Acta Biomaterialia 113 (2020) 23–41

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

Review article

β -tricalcium phosphate for bone substitution: Synthesis and

properties
Marc Bohner1,∗, Bastien Le Gars Santoni, Nicola Döbelin
RMS Foundation, Bischmattstrasse 12, CH-2544 Bettlach, Switzerland

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

Article history: β -tricalcium phosphate (β -TCP) is one the most used and potent synthetic bone graft substitute. It is
Received 29 April 2020 not only osteoconductive, but also osteoinductive. These properties, combined with its cell-mediated re-
Revised 21 May 2020
sorption, allow full bone defects regeneration. Its clinical outcome is sometimes considered to be “un-
Accepted 12 June 2020
predictable”, possibly due to a poor understanding of β -TCP physico-chemical properties: β -TCP crys-
Available online 19 June 2020
tallographic structure is not fully uncovered; recent results suggest that sintered β -TCP is coated with
Keywords: a Ca-rich alkaline phase; β -TCP apatite-forming ability and osteoinductivity may be enhanced by a hy-
Calcium phosphate drothermal treatment; β -TCP grain size and porosity are strongly modified by the presence of minute
Sintering amounts of β -calcium pyrophosphate or hydroxyapatite impurities. The aim of the present article is to
Osteoconduction provide a critical, but still rather comprehensive review of the current state of knowledge on β -TCP, with
Osteoinduction a strong focus on its synthesis and physico-chemical properties, and their link to the in vivo response.
Scaffold
Granule
Bone Statement of significance
Doping

The present review documents the richness, breadth, and interest of the research devoted to β -
tricalcium phosphate (β -TCP). β -TCP is synthetic, osteoconductive, osteoinductive, and its resorption is
cell-mediated, thus making it one of the most potent bone graft substitutes. This comprehensive review
reveals that there are a number of aspects, such as surface chemistry, crystallography, or stoichiometry
deviations, that are still poorly understood. As such, β -TCP is still an exciting scientific playground despite
a 50 year long history and > 200 yearly publications.
© 2020 The Authors. Published by Elsevier Ltd on behalf of Acta Materialia Inc.
This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/)

1. Introduction alternatives, synthetic materials are particularly attractive due to

the absence of disease transmission risk and reproducibility of
A few million patients need a bone graft every year [1]. Typical their chemical composition and porous architecture.
uses include the filling of a bony defect resulting from an impacted A large variety of synthetic materials have been proposed
cancellous bone [2–4], sinus lift augmentation for the placement of and used as bone graft, including metals, polymers, and ceram-
dental implants [5–7], or the filling of bony gaps after osteotomies ics [15,17,18,20]. However, the most studied materials are calcium
[4,8–10]. In the majority of the cases, the bone graft is harvested phosphate ceramics, in particular hydroxyapatite (Ca10 (PO4 )6 (OH)2 ;
from the patients themselves (“autograft”), but due to the related HA) [21,22], β -tricalcium phosphate (β -Ca3 (PO4 )2 ; β -TCP) [21],
costs [11] and morbidity [12–14] of the surgical procedure, there and their mixtures called biphasic calcium phosphates (BCP) [23–
is an increasing demand for other bone graft sources. These bone 25]. This interest is related to the fact that the main component of
graft substitutes are plant-derived, animal-derived (“xenografts”), bone is an apatitic calcium phosphate mineral.
human-derived (“allografts”), and synthetic [15–20]. Among these HA implants are generally synthesized by high-temperature sin-
tering [26,27] or hydrothermal conversion of a calcium carbonate
∗ template [28]. In both cases, HA is much more crystalline than
Corresponding author.
E-mail address: [email protected] (M. Bohner). bone mineral, thus making these implants chemically more sta-
1
Prof. Marc Bohner was an editor of the journal during the review period of the ble and accordingly non-degradable upon implantation [29–33].
article.

https://doi.org/10.1016/j.actbio.2020.06.022
1742-7061/© 2020 The Authors. Published by Elsevier Ltd on behalf of Acta Materialia Inc. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/)
M. Bohner, B.L.G. Santoni and N. Döbelin Acta Biomaterialia 113 (2020) 23–41

[67] reported for example that the β -α phase transition tempera-

ture increased from 1150 °C with 0 mol% Mg phosphate to 1540 °C
with 8 mol% Mg phosphate.

