be prepared 427
368 the characteristics of product becomes much more important than after 6 h of mechanical alloying. 428
369 financial considerations. On the other hand, current interest in the
370 synthesis of artificial HAp is to mimic in vivo biomineralization, 2.2. Wet methods 429
371 where the HAp phase is biologically generated with the aid of body
372 fluids. Therefore, the solid-state method definitely cannot be As mentioned before, HAp powder generated from a typical dry 430
373 exploited for a biomimetic synthesis. All of these reasons make method is usually large in size and irregular in shape. Therefore, 431
23 April 2013
Table 3
Various HAp nanostructures with modulated shapes.
Shape Name(s) in literature Approx. size range Method(s) of

synthesis*
irregular, formless, sphere 5 nm–200 lm ss, mch, cc, hl, sg,
hth, em, sch, ht,
bs, cp
sphere, microsphere, nanosphere, ball 10 nm–1000 lm mch, cc, sg, hth,

em, sch, ht, bs, cp
rod, needle, tube, filament, fiber, wire, whisker, prism, worm, hexagonal length: 10 nm–150 lm, diameter: 3 nm–50 lm, ss, mch, cc, hl, sg,
prism, platelet, lath, strip aspect ratio: 2–1200 hth, em, sch, ht,
bs, cp
plate, flake, sheet length: 40 nm–50 lm, width: 20 nm–35 lm, cc, hth, bs, cp
thickness: 5 nm–3 lm
self-assembled nanorods, bundles of nanorods, oriented bundle, length: 200 nm–80 lm, width: 100 nm–50 lm cc, hl, hth, bs, cp
oriented raft, enamel prism-like structures, clusters of nanotubes, (organized nanorods of 10 nm–13 lm diameter and
oriented array of bundled needles, packed nanorods 200 nm–75 lm length)
dandelion, chrysanthemum, flower, feathery structure, bundle of fibers, 1–8 lm (organized nanorods of 80–500 nm hth, em, bs, cp
self-assembled nanorods, rosette diameter and 600 nm–5 lm length)
leaf, flake, sheet, plate 800 nm–10 lm (organized nanoplates of 20– cc, hl, cp
100 nm thickness)
flower 700 nm–60 lm (organized petals of 20 nm–10 lm cc, hth, bs

width and 180 nm–50 lm length)
porous microsphere, mesoporous sphere 0.5–7 lm (pores of 20–150 nm) hth, cp
bowknot, self-assembled nanorods 1.5–2.5 lm (organized nanorods of 100–150 nm cp

