Acta Biomaterialia 7 (2011) 3536–3546

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Acta Biomaterialia
journal homepage: www.elsevier.com/locate/actabiomat

Review

a-Tricalcium phosphate: Synthesis, properties and biomedical applications

R.G. Carrodeguas ⇑, S. De Aza
Instituto de Cerámica y Vidrio, CSIC, C/Kelsen, 5-28049 Madrid, Spain

a r t i c l e i n f o a b s t r a c t

Article history: Nowadays, a-tricalcium phosphate (a-TCP, a-Ca3(PO4)2) is receiving growing attention as a raw material
Received 22 March 2011 for several injectable hydraulic bone cements, biodegradable bioceramics and composites for bone repair.
Received in revised form 10 June 2011 In the phase equilibrium diagram of the CaO–P2O5 system, three polymorphs corresponding to the
Accepted 10 June 2011
composition Ca3(PO4)2 are recognized: b-TCP, a-TCP and a0 -TCP. a-TCP is formed by heating the low
Available online 16 June 2011
-temperature polymorph b-TCP or by thermal crystallization of amorphous precursors with the proper
composition above the transformation temperature. The a-TCP phase may be retained at room temper-
Keywords:
ature in a metastable state, and its range of stability is strongly influenced by ionic substitutions. It is as
a-Tricalcium phosphate
b-Tricalcium phosphate
biocompatible as b-TCP, but more soluble, and hydrolyses rapidly to calcium-deficient hydroxyapatite,
Synthesis which makes a-TCP a useful component for preparing self-setting osteotransductive bone cements and
Thermal stability biodegradable bioceramics and composites for bone repairing. The literature published on the synthesis
Phase transition and properties of a-TCP is sometimes contradictory, and therefore this article focuses on reviewing and
critically discussing the synthetic methods and physicochemical and biological properties of a-TCP-based
biomaterials (excluding a-TCP-based bone cements).
Ó 2011 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

1. Introduction
There are three polymorphs of TCP: the low-temperature b-TCP,
and the high-temperature forms, a- and a0 -TCP. The last one lacks
practical interest because it only exists at temperatures >1430 °C
and reverts almost instantaneously to a-TCP on cooling below the
transition temperature. In contrast, b-TCP is stable at room
temperature and transforms reconstructively [1,2] at 1125 °C to
a-TCP, which can be retained during cooling to room temperature
[3]. Several phase equilibrium diagrams have been proposed to de-
scribe the phase relationships in the CaO–P2O5 system [4–8]. The
main difference between them is to consider [4,7] or not to con-
sider [5,6,8] the existence of a TCP solid solution field at the high
P2O5 content side of the TCP composition.
The more recent study is that by Kreidler and Hummel [8], in
which TCP solid solution was not found (Fig. 1). They considered
that loss of P2O5 at temperatures >1600 °C was the cause for a mix-
ture of Ca2P2O7 and Ca3(PO4)2 to shift to the composition of Ca3
(PO4)2 and subsequent finding of this phase by X-ray analysis in
the work by Welch and Gutt [7], leading them to misinterpret their
experimental results [8].
a- and b-TCP are currently used in several clinical applications
in dentistry, maxillo-facial surgery and orthopaedics: b-TCP is the
component of several commercial mono- or biphasic bioceramics
⇑ Corresponding author. Tel.: +34 917 355 840; fax: +34 917 355 843.
E-mail address: rgc@icv.csic.es (R.G. Carrodeguas).
and composites, and a-TCP is the major constituent of the powder
component of various hydraulic bone cements [9,10].
In spite of having the same chemical composition, a- and b
-TCP differ considerably in their structure, density and solubility,
which in turn determine their biological properties and clinical
applications.
b-TCP is used mainly for preparing biodegradable bioceramics
shaped as dense and macro-porous granules and blocks, whereas
the more soluble and reactive a-TCP is used mainly as a fine pow-
der in the preparation of calcium phosphate cements, although
some commercial bioceramic granules and blocks made of a-TCP
may be found on the market. Both b- and a-TCP materials are used
in clinics for bone repair and remodelling applications.
Some commercial calcium phosphate bone cements using
a-TCP in their formulae are listed in Table 1. Detailed descriptions
and discussion of the physico-chemical and biological properties of
a-TCP-based bone cements can be found in previous reviews by
other authors [9–20]. Additional information on the properties
and applications of a-TCP may be found in Refs. [3,9,21–25].
2. Structural characteristics of a-TCP and its polymorphs
a-TCP crystalline structure was related to that of the mineral
glaserite (K3Na(SO4)2) by Dickens and Brown in 1972 [26] and later
studied in detail by Mathew et al. in 1977 [27] and more recently
by Yashima and Sakai [28]. a-TCP crystallizes in the monoclinic
crystal system and belongs to the space group P21/a. Cell

1742-7061/$ - see front matter Ó 2011 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.actbio.2011.06.019
 R.G. Carrodeguas, S. De Aza / Acta Biomaterialia 7 (2011) 3536–3546 3537

Fig. 1. Phase relationships in the CaO–P2O5 system according to Kreidler and
Hummel (this phase equilibrium diagram was published in Ref. [8], ÓElsevier).
Fig. 2. Schematic representation of the projections of the a-TCP, b-TCP and a0 -TCP
unit cells along the [0 0 1] direction [27–31]: Ca2+, green; P5+, magenta; O2 has not
been represented for the sake of clarity. C-C, cation–cation column; C-A, cation–
anion column. Thin-solid-line rhombus inscribed within the unit cell of a-TCP
outlines a cell related to that of hydroxyapatite.

Table 1
Commercial a-TCP-based bone cements.