2.2. Crystal structure

β -TCP crystallizes in the rhombohedral space group R3c [81,82]

and is usually described in the trigonal setting with unit cell di-
mensions varying from study to study: 10.35 to 10.53 Å for the “a”
axis, and 36.89 to 37.63 Å for the “c” axis [66,81–88]. These large
variations are most likely due to the presence of elemental impuri-
ties in some of the analyzed structures. Chemically pure β -TCP has
probably cell dimensions in these ranges: a = 10.435–10.438 Å and
c = 37.39–37.43 Å [82,86,89,90] (Table 1). The published density
varies between 3.03 and 3.13 g/cm3 , but the majority of published
Fig. 1. . Evolution of the yearly number of publications containing “beta tricalcium values are close to 3.07 g/cm3 [81,91].
phosphate” and “bone” in the abstract, title, or keywords (Scopus database, March One β -TCP unit cell contains 63 Ca atoms, and 42 PO4 groups.
26, 2020; time period: 1975–2019).
Ca atoms are distributed in 5 different Ca sites (Fig. 2a and b). A
peculiarity of the structure is that only 50% of the 6 Ca(4) sites are
occupied by a Ca atom [81,84,92]. Using a pair potential model, Jay
The absence of degradation may lead to bone deformities [34] and
et al. [92] concluded that the partial Ca(4) occupancy is not ran-
to a long-term increase of bone fracture risk around HA bone
dom, i.e. the half occupancy is in a 1/3, 2/3 repeating pattern down
substitute [31]. It may also require the permanent use of other-
the c axis (Fig. 2a). In other words, the β -TCP structure is made
wise temporarily-used osteosynthesis fixation [31]. Contrary to sin-
of two repeating planar domains, one with a Ca/P molar ratio of
tered HA, β -TCP is resorbable and is readily replaced by new bone
60/42 = 1.429, and one with a Ca/P molar ratio of 66/42 = 1.571.
[30,32–37]. Its solubility is close to that of bone mineral, and as
This conclusion is supported by the studies of Matsunaga et al.
a result, β -TCP is not soluble in physiological conditions [38], but
[84] and Yin et al. [93]. Interestingly, Jay et al. mentioned that the
is resorbed by cells, generally osteoclasts (the cells provoke a lo-
exact occupancy pattern might be different because their simula-
cal acidification that leads to β -TCP dissolution) [30,39–41]. Beside
tions only considered a limited number of computational alterna-
this osteotransductive ability, some studies have shown the high
tives [92]. They proposed that the structure could consist of nu-
osteoinductive potential of β -TCP [42]. As such, β -TCP has emerged
merous small ordered domains that would appear disordered by x-
as one of the most attractive bone graft substitute materials.
ray diffraction (XRD) due to the long-range nature of the XRD mea-
Even though the first studies and clinical applications of β -TCP
surements. Several studies [83,94,95] predicted that β -TCP should
were performed before 1980 [43–52], it is only after the turn of the
have 5 resonances by 31 P magic angle spinning nuclear magnetic
century that research on β -TCP for bone applications has soared
resonance (31 P MAS-NMR), but at least 16 bands were detected
(Fig. 1). For the last years, several hundreds of articles have been
[83,95,96], suggesting an ordering of the vacancies within the β -
published yearly. Despite the high number of articles, there is to
TCP structure and the presence of a superstructure with symme-
the best of our knowledge no broad review article devoted to β -
try lower than R3c [96]. The latter remark is in accordance with
TCP. The aim of the present article is to review the synthesis and
statements made by Jay et al. [92] and Matsunaga et al. [84]. It is
properties of β -TCP in the context of bone graft substitution. The
also in accordance with experimental XRD data since Rietveld re-
manuscript comprises the following dedicated sections: (i) Physical
finement of β -TCP XRD data using published crystal structures in
properties; (ii) Synthesis; (iii) Powders, granules, and scaffolds; (iv)
space group R3c usually leaves some systematic misfits, and never
Sintering; (v) Biological response; and (vi) Conclusion.
reaches the quality of fit typically observed with other calcium
phosphate phases such as HA (Fig. 3). This suggests that the sym-
2. β-TCP physical properties metry is in fact lower than that of the R3c space group used as ref-
erence, or that a longer range order (super-cell) is present that is
Pure β -TCP is a brittle, white solid, whose color may change not adequately described by the R3c space group. It is also remark-
depending on the presence of impurities. For example, Mn-doped able that osteoclastic resorption of β -TCP leads to the formation of
β -TCP is intense pink [53,54], Cu-doped β -TCP is blue and some- thin pillars [85,97,98] aligned along the c axis of the β -TCP crystal
times violet/purple [55], Cr-doped β -TCP is green [56]. The most structure [85]. Such a morphology is difficult to explain assuming
relevant physical properties for bone substitution are the thermal a homogeneous lattice composition.
stability range and the crystal structure. Details are given hereafter. The structure of hydrogen-substituted β -TCP
(Ca20 (HPO4 )2 (PO4 )12 ; H-β -TCP), which is produced by precipi-
2.1. Thermal stability tation in ethylene glycol, is slightly different from that of pure
β -TCP. According to Staehli et al. [99], the Ca(4) sites also play an
β -TCP is a high-temperature phase that is typically ob- important role in the structure of H-substituted β -TCP (H-β -TCP):
tained by thermal conversion of amorphous calcium phosphate all Ca(4) sites are filled with an H atom and the neighboring PO4
[57–61] or calcium-deficient hydroxyapatite (Ca9 (PO4 )5 (HPO4 )OH; group is inverted (Fig. 2c). A similar substitution model has been
CDHA) [50,62–72] above 650-750°C. β -TCP has two allotropic observed in natural whitlockite (Ca18 Mg2 (HPO4 )2 (PO4 )12 ; WH)
phases, namely α -TCP above 1115-1150°C [58,67,69,73–77] and α ’- [100,101].
TCP above 1430-1470°C [69,74–80]. Hudon and Jung [77] presented
recently a very thorough study on the phase stability of calcium 3. β-TCP synthesis
phosphates and came to the conclusion that the β -α and the α -
α ’ phase transitions occur at 1125 °C and 1470 °C, respectively. β -TCP can be synthesized by solid-state reaction, thermal con-
They also pointed out that these temperatures vary over a very version, and precipitation. The aim of this section is to present and
broad range in the presence of elemental impurities. Enderle et al. discuss these three synthesis methods. The last two parts of this