diameter and 1–2 lm length)
dumbbell 2–3 lm (organized nanoparticles of 50 nm size) cc
*
ss: solid-state synthesis, mch: mechanochemical method, cc: conventional chemical precipitation, hl: hydrolysis method, sg: sol–gel method, hth: hydrothermal method,
em: emulsion method, sch: sonochemical method, ht: high-temperature processes, bs: synthesis from biogenic sources, cp: combination procedures.
Fig. 4. Preparation of HAp powder via solid-state method.
23 April 2013
432 wet methods have conventionally been applied to the preparation gen phosphate asthe PO43 source. A typical procedure involves 483
433 of HAp particles having a nanosized structure with a regular mor- the dropwise addition of one reagent to another under continuous 484
434 phology. In addition, from a fundamental perspective aimed at and gentle stirring, while the molar ratio of elements (Ca/P) is kept 485
435 understanding the in vivo biomineralization process, the growth at stoichiometry according to its ratio in HAp (1.67) [114–119]. As 486
436 pathways of HAp crystals in solution have been the subject of the last step, the resultant suspension may be aged under atmo- 487
437 increasing interest over the past decade [19,98]. Wet chemical spheric pressure [99,115,119] or immediately washed, filtered, 488
438 reactions have advantages in their ability to control the morphol- dried and crushed into a powder [116,118]. Recently, Paz et al. 489
439 ogy and the mean size of powder, and, based on many experimen- [120] reported the use of supersaturated calcium solutions as a 490
440 tal data, they are the most promising techniques for the fabrication biomimetic process to prepare HAp nanoparticles. They showed 491
441 of nanosized HAp. The popularity of wet methods is also reflected that the morphology, crystallinity and size distribution of the 492
442 in Fig. 3, where a simple calculation reveals that wet methods ac- resulting nanoparticles are strongly dependent on the synthesis 493
443 counts for more than 60% of all articles. Indeed, wet processes are method and ripening time. For example, while normal chemical 494
444 usually easy to conduct and growth conditions can be directly con- precipitation resulted in nanoparticles with a needle-like morphol- 495
445 trolled by adjusting the reaction parameters. One of the main po- ogy of 23 nm in width and 62 nm in length, with a particle size 496
446 tential disadvantages, however, is the low preparation distribution of 27–118 nm (determined by TEM and a particle size 497
447 temperature compared to dry methods, resulting in the generation analyzer), biomimetic synthesis based on a supersaturated solu- 498
448 of CaP phases other than HAp (see Table 1) and/or the lowering of tion led to a spherical powder of 23 nm in size, with a narrower 499
449 the crystallinity of the resultant powder. In addition, various ions size distribution of 15–41 nm. 500
450 in aqueous solution can be incorporated into the crystal structure, A powder prepared by simple precipitation is, however, usually 501
451 leading to trace impurities. non-stoichiometric and poorly crystallized without any regular 502
452 Solution-based reactions, which are accomplished in an organic shape [121–123]. Many factors are claimed to cause these draw- 503
453 solvent or, more usually, in water, can be conducted at ambient backs, including the high chemical affinity of HAp to some ions, 504
454 temperature or elevated temperatures (lower than, close to or the complex nature of the CaP crystals, hydrogen-bonded interac- 505
455 higher than boiling point of the solvent). Moreover, reactions can tions among the HAp particles and the role of the kinetic parame- 506
456 be performed by a number of technical routes involving diverse ters, which, depending on the experimental conditions, prevail 507
457 chemicals and auxiliary additives and apparatus. The following over the thermodynamic parameters [59,124]. For example, the 508
458 simplified equations show some of the well-known chemical reac- non-stoichiometric feature may occur as a result of vacancies in 509
459 tions adopted for the wet synthesis of HAp: the crystal lattice [125,126], the substitution of diverse ions such 510
460
10CaðNO3 Þ2 þ 6ðNH4 Þ2 HPO4 þ 8NH4 OH ! Ca10 ðPO4 Þ6 ðOHÞ2 þ 20NH4 NO3 þ 6H2 O ð9Þ
as carbonate, potassium and chloride [59,127] or the presence of 511
10CaðNO3 Þ2 þ 6ðNH4 Þ3 PO4 þ 2H2 O ! Ca10 ðPO4 Þ6 ðOHÞ2 þ 18NH4 NO3 þ 2HNO3 ð10Þ additional phases [59,128], etc. Therefore, a precise control over 512
10CaðNO3 Þ2 þ 6KH2 PO4 þ 20NH4 OH ! Ca10 ðPO4 Þ6 ðOHÞ2 þ 6KOH þ 20NH4 NO3 þ 12H2 O ð11Þ the processing conditions is always advised for the preparation of 513
10CaðNO3 Þ2 þ 6H3 PO4 þ 20NH4 OH ! Ca10 ðPO4 Þ6 ðOHÞ2 þ 20NH4 NO3 þ 18H2 O ð12Þ a powder with minimal defects. Supplementary Table S3 presents 514
10CaðNO3 Þ2 þ 6ðNH4 Þ2 HPO4 þ 20NaOH ! Ca10 ðPO4 Þ6 ðOHÞ2 þ 20NaNO3 þ 12NH3 þ 18H2 O ð13Þ recent attempts to synthesize HAp using precipitation methods. 515
10CaðNO3 Þ2 þ 6ðNH4 Þ2 HPO4 þ 2H2 O ! Ca10 ðPO4 Þ6 ðOHÞ2 þ 12NH4 NO3 þ 8HNO3 ð14Þ
As the table indicates, the pH value and temperature employed 516
10CaðNO3 Þ2 þ 6Na2 HPO4 þ 2H2 O ! Ca10 ðPO4 Þ6 ðOHÞ2 þ 12NaNO3 þ 8HNO3 ð15Þ
10CaðNO3 Þ2 þ 6H3 PO4 þ 2NH4 OH ! Ca10 ðPO4 Þ6 ðOHÞ2 þ 2NH4 NO3 þ 18HNO3 ð16Þ during the precipitation reaction and/or the aging step are the 517
10CaðOHÞ2 þ 6ðNH4 Þ2 HPO4 ! Ca10 ðPO4 Þ6 ðOHÞ2 þ 12NH3 þ 18H2 O ð17Þ most challenging factors. Indeed, to obtain a single-crystal HAp 518
10CaðOHÞ2 þ 6H3 PO4 ! Ca10 ðPO4 Þ6 ðOHÞ2 þ 18H2 O ð18Þ with high phase purity, the precipitation reaction is usually con- 519
10CaCl2 þ 6ðNH4 Þ2 HPO4 þ 8NH4 OH ! Ca10 ðPO4 Þ6 ðOHÞ2 þ 20NH4 Cl þ 6H2 O ð19Þ ducted at a high pH or a high temperature, or both. Whenever 520
10CaCl2 þ 6K2 HPO4 þ 2H2 O ! Ca10 ðPO4 Þ6 ðOHÞ2 þ 12KCl þ 8HCl ð20Þ
the pH value must be lowered (e.g. to achieve a specific morphol- 521
10CaCO3 þ 6NH4 H2 PO4 þ 2H2 O ! Ca10 ðPO4 Þ6 ðOHÞ2 þ 3ðNH4 Þ2 CO3 þ 7H2 CO3 ð21Þ
10CaSO4 2H2 O þ 6ðNH4 Þ2 HPO4 ! Ca10 ðPO4 Þ6 ðOHÞ2 þ 6ðNH4 Þ2 SO4 þ 4H2 SO4 þ 18H2 O ð22Þ
ogy), the temperature should be raised and vice versa [104,129– 522
6CaSO4 2H2 O þ 4CaðOHÞ2 þ 6ðNH4 Þ2 HPO4 ! Ca10 ðPO4 Þ6 ðOHÞ2 þ 6ðNH4 Þ2 SO4 þ 18H2 O ð23Þ 134]. This leads to a dramatic decrease in the generation of phase 523
3CaðH2 PO4 Þ2 H2 O þ 7CaðOHÞ2 ! Ca10 ðPO4 Þ6 ðOHÞ2 þ 15H2 O ð24Þ impurities (e.g. dibasic calcium phosphate anhydrate (DCPA) and 524
Ca5 ðP3 O10 Þ2 þ 5Ca2þ þ 6H2 O ! Ca10 ðPO4 Þ6 ðOHÞ2 þ 10Hþ ð25Þ octacalcium phosphate (OCP)), resulting in HAp as a dominant 525
10 10 phase [104,113,133–135]. 526
462 Can C12 H222n O11 þ 6ðNH4 Þ2 HPO4 þ 2H2 O ! Ca10 ðPO4 Þ6 ðOHÞ2 þ 12NH3 þ Ca12 H22 O11 ð26Þ
n n
More recent approaches, according to Supplementary Table S3, 527
463 Each reaction can be exploited to create a specific method for propose alternative routes based on various additives and/or mod- 528
464 preparing HAp. In the following sections, we have classified these ification of the main procedure. A well-known example is based on 529
465 methods into six groups and have described the characteristics of the biomimetic templating systems, in which the characteristics of 530
466 the powder obtained from each. powder, especially morphology and crystallinity, can be controlled 531
at significantly lower temperatures and pHs. In this strategy, vari- 532
467 2.2.1. Conventional chemical precipitation ous macromolecules act as a soft temporary template or nucleation 533
468 Among the various wet processing methods, conventional centers to modulate the morphology and increase the crystallinity, 534
469 chemical precipitation is the simplest route for the synthesis of according to Fig. 7 [136–147]. Indeed, macromolecules adsorb on 535
470 nanosized HAp. The chemical precipitation is based on the fact the crystal surface and influence the crystal growth of seeds 536
471 that, at room temperature and pH 4.2, HAp is the least soluble [143–150]. The first major examples of macromolecular templat- 537
472 and usually the most stable CaP phase in an aqueous solution ing of HAp took place in the 1990s, when researchers tried to syn- 538
473 [8,99–103]. The precipitation reaction is, however, usually con- thesize HAp particles of complex shapes. For instance, Antonietti 539
474 ducted at pH values higher than 4.2 and temperatures ranging et al. [151] employed a double-hydrophilic block copolymer con- 540
475 from room temperature to temperatures close to (though not at) sisting of a long poly(ethylene oxide) block and a short poly(meth- 541
476 the boiling point of water [104–113]. Fig. 6 shows a schematic dia- acrylic acid) block, modified by partial alkylation with 542
477 gram of the steps involved in the chemical precipitation of HAp, dodecylamine as a dispersed template for controlled precipitation 543
478 along with the parameters proposed to affect the characteristics of calcium phosphate from aqueous solution at different pH values. 544
479 of the powder. To produce HAp nanoparticles, chemical precipita- In recent years, however, attention has usually been directed to- 545
480 tion can be accomplished using various calcium- and phosphate- wards simpler templating systems – not just because of their sim- 546
481 containing reagents, e.g. calcium hydroxide or calcium nitrate as plicity, but also because the use of medically harmful substances 547
482 the Ca2+ source and orthophosphoric acid or diammonium hydro- should be kept to a minimum. 548
23 April 2013
Fig. 5. Preparation of HAp nanoparticles via mechanochemical method.
549 More recent macromolecules used for soft templating of HAp finally obtained. More recently, Shkilnyy et al. [158] showed that 601
550 are popular surfactants, including cetyl trimethyl ammonium bro- poly(ethylene oxide)-b-poly(L-lysine) block copolymers lead to an 602
551 mide (CTAB), PEGs having different molecular weights, and various interesting morphology of calcium phosphate; electron micros- 603
552 Tweens. Surfactants, as amphiphilic molecules with a hydrophobic copy showed that a porous material with channel-like features 604
553 tail and a hydrophilic head, can self-assemble to form micelles as forms. They indicated that this morphology is the result of the 605
554 soon as their concentration exceeds the critical micelle concentra- aggregation of nanosized rod-like primary particles, which changes 606
555 tion. At a certain concentration and pH, micelles with a specific upon drying to exhibit the observed channel-like features. Com- 607
556 shape are formed and act as nucleation centers for crystal growth parison experiments conducted in the absence of polymer but with 608
557 [152–154]. Regarding CTAB, the most popular surfactant in the the block copolymers showed that this morphology only forms in 609
558 synthesis of HAp, the molecules are ionized to create cations of a the presence of the copolymer blocks, suggesting a distinct interac- 610
559 Q2 tetrahedral structure, followed by the formation of a stern layer tion of the polymeric additive with either the crystal or the phos- 611
560 through the cationic moieties constitutes [136,152–155]. Sur- phate ions prior to mineralization. 612
561 rounding this ionic mantle, the PO43 counter-ions with oriented Besides macromolecules, attempts have also been made to con- 613
562 water molecules may form an outer diffuse layer, starting the trol the characteristics of HAp using small organic compounds 614
563 nucleation process. Liu et al. [154] synthesized HAp nanorods [159–171]. Li and Meng [172], for example, prepared nanosized 615
564 50–80 nm in diameter and 0.5–1.2 lm in length (determined by HAp using titration of a supersaturated solution of lime chelated 616
565 TEM) using surfactants of CTAB and PEG 400. Zhang and Zhu with citric acid, using orthophosphoric acid. They suggested that 617
566 [124] controlled the morphology of fluoride-substituted HAp nano- the chelating agent inhibits crystal growth and results in the short- 618
567 particles by adding Tween-80. They claimed that morphological ening of the a-axis and lengthening of the c-axis in the crystal cells. 619
568 changes can occur as a result of difference between the growth Recently, Martins et al. [173] described a precipitation method by 620
569 rates of crystal faces resulting from the adsorption of Tween. In- which dumbbell-shaped and needle-like particles were precipi- 621
570 deed, without the addition of any surfactant, the resultant FHAp tated at physiological temperature (i.e. 37 °C). According to their 622
571 showed a spheroidal shape with a relatively broad size distribution results, in the presence of citrate molecules, a small variation in 623
572 of 80–300 nm (determined by field emission scanning electron the starting pH of the solution switches the morphology from 624
573 microscopy (FESEM)). In contrast, FHAp synthesized in the pres- micrometric bundles to nanometric needles. They explained the 625
574 ence of Tween-80 has a relatively uniform rod-like shape, with role of the citrate species in terms of supersaturation of solution 626
575 an average diameter of about 50 nm. and the development of particles’ surface charge. In fact, the 627
576 Several attempts have also been made to determine the effect of anisotropy of surface charge distribution arising from the adsorp- 628
577 PEG on the chemical precipitation of HAp nanoparticles [154–157]. tion of citrate species onto preferential crystal facets was found 629
578 According to the studies, PEG molecules modify the surface of to affect the formation of specific shapes by the oriented aggrega- 630
579 nanocrystals and act as a dispersing agent during the process of tion of the primary particles. By contrast, when the pH value is in- 631
580 synthesis. Recently, Qiu et al. [157] synthesized spherical HAp creased, the adsorption of more negatively charged species 632
581 30–50 nm diameter in the presence of PEG, by a reaction pathway increases the negative charge of the particle shell and promotes 633
582 described in Fig. 8. Their results show that the crystallinity of resul- particle repulsion, resulting in the prevention of particle agglomer- 634
583 tant powder was higher in the presence of PEG. To explain the mor- ation and hence maintaining the nanometric size of the particles. 635
584 phological and structural effects of PEG, they investigated the Many researchers have also used the addition of urea, in place of 636
585 interaction between Ca2+ and PEG by the electrical conductivity. NH4OH or NaOH, to adjust the pH value, and claim that it gives 637
586 Their results reveal that PEG reduces the transfer rate of Ca2+ in more homogeneous precipitation and further phase transforma- 638
587 the process of HAp crystallization, indicating the interaction be- tion to HAp [98,174–181]. According to the literature, CO32– ions 639
588 tween PEG and HAp. According to Fig. 8, when PEG is dissolved released from the urea during hydrolysis can incorporate into the 640
589 in aqueous solution, a PEG–OH bond is first formed and then che- HAp crystals, leading to a carbonated structure paralleling human 641
590 lated with Ca2+ released from Ca(NO3)2 to form a PEG–O–Ca2+–O– bone apatite. Recently, Zhang et al. [182] investigated the effect of 642
591 PEG bond. This then reacts with the PO43 from (NH4)3PO4 to pro- urea concentration on the phase composition and morphology of 643
592 duce the HAp crystal nucleus. It was found that a large deposit is the precipitated powder. According to their results, the slow 644
593 generated in a short time when there is no or little PEG, indicating adjustment on pH by hydrolysis of 0.5 M urea leads to a mixture 645
594 the rapid generation of HAp. With increasing concentration of PEG, of OCP and HAp with a ribbon-like morphology, whereas a sin- 646
595 the initial deposits gradually decrease and longer times are re- gle-phase HAp can be obtained upon hydrolysis of 0.03 M urea. 647
596 quired to produce large quantities of particles, indicating that More recently, our group [183] demonstrated that the aspect ratio 648
597 PEG reduces the release rate of Ca2+ and hence restrains the forma- of fibrous precipitated HAp decreases slightly in the presence of 649
