Acta Biomaterialia 151 (2022) 70–87
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Acta Biomaterialia
journal homepage: www.elsevier.com/locate/actbio
Review article
α -TCP-based calcium phosphate cements: A critical review
Matheus C. Tronco, Júlia B. Cassel, Luís A. dos Santos∗
Biomaterials Laboratory, Materials Department, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS 91501-970, Brazil
a r t i c l e
i n f o
Article history:
Received 11 May 2022
Revised 4 August 2022
Accepted 17 August 2022
Available online 24 August 2022
Keywords:
α -TCP
Calcium phosphate cements
Bioceramics
Bioresorbable
a b s t r a c t
Calcium phosphates are promising materials for applications in bone repair and substitution, particularly
for their bioactivity and ability to form self-setting cements. Among them, α -tricalcium phosphate (α TCP) stands out due to its high solubility, its hydration reaction and bioresorbability. The synthesis of α TCP is particularly complex and the interactions between some of the synthesis parameters are still not
completely understood. The variety of methods available to synthesize α -TCP has provided a substantial
variance in the properties of α -TCP-based cements and the decision about which method, parameters
and starting reagents will be used for the powder’s synthesis is determinant of the properties of the
resulting material. Therefore, this review paper focuses on α -TCP’s synthesis and properties, presenting
the synthesis methods currently in use as well as a discussion of how the synthesis parameters and the
cement preparation affect the reactivity and mechanical properties of the material, providing a guide for
the selection of the most suitable process for each α -TCP application.
Statement of significance
α -TCP is a calcium phosphate and it is currently one of the most investigated bioceramics for applications
that explore its bioresorbability and the hydration reaction of α -TCP-based cements. Despite the increasing number of publications on the topic, there are still aspects not well understood. This review article
aims at contributing to this fascinating subject by offering an update on the state of the art of α -TCP’s
synthesis methods, while also addressing topics that are not often discussed about this material, such
as the preparation of α -TCP-based cements and how its parameters affect the properties of the resulting
cements.
© 2022 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.
1. Introduction
The development of bone substitutes is a prominent field
within biomaterials research, as their demand in medical applications is growing due to the increase in life expectancy, accidents and injuries, combined with technical advances that allow
for better options of treatment for patients. Calcium phosphates
have been widely investigated for applications in bone repair and
substitution since the beginning of the 20th century [1]; as their
chemical composition is closely related to that of the inorganic
part of natural bone tissue, these materials generally offer good
biocompatibility, especially when compared to other bone repairing materials such as titanium and stainless steel [2]. Since the
early 1980s, based on work conducted by LeGeros [3] and Brown
and Chow [4], calcium phosphates are also used for producing self-
∗
Corresponding author.
E-mail addresses: ctr.matheus@gmail.com (M.C. Tronco), juliabcassel@gmail.com
(J.B. Cassel), luis.santos@ufrgs.br (L.A. dos Santos).
https://doi.org/10.1016/j.actbio.2022.08.040
1742-7061/© 2022 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.
setting cements at body temperature. These cements typically set
as a bioresorbable phase that can be replaced by new bone tissue. Among the calcium phosphates, α -tricalcium phosphate (α TCP, Ca3 (PO4 )2 ) is of particular interest due to its several advantageous properties, such as high solubility in aqueous solutions,
its hydration reaction occurring at physiological pH and the precipitation of calcium-deficient hydroxyapatite (CDHA) after setting,
which results in a significantly bioresorbable material.
TCP has three polymorphs: β -, α - and α ’-TCP. In pure TCP, β TCP is stable up to 1120 °C; above this temperature it transforms
to α -TCP, which is stable from 1120 to 1430°C and can be retained
as a metastable phase at room temperature [5]; above 1430°C the
stable phase is α ’-TCP, which cannot exist at room temperature
[6,7]. The β -TCP structure was first described by Dickens et al.
[8], and later refined by Yashima et al. [9]; this phase crystallizes
in the rhombohedral system and belongs to the space group R3c,
with unit cell parameters a = b = 10.4352 Å, c = 37.4029 Å. α TCP crystallizes in the monoclinic system and belongs to the space
group P21 /a, and the parameters of the unit cell are a = 12.859 Å,
M.C. Tronco, J.B. Cassel and L.A. dos Santos
Acta Biomaterialia 151 (2022) 70–87
Table 1
Main methods to synthetize α -TCP.
b = 27.354 Å, c = 15.222 Å, β = 126.35°, as determined by Mathew
et al. [5] and revised by Yashima and Sakai [10]. A discussion of
the structural differences between β -, α - and α ’-TCP is found in
Carrodeguas and Aza [11].
Both α - and β -TCP are used in clinical applications of bone
repair, with the β - phase typically used for preparing bone graft
substitutes, while the α - phase is used as a major component of
several hydraulic bone cements [1,12]. The phase purity of the
obtained TCP influences various biological properties of the final
product, as the structural differences between these phases affect
the solubility, reactivity and biodegradability of the material. α -TCP
has higher solubility in aqueous solutions than the β -phase, which
gives it its higher reactivity and resorbability and allows its hydration to CDHA, which is crystallographically, chemically and morphologically more similar to the mineral phase of bone [1,13,14].
The preparation of α -TCP–based cements is particularly complex,
since many parameters are involved in the determination of the
properties of calcium phosphate cements (CPC), such as the particle size, liquid-to-powder (L/P) ratio, and fraction of amorphous
phase present. Therefore, variations in composition resulting from
the synthesis, such as the presence of β -TCP or hydroxyapatite
(HA) impurities in the final product [15,16], and in the properties
of these cements are often observed. This review paper focuses on
α -TCP’s synthesis and properties, discussing the synthesis methods currently available and how the synthesis parameters, such as
temperature and pH, can affect the reactivity and mechanical properties of the material, with particular attention to the α -TCP–based
cements.
sition, crystallinity, crystallite size, Ca/P ratio and specific surface
area (SSA) [18,19].
This section provides an overview of the main methods used to
synthesize α -TCP. The methods presented here are classified into
three categories: solid-state reaction, wet chemical reaction, and
alternative methods. This classification is summarized in Table 1.
2.1. Solid-state reaction
This is the most conventional method to synthesize α -TCP,
comprising about 65% of the reviewed papers (Fig. 1(a)). In this
method, solid reagents in the form of powders are mixed and
then calcined at high temperatures. A sequence of solid-state reactions occurs, culminating on the formation of β -TCP and its further transformation to the high-temperature polymorph α -TCP at
temperatures above the β →α transition temperature. Powders are
usually milled after calcination due to the coarse particle size resulting from the high temperature treatment [20].
The reagents usually employed as starting powders and their
corresponding global reactions to form TCP are:
2. Synthesis methods
In order to obtain α -TCP, it is necessary to perform a thermal
treatment on a calcium phosphate precursor with a calcium-tophosphorous (Ca/P) ratio close to 1.50 [17], being the proportion
of Ca to P atoms in pure TCP. The precursor may be amorphous
calcium phosphate (ACP), CDHA or β -TCP. There is a variety of
methods available to prepare these precursors, which, in combination with the synthesis conditions, will determine most of the
properties of the resulting α -TCP powder, such as phase compo-
CaCO3 (s) + 2CaHPO4 (s) → Ca3 (PO4 )2 (s) + CO2 (g) + H2 O (g)
[21–23]
(1)
CaCO3 (s) + Ca2 P2 O7 (s) → α -Ca3 (PO4 )2 (s) + CO2 (g) [22, 24]
(2)
3CaCO3 (s) + 2NH4 H2 PO4 (s) → Ca3 (PO4 )2(s) + 3H2 O (g) +
3CO2(g) + 2NH3(g) [22, 25]
(3)
Ca10 (PO4 )6 (OH)2 (s) + 2CaHPO4 (s) → 4Ca3 (PO4 )2 (s) + 2H2 O (g)
[26]
(4)
Mortier et al. [27] found that stoichiometric mixtures of HA and
anhydrous dicalcium phosphate (DCPA, CaHPO4 ), as well as CDHA
with Ca/P= 1.50, transform directly into β -TCP within the temperature range of 70 0–10 0 0°C, and it is possible to obtain the α 71
M.C. Tronco, J.B. Cassel and L.A. dos Santos
Acta Biomaterialia 151 (2022) 70–87
Fig. 1. (a) Proportion of use of the main α -TCP synthesis methods in reviewed papers; (b) proportion of use of α -TCP synthesis methods on papers published over the last
five years. SS: solid-state reaction; WS: wet chemical reaction; AM: alternative methods. Total number of papers considered on the construction of the graph: 136.
phase with further heat treatment at higher temperatures. Since
then, some authors reported the use of HA and DCPA as precursors
(Eq. (4)) in a mixture with Ca/P= 1.50 [26,28]. However, the most
recent use of this combination of precursors among the papers reviewed was reported in 1996 [28]. This indicates that this combination is not a typical choice, despite Famery et al. [26] suggesting
that the transformation of β -TCP to α -TCP may be easier for powders produced from the reaction between HA and DCPA than for
those produced from the reaction between CaCO3 and DCPA at increased temperatures.
Calcium pyrophosphate (CPP, γ -Ca2 P2 O7 ) can be prepared by
dehydration of DCPA [22,29,30] or of its dihydrate form (DCPD,
CaHPO4 .2H2 O) [31–33]; most researchers choose to synthesize CPP
by this route rather than purchasing it. In fact, the dehydration of
dicalcium phosphate is one of the steps of the synthesis starting
from CaCO3 and CaHPO4 [21,34]. Durucan and Brown [22] compared the reactivity of α -TCP prepared according to each of the
three routes in Eqs. (1)–(3) using the same Ca source, which was
also used to synthesize CPP and CaHPO4 . They found that α -TCP
synthesized from CPP and CaCO3 had higher reactivity than α -TCP
prepared with CaHPO4 and CaCO3 , which was attributed to the difference in SSA of the materials; α -TCP prepared from CaCO3 and
NH4 H2 PO4 was the least reactive of all three.
Regarding the crystalline phases obtained after synthesis by
solid-state reaction, no significant differences were observed that
could be directly related to the choice of any particular combination of reagents, considering the literature reviewed.
9Ca(NO3 )2 .4H2 O + 6(NH4 )2 HPO4 → 3Ca3 (PO4 )2 + 36H2 O
+ 18HNO3 + 12NH3
(7)
9CaCl2 + 6Na3 PO4 → 3Ca3 (PO4 )2 + 18NaCl
(8)
Wet reaction methods require a more careful control of the
synthesis parameters (such as pH, temperature, concentration and
Ca/P ratio) in comparison to solid-state reactions [40,41]. The formation of undesired by-products such as CPP and HA is quite
common, and is often the result of Ca/P ratios differing from
1.50 [17,42,43]. The order of addition of the reagents can also
affect the result of the synthesis. Thürmer et al. [39] evaluated
the influence of the order of addition of the reagents to prepare α -TCP according to Eq. (6). Using H3 PO4 as the titrant and
Ca(NO3 )2 .4H2 O as the titrated species resulted in high-purity α TCP; when Ca(NO3 )2 .4H2 O was used as the titrant, the resulting
material contained β -TCP as an impurity for all evaluated calcination temperatures.
2.3. Alternative methods
Besides solid-state and wet chemical reactions, which are the
most widely applied methods in the synthesis of α -TCP, some
other processes have been attempted with occasional success in
obtaining this material. This section provides an overview of the
literature published on these methods.
2.2. Wet chemical reaction
2.3.1. Combustion
self-propagating high temperature combustion synthesis (SHS)
consists of mixing easily oxidized reactants with an organic fuel
and heating the mixture until auto-ignition occurs, initiating a
rapid and self-sustained reaction [44,45]. Conventional combustion
synthesis utilizes solid-state reactions of reagents in powder form,
while in decomposition combustion synthesis (DCS) the reagents
are mixed in a solution and form a gelatinous foam prior to ignition [45,46]. In general, aqueous solutions of the precursors are
used for DCS; nevertheless, simulated body fluid (SBF) has also
been used as the solution medium for this synthesis [47]. The reaction product is multiphasic in nature; it usually consists of a
dry powder or foam composed of TCP, HA and CPP, which may
also contain ACP [45,48,49], and high-purity α -TCP can be produced by thermal treatment of the reaction product [44,46]. Several parameters influence the combustion reactions, including nature of the fuel, fuel-to-oxidizer ratio, auxiliary oxidizers, and pH
[44]. The synthesis time is significantly lower than for solid-state
or wet chemical reactions, and it is possible to achieve complete
conversion of reactants even with short residence periods at high
temperature [46,49]. Most researchers utilize Ca(NO3 )2 .4H2 O and
(NH4 )2 HPO4 as the Ca and P sources and urea (or urea and glycine)
as the fuel [44–47]. The process is relatively simple, not requiring
Wet chemical reaction is a common method to prepare calcium
phosphates, and its use to synthesize α -TCP has been increasing
recently (Fig. 1(b)). It has not been possible to obtain α -TCP directly by wet chemical reaction so far [35,36]. Therefore, chemical reactions in liquid solutions are used to prepare ACP or CDHA
precipitates with a molar Ca/P ratio close to 1.50; these precipitates are then washed, dried and calcined to obtain the desired α TCP phase. This method offers the possibility to obtain this phase
at both high and low temperatures, depending on the precursor
formed by the precipitation reaction: CDHA firstly crystallizes into
β -TCP, and, thus, needs high-temperature treatment to transform
into α -TCP; conversely, ACP can crystallize to α -TCP before β -TCP
at much lower temperatures [20].
The global reactions for the most used combinations of reagents
are:
9Ca(OH)2 + 6H3 PO4 → 3Ca3 (PO4 )2 + 18H2 O [37]
(5)
9Ca(NO3 )2 .4H2 O + 6H3 PO4 → 3Ca3 (PO4 )2 + 36H2 O + 18HNO3
[38, 39]
(6)
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Acta Biomaterialia 151 (2022) 70–87
Ca2 P2 O7 + CaO → β -Ca3 (PO4 )2
such strict control of parameters as observed for the wet chemical
reaction method.
β -TCP is then transformed to the α - phase upon heating above
the transition temperature, determined by Nurse et al. to be 1125°C
for pure TCP [7]:
2.3.2. Flame spray pyrolysis
in this method, a solution with a determined Ca/P ratio is fed
by a carrier gas into a diffusion flame composed of fuel and oxidizer gases; the flame ignites the material, promoting the reactions [40,50]. The synthesis product is usually ACP, due to the
rapid cooling rate inherent to the process, and it can be transformed in α -TCP by further heat treatments [19,51]. However, Cho
et al. [50] prepared α -TCP powders directly by flame spray pyrolysis without further heat treatments; the α - phase was stable up to
700 °C. For their synthesis, the reagents used were Ca(NO3 )2 .4H2 O
and (NH4 )2 HPO4 , with ethanol and distilled water as solvents; others authors used calcium oxide (CaO) dissolved in 2-ethylhexanoic
acid and tributyl phosphate [19,40,51]. Cho et al. [50] also observed
that the proportion of ethanol to water in the solvent affected the
temperature of the diffusion flame and the morphologies of the resulting powders.
β -Ca3 (PO4 )2 → α -Ca3 (PO4 )2
Ca10 (PO4 )6 (OH)2 + Ca2 P2 O7 → 4Ca3 (PO4 )2 + H2 O ↑
[27, 36]
2.3.4. Sol-gel
In this method, a solution containing a Ca precursor is prepared, matured for several hours and then mixed with a P precursor solution, forming a transparent sol. The sol is aged until
it forms a white dry gel, which is calcined to obtain CDHA. Heat
treatment at high temperature leads to formation of α -TCP [55].
Sayer et al. [56] obtained Si-doped α -TCP by calcining HA synthesized via sol-gel in the presence of colloidal SiO2 , which was
added to the solution before aging. The powder was calcined at
10 0 0°C, obtaining Si-TCP as the main phase, along with HA, β -TCP
and an amorphous phase. Roozbahani et al. [55] also prepared Sistabilized α -TCP but using a two-step process, consisting of preparation of CDHA via sol-gel and then milling the powder with SiO2
before thermal treatment. The resultant material was pure, wellcrystallized α -TCP nanopowder. Gozalian et al. [57] used a sol-gel
synthesis with a higher Ca/P ratio (1.67), obtaining a mixture of α TCP, HA and residual CaO, which is usually formed during sol-gel
synthesis of HA.
(13)
Wet chemical reactions can produce two different calcium
phosphate precursors, ACP or CDHA, depending on the initial
reagents. Starting from calcium hydroxide and phosphoric acid
(Eq. (5)) forms CDHA as an intermediate, as follows:
9Ca(OH)2 + 6H3 PO4 → Ca9 (HPO4 )(PO4 )5 OH + 17H2 O [37] (14)
Transformation of CDHA into α -TCP upon calcination:
Ca9 (HPO4 )(PO4 )5 OH → 3Ca3 (PO4 )2 + H2 O [37, 59]
(15)
The transformation in Eq. (15) occurs by the loss of adsorbed
water and dehydration of HPO4 2− ions into pyrophosphate ions between 20–700 °C, and then a reaction between the OH− ions of
apatite and the pyrophosphate ions formed between 70 0–80 0 °C,
leading to the formation of TCP [27,35]. Using Ca(NO3 ).4H2 O instead of Ca(OH)2 as the Ca source (Eq. (6)) gives a similar result,
with additional formation of HNO3 as a by-product in the first step.