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M. Bohner, B.L.G. Santoni and N. Döbelin Acta Biomaterialia 113 (2020) 23–41

Table 1.
Comparison of β -TCP lattice parameters “a” and “c” found in literature studies.

Study Lattice parameter a [Å] Lattice parameter c [Å]

Dickens et al. [81] 10.439 ± 0.001 37.375 ± 0.006

Gibson et al. [66] 10.431 (800 °C); 10.439 37.328 (800 °C); 37.425
(1000 °C); 10.441 (1100 °C) (1000 °C); 37.458 (1100 °C)
Yashima et al. [82] 10.4352 ± 0.0002 37.4029 ± 0.0005
Obadia et al. [83] 10.426 37.435
Yoshida et al. [131] 10.441 37.403
Kannan et al. [68] 10.438 37.399
Liang et al. [87] 10.3513 36.8898
Kannan et al. [90] 10.4380 ± 0.0004 37.4016 ± 0.0017
Jay et al. [314] 10.43 37.40
Matsunaga et al. [84] 10.53 37.63
Frasnelli et al. [86] 10.4357 ± 0.0006 37.389 ± 0.002
Gallo et al. [85] 10.427 ± 0.001 37.451 ± 0.002

Fig. 2. . (a) β -TCP structure in which a row of Ca(4) sites is highlighted in yellow; Color code: Ca atoms in blue, P atoms in green, O atoms in red (drawing created with
VESTA [310]); (b) Illustration of the Ca4 and P1O4 atomic arrangement in the stoichiometric β -TCP crystal model [81] and (c) a hydrogen-substituted β -TCP model where
≈80% of the P1O4 tetrahedra are inverted and protonated (reproduced from Fig. 1, [99]).

section are devoted to the presence of elemental impurities in β - [74,103,105], dicalcium phosphate dihydrate (CaHPO4 •2H2 O; DCPD)
TCP (“doping”) and to surface changes occurring during sintering [102], calcium pyrophosphate (Ca2 P2 O7 ; CPP), or ammonium phos-
because of the evaporation of phosphate species. phate ((NH4 )2 (HPO4 )) [67]. The reaction between CC and DCP can
be written:
3.1. Solid-state reaction
CaCO3 + 2 CaHPO4 → CaCO3 + Ca2 P2 O7 + H2 O → β -Ca3 (PO4 )2
β -TCP can be produced by solid-state reaction of a calcium- + CO2 + H2 O (1)
rich phase, such as calcium carbonate (CaCO3 ; CC) [67,74,102,103],
calcium hydroxide (Ca(OH)2 ) [103], and HA [74,104,105], with a To obtain pure β -TCP, a particular care must be taken to mix
phosphate-rich phase, such as dicalcium phosphate (CaHPO4 ; DCP) thoroughly the two raw materials. If two components are dis-