598 tion of HAp crystals. When the rate of calcium release and the de- urea, while the crystalline fraction increases. Our results also indi- 650
599 posit rate of the crystal nucleus achieve a dynamical equilibrium, cated that the Ca/P ratio of HAp nanoparticles increases slightly in 651
600 HAp nucleus is deposited isotropically, and spherical particles are the presence of urea. 652
23 April 2013
Fig. 6. Preparation of HAp nanoparticles via conventional chemical precipitation.
686
653 Besides other parameters, the mixing rate of the reactants, the 10CaHPO4 þ 2H2 O ! Ca10 ðPO4 Þ6 ðOHÞ2 þ 4H3 PO4 ð27Þ
654 calcination temperature (if applicable), the drying method, the sol- 10CaHPO4 þ 12OH ! Ca10 ðPO4 Þ6 ðOHÞ2 þ 4PO3
4 þ 10H2 O ð28Þ
655 vent system and the concentration of the reactants have all been re-
6CaHPO4 þ 4CaðOHÞ2 ! Ca10 ðPO4 Þ6 ðOHÞ2 þ 6H2 O ð29Þ
656 ported to affect the characteristics of the final powder [184–192].
657 For example, the mixing rate determines the rate of the reaction 6CaHPO4 þ 4CaCO3 þ 2H2 O ! Ca10 ðPO4 Þ6 ðOHÞ2 þ 4H2 CO3 ð30Þ
658 and hence the chemical structure of the powder. Usually, a slow 10CaHPO4 2H2 O ! Ca10 ðPO4 Þ6 ðOHÞ2 þ 18H2 O þ 12Hþ þ 4PO3
4 ð31Þ
659 titration is advised to improve the chemical homogeneity and stoi- 6CaHPO4 2H2 O þ 4CaðOHÞ2 ! Ca10 ðPO4 Þ6 ðOHÞ2 þ 18H2 O ð32Þ
660 chiometry of the final product. Moreover, the addition rate is
10Ca3 ðPO4 Þ2 þ 6H2 O ! 3Ca10 ðPO4 Þ6 ðOHÞ2 þ 2PO3
4 þ 6H
þ
ð33Þ
661 strongly linked to the pH obtained at the end of the synthesis and
662 to the stability of the suspension [65,192]. Recently, Wang et al. 10Ca3 ðPO4 Þ2 þ 6OH ! 3Ca10 ðPO4 Þ6 ðOHÞ2 þ 2PO3
4 ð34Þ 688
663 [193] investigated the effects of the solvent system (pure water
During the 1990s, some attention had also been given to the 689
664 and a water/ethanol mixture) and the type of drying method (atmo-
hydrolysis of OCP [194,195]. However, in the last decade, this type 690
665 spheric drying, vacuum drying and freeze-drying) on the character-
of conversion has not been of great interest for the preparation of 691
666 istics of the resulting powder. They concluded that, by increasing
HAp particles, probably because of the slow rate of OCP hydrolysis 692
667 the proportion of ethanol in the solvent system, the size of the par-
and/or the good ability of OCP to incorporate impurity species, 693
668 ticles increases and the dispersibility decreases, owing to higher
including additives and foreign ions used for its transformation 694
669 supersaturation. According to TEM observations, the diameter of
to HAp. 695
670 their nanoparticles synthesized in water was about 20–30 nm,
Aqueous hydrolysis of CaP phases into HAp usually proceeds 696
671 while in ethanol it was about 100–150 nm. Indeed, HAp, as an alka-
by dissolution and precipitation processes [196–200]. Indeed, for- 697
672 lescent salt, has a low solubility in water and even lower solubility
mation of HAp crystals through many other wet methods also 698
673 in ethanol, leading to an increase in supersaturation and thus in the
proceeds via one or more intermediate phases having a transitory 699
674 growth of particles with an increasing amount of ethanol. The meth-
existence [59,134]. The hydrolysis method is, however, consid- 700
675 od of drying was also found to be important in determining both the
ered as a distinct method when one intends to convert a prepre- 701
676 morphology and the dispersibility. The size of the particles dried by
pared or a commercially available CaP into HAp. Supplementary 702
677 means of atmospheric drying was slightly smaller than those dried
Table S4 presents various attempts to synthesize HAp using this 703
678 by freeze-drying. Moreover, particles dried under vacuum condi-
approach. Among the CaP salts, acidic phases such as DCPA and 704
679 tions were nearly spherical, with a few rods, and their dispersibility
DCPD are thermodynamically less stable under pH values higher 705
680 was poorer. Wang et al. concluded that the powder dried using
than 6–7 and undergo transformation into a more stable CaP, 706
681 freeze-drying had an ultrafine structure with the best dispersibility.
e.g. HAp, through the pathways illustrated in Fig. 9 [201–207]. 707
These phase transformations depend strongly on the pH value, 708
682 2.2.2. The hydrolysis method temperature and presence of other ions besides excess calcium 709
683 HAp nanoparticles can be prepared by the hydrolysis of other and phosphate. Stulajterova and Medvecky [205] studied the con- 710
684 CaP phases, including DCPA, dibasic calcium phosphate dehydrate version of DCPD into HAp by the hydrolysis of DCPD in alkaline 711
685 (DCPD) and TCP, according to the following (simplified) equations: solutions at a temperature of 39 °C with or without additional 712
Fig. 7. Formation mechanism of rod-like HAp nanoparticles based on different templating systems.
23 April 2013
Fig. 8. Proposed reaction pathway for the preparation of HAp nanoparticles in the presence of PEG molecules.
713 calcium ions. According to the results, calcium-deficient HAp is 2.2.3. The sol–gel method 758
714 formed by the phase transformation of DCPD in an aqueous solu- The sol–gel method was one of the first methods proposed for 759
715 tion having an initial pH of 10.8 at a temperature of 39 °C, the wet synthesis of HAp. However, coating of different substrates 760
716 whereas stoichiometric HAp, which the thermodynamically most seems to have a major contribution to the sol–gel processing of 761
717 stable form of CaP, is obtained in a solution without excess Ca2+ HAp, and only a few studies have directly focused on the sol–gel 762
718 only after a long hydrolysis time. Indeed, the presence of Ca2+ synthesis of HAp nanoparticles (Supplementary Table S5). Sol–gel 763
719 ions can accelerate the conversion of DCPD into calcium-deficient offers advantage of molecular-level mixing of reactants, improving 764
720 HAp. Stulajterova and Medvecky’s results also confirmed the sur- the chemical homogeneity of the resulting powder [210–215]. Low- 765
721 face nucleation of HAp and the gradual transformation of DCPD temperature formation and fusion of the prepared crystals are other 766
722 by a dissolution–precipitation mechanism. The hydrolysis method notable advantages of the sol–gel process. In fact, temperatures 767
723 is also considered to be an interesting way to modify the charac- higher than 1000 °C are usually advised to sinter HAp crystals pre- 768
724 teristics of a preprepared HAp powder. Seo and Lee [208] synthe- pared from other wet methods, whereas temperatures several hun- 769
725 sized HAp whiskers by refluxing the aqueous slurry of dred degrees lower are required for calcination and sintering of sol– 770
726 commercial-grade HAp at 80 or 100 °C for 24 h in the presence gel HAp, leading to a decrease in degradation during the sintering. 771
727 of ethylenediamine tetraacetic acid (EDTA). They adjusted the Additionally, a powder obtained by a typical sol–gel method usually 772
728 pH of the solution to 7 or 9 and used hydrogen peroxide to pro- exhibits a stoichiometric structure with a large surface area and a 773
729 mote the precipitation of HAp crystals. According to their results, small cluster size (ranging from 50 nm to about 1 lm, depending 774
730 the higher the H2O2 concentration, the pH value and the refluxing on the processing parameters) [216–220]. In vitro studies have re- 775
731 temperature, the longer and thinner the whiskers formed. Indeed, ported that the bioresorbability of the sol–gel HAp is higher than 776
732 HAp powder is converted into HAp whiskers by a simple dissolu- conventional powder and is close to biological apatite [221]. Major 777
733 tion–reprecipitation process, in which amorphous reprecipitates disadvantages include the generation of secondary phase (usually 778
734 initially form in the Ca(EDTA)2–PO43 mixed solution and then calcium oxide, CaO) and the high cost of some of the starting mate- 779
735 grow continuously into long, thin HAp whiskers. FESEM micro- rials, especially alkoxide-based precursors. Secondary CaO phase 780
736 graphs showed that whiskers produced at 100 °C with 6% H2O2 has been demonstrated to be harmful to the biocompatibility of 781
737 at pH 9 had the highest aspect ratio of about 50–60 (a length HAp and therefore attempts have been made to remove the coexis- 782
738 of 3 lm and a width of 50 nm). ting CaO, either through washing of the calcined powder using a di- 783
739 As mentioned at the beginning of this subsection, HAp can also lute acid solution (mainly HCl) or modification of the main 784
740 be obtained by the hydrolysis of TCP under certain conditions. procedure, e.g. through increasing the aging time [222–224]. 785
741 TenHuisen and Brown [209] presented an investigation of factors The conventional sol–gel process involves the preparation of a 786
742 affecting the kinetics of calcium-deficient HAp formation from a- 3-D inorganic network by mixing alkoxides (or other suitable pre- 787
743 TCP. For this, they investigated the relationships between the cursors) in either an aqueous or an organic phase, followed by 788
744 rates of hydrolysis, the reaction temperature and microstructural aging at room temperature, gelation, drying on a hot plate and fi- 789
745 development by isothermal calorimetry under different hydroly- nally removing of organic residues from the resulting dried gel 790
746 sis conditions. They showed that the hydrolysis of TCP to HAp oc- using post-heat treatment (calcination) [225–229]. The overall 791
747 curs by a nucleation and growth mechanism. Moreover, according procedure is illustrated in Fig. 10. In the solution phase, reaction 792
748 to the results, there is a linear relationship between hydrolysis between the calcium and phosphorus precursors occurs slowly; 793
749 temperature and HAp surface area, and the crystallites become this is why a long period of aging is usually required for the apatitic 794
750 Q3 more regular as the reaction temperature is increased. In the last phase to form. Moreover, the thermal treatment step has been 795
751 decade, a number of attempts have been made to synthesis HAp found to be critical in the generation of pure HAp and the expulsion 796
752 of different shapes by hydrolysis of TCP under different experi- of residual organic parts, gaseous products and water molecules 797
753 mental conditions (Supplementary Table S4). For example, Park from the porous gel [211–214,227]. Indeed, insufficient aging 798
754 et al. [197] synthesized HAp whiskers of different aspect ratios and/or uncontrolled gelation and heat treatment may cause the 799
755 by the hydrolysis of a-TCP. They showed that In recent decade as- generation of various impurities, mainly CaO, Ca2P2O7, Ca3(PO4)2 800
756 pect ratio, stoichiometry and thermal stability of obtained HAp and CaCO3 [222,223]. Further, the rate of gelation, the nature of 801
757 are all strongly dependent on the pH of the hydrolysis. the solvent, and the temperature and pH employed during the pro- 802
23 April 2013
803 cess strongly depend on the chemical nature of the reagents used the hydrothermal conditions is relatively stoichiometric and highly 856
804 in the sol–gel synthesis. crystalline [248–253]. Moreover, phase purity and Ca/P ratio of 857
805 As in other wet methods, a number of precursors can be HAp precipitate significantly improve with increasing the hydro- 858
806 exploited in a typical sol–gel process (see also Fig. 10). In the thermal temperature [254–258]. However, elevated temperature 859
807 majority of cases, calcium diethoxide or calcium nitrate is reacted and pressure need expensive equipments, making the hydrother- 860
808 with triethylphosphite or triethylphosphate, either in an aqueous mal process more expensive than some of the other wet methods. 861
809 or organic solution [228–233]. A general reaction may be shown So far, an abundance of data regarding the hydrothermal syn- 862
810 as follows: thesis of HAp has been published, leading to some discrepancies 863
811 in the optimum experimental conditions. A well-known example 864
6CaðNO3 Þ2 þ 6ðC2 H5 OÞ3 PðOÞ ! Ca10 ðPO4 Þ6 ðOHÞ2 is the conditions by which elongated structures can be obtained; 865
813 þ byproducts ð35Þ some studies show that the rod-like HAp is synthesized in acidic 866
[251,259,260] or approximately neutral conditions [261,262], and 867
814 Hsieh et al. [223] prepared nanocrystalline HAp according to the others show that the nanorods are synthesized in alkaline condi- 868
815 above reaction and studied the effect of gelation rate on the apatite tions [249,263,264]. Recently, we [265] have reported that HAp 869
816 formation. They reported that fast gelation leads to a high CaO gen- nanorods having high crystallinity and high aspect ratio could sim- 870
817 eration, whereas slow gelation results in a minor CaO, which can ply be prepared through precipitation at approximately neutral 871
818 be easily washed out by distilled water. Recently, nonalkoxide conditions followed by a hydrothermal treatment at 200 °C for 872
819 sol–gel processing of HAp without any need for adjusting pH has 60 h. In this case, the nanoparticles show high dispersion stability, 873
820 also been developed [221,234–238]. For this, a Ca precursor, usu- indicating their high surface charge and low tendency for agglom- 874
821 ally Ca(NO3)2, and phosphoric pentoxide are first mixed in ethanol, eration. Fig. 11 shows the SEM and TEM photomicrographs of a 875
822 resulting in a stable sol, followed by aging (usually at room tem- typical rod-like HAp nanopowder synthesized under typical hydro- 876
823 perature), drying (100–150 °C) and finally heat treatment at ele- thermal conditions [183]. It is usually suggested that the formation 877
824 vated temperatures (300–900 °C). The as-prepared powder was of rod-like crystals through the hydrothermal crystallization com- 878
825 indicated to have a nanocrystalline structure, the crystallite size prises two main stages, including nucleation step in which tiny 879
826 and crystallinity of which can increase with increasing the calcina- crystalline nuclei in a supersaturated medium are formed (reaction 880
827 tion temperature. Fathi et al. [221] reported that HAp powder syn- of ions), and growth step in which nuclei continuously grow into 881
828 thesized by this process exhibits a nanoscaled (25 nm) and the final shape and size (hydrothermal treatment) [183,266]. 882
829 carbonated apatitic structure paralleling human bone apatite. Fathi Fig. 12 schematically illustrates these two steps. Very recently, 883
830 et al.’s results also indicated that the morphology, crystallinity and we [183,267] used different experimental design approaches to 884
831 crystallite size of the sol–gel HAp nanoparticles depend on the cal- evaluate various processing parameters involved in these two 885
832 cination temperature. In another study, Feng et al. [235] investi- steps. We demonstrated that temperature and pH are the most sig- 886
833 gated the effect of aging time on the particle size. TEM nificant factors affecting the structural and morphological charac- 887
834 observations showed that HAp nanopowders with different sizes teristics of HAp nanoparticles. According to our results, aspect ratio 888
835 of 10–15, 15–25 and 50–80 nm can be obtained after 4, 48 and of the fibrous nanoparticles (determined from SEM analysis) stee- 889
836 72 h of aging, respectively. This suggests that aging can contribute ply decreases with increasing the pH value. We also showed that 890
837 to powder growth and agglomeration. different morphologies ranging from rod-like to spherical nanopar- 891
ticles with various characteristics can be obtained by controlling 892
838 2.2.4. The hydrothermal method the driving force of the chemical reaction. In Fig. 13, we summa- 893
839 Here the hydrothermal process, as one of the most common rized our recent results on the preparation of HAp nanoparticles 894
840 methods for preparation of HAp, is usually identified by the reac- under different hydrothermal conditions [267]. According to the 895