The reagents in Eq. (7) can lead to two calcium phosphate precursors, CDHA and ACP, depending on synthesis conditions. Thermal evolution from CDHA to TCP occurs in a similar way to that
described in Eqs. (14) and (15), with additional formation of HNO3
and NH3 as by-products in the first step (Eq. (14)).
When ACP is the precursor, formation of α -TCP occurs by crystallization of the amorphous phase. Eanes [60] showed that ACP
crystallizes into α -TCP upon heat treatment in absence of water at
temperatures in which the α - phase is unstable, and α -TCP forms
even in the presence of the β - phase. Eanes suggested that the
crystallization of ACP to α - and β -TCP are two independent events
controlled by kinetic factors, which explains why it is possible to
obtain pure α -TCP below the β →α transition temperature. The fact
that the unstable α -TCP crystallizes before the stable β - phase is
3. Thermal evolution from precursors to α-TCP
The synthesis of α -TCP by the solid-state method comprises a
series of reactions. For CaCO3 and CaHPO4 as initial reagents, as in
Eq. (1), the process is as follows [21,34]:
420–520°C: dehydration of dicalcium phosphate to form CPP:
(9)
70 0–90 0°C: decomposition of calcium carbonate:
CaCO3 → CaO + CO2 ↑
(12)
The process follows a similar path if the starting reagents are
CaCO3 and CPP, excluding only the first step as CPP is already
formed. The synthesis of α -TCP from CaCO3 and NH4 H2 PO4 Eq.
(3)) is much more complex. TenHuisen and Brown [58] studied
the reaction path to form α -TCP by this route, which starts with
the melting of NH4 H2 PO4 into an acidic liquid and its reaction
with CaCO3 , liberating NH3 , CO2 and H2 O gases. This is followed
by the formation of several intermediate phases, both amorphous
and crystalline. Between 80 0–90 0 °C, the decomposition of the remaining CaCO3 results in a mixture of CaO, HA and β -CPP, which
forms phase-pure β -TCP and finally α -TCP. This route is not commonly used, appearing in only three papers out of 136 considered.
This may be due to the poor reactivity of the α -TCP obtained from
these reagents in comparison to that obtained from reagents in
Eqs. (1) and ((2) [22], as well as to the complexity of the reactions
involved.
The formation of α -TCP from HA and DCPA (Eq. (4)) occurs
by reaction of HA with β -CPP, formed from the decomposition
of DCPA as shown in Eq. (9). The reaction appears to start at
600°C, but its rate only becomes appreciable at higher temperatures (above 900 °C) [27]. The reaction is as follows:
2.3.3. Hydrothermal synthesis
Jokic et al. [52,53] and Kojic et al. [54] used a modified hydrothermal method to obtain CDHA and further transform it to α TCP. In this method, CDHA is prepared by the hydrothermal decomposition of urea and EDTA chelates. These reagents are dissolved in
a solution with Ca and P sources and the solution is annealed at
160°C in a sealed tube. The P source was NaH2 PO4 , and for the Ca
source Jokic et al. used CaCl2 [52,53], while Kojic et al. opted for
Ca(NO3 )2 [54]. The particles obtained are washed, dried and heattreated to produce α -TCP [52]. The resulting material is a mixture
of calcium phosphates and it is possible to have α -TCP as the preponderant phase [53].
2CaHPO4 → Ca2 P2 O7 + H2 O ↑
(11)
(10)
780–1100°C: reaction between CPP and calcium oxide:
73
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Acta Biomaterialia 151 (2022) 70–87
in accordance with Ostwald’s step rule on the law of successive reactions. Van Santen [61] elucidated this rule by showing that, under certain conditions, a transformation passing through an unstable intermediate minimizes the entropy increase of the system in
comparison to a direct transformation. Researchers have suggested
that α -TCP forms faster from ACP than β -TCP [62]. A possible explanation is that the short-range structure of ACP is more similar
to the structure of α -TCP, belonging to the space group P2l /a, than
to that of β -TCP, belonging to the space group R3c [63]. Wet chemical reactions starting from CaCl2 and Na3 PO4 (Eq. (8)) also lead to
the formation of ACP, which crystallizes into α -TCP as previously
described [62,64].
Combustion synthesis methods result in a mixture of calcium
phosphates; the formation of α -TCP depends on the composition of
the mixture and conditions of the heat treatment applied. In fact,
the mechanism of reactions in combustion synthesis is quite complex [44]. The other alternative methods obtain either ACP, in the
case of flame spray pyrolysis, or CDHA, for hydrothermal and solgel syntheses. Maciejewski et al. [51] studied the thermal evolution
of ACP prepared by flame synthesis. The first phases to crystallize within the temperature range of 60 0–70 0 °C, were α -TCP and
CPP, depending on the Ca/P ratio. α -TCP was transformed into β TCP between 870–950 °C; above 1140 °C, β -TCP transformed back
into the α - phase. This evolution was similar to the one observed
by Somrani et al. [65] for ACP prepared by wet chemical reaction.
Gozalian et al. [57] studied the thermal evolution of precursors of
α -TCP synthesized via the sol-gel method. The initial material was
amorphous; first phase to crystallize is CDHA, followed by β -TCP
and then α -TCP, at 1200 °C. The behavior was similar to the one
observed by Jokic et al. [53] for CDHA prepared by hydrothermal
synthesis.
This formula represents an apatite structure containing Ca defects and substitution of some PO4 3− groups by HPO4 2− . X= 0 corresponds to HA, while X = 1 corresponds to CDHA with a Ca/P of
1.50, the same value as in TCP and, thus, the one generally used
to synthesize both α - and β -TCP. For X between 0 and 1, CDHA
decomposes into biphasic mixtures of HA and TCP above 700 °C
according to the overall reaction (Eq. (16)):
Ca10-x (HPO4 )x (PO4 )6-x (OH)2-x → (1-x)Ca10 (PO4 )6 (OH)2 +
3xCa3 (PO4 )2 + xH2 O [35, 36, 68, 69]
(16)
Maintaining a Ca/P ratio close to 1.50 should lead to β - and/or
α -TCP after calcination, depending on calcining temperature; for a
Ca/P ratio between 1.50 and 1.67, a mixture of HA and TCP will
be produced [36,68]. To prepare CDHA via wet chemical reaction,
the pH of the solution is maintained between 7 and 9 and the reaction temperature is approximately 30–60 °C. Adjustments of pH
are usually made by adding concentrated ammonium hydroxide
(NH4 OH) to the solution, which can be done once at the beginning of the synthesis [59,68] or, alternatively, by monitoring the
pH continuously during the reaction and adding NH4 OH as needed
to maintain the pH within the desired range [43]. Variations in pH
can lead to the formation of other phases; Thürmer et al. [39] performed the synthesis adjusting the pH to 4.0, which resulted in
the formation of CPP as the predominant phase and the subsequent melting of the material at the highest calcination temperatures used (above 1400 °C). According to Destainville et al. [70],
the Ca/P ratio of precipitates is proportional to the pH value, due
to its effect on the kinetics of precipitation reactions of wet chemical synthesis. The authors observed that, for synthesis of β -TCP,
a pH of 8.0 resulted in precipitates with Ca/P ratio of 1.51, due to
the crystallization of some CDHA; the final composition contained
5 wt. % HA. A pH of 6.0 led to precipitates with a Ca/P ratio of
1.48, containing some DCPA as a second phase; after calcination,
the material was composed of β -TCP and 5 wt. % CPP. Zima et al.
[71] obtained α -TCP with 7 wt. % HA after synthesis with pH ranging from 5.0 to 5.5, but no information was provided regarding
the Ca/P ratio of reagents. Bakan [72] was able to synthesize pure
phase β -TCP by wet chemical reaction performed at pH 5.5; the
Ca/P ratio of 1.55 used in the synthesis might have compensated
for the tendency of deviation of Ca/P ratio toward lower values under acidic pH. The Ca/P ratio of the precipitates is also affected by
the aging time, gradually increasing as the solution is aged or maturated for longer periods [70,73].
The synthesis of ACP by wet precipitation is particularly difficult, since this is a metastable phase and readily undergoes hydration through a dissolution-recrystallization mechanism, precipitating as CDHA [64]. ACP is a transient phase in the process of
HA synthesis in solution; its structure contains only short-range
ordering [74]. Ca9 (PO4 )6 clusters (also known as “Posner’s clusters”) are the first arranged structure formed during calcium phosphate precipitation, being subsequently agglomerated and forming
larger spherical particles surrounded by water as shown in Eq. (17)
[64,65]. These agglomerated ACP clusters are unstable and convert
into crystalline HA in solution according to Eq. (18):
4. Synthesis of calcium phosphate precursors
4.1. Calcium to phosphorous ratio
The Ca/P ratio is one of the most important parameters in determining the content of α -TCP in the final synthesis product. α TCP has a Ca/P ratio of 1.50, and so the mixture of reagents or
calcium phosphate precursors is calculated to achieve a Ca/P ratio close to this value. However, it must be considered that the
Ca/P ratio of the synthesized material may differ from the one expected. In the wet chemical reaction synthesis of TCP, slight deviations of the Ca/P ratio relative to the theoretical value are likely to
occur. A higher Ca/P ratio favors the formation of minor amounts
of HA, while Ca/P ratios lower than 1.50 often result in the formation of CPP as an impurity or second phase [40,43]. Brazete et al.
[43] and Maciejewski et al. [51] detected CPP impurities when using a Ca/P ratio of 1.50 in wet chemical reaction and flame synthesis methods, respectively; the use of a slight excess of Ca was
effective in preventing the formation of CPP. In the solid-state synthesis, a certain loss of PO4 may occur by evaporation during the
thermal treatment, which deviates the Ca/P ratio to values higher
than 1.50 and can result in phase changes on the surface layers of
the material [66]. The deviation of the Ca/P ratio depends on the
temperature and duration of the thermal treatment and also on the
furnace conditions, such as ventilation and pressure [66,67]. Therefore, it may be necessary to compensate for the PO4 loss to obtain
a Ca/P ratio of 1.50, depending on the synthesis conditions.
4.2. Preparation of CDHA and ACP precursors via wet chemical
reaction and alternative methods
Ca2+ + PO4 3− → Ca9 (PO4 )6 .xH2 O → [Ca9 (PO4 )6 ]n .mH2 O
(17)
[Ca9 (PO4 )6 ]n .mH2 O → nCa9 (PO4 )6 + Ca2+ →
Ca10-x (HPO4 )x (PO4 )6-x (OH)2-x (0 ≤ X ≤ 1)
(18)
The structure of Ca9 (PO4 )6 is similar to that of HA [65], but
presents some distorted positions; atoms in those positions have
a tendency to rearrange to form a more stable structure of HA,
which is likely the reason for the rapid conversion of ACP to HA
Calcium-deficient apatites can be represented by a general formula, considering that their Ca/P ratio lies between 1.50 and 1.67:
Ca10-x (HPO4 )x (PO4 )6-x (OH)2-x .nH2 O (0 ≤ X ≤ 1) [27]
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Acta Biomaterialia 151 (2022) 70–87
[64]. At room temperature, ACP is usually stable up to about 5 h;
lower temperatures can extend this time, and drying the precipitates will stop the hydrolysis process [75]. On the other hand, according to Döbelin et al. [19], ACP prepared by flame spray synthesis is completely dehydrated and, therefore, does not present
cluster arrangements. As the charge balance of CDHA typically involves hydration or precipitation reactions, the possibility of forming CDHA upon thermal treatment of a fired raw material is questionable [19].
Several parameters can affect the transformation of ACP into
CDHA, including aging time, pH and composition of solution, ACP
particle size, and temperature [74]. Researchers successfully prepared ACP by keeping the pH alkaline by the addition of concentrated NH4 OH; further thermal treatment of ACP resulted in materials with α -TCP-rich content [17,42,65,75]. Drying or lyophilizing
the precipitates is also a common procedure [20,62,74].
Li et al. [64] proposed a complexation mechanism using polymers to stabilize the ACP prepared by wet chemical reaction,
avoiding the formation of HA. The polymers form complexes with
Ca(II) and are incorporated into the ACP clusters instead of water, which retards the precipitation of ACP into crystalline HA due
to steric hindrance. Using polyethylene glycol (PEG) as the complexing agent, ACP remained stable in the solution for up to 18 h
[74]. Zou et al. [62] successfully prepared α -TCP by the described
method, using CaCl2 and Na3 PO4 in solution with PEG at 5°C and
freeze-drying the precipitates for 48 h. An adaptation to this technique was proposed using β -cyclodextrin (β -CD) as the complexing agent, which allowed a higher reaction temperature (25°C) and
lower polymer content [76]. The principle is similar to the use of
PEG; β -CD molecules are adsorbed on the surface of the ACP precipitates, reducing their solubility. The use of β -CD allowed the
stabilization of ACP in solution for more than 24 h. Based on this
work, Wang et al. [63] and Ge et al. [77,78] successfully employed
β -CD to obtain ACP with a Ca/P ratio of 1.50 and then convert it
to α -TCP. Wang et al. [63] also evaluated the effect of the reaction
temperature during ACP preparation on the final phases obtained.
Pure α -TCP was only achieved for ACP prepared at 25 ± 3°C, the
same temperature used by Li et al. [76]; for ACP prepared at 18 or
30°C, the result was a mixture of α - and β -TCP.
Washing the precipitates from wet chemical reactions is a common procedure to remove soluble ions remaining from the initial solution and adsorbed ions from the surface of precipitates,
such as K+ , Na+ , NH4 + , NO3 − and Cl− [59,62,76]. Sinusaite et al.
[42] found that the solvent used for washing the as-prepared precipitates from wet chemical synthesis of TCP determines the formation of an amorphous (ACP) or crystalline (CDHA) structure,
thus affecting the TCP phases obtained after thermal treatment of
the precipitates. Acetonitrile (ACN) and alcohols (ethanol and isopropanol) led to the formation of ACP, while water and acetone or
lower amounts of solvents favored the formation of CDHA. A possible explanation is that ACN, ethanol and isopropanol can bond
to water molecules from the reaction medium, reducing the interaction of these molecules with the precipitated particles and,
thus, interrupting the process of agglomeration of ACP clusters and
their hydration into CDHA. Moreover, these solvents accelerate the
drying of precipitates, leaving them in contact with water for a
shorter period which slows the transformation of ACP to CDHA
[42,75]. Vecbiskena et al. [75] studied the effect of treating the
precipitates with either water or ethanol. Precipitates treated with
ethanol and further dried in oven formed α -TCP after calcination
at relatively low temperatures (70 0–80 0 °C). For samples that were
only washed with water and lyophilized, it was not possible to obtain pure α -TCP [75]. These results corroborate the evidence that
precipitates treated with ethanol retain the ACP structure due to a
reduction in the interactions of water molecules with the calcium
phosphate precipitates.
Fig. 2. Percentage of papers applying each temperature range for calcination of α TCP precursor relative to the total amount of papers considered for each synthesis
method. SS: solid-state reaction; WS: wet chemical reaction; AM: alternative methods. Total number of papers considered was 90 for SS, 41 for WS and 15 for AM. All
reference articles were used for the construction of this graph [1–195].
On a final note, it is important to mention that not every ACP
type transforms into α -TCP [19]. ACP may possess different structures, and Li et al. [74] found that the short-range order of the
structure changes with aging in the solution. At shorter aging
times, the structure of ACP resembles that of HA, and, thus, favors
the crystallization of α -TCP on calcination; with increasing aging
times, the structure becomes more similar to that of β -TCP, and
this phase crystallizes first. The pH of the solution affects the crystallization of ACP; higher pH favored the formation of α -TCP, while
pH of 8 or 9 resulted in β -TCP and neutral pH favored the formation of CPP, due to HPO4 2− ions entering the structure of ACP [74].
Cacciotti et al. [35] also noted the presence of CPP under neutral
pH conditions during synthesis. Li et al. [74] attributed the differences in crystallization of TCP phases to the structures of ACP being different under different solution pH conditions for the same
aging time. These observations allow the use of aging time and pH
to control the α -TCP content in the final product [74].
5. Temperature of calcination and dwelling time
In order to obtain α -TCP, the calcium phosphate precursor must
be calcined at a certain temperature. Usually, the synthesis routes
form β -TCP prior to the desired α - phase; therefore, it is required
that calcination is performed above the β →α transformation temperature. This temperature was determined by Nurse et al. [7] as
1125 °C; however, in practice this temperature is considered too
low to achieve a complete transformation. The β →α transformation temperature may be affected by several factors, such as the
presence of impurities in the reagents or precursors, deviations
of the Ca/P ratio resulting in the formation of secondary phases,
or doping elements intentionally added during synthesis [79,80].
Thermal analyses carried out in different reports have identified
the β →α transformation temperature as 1115 ± 10 °C [81], 1150 °C
[70,82], 1157–1195 °C [43] and 1182.4 °C [16].
For the synthesis of undoped α -TCP by solid-state reaction, the
calcination temperature chosen is usually between 1300 and 1400
°C, as can be seen in Fig. 2 which shows the percentage of papers
reporting each temperature range for each synthesis method. Synthesizing α -TCP by wet chemical reaction offers two possibilities
for calcination temperature, depending on the calcium phosphate
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Acta Biomaterialia 151 (2022) 70–87
Fig. 3. Percentage of papers applying each dwelling time range for calcination of α TCP precursor relative to the total number of papers considered for each synthesis
method. SS: solid-state reaction; WS: wet chemical reaction; AM: alternative methods. Total number of papers considered was 81 for SS, 39 for WS and 17 for AM.