Brand name Manufacturer Powder composition

CementekÒ Teknimed SA, France a-TCP + TTCP
MimixÒ Biomet, USA a-TCP + TTCP
CalcibonÒ Biomet, Europe a-TCP + DCP + CC + PHA
Norian SRSÒ Norian, USA a-TCP + CC + MCPM
BiopexÒ Mitsubishi Materials Co., Japan a-TCP + TTCP + DCPD + HAp
MCPC Biomatlante, France a-TCP + ACP + BCP
Callos™ Skeletal Kinetics, USA a-TCP + CC + MCPM
TTCP, tetracalcium phosphate, Ca4(PO4)2O; DCP, dicalcium phosphate CaHPO4;
DCPD, dicalcium phosphate dehydrate; CC, calcium carbonate, CaCO3; HAp,
hydroxyapatite, Ca10(PO4)6(OH)2; MCPM, monocalcium phosphate monohydrate,
Ca(H2PO4)2.H2O; PHA, precipitated HAp, Ca10  x(HPO4)x(PO4)6  x(OH)2  x; ACP,
amorphous calcium phosphate; BCP, biphasic calcium phosphate, HAp + b-TCP.
Fig. 3. Fractional projections of the a-TCP, b-TCP and a0 -TCP unit cells on the bc
plane showing the disposition of constituent atoms in columns oriented along
direction [0 0 1]. Ca2+, green; P5+, magenta; O2 has not been represented for the
sake of clarity. C-C, cation–cation column; C-A, cation–anion column; A, A column;
parameters (a, b, c, a, b and c), cell volume (V), number of formula
B, B column.
units per cell (Z), volume per formula unit (V0), theoretical density
(Dth) and the projections of the unit cells along the [0 0 1] direction
are displayed in Table 2 and Fig. 2, respectively, for a-TCP [27,28]
and its polymorphs b-TCP [29,30] and a0 -TCP [28,31].
total number of six surround each C-A column. C-C columns are
Ca and PO4 ions constituting the unit cells of a-TCP and its poly-
quite distorted from the straight line, as shown in Fig. 3 [27].
morphs are packed in columns along the [0 0 1] direction. Two
The thin solid-line rhombus inscribed within the unit cell of
types of columns exist in a-TCP: one, named C-C in Figs. 2 and 3,
a-TCP in Fig. 2 outlines a cell related to that of hydroxyapatite,
contains only Ca cations and the other, named C-A, contains both
in which the OH columns could replace the C-C columns at the cell
Ca cations and PO4 anions. Each C-C column is surrounded by six
corners. By analogy, the Ca–PO4 columns in hydroxyapatite may be
C-A columns, and in turn, alternating C-C and C-A columns to the
considered as very distorted C-A ‘‘columns’’, and each column is
surrounded by three C-A columns as in a-TCP, and by two C-C
and one OH column [27].
Table 2 A significant structural difference between a-TCP and b-TCP is
Structural data of a-TCP and its polymorphs. that there are no C-C columns in the latter. Instead, there are
Property Ca3(PO4)2 polymorph two types of C-A columns in b-TCP, A columns with the sequence
b-Ca3(PO4)2 [30] a-Ca3(PO4)2 [28] a0 -Ca3(PO4)2 [28] . . .–P–Ca–Ca–P–. . ., B columns with the order . . .–P–Ca–Ca–Ca–P–
P–. . ., and each A column is surrounded by six B columns, while
Symmetry Rhombohedral Monoclinic Hexagonal
Space group R3C P21/a P63/mmc
each B column is surrounded by two A and four B columns [30].
a (nm) 1.04352(2) 1.2859(2) 0.53507(8) In contrast, a0 -TCP consists of C-C and C-A columns alternating
b (nm) 1.04352(2) 2.7354(2) 0.53507(8) similarly to a-TCP (see Fig. 2) [28,31].
c (nm) 3.74029(5) 1.5222(3) 0.7684(1) The structure of a-TCP is less densely packed than b-TCP, and
a (°) 90 90 90
more densely than a0 -TCP, as shown by the volumes per formula
b (°) 90 126.35(1) 90
c (°) 120 90 120 unit (V0) and the calculated theoretical density (Dth) of the three
Z 21 24 1 substances listed in Table 2. The difference in packing densities
V (nm3) 3.5272(2) 4.31(6) 0.19052(8) of the three polymorphs is consistent with thermodynamic consid-
V0 (nm3) 0.1680(2) 0.180(6) 0.19052(8) erations and with their stability temperature ranges. In addition, it
Dth (g cm3) 3.066 2.866 2.702
should be expected that, in a physiological environment, the
3538 R.G. Carrodeguas, S. De Aza / Acta Biomaterialia 7 (2011) 3536–3546

Fig. 4. Calculated X-ray diffraction pattern of a-TCP and its polymorphs (2hmin = 5°;
2hmax = 60; step size = 0.05; k(Cu Ka1)=0.1540562 nm; Pol = 0.5; Mono-
chrom = none; Ua = Ub = Uc = 0.5) (MS Modeling v.4.0.0.0, Accelrys Software, 2005).

dissolution and degradation of the ‘‘looser’’ a-TCP structure pro-

ceeds faster than b-TCP, as has been observed experimentally
[11,23,32].