841 tion of chemicals in an aqueous solution at elevated temperature figure, the high pH value results in an isotropic or weak-anisotropic 896
842 and pressure. Hydrothermal synthesis can also simply be consid- growth; that is, the crystallites can grow to form spherical nano- 897
843 ered as a chemical precipitation in which the aging step is con- particles or at most very short nanorods. However, with a decrease 898
844 ducted at a high temperature – typically above the boiling point in pH value of suspension, an anisotropic growth occur; that is, 899
845 of water – inside an autoclave or pressure vessel [239–247]. Sup- crystallites will grow into one-dimensional nanorods or two- 900
846 plementary Table S6 presents recent progress in the hydrothermal dimensional nanoplates. Additionally, more complicated shapes, 901
847 synthesis of HAp powder. As indicated in the table and also shown including three-dimensional feathery structure, three-dimensional 902
848 in Table 3, hydrothermal method has usually been exploited to microcubes, and three-dimensional microfibers are only obtained 903
849 prepare 1-D nanosized HAp (i.e. nanorods), owing to its capability if the pH value decreases to 4, a pH which other CaP phases (i.e. 904
850 to induce 1-D growth, though synthesis of specific and often unu- DCPA, DCPD, and OCP) become dominant (Fig. 13). Recently, 905
851 sual morphologies by using specific conditions and/or additives hydrothermal conditions by which a well-defined plate-shaped 906
852 has also been reported. Furthermore, as demonstrated in Fig. 3, structure can be obtained have also been reported [268,269]. 907
853 hydrothermal process is ranked as the third most popular method The most notable disadvantage of hydrothermal method is the 908
854 after the conventional precipitation and combination methods. It poor capability of the process to control the morphology and size 909
855 has been demonstrated that HAp nanoparticles obtained from distribution of nanoparticles. Indeed, the morphology of particles 910
Fig. 9. Possible routes for phase transformation of DCPD and DCPA to HAp [267].
23 April 2013
911 obtained by a normal hydrothermal method is usually irregular, clusters with high specific surface energy occurs due to high 957
912 spherical, or at most rod-like, with a very broad size distribution concentration of OH (pH = 12). In other words, growth rate of 958
913 (determined usually by analysis of TEM, FESEM, or SEM photomi- the facets of the primary clusters can be controlled by absorption 959
914 crographs), e.g. 0.7–3.0 lm [250], 10–80 nm [254], or 9–152 nm of OH on the facets. Because of ionic interactions, the surface hy- 960
915 [270]. Same as other chemical precipitations, to improve the proce- droxyl groups act as the active sites for adsorption of Ca–EDTA 961
916 dure, a number of organic modifiers can be used, of which two complexes. Subsequently, the Ca–EDTA complexes were integrated 962
917 types, including calcium chelating agents and various organic sur- into the active sites of obtained crystallite. The space inhibitions of 963
918 factants are more usual. EDTA as the most well-known calcium Ca-complex molecules with each other prevent the Ca atoms to be 964
919 chelating agent acts as a hexadentate unit by wrapping itself ordered according to the intrinsic crystal structure of HAp; there- 965
920 around the Ca2+ ion with four oxygens and two nitrogens to form fore, adsorbed Ca–EDTA molecules on the surface dictate a 3D pat- 966
921 several five-member chelate rings [271–275]. Following the che- tern structure for further growth in hydrothermal conditions 967
922 lating process, the resultant complex can be decomposed by a con- (Fig. 14). During the subsequent hydrothermal treatment, Ca-com- 968
923 trolled hydrothermal treatment. It has been found that in the plexes decompose and HAp crystals are grown on the previously 969
924 presence of EDTA, longer crystals under milder hydrothermal tem- formed pattern according to anisotropic growth along the c-axis, 970
925 peratures can be obtained [264,271,272,275]. This can be ex- and a dandelion-like HAp is finally obtained. 971
926 plained by the fact that EDTA can strongly chelate the free HAp powders of desired characteristics can also be fabricated 972
927 calcium ions, and subsequently control the crystal growth of HAp with the aid of organic modifiers, such as PEG, Tween-20, and d- 973
928 nucleus. In fact, as a result of complexation, concentration of free sorbitol, by different hydrothermal temperatures [260,276–283] 974
929 calcium ions dramatically decreases, leading to the HAp nuclei (for details, see Supplementary Table S6). For example, PEG is ben- 975
930 with smaller size and quantity. During the hydrothermal treat- eficial to the formation of HAp nanorods with a larger aspect ratio 976
931 ment, calcium ions are released and each individual nucleus will at high synthesis temperature; Tween-20 favors the formation of 977
932 grow to the distinct single needle-like particles and finally to small-sized nanorods; and D-sorbitol helps the formation of 978
933 well-separated long fibers. Zhu et al. [264], recently, reported that nanorods with long length at low synthesis temperatures [270]. 979
934 hydrothermal temperature of around 160 °C and a low pH value, Recently, a novel hydrothermal method based on the liquid–so- 980
935 with the molar ratio of EDTA/Ca = 1 can lead to a large HAp prism. lid–solution strategy has been developed by Wang et al. to synthe- 981
936 Fabrication of dandelion-like HAp nanostructures through EDTA at size surface-modified HAp nanorods of various aspect ratios [284]. 982
937 the very high pH value of 12 has recently been reported by Lak According to this strategy, controlled growth of HAp nanorods with 983
938 et al. [273]. According to the results, the obtained 3D dandelion- tunable morphology can be achieved by properly tuning the inter- 984
939 like nanostructures were composed of radially oriented nanorods faces between surfactants and the central atoms of HAp. For this, 985
940 with an average diameter of 200 nm. They showed that all the linoleic acid and its corresponding sodium salts were chosen as an- 986
941 nanorods were grown individually from a central spherical core ionic surfactants to complex with Ca2+ on the surface of HAp. 987
942 and no considerable aggregation occurred between them. Indeed, Moreover, octadecylamine, which reacts with linoleic acid to form 988
943 all the nanorods were densely aligned perpendicular to the surface cationic surfactants because of its basicity, was adopted because of 989
944 of the core. Because no additional templates were used in the syn- its possible interaction with the anion group of PO43–. In the re- 990
945 thesis process, the dandelion-like nanostructures were thought to ported procedure, octadecylamine (or sodium linoleate), linoleic 991
946 be self-assembled. In other words, EDTA affected the self-assembly acid, and ethanol were mixed together under agitation, followed 992
947 of the initially formed precipitates and culminated in the formation by adding Ca(NO3)2 to form the liquid (ethanol/ linoleic acid), solid 993
948 of 3D dandelion-like nanostructures during the hydrothermal (sodium linoleate), and solution (Ca(NO3)2 aqueous solution) 994
949 treatment. Fig. 14 schematically illustrates the steps involved in phases. After the ion-exchange of Ca2+ and Na+, a solution of Na3- 995
950 this process. According to the figure, EDTA wraps itself around PO4 was added to react with the calcium linoleate. The mixture 996
951 the calcium ion to form Ca–EDTA molecular complexes. It is was finally agitated and hydrothermally treated at a controlled 997
952 well-known that pH value has a considerable effect on Ca–EDTA temperature. Wang et al. suggested that along with the reaction 998
953 complex stability, and increasing the pH value enhances the com- process, the linoleic acid absorbs on the surface of the in situ gen- 999
954 plex stability. Lak et al. indicated that pH value plays a key role in erated HAp nanorods, with the alkyl chains left outside and then, a 1000
955 the synthesis of dandelion-like structures in the presence of EDTA. spontaneous phase-separation process occurs because HAp nano- 1001
956 Indeed, the strong absorption of OH ions on the planes of initial crystals settle and because of the incompatibility between the 1002
Fig. 10. Preparation of HAp nanoparticles via sol–gel process.
23 April 2013
1003 hydrophobic alkyl chains and their hydrophilic surrounding. Syn- main procedure make the emulsion technique to be an appropriate 1049
1004 thesis of HAp nanoparticles based on using CTAB under hydrother- method. 1050
1005 mal conditions has also been reported [268,272,285,286]. For A microemulsion is a thermodynamically stable, isotropic trans- 1051
1006 example, rod-like and dandelion-like HAp nanoparticles have re- parent dispersion of two immiscible liquids, such as water and or- 1052
1007 cently been synthesized through CTAB and CTAB/PEG systems, ganic, stabilized by the presence of surface active agents (i.e. 1053
1008 respectively (see Supplementary Table S6) [287]. In addition to surfactants). Surfactants as amphiphilic molecules with a hydro- 1054
1009 the conventional organic modifiers, some attempts have also been philic head connected to a hydrophobic tail can reduce the surface 1055
1010 made to exploit the more recently developed organic materials in tension of the immiscible liquids, resulting in a dispersed phase 1056
1011 controlling the crystal growth of HAp. Zhang et al. [288], for in- confined in nanometer regimes; the generated emulsion is thus 1057
1012 stance, synthesized HAp nanorods (80 nm by 10 nm, with aspect capable of delivering nanosized particles when the reaction is con- 1058
1013 ratio of about 8) with narrow particle size distribution in the pres- fined in the nanosized domains. Emulsion process depends 1059
1014 ence of anionic starburst dendrimers. Very recently, Zhu et al. strongly on the type of surfactant(s) used and concentration of 1060
1015 [289] synthesized rod-like HAp nanoparticles of various aspect ra- the surfactant(s) present in the liquid medium [290,291,299]. For 1061
1016 tios (e.g. 8.0 ± 0.9 and 4.0 ± 0.8) by means of low-temperature example, various organized assemblies of surfactants, such as mi- 1062
1017 hydrothermal method in the presence of N-[(2-hydroxy-3-trime- celles and vesicles, can be obtained depending on chemical struc- 1063
1018 thylammonium) propyl] chitosan chloride (HTCC) as a cationic ture of the surfactant, especially its molecular weight and 1064
1019 polymer template. Fig. 15 shows the schematic description of the relative size of the hydrophobic tail with respect to the hydrophilic 1065
1020 reaction. According to the figure, HTCC molecules are first incorpo- head. These assemblies have been shown to provide a suitable 1066
1021 rated into PO43– and OH anions by charge and stereochemical environment for the controlled growth of nanoparticles. The 1067
1022 complementarily, and the rigid chains of polymer molecules are hydrophobic monolayer surrounded by nanoparticles (i.e. surfac- 1068
1023 then converted to extended chains as a result of the subsequent tants) can subsequently be removed easily by calcination, during 1069
1024 decrease in surface energy. The resultant extended chains are con- which the resulting powder may also undergo little growth in crys- 1070
1025 nected through the ion bonds of PO43– to form a 2D structure, fol- tallite and particle sizes [294,299,300]. 1071
1026 lowed by formation of a 3D rod-like morphology through self- Up to now, three main categories of surfactants have been em- 1072
1027 assembling of 2D layers via hydrogen bond interactions. Finally, ployed in the microemulsion synthesis of HAp, including ionic (cat- 1073
1028 nucleation and subsequent crystal growth can occur upon adding ionic and anionic) surfactants, nonionic surfactants, and block- 1074
1029 the Ca precursor and hydrothermal treatment, respectively. Zhu copolymers with different molecular weights. The different chem- 1075
1030 et al. also suggested that the size and morphology of nanoparticles ical nature and molecular weights of these surfactants makes it 1076
1031 can be tailored by varying the synthesis conditions, including pH, possible to produce various organized assemblies (spheres, rods, 1077
1032 hydrothermal temperature, and ratio of phosphate ions to the qua- discs, bicontinuous, etc.) and therefore specific HAp particles’ 1078
1033 ternary ammonium in the template. geometries. Supplementary Table S7 shows recent progress in 1079
the emulsion synthesis of HAp. As indicated in the table, emulsion 1080
1034 2.2.5. Emulsion method process can be accomplished by three main routes, including 1081
1035 The precise control over morphology, size, and size distribution water-in-oil emulsion, oil-in-water emulsion, and water-in-oil- 1082
1036 of grains or particles is extremely important and certainly difficult; in-water double emulsion. The mechanism of these emulsification 1083
1037 especially when one intends to produce nanoscopic material with systems have been schematically illustrated in Fig. 16. Our estima- 1084
1038 minimal agglomeration and aggregation. Emulsion processing of tion, however, shows that the synthesis of HAp is usually con- 1085
1039 HAp particles was initially introduced to refine the clustering and ducted through the water-in-oil system accounted for about 70% 1086
1040 to restrict the formation of hard agglomerates [290]; however, this of all papers related to the emulsion synthesis of HAp. The 1087
1041 technique is now a subject of great interest not only to prepare an water-in-oil emulsion is based on a transparent inverse micro- 1088
1042 agglomerate-free ceramic powder, but also to control the microemulsion system containing reverse micelles dispersing in a con- 1089
1043 structure and morphology of resulting particles. Indeed, among tinuous oil phase [301–304]. Each micelle consists of solution 1090
1044 many different wet processes developed for HAp synthesis, emul- droplets surrounded by certain surfactant molecular groups, form- 1091
1045 sion method is suggested to be more efficient to reduce the particle ing a ‘‘water pool’’ suspended in the oil phase. Following the addi- 1092
1046 size, to control the morphology, and to limit the agglomeration of tion of the second microemulsion containing another reagent, 1093
1047 HAp particles [291–298]. Moreover, simplicity and mild synthesis fusion–fission between the reverse micelles causes the reaction be- 1094
1048 condition without any high-temperature requirement during the tween calcium and phosphate ions and finally formation of HAp 1095
Fig. 11. (a) SEM and (b) TEM images of rod-like HAp nanoparticles [183].
23 April 2013
Fig. 12. Two-step process of preparation of rod-like HAp nanoparticles under hydrothermal conditions.
Fig. 13. Effect of pH, temperature, and duration of hydrothermal treatment on phase, morphology, and particle size of the CaP powder [267].
1096 crystals, as illustrated in Fig. 17 [304–306]. Taking into account the As mentioned before, depending on the nature of surfactant(s), 1112
1097 templating role of each micelle as an independent micro- or nano- HAp nanoparticles of different characteristics (size, shape, crustal- 1113
1098 reactor, final morphology and particle size of HAp particles (for linity, etc.) can be produced. Sun et al. [307], for example, synthe- 1114
1099 example, spherical and rod-like morphologies in Fig. 17) will be sized the single-crystal HAp nanorods of 8–15 nm in diameter and 1115
1100 same as the shape and size of the micelles, respectively. Further- 25–50 nm in length using polyoxyethylene (TX-100) and CTAB. 1116
1101 more, morphology and crystallinity of the resulting powder can They indicated that homogeneity in size and shape of HAp particles 1117
1102 be adjusted through electrostatic interactions between head group observed by TEM can be attributed to the different stabilization 1118
1103 of ionic surfactants and oppositely charged groups on HAp seeds, functions of different kinds of surfactant on the interfacial layer; 1119