All reference articles were used for the construction of this graph [1–195].
Fig. 4. Percentage of α -TCP phase obtained during synthesis by solid-state reaction
and wet chemical reaction methods as a function of the dwelling time at the calcination temperature. All reference articles were used for the construction of this
graph [1–195].
precursor formed by the reaction. If the precursor is CDHA then it
will lead to the formation of β -TCP and, thus, it will be necessary
to calcine the material above the β →α transformation temperature, as is done in solid-state reactions. If the precursor is ACP, it
is possible to synthesize α -TCP at temperatures as low as 650 °C
through crystallization of ACP, resulting in a high-purity powder
with α -TCP content of 97 wt. % or higher [20]. In their work regarding the thermochemical behavior of ACP, Eanes [60] showed
that it is possible to crystallize ACP to α -TCP and/or β -TCP by submitting it to heat treatment in the absence of water. The α -TCP
phase appeared at around 600°C, similar to the temperature reported by Somrani et al. [65]. This temperature depends on conditions such as solution concentration and Ca/P ratio of the material.
A higher solution concentration favors the formation of α -TCP at
lower temperatures [60]; the presence of CPP, reported to inhibit
the crystallization of ACP, shifts the temperature of formation of
α -TCP to higher values [51,83]. α -TCP formed at low temperatures
transforms to β -TCP at around 900 °C [51,65].
The use of higher calcination temperatures affects the hydraulic
reactivity of α -TCP, diminishing the formation of CDHA by hydration. This occurs due to excessive temperature leading to deadburning and microstructural coarsening, which hinders the α -TCP
dissolution [22,23].
The dwelling time at the calcination temperature must be sufficient to allow the complete transformation of β -TCP to α -TCP,
and this will depend on the amount of material being synthesized.
Fig. 3 shows the percentage of papers per dwelling time interval
for each synthesis method. For solid-state reactions, most authors
utilize a dwelling time between 4 and 6 h, and the shortest time
reported was 1 h [22,84]. For synthesis by wet chemical reaction,
most authors used shorter dwelling times of less than 4 h; the
shortest dwelling time found in the literature was 5 min, for which
ACP was used as the precursor [20]. Despite the shorter dwelling
time usually employed, so far there is no evidence that the β →α
transformation occurs faster when precursors are synthesized by
wet chemical reactions in comparison to solid-state reactions. The
wet chemical reaction can be considered a faster method of synthesis if the precursor is ACP; in this case, the β →α transformation is not involved, and the kinetics of transformation from ACP
to α -TCP appear to be more favorable due to the lower energy of
formation.
α -TCP, longer dwelling times do not seem to affect the amount
of α -TCP phase produced during the synthesis [23], as can be
Given that there is enough time to complete the formation of
observed in Fig. 4. However, if CPP impurities are present, a
prolonged time at the calcination temperature may increase the
amount of amorphous phase, which derives from the liquid phase
formed between TCP and CPP, and thus reduce the proportion of
crystalline phases of the material [16]. Prolonged firing may also
reduce the reactivity of the material due to microstructural coarsening, as shown by Cicek et al. [23].
5.1. Cooling rate and quenching
Several authors have analyzed the influence of cooling rate on
the β ↔α transformation and properties of TCP produced. Some
works affirm that quenching is necessary to retain the α -TCP phase
and prevent α →β reversion in order to obtain pure α -TCP [23],
and others have adopted it using the justification that it should
help stabilize the α - phase at room temperature [44,85]. Brazete
et al. [43] studied the relationship between CPP impurities and the
cooling rates necessary to obtain phase-pure α -TCP, and concluded
that quenching effectively prevented the α →β reversion and that
it is not possible to obtain pure α -TCP when starting from β -TCP
at slow cooling rates.
However, data reported in the literature does not support this
claim. Several research groups were able to achieve phase-pure α TCP without quenching by solid-state reaction [33,41,79,86] and
wet chemical reaction [13,39]. Moreover, quenching did not completely prevent the formation of the β -TCP phase in some works
[21,31,87–89]. Fig. 5 presents a comparison between reports in
which the material was quenched from the calcination temperature down to room temperature and reports in which slower cooling methods were used, such as cooling freely inside the furnace
or at a controlled slow rate; in all reports considered, phase-pure
α -TCP was obtained. As can be seen in Fig. 5, of the total of reports detailing synthesis by solid-state reaction with quenching,
only approximately 51% reported 100% α -TCP formation. For the
solid-state reaction without quenching, about 85% of reports described phase-pure α -TCP formation. This indicates that quenching
is neither a necessity for producing an α -TCP-rich material nor a
guarantee that the synthesis will be successful, and it is possible
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Acta Biomaterialia 151 (2022) 70–87
Fig. 5. Percentage of papers in which phase-pure α -TCP was obtained at each temperature range, relative to the total number of papers reporting syntheses (A) with and
(B) without quenching via the solid-state reaction (SS) and wet chemical reaction (WS) methods. Total number of papers considered for SS: with quenching= 53; without
quenching= 13. Total number of papers considered for WS: with quenching= 3; without quenching= 34. All reference articles were used in the construction of these graphs
[1–195].
to produce phase-pure α -TCP regardless of quenching or synthesis
method.
It is recognized that the β ↔α transformation has a reconstructive character and, therefore, requires a considerable amount of energy to occur [16,43,80]. Monma and Goto [90] estimated that the
activation energy of the β →α transformation was 250 kcal·mol−1 ,
and showed that no α →β reversion occurred even at slow cooling rates (2–5 °C·min−1 ). α →β reversion was only observed after heating α -TCP below the transition temperature for a sufficient amount of time, or by using a ground α -TCP powder and
a very slow cooling rate (2 °C·min−1 ). If the cooling rate is very
slow, the material may be subjected to a high temperature (below the β →α transition) for enough time to generate an effect
similar to a thermal treatment, resulting in the formation of β TCP. Duncan et al. [79] observed α →β transformation after annealing α -TCP at 10 0 0 °C for several hours. Even then, after 8 h of
annealing the β -TCP content only increased up to approximately
12% for the α -TCP synthesized with low-Mg reagents, evidence
that this transformation requires a considerable amount of energy
to occur. However, it has been shown that milling promotes the
α →β transformation at lower temperatures, such as 600 °C, at
which unmilled α -TCP would otherwise be stable [91]. The nonreversibility of the β →α transformation at slow cooling rates was
also confirmed in recent work [80]. Therefore, the presence of β TCP impurities in α -TCP even after quenching is not likely caused
by an insufficiently fast quenching process allowing partial reversion during cooling, as proposed by some authors [23,92,93]. According to Carrodeguas and Aza [11], β -TCP impurities may form
due to an insufficient dwelling time to complete the β →α transformation, or to an unexpected increase in the transition temperature due to the presence of impurities. As partial reversion only
occurs if the cooling rate is too slow, the most likely explanation for the presence of β -TCP impurity is an incomplete β →α
transformation due to either insufficient time or temperature of
calcination.
Carrodeguas et al. [81] argues that the reason for the difficulty
in obtaining pure α -TCP via cooling from above the β →α transition temperature is the existence of a biphasic region in the phase
equilibrium diagram of the Mg3 (PO4 )2 -Ca3 (PO4 )2 system, in accordance with the Contact Rule of Phase Regions. As Mg impurities
are common in precursors for TCP synthesis the system becomes
contaminated. In systems not free of Mg, β -TCP appears as a second phase due to thermodynamics; therefore, suggesting the use of
quenching to retain the α -TCP phase in these systems is not valid.
The literature supports these findings as instances where pure α -
TCP was obtained without quenching were demonstrated, so long
as the temperature of calcination was higher than the range where
α - and β - phases may coexist [32,33,94].
When CPP is present in TCP precursors the effect of the cooling rate on the final composition of TCP can be rather complex, as
discussed by Torres et al. [16]. CPP shifts the β →α transformation
to higher temperatures, as previously reported by Ryu et al. [95].
Besides this, the TCP-CPP system forms an eutectic point around
1286°C, and the liquid phase formed at this temperature reduces
the activation energy required for the β ↔α transformation, therefore facilitating the α →β reversion during cooling [16]. The idea
that CPP interferes with the α ↔β transformation was previously
proposed by Welch and Gutt [96], although they attributed the effect to the formation of a solid solution of CPP, since they were
considering a sample calcined below the eutectic point of the TCPCPP system. Torres et al. [16] also observed that an increase in the
cooling rate from 5 to 13 °C·m−1 resulted in a decrease in α -TCP
and amorphous phase contents in the synthesized material. The
authors attributed this effect to changes in composition and chemical activity of the solid phase caused by the presence of liquid,
which would interfere with the kinetics of the α ↔β transformation. Under the conditions studied, quenching was the only way to
obtain α -TCP as the sole crystalline phase, although this also increased the amorphous content of the material. The authors concluded that quenching may be effective in hindering the α →β reversion when CPP is present. Brazete et al. [43] also confirmed this
observation when a β -TCP precursor containing some CPP impurity
was used; only quenching from 1500°C produced phase-pure α TCP. When the authors used a Ca/P ratio of 1.51 to avoid formation
of CPP, it was possible to obtain pure α -TCP using a cooling rate
of 20 °C·min−1 and calcination temperatures of 1250 and 1500 °C.
Different to other literature reports, Brazete et al. [43] observed
that a cooling rate of 5 °C·min−1 was insufficient to retain 100%
of the α - phase during cooling; according to the authors, this discrepancy could be attributed to a lack of quantitative phase analysis in other works. However, the DSC analysis performed by the
authors at a cooling rate of 5 °C·min−1 did not show any event attributable to α →β reversion; this is different than in the work by
Torres et al. [16], in which it was possible to detect by DSC the
thermal events corresponding to the α →β reversion upon cooling.
The above discussion leads to the conclusion that quenching is
not necessary to synthesize phase-pure α -TCP; its necessity is significantly dependent on the composition of the precursors. There
is still some controversy regarding what should be the minimum
cooling rate necessary to obtain phase-pure α -TCP, and it seems
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Acta Biomaterialia 151 (2022) 70–87
Table 2
Mg content (in wt. %) of some reagents used in α -TCP synthesis, as given
by different chemical suppliers.
Supplier
CaCO3
H3 PO4
Ca(NO3 )2
(NH4 )2 HPO4
Merck
Sigma-Aldrich
Fluka
Fischer Scientific
Roth
Panreac
Vetec
≤0.02
≤0.01
≤0.02
≤0.02
-
≤5 ppm
≤0.001
≤0.002
≤0.05
≤0.01
≤0.01
-
≤0.0005
≤0.0005
≤0.0005
-
from 1125 °C to nearly 1400 °C; within this temperature range,
both α and β -TCP are present as a solid solution.
Since Mg has such a remarkable effect on the β →α transformation, its presence as an impurity in reagents used for the
synthesis of α -TCP can affect the phase purity of the produced
material. Different authors have investigated the effect of Mg in
solid-state synthesis of α -TCP. Duncan et al. [79] analyzed the
chemical composition of commercial CaHPO4 from four different suppliers and attempted to synthesize α -TCP for each of the
four sourced precursors; the results were compared to α -TCP obtained from CaHPO4 prepared by the researchers using Ca(OH)2
and H3 PO4 . The Mg content in the commercial CaHPO4 (decomposed to Ca2 P2 O7 ) ranged from 0.07–0.60 wt. % Mg (corresponding to 0.3–2.5 at. %), and was below the detection limit in the prepared Mg-free CaHPO4 ; the other reagent used was CaCO3 with a
concentration of 0.004% Mg. Only the α -TCP produced with Mgfree CaHPO4 Mg was phase-pure, while the other produced samples contained β -TCP impurities in amounts proportional to the
Mg content of the reagent used.
Since MgCO3 is commonly associated with CaCO3 , Mg is also
a frequent impurity in this Ca source [58]. TenHuisen and Brown
[58] observed that when using a commercial CaCO3 containing
0.49 wt. % Mg, it was only possible to obtain mixtures of α and β -TCP via solid-state reaction with NH4 H2 PO4 ; when highpurity CaCO3 was used (0.01 wt. % Mg), pure α -TCP could be obtained at as low as 1150 °C. Cicek et al. [23] synthesized α -TCP
using commercial CaCO3 and CaHPO4 derived from it, and precursors from three different suppliers were tested. Chemical analysis
showed that the Mg content in CaCO3 ranged from 0.003–0.105
wt. % (0.01–0.45 at. %); after calcination at 1200°C, the samples
produced with lower-Mg CaCO3 were phase-pure α -TCP, while the
sample synthesized with CaCO3 containing 0.105 wt. % Mg had β TCP as an impurity. Motisuke et al. [41] prepared α -TCP by solidstate synthesis using commercial and lab-made reagents. The Mg
content of the commercial reagents was 0.88 wt. % for CaCO3 and
0.28 wt. % for CaHPO4 ; the lab-made CaCO3 had 0.037 wt. % Mg
and the Mg content in the CaHPO4 was below the detection limit
of 0.0 0 02 wt. %. After calcination at 120 0°C and above, α -TCP produced with the lab-made reagents was phase-pure while that obtained from commercial reagents contained β -TCP impurities for
all calcination temperatures examined.
Marchi et al. [37] measured 0.22 wt. % Mg in undoped β TCP powders prepared by a wet chemical reaction of Ca(OH)2 and
H3 PO4 , due to impurities of the reagents; however, the authors did
not analyze the chemical composition of each individual precursor.
There were no reports among the reviewed literature discussing
the chemical purity of reagents used in the synthesis of α -TCP
by wet chemical reactions. Information publicly available on the
websites of chemical suppliers regarding the Mg content of some
reagents used for α -TCP synthesis is presented in Table 2. No information was available for CaHPO4 and Ca(OH)2 .
The reagents mostly used in solid-state reaction and wet chemical reaction synthesis routes are presented in Fig. 7. It should
Fig. 6. Phase equilibrium diagram of the Mg3 (PO4 )2 –Ca3 (PO4 )2 system in the region
of 0–20 mol. % Mg (redrawn from Carrodeguas et al. [81]).
to also depend on the precursors’ composition. Since the presence
of impurities also affects the β →α transformation temperature, it
has become important to know the chemical composition of the
reagents used for the synthesis in order to choose an appropriate
calcination temperature and cooling rate to obtain the desired result.
6. Phase purity
Phase purity is an important characteristic when it comes to
materials selection. Its importance is even more significant in the
field of biomaterials, where impurities can not only change the expected properties of an implant but also cause adverse reactions in
the surrounding tissues. When it comes to the synthesis of calcium
phosphate powders, most impurities come from different phases of
the same material or from other calcium phosphate compounds. In
the case of α -TCP, it is common to detect some amount of β -TCP,
which is the stable phase of tricalcium phosphate at room temperature [16,97,98], as well as low amounts of HA [71,99].
The phase purity of α -TCP influences various properties of the
material, as the presence of other calcium phosphates can affect
its solubility, reactivity, bioresorbability, and behavior in biological
environments, among other properties. Innumerous factors influence the purity of the obtained α -TCP powder, such as the calcination temperature and the Ca/P ratio; one of the most important
is the chemical composition of the precursors used for the synthesis [41,79]. Metal ions such as Sr2+ , Zn2+ and Mg2+ alter the
stability of α - and β - phases by substituting Ca2+ ions in the TCP
lattice, stabilizing the β -TCP phase [14,16,80,82,100–103]. This stabilization shifts the β →α transformation to higher temperatures
and can decrease its kinetic rate, making it more difficult to obtain
pure α -TCP [80]. On the other hand, some elements can stabilize
the α - phase, as is the case when Si substitutes P atoms [56,104–
107]. Most of these ions are introduced deliberately during synthesis by doping the reagents before calcination; however, they can
also be present as impurities in the synthesis precursors, making
it difficult to obtain pure α -TCP [108].
The substitution of Ca2+ by Mg2+ is widely investigated; this
element has a strong stabilizing effect for the β - phase and significantly shifts the phase transformation temperature of TCP even
when present in minor quantities [109,110]. Enderle et al. [82] attempted to determine the β →α transformation temperature as a
function of Mg content, based on the phase equilibrium diagram
of the system Mg3 (PO4 )2 –Ca3 (PO4 )2 originally proposed by Ando
[111]. Carrodeguas et al. [81] later revised this diagram, including
the biphasic regions β +α -TCPSS and α +α ’-TCPSS . According to the
phase diagram (redrawn in Fig. 6), as low as 1 mol. % Mg is enough
to raise the temperature at which α -TCP is the sole stable phase
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Acta Biomaterialia 151 (2022) 70–87
Fig. 7. Proportion of reagents used in (A) solid-state syntheses and (B) wet chemical syntheses of α -TCP per total number of papers on each method. All referenced articles
were used in the construction of this graph [1–195].
reagents with very low Mg contents that were synthesized by the
authors [41]; the other two used high-purity CaCO3 and CaHPO4
or CPP derived from it [22,86]; one used high-purity CaCO3 and
NH4 H2 PO4 ; and the final one reported obtaining pure α -TCP only
when CaCO3 batches with the lowest Mg contents (0.003 and
0.009 wt. %) were used [23]. If high-purity reagents for solid-state
synthesis are not available, then the wet chemical reaction may be
the best choice for producing pure α -TCP.