3. Identification and characterization techniques

Crystalline a-TCP is usually identified, and sometimes quanti-

fied when mixed with other calcium phosphates by means of
X-ray or neutron diffraction. The calculated X-ray diffraction pat-
tern for Cu Ka is displayed in Fig. 4 for a-TCP and its polymorphs. Fig. 5. Phosphorus L2,3-edge (a) and phosphorus K-edge (b) XANES spectra of a-
X-ray diffraction is a useful tool for differentiating a- and b- and b-TCP (redrawn from Ref. [33], Ó2010, with permission from Elsevier).
polymorphs.
X-ray absorption near edge structure (XANES) spectroscopy has
also been proposed as a useful technique for identifying and differ-
entiating calcium phosphate-based biomedical materials. In con-
trast to traditional techniques such as X-ray diffraction, neutron
diffraction and energy dispersive spectroscopy, XANES spectros-
copy provides information on the valence, oxidation state, coordi-
nation number of individual elements as well as the chemical
structure of compounds. In Fig. 5, distinctive characteristics are ob-
served for (a) the P L2,3- and (b) the P K-edge XANES spectra of
a-and b-TCP [33].
Other instrumental tools often employed in identifying and
characterizing a-TCP are Fourier-transform infrared [34], Raman
[34] and 31P MAS-NMR [35] spectroscopies. Typical IR and Raman
spectra of a-TCP are shown in Fig. 6, and the main absorption
bands and their characteristics are listed in Table 3 for a- and
b-TCP [34,36].
High-resolution 31P solid-state nuclear magnetic resonance
spectroscopy has been employed to analyse bioceramic composi-
tion and to estimate osteoformation during implantation [37].
31
P MAS-NMR spectra of a-TCP, as reported by Bohner et al. [35],
and b-TCP [38] are presented in Fig. 7.
In contrast to hydroxyapatite [39,40] and b-TCP [41], there are
no standards establishing the requirements of chemical composi-
tion for a-TCP-based materials intended for surgical implants. Nev-
ertheless, chemical analysis is almost customary for an exact
characterization of a-TCP and the other calcium orthophosphates
used as bone repairing materials. In particular, Ca and P contents,
their molar ratio and minor and trace elements exert marked influ-
ence on the thermal stability, phase purity and solubility of a-TCP,
as discussed below. Quantitative X-ray fluorescence methods have
been employed successfully to determine Ca and P contents in pure
and substituted a-TCP as well as minor and trace amounts of Mg
and Si, among other elements [42,43]. In addition, keeping in mind
that b-TCP and HAp are practically identical to a-TCP from the Fig. 6. (a) Typical FTIR spectra and (b) Raman spectra of crystalline a- and b-TCP
point of view of chemical constitution, analytical methods (redrawn from Ref. [34] with permission, http://www.informaworld.com).
 R.G. Carrodeguas, S. De Aza / Acta Biomaterialia 7 (2011) 3536–3546 3539

Table 3
Main bands and their characteristics wavenumbers and intensities in IR and Raman spectra of a- and b-TCP [34,36].

Normal modes Free PO3 1

4 (cm )
a-TCP b-TCP
1 1
IR (cm ) Raman (cm ) IR (cm1) Raman (cm1)
Symmetric P–O stretching, m1 938 954 (s) 954 (w, sh) 972 (s) 948 (s)
964 (s) 945 (s) 970 (s)
976 (s)
Symmetric P–O bending doubly degenerate, m2 420 415 (w) 421 (w) 419 (vw) 406 (m)
430 (w) 451 (w) 438 (vw) 442 (m)
454 (w) 458 (vw) 481 (m)
463 (w) 497 (vw)
471 (w)
Anti-symmetric P–O stretching triply degenerate, m3 1017 984 (s) 998 (s) 1025 (s) 1017 (w, br)
997 (s) 1012 (w) 1044 (s) 1048 (vs)
1013 (s) 1027 (w) 1066 (w, sh)
1025 (s) 1058 (w) 1083 (w, sh)
1039 (s) 1077 (w)
1055 (s)
Anti-symmetric P–O bending triply degenerate, m4 567 551 (s) 563 (s) 544 (w, sh) 549 (w)
563 (s) 577 (s) 555 (s) 573 (w)
585 (s) 593 (s) 594 (w, sh) 547 (w)
597 (s) 610 (s) 609 (s) 609 (w)
613 (s) 620 (s)

vs, very strong; s, strong; m, medium; w, weak; vw, very weak; sh, shoulder; br, broad.

Table 4
Solubility of some calcium orthophosphates [32].

Ca/P Compound log Kps Solubility (mg L1)

25 °C 37 °C 25 °C 37 °C
1.0 CaHPO42H2O 6.59 6.73 87 74
1.0 CaHPO4 6.90 7.04 48 41
1.33 Ca8(HPO4)2(PO4)45H2O 96.6 98.6 0.025 0.018
1.5 a-Ca3(PO4)2 25.5 28.5 0.97 0.24
1.5 b-Ca3(PO4)2 28.9 29.6 0.20 0.15
1.67 Ca10(PO4)6(OH)2 116.8 117.2 0.00010 0.000096
2.0 Ca4(PO4)2O 38–44 37–42 0.28–0.038 0.39–0.075

P dissolved from calcium orthophosphates decreases in the order

TTCP > a-TCP > DCPD > DCPA > OCP > b-TCP > HAp. However, in
those conditions, HAp is the most stable of all calcium orthophos-
phates, and in this way it should precipitate as a-TCP dissolution
progresses. This is the thermodynamic base of calcium phosphate
cements derived from a-TCP, which set as result of Eq. (1)
[10,16,17].
3a-Ca3 ðPO4 Þ2ðsÞ þ H2 OðgÞ ! Ca9 ðHPO4 ÞðPO4 Þ5 ðOHÞðsÞ ð1Þ