1104 as shown in Fig. 18 [299,307,308]. Indeed, by choosing a specific while TX-100 was suggested to act as a tridimensional stabilizer, 1120
1105 surfactant(s) and therefore a specific templating system, the elec- function of CTAB as an ionic surfactant is the electrostatic stabiliza- 1121
1106 trostatic field is changed, allowing the characteristics of resulting tion of the microemulsion system. Additionally, they demonstrated 1122
1107 powder to be controlled. Especially in the case of nanowires, for- that incorporating alcohols (n-butanol and n-hexanol) as co-sur- 1123
1108 mation of amorphous nuclear/surfactant complex and the electro- factant can improve the interfacial properties of the microemulsion 1124
1109 static field inside the reverse micelles maintain the unidirectional from a microstructural standpoint; the alcohol modifies the surfac- 1125
1110 and irreversible fusion of the reverse micelles, resulting in one- tant packing parameters by absorbing to the interfacial film and 1126
1111 dimensional growth of crystals [300,309–314]. thus influencing the radius of curvature of microemulsion droplets. 1127
23 April 2013
Fig. 14. Hydrothermal synthesis of dandelion-like HAp nanostructures in the presence of EDTA.
1128 In a similar study, Guo et al. [311] synthesized HAp nanoparticles or rod-like can be obtained simply by adjusting the conditions of 1168
1129 by a reverse microemulsion with a mixed surfactant system of the emulsion system. Their study revealed that increasing the A/ 1169
1130 TX-100 and Tween-80. They reported that microemulsion route O ratio increases specific surface area of synthesized powder, and 1170
1131 leads to a significant improvement in particle size and degree of according to the BET data, the highest surface area can be obtained 1171
1132 particle agglomeration compared to the conventional direct pre- with NP5 at A/O ratio of 1:5 and pH 7 after calcinations at 450 °C. It 1172
1133 cipitation method. Moreover, TEM observations showed that dif- was also observed that increase in pH decreased the aspect ratio of 1173
1134 ferent particle size and size distribution (e.g. 21–57 or 28– the powder and nearly spherical nanopowder was obtained with 1174
1135 64 nm) can be obtained depending on the weight ratio of TX-100 NP12 at pH 9. According to the results, hydrophilic head groups 1175
1136 and Tween 80. Lai et al. [312] investigated the nucleation kinetics of NP5 or NP12 act as a coordination site for Ca2+, providing the 1176
1137 of CaP nanoparicles in the reverse micelle solution. Their reaction necessary confinement in two dimensional spaces to direct the 1177
1138 system consisted of CTAB, cyclohexane, and n-pentanol. They mineral growth and form the elongated crystals. In the system 1178
1139 found that the initial amorphous nuclei in reverse micelles were with lower water content (A/O = 1:15), i.e. higher organic phase 1179
1140 mainly composed of DCPA rather than HAp because of the kinetic and higher surfactant ratio, the stability of the micelle was found 1180
1141 favor of DCPA. Moreover, results showed that nucleation rates in to be affected due to lower hydrogen bonding available with the 1181
1142 reverse micelle solution are lower than those conducted in aque- aqueous core. As a result, the surfactant-micelle equilibrium is 1182
1143 ous solution. They suggested that reverse micelles might condense shifted and dynamic exchange with other micelles and isolated 1183
1144 reaction solution thus increasing its concentration. An increase in surfactant molecules in the organic phase would be significantly 1184
1145 ion strength makes reverse micelles invulnerable which might dis- faster, forming micelles with larger size. In this case, the nucleation 1185
1146 favor the effective coalescence and the nucleation process as well. and mineral growth of HAp crystals take place in the micelle of 1186
1147 From our study, we [308] prepared HAp nanoparticles of 75–98 nm roughly spherical shape leading to the formation of nanopowder 1187
1148 in size using a mixed surfactant system comprising CTAB, n-pent- with a lower aspect ratio. 1188
1149 anol, and Span-60. According to the results, Span-60 as a nonionic
1150 surfactant can effectively deter the formation of rod-like morphol- 2.2.6. Sonochemical method 1189
1151 ogy by decreasing the electrostatic field inside the reverse micelles. Sonochemical methods, which always yield nanosized products, 1190
1152 In this case, the CTAB molecules didn’t have any significant role in are based on the chemical reactions activated by powerful ultra- 1191
1153 controlling the morphology, and are only used to control particle sound radiation. Supplementary Table S8 presents recent progress 1192
1154 size. Li et al. [300] synthesized nanocrystalline HAp particles of in the sonochemical synthesis of HAp nanoparticles. The physical 1193
1155 spherical (25–35 nm) and rod-like (10–80 nm 140–180 nm) mor- mechanism behind the sonochemical synthesis is acoustic cavita- 1194
1156 phologies using reverse microemulsion at room temperature. They tion in an aqueous phase where the formation, growth and collapse 1195
1157 reported that no obvious other’s phase occurred after as-prepared of microbubbles occur according to Fig. 19 [315,316]. Indeed, reac- 1196
1158 particles calcined under different temperatures up to 700 °C. Re- tivity of chemicals is stimulated to accelerate the heterogeneous 1197
1159 cently, Saha et al. [299] have investigated the effect of processing reactions between liquid and solid reactants [317]. It has recently 1198
1160 parameters, including type of surfactant, aqueous to organic ratio been demonstrated that sonication increases the rate of HAp crys- 1199
1161 (A/O), Ca2+ concentration, pH, and aging time on the characteristics tal growth up to 5.5 times [318]. It has also been reported that HAp 1200
1162 of final powder. They used isooctane, hexane, and cyclohexane as nanoparticles synthesized by a sonochemical process possess more 1201
1163 organic solvents, and dioctyl sulfosuccinate sodium salt (AOT), uniform, smaller, and purer crystals with minimal agglomeration 1202
1164 dodecyl phosphate (DP), poly (oxyethylene)5 nonylphenol ether [318–321]. These nanoparticles can significantly enhance the sin- 1203
1165 (NP5), and poly(oxyethylene)12 nonylphenol ether (NP12) as sur- tering kinetics, due to the higher surface area, and therefore the 1204
1166 factants to make the emulsion. According to the results, HAp nano- mechanical properties of final product. Cao et al. [322] prepared 1205
1167 particle of different morphologies such as spherical, needle shape needle-like nanocrystalline HAp by the ultrasonic precipitation 1206
23 April 2013
Fig. 15. Preparation of rod-like HAp nanoparticles using low-temperature hydrothermal treatment in the presence of HTCC as a cationic polymer template.
1207 using urea as organic modifier. They showed that addition of urea temperature processes can be performed by two techniques, 1254
1208 favors the formation of HAp nanoparticles. They also found an including combustion and pyrolysis. 1255
1209 Arrhenius relationship between the rate of HAp formation and
1210 the reaction temperature. According to the Arrhenius-derived
2.3.1. Combustion 1256
1211 equation, activation energy of the formation of HAp nanoparticles
Combustion method or solution combustion method, a conven- 1257
1212 under ultrasonic irradiation was calculated to be 59.9 kJ/mol. They
tional process to prepare various oxide ceramics, is being consid- 1258
1213 finally concluded that HAp content should increase with increasing
ered to be a promising method for preparation of CaP nanocrystals 1259
1214 the preparation temperature and/or time. In another study, Kim
[325–327]. The basis of combustion technique comes from thermo- 1260
1215 and Saito [317] used an aqueous suspension containing phosphoric
chemical concepts used in the field of propellants and explosives 1261
1216 acid and calcium hydroxide and applied the ultrasonic irradiation
chemistry. The key feature of the combustion synthesis of HAp is 1262
1217 to investigate the sonochemical effects on the preparation of
its ability to quickly produce powder with high purity in a single 1263
1218 HAp. They concluded that single phase HAp could be synthesized
step operation. Moreover, the approach has advantages of inexpen- 1264
1219 after 60 min sonication. Similarly, their results showed that the
sive raw materials, relatively simple preparation process, and well 1265
1220 HAp formation can be significantly promoted under sonochemical
chemical homogeneity of synthesized powder as a result of intimate 1266
1221 conditions. Recently, Han et al. [323] synthesized stable HAp nano-
blending of constituents [328–331]. As illustrated in Fig. 20, solu- 1267
1222 particles from Ca(H2PO4)2 and Ca(OH)2 aqueous solutions by using
tion combustion processing of HAp involves a very rapid exothermic 1268
1223 the ultrasound irradiation and adding glycosaminoglycans (GAGs)
and self-sustaining redox reaction between oxidants (calcium 1269
1224 as regulation additive. According to their study, an increase in the
nitrate and HNO3) and a suitable organic fuel (e.g. glycine, urea, su- 1270
1225 irradiation time will increase the particle size a little and improve
crose, citric acid, and succinic acid) in an aqueous phase [332–334]. 1271
1226 the crystallinity degree. They reported that the size distribution
For this, the aqueous stock solutions of Ca(NO3)2 and (NH4)2HPO4 1272
1227 and surface charge of nanoparticles are also affected by concentra-
are first mixed, followed by adding the concentrated HNO3 to dis- 1273
1228 tion of GAGs. Based on DLS analysis, with the GAG concentration of
solve the resulting white precipitate; a single or a mixture of two 1274
1229 0.35 g/L, optimized HAp powder was reported to be obtained with
or more fuels are subsequently incorporated into the resulting solu- 1275
1230 number-average particle size of 22 nm in 85% area and 55 nm in
tion. The reaction can be initiated by heating the mixture in a fur- 1276
1231 15% area between 18 nm and 117 nm. Indeed, GAGs interact
nace at a fairly low temperature (e.g. 300 °C); this is then followed 1277
1232 strongly with HAp through electrostatic interactions between the
by a sudden increase in temperature, as a result of the combustion, 1278
1233 anionic domains on the GAG macromolecule (carboxyl and sul-
to a maximum value. The final step is the fast cooling of mixture to 1279
1234 phate) and the cationic sites on HAp mineral (calcium), leading
induce maximum nucleation and to prevent any further particle 1280
1235 to the control of HAp nucleation and growth. Han et al. [324] also
growth. Exothermicity of the combustion reaction supplies the heat 1281
1236 investigated the change of phase composition and morphology of
required to maintain the temperature of the system, and once initi- 1282
1237 sonochemically synthesized HAp nanoparticles during thermal
ated, no external heating is needed anymore [328,329]. The result- 1283
1238 treatment. More recently, Rouhani et al. [318] proposed a rapid
ing product is usually soft agglomerates of very fine particles. 1284
1239 method to prepare ball-like HAp nanoparticles by sonication of a
Several processing parameters, including fuel to oxidizer ratio 1285
1240 pseudo-body solution (PBS) containing inorganic ions. According
[328,335], initial furnace temperature [328,335], nature of the fuel 1286
1241 to the results, the sonication time is an important factor affecting
[329,333,336], and quantity of the initial precursor [335] have been 1287
1242 the formation of crystalline phase of nanoparticles; so that a
reported to affect the maximum reaction temperature (i.e. flame 1288
1243 15 min sonication (28–34 kHz, 100 W) at 37 °C resulted in a pure
temperature), and accordingly the characteristics of the final pow- 1289
1244 HAp. Their results clearly showed that the particles generated by
der (see also Supplementary Table S9). In particular, different fuels 1290
1245 sonication were generally smaller and more spherical than those
have proved to be capable of delivering different flame tempera- 1291
1246 obtained without sonication. Comparison of the particle size dem-
tures ranging from 100 to 900 °C (e.g. citric acid: 150 °C; succinic 1292
1247 onstrated that sonication decreased the particle size from 30 nm
acid: 425 °C; urea: 800 °C; glycine: 890 °C). Ghosh et al. have 1293
1248 (corresponding to specific surface area of 63 m2/g) to 18 nm (corre-
recently published several papers on the preparation of nanosized 1294
1249 sponding to specific surface area of 107 m2/g).
HAp using combustion method [328,335,337]. According to their 1295
study [337], different combinations of urea and glycine and occa- 1296
sional addition of small amounts of highly water-soluble glucose, 1297
1250 2.3. High-temperature processes a fuel with a lower decomposition temperature (180 °C), lead to 1298
different flame temperatures, and therefore different HAp products. 1299
1251 High-temperature processes can be identified by their elevated Indeed, thermochemistry of combustion reaction can be controlled 1300
1252 temperatures used to burn or partially burn the precursors. by tailoring the fuel composition. For example, a very small quantity 1301
1253 According to the literature (see Supplementary Table S9), high- of glucose added to either urea or glycine, significantly reduced the 1302
23 April 2013
Fig. 16. Three main routes of emulsification in the emulsion synthesis of HAp nanoparticles.
Fig. 17. Fusion process of the reverse micelles containing different ions to form HAp nanoparticles of spherical morphology (condition I) or rod-like morphology (condition II).
1303 flame temperature. On the other hand, with increasing the percent- diameters ranging from 20 nm to 120 nm (determined by FESEM) 1320
1304 age of glucose, the vigorous mode of self-propagating combustion could be prepared simply by an optimized reaction. Similarly, Sas- 1321
1305 reaction becomes smouldering in nature. BET results showed that ikumar and Vijayaraghavan [329] have synthesized HAp nanoparti- 1322
1306 specific surface area of powder obtained from glucose–stoichiome- cles by the combustion synthesis route, using citric acid and 1323
1307 tric urea/glycine mixed fuel was higher than that obtained from succinic acid as fuels. According to the results, carbonated HAp 1324
1308 urea–glycine composition. Additionally, based on DLS analysis, par- can be obtained either through citric acid or succinic acid, whereas 1325
1309 ticle size distribution of as-prepared powder was found to decrease b-TCP is only formed when a mixture of them is used. However, by 1326
1310 with increase in urea content. Ghosh et al. [335] also demonstrated adding the citric acid to the succinic acid, the auto ignition temper- 1327
1311 that a decrease in both batch size and initial furnace temperature ature of succinic acid was found to decrease to lower temperatures. 1328
1312 and/or an increase in fuel to oxidizer ratio result in a decrease in
1313 crystallite size. Very recently, they [328] showed that stoichiome- 2.3.2. Pyrolysis 1329
1314 tric glycine–calcium nitrate leads to the higher flame temperature To produce a stoichiometric single-crystal HAp, processing con- 1330
1315 compared to stoichiometric urea–calcium nitrate system, resulting ditions involved in various wet and dry methods usually need to be 1331
1316 in a powder with lower specific surface area. Moreover, in both strictly controlled. Some post treatments and/or long-term aging 1332
1317 cases of glycine and urea, combustion with excess fuel produced under elevated temperatures may also be required to achieve a 1333
1318 particles with higher surface area. They also indicated that well high crystalline product. By contrast, HAp particles fabricated di- 1334
1319 crystalline and weekly agglomerated nanosized powder having rectly by a rapid pyrolysis-based method have been reported to 1335
23 April 2013
foaming action of CO2 generated by decomposition of urea. In an- 1375