7. α-TCP cement reactivity
The preparation of calcium phosphate cements (CPC) is one of
the main applications of α -TCP. A CPC consists of a solid and a liquid phase which are mixed and allowed to set under certain conditions; the setting reaction forms a calcium phosphate precipitate
and induces the hardening of the cement [112]. The functionality
of calcium phosphate cements is substantially dependent on their
reactivity, since the setting time of the cement should allow a sufficient period for the material to be injected or molded, allowing
the surgeon to finish the procedure shortly after cement placement [30,112]. Cements based on α -TCP are particularly interesting
for bone regeneration due to the formation of CDHA, a compound
similar to biological bone hydroxyapatite [113,114]. This reaction
was first described by Monma and Kanazawa [115]; however, the
first CPC formulation containing substantial concentrations of α TCP with an acceptable setting time for clinical applications was
developed by Ginebra et al. [116].
α -TCP hydration is heterogeneous with a specific reaction profile determined by solid state reactions, liquid diffusion and reaction kinetics, which can be affected by the morphology, crystallinity and particle size of the powder. These parameters can affect the reaction rate and, in some cases, not allow the complete
transformation of α -TCP in CDHA [23,117]. Therefore, it is important to have a clear understanding of the processes involved during the hardening of the material in order to optimize the setting
time. Ginebra et al. [112] studied the evolution of the microstructure during the setting of α -TCP–based cements and were able to
identify four main stages of reaction. The first stage occurs for up
to 30 min after mixing of the CPC; during this period the initial powder presents a detached and sandy appearance. The second stage occurs between 30 min to 8 h post-mixing, and in this
stage the finer TCP particles have completely dissolved while a minor layer of CDHA crystals starts to surround the larger particles
which have not dissolved completely. The third stage of the reaction occurs from 8 to 64 h post-mixing, during which the remaining α -TCP particles continue to dissolve, although at a lower rate
due to the formation of a shell layer covering the particles. Finally,
in the last stage, the orientation of the crystals starts to present a
more compact and entangled appearance. To simplify the reaction
and how the characteristics of the obtained powder can influence
Fig. 8. Comparison between purity of obtained α -TCP synthesized by three routes:
solid-state synthesis (SS), wet chemical synthesis (WS) and alternative methods
(AM). Total number of papers considered: 67 for SS, 39 for WS and 10 for AM. All
reference articles were used in the construction of this graph [1–195].
be noted that most authors who opt for the synthesis route with
CaCO3 and CPP obtain the CPP via thermal decomposition of
CaHPO4 ; hence, in almost every report on solid-state synthesis the
phosphate precursor is ultimately CaHPO4 . For wet chemical synthesis, Ca(NO3 )2 is the Ca source in 73% of papers and (NH4 )2 HPO4
is the phosphate source in 63% of them. Considering the data available in Table 2 and the content of Mg measured by Duncan et al.
[79] for CaHPO4 and by Cicek et al. [23] for CaCO3 , it seems reasonable to assume that, in general, reagents used in solid-state
syntheses of α -TCP tend to have a more significant Mg content in
comparison to the reagents used for wet chemical reactions. This
could help to explain the observed tendency of obtaining α -TCP
in higher purity when using the wet chemical reaction method, as
shown in Fig. 8, and may also justify the observed tendency of increase on the use of the wet chemical reaction instead of the solidstate reaction presented in Fig. 1.
The more significant content of Mg impurities also justifies the
use of higher calcination temperatures in solid-state syntheses, as
can be seen in Fig. 2. Nonetheless, it is possible to obtain α -TCPrich materials via solid-state synthesis at lower temperatures, such
as 1200°C, as long as the content of reagent impurities, in particular Mg, is controlled. Fig. 5 shows six papers in which pure
α -TCP could be synthesized by solid-state reaction at calcination
temperatures between 1200 and 1300 °C, with quenching used in
two cases and not used in four. Of those, two reported the use of
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Acta Biomaterialia 151 (2022) 70–87
When it comes to controlling the reactivity of the α -TCP powder, the synthesis method and the precursors of the obtained material should also be considered. Regarding the influence of the
solid state synthesis precursors, Durucan and Brown [22] investigated the differences in the reactivities of powder obtained from
mixing CaCO3 with NH4 H2 PO4 , CaHPO4 and Ca2 P2 O7 . The authors
found that α -TCP synthesized with the Ca2 P2 O7 mixture had a
larger surface area than when other precursors were used, even
though the particle size remained similar between the powders.
This difference in the particle surface area, owing to surface defects, resulted in a faster dissolution rate of the powder and, consequently, a lower setting time. However, it is also important to
verify the impurities in the precursors used in the synthesis of the
α -TCP. Cicek et al. [23] showed that it is possible to obtain different reactivities by controlling the impurity content of the starting mineral precursor, rather than by other physical factors. They
investigated α -TCP synthesis using three different CaCO3 batches
as a precursor, each with a different impurity content. They found
that due to the higher electronegativity of the Mg2+ impurities in
the precursor, compared to that of Ca2+ , there is a stronger interaction between the atoms in the material. Hence, the presence
of Mg2+ impurities results in an enhancement of the stability of
α -TCP, which, consequently, decreases its solubility and reactivity.
Regarding α -TCP synthesis by wet chemical reaction, there are no
papers assessing the influence of precursors on reactivity of α -TCP.
By only considering the lower probability of wet chemical reaction precursors containing Mg2+ impurities, as previously stated, it
can be inferred that this method can produce more reactive α -TCP
particles. However, a study performed by Monma et al. [124] concluded that the hydration activity of α -TCP was higher when it was
obtained by the solid state reaction, compared to the powders obtained from the decomposition of CDHA and ACP.
When considering the influence of the synthesis parameters on
the reactivity of the material, it is also important to consider the
temperature of calcination of α -TCP powders. Durucan and Brown
[22] investigated the influence of this parameter on the reactivity of the cement by comparing the reactivity of powders calcined
at 110 0, 120 0 and 130 0 °C. They found that increasing the firing
temperature resulted in a significant reduction in the specific surface area and, consequently, in the hydration rate of the obtained
particles. This shows that syntheses performed at lower calcination temperatures are preferential when a higher reactivity of the
cement is required. Nevertheless, Bohner et al. [99] showed that
when synthesizing α -TCP particles at 60 0–70 0 °C it is difficult to
create surface defects, which are essential for initiating particle
dissolution. As a result, they observed an induction period of several hours for the hydration of these powders.
Another technique used to improve the reactivity of the cement is the addition of additives or nucleation seeds. Monma et al.
[124] investigated the influence of different additives on the liquid phase of the cement. They verified that the addition of NH4 Cl
caused an acceleration in the hydration reaction, an effect that has
also been observed for various NH4 + and Na+ inorganic salts. However, they observed a substantially inhibitory effect of additives
containing Ca2+ , Mg2+ and other divalent metal inorganic salts.
Pina et al. [113] also investigated the composition of the setting
liquid on the hydration reaction of α -TCP–based cements. They
showed a clear effectiveness of Na2 HPO4 solutions and citric acid
solutions as setting liquids. The effectiveness of aqueous solutions
of Na2 HPO4 in reducing the setting time of CPCs was attributed
by Fernández et al. [125] to the common ion effect, which intensifies the supersaturation of the reactant solution and accelerates
the precipitation of CDHA. Irbe and Loca [126] also investigated the
setting reaction acceleration properties of sodium and potassium
salts in pre-mixed α -TCP-based cement using glycerol as the liquid phase. They found that, regarding the cohesion, pH, compres-
the reactivity of the cement, it can be assumed that the reaction
occurs via two major processes: firstly, the supersaturation of the
reactant solution with Ca2+ and PO4 3− ions provided by the dissolution of the α -TCP particles and, secondly, the precipitation of
CDHA forming an entangled network [23,113]. Hence, the transformation kinetics can be fitted to a model that assumes only two
main rate-limiting mechanisms. Initially, the setting is controlled
by the dissolution rate of the α -TCP particles, i.e., by the surface
area of the reactants, and subsequently by the diffusion of the reactants through the CDHA shell layer [116,118,119] or by the nucleation and growth of the apatite crystals [116,120].
Most studies focus on reducing the setting time of the cement
by optimizing the initial stage of the reaction. In order to enhance
the dissolution rate of the particles, several researchers analyzed
the contribution of particle size on the setting properties of the cement. Ginebra et al. [92] investigated the effect of particle size on
the reactivity of α -TCP powders by comparing powders with different particle size distributions. It was concluded that the transformation of α -TCP to CDHA with the finer particle size was accelerated compared to when the coarser particles were used, due
to a higher solubilization rate of the powder. The finer distribution
resulted in the production of the apatitic phase after 2 h of reaction and this phase was the predominant one in the material after
8 h; while in the coarse powder, the apatitic phase was barely detectable after 2 h and was scarce even after 8 h of reaction. These
results were corroborated by Bohner et al. [99], who also studied
the contributory effect of different particle sizes on the reaction
of CPC and found a significant acceleration of the setting process
by prolonged milling times and a reduction in the particle size of
the powder. Even though particle size is one of the most important parameters when considering the reactivity of α -TCP cements,
particles with the same particle size can present different transformation rates, since surface defects on the particles can influence
their surface area. Therefore, it is important that the surface area
of the particles is considered when discussing the reactivity of the
cements, as larger surface areas result in faster dissolution and supersaturation rates and, consequently, a faster hydration of the material [22,121].
Even though these studies revealed that the reactivity of α -TCP
could be increased by prolonged milling, after a certain time it
is not possible to detect a further increase in the surface area of
the particles and no further decrease of particle size through this
process. However, even when there is no change in these parameters, the milling process continues to increase the reactivity of the
powder [122]. Gbureck et al. [123] demonstrated for the first time
that it was possible to obtain a mechanically-induced transformation from crystalline α -TCP to an X-ray amorphous phase (ACP)
through prolonged milling. It was also shown that this phase increased the solubility of the TCP powders, resulting in a more extensive supersaturation of the reactant solution and a faster setting reaction. They were able to reduce the time to obtain >90% of
hydration of α -TCP to CDHA in water from approximately 7 days
to between 4–6 h by milling the TCP powder in ethanol for 24 h.
The connection between the amorphous phase and the cement’s
reactivity was also investigated by Camiré et al. [119] and Hurle
et al. [122], whose results corroborate those reported by Gbureck
et al. Camiré et al. showed using isothermal calorimetry that when
α -TCP is milled long enough to produce an amorphous phase, the
second peak on the microcalorimetry spectra, corresponding to the
diffusion-controlled part of the α -TCP hydration, disappears. This
suggests that most of the transformation to CDHA is finished after
the first stage of the reaction, which is controlled by the dissolution rate of the particles [119]. Hurle et al. showed that, in contrast
to crystalline α -TCP, ACP immediately started to dissolve after the
cement preparation, demonstrating the significant solubility of this
material [122].
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Acta Biomaterialia 151 (2022) 70–87
sive strength of the CPC and the kynetic of the hydration reaction,
a mixture of acidic and basic potassium phosphates (KH2 PO4 and
K2 HPO4 , respectively) with 5.7 × 10−4 to 11.4 × 10−4 mol per 1 g
of α -TCP resulted in a cement paste with the most suitable properties, achieving complete hydration of α -TCP to CDHA after 96h. The
compositions with 5.7 × 10−4 mol per 1g α -TCP of acidic sodium
or potassium phosphates (NaH2 PO4 and KH2 PO4 ) were also suitable for application, however they showed slower hydration rate,
which could not be ideal for certain applications [126]. Regarding the use of nucleation seeds, Durucan and Brown [22] demonstrated that the setting time of α -TCP cements can be decreased
by HA seeding at a weight proportion greater than 1%. This addition to the cement resulted in shorter times for both the nucleation and the growth of CDHA crystals and, at additions higher
than 5 wt. %, the growth of CDHA crystals occurs without the nucleation stage. Other additions to the cement powder such as carbonates, pyrophosphates and magnesium salts were investigated
by Ginebra et al. [89]. The additions of carbonates and pyrophosphates were clearly detrimental to the setting of the cement, and
the addition of magnesium salts significantly inhibited the reaction, since Mg2+ ions can retard or even prevent the precipitation
and growth of CDHA. The inhibitory effect of pyrophosphates was
also verified by Weichhold et al. [127]. They demonstrated that
a solution with 0.05 wt.% tetrasodium pyrophosphate decahydrate
(Na4 P2 O7 .10H2 O) was already enough to prevent α -TCP hydration
up until 14 days at room temperature, due to the adsorption of pyrophosphate ions on the surface of the α -TCP particles. Other ions
are also detrimental to the setting reaction, as shown by Bohner
et al. [128]. They found that, apart from Mg2+ , Ni2+ , Ba2+ and Sr2+
ions also presented a high retardation effect on the hydration of
α -TCP, with Ni2+ and Ba2+ showing higher efficiency on the inhibition of the reaction, possibly due to the higher energy required
to incorporate these cations into the lattice of hydroxyapatite.
An innovative method to guarantee a lower setting time in
the cements, initially proposed by Santos et al. [129], is modifying the α -TCP cement paste with water-soluble monomers,
so that there is a mutual influence of the inorganic cement setting and organic polymerization reaction on the paste
[130]. Christel et al. [131] showed that when 30–70% of
poly(hydroxyethyl)methacrylate (PHEMA) was used in the α -TCP
cement, a decrease in the setting time of the paste could be observed. However, XRD analyses revealed that the degree of transformation of α -TCP to CDHA was lower for the polymer-modified
cements, with only 54–57% CDHA observed in the material after
24 h of reaction. The authors proposed that this reduced transformation rate is due to the increased viscosity of the reactant liquid after the hydrogel formation, which slows down the diffusion
rate of the inorganic ions and, therefore, retards the CDHA crystal
growth.
strength [132,133]. It is expected that the number of contact points
increases as the crystals grow, developing a network that is able to
withstand mechanical loads [93]. The mechanical properties evolve
with the setting reaction: as-set cements have a negligible content of precipitated CDHA and the compressive strength is generally low; as the reaction progresses, the precipitates form and
the entanglement of crystals promotes an enhancement in the mechanical strength [133].
Several parameters influence the setting reaction and the microstructure of α -TCP cements and, thus, affect their mechanical
properties. The mechanical strength depends fundamentally on the
size of defects, such as pores and cracks, and on fracture toughness [134]. However, many factors can influence the mechanical
behavior of the α -TCP cement, including liquid to powder ratio
(L/P), composition of the liquid phase, particle size of the solid
phase, porosity of the cement, use of additives, mold design, precompaction, and preparation of the cement (manual or mechanized), among others [39,45,123]. Hence, it is difficult to isolate
their effects and observe direct correlations between the mechanical strength and one specific factor, as well as to compare mechanical properties from distinct reports [39,45].
If present, the β -TCP phase does not participate in the hydration reaction [123], and its presence can reduce the mechanical
properties of the α -TCP cement since it does not contribute to the
formation of the interlocking crystals network [39]. This effect was
observed by Sariibrahimoglu et al. [135], who attributed this to a
lower degree of entanglement of the precipitated apatite crystals
during setting of cements containing the non-setting β -TCP phase;
mechanical properties decreased with increasing β -TCP content.
Ginebra et al. [89] observed a detrimental effect of β -TCP addition
toward the compressive strength of α -TCP cement; the addition of
CPP and sintered HA, on the other hand, seemed to slightly increase the cement strength. However, the authors mentioned that
it is unclear whether CPP and HA affect the mechanical properties
in the same way when they are formed during the synthesis of
α -TCP.
Gbureck et al. [123] studied the effect of morphology and size
of the CDHA precipitates on the mechanical properties of α -TCP cements by comparing cements with similar porosities processed by
milling. α -TCP was synthesized using the solid-state method. After
high-energy ball milling, the authors obtained a maximum compressive strength of 74.5 MPa for α -TCP milled in ethanol for 1 h,
and 82.0 MPa for α -TCP milled in the dry state for 4 h (the powders milled under these two conditions had a particle size close
to 7 μm); further milling reduced the strength in both cases. The
authors found that mechanical activation (milling) influences the
microstructure of α -TCP cements. Initially, milling induced the formation of the amorphous phase, which enhanced solubility and accelerated the setting reaction, increasing the strength in comparison to non-milled specimens. Further milling was detrimental to
the mechanical properties due to the formation of smaller CDHA
crystals upon hydration of α -TCP.
Thürmer et al. [39] also investigated the effect of milling, but
for α -TCP synthesized by a wet chemical reaction. The highest
compressive strength obtained was 25.73 MPa for the non-milled
sample; the strengths obtained were lower than those found by
Gbureck et al. [123]; however, the samples studied by Thürmer
et al. were not pre-compressed as were the ones evaluated by
Gbureck et al. In this case, the variation in the average particle
size influenced the compressive strength, for which the best result was obtained for the sample without additional milling and,
therefore, with larger particle size. The samples with higher compressive strengths (non-milled and milled for 8 h in ethanol) were
the ones that showed larger and more interlocked precipitated apatite crystals on the fracture surface. The authors concluded that it
may not be necessary to mill α -TCP prepared by wet chemical re-
8. Mechanical properties
As α -TCP is widely investigated for use in CPC, the majority of
reports in the literature focus on the mechanical properties of α TCP–based cements. In these cements, the main solid component is
α -TCP, which can be combined with different calcium phosphates
or other solids such as CaCO3 ; the liquid is usually water or a solution of Na2 HPO4 , which acts as an accelerant for the setting reaction.