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M. Bohner, B.L.G. Santoni and N. Döbelin Acta Biomaterialia 113 (2020) 23–41

Fig. 3. Rietveld refinements of β -TCP samples using one of the published structure models (here: [81]) result in systematic misfits (top, arrows and inlay). Other phases
measured and refined under identical conditions result in better fit statistics (hydroxyapatite, bottom).

tributed inhomogeneously, contamination phases may appear such 3.2. Thermal conversion
as HA in the Ca-rich domains, and β -CPP in the phosphate-rich
domains. An intermediate pre-sintering and homogenization step Another common method to produce β -TCP is by thermal
(e.g. at 900 °C) might be useful for this matter [105]. It is also ad- conversion of amorphous calcium phosphate [57–61] or calcium-
visable to use raw materials that have a composition close to the deficient hydroxyapatite (Ca9 (PO4 )5 (HPO4 )OH; CDHA) [50,62–
composition of β -TCP (Ca/P molar ratio = 1.50), for example, di- 72,112] (Fig. 4g) above 650–750° C. Typical raw materials used for
calcium phosphate (Ca/P = 1.00) and hydroxyapatite (Ca/P = 1.67). the aqueous precipitation of ACP and CDHA include calcium nitrate
Nevertheless, it is much easier to get pure calcium carbonate (Ca(NO3 )2 ) [50,63,67,68,70,72,104,113,114], calcium hydroxide [64],
(Ca/P = ∞) or ammonium phosphate (Ca/P = 0.00) powders than ammonium phosphate ((NH4 )2 (HPO4 )) [50,63,67,68,70,72,104,113],
pure calcium phosphate phases. When using ammonium phos- and phosphoric acid (H3 PO4 ) [64,71]. When using calcium nitrate
phate, melting occurs during solid-state reaction [73] leading to and ammonium phosphate, the pH of the reaction is kept constant
highly agglomerated β -TCP. Further processing, for example for slip by adding ammonia (NH3 ) during the precipitation reaction:
casting, becomes complicated. Also, ammonia fumes are not only
dangerous, but highly corrosive, which may damage metallic lab- 9 Ca(NO3 )2 + 6 (NH4 )2 (HPO4 ) + 6 NH3 + H2 O
ware. → Ca9 (HPO4 )(PO4 )5 OH + 18 (NH4 )(NO3 ) (2)
It is generally assumed that β -TCP has a unique composition
(= Ca3 (PO4 )2 ), in agreement with the phase diagrams of Hudon et The final thermal transformation into β -TCP is:
al. [77,106], Trömel et al. [78,107], and Kreidler et al. [108]. How-
ever, other authors have reported a solid solution below [109,110] Ca9 (HPO4 )(PO4 )5 OH → 3 β -Ca3 (PO4 )2 + H2 O (3)
and/or above [110,111] a Ca/P molar ratio of 1.50. This would mean
that phase-pure β -TCP could have different Ca/P molar ratios. Since β -TCP obtained by ACP or CDHA conversion is more homogeneous
no details have been provided to support the presence of a solid than with solid-state reaction [70]. Also, it gives the opportunity
solution, the question is still open. to incorporate elemental impurities such as Zn [68], or Mg [70] by
the addition of Zn or Mg nitrate in the solution, or to obtain fibers

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M. Bohner, B.L.G. Santoni and N. Döbelin Acta Biomaterialia 113 (2020) 23–41

Fig. 4. Various β -TCP particle morphologies: (a, b, c) Morphologies of β -TCP particles precipitated in ethylene glycol [99,120,192]; (d) Amorphous calcium phosphate (ACP)
powder obtained by flame-spray synthesis (taken from [59]); (e) ACP powder after conversion to β -TCP at 800 °C [59]; (f) Morphology of a commercial β -TCP powder
(Aldrich, Art No 20218); (g) Calcium-deficient hydroxyapatite (CDHA) powder; (h) β -TCP powder obtained by calcining the CDHA powder shown in (g) at 850 °C; (i) β -TCP
fibers (Courtesy of T. Ikeda; [115,116]).