other study, Aizawa et al. [339] investigated the effect of pyrolysis 1376
temperature and concentration of the starting solutions on the 1377
pyrolysis synthesis of HAp. For this, they used HNO3 solutions con- 1378
taining different concentrations of Ca(NO3)2 and (NH4)2HPO4 with 1379
the Ca/P ratio of 1.67. These solutions were sprayed into a heating 1380
zone composed of two electric furnaces; the lower furnace for 1381
evaporation of solvent from the droplets (300–500 °C) and the 1382
upper furnace for pyrolysis of the precipitated salts (750–900 °C). 1383
They reported that a pure and easily sinterable HAp powder can 1384
be obtained when the spray-pyrolysis temperature was 850 °C 1385
for the upper furnace and 400 °C for the lower one. The resulting 1386
powder was composed of spherical particles in a submicron-size 1387
range. Moreover, specific surface area of the prepared particles 1388
was reported to significantly decrease with increasing the concen- 1389
tration of starting solution. Very recently, Itatani et al. [340] pre- 1390
pared submicronic HAp powder by spray pyrolysis of precursor 1391
solution containing Ca(NO3)2, (NH4)2HPO4 and concentrated 1392
HNO3 at 600 °C using an ultrasonic vibrator. They reported that 1393
the resulting powders were composed of spherical agglomerates; 1394
the agglomerate diameter decreased with decreasing concentra- 1395
tion of spraying solution. For example, mean diameter of agglom- 1396
erates obtained by the spray pyrolysis of a solution with very 1397
Fig. 18. Electrostatic field proposed to be generated inside the reverse micelles;
enlarged illustration shows the interaction between the HAp crystal and a cationic low concentration of reactants was as small as 0.34 lm (deter- 1398
surfactant. mined by TEM). 1399
As mentioned before, pyrolysis synthesis of HAp particles can 1400
also be performed in the flame, where the reactions of vapor-phase 1401
1336 be stoichiometric, homogeneous, and highly crystalline [338–340]. precursors take place at a significantly higher temperature com- 1402
1337 In a typical pyrolysis, particles can form from reactants in a gas pared to the furnace. Indeed, a flame can provide a sufficiently high 1403
1338 phase generated by physical evaporation of liquid precursors. In temperature to form a uniform and dense HAp structure. Although 1404
1339 comparison with the combustion method, no fuel mixed with the furnace temperature is more accurate and controllable, but the 1405
1340 reactants is needed in the pyrolysis synthesis and the process flame temperature can also be easily adjusted by varying fuel 1406
1341 can be easily scaled up for continuous production of HAp particles. and oxidizer flow rates. As a disadvantage, small decomposition 1407
1342 It should be mentioned that the pyrolysis method can also be clas- of HAp into the a-TCP has been reported [338], because of high 1408
1343 sified under a broad category generally known as aerosol methods temperature of flame (usually above 2000 °C). Recently, Cho and 1409
1344 (or gas-phase methods), in which gas-to-particle or liquid-to-par- Kang [338] prepared nanosized HAp with high crystallinity and 1410
1345 ticle conversions occure in an aerosol decomposition process. appropriate stoichiometry (1.69) by high-temperature flame 1411
1346 Pyrolysis method, sometimes known as ‘‘spray pyrolysis’’, in- spray pyrolysis followed by a post-treatment at temperatures be- 1412
1347 volves spraying the precursor solutions into a flame or a hot zone tween 400 and 1000 °C. They also investigated the effect of PEG 1413
1348 of an electric furnace using an ultrasonic generator. This is then fol- added to the spray solution on morphology, mean size, and crystal- 1414
1349 lowed by reaction of the generated vapors and gases at high tem- linity of resulting powder. They reported that the mean sizes of 1415
1350 peratures to produce final powder, typically in an aggregated and HAp powders were changed from several tens to several hundreds 1416
1351 agglomerated form [340–342]. In fact, the high temperature leads nanometers depending on the concentration of PEG added to the 1417
1352 to the complete evaporation of precursor droplets followed by spray solutions. For example, pyrolysis of a solution with low con- 1418
1353 nucleation and growth of nanoparticles in the gas phase. Fig. 21 centration of 0.1 M PEG led to a powder with mean size less than 1419
1354 shows the schematic illustration of the equipment. According to 100 nm. 1420
1355 the figure, size of the particles is strongly dependent upon size of As a disadvantage of pyrolysis process, secondary aggregations 1421
1356 the droplets generated during the process; thus, some attempts are usually formed during the pyrolysis, resulting in a decrease in 1422
1357 have been made to reduce particle size by formation of fine drop- specific surface area. To address this problem, An et al. [345] em- 1423
1358 lets [338,342]. ployed a salt-assisted decomposition approach; a process by which 1424
1359 So far, few studies have investigated the pyrolysis synthesis of nanosized particles without any significant agglomeration can be 1425
1360 HAp powder (Supplementary Table S9). Vallet-Regi et al. [343] prepared by addition of a specific salt to the precursor solution. 1426
1361 published an early study on the pyrolysis synthesis of HAp. They For this, a solution mists containing Ca(NO3)2, H3PO4, and NaNO3 1427
1362 produced an aerosol with ultrafine droplets (2–4 lm) by ultrasonic were generated by an ultrasonic atomizer and carried into a fur- 1428
1363 frequency of a precursor solution containing CaCl2 and (NH4)H2- nace which was preheated to a given temperature (either 500 or 1429
1364 PO4. The aerosol flow was then passed through a long tubular fur- 700 °C). In this procedure, NaNO3 acts as a matrix to interrupt 1430
1365 nace at temperature of 500 °C, leading to submicronic HAp agglomerate formation of the primary nanoparticles. The nano- 1431
1366 particles. Following this study, Aizawa et al. [344] examined effect sized particles are subsequently obtained by removing the salts 1432
1367 of urea as a foaming agent on the formation of HAp through the from the secondary particles comprising salts and HAp using a sim- 1433
1368 spray-pyrolysis technique. They found that crystalline phases of ple washing step. It was reported that the synthesized nanoparti- 1434
1369 the powders prepared from the spraying solution without urea cles were rod-like and single phase with high crystallinity and 1435
1370 were HAp and a small amount of b-TCP; however, only carbon- good stoichiometry. In addition, the particle size (determined by 1436
1371 ate-containing HAp was formed from the solutions with urea. TEM) and aspect ratio was demonstrated to be affected by the salt 1437
1372 The SEM observations showed that the particle size of the as-pre- quantity and synthesis temperature. 1438
1373 pared powder decreased with increasing urea concentration in the Finally, we should mention that there are some other densifica- 1439
1374 spraying solution. This reduction of particle size may be due to the tion methods which are similar to the spray pyrolysis, except for 1440
23 April 2013
Fig. 19. Mechanism proposed to be involved in the sonochemical synthesis of HAp nanoparticles.
Fig. 20. Preparation of HAp nanoparticles via solution combustion method.
1441 the type of precursor and some technical details. The most well- tracted material, but also due to the economical and 1472
1442 known example is spray drying method that typically uses colloi- environmental benefits of waste recovery [346–350]. Preparation 1473
1443 dal HAp particles (i.e. HAp sols) as precursor to produce particulate of HAp using biowastes usually involves a few h annealing during 1474
1444 materials. A typical spray drying process involves three steps: feed- which the organic materials in the bone get removed, leaving pure 1475
1445 ing suspended HAp slurry to a nozzle; atomizing of suspension into HAp as the residue (Fig. 22(a)) [351–357]. According to Fig. 22(a), 1476
1446 a stream of heated air flowing through an evaporation chamber; beside the simple thermal annealing (i.e. calcination), some other 1477
1447 and finally trapping of the resulting particles by an electrostatic extraction processes, including enzymatic hydrolysis, plasma pro- 1478
1448 precipitator [71,72]. Accordingly, there is always a preliminary cessing, subcritical water processing, and alkaline hydrothermal 1479
1449 chemical step to synthesize the phase of HAp; thus, the spray dry- hydrolysis can also be used [348,358,359]. Moreover, some at- 1480
1450 ing and other similar methods (such as thermal spraying) should tempts have been made to reduce the particle size of powder to 1481
1451 be considered as a complement of other methods. Additionally, the nanometric scale [360,361]. For example, Ruksudjarit et al. 1482
1452 spray drying usually results in spherical granules or large microm- [361] synthesized nanocrystalline HAp from bovine bone by a vi- 1483
1453 eter-sized particles having a hollow structure [61,62,73] which bro-milling technique. They demonstrated that vibro-milling 1484
1454 have not been discussed here, as they are outside the scope of this method can separate and disperse the HAp nanocrystals from its 1485
1455 article. parent bone structure. For this, the bovine bone was deproteinized 1486
using hot water, calcined at 800 °C, crushed into small pieces, and 1487
1456 2.4. Synthesis from biogenic sources finally milled in a ball mill pot for at least 24 h. The resulting pow- 1488
der was then ground by vibro-milling apparatus for various milling 1489
1457 HAp ceramic generated partially or entirely from biogenic times. According to the results, HAp powder with diameter less 1490
1458 sources is proposed to be accepted better by the living organs, be- than 100 nm can be obtained when the milling duration is 2, 4, 1491
1459 cause of its physicochemical similarity to the human bone apatite. or 8 h. Recently, Barakat et al. [348] used conventional thermal 1492
1460 Supplementary Table S10 shows recent studies on the production decomposition, subcritical water process (hot liquid water under 1493
1461 of HAp using various biogenic sources. A careful look at the table pressure), and alkaline hydrothermal method to, respectively, 1494
1462 reveals five different groups, including extraction of minerals from decompose, dissolve, and hydrolyze the organic compounds of bo- 1495
1463 biowastes, synthesis from eggshells, synthesis from exoskeleton of vine bone. Their results showed that all these methods have the 1496
1464 marine organisms, synthesis with the aid of natural biomolecules, ability to remove organic matters of bone and to produce pure 1497
1465 and synthesis using biomembranes. This can schematically be HAp with an average yield of 65%. Moreover, thermal processing 1498
1466 summarized in Fig. 22. resulted in nanorod HAp of about 300 nm in length, whereas sub- 1499
1467 According to Supplementary Table S10, extraction of biominer- critical water and alkaline hydrothermal processes led to HAp 1500
1468 als from biowastes (mainly bovine bones, fish-scales, and fish nanoparticles possessing small nanoflakes. More recently, a rapid 1501
1469 bones) is the most well-known method for the preparation of plasma processing has been used to extract HAp from bovine bone 1502
1470 HAp using biogenic sources. This is an interesting process, in par- [359]. According to the results, only 90 s plasma processing using 1503
1471 ticular, not only because of some superior characteristics of the ex- transferred arc plasma results in an organic free bovine HAp. 1504
23 April 2013
1505 Besides the hard tissues of animals, some attempts have also internal morphology, phytogenic calcium carbonates are usually 1537
1506 been made to produce HAp, especially carbonated HAp, using egg- used in the original form, e.g. in fragments in the case of algae 1538
1507 shell waste [362–365]. As indicated in Fig. 22(b), eggshells are and in shaped blocks in the case of corals [375,377,380]. Indeed, 1539
1508 composed mainly of calcium carbonate (95–97%), and thus, can the inherent differences between vegetative structures of different 1540
1509 be adapted as a calcium precursor in the synthesis of HAp [366]. marine species lead to the HAp blocks having different internal 1541
1510 Typically, the eggshells are first heated at 900 °C in a furnace to morphologies and pore sizes. For example, HAp prepared using 1542
1511 decompose organic matter and to convert calcium carbonate to corals typically has a pore size of several hundreds of microns, 1543
1512 calcium oxide which in turn on exposure to atmosphere forms cal- whereas pore size of that synthesized using the marine algae rarely 1544
1513 cium hydroxide (Ca(OH)2); the as-prepared Ca(OH)2 is subse- exceeds a few micrometers [375–378]. The larger and higher 1545
1514 quently reacted with a suitable phosphorus precursor to produce macroporosity of the structure, similar to the natural cancellous 1546
1515 HAp crystals [366–368]. Some researchers have also tried to re- bone, has been reported to result in earlier bone mineralization 1547
1516 place the heating step by a chemical treatment; for example, egg- during the implantation; and hence corals-generated HAps are 1548
1517 shells can be treated by HNO3 or HCl to produce Ca(NO3)2 and claimed to be more beneficial to bone repair applications. 1549
1518 CaCl2, respectively [364,369]. Recently, Boonyang et al. [370] con- Synthesis of nanosized particles in the presence of various bio- 1550
1519 ducted a hydrothermal reaction at 250 °C between crocodile egg- molecules extracted from diverse natural materials, as indicated 1551
1520 shells and three different phosphate precursors, including in Fig. 22(d), is the fourth approach for the preparation of HAp using 1552
1521 (NH4)2HPO4, Ca3(PO4)2, and H3PO4. They reported that only (NH4)2- natural sources [364,381–384]. For example, Zhao et al. [364] have 1553
1522 HPO4 and Ca3(PO4)2 gave monophase HAp within 25 and 8 h of reported that ovalbumin (a natural biosurfactant) extracted from 1554
1523 treatment, respectively. Moreover, microstructure of the as-pre- egg white affects the morphology and surface charge of the HAp 1555
1524 pared HAps was reported to be clusters of agglomerated plate-like powder. Indeed, interactions between ovalbumin and HAp crystals 1556
1525 crystals. were found to have a great effect on the surface charges of particles. 1557
1526 According to Fig. 22(c), calcium carbonates present in skeleton According to the results, large HAp spindle-like particles aggregated 1558
1527 of various marine species are other natural raw materials exploited from needle-like nanocrystals of 20–50 nm in length and 2–6 nm in 1559
1528 in the synthesis of HAp. A typical procedure involves ion exchang- thickness can be obtained in the presence of ovalbumin. Recently, 1560
1529 ing under hydrothermal conditions, for example, according to the various biomolecules originated from orange peel, potato peel, 1561
1530 following reaction [371–376]: egg shell, papaya leaf, and calendula flower were reported to affect 1562
the characteristics of HAp powder [384]. According to the studies, 1563
1531
the extracted biomolecules (amino acids, carotene, papain, carote- 1564
10CaCO3 þ 6ðNH4 Þ2 HPO4 þ 2H2 O
noids, vitamins, etc.), as the medicinally important materials, can 1565
1533 ! Ca10 ðPO4 Þ6 ðOHÞ2 þ 6ðNH4 Þ2 CO3 þ 4H2 O þ 4CO2 ð36Þ exert a significant control on the synthesis of nanosized HAp. In- 1566
deed, only small quantities of the biomolecules led to a significant 1567
1534 Calcium carbonate originated from marine species usually
change in both size and morphology of resulting powder. 1568
1535 exhibits characteristic porosity and interconnectivity similar to
As indicated in Fig. 22(e) and Supplementary Table S10, a few 1569
1536 that found in human bone [375–379]. To maintain this unique
studies have recently reported on the utilization of natural mem- 1570
brane to produce HAp nanostructures using a diffusion-controlled 1571
nucleation mechanism. For example, eggshell membrane – a struc- 1572
ture constructed from interwoven fibers of collagen with nanome- 1573