However, empirical systems do not always fulfil thermody-

Fig. 7. 31P MAS-NMR spectra of a-TCP (redrawn from Ref. [35] with kind
permission from Springer Science + Business Media) and b-TCP (redrawn from
Ref. [38] with permission, Ó2009 Wiley Periodicals, Inc.).
standardized [44] and developed [45–49] for the formers may be
used for chemical characterization of a-TCP.
4. Solubility and biodegradability
The structural differences between b- and a-polymorphs of TCP
are responsible for their different chemical and biological proper-
ties, among them, solubility and biodegradability.
Solubility products of a-TCP and other calcium orthophos-
phates are listed in Table 4 [23,32], and the calculated isotherms
of solubility at 37 °C are represented in Fig. 8 as the log of the con-
centration of (a) Ca and (b) P vs pH [11]. The analysis of Fig. 8 re-
veals that at physiological pH (7.2–7.4) the concentration of Ca and
namic predictions and other calcium phosphates, different from
Hap, may be obtained as result of the dissolution of a-TCP [9,10].
In contrast, the increase in solubility of a-TCP is considerable at
pH < 5, and other calcium phosphates different from HAp may exist
in thermodynamic equilibrium with the saturated solution (see
Fig. 8) [11]. The increase in solubility of a-TCP by diminishing pH
from 7.4 to 5.4 is illustrated in Fig. 9, where kinetic curves of dis-
solution at both pH are plotted for a- and b-TCP [50].
It has been well documented that the setting reaction of Eq. (1)
taking place in a-TCP-based cements is initially controlled by a
surface reaction that depends on the dissolution rate of the pow-
dered reagent. Thus, modulation of the dissolution rate of a-TCP
is very important in controlling the overall setting reaction [18].
There are several approaches to modifying the dissolution rate of
a-TCP powders [18]: (i) change in the contact area between pow-
der and mixing liquid; (ii) change in the powder solubility in the
mixing liquid; (iii) change in the saturation of the mixing liquid
towards a-TCP; (iv) use of dissolution inhibitors; (v) surface
modification (passivation [51,52] or activation [53] of the surface).
3540 R.G. Carrodeguas, S. De Aza / Acta Biomaterialia 7 (2011) 3536–3546
Fig. 8. Solubility phase diagram for the ternary system Ca(OH)2–H3PO4–H2O, at
37 °C: (a) solubility isotherms showing log [Ca] and pH of solution in equilibrium
with various salts; (b) solubility isotherms showing log [P] and pH of the solutions
(redrawn from Ref. [11], with permission from The Ceramic Society of Japan).
Fig. 9. Kinetics of dissolution in vitro of ArrowBone™-a and -b granules consisting
of a- and b-TCP, respectively, at pH 5.4 (MES buffer) and 7.4 (Tris buffer) (redrawn
from Ref. [44]).
5. Commercially available a-TCP
Whereas commercial b-TCP products with different degrees of
quality can easily be found in the market, suppliers of a-TCP are
quite rare and dispersed throughout the world. Only a few manu-
facturers and distributors of a-TCP could be found during a survey
carried out on scientific and commercial databases on the Web.
Taihei Chemical Industrial Co. Ltd. (Osaka, Japan) manufactures
technical grade a-TCP [54]. According to the manufacturer, the
product is supplied as white granulate of 1.0–2.0 g cm3 bulk den-
sity with granule size <1.7 mm and specific surface area in the
range 0.1–2.0 m2 g1. The pH of an aqueous suspension of the
material is in the range 7–10. No further information on chemical
and phase purity of the product is provided by the manufacturer.
Wako Pure Chemical Industries Ltd (Osaka, Japan) is another
Japanese manufacturer of a-TCP, with subsidiaries in Germany
and the USA [55]. They offer a product named ‘‘apatite alpha-
TCP, monoclinic’’, but no further information on the chemical char-
acteristics is provided online.
Ensail Beijing Co. Ltd (Beijing, China) is a manufacturer of cal-
cium-based biomaterials, including a-TCP. It is supplied as high
purity (>99%) single-phase powder with particle size <50 lm. The
Ca/P ratio of the product is 1.5 and the levels of As, Cd, Hg and
Pb, fulfil the requirements of the ASTM standard [56]. The manu-
facturer claims that the product is suitable as a raw material for
calcium phosphate cements as well as for bioceramics for ortho-
paedic implants [57].
A few reagent grade a-TCP are also commercially available. Sig-
ma–Aldrich Co. (St. Louis, USA) distributes a sintered powder con-
sisting of >75% a-phase and <25% b-phase, hydroxyapatite and/or
calcium pyrophosphate (CPP). According to the manufacturer, the
product is suitable as a standard for the analysis of bone cements
[58].
Zimmer Dental GmbH (Freiburg, Germany) offers biomedical
grade a-TCP bioceramic granules approved for clinical applica-
tions. BiobaseÒ was licensed by the German Board of Public Health
as early as 1991. BiobaseÒ consists of granules with several size
ranges, 0.2–0.5 and 0.5–1.40 mm, intended for dental applications,
and 1.40–3.2, 3.2–5.0 and 5.0–8.0 mm for orthopaedics [59]. Bio-
baseÒ is distributed in Africa by Implant Support Services CC (Pre-
toria, South Africa) [60].
InnoTERE GmbH (Dresden, Germany) produces a-TCP 13-1000,
which is described as particulate a-TCP with a phase purity P95%
and particle size 61 mm. According to the manufacturer, a-TCP 13-
1000 is intended ‘‘for laboratory use’’ only, even though they might
deliver ‘‘different bulk sizes, custom packing and raw materials for
the production of medical devices on query’’ [61].
BrainBase Corporation (Tokyo, Japan) markets biomedical grade
a-TCP granules under the brand name ArrowBone™-a. The prod-
uct consists of single-phase a-TCP shaped in open porous (75%
porosity) granules of size 250–1000 lm [50].
6. Synthesis of a-TCP
Most of the published research dealing with a-TCP has been
carried out on lab-made products, probably because of the
above-mentioned shortage of commercial products. Basically, the
synthesis of a-TCP is accomplished by thermal transformation of
a precursor with molar ratio Ca/P  1.5 (calcium-deficient
hydroxyapatite, CDHA; amorphous calcium phosphate, ACP; or
b-TCP) previously obtained [62–68], or by solid-state reaction of
a mixture of solid precursors at high temperatures [12,15,27,28,
31,35,64,69–76]. Self-propagating high-temperature synthesis