[115,116] (Fig. 4i). However, particles are still agglomerated (Fig. composed into stoichiometric β -TCP and CPP below 550 °C. Cur-
4e–h). rently, H-β -TCP has been hardly studied, so there is only informa-
tion about its structure [99], and its dissolution mechanisms [117].
3.3. Direct precipitation of (H-)β -TCP Speculating, it is likely that H-β -TCP solubility is slightly higher
than that of β -TCP, but still not high enough to make H-β -TCP
β -TCP has been shown to precipitate in organic media, for ex- soluble in vivo (at pH 7.4). Resorption would most likely be cell-
ample in ethylene glycol [99,117–120] (Fig. 4a–c), methanol [121], mediated.
tetrahydrofurane [122], and ethyl propionate [123]. β -TCP has also Alternative methods to those presented herein include the cal-
been observed to occur during autoclaving of ACP [124,125] and cination of amorphous calcium phosphate powders produced by
α -TCP [126,127]. Sometimes, a combination of organic synthesis flame-spray synthesis [129] (Fig. 4d and e) or by organic synthe-
and autoclaving has led to phase-pure β -TCP [123,128]. The β - sis [130].
TCP particles are typically in the nanometer range (Fig. 4a–c). For
example, Kjellin et al. [123] reported a specific surface area of 3.4. Chemical doping
65 m2 /g, which corresponds to an equivalent spherical diameter
of ≈30 nm. The porous spherical β -TCP particles produced by Zhu Metal impurities can be easily incorporated into β -TCP
et al. [128] were smaller than 100nm in diameter. [84,131,132]. Doping with divalent cations smaller than Ca2+ such
A thorough analysis of the crystallographic structure of the β - as Mg2+ and Zn2+ preferentially occurs on the Ca(4) and Ca(5)
TCP produced in ethylene glycol has revealed the formation of an sites [67,102,133], whereas larger divalent cations such as Sr2+
H-substituted β -TCP (H-β -TCP; [99]) where Ca atoms are partially preferentially occupy sites Ca(1)-Ca(4), but not Ca(5) [102,134].
substituted with H atoms (Fig. 2c). The experimental Ca/P molar Mono- and trivalent cations can substitute Ca2+ on the partially
ratio (1.443 ± 0.003) was reported to be close to the theoretical occupied Ca(4) site. Charge balance is maintained by adjusting the
ratio of 20/14 = 1.427 corresponding to Ca20 (HPO4 )2 (PO4 )12 . It is number of Ca(4) vacancies [131]. Si4+ can substitute P5+ on the
currently unclear if all β -TCP particles produced by precipitation tetrahedral sites in the PO4 groups [135]. This “doping” is often an
have the H-β -TCP composition, but it is likely. For example, Kjellin uncontrolled side effect of elemental impurities in the Ca raw ma-
et al. [123] observed the consumption of water during their β -TCP terials. However, it can also be used in a controlled manner with
synthesis, which is a condition for the presence of hydrogenophos- the aim to modify β -TCP biological properties. In the 1980’s and
phate (HPO4 2− ) groups in the crystallographic structure. Also, their 1990’s, researchers doped β -TCP with ions that are readily present
β -TCP did not form in the absence of water. Importantly, whitlock- in the human body, such as Na, Mg, K, and Mg [83,85,136–142].
ite mineral [100,101], which gave its name to the β -TCP structure, The underlying strategy was to modify β -TCP solubility and resorp-
can also precipitate and has a similar chemical composition as H- tion properties without diminishing β -TCP biocompatibility (Tables
β -TCP, but with a small amount of Mg ions. Staehli et al. [99] re- 2 and 3). More recent studies have focused on the therapeutic po-
ported that H-β -TCP was thermally less stable than β -TCP and de- tential of doping agents. Authors have for example tried to confer