ter-sized pores in between them – can be exploited to control the 1574
diffusion of phosphate ions towards calcium ions during the HAp 1575
nucleation [385,386]. As a result of slow and controlled movement 1576
of ions across the membrane, HAp structures with a specific mor- 1577
phology can be obtained. Recently, Zhang et al. [385,387] fabri- 1578
cated the flower-like structures of HAp (see Table 3) either using 1579
eggshell membrane or bamboo membrane. They reported that 1580
flower-like HAp agglomerates with high crystallinity can be pro- 1581
duced on the upper or lower side of the both membranes (see 1582
Fig. 22(e)). Moreover, as a result of intrinsic differences between 1583
bamboo membrane (mainly composed of cellulose) and eggshell 1584
membrane (mainly composed of proteins), the as-prepared struc- 1585
tures were different in terms of morphology and other characteris- 1586
tics. Additionally, both the morphology and the crystal structure of 1587
agglomerates were indicated to be influenced by temperature, pH 1588
value, and holding time. For example, based on TEM analysis, flow- 1589
er-like structures composed of nanosheets with a length of 20– 1590
80 nm and a width of 20–40 nm can be obtained on the upper side 1591
of the eggshell membrane at temperature of 37.5 °C, pH value of 1592
7.4, and holding time of 12 days. Very recently, Neelakandeswari 1593
et al. [386] prepared needle-like HAp nanoparticles using eggshell 1594
membranes. Again, both the structure and morphology of powder 1595
were reported to be affected by pH of the reaction. 1596
2.5. Combination procedures 1597
Fig. 21. Schematic diagram illustrating the equipment setup for the preparation of To improve the properties of final product, two or more distinct 1598
HAp nanoparticles via flame spray pyrolysis.
methods can be combined to create a synergistic strategy [388– 1599
390]. As indicated in Supplementary Table S11, many hybrid tech- 1600
23 April 2013
Fig. 22. Preparation of HAp via biogenic sources: (a) extraction of minerals from biowaste; (b) synthesis from eggshells; (c) synthesis from exoskeleton of marine organisms;
(d) synthesis with the aid of naturally derived biomolecules; and (e) synthesis using biomembranes.
1601 niques mainly hydrothermal–mechanochemical [391–401], hydro- ture of reaction remains close to the room temperature; and that 1623
1602 thermal–hydrolysis [402–410], and hydrothermal–microemulsion is why any external heating or pressure vessel is not required in a 1624
1603 combinations [411–416] have been developed over the past dec- normal wet mechanochemical process [395,397,399,401]. Recently, 1625
1604 ade. However, the most well-known approach is to combine the Abdel-Aal et al. [392] used statistical design approach to determine 1626
1605 mechanochemical method with the hydrothermal procedure the optimum experimental conditions. Their results revealed that 1627
1606 through incorporation of an aqueous phase into the system. The milling time is the most significant factor affecting the particle size; 1628
1607 resulting mechanochemical–hydrothermal hybrid, sometimes the longer the milling time, the smaller the crystallite size. Accord- 1629
1608 known as wet mechanochemical, can accelerate those kinetic pro- ing to the results, nanosized particles with a narrow size distribu- 1630
1609 cesses that usually limit the rate of reaction in a conventional tion of 10 to 20 nm (determined by TEM) can be obtained at 1631
1610 mechanochemical method (i.e. dissolution, diffusion, and adsorp- optimized conditions. 1632
1611 tion) [393–396,400]. Suchanek et al. [398] used this method to pre- Hydrothermal–hydrolysis and hydrothermal–microemulsion 1633
1612 pare crystalline carbonated HAp at room temperature by milling a hybrids are other well-known combinations, according to Supple- 1634
1613 slurry at the rotation speed of 1500 rpm for 1 h and then at mentary Table S11. Hydrothermal–hydrolysis process, which is 1635
1614 800 rpm for 4 h. According to the study, the resulting powder con- used to accelerate the kinetic of hydrolysis, can be simply con- 1636
1615 sisted of equiaxed nanocrystals of about 20 nm in diameter (deter- ducted by hydrolysis of a CaP phase, usually DCPD or TCP, under 1637
1616 mined by TEM), which formed larger aggregates with 0.35–1.63 lm elevated temperatures and pressures. For example, Liu et al. [402] 1638
1617 in size (determined by DLS). Compared to the hydrothermal process have converted a-TCP to HAp using this combination method in 1639
1618 where a lot of energy is usually required to generate elevated tem- the presence of excess calcium ions. They showed that well HAp 1640
1619 peratures, high energy consumption can be avoided in the com- crystals with different morphologies (microflowers, microplates, 1641
1620 bined method. In fact, while the activation of slurry results in packed nanorods, and microrods) can be obtained by adjusting 1642
1621 local zones of high temperatures, up to 700 °C, due to the friction the reaction temperature and concentration of extra ions. Hydro- 1643
1622 effects and adiabatic heating of gas bubbles, the overall tempera- thermal–microemulsion hybrid, also known as solvothermal, can 1644
23 April 2013
Fig. 23. Three main routes for preparation of HAp nanoparticles via microwave-assisted synthesis.
1645 offer some further benefits. It is known that rod-like nanoparticles now a subject of interest to synthesize HAp nanoparticles in a less 1684
1646 with narrow particle size distribution can be obtained through energy-consuming and more reproducible manner. In actual prac- 1685
1647 microemulsion technique, although the resulting nanorods exhibits tice, microwave treatment results in rapid and uniform heating of 1686
1648 low crystallinity with low aspect ratio (see Section 2.2.5). On the entire bulk of the substance to the temperature of treatment with- 1687
1649 other hand, the hydrothermal synthesis usually leads to highly out any significant thermal stress or temperature gradient [425– 1688
1650 crystalline particles of elongated shape, but usually in an agglomer- 428]. This can increase the reaction kinetics and effectively reduce 1689
1651 ated form with a wide particle size distribution. The solvothermal duration of the process [428–432]. As a result of fast homogenous 1690
1652 synthesis, which brings together these two different approaches, nucleation, microwave synthesis of HAp nanoparticles is usually 1691
1653 can therefore provide a unique method to prepare the crystalline accomplished in less than 30 min. It is believed that microwave 1692
1654 rod-like nanoparticles with minimal agglomeration and narrow irradiation may also lead to a powder having some improved char- 1693
1655 size distribution. For example, stoichiometric HAp nanorods with acteristics, including smaller size, higher purity, and narrower size 1694
1656 25–40 nm in diameter and 55–350 nm in length have been re- distribution. Supplementary Table S12 presents recent progress in 1695
1657 ported to be obtained by a solvothermal system comprising CTAB, the microwave synthesis of HAp nanoparticles. A careful look at 1696
1658 n-pentanol, n-hexane, and water [412]. For this, the nucleation of the table reveals that the microwave processing of HAp can be con- 1697
1659 HAp first occurs at room temperature within the reverse micelles ducted under either refluxing or hydrothermal conditions or even 1698
1660 and then generated nuclei start to grow under high temperature at atmospheric conditions with short time or long time irradiation, 1699
1661 and pressure. Sometimes, some procedures without having the as also schematically illustrated in Fig. 23. Moreover, several at- 1700
1662 templating system are also named as solvothermal, owing to the tempts have also been made to combine the microwave irradiation 1701
1663 fact that a mixture of water and a water-miscible organic solvent with solid-state [433–435], hydrolysis [436,437], sonochemical 1702
1664 is employed during the synthesis [417,418]. For example, Ma [438], and solution combustion [439,440] methods. 1703
1665 et al. [419] prepared HAp microtubes using CaCl2 and NaH2PO4 in There are several examples for microwave synthesis of HAp un- 1704
1666 a solvent mixture of water/N,N-dimethylformamide (DMF) at der refluxing system [425,431,441,442]. Kumar et al. [425] recently 1705
1667 160 °C. However, according to our classification, these procedures described the synthesis of HAp nanostrips of 50–70 nm in diameter 1706
1668 cannot be considered as a real hybrid due to the absence of the and 50–100 nm in length by refluxing an aqueous solution under 1707
1669 microemulsion system. microwave irradiation in the presence of EDTA. They demonstrated 1708
1670 All mentioned methods in Supplementary Table S11 are sub- that EDTA plays an important role in controlling the morphology of 1709
1671 stantially based on combination of two distinct methods described the powder. In a similar study, Kalita and Verma [431] synthesized 1710
1672 in Sections 2.1–2.4. However, there are also several contributions highly crystalline HAp nanopowder of 5–30 nm in size having a 1711
1673 to the combination of previously described methods with a new mixed (elliptical and rod-shape) morphology with the aid of EDTA 1712
1674 procedure, so that one may consider them as a hybrid process. and microwave irradiation. Liu et al. [441,442] synthesized bow- 1713
1675 The most well-known example is microwave-assisted methods, knot-like and flower-like HAp nanostructures (see Table 3) using 1714
1676 in which microwave irradiation is used to activate the reaction. microwave assisted reactions. They suggested that shape of crystals 1715
1677 In contrast to the conventional procedures, where the material is can be easily controlled by adjusting the stability of Ca–EDTA com- 1716
1678 externally heated through conduction, microwave heating involves plex and the hindrance effect of OH on the crystallite facets. Micro- 1717
1679 in situ conversion of microwave energy into heat using the inher- wave-assisted reactions can also simply be conducted at 1718
1680 ent properties of reaction mixture [420–422]. Microwave process- atmospheric conditions without refluxing system, either through a 1719
1681 ing of HAp particles was initially employed for sintering of HAp short time or long time irradiation [428,443–448]. Arami et al. 1720
1682 ceramics to produce a dense material with improved physical [449] synthesized HAp nanostrips of 10 nm in width and 55 nm in 1721
1683 and mechanical properties [423,424]; however, this technique is length, via 5 min microwave irradiation of a precursor (pH = 12) 1722
23 April 2013
1723 comprising Ca(NO3)2, Na2HPO4, NaOH, and CTAB. Siddharthan et al. (d) Synthesis from biogenic sources. To produce HAp ceramics 1785
1724 [450] synthesized HAp nanoparticles by microwave irradiation to a various natural materials, mainly bone waste, eggshells, exo- 1786
1725 precursor of Ca(NO3)2 and H3PO4 until drying the precipitate. skeleton of marine organisms, naturally derived biomole- 1787
1726 According to the results, the power of irradiation was found to affect cules, and biomembranes, have been employed over the 1788
1727 both the particle size and the particle shape. As just mentioned, past decade. This field is expected to attract more attention 1789
1728 microwave reactions can also be accomplished under hydrothermal in the near future, owing to the better physicochemical 1790
1729 conditions. While in the conventional hydrothermal procedures, a properties of the HAp generated from biogenic sources. 1791
1730 stainless steel vessel is usually used, a typical microwave–hydro- However, some of these materials can be exclusively used 1792
1731 thermal technique employs a polymeric reactor which is transparent to produce HAp blocks or at most HAp particles of large size. 1793
1732 to microwaves. The procedure involves a few min microwave irradi- This stresses the need for further work in the area. 1794
1733 ation to result in rapid formation of HAp precipitate [432,451–453]. (e) Combination procedures. These methods, as relatively new 1795
1734 Katsuki and Furuta [430] synthesized HAp nanorods with 5–50 nm strategies, employ two or more distinct procedures to 1796
1735 in diameter and 30–300 nm in length from gypsum (CaSO4.2H2O) synthesize HAp nanoparticles. Among several possibilities, 1797
1736 powder reacted with (NH4)2HPO4 solution, using 5 min micro- combinations of hydrothermal–mechanochemical, hydro- 1798
1737 wave–hydrothermal treatment at 100 °C. They showed that the thermal–hydrolysis, and hydrothermal–microemulsion have 1799
1738 introduction of microwaves into the hydrothermal process leads to received more attention. Reports on various hybrids 1800
1739 an increase in HAp formation by approximately two orders of mag- employed microwave method have also been published 1801
1740 nitude. Recently, Han et al. [454] synthesized nanosized HAp powder recently. In general, combination procedures open exciting 1802
1741 by a microwave–hydrothermal treatment at 600 psi and 300 °C for possibilities to improve the characteristics of HAp 1803
1742 up to 30 min. They reported that applied microwave power and mole nanoparticles. 1804
1743 ratio of Ca/P are among the important factors affecting the character- 1805
1744 istics of HAp. According to the results, low microwave power of Despite the great variety of methods for preparation of HAp 1806
1745 450 W and Ca/P ratio of 1.57 lead to a mixed CaP compound includ- nanoparticles, only a few of them are satisfactory in terms of eco- 1807
1746 ing Ca(OH)2, CaHPO4 and HAp, whereas running the reaction at nomics or performance, mainly due to the diverse materials 1808
1747 550 W power and Ca/P 1.67 results in monophase HAp. needed in the synthesis, complicated and expensive processes, 1809
serious aggregation and agglomeration, wide particle size distribu- 1810
tion, and various phase impurities which usually occur in the crys- 1811
1748 3. Conclusion and outlook tal structure. For example, in a typical wet method, production of 1812
HAp requires a precise control over the reaction conditions along 1813
1749 In the review article presented here, the preparation methods of with a long-term aging in the final step. On the other hand, there 1814
1750 HAp nanoparticles were classified as follows: seems to be little effort on scaling up the introduced methods; 1815
and unfortunately little work has been reported to evaluate the 1816
1751 (a) Dry methods. Dry methods, which can be identified in con- biological interactions of the prepared nanoparticles, at least in 1817
1752 trast to wet methods where a solvent is always used, can be the open literature. To address these issues, new synthesis routes 1818
1753 performed in two main ways: solid-state synthesis and mech- which can practically be put to use in the biomaterials industries 1819
1754 anochemical process. These methods have the convenience of have to be established. Future studies must also consider all as- 1820
1755 producing highly crystalline HAp from relatively inexpensive pects of an effective and feasible synthetic route and examine 1821
1756 raw materials. The main disadvantage is the large size of par- the biological characteristics of the prepared powder. An alterna- 1822
1757 ticles in the case of solid-state synthesis and the low phase tive approach may be to develop innovative and practical combina- 1823
1758 purity of HAp in the case of mechanochemical process. In tions, e.g. mechanochemical–solvothermal method or microwave– 1824
1759 recent years, progress in preparing HAp using dry methods, assisted sol–gel process. Moreover, synthesis of nanoparticles with 1825
1760 especially solid-state method, has been very slow. new characteristics, e.g. novel 3D morphologies, can also be an- 1826
1761 (b) Wet methods. Aqueous solutions of various sources for other interesting challenge for future research. 1827
1762 phosphate and calcium ions are employed and HAp crystals
1763 are normally produced by precipitation. Wet processes can
1764 be performed by a number of technical routes classified into Appendix A. Figures with essential colour discrimination 1828
1765 six groups: conventional chemical precipitation, hydrolysis