[77] and combustion synthesis [78–80] have also been employed.
6.1. Thermal transformation of a precursor with Ca/P  1.50
Thermal decomposition of CDHA into a-TCP is represented in
Eq. (2).
Ca9 ðHPO4 ÞðPO4 Þ5 ðOHÞðsÞ ! 3a-Ca3 ðPO4 Þ2ðsÞ þ H2 OðgÞ T P 1150  C
ð2Þ
Camiré et al. [64] employed a CDHA precursor obtained by
precipitation from a solution containing Ca(NO3)2 and (NH4)2HPO4
with molar ratio Ca/P = 1.5, followed by thermal transformation
into a-TCP by heating at 1250 °C for 2 h. Jokic et al. [65] also pre-
pared a-TCP powder by thermal decomposition of CDHA (Ca/
P = 1.56) obtained by the hydrothermal method according to Eq.
(2). CDHA decomposed into b-TCP at T P 800 °C and b-TCP, in turn,
 R.G. Carrodeguas, S. De Aza / Acta Biomaterialia 7 (2011) 3536–3546
started to transform into a-TCP at T P 1200 °C. Maximum trans-
formation was obtained after heating for 2 h. at 1500 °C even
though a small amount of HAp remained untransformed, obviously
because of the positive deviation from the proper stoichiometry to
get pure TCP, i.e. Ca/P = 1.5.
Similarly to Eq. (2), Eq. (3) represents the thermal transforma-
tion of ACP into a-TCP.
Ca9 ðPO4 Þ6  nH2 OðsÞ ! a-Ca3 ðPO4 Þ2ðsÞ þ nH2 OðgÞ
a-TCP has been synthesized at temperatures much lower than
the transition temperature of 1130 °C predicted by the phase dia-
gram in Fig. 1. Somrani et al. [62] found that ACP (Ca/P = 1.52) pre-
pared by double decomposition from aqueous solutions of
Ca(NO3)24H2O and (NH4)2HPO4 is almost totally converted into
a-TCP (4–7% b-TCP) by heating to 600–800 °C. However, on heating
to 900 °C, pure b-TCP was obtained. The apparent contradiction
had been previously reported by Eanes [81] and was explained in
the light of the Ostwald step rule.
Bohner et al. [66] prepared nanosized ACP powders by flame
synthesis, which rendered a-TCP (b-TCP 66%, HAp traces) by ther-
mal treatment at temperatures as low as 600 °C. Increasing the
temperature to 700 °C favoured the formation of b-TCP (40–60%),
and pure b-TCP was obtained at 800 °C. A more detailed study on
the evolution of crystalline phases during the thermal treatment
of the ACP performed by Döbelin et al. [67,68] showed similar
results.
Thermal transformation of crystalline b-TCP is the most direct
and perhaps the simplest and cheapest approach to the synthesis
of a-TCP. According to the phase equilibrium diagram in Fig. 1, a
temperature >1130 °C should be enough to accomplish the b- to
a-TCP transformation. Kitamura et al. [63] employed commercial
b-TCP powder with a mean particle diameter <45 lm to prepare
porous blocks of sintered a-TCP. The starting powder was sus-
pended in an aqueous starch solution, and polyurethane sponges
were impregnated in the slurry by dipping. After drying, the poly-
urethane sponge was burned out by gradually heating to 1000 °C.
Total conversion of the resulting porous blocks into a-TCP was
achieved by heating to 1400 °C for 12 h. and cooling to room tem-
perature in the furnace.
6.2. Solid-state reaction of precursors
Solid-state reaction between solid precursors is the preferred
synthetic route in the literature reports. The solid-state reactions
employed most are listed below:
CaCO3ðsÞ þ 2CaHPO4ðsÞ ! a-Ca3 ðPO4 Þ2ðsÞ þ CO2ðgÞ
þ H2 OðgÞ ½12; 15; 27; 28; 31; 64; 69—73; 76
3CaCO3ðsÞ þ 2NH4 H2 PO4ðsÞ ! a-Ca3 ðPO4 Þ2ðsÞ þ 3CO2ðgÞ
þ 3H2 OðgÞ þ 2NH3ðgÞ ½71; 75
CaCO3ðsÞ þ Ca2 P2 O7ðsÞ ! a-Ca3 ðPO4 Þ2ðsÞ þ CO2ðgÞ ½64; 71; 74; 82
Ca10 ðPO4 Þ6 ðOHÞ2ðsÞ þ 2CaHPO4ðsÞ ! 4a-Ca3 ðPO4 Þ2ðsÞ
þ 2H2 OðgÞ ½35; 69
The synthesis is carried out obeying the general rules for solid-
state reactions, i.e. solid precursors are milled together to reduce
particle size, increase the contact area and mix them intimately.
Wet milling is generally preferred. After milling, the mixture of
powders may be directly heated above the transformation temper-
ature or previously pressed to improve contact between particles.
The recommended reaction temperatures varied between 1250
and 1500 °C, and the dwell time was between 2 and 48 h. Most
authors recommend quenching to avoid the reversion of the a-
phase, in spite of the well-recognized reconstructive character of
3541
the first-order a ? b transformation [42,83] and the significant
measured value of the apparent activation energy for the b M a
transformation of 1.0467 MJ mol1 [84].
In contrast, the resulting a-TCP often presented variable
amounts of other crystalline phases, mainly b-TCP ([12,15,35,64
,69,70,74,82] or HAp [74,82].
6.3. Self-propagating high-temperature and combustion synthesis
ð3Þ
Ayers et al. [78,79] prepared pellets of a mixture of powders of
CaO and P2O5 in mol ratio of 3:1. After reacting under argon by
heating a tungsten filament to the point of igniting the bottom of
the reactant pellet, a-TCP containing significant amounts of HAp
and b-TCP was obtained.
Auto-combustion of aqueous dissolutions of calcium and phos-
phate salts with the required Ca/P molar rate and containing an or-
ganic fuel such as urea was also employed by Burkes et al. [77] and
Volkmer et al. [80] to synthesize a-TCP.
6.4. Effects of ionic substitutions on the synthesis of a-TCP
It is well documented that some ionic substitutions may exert a
drastic effect on the thermodynamic relationships between a- and
b-TCP [85,86]. For example, partial substitution of Mg for Ca in TCP
increases the thermal stability of the b-phase [42,69,83,87,88] and
gives rise to a binary phase field where b + a-Ca3(PO4)2 solid solu-
tions coexist. This binary field lies between the single-phase fields
of b- and a-Ca3(PO4)2 solid solution in the Ca3(PO4)2-rich zone of
the system Ca3(PO4)2–Mg3(PO4)2 [42,88]. In the same way, partial
substitutions of Zn and Sr ions for Ca have a similar effect to Mg
[89,90]. Taking this into account, the need to exclude Mg, Sr, Zn
and any other impurity able to stabilize the b-phase from the
raw materials employed in the synthesis of a-TCP becomes evident
[42,91].
Alternatively, when PO4 is partially substituted for SiO4, the
a-phase is stabilized, and the temperature of the polymorphic
transformation decreases [86,92]. Thus, doping with silicate has
been employed to synthesize pure phase a-TCP [43,91,93–95]. Sil-
icate-doped a-TCP presents a faster initial reaction in aqueous
solution of Na2HPO4 and a slower secondary reaction than pure