The compressive strength of the cement is correlated to the
extent of hydration of α -TCP and precipitation of CDHA crystals
[93,112]. Hydration of α -TCP allows the precipitation of CDHA crystals on the cement surface; the formation of a network of interlocking crystals is responsible for the hardening characteristics of
the cement [39]. The morphology and size of these crystals, as well
as their arrangement and packing density, determine the cement’s
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Acta Biomaterialia 151 (2022) 70–87
actions to achieve higher compressive strength, unlike in cements
prepared by solid-state syntheses.
Camiré et al. [30] observed a relationship between the crystal
size of CDHA precipitates and the rate of strength development of
α -TCP cements, in which a longer milling time resulted in smaller
apatite crystals and a shorter time to achieve the maximum compressive strength. However, the authors found no correlation between the milling time and the final mechanical strength of the
cement and suggested the existence of a more complex relationship between milling time, particle size, crystal size of precipitates
and the cement strength. The crystallinity also appears to affect
the mechanical properties, as Moreno et al. [34] observed that the
average values of compressive strength of α -TCP cements seem to
decrease with faster cooling rates during production of CPC from
α -TCP, producing less-ordered CDHA crystals which indicates less
entanglement.
Volkmer et al. [45] produced CPC from α -TCP prepared via combustion synthesis and reported an increase in compressive strength
with longer milling times due to the smaller particle size of the
milled powder, which allowed a reduction of the L/P ratio and contributed to a decrease in porosity, consequently increasing the mechanical strength. The highest compressive strength achieved was
30.4 MPa for a milling time of 180 min in ethanol; these samples
presented a higher amount of CDHA precipitated on the surface of
the material and the needle-like structures were larger, in agreement with the previously mentioned reports [39,123].
Using a cement composed of 61% α -TCP prepared via solid-state
reaction with addition of 26% dicalcium phosphate, 10% CaCO3 , 3%
HA, Shahrezaei et al. [132] found that a decrease in particle size
from milling led to an increase in compressive strength; according to the authors, the smaller particle size favored the formation
of needle-like apatite crystals, enhancing the cement strength. Motisuke et al. [108] produced a Si-α -TCP–based CPC with a compressive strength higher than the control α -TCP cement, which was
attributed to the smaller size of the apatite crystals formed during hydration of Si-α -TCP cement leading to a more effective entanglement and to a lower amount of pores; this explanation appears to contradict the results observed by Gbureck et al. [123] and
Thürmer et al. [39]. Using a commercial α -TCP cement, Konishi
et al. [136] also observed an increase in compressive strength of
cement specimens with longer milling times, which was attributed
to the decrease in particle size of α -TCP powders. These results
evidence the complexity of the concurrent effects of milling time,
particle size and CDHA crystal size on the mechanical properties of
α -TCP cements, as suggested by Camiré et al. [30].
The setting and hardening environment can also affect the mechanical properties of the cement. Yokoyama et al. [137] found
lower values of compressive strength for α -TCP cements incubated
in physiological saline (PBS) compared to those incubated in 100%
humidity. As for set cements, Sariibrahimoglu et al. [135] observed
no effect of immersion in PBS on the compressive strength for a
period of up to 6 weeks. Oh et al. [138] reported an increase in
compressive strength of cements after immersion in PBS for 7 days,
but prolonged soaking for 28 days resulted in a slight reduction of
strength, attributed to the hydrolytic degradation of the cements
over time which can create pores and voids that weaken the material.
Porosity is a major determining factor for the mechanical properties of α -TCP. Ceramic materials tend to become more brittle as
their porosity increases [139]; Liu et al. [134] observed that, for
the same cement composition, increasing porosity decreases the
Young’s modulus, fracture toughness, flexural strength and compressive strength of α -TCP cements. An increase in L/P ratio is expected to cause an increase in the porosity of the cements; hence,
it is usually associated with a reduction of the cement strength
[34], as has been verified in several reports [133,134,140]. Decreas-
ing the L/P ratio is one way to obtain cements with a more compacted microstructure and smaller pore size [133]; however, a certain degree of porosity is necessary for materials used in bone repair, as it stimulates the formation of new bone tissue to replace
the implant [139]. Moreover, the pores provide solution permeability, increasing the contact of the material with the solution and,
hence, favoring the setting reaction and precipitation of apatite
[133]. Researchers often try to reach an adequate balance between
porosity and mechanical properties.
Even though the use of accelerators is often needed to achieve
suitable setting times for α -TCP cements, its presence can reduce
the compressive strength of cements, as shown by Ginebra et al.
[89,116], who found higher compressive strength values for cements prepared with only water as the liquid phase in comparison
to Na2 HPO4 solutions. However, the use of liquid phases distinct
from pure water can also be beneficial to the cement’s mechanical properties. Some authors reported higher compressive strength
for cements prepared with citric acid solutions. This effect was attributed to its better ability to adsorb onto calcium phosphates,
which prevents agglomeration of particles, favoring their contact
with the liquid and, consequently, the hydration reaction [137,141];
a better dispersion of particle agglomerates can also be achieved
using trisodium citrate [142]. Czechowska et al. [143] observed that
the addition of chitosan to the liquid phase seemed to be detrimental to the compressive strength of the cements, as it disturbed
the interconnections between calcium phosphate grains. Oh et al.
[138], on the other hand, found that CPC prepared with a chitosan
solution in acetic acid had a higher compressive strength than its
counterpart prepared with a solution of 5% Na2 HPO4 . The presence
of unreacted liquid phase can be detrimental to the mechanical
strength, as it creates porosity in the cement microstructure [142].
Gbureck et al. [142] used fillers to obtain a bimodal particle size
distribution, with which it was possible to produce a workable cement paste using a lower L/P ratio. This strategy was effective in
producing cements with higher compressive strength, but the addition of fillers also led to a lower degree of conversion of the material into CDHA, since the fillers used either had little involvement
in the cement setting reaction or were completely unreactive.
Several reports have investigated the mechanical properties of
macroporous α -TCP cements. Macroporous cements are usually intended to be used as scaffolds for bone tissue engineering (BTE);
for this application, having adequate porosity and pore interconnectivity is of higher importance than mechanical strength, which
needs to be only high enough so that the material is able to maintain its structural integrity while tissue growth and vascularization
occur [144]. The introduction of macroporosity causes a substantial reduction in mechanical strength of the cement; however, the
mechanical properties of macroporous CPC are also affected by the
CPC matrix composition, pore size and geometry [145]. Valle et al.
[146] obtained an α -TCP cement foamed with albumen, which had
a porosity of 75% and compressive strength of approximately 0.86
MPa, while the control cement reached approximately 27 MPa. In
another work using albumen to produce α -TCP foams, the authors
achieved similar results and observed that the use of accelerant
and the amount of foaming agent had a significant effect on total
porosity and compressive strength [145].
Zhang et al. [147] used mannitol as the foaming agent for
α -TCP cement and observed the same trend of decreasing mechanical properties with increasing porosity. The authors detected
unreacted α -TCP and observed that its amount was proportional
to the presence of cracks, which induced a decrease in the cement’s Young’s modulus; the toughness was not affected by the
microcracking. A coarser powder produced specimens with more
unreacted α -TCP and, thus, more microcracking, in comparison
to those prepared with finer powder (having a smaller particle
size).
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Acta Biomaterialia 151 (2022) 70–87
Almirall et al. [144] produced macroporous α -TCP cement using
a solution of H2 O2 in water as the foaming agent. The powder with
a finer particle size produced a less porous cement with smaller
pores. Increasing porosity and, in particular, introducing macroporosity strongly decreased the mechanical properties. Compressive
strength and diametral tensile strength (DTS) were directly correlated to the total porosity, decreasing as porosity increased. The
highest compressive strength of foamed specimens was 8.81 MPa,
corresponding to the lowest total porosity (ca. 51%); the DTS of this
specimen was 4.31 MPa.
The highest values of compressive strength of α -TCP reported
in the literature are for the sintered material. Although sintering
of β -TCP is more studied, aiming at its use as a substitute for cortical bone, it is possible to achieve high compressive strength by
sintering α -TCP, making it a viable option for applications requiring higher mechanical strength. Jian Wen et al. [139] obtained sintered blocks with compressive strengths higher than 100 MPa at
a range of sintering temperatures, with a maximum compressive
strength of approximately 230 MPa. However, prior to sintering the
material is usually pre-compressed in a mold which renders it less
clinically relevant, since one of the most prominent advantages of
using CPCs is that they can be molded to the desired shape during surgery and then self-harden under environmental conditions
in the body.
An alternative process to produce implants with complex geometries is 3D printing, which is being increasingly investigated
for bone repair applications. Several reports have given values for
the compressive strengths of 3D printed samples of α -TCP. Bertol
et al. [33] studied post-processing treatments for 3D-printed samples and reported compressive strength values within the range of
4.0–6.4 MPa, with an average porosity of 52% for samples treated
by immersion in phosphoric acid; the effect was explained by the
increase in reaction of TCP into brushite and monetite, with a consequent decrease in porosity and α -TCP content. Chinellato et al.
[148] obtained a maximum compressive strength of 3.4 MPa for
printed scaffolds after sintering at 1600 °C. However, these values are considered low and, therefore, 3D-printed α -TCP parts are
currently only suitable for non-load bearing applications or when
combined with materials of higher mechanical properties [149].
aspects of the relationship between synthesis, structure and properties of α -TCP and α -TCP–based cements.
Funding
This work has been supported by Brazilian research agencies:
CAPES, CNPq and FAPERGS.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to
influence the work reported in this paper.
References
[1] S.V. Dorozhkin, Calcium orthophosphate cements for biomedical application,
J. Mater. Sci. 43 (9) (2008) 3028–3057, doi:10.1007/s10853- 008- 2527- z.
[2] R.Z. LeGeros, J.P. LeGeros, Calcium phosphate biomaterials: an update, J.
Wuhan Univ. Technol. Mater. Sci. Ed. 20 (2005) 1–6 no. SUPPL, doi:10.5466/
ijoms.4.117.
[3] R.Z. LeGeros, A. Chohayeb, A. Schulman, Apatitic calcium phosphates: possible
dental restorative materials, J. Dent. Res. 61 (1982) 343 no. special issue.
[4] W.E. Brown, L.C. Chow, A new calcium phosphate setting cement, J. Dent. Res.
62 (1983) 672 no. special issue.
[5] M. Mathew, L.W. Schroeder, B. Dickens, W.E. Brown, The crystal structure of
α -Ca3 (PO4 )2 , Acta Crystallogr. Sect. B Struct. Crystallogr. Cryst. Chem. 33 (5)
(1977) 1325–1333, doi:10.1107/s0567740877006037.
[6] R.W. Nurse, J.H. Welch, W. Gutt, A new form of tricalcium phosphate, Nature
182 (6) (1958) 1230.
[7] R.W. Nurse, J.H. Welch, W. Gutt, High-temperature phase equilibria in the system dicalcium silicate-tricalcium phosphate, J. Chem. Soc. (1959) 1077–1083
no. 0.
[8] B. Dickens, L.W. Schroeder, W.E. Brown, Crystallographic studies of the role
of Mg as a stabilizing impurity in β -Ca3 (PO4 )2 . The crystal structure of
pure β -Ca3 (PO4 )2 , J. Solid State Chem. 10 (3) (1974) 232–248, doi:10.1016/
0 022-4596(74)90 030-9.
[9] M. Yashima, A. Sakai, T. Kamiyama, A. Hoshikawa, Crystal structure analysis
of β -tricalcium phosphate Ca3 (PO4 )2 by neutron powder diffraction, J. Solid
State Chem. 175 (2) (2003) 272–277, doi:10.1016/S0022- 4596(03)00279- 2.
[10] M. Yashima, A. Sakai, High-temperature neutron powder diffraction study of
the structural phase transition between α and α phases in tricalcium phosphate Ca3 (PO4 )2 „ Chem. Phys. Lett. 372 (5–6) (2003) 779–783, doi:10.1016/
S0 0 09-2614(03)0 0505-0.
[11] R.G. Carrodeguas, S. De Aza, α -Tricalcium phosphate: synthesis, properties
and biomedical applications, Acta Biomater. 7 (10) (2011) 3536–3546, doi:10.
1016/j.actbio.2011.06.019.
[12] M. Bohner, B.L.G. Santoni, N. Döbelin, β -tricalcium phosphate for bone substitution: synthesis and properties, Acta Biomater. 113 (2020) 23–41, doi:10.
1016/j.actbio.2020.06.022.
[13] D. Correa, A. Almirall, R.G. Carrodeguas, L.A. dos Santos, A.H. De Aza, J. Parra,
L. Morejón, J.A. Delgado, α -Tricalcium phosphate cements modified with β dicalcium silicate and tricalcium aluminate: physicochemical characterization,
in vitro bioactivity and cytotoxicity, J. Biomed. Mater. Res. Part B Appl. Biomater. 103 (1) (2015) 72–83 Jan., doi:10.1002/jbm.b.33176.
[14] H. Ji, Z. Huang, Z. Xia, M.S. Molokeev, M. Chen, V.V. Atuchin, M. Fang,
Y. Liu, X. Wu, Phase transformation in Ca3 (PO4 )2 :Eu2+ via the controlled
quenching and increased Eu2+ content: identification of new cyan-emitting
α -Ca3 (PO4 )2 :Eu2+ phosphor, J. Am. Ceram. Soc. 98 (10) (2015) 3280–3284,
doi:10.1111/jace.13787.
[15] A.F. Vásquez, S. Domínguez, L.A. Loureiro dos Santos, α -TCP cements prepared by syringe-foaming: Influence of Na2 HPO4 and surfactant concentration, Mater. Sci. Eng. C 81 (2017) 148–155 no. AugustDec., doi:10.1016/j.msec.
2017.07.056.
[16] P.M.C. Torres, J.C.C. Abrantes, A. Kaushal, S. Pina, N. Döbelin, M. Bohner,
J.M.F. Ferreira, Influence of Mg-doping, calcium pyrophosphate impurities and
cooling rate on the allotropic α ↔β -tricalcium phosphate phase transformations, J. Eur. Ceram. Soc. 36 (3) (2016) 817–827, doi:10.1016/j.jeurceramsoc.
2015.09.037.
[17] L. Sinusaite, A. Popov, E. Raudonyte-Svirbutaviciene, J. Yang, A. Kareiva,
A. Zarkov, Effect of Mn doping on the low-temperature synthesis of tricalcium phosphate (TCP) polymorphs, J. Eur. Ceram. Soc. 39 (10) (2019) 3257–
3263, doi:10.1016/j.jeurceramsoc.2019.03.057.
[18] J. Kolmas, A. Kaflak, A. Zima, A. Lósarczyk, Alpha-tricalcium phosphate synthesized by two different routes: structural and spectroscopic characterization, Ceram. Int. 41 (4) (2015) 5727–5733 May, doi:10.1016/j.ceramint.2014.
12.159.
[19] N. Döbelin, T.J. Brunner, W.J. Stark, M. Fisch, E. Conforto, M. Bohner, Thermal
treatment of flame-synthesized amorphous tricalcium phosphate nanoparticles, J. Am. Ceram. Soc. 93 (10) (2010) 3455–3463, doi:10.1111/j.1551-2916.
2010.03856.x.
9. Conclusion
Three decades ago, α -TCP was proposed as a component of
bone cements suitable for clinical applications. Since then, several
synthesis methods and cement formulations have been developed
for this material. As stated above, over the subsequent years α -TCP
has become one of the most promising materials for many bone
repair applications.
The variety of methods available to synthesize α -TCP has provided a substantial variance in the properties of the CPCs. Therefore, the decision about which method, parameters and starting
reagents will be used for the powder’s synthesis is determinant of
the properties of the resulting material, and, hence, the intended
application should be considered in order to select the most suitable process in each case. The composition of the reagents, especially the presence of Mg impurities, must be strictly controlled if
α -TCP-rich material is required. Particle size and surface area of
the α -TCP particles have a significant influence on the hydration
reaction, which can also be affected by milling processes, calcination temperature, and other factors. The mechanical properties of
α -TCP–based cements depend on many variables, and their individual effects are difficult to isolate.
There is still a wide range of development opportunities on
more recent α -TCP applications, such as 3D-printed implants, and
further investigations are still needed to elucidate some intricate
83
M.C. Tronco, J.B. Cassel and L.A. dos Santos
Acta Biomaterialia 151 (2022) 70–87
[20] Z. Irbe, D. Loca, A. Pura, L. Berzina-Cimdina, Synthesis and properties of α tricalcium phosphate from amorphous calcium phosphate as component for
bone cements, Key Eng. Mater. (2017) 182–186 vol. 721 KEM, doi:10.4028/
www.scientific.net/KEM.721.182.
[21] N. Jinlong, Z. Zhenxi, J. Dazong, Investigation of phase evolution during the
thermochemical synthesis of tricalcium phosphate, J. Mater. Synth. Process. 9
(5) (2001) 235–240, doi:10.1023/A:1015243216516.
[22] C. Durucan, P.W. Brown, Reactivity of α -tricalcium phosphate, J. Mater. Sci. 37
(5) (2002) 963–969, doi:10.1023/A:1014347814241.