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Table 2. surface chemical changes have been shown to modify β -TCP chem-
Functional aim of cation-doped β -TCP.
ical and biological properties [59,163,164].
Property References There has been a number of studies devoted to β -TCP surface
Mechanical [74,83,89,138,142,250,315] modification. For example, β -TCP has been coated with a poly-
Crystallographical / structural [83,102,131,138,316–319] mer to mitigate its brittle nature [165–171]. Polymer coatings have
Solubility change [316] sometimes been used as drug delivery system [172] or to improve
Increase of resorption rate [137,140,148] β -TCP (in vitro) biological properties [173]. In fact, considering
Reduction of resorption rate [85,250,297–299]
the relatively poor bone regenerative and osteoconductive proper-
Osteogenic, osteoconduction [53,54,68,146,152–154]
Angiogenic, oxygen transport [143–145] ties of polymers compared to β -TCP [174], it appears more inter-
Antibacterial [144,146–151] esting to use polymer-free coating approaches, for example using
Anti-osteoporotic [54,89,96,149,299,320] graphene oxide [175], or minerals, such as whitlockite [176], ap-
Hyperthermia / cancer [321,322]
atites [177,178], and perhaps bioactive glass [179]. Currently, the
Luminescence [56,323–328]
Magnetic properties / MRI contrast agent [329,330] use of an apatite layer appears particularly promising in the con-
text of osteoinductivity [161,180]. Among other studies devoted to
β -TCP surface modification, Kunze et al. [181] treated β -TCP sur-
face in diluted phosphoric acid solution to improve the mechanical
β -TCP with angiogenic [143–145], antimicrobial [144,146–151], or properties of β -TCP-P(L,DL)LA composites. β -TCP surface has also
osteogenic [53,54,68,146,152–154] properties using e.g. Ag, Cu, Li, been coated with heparin to modify its “osteo-immunomodulatory
Sr, or Zn cations (Table 2). Since many cations are biologically rel- effects” [182]. However, no in vivo evidence was provided to sup-
evant, and considering the research novelty of the approach, the port the claim.
number of studies devoted to ion-doped β -TCP has literally ex-
ploded (Table 3). These research efforts have however not been 4. β-TCP powders, granules, and scaffolds with controlled
translated into commercial successes, perhaps because a therapeu- geometry
tic claim on ion-doped β -TCP is a regulatory burden for companies
aiming at launching a product. One may also add that it is not easy 3D (paste) printing extrusion, also called robocasting, requires
to demonstrate that the action of a metallic dopant is due to its the use of highly de-agglomerated, spherical, and fine β -TCP pow-
chemical nature and not due to its physico-chemical effect on β - ders to prevent nozzle clogging [183,184]. Since β -TCP powders
TCP (e.g. change of solubility) [155–157]. tend to contain agglomerates of a few dozen micrometers in size
(Fig. 4f), printed rods are typically larger than 100 μm in diame-
ter [185]. Contrarily, too fine powders require too much liquid for
3.5. Surfaces achieving pastes and slurries with suitable rheological properties
[186,187]. This may result in mechanically weak hydraulic cements
Modification of surface chemistry is a well-known problem in [186], and difficulties in slip-casting applications for the synthesis
ceramic sintering. Surprisingly, this topic is hardly addressed in of β -TCP ceramics [187]. In 3D printing, powders should be neither
the bioceramic field. This is quite puzzling considering the impor- too coarse, nor too fine [188]. These examples underline the impor-
tance of surfaces for the in vivo fate of a biomaterial, and the ef- tance of being able to control the particle size and shape of β -TCP
forts made to dope β -TCP with biologically active ions (Table 3; particles, particularly in the sub-micrometer range. At the macro
see above). This is even more surprising knowing that phospho- scale, a control of the geometry is also required since β -TCP ge-
rus species evaporate during β -TCP sintering [109,158,159], which ometry controls the biological response [189,190]. The aim of this
may modify β -TCP surface. For example, Rangavittal et al. [160] ob- section is to review methods used to control the size and shape of
served the decomposition of β -TCP into CaO under an electron β -TCP particles, and to produce scaffolds with a controlled archi-
beam. Maazouz et al. [161] detected the presence of an alkaline tecture.
Ca-rich specie at the surface of sintered β -TCP and concluded that
it must be a calcium hydroxide or calcium carbonate layer, consid- 4.1. Size and shape of β -TCP particles
ering that CaO is very unstable in atmospheric conditions. These
experimental results are supported by a recent study of Döbelin Controlling the size of β -TCP particles can be achieved by a top-
et al. [162], who predicted the formation of CaO on the surface of down or a bottom-up approach. The top-down approach consists
a thermally treated β -TCP using a thermodynamic approach. These in comminuting β -TCP blocks produced by solid-state sintering or

Table 3.
List of studies devoted to metal-doped β -TCP up to an atomic number of 71 (Lu). Beside biological targets, quite
some work has been done with lanthanides to provide β -TCP with thermo- or photoluminescence.