a-TCP [96].
The benefits of silicate-doping from the biological point of view
are a matter of discussion. Several in vitro and in vivo studies have
found enhanced osteogenesis for silicon-substituted calcium
phosphates in comparison with pure materials. The effect has been
attributed to silicon species released from the materials which are
able to stimulate bone regeneration and remodelling, among other
factors [97]. However, at present no experimental evidence sup-
ð4Þ ports the statement that silicon ionic species from Si-substituted
calcium phosphates are at therapeutic levels, and the linkage be-
tween the improved biological performance of silicon-substituted
ð5Þ
calcium phosphates and the release of silicon species to the phys-
ð6Þ iological medium have not yet been proved [98].
6.5. Thermodynamic considerations relevant to the synthesis of a-TCP
ð7Þ
From the review of published data relating to the synthesis of
a-TCP presented above, several contradictory results are revealed.
First, most of the synthetic methods reported yield of minor
amounts of foreign phases, mainly b-TCP, HAp and CPP.
The presence of b-TCP has sometimes been attributed to partial
reversion during quenching of the a-TCP already formed [12,15].
However, it should be noted that the polymorphic transformation
b M a is reconstructive [42,83], according to the Buerger classifica-
tion, i.e. ‘‘involves a major reorganization of the crystal structure,
in which many bonds have to be broken and new bonds formed’’
3542 R.G. Carrodeguas, S. De Aza / Acta Biomaterialia 7 (2011) 3536–3546
[99], so considerable energy has to be provided to the system to
transform from one polymorph to another. Thus, reverting from
a- to b-phase should be unfeasible, unless either a very slow cool-
ing rate or a large dwell at temperature slightly below that of
transformation is used. In addition, it has been shown that it is pos-
sible to obtain pure phase a-TCP with a cooling rate as moderate as
10 °C min1 [35,42].
Thus, the presence of b-TCP in the final product may indicate
that:
(a) Equilibrium has not been reached and longer dwell is
needed above the temperature of the polymorphic
transformation (see diagram in Fig. 1).
(b) Equilibrium has been reached, but the temperature of
the polymorphic transformation is higher than
expected from Fig. 1 because of the presence of impuri-
ties stabilizing the b-phase in the reaction mixture (see
the phase equilibrium diagram for the system Ca3(PO4)2
–Mg(PO4)2 in Ref. [42]). Then the temperature required
to obtain pure a-TCP has to be increased above the
transformation temperature in the corresponding
phase equilibrium diagram.
(c) Partial reversion of the high-temperature a-phase has
taken place as a result of too slow a cooling rate. In such
a case, either the cooling rate must be increased or the
volume of the product mass must be diminished to
improve heat conduction and removal.
However, the appearance of small amounts of HAp or CPP to-
gether with the main phase of a-TCP indicates certain deviation
of the theoretical Ca/P molar ratio 1.50. According to the diagram
in Fig. 1, TCP does not form solid solutions with CPP or tetracalcium
phosphate (Ca4O(PO4)2, TTCP), and there are binary fields at both
sides of the compositional line of TCP. Negative deviations from
the stoichiometric ratio of 1.50 may produce TCP with some CPP,
Fig. 10. (a) b-TCP and (b) a-TCP porous block inside Ti chambers and implanted
during 8 weeks in 0.5 mm deep circular slits in Japanese white rabbit calvarias. The
a-TCP block is considerably more biodegraded than the b-TCP. (Reproduced with
permission from Yamada et al. [109], Ó2006 Wiley Periodicals, Inc.).
Fig. 11. System CaO–P2O5–H2O at a fixed P(H2O) = 500 mm Hg (reproduced from Ref.
[100] with permission).
whereas positive deviations may render TCP with TTCP in anhy-
drous conditions. However, the atmosphere existing in the lab dur-
ing synthesis of a-TCP usually contains some degree of humidity,
which makes the diagram in Fig. 1 useless. In wet conditions, the
valid diagram for the CaO–P2O5–H2O system is displayed in
Fig. 11, and explains the presence of HAp as an impurity for posi-
tive deviations of the stoichiometric Ca/P molar ratio of 1.50
[100]. Both impurities, CPP and HAp, may be avoided with accurate
adjustment of the Ca/P ratio in the reaction mixture during
synthesis.
7. Biological behaviour
The biological behaviour of a-TCP-based biomaterials has been
studied in several in vitro [101–105] and in vivo [106–111] studies.
Mayr-Wohlfart et al. [101] tested three-dimensional porous
scaffolds of a-TCP (BIOBASE, Germany), bioglass, glass–ceramic
and solvent dehydrated bone for proliferation and differentiation
rates of human osteoblast-like cells (SaOS-2) cultured in vitro.
The results showed that cells proliferate and differentiate into
osteoproductive osteoblasts better on the a-TCP scaffolds than on
the other materials tested. Ehara et al. [102] also studied the effects
of a-TCP and TTCP on the proliferation, differentiation and miner-
alization of cultures of newborn mouse calvaria-derived MC3T3-
E1. It was found that the presence of a-TCP or TTCP increased
the pH of the culture media and had no influence on cell prolifer-
ation, but did on osteoblast differentiation and mineralization. The
authors concluded that a-TCP and TTCP promote osteogenesis by
increasing collagen synthesis and calcification of the extracellular
matrix.
Similarly, surface- and non-surface-related cell viability of
several commercial bone substitute materials, a-TCP (BioBase,
Germany) and b-TCP (Cerasorb, Germany) among them, was eval-
uated towards cultures of human primary osteoblasts, bone mar-
row mesenchymal cells and non-adherent myelomonocytic cells.
The report concluded that a- and b-TCP support surface- and
non-surface-related cell viability [104]. In the same sense, Seebach
et al. [105] compared six bone-graft substitutes with regard to cell
seeding efficiency, metabolism and growth behaviour of human
mesenchymal stem cells (MSC). a-TCP (BioBase, Germany) and b-
TCP (ChronOs and Vitoss) were among the tested materials. The
MSC growth is in the order Vitoss, BioBase and ChronOs. The differ-
ences in cell adhesion between a- and b-TCP-based materials was