1766 method, sol–gel method, hydrothermal method, emulsion Certain figures in this article, particularly Figures 1, 4–7, 12–19 1829
1767 method, and sonochemical method. Wet chemical methods and 20–23 are difficult to interpret in black and white. The full col- 1830
1768 have the advantages in precise control over the morphology our images can be found in the on-line version, at http://dx.doi.org/ 1831
1769 and size of particles, and based on the statistical analysis, 10.1016/j.actbio.2013.04.012. 1832
1770 they are the most promising methods for the synthesis of
1771 nanosized HAp. However, difficulties in controlling the crys- Appendix B. Supplementary data 1833
1772 tallinity and phase purity of nanoparticles, and some techni-
1773 cally intricate and time-consuming details make some wet Supplementary data associated with this article can be found, in 1834
1774 procedures unsuitable for scaling up to produce large quan- the online version, at http://dx.doi.org/10.1016/j.actbio.2013.04. 1835
1775 tities of HAp. 012. 1836
1776 (c) High-temperature processes. These methods, which have
1777 the convenience of avoiding undesirable CaP phases, are
1778 used to produce HAp with high crystallinity and good chem- References 1837
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ACTBIO 2680 No.

of Pages 31, Model 5G

Acta Biomaterialia xxx (2013) xxx–xxx

Contents lists available at SciVerse ScienceDirect

7 Mehdi Sadat-Shojai ⇑, Mohammad-Taghi Khorasani, Ehsan Dinpanah-Khoshdargi, Ahmad Jamshidi

2 M. Sadat-Shojai et al. / Acta Biomaterialia xxx (2013) xxx–xxx

M. Sadat-Shojai et al. / Acta Biomaterialia xxx (2013) xxx–xxx 3

Name Symbol(s) Formula Ca/P

4 M. Sadat-Shojai et al. / Acta Biomaterialia xxx (2013) xxx–xxx

occurs upon mixing the reactants, and anisotropic growth is 264

nano particles embedded in

one synthesizes an elongated shape (i.e. the geometry indicated 281

that elongated shapes should be named according to their axial 283

a rod. Although this nomenclature scheme is somewhat arbi- 286

of the terms used in any morphological descriptions. 288

2.1. Dry methods 289

Dry methods do not use a solvent, unlike wet methods. 290

According to the literature, the characteristics of a powder syn-

thesized by a dry method are not strongly inﬂuenced by the 292

precisely controlled conditions, making them suitable for mass 294

production of powders. A number of researchers have therefore 295

adapted well-known dry methods, including solid-state synthe- 296

sis and the mechanochemical process, for the preparation of 297

2.1.1. Solid-state synthesis 299

Solid-state reaction, as a relatively simple procedure, can be 300

employed in the mass production of HAp powder [78–81]. Sup-

plementary Table S1 shows recent progress in the synthesis of 302

HAp powder using the solid-state method. In a typical proce- 303

and phosphate-containing chemicals of various types or simply 306

a previously prepared CaP salt. The high temperature of calcina- 307

tion leads to the formation of a well-crystallized structure. The 308

general process is shown in Fig. 4. As a disadvantage, the pow- 309

der synthesized by a solid-state reaction often exhibits hetero- 310

geneity in its phase composition, owing to the small diffusion 311

coefﬁcients of ions within the solid phase [79,80]. Recently, Pra-

with a single phase, using powder mixing and cold pressing.

For this, samples were prepared by mixing the ingredients, fol-

lowed by sintering the cold-compacted pellets at various tem-

peratures up to 1250 °C. However, this powder was irregular 317

in shape, with micron-sized grains. Some attempts have also 318

been made to achieve a powder with a regular shape or a nano- 319

pare one-dimensional (1-D) HAp. The MSS technique is based 322

on the use of low-melting ﬂuxing agents, e.g. alkali chlorides, 323

sulfates, carbonates or hydroxides, as the medium for the reac- 324

tion. In this study, a previously synthesized submicron HAp 325

M. Sadat-Shojai et al. / Acta Biomaterialia xxx (2013) xxx–xxx 5

the solid-state process unattractive, both scientiﬁcally and techno- 374

2.1.2. The mechanochemical method 376

6 M. Sadat-Shojai et al. / Acta Biomaterialia xxx (2013) xxx–xxx

Shape Name(s) in literature Approx. size range Method(s) of

sphere, microsphere, nanosphere, ball 10 nm–1000 lm mch, cc, sg, hth,

ﬂower 700 nm–60 lm (organized petals of 20 nm–10 lm cc, hth, bs

porous microsphere, mesoporous sphere 0.5–7 lm (pores of 20–150 nm) hth, cp

bowknot, self-assembled nanorods 1.5–2.5 lm (organized nanorods of 100–150 nm cp

dumbbell 2–3 lm (organized nanoparticles of 50 nm size) cc

Fig. 4. Preparation of HAp powder via solid-state method.

M. Sadat-Shojai et al. / Acta Biomaterialia xxx (2013) xxx–xxx 7

8 M. Sadat-Shojai et al. / Acta Biomaterialia xxx (2013) xxx–xxx

Fig. 5. Preparation of HAp nanoparticles via mechanochemical method.

M. Sadat-Shojai et al. / Acta Biomaterialia xxx (2013) xxx–xxx 9

Fig. 6. Preparation of HAp nanoparticles via conventional chemical precipitation.

10 M. Sadat-Shojai et al. / Acta Biomaterialia xxx (2013) xxx–xxx

M. Sadat-Shojai et al. / Acta Biomaterialia xxx (2013) xxx–xxx 11