Element References Element References

Li [131,152,315,319,331] Ag [147,150,151]
Na [83,131,138,140,142,315,319] Cd [316]
Mg [74,85,89,131,137,250,297,298,315,316] Ba [316]
Al [131] La [323]
K [131,315,332] Ce [322]
Cr [56] Pr [323]
Mn [53,54,146,147,154,316–318] Nd [323]
Fe [145,316,317,321] Sm [326]
Co [143,316,317] Eu [323,325,327]
Ni [316,317] Gd [323,329,330]
Cu [144,147,148,316,317] Dy [323–325,328]
Zn [68,102,147,149,153,250,299,316,317] Tm [323,324]
Ga [96] Yb [323]
Sr [89,102,316,320]

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M. Bohner, B.L.G. Santoni and N. Döbelin Acta Biomaterialia 113 (2020) 23–41

by phase conversion. Large material volumes can be treated in a Robocasted samples are obtained by extruding a filament of a
relatively short time, but once a certain threshold particle size has calcium phosphate paste onto a movable support platform. The
been reached, the powder does not become finer, but amorphous. pores are created by the gaps between the extruded filaments (Fig.
For example, Gbureck et al. [191] observed the smallest mean par- 5i). The method is rapid, versatile, and scalable. However, the spa-
ticle size (d50 value; 2.62 μm) after 8 h of planetary ball milling. tial resolution is typically larger than 100 μm. Also, pores have
At this time point, the relative crystallinity was 58%. After 24 h, the a convex curvature, which is often considered to be detrimental
d50 value and the crystallinity were 2.80 μm and 26%, respectively. to bone formation [220], in particular ectopically [221–223]. In
Attrition may lead to slightly finer powders than ball milling, but the polymer-bead mold impregnation method, beads (e.g. PMMA,
to obtain much finer powders, it is imperative to produce β -TCP by paraffin) are packed into a mold and sintered/consolidated either
precipitation or by thermal conversion of nanosized ACP or CDHA thermally [214] or chemically with a solvent [215]. A calcium phos-
powders (bottom-up approach). As mentioned previously, Kjellin phate slurry is then poured into the resulting 3D mold, and dried.
et al. [123] reported a specific surface area of 65 m2 /g for a β - The resulting green body is debinded and sintered. The removal of
TCP powder produced in ethyl propionate, which corresponds to an the beads during debinding creates concave pores in the sintered
equivalent spherical diameter of ≈30 nm. However, their β -TCP ap- calcium phosphate scaffold (Fig. 5e and f). The pore interconnec-
peared agglomerated. Contrarily, de-agglomerated β -TCP powders tion size is defined by the size of the necks formed during poly-
with an equivalent spherical diameter in the order of 100 nm were mer bead debinding. Limitations include a narrow porosity range
synthesized in ethylene glycol (Fig. 4a). and a dependence between porosity and pore interconnection size.
Controlling the shape of β -TCP particles is essential for e.g. the Stereolithography, and the 3D printed mold impregnation method
synthesis of strong and injectable β -TCP based calcium phosphate are probably the most versatile as there is an almost complete ge-
cements [183,184] or the fabrication of strong and tough β -TCP ometrical freedom. In stereolithography, a monomer-based β -TCP
based composite [120]. Currently, the only methods that can be slurry is polymerized layer-by-layer [217,218]. The main geomet-
used to control the shape of β -TCP particles at the micro-scale rical limitation is related to the need to remove the unpolymer-
are hydrothermal- and solution-based. For example, uniform de- ized slurry from the pores. In the 3D printed mold impregnation
agglomerated micrometric H-β -TCP particles and platelets can be method, a 3D polymer mold is first printed and then used as mold
obtained in ethylene glycol (Fig. 4a–c) [120,192]. Unfortunately, the for slip-casting [216,224,225] (Fig. 5g and h). Geometrical freedom
yield is very low (a few dozen mg per Liter). H-β -TCP platelet with is limited by the need to be able to penetrate all mold cavities with
high aspect ratios, which are wanted for strong and tough compos- the slurry.
ite applications [120], can be synthesized in ethylene glycol, but
the particles are either mixed with different H-β -TCP particle ge-
4.4. Micropores
ometries (Fig. 4b) or with monetite (DCP) particles [192].