explained by the difference in surface charge density, which is low-
er for b-TCP [105].
However, Tamai et al. reported that a-TCP is more cytotoxic
than HAp, b-TCP and TTCP and as cytotoxic as FAp towards
 R.G. Carrodeguas, S. De Aza / Acta Biomaterialia 7 (2011) 3536–3546
in vitro cultured Chinese hamster V79 lung fibroblasts [103]. The
cytotoxic effects of a-TCP and FAp were evidenced both in cultures
of cells directly seeded onto the materials and in cultures made in
the presence of extracts of the materials. It was proposed that the
cytotoxicity of FAp was due to fluorine ions extracted in the culture
medium, whereas the decrease in pH of the medium caused by the
phosphoric acid generated during the hydrolysis of a-TCP was the
cause of the cytotoxicity of this material.
a-TCP in solid and paste forms was neither toxic nor irritant
when tested on intact rabbit skin [111]. In vivo biodegradation of
granules of a-TCP (3.2–5.0 mm diameter) and b-TCP (1.0–2.0 mm
diameter) was evaluated in bilateral artificial bone defects created
in the tibial head of Goettingen minipigs. Fluorescent markers
were administered to the experimental subjects during the periods
of observation. Bony regeneration proceeded basally and on the
sides of the defects, according to an angiogenetic reossification pat-
tern. Resorption of the implanted materials was due to hydrolytic
and cellular degradation processes. After 86 weeks, 95–97% of both
a- and b-TCP were resorbed. Both a- and b-TCP showed a compa-
rable degradation process, and the remains of material were
completely integrated into newly formed bone trabeculae. In com-
parison, empty control defects showed only sparse reossification,
according to which both tested materials were classified as bone-
rebuilding materials [106].
Kihara et al. [107] performed an in vivo test to observe the bio-
degradation process of particles (300 lm diameter) of pure a-TCP
and to determine its efficacy as a space maintainer in bilateral cra-
nial bone defects in rabbits. One defect in each animal was left
empty and used as control. A ‘‘reticulate structure’’ was developed
in the particles after 1 week as a consequence of the degradation of
a-TCP, and new bone was observed after 8 weeks. The amount of
new bone was not significantly different for experimental and con-
trol groups in any of the observation periods (1, 4 and 8 weeks).
However, in the experimental groups, new bone deposited on the
surface of a-TCP particles was observed in the very centre of the
defect, whereas fibrous connective tissue was predominant at the
centre of control sites. The results suggested that a-TCP is a
degradable osteoconductive material, able to act as a space main-
tainer for bone regeneration [107].
The osteoconducting ability of a-TCP-based bone filler powder
was tested in comparison with Ti–6Al–4V rods and polymethyl-
methacrylate bone cement. The sites of implantation were holes
drilled in the left and right sides of the femoral condyles of adult
New Zealand rabbits. The observation periods were 1, 3 and
9 weeks. Osteoconduction was evaluated by measuring the affinity
index, bone density and X-ray diffraction at the implants. More in-
tense diffraction peaks of HAp which increased with time were ob-
served in sites that received a-TCP, indicating that HA was formed
at the expense of a-TCP hydrolysis. Furthermore, there was more
bone density increase in groups containing the a-TCP bone filler
powder. The results suggested that HA formed by hydrolysis of
the a-TCP bone filler powder could play some role in enhancing
osteoconducting ability [108].
Yamada et al. [109] conducted a histological and histomorpho-
metrical study to compare a-TCP and b-TCP as bone graft material
for augmenting alveolar ridges. The animal model employed por-
ous a- and b-TCP blocks inserted in Ti cylindrical cages, and the
set was implanted in 0.5-mm-deep circular slits in Japanese white
rabbit calvaria. Animals were sacrificed after 2, 4 and 8 weeks
[109]. No significant difference was observed after 2 weeks, but
significant differences were observed between both materials after
4 and 8 weeks. The blocks of a-TCP notably started degrading after
4 weeks, whereas degradation of b-TCP blocks had just begun at
that time and scarcely progressed after 8 weeks (Fig. 10a). How-
ever, a-TCP blocks were severely degraded after 8 weeks, as shown
in Fig. 10b. Residual a-TCP particles surrounded by newly formed
3543
bone decreased over time, and both particles and newly formed
bone were simultaneously absorbed by osteoclast-like cells. The
results suggested that a-TCP particles surrounded by newly
formed bone may disappear progressively from bone and could
be incorporated into the bone remodelling cycle in combination
with newly formed bone [109].
a-TCP particles have also been evaluated as drug carriers of
simvastin, which is a drug able to stimulate BMP-2 and VEGF
mRNA expression in osteoblasts and promote bone growth. Bilat-
eral 5-mm-diameter calvarial defects were created in adult Wistar
rats and filled with a-TCP particles containing different doses of
simvastin. Empty defects were used as controls. The observation
periods were 2, 4 and 8 weeks [110]. Simvastin doses >0.1 mg
caused inflammation of the surrounding soft tissue, but the micro-
tomography analysis revealed that the a-TCP with 0.1 mg simva-
stin yielded significantly higher volumes of bone than control
group at all periods of time. The percentage of defect closure, bone
mineral content and bone mineral density were also higher in the
group of a-TCP with 0.1 mg simvastin than in the others [110]. Par-
ticulate a-TCP is a good carrier for simvastin and probably for other
bone-growth-stimulating drugs.
The potential of a-TCP powder (particle size 4–10 lm) as a cap-
ping agent for exposed dental pulp was tested in anterior teeth of
Macaca fuscata with pulp amputation. No inflammation was ob-
served in the residual dental pulp at any time during the experi-
mental period of 3 months. Bone-like hard tissue was induced in
the pulp capped with a-TCP, and its potential for clinical applica-
tion to exposed dental pulp was confirmed [112].
8. Clinical applications
Published scientific literature dealing with clinical applications
of a-TCP-based materials is practically limited to a-TCP bone ce-