[23] G. Cicek, E.A. Aksoy, C. Durucan, N. Hasirci, Alpha-tricalcium phosphate (α TCP): solid state synthesis from different calcium precursors and the hydraulic reactivity, J. Mater. Sci. Mater. Med. 22 (4) (2011) 809–817, doi:10.
1007/s10856- 011- 4283- x.
[24] L.A. Vasconcellos, L.A. Dos Santos, Calcium phosphate cement scaffolds with
PLGA fibers, Mater. Sci. Eng. C 33 (3) (2013) 1032–1040, doi:10.1016/j.msec.
2012.10.019.
[25] X. Wei, O. Ugurlu, M. Akinc, Hydrolysis of α -tricalcium phosphate in simulated body fluid and dehydration behavior during the drying process, J. Am.
Ceram. Soc. 90 (8) (2007) 2315–2321, doi:10.1111/j.1551-2916.2007.01682.x.
[26] R. Famery, N. Richard, P. Boch, Preparation of a- and b-tricalcium phosphate ceramics, with and without magnesium addition, Ceram. Int. 20 (1994)
327–336.
[27] A. Mortier, J. Lemaitre, P.G. Rouxhet, Temperature-programmed characterization of synthetic calcium-deficient phosphate apatites, Thermochim. Acta 143
(1989) 265–282 no. C, doi:10.1016/0040- 6031(89)85065- 8.
[28] M. Bohner, J. Lemaître, A.P. Legrand, J.B.D.E. De la Caillerie, P. Belgrand, Synthesis, X-ray diffraction and solid-state 31P magic angle spinning NMR study
of α -tricalcium orthophosphate, J. Mater. Sci. Mater. Med. 7 (7) (1996) 457–
463, doi:10.10 07/BF0 0122016.
[29] S. Jegou Saint-Jean, C.L. Camiré, P. Nevsten, S. Hansen, M.P. Ginebra,
Study of the reactivity and in vitro bioactivity of Sr-substituted α -TCP cements, J. Mater. Sci. Mater. Med. 16 (11) (20 05) 993–10 01, doi:10.10 07/
s10856- 005- 4754- z.
[30] C.L. Camiré, P. Nevsten, L. Lidgren, I. McCarthy, The effect of crystallinity on
strength development of alpha-TCP bone substitutes, J. Biomed. Mater. Res. B.
Appl. Biomater. 79 (2006) 159–165 no. B, doi:10.1002/jbm.b.30526.
[31] E.C.S. Rigo, L.A.D.O.S. Santos, R.G. Carrodeguas, L.C.O. Vercik, A.O. Boschi,
R.G. Carrodeguas, α -Tricalcium phosphate- and tetracalcium phosphate/dicalcium phosphate-based dual setting cements, Lat. Am. Appl.
Res. 37 (2007) 267–274.
[32] R.S. Vieira, W.T. Coelho, M.B. Thürmer, J.M. Fernandes, L.A. Santos, Evaluation of α -tricalcium phosphate cement obtained at different temperatures,
Mater. Sci. Forum 727–728 (2012) 1187–1192, doi:10.4028/www.scientific.net/
MSF.727-728.1187.
[33] L.S. Bertol, R. Schabbach, L.A. Loureiro dos Santos, Different post-processing
conditions for 3D bioprinted α -tricalcium phosphate scaffolds, J. Mater. Sci.
Mater. Med. 28 (10) (2017) Oct., doi:10.1007/s10856- 017- 5989- 1.
[34] D. Moreno, F. Vargas, J. Ruiz, M.E. López, Solid-state synthesis of alpha tricalcium phosphate for cements used in biomedical applications, Bol. Soc. Esp.
Ceram. Vidr. (2019) 0–7, doi:10.1016/j.bsecv.2019.11.004.
[35] I. Cacciotti, A. Bianco, High thermally stable Mg-substituted tricalcium phosphate via precipitation, Ceram. Int. 37 (1) (2011) 127–137, doi:10.1016/j.
ceramint.2010.08.023.
[36] T.V. Safronova, V.I. Putlyaev, O.A. Avramenko, M.A. Shekhirev, A.G. Veresov,
Ca-deficient hydroxyapatite powder for producing tricalcium phosphate based
ceramics, Glas. Ceram. 68 (1–2) (2011) 28–32 (English Transl. Steklo i
Keramika), doi:10.1007/s10717- 011- 9315- y.
[37] J. Marchi, A.C.S. Dantas, P. Greil, J.C. Bressiani, A.H.A. Bressiani, F.A. Müller,
Influence of Mg-substitution on the physicochemical properties of calcium
phosphate powders, Mater. Res. Bull. 42 (6) (2007) 1040–1050, doi:10.1016/
j.materresbull.2006.09.015.
[38] M.B. Thürmer, R.S. Vieira, J.M. Fernandes, W.T.G. Coelho, L.A. dos Santos,
Synthesis of alpha-tricalcium phosphate by wet reaction and evaluation of
mechanical properties, Mater. Sci. Forum 727–728 (2012) 1164–1169, doi:10.
4028/www.scientific.net/MSF.727-728.1164.
[39] M.B. Thürmer, C.E. Diehl, L.A.L. dos Santos, Calcium phosphate cements
based on alpha-tricalcium phosphate obtained by wet method: Synthesis and
milling effects, Ceram. Int. 42 (16) (2016) 18094–18099 Dec., doi:10.1016/j.
ceramint.2016.08.115.
[40] S. Loher, W. Stark, M. Maciejewski, A. Baiker, S. Pratsinis, D. Reichardt,
F. Maspero, F. Krumeich, D. Günther, Fluoro-apatite and calcium phosphate
nanoparticles by flame synthesis, Chem. Mater. 17 (1) (2005) 36–42, doi:10.
1021/cm048776c.
[41] M. Motisuke, R.G. Carrodeguas, C.A.C. Zavaglia, Mg-free precursors for the
synthesis of pure phase Si-doped a-Ca 3 (PO4 )2 , Key Eng. Mater. 361-363
(2008) 199–202 I.
[42] L. Sinusaite, I. Grigoraviciute-Puroniene, A. Popov, K. Ishikawa, A. Kareiva,
A. Zarkov, Controllable synthesis of tricalcium phosphate (TCP) polymorphs
by wet precipitation: effect of washing procedure, Ceram. Int. 45 (9) (2019)
12423–12428, doi:10.1016/j.ceramint.2019.03.174.
[43] D. Brazete, P.M.C. Torres, J.C.C. Abrantes, J.M.F. Ferreira, Influence of the Ca/P
ratio and cooling rate on the allotropic α ↔β -tricalcium phosphate phase
transformations, Ceram. Int. 44 (7) (2018) 8249–8256, doi:10.1016/j.ceramint.
2018.02.005.
[44] T.M. Volkmer, L.L. Bastos, V.C. Sousa, L.A. Santos, Obtainment of α -tricalcium
phosphate by solution combustion synthesis method using urea as com-
bustible, Key Eng. Mater. 396–398 (2009) 591–594, doi:10.4028/www.
scientific.net/kem.396-398.591.
[45] T.M. Volkmer, F. Lengler, O. Barreiro, V.C. Sousa, L.A. dos Santos, Novel method
for the obtainment of nanostructured calcium phosphate cements: synthesis,
mechanical strength and cytotoxicity, Powder Technol. 235 (2013) 599–605,
doi:10.1016/j.powtec.2012.10.025.
[46] N. Vollmer, K.B. King, R. Ayers, Biologic potential of calcium phosphate
biopowders produced via decomposition combustion synthesis, Ceram. Int. 41
(6) (2015) 7735–7744 Jul., doi:10.1016/j.ceramint.2015.02.105.
[47] A.C. Tas, Combustion synthesis of calcium phosphate bioceramic powders, J.
Eur. Ceram. Soc. 32 (9) (20 0 0) 2389–2394, doi:10.10 02/chin.20 0109243.
[48] R. Ayers, S. Nielsen-Preiss, V. Ferguson, G. Gotolli, J.J. Moore, H.J. Kleebe,
Osteoblast-like cell mineralization induced by multiphasic calcium phosphate
ceramic, Mater. Sci. Eng. C 26 (8) (2006) 1333–1337 Sep., doi:10.1016/j.msec.
2005.08.028.
[49] R. Ayers, N. Hannigan, N. Vollmer, C. Unuvar, Combustion synthesis of heterogeneous calcium phosphate bioceramics from calcium oxide and phosphate
precursors, Int. J. Self Propagating High Temp. Synth. 20 (1) (2011) 6–14 Mar.,
doi:10.3103/S1061386211010031.
[50] J.S. Cho, D.S. Jung, J.M. Han, Y.C. Kang, Nano-sized α and β -TCP powders prepared by high temperature flame spray pyrolysis, Mater. Sci. Eng. C 29 (4)
(2009) 1288–1292, doi:10.1016/j.msec.2008.10.020.
[51] M. Maciejewski, T.J. Brunner, S.F. Loher, W.J. Stark, A. Baiker, Phase transitions
in amorphous calcium phosphates with different Ca/P ratios, Thermochim.
Acta 468 (1–2) (2008) 75–80, doi:10.1016/j.tca.2007.11.022.
[52] B. Jokic, I. Jankovic-Castvan, D. Veljković, R. Petrović, S. Drmanic,
D. Janaćković, Preparation of α -TCP cements from calcium deficient hydroxyapatite obtained by hydrothermal method, Key Eng. Mater. 309–311
(2006) 821–824, doi:10.4028/www.scientific.net/kem.309-311.821.
[53] B. Jokic, I. Jankovic-Castvan, D.J. Veljovic, D. Bucevac, K. Obradovic-Djuricic,
R. Petrovic, D.J. Janackovic, Synthesis and settings behavior of α -TCP from
calcium deficient hyroxyapatite obtained by hydrothermal method, J. Optoelectron. Adv. Mater. 9 (6) (2007) 1904–1910.
[54] Z. Kojic, D. Stojanovic, S. Popadic, M. Jokanovic, D. Janackovic, The irritative
property of α -tricalcium phosphate to the rabbit skin, Gen. Physiol. Biophys.
28 (2009) 168–173 no. Special Issues, doi:10.4149/gpb_2009_02_168.
[55] M. Roozbahani, M. Alehosseini, M. Kharaziha, R. Emadi, Nano–calcium phosphate bone cement based on Si-stabilized α -tricalcium phosphate with improved mechanical properties, Mater. Sci. Eng. C 81 (2017) 532–541 no. August, doi:10.1016/j.msec.2017.08.016.
[56] M. Sayer, A.D. Stratilatov, J. Reid, L. Calderin, M.J. Stott, X. Yin, M. MacKenzie,
T.J.N. Smith, J.A. Hendry, S.D. Langstaff, Structure and composition of siliconstabilized tricalcium phosphate, Biomaterials 24 (3) (2003) 369–382, doi:10.
1016/S0142- 9612(02)00327- 7.
[57] A. Gozalian, A. Behnamghader, M. Daliri, A. Moshkforoush, Synthesis and
thermal behavior of Mg-doped calcium phosphate nanopowders via the sol
gel method, Sci. Iran. 18 (6) (2011) 1614–1622, doi:10.1016/j.scient.2011.11.014.
[58] K.S. TenHuisen, P.W. Brown, Phase evolution during the formation of α tricalcium phosphate, J. Am. Ceram. Soc. 82 (10) (1999) 2813–2818, doi:10.
1111/j.1151-2916.1999.tb02161.x.
[59] M. Fathi, A. El Yacoubi, A. Massit, B. Chafik El Idrissi, Wet chemical method
for preparing high purity β and α -tricalcium phosphate crystalline powders,
Int. J. Sci. Eng. Res. 6 (6) (2015) 139–143.
[60] E.D. Eanes, Thermochemical studies on amorphous calcium phosphate, Calcif.
Tissue Res. 5 (1) (1970) 133–145, doi:10.1007/BF02017543.
[61] R.A. Van Santen, The Ostwald step rule, J. Phys. Chem. 88 (24) (1984) 5768–
5769, doi:10.1021/j150668a002.
[62] C. Zou, K. Cheng, W. Weng, C. Song, P. Du, G. Shen, G. Han, Characterization and dissolution-reprecipitation behavior of biphasic tricalcium phosphate powders, J. Alloys Compd. 509 (24) (2011) 6852–6858 Jun., doi:10.1016/
j.jallcom.2011.03.158.
[63] S. Wang, Y. Wang, K. Sun, X. Sun, Low temperature preparation of α tricalcium phosphate and its mechanical properties, Process. Appl. Ceram. 11
(2) (2017) 100–105, doi:10.2298/PAC1702100W.
[64] Y.B. Li, W.J. Weng, K. Cheng, P.Y. Du, G. Shen, G.R. Han, Complexes of
Ca(II) with polymers as precursors for preparation of amorphous calcium phosthate, Mater. Sci. Technol. 20 (9) (2004) 1075–1078, doi:10.1179/
026708304225019740.
[65] S. Somrani, C. Rey, M. Jemal, Thermal evolution of amorphous tricalcium
phosphate, J. Mater. Chem. (2003) 888–892, doi:10.1039/b210900j.
[66] N. Döbelin, Y. Maazouz, R. Heuberger, M. Bohner, A.A. Armstrong, A.J.W. Johnson, C. Wanner, A thermodynamic approach to surface modification of calcium phosphate implants by phosphate evaporation and condensation, J. Eur.
Ceram. Soc. 40 (15) (2020) 6095–6106, doi:10.1016/j.jeurceramsoc.2020.07.
028.
[67] D. Griesiute, E. Raudonyte-Svirbutaviciene, A. Kareiva, A. Zarkov, The influence of annealing conditions on the Ca/P ratio and phase transformations in bulk calcium phosphates, CrystEngComm 24 (6) (2022) 1166–1170,
doi:10.1039/D1CE01625C.
[68] S. Kannan, I.A.F. Lemos, J.H.G. Rocha, J.M.F. Ferreira, Synthesis and characterization of magnesium substituted biphasic mixtures of controlled
hydroxyapatite/β -tricalcium phosphate ratios, J. Solid State Chem. 178 (10)
(2005) 3190–3196, doi:10.1016/j.jssc.20 05.08.0 03.
[69] N. Döbelin, T.J. Brunner, W.J. Stark, M. Eggimann, M. Fisch, M. Bohner, Phase
evolution of thermally treated amorphous tricalcium phosphate nanoparti-
84
M.C. Tronco, J.B. Cassel and L.A. dos Santos
Acta Biomaterialia 151 (2022) 70–87
cles, Key Eng. Mater. 396–398 (2009) 595–598, doi:10.4028/www.scientific.
net/kem.396-398.595.
[70] A. Destainville, E. Champion, D. Bernache-Assollant, E. Laborde, Synthesis, characterization and thermal behavior of apatitic tricalcium phosphate,
Mater. Chem. Phys. 80 (1) (2003) 269–277, doi:10.1016/S0254-0584(02)
00466-2.
[71] A. Zima, J. Czechowska, D. Siek, R. Olkowski, M. Noga, M. LewandowskaSzumiel, A. Slosarczyk, How calcite and modified hydroxyapatite influence physicochemical properties and cytocompatibility of alpha-TCP based
bone cements, J. Mater. Sci. Mater. Med. 28 (8) (2017) Aug., doi:10.1007/
s10856- 017- 5934- 3.
[72] F. Bakan, A systematic study of the effect of pH on the initialization of Cadeficient hydroxyapatite to β - TCP nanoparticles, Materials 12 (3) (2019)
(Basel), doi:10.3390/ma12030354.
[73] B.L.G. Santoni, L. Niggli, G.A. Sblendorio, D.T.L. Alexander, C. Stähli, P. Bowen,
N. Döbelin, M. Bohner, Chemically pure β -tricalcium phosphate powders: Evidence of two crystal structures, J. Eur. Ceram. Soc. 41 (2) (2021) 1683–1694,
doi:10.1016/j.jeurceramsoc.2020.09.055.
[74] Y. Li, W. Weng, K.C. Tam, Novel highly biodegradable biphasic tricalcium
phosphates composed of α -tricalcium phosphate and β -tricalcium phosphate,
Acta Biomater. 3 (2) (2007) 251–254, doi:10.1016/j.actbio.2006.07.003.
[75] L. Vecbiskena, K.A. Gross, U. Riekstina, T.C.K. Yang, Crystallized nano-sized
alpha-tricalcium phosphate from amorphous calcium phosphate: microstructure, cementation and cell response, Biomed. Mater. 10 (2) (2015) 25009,
doi:10.1088/1748-6041/10/2/025009.
[76] Y. Li, T. Wiliana, K.C. Tam, Synthesis of amorphous calcium phosphate using
various types of cyclodextrins, Mater. Res. Bull. 42 (5) (2007) 820–827, doi:10.
1016/j.materresbull.2006.08.027.
[77] P. Ge, K. Sun, Y. Ding, T. Ge, Synthesis and characterisation of
Zn3 Ga2 SnO8 :Cr3+ , Yb3+ , Er3+ /α -tricalcium phosphate up-converted and
persistent luminescence phosphor, Ceram. Int. 46 (11) (2020) 17540–17544
Aug., doi:10.1016/j.ceramint.2020.04.052.
[78] P. Ge, K. Sun, H. Li, F. Yang, Low temperature preparation of α -tricalcium
phosphate up-converted luminescence nano phosphor, Optik 203 (2020)
(Stuttg)Feb., doi:10.1016/j.ijleo.2019.164040.