ments. They are used in dentistry, craniofacial and maxillo-facial
surgery, and orthopaedics, vertebroplasty and kyphoplasty proce-
dures and as drug carriers; however, more detailed discussion is
beyond the aim of this paper. Recent and excellent reviews have
been already published on the subject [9,10,19,20,113].
Recommended dental and orthopaedic applications for the
a-TCP-based commercial granulates BiobaseÒ [59] and Arrow-
Bone™ [62] are listed in Table 5.
However, the scientific reports dealing with the applications in
Table 5 are extremely scarce, and the only data dealing with the
clinical performance of the materials are the technical information
at the manufacturers’ websites.
Table 5
Recommended dental and orthopaedic applications for the a-TCP-based commercial
granulates BiobaseÒ [59] and ArrowBone™ [62].
Dentistry Periodontology Two and three wall bony defects, can be
used with or without membranes
Implantology Defect augmentation following extraction
to create an implant baseElevation of
sinus floorGaps between extraction
socket and implant in case of immediate
implant placement
Cysts Defects resulting from cyst removal
Dental and Defects resulting from apicectomyDefects
Maxillo-facial resulting from the removal of impacted
surgery teethDefects resulting from corrective
osteotomiesAll other shapes of bony
craters and facial bone defects
Orthopaedics Filling of bone defects and cysts
Replenishment of the donor site of autogenous bone
Addition to cancellous bone in spinal fusion, vertebral body
replacement and joint replacement
3544 R.G. Carrodeguas, S. De Aza / Acta Biomaterialia 7 (2011) 3536–3546
The effect of a combination of an oily Ca(OH)2 suspension
(OsteoinductalÒ, Osteoinductal GmbH, Muenchen, Germany) with
a-TCP (BiobaseÒ a-pore, Biovision GmbH, Ilmenau, Germany) vs
a-TCP alone in the treatment of one- and two-wall intrabony pock-
ets were clinically tested in a 6-month trial. The results demon-
strated that both treatments may result in significant probe
depth reduction and clinical attachment level gain over a period
of 6 months. The combination of OsteoinductalÒ and a-TCP may,
however, also improve the healing process [114,115].
9. Concluding remarks
Two decades ago a-TCP was proposed as component of several
bone cements. Since then, granules, blocks and composites consist-
ing of a-TCP have also received growing attention as bone repair-
ing materials. However, commercial a-TCP, reagent or biomedical
grade, are very scarce. This forces researchers and developers to
synthesize it themselves.
Thermal transformation of b-TCP above the temperature corre-
sponding to the polymorphic transformation b ? a is the rational
way to synthesize a-TCP. Thus all synthetic routes available for
the synthesis of b-TCP may be adapted to obtain the high-temper-
ature polymorph a-TCP. However, involuntary or intentional
impurities in the precursors used in the synthesis and the exact
stoichiometry of the reactants affect the phase purity of the a-
TCP obtained. Impurities of Mg, Sr and Zn substituting Ca stabilize
the b-phase, whereas small amounts of Si substituting P stabilize
the a-phase. Moreover, even though a-TCP is thermodynamically
metastable at temperatures <1100 °C, it may be preserved under
this temperature without the need to quench. The reason for this is
that the polymorphic transformation b M a is reconstructive, and
considerably activation energy is involved. So a-TCP phase may
be retained <1100 °C, unless quasi-equilibrium conditions (extre-
mely slow cooling rates) are employed. Cooling rates as low as
10 °C min1 may be used without risk of reversion to the b-phase.
From the biological point of view, a-TCP is non-toxic, osteocon-
ductive and bioactive, both in vitro and in vivo. The main reason for
the growing interest in a-TCP as a bone implant material is its
biodegradability. It is more bioreabsorbable than HAp, b-TCP and
biphasic (HAp/b-TCP) bioceramics currently used in clinical
practice. This makes a-TCP an ideal implant material, able to be
replaced by new bone faster than the other calcium–phosphate-
based materials available in the market nowadays. In addition, it
may be used as a biodegradable carrier for controlled release of
drugs, macromolecules or cells.
As set out above, a-TCP seems to be an interesting option for the
design of new biomaterials for emerging bone repairing therapeu-
tic procedures based on tissue engineering and regenerative
medicine.
Acknowledgments
R.G. Carrodeguas pays tribute to Prof. De Aza’s memory. Salva-
dor De Aza (Madrid, 1933–2011) devoted his fruitful scientific life
to theoretical and experimental studies of phase equilibrium dia-
grams and their application to the design of ceramics with specific
properties. Even when Prof. De Aza retired in 2003, he continued to
be active until a few days before his passing on 13 April 2011,
shortly after this paper was sent for publishing. The main contribu-
tions of Prof. De Aza to the field of bioceramics are: the prediction
and demonstration of the first bioactive polycrystalline P-lacking
material, wollastonite, in contrast to the well-known P-containing
bioglasses and glass–ceramics; the design and development of the
first bulk-bioactive bioceramic, BioeutecticÒ, when only superfi-
cially bioactive materials were known; and studies on the influ-
ence of several impurities on phase transformations in tri-
calcium phosphate, with considerable relevance to the synthesis
of pure-phase polymorphs. Those who enjoyed Prof. De Aza’s deal-
ing and friendship will always remember him not only for his clar-
ity of mind and wisdom to face and solve scientific problems, but
also for his humanism, friendliness and willingness to listen and
share with everybody his sound knowledge of life.
The ‘‘Junta para Ampliación de Estudios (JAE)’’ of CSIC, Spain, is
acknowledged for supporting R.G. Carrodeguas through contract
JAEDOC087-2009. Support from Project CICYT MAT2010-17753 is
also acknowledged.
Appendix A. Figures with essential colour discrimination
Certain figures in this article, particularly Figs. 2, 3 and 10, are
difficult to interpret in black and white. The full colour images
can be found in the on-line version, at doi:10.1016/j.actbio.2011.
06.019).
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