[79] J. Duncan, J.F. MacDonald, J.V. Hanna, Y. Shirosaki, S. Hayakawa, A. Osaka,
J.M.S. Skakle, I.R. Gibson, The role of the chemical composition of monetite
on the synthesis and properties of α -tricalcium phosphate, Mater. Sci. Eng. C
34 (1) (2014) 123–129, doi:10.1016/j.msec.2013.08.038.
[80] M. Frasnelli, V.M. Sglavo, Effect of Mg2+ doping on beta-alpha phase transition in tricalcium phosphate (TCP) bioceramics, Acta Biomater. 33 (2016)
283–289, doi:10.1016/j.actbio.2016.01.015.
[81] R.G. Carrodeguas, A.H. De Aza, X. Turrillas, P. Pena, S. De Aza, New approach to the β →α polymorphic transformation in magnesium-substituted
tricalcium phosphate and its practical implications, J. Am. Ceram. Soc. 91 (4)
(2008) 1281–1286, doi:10.1111/j.1551-2916.2008.02294.x.
[82] R. Enderle, F. Götz-Neunhoeffer, M. Göbbels, F.A. Müller, P. Greil, Influence
of magnesium doping on the phase transformation temperature of β -TCP ceramics examined by Rietveld refinement, Biomaterials 26 (17) (2005) 3379–
3384, doi:10.1016/j.biomaterials.2004.09.017.
[83] H. Fleisch, R.G.G. Russell, S. Bisaz, J.D. Termine, A.S. Posner, Influence of pyrophosphate on the transformation of amorphous to crystalline calcium phosphate, Calcif. Tissue Res. 2 (1) (1968) 49–59, doi:10.1007/BF02279193.
[84] L. Morejón-Alonso, O.J.B. Ferreira, R.G. Carrodeguas, L.A. Dos Santos, Bioactive
composite bone cement based on α -tricalcium phosphate/tricalcium silicate,
J. Biomed. Mater. Res. Part B Appl. Biomater. 100 B (1) (2012) 94–102 Jan.,
doi:10.1002/jbm.b.31926.
[85] E.B. Montufar, Y. Maazouz, M.P. Ginebra, Relevance of the setting reaction to
the injectability of tricalcium phosphate pastes, Acta Biomater. 9 (4) (2013)
6188–6198, doi:10.1016/j.actbio.2012.11.028.
[86] R. Harrison, Z. Criss, S. Modi, J. Hardy, C. Schmidt, L. Suggs, M. Murphy, Mechanical properties of α -tricalcium phosphate-based bone cements incorporating regenerative biomaterials for filling bone defects exposed to low mechanical loads, J. Biomed. Mater. Res. Part B Appl. Biomater. 104 (1) (2016)
149–157, doi:10.1002/jbm.b.33362.
[87] L.A. Dos Santos, R.G. Carrodéguas, S.O. Rogero, O.Z. Higa, A.O. Boschi, A.C.F. De
Arruda, α -Tricalcium phosphate cement: ‘in vitro’ cytotoxicity, Biomaterials 23
(9) (2002) 2035–2042, doi:10.1016/S0142-9612(01)00333-7.
[88] L. Morejón-Alonso, R.G. Carrodeguas, L.A. dos Santos, Development and characterization of α -tricalcium phosphate/monocalcium aluminate composite
bone cement, J. Biomed. Sci. Eng. 05 (08) (2012) 448–456, doi:10.4236/jbise.
2012.58057.
[89] M. P. Ginebra, M. G. Boltong, E. Fernandez, J. A. Planell, and F. C. M. Driessens,
“Effect of various additives and temperature on some properties of an apatitic
calcium phosphate cement,” 1995.
[90] H. Monma, M. Goto, Behavior of the alfa-beta phase transformation in tricalcium phosphate, Yogyo-Kyokai-Shi 91 (10) (1983) 473–475.
[91] N. Döbelin, L. Galea, U. Eggenberger, J.M.F. Ferreira, M. Bohner, Recrystallization of amorphized α -TCP, Key Eng. Mater. 493–494 (2012) 219–224,
doi:10.4028/www.scientific.net/KEM.493-494.219.
[92] M.P. Ginebra, F.C.M. Driessens, J.A. Planell, Effect of the particle size on the
micro and nanostructural features of a calcium phosphate cement: a kinetic
analysis, Biomaterials 25 (17) (2004) 3453–3462, doi:10.1016/j.biomaterials.
2003.10.049.
[93] E. Fernández, M. Ginebra, M. Boltong, F. Driessens, J. Ginebra, E. De Maeyer,
R. Verbeeck, J. Planell, Kinetic study of the setting reaction of a calcium phos-
phate bone cement, J. Biomed. Mater. Res. 32 (3) (1996) 367–374, doi:10.
1002/(SICI)1097- 4636(199611)32:3<367::AID- JBM9>3.0.CO;2- Q.
[94] I.V. Fadeeva, Y.Y. Filippov, A.S. Fomin, N.V. Petrakova, A.V. Knotko, A.P. Ryzhov,
V.I. Putlyaev, S.M. Barinov, Microstructure and properties of α -tricalcium
phosphate-based bone cement, Inorg. Mater. 53 (3) (2017) 292–299, doi:10.
1134/S0 020168517030 049.
[95] H.S. Ryu, H.J. Youn, K.S. Hong, B.S. Chang, C.K. Lee, S.S. Chung, An improvement in sintering property of β -tricalcium phosphate by addition of
calcium pyrophosphate, Biomaterials 23 (3) (2002) 909–914, doi:10.1016/
S0142-9612(01)00201-0.
[96] J. H. Welch and W. Gutt, “High-temperature studies of the system calcium
oxide-phosphorus pentoxide,” no. 4442, pp. 4442–4444, 1961.
[97] L.A. Dos Santos, R.G. Carrodeguas, A.O. Boschi, A.C.F. de Arruda, Dual-setting
calcium phosphate cement modified with ammonium polyacrylate, Artif. Organs 27 (5) (2003) 412–418.
[98] L.A. Dos Santos, L.C. De Oliveira, E.C. Da Silva Rigo, R. Garcia Carrodéguas;,
A.O. Boschi, A.C.F. De Arruda, Fiber reinforced calcium phosphate cement, Artif. Organs 24 (3) (20 0 0) 212–216, doi:10.1046/j.1525-1594.20 0 0.06541.x.
[99] M. Bohner, R. Luginbühl, C. Reber, N. Doebelin, G. Baroud, E. Conforto, A physical approach to modify the hydraulic reactivity of α -tricalcium phosphate
powder, Acta Biomater. 5 (9) (2009) 3524–3535, doi:10.1016/j.actbio.2009.05.
024.
[100] M. Schumache, A. Henß, M. Rohnke, M. Gelinsky, A novel and easy-to-prepare
strontium(II) modified calcium phosphate bone cement with enhanced mechanical properties, Acta Biomater. 9 (7) (2013) 7536–7544 Jul., doi:10.1016/j.
actbio.2013.03.014.
[101] A. Lode, C. Heiss, G. Knapp, J. Thomas, B. Nies, M. Gelinsky, M. Schumacher,
Strontium-modified premixed calcium phosphate cements for the therapy of
osteoporotic bone defects, Acta Biomater. 65 (2018) 475–485 Jan., doi:10.1016/
j.actbio.2017.10.036.
[102] T. Yu, S. Zeng, X. Liu, H. Shi, J. Ye, C. Zhou, Application of Sr-doped octacalcium phosphate as a novel Sr carrier in the α -tricalcium phosphate bone
cement, Ceram. Int. 43 (15) (2017) 12579–12587, doi:10.1016/j.ceramint.2017.
06.135.
[103] H. Shi, S. Zeng, X. Liu, T. Yu, C. Zhou, Effects of strontium doping on the
degradation and Sr ion release behaviors of α -tricalcium phosphate bone cement, J. Am. Ceram. Soc. (2018), doi:10.1111/ijlh.12426.
[104] G. Mestres, C.L. Van, M.P. Ginebra, Silicon-stabilized α -tricalcium phosphate
and its use in a calcium phosphate cement: characterization and cell response, Acta Biomater. 8 (3) (2012) 1169–1179 Mar., doi:10.1016/j.actbio.2011.
11.021.
[105] J.W. Reid, L. Tuck, M. Sayer, K. Fargo, J.A. Hendry, Synthesis and characterization of single-phase silicon-substituted α -tricalcium phosphate, Biomaterials
27 (15) (2006) 2916–2925 May, doi:10.1016/j.biomaterials.2006.01.007.
[106] I.M. Martínez, P. Velásquez, L. Meseguer-Olmo, A. Bernabeu-Esclapez, P.N. De
Aza, Preparation and characterization of novel bioactive α -tricalcium phosphate doped with dicalcium silicate ceramics, Mater. Sci. Eng. C 32 (4) (2012)
878–886, doi:10.1016/j.msec.2012.02.006.
[107] W. Xiang, M. Akinc, Si, Zn-modified tricalcium phosphates: a phase composition and crystal structure study, Key Eng. Mater. 284–286 (2005) 83–86,
doi:10.4028/www.scientific.net/kem.284-286.83.
[108] M. Motisuke, G. Mestres, C.O. Renó, R.G. Carrodeguas, C.A.C. Zavaglia,
M.P. Ginebra, Influence of Si substitution on the reactivity of α -tricalcium
phosphate, Mater. Sci. Eng. C 75 (2017) 816–821, doi:10.1016/j.msec.2017.02.
099.
[109] J. Ando, Tricalcium phosphate and its variation, Bull. Chem. Soc. Jpn. 31 (2)
(1958) 196–201, doi:10.1246/bcsj.31.196.
[110] N. Matsumoto, K. Yoshida, K. Hashimoto, Y. Toda, Thermal stability of β tricalcium phosphate doped with monovalent metal ions, Mater. Res. Bull. 44
(9) (2009) 1889–1894, doi:10.1016/j.materresbull.2009.05.012.
[111] J. Ando, Phase diagrams of Ca3 (PO4 )2 -Mg3 (PO4 )2 and Ca3 (PO4 )2 -CaNaPO4 ,
Bull. Chem. Soc. Jpn. 31 (2) (1958) 201–205.
[112] M.P. Ginebra, E. Fernández, E.A.P. De Maeyer, R.M.H. Verbeeck, M.G. Boltong,
J. Ginebra, F.C.M. Driessens, J.A. Planell, Setting reaction and hardening of
an apatitic calcium phosphate cement, J. Dent. Res. 76 (4) (1997) 905–912,
doi:10.1177/0 0220345970760 041201.
[113] S. Pina, S.M. Olhero, S. Gheduzzi, A.W. Miles, J.M.F. Ferreira, Influence of setting liquid composition and liquid-to-powder ratio on properties of a Mgsubstituted calcium phosphate cement, Acta Biomater. 5 (4) (2009) 1233–
1240, doi:10.1016/j.actbio.2008.11.026.
[114] M.B. Thürmer, C.E. Diehl, F.J.B. Brum, L.A. dos Santos, Development of dualsetting calcium phosphate cement using absorbable polymer, Artif. Organs 37
(11) (2013) 992–997, doi:10.1111/aor.12236.
[115] H. Monma, T. Kanazawa, The hydration of -tricalcium phosphate, Yogyo-Kyokai-Shi 84 (4) (1976) 209–213.
[116] M.P. Ginebra, E. Fernández, M.G. Boltong, O. Bermúdez, J.A. Planell,
F.C.M. Driessens, Compliance of an apatitic calcium phosphate cement with
the short-term clinical requirements in bone surgery, Orthopaed. Dent.
(1994).
[117] S. Sarda, E. Fernández, M. Nilsson, M. Balcells, and J. A. Planell, “Kinetic study
of citric acid influence on calcium phosphate bone cements as water-reducing
agent,” 2002.
[118] T.J. Brunner, R.N. Grass, M. Bohner, W.J. Stark, Effect of particle size, crystal
phase and crystallinity on the reactivity of tricalcium phosphate cements for
bone reconstruction, J. Mater. Chem. 17 (38) (2007) 4072–4078, doi:10.1039/
b707171j.
85
M.C. Tronco, J.B. Cassel and L.A. dos Santos
Acta Biomaterialia 151 (2022) 70–87
properties and biomimetic behaviour of α -TCP-chitosan based materials, Ceram. Int. 40 (4) (2014) 5523–5532 May, doi:10.1016/j.ceramint.2013.10.142.
[144] A. Almirall, G. Larrecq, J.A. Delgado, S. Martínez, J.A. Planell, M.P. Ginebra, Fabrication of low temperature macroporous hydroxyapatite scaffolds by foaming and hydrolysis of an α -TCP paste, Biomaterials 25 (17) (2004) 3671–3680,
doi:10.1016/j.biomaterials.2003.10.066.
[145] M.P. Ginebra, J.A. Delgado, I. Harr, A. Almirall, S. Del Valle, J.A. Planell, Factors affecting the structure and properties of an injectable self-setting calcium phosphate foam, J. Biomed. Mater. Res. Part A 80 (2007) 351–361 no. A,
doi:10.1002/jbm.a.
[146] S. Del Valle, N. Miño, F. Muñoz, A. González, J.A. Planell, M.P. Ginebra, In vivo
evaluation of an injectable macroporous calcium phosphate cement, J. Mater.
Sci. Mater. Med. 18 (2) (2007) 353–361, doi:10.1007/s10856- 006- 0700- y.
[147] J.T. Zhang, F. Tancret, J.M. Bouler, Fabrication and mechanical properties of
calcium phosphate cements (CPC) for bone substitution, Mater. Sci. Eng. C 31
(4) (2011) 740–747, doi:10.1016/j.msec.2010.10.014.
[148] F. Chinellato, J. Wilbig, D. Al-Sabbagh, P. Colombo, J. Günster, Gas flow assisted powder deposition for enhanced flowability of fine powders: 3D printing of α -tricalcium phosphate, Open Ceram. 1 (2020) 10 0 0 03 no. February,
doi:10.1016/j.oceram.2020.10 0 0 03.
[149] L.S. Bertol, R. Schabbach, L.A.L. Dos Santos, Dimensional evaluation of
patient-specific 3D printing using calcium phosphate cement for craniofacial
bone reconstruction, J. Biomater. Appl. 31 (6) (2017) 799–806, doi:10.1177/
0885328216682672.
[150] C. Durucan, P.W. Brown, α -Tricalcium phosphate hydrolysis to hydroxyapatite
at and near physiological temperature, J. Mater. Sci. Mater. Med. 11 (20 0 0)
365–371.
[151] M. Bohner, T.J. Brunner, N. Doebelin, R. Tang, W.J. Stark, Effect of thermal
treatments on the reactivity of nanosized tricalcium phosphate powders, J.
Mater. Chem. 18 (37) (2008) 4460–4467.
[152] E.B. Montufar, M. Casas-Luna, M. Horynová, S. Tkachenko, Z. Fohlerová, S. Diaz-de-la-Torre, K. Dvorak, L. Celko, J. Kaiser, High strength, biodegradable and
cytocompatible alpha tricalcium phosphate-iron composites for temporal reduction of bone fractures, Acta Biomater. 70 (2018) 293–303.
[153] M. Bohner, T.J. Brunner, W.J. Stark, Controlling the reactivity of calcium phosphate cements, J. Mater. Chem. 18 (46) (2008) 5669–5675.
[154] F. Buchanan, L. Gallagher, V. Jack, N. Dunne, Short-fibre reinforcement of calcium phosphate bone cement, Proc. Inst. Mech. Eng. Part H J. Eng. Med. 221
(2) (2007) 203–211.
[155] S. Takagi, L.C. Chow, S. Hirayama, A. Sugawara, Premixed calcium-phosphate
cement pastes, J. Biomed. Mater. Res. Part B Appl. Biomater. 67 (2) (2003)
689–696.
[156] M.P. Ginebra, A. Rilliard, E. Fernández, C. Elvira, J. San Román, J.A. Planell,
Mechanical and rheological improvement of a calcium phosphate cement by
the addition of a polymeric drug, J. Biomed. Mater. Res. 57 (1) (2001) 113–118.
[157] S.K. Lee, S.K. Lee, S.I. Lee, J.H. Park, J.H. Jang, H.W. Kim, E.C. Kim, Effect of
calcium phosphate cements on growth and odontoblastic differentiation in
human dental pulp cells, J. Endod. 36 (9) (2010) 1537–1542.
[158] H.A.I. Cardoso, M. Motisuke, A.C.D. Rodas, O.Z. Higa, C.A.C. Zavaglia, pH evolution and cytotoxicity of [Alpha]-tricalcium phosphate cement with three different additives, Key Eng. Mater. 493–494 (2012) 403–408.
[159] W. Liu, J. Zhang, P. Weiss, F. Tancret, J.M. Bouler, The influence of different cellulose ethers on both the handling and mechanical properties of calcium phosphate cements for bone substitution, Acta Biomater. 9 (3) (2013)
5740–5750 Mar..
[160] K. Hurle, J. Neubauer, M. Bohner, N. Doebelin, F. Goetz-Neunhoeffer,
Calorimetry investigations of milled α -tricalcium phosphate (α -TCP) powders
to determine the formation enthalpies of α -TCP and X-ray amorphous tricalcium phosphate, Acta Biomater. 23 (2015) 338–346.
[161] T.J. Brunner, M. Bohner, C. Dora, C. Gerber, W.J. Stark, Comparison of amorphous TCP nanoparticles to micron-sized a-TCP as starting materials for calcium phosphate cements, J. Biomed. Mater. Res. B. Appl. Biomater. 83 (2007)
400–407 no. B.
[162] M. Kon, L.M. Hirakata, Y. Miyamoto, H. Kasahara, K. Asaoka, Strengthening
of calcium phosphate cement by compounding calcium carbonate whiskers,
Dent. Mater. J. 24 (1) (2005) 104–110.
[163] E. Fernández, F.J. Gil, S.M. Best, M.P. Ginebra, F.C.M. Driessens, J.A. Planell,
Improvement of the mechanical properties of new calcium phosphate bone
cements in the CaHPO4 -α -Ca3 (PO4 )2 system: compressive strength and microstructural development, J. Biomed. Mater. Res. 41 (4) (1998) 560–567.
[164] E.B. Montufar, T. Traykova, C. Gil, I. Haar, A. Almirall, A. Aguirre, E. Engel,
J.A. Planell, M.P. Ginebra, Foamed surfactant solution as a template for self-setting injectable hydroxyapatite scaffolds for bone regeneration, Acta Biomater. 6 (3) (2010) 876–885.
[165] M.P. Ginebra, E. Fernandez, F. Driessens, M. Boltong, J. Muntasell, J. Font,
J. Planell, The effects of temperature on the behaviour of an apatitic calcium
phosphate cement, J. Mater. Sci. Mater. Med. 6 (12) (1995) 857–860.
[166] A. Ewald, D. Hösel, S. Patel, L.M. Grover, J.E. Barralet, U. Gbureck, Silver-doped
calcium phosphate cements with antimicrobial activity, Acta Biomater. 7 (11)
(2011) 4064–4070.
[167] E.M. Ooms, J.G.C. Wolke, J.P.C.M. Van Der Waerden, J.A. Jansen, Use of injectable calcium-phosphate cement for the fixation of titanium implants: an
experimental study in goats, J. Biomed. Mater. Res. Part B Appl. Biomater. 66
(1) (2003) 447–456.
[168] J. Zhang, W. Liu, O. Gauthier, S. Sourice, P. Pilet, G. Rethore, K. Khairoun,
J. Bouler, F. Tancret, P. Weiss, A simple and effective approach to prepare
[119] C.L. Camiré, U. Gbureck, W. Hirsiger, M. Bohner, Correlating crystallinity and
reactivity in an α -tricalcium phosphate, Biomaterials 26 (16) (2005) 2787–
2794, doi:10.1016/j.biomaterials.20 04.08.0 01.
[120] M.P. Ginebra, E. Fernández, F.C.M. Driessens, J.A. Planell, Modeling of the hydrolysis of α -tricalcium phosphate, J. Am. Ceram. Soc. 82 (10) (2004) 2808–
2812, doi:10.1111/j.1151-2916.1999.tb02160.x.
[121] M. Bohner, A.K. Malsy, C.L. Camiré, U. Gbureck, Combining particle size distribution and isothermal calorimetry data to determine the reaction kinetics of
α -tricalcium phosphate-water mixtures, Acta Biomater. 2 (3) (2006) 343–348,
doi:10.1016/j.actbio.2006.01.003.
[122] K. Hurle, J. Neubauer, M. Bohner, N. Doebelin, F. Goetz-Neunhoeffer, Effect
of amorphous phases during the hydraulic conversion of α -TCP into calciumdeficient hydroxyapatite, Acta Biomater. 10 (9) (2014) 3931–3941, doi:10.1016/
j.actbio.2014.03.017.
[123] U. Gbureck, J.E. Barralet, L. Radu, H.G. Klinger, R. Thull, Amorphous atricalcium phosphate: preparation and aqueous setting reaction, J. Am. Ceram.
Soc. 87 (6) (2004) 1126–1132, doi:10.1111/j.1551-2916.2004.01126.
[124] H. Monma, M. Goto, T. Kohmura, Effect of additives on hydration and hardening of tricalcium phosphate, Gypsum Lime 188 (188) (1984).
[125] E. Fernández, M.G. Boltong, M.P. Ginebra, O. Bermúdez, F.C.M. Driessens,
J.A. Planell, Common ion effect on some calcium phosphate cements, Clin.
Mater. 16 (2) (1994) 99–103, doi:10.1016/0267-6605(94)90103-1.
[126] Z. Irbe, D. Loca, Soluble phosphate salts as setting aids for premixed calcium
phosphate bone cement pastes, Ceram. Int. 47 (17) (2021) 24012–24019 Sep.,
doi:10.1016/j.ceramint.2021.05.110.
[127] J. Weichhold, F. Goetz-Neunhoeffer, K. Hurle, U. Gbureck, Pyrophosphate ions
inhibit calcium phosphate cement reaction and enable storage of premixed
pastes with a controlled activation by orthophosphate addition, Ceram. Int.
48 (11) (2022) 15390–15404 Jun., doi:10.1016/j.ceramint.2022.02.073.
[128] M. Bohner, H. Tiainen, P. Michel, N. Döbelin, Design of an inorganic dual-paste
apatite cement using cation exchange, J. Mater. Sci. Mater. Med. 26 (2) (2015)
1–13 Feb., doi:10.1007/s10856-015-5400-z.
[129] L.A. Dos Santos, L.C. De Oliveira, E.C.S. Rigo, R.G. Carrodeguas, A.O. Boschi,
A.C.F. De Arruda, Influence of polymeric additives on the mechanical properties of α -tricalcium phosphate cement, Bone 25 (2) (1999) 99–102 SUPPL. 1,
doi:10.1016/S8756-3282(99)00143-X.
[130] K. Hurle, T. Christel, U. Gbureck, C. Moseke, J. Neubauer, F. Goetz-Neunhoeffer,
Reaction kinetics of dual setting α -tricalcium phosphate cements, J. Mater.
Sci. Mater. Med. 27 (1) (2016) 1–13, doi:10.1007/s10856-015- 5616- y.
[131] T. Christel, M. Kuhlmann, E. Vorndran, J. Groll, U. Gbureck, Dual setting α tricalcium phosphate cements, J. Mater. Sci. Mater. Med. 24 (3) (2013) 573–
581, doi:10.1007/s10856- 012- 4828- 7.
[132] M. Shahrezaei, J. Shahrouzi, S. Hesaraki, A. Zamanian, The effect of α -TCP particle size on mechanical and setting properties of calcium phosphate bone
cements, J. Arch. Mil. Med. 2 (2) (2014) May, doi:10.5812/jamm.16516.
[133] A. Zamanian, J. Shahrouzi, S. Hesaraki, The effect of paste concentration on
mechanical and setting properties of calcium phosphate bone cements, Adv.
Chem. Eng. Res. 1 (1) (2012) December[Online]. Available: www.seipub.org/
acer .
[134] W. Liu, J. Zhang, G. Rethore, K. Khairoun, P. Pilet, F. Tancret, J.M. Bouler,
P. Weiss, A novel injectable, cohesive and toughened Si-HPMC (silanizedhydroxypropyl methylcellulose) composite calcium phosphate cement for
bone substitution, Acta Biomater. 10 (7) (2014) 3335–3345, doi:10.1016/j.
actbio.2014.03.009.
[135] K. Sariibrahimoglu, J.G.C. Wolke, S.C.G. Leeuwenburgh, L. Yubao, J.A. Jansen,
Injectable biphasic calcium phosphate cements as a potential bone substitute,
J. Biomed. Mater. Res. Part B Appl. Biomater. 102 (3) (2014) 415–422 Apr.,
doi:10.1002/jbm.b.33018.
[136] T. Konishi, M. Mizumoto, M. Honda, Y. Horiguchi, K. Oribe, H. Morisue, K. Ishii,
Y. Toyama, M. Matsumoto, M. Aizawa, Fabrication of novel biodegradable
α -tricalcium phosphate cement set by chelating capability of inositol phosphate and its biocompatibility, J. Nanomater. 2013 (2013), doi:10.1155/2013/
864374.
[137] A. Yokoyama, S. Yamamoto, T. Kawasaki, T. Kohgo, M. Nakasu, Development of
calcium phosphate cement using chitosan and citric acid for bone substitute
materials, Biomaterials 23 (4) (2002) 1091–1101, doi:10.1016/S0142-9612(01)
00221-6.
[138] S.A. Oh, G.S. Lee, J.H. Park, H.W. Kim, Osteoclastic cell behaviors affected by
the α -tricalcium phosphate based bone cements, J. Mater. Sci. Mater. Med. 21
(11) (2010) 3019–3027, doi:10.1007/s10856-010-4152-z.
[139] J. Wen, I.Y. Kim, K. Kikuta, C. Ohtsuki, Optimization of sintering conditions
for improvement of mechanical property of a-tricalcium phosphate blocks,
Glob. J. Biotechnol. Biomater. Sci. 1 (2016) 0 01–0 07 [Online]. Available: www.
peertechz.com .
[140] M. Espanol, R.A. Perez, E.B. Montufar, C. Marichal, A. Sacco, M.P. Ginebra, Intrinsic porosity of calcium phosphate cements and its significance for drug
delivery and tissue engineering applications, Acta Biomater. 5 (7) (2009)
2752–2762, doi:10.1016/j.actbio.2009.03.011.
[141] S. Zeng, H. Shi, T. Yu, C. Zhou, Enhanced hydrated properties of α -tricalcium
phosphate bone cement mediated by loading magnesium substituted octacalcium phosphate, Adv. Powder Technol. 28 (12) (2017) 3288–3295, doi:10.
1016/j.apt.2017.10.006.
[142] U. Gbureck, K. Spatz, R. Thull, J.E. Barralet, Rheological enhancement of mechanically activated α -tricalcium phosphate cements, J. Biomed. Mater. Res.
Part B Appl. Biomater. 73 (1) (2005) 1–6, doi:10.1002/jbm.b.30148.
[143] J. Czechowska, A. Zima, Z. Paszkiewicz, J. Lis, A. Ślósarczyk, Physicochemical
86
M.C. Tronco, J.B. Cassel and L.A. dos Santos
Acta Biomaterialia 151 (2022) 70–87
[183] A.F.V. Niño, L.A.L. Dos Santos, Preparation of an injectable macroporous α -TCP
cement, Mater. Res. 19 (4) (2016) 908–913 Jul..
[184] L. Tonietto, A.F. Vasquez, L.A. dos Santos, J.B.B. Weber, Histological and structural evaluation of growth hormone and PLGA incorporation in macroporous
scaffold of α -tricalcium phosphate cement, J. Biomater. Appl. 33 (6) (2019)
866–875 Jan..
[185] J.W. Reid, A. Pietak, M. Sayer, D. Dunfield, T.J.N. Smith, Phase formation and
evolution in the silicon substituted tricalcium phosphate/apatite system, Biomaterials 26 (16) (2005) 2887–2897 Jun..
[186] J. Czechowska, A. Zima, D. Siek, A. Ślósarczyk, Influence of sodium alginate
and methylcellulose on hydrolysis and physicochemical properties of α -TCP
based materials, Ceram. Int. 44 (6) (2018) 6533–6540 Apr..
[187] L. Xie, H. Yu, Y. Deng, W. Yang, L. Liao, Q. Long, Preparation, characterization
and in vitro dissolution behavior of porous biphasic α /β -tricalcium phosphate
bioceramics, Mater. Sci. Eng. C 59 (2016) 1007–1015.
[188] D. Siek, A. Slosarczyk, A. Przekora, A. Belcarz, A. Zima, G. Ginalska,
J. Czechowska, Evaluation of antibacterial activity and cytocompatibility of
α -TCP based bone cements with silver-doped hydroxyapatite and CaCO3, Ceram. Int. 43 (16) (2017) 13997–14007 Nov..
[189] Y.M. Sahin, Z. Orman, S. Yucel, In vitro studies of α -TCP and β -TCP produced from clinocardium ciliatum seashells, J. Aust. Ceram. Soc. 56 (2) (2020)
477–488.
[190] L. Sinusaite, A. Popov, E. Raudonyte-Svirbutaviciene, J.C. Yang, A. Kareiva,
A. Zarkov, Effect of Mn doping on hydrolysis of low-temperature synthesized
metastable alpha-tricalcium phosphate, Ceram. Int. (2021) 1–6 no. January.
[191] L. Sinusaite, A. Antuzevics, A.I. Popov, U. Rogulis, M. Misevicius, A. Katelnikovas, A. Kareiva, A. Zarkov, Synthesis and luminescent properties of Mn-doped
alpha-tricalcium phosphate, Ceram. Int. 47 (4) (2021) 5335–5340.
[192] A. Kazuz, Z. Radovanovic, D.J. Veljovic, V. Kojic, V. Miletic, R. Petrovic,
D.J. Janackovic, α -Tricalcium phosphate/fluorapatite based composite cements: Synthesis, mechanical properties, and biocompatibility, Ceram. Int. 46
(16) (2020) 25149–25154.
[193] D. Luo, C. Tong, Y. Zhu, C. Xu, Y. Li, Color tracing in the hydration process of
α -Ca3 (PO4 )2 :Eu, J. Lumin. 219 (2020) 116863 no. October 2019.
[194] S. Al-Maawi, M. Barbeck, C. Herrera-Vizcaíno, R. Egli, R. Sader, C.J. Kirkpatrick,
M. Bohner, S. Ghanaati, Thermal treatment at 500°C significantly reduces the
reaction to irregular tricalcium phosphate granules as foreign bodies: an in
vivo study, Acta Biomater. 121 (2021) 621–636.
[195] R.J. Egli, S. Gruenenfelder, N. Doebelin, W. Hofstetter, R. Luginbuehl,
M. Bohner, Thermal treatments of calcium phosphate biomaterials to tune
the physico-chemical properties and modify the in vitro osteoclast response,
Adv. Eng. Mater. 13 (3) (2011) 102–107.
injectable macroporous calcium phosphate cement for bone repair: syringe–
foaming using a viscous hydrophilic polymeric solution, Acta Biomater. 31
(2016) 326–338.
[169] I. Khairoun, M. G. Boltong, F. C. M. Driessens, and J. A. Planell, “Effect of calcium carbonate on the compliance of an apatitic calcium phosphate bone cement,” 1997.
[170] H.S. Lee, S.Y. Kwon, E.M. Seo, Y.H. Kim, S.S. Kim, Preparation and characterization of alpha-tricalcium phosphate cements incorporated with polyamino
acids, Macromol. Res. 19 (1) (2011) 90–96.
[171] C.L. Camiré, S. Jegou Saint-Jean, S. Hansen, I. McCarthy, L. Lidgren, Hydration
characteristics of α -tricalcium phosphates: comparison of preparation routes,
J. Appl. Biomater. Biomech. 3 (2) (2005) 106–111.
[172] M. Motisuke, R.G. Carrodeguas, C.A.C. Zavaglia, A comparative study between
α -TCP and Si-α -TCP calcium phosphate cement, Key Eng. Mater. 396–398
(2009) 201–204.
[173] S. Panzavolta, P. Torricelli, B. Bracci, M. Fini, A. Bigi, Alendronate and
Pamidronate calcium phosphate bone cements: setting properties and in vitro
response of osteoblast and osteoclast cells, J. Inorg. Biochem. 103 (1) (2009)
101–106.
[174] H. Shi, W. Zhang, X. Liu, S. Zeng, T. Yu, C. Zhou, Synergistic effects of citric
acid - sodium alginate on physicochemical properties of α -tricalcium phosphate bone cement, Ceram. Int. 45 (2) (2019) 2146–2152.
[175] E. Boanini, S. Panzavolta, K. Rubini, M. Gandolfi, A. Bigi, Effect of strontium
and gelatin on the reactivity of α -tricalcium phosphate, Acta Biomater. 6 (3)
(2010) 936–942.
[176] A. Bigi, B. Bracci, S. Panzavolta, Effect of added gelatin on the properties of
calcium phosphate cement, Biomaterials 25 (14) (2004) 2893–2899.
[177] P. Zhao, K.N. Sun, T.R. Zhao, X.H. Ren, Effect of CNTs on property of calcium
phosphate cement, Key Eng. Mater. 336–338 (2007) 1606–1608.
[178] A. Bigi, E. Boanini, G. Maglio, M. Malinconico, R. Palumbo, S.T. Scafati,
PLLA based composites with α -tricalcium phosphate and a PLLA-PEO diblock
copolymer, Macromol. Symp. 234 (2006) 26–32.
[179] L.A. Dos Santos, R. Garcia Carrodéguas, A. Ortega Boschi, A.C. Fonseca De
Arruda, Fiber-enriched double-setting calcium phosphate bone cement, J.
Biomed. Mater. Res. Part A 65 (2) (2003) 244–250.
[180] H.L.R. Alves, L.A. Dos Santos, C.P. Bergmann, Injectability evaluation of tricalcium phosphate bone cement, J. Mater. Sci. Mater. Med. 19 (5) (2008)
2241–2246 May.
[181] L. Morejón-Alonso, R.G. Carrodeguas, L.A. Dos Santos, Effects of silica addition
on the chemical, mechanical and biological properties of a new α -tricalcium
phosphate/tricalcium silicate cement, Mater. Res. 14 (4) (2011) 475–482.
[182] M.A. Aghayan, M.A. Rodríguez, Influence of fuels and combustion aids on solution combustion synthesis of bi-phasic calcium phosphates (BCP), Mater.
Sci. Eng. C 32 (8) (2012) 2464–2468.
87