Micropores (0.1–100 μm in diameter) have a positive effect on

4.2. Granules β -TCP biological response, not only to improve resorption but also
to boost osteoinduction [42,226–229]. Accordingly, it is relevant
The most efficient approach to produce granules is to manu- to review methods to control β -TCP microporosity and micropore
facture large blocks, to crush them, and to classify the resulting size. The volume fraction of micropores in a ceramic (= microp-
particles by sieving (Fig. 5d). This allows a good control of the orosity) decreases with an increase of sintering temperature and
granule size, but no control of the granule shape and the inter- time. In parallel, micropore size increases. Therefore, it is difficult
granular pore space [193–195]. To solve these issues, more ad- to vary the micropore size without varying the microporosity and
vanced manufacturing approaches must be used, such as robocast- vice-versa. Dellinger et al. [230] added PMMA micro spheres into
ing [196] (Fig. 5a), injection molding [196–199] (Fig. 5b), and 3D an HA slurry to create spherical micropores in HA scaffolds. This
printing [200–202] (Fig. 5c). Unfortunately, 3D printing and robo- or a similar approach has been adopted by various groups [231–
casting have a limited resolution (typically > 100 μm), and man- 234] (Fig. 6a and b). A second approach is to add CDHA (often
ufacturing costs increase rapidly with a decrease of granule size. called “tricalcium phosphate”) into the paste [208,209]. CDHA is
Importantly, the ability to produce “granules” with controlled ge- a solid, so it has no direct effect on the microporosity, but since
ometry can be used for the production of topologically interlocked CDHA has a high specific surface area (typically > 50 m2 /g), it re-
3D constructs [201,203]. Such constructs are much more resilient quires more water to keep the same viscosity, thus resulting in
than monolithic solids and could be of interest for impaction graft- microporosity after sintering. Interestingly, CDHA is used in the
ing [204]. food industry as thickener for e.g. yogurts (additive number E341).
A third approach is to use additives that favor grain growth (see
“control of grain size” for more details about “grains”) instead of
4.3. Scaffolds
densification, such as sodium oxide [235] or sodium phosphate
[209] (Fig. 6c). The main advantage is that the micropores are in-
Due to the resorbable nature of β -TCP, macropore-free micro-
terconnected; the main disadvantage is that the composition of the
porous β -TCP scaffolds are invaded and replaced by bone quite
scaffold is modified, and that the size and shape of the micropores
readily [205–207]. However, the presence of interconnected macro-
cannot be controlled very well. Importantly, interconnected micro-
pores (> 100 μm in diameter) markedly accelerates this process
pores can be invaded by woven bone provided the interconnection
[36]. It is therefore important to produce macroporous β -TCP scaf-
size is in the order of a few micrometers, as in Fig. 7c [36].
folds with a controlled architecture. Numerous approaches have
been proposed for that purpose, including emulsification [208,209],
foaming [210,211], ice-templating [212], polymer foam impregna- 5. β-TCP sintering
tion [167,194,213], polymer-bead mold impregnation [178,214,215]
(Fig. 5e and f), 3D printed mold impregnation [216] (Fig. 5g and Sintering is a very important aspect of ceramic processing
h), stereolithography [217,218], 3D printing [219], and robocasting because it determines (among others) the residual porosity and
[185] (Fig. 5i). Among these, mold impregnation, stereolithography, accordingly the mechanical properties of the final product. The
and robocasting are probably the most interesting methods to con- term sintering describes a thermal treatment inducing ion dif-
trol the scaffold architecture, as described hereafter. fusion, which leads to consolidation of the ceramic body and/or

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M. Bohner, B.L.G. Santoni and N. Döbelin Acta Biomaterialia 113 (2020) 23–41

Fig. 5. Example of β -TCP granules and scaffolds with reproducible architectures produced by (a) 3–4 mm robocast granules ([196]; courtesy of S. Heinemann, INNOTERE
GmbH, Germany), (b) 4–5 mm injection moulded granules ([196], courtesy of G. Hettich), (c) 3D printed JAXTM granules [202], (d) β -TCP granules obtained by crushing a
large β -TCP block and classification, (e) Control of the pore interconnection size (arrow) in the polymer-bead mold impregnation method; fenestration size ≈ 180 μm [215];
(f) same as (e) but with a fenestration size of ≈ 240 μm [215]; (g) Example of a hydroxyapatite sample obtained by the 3D printed mold impregnation method (courtesy of
D. Marchat; [225]); (h) same as (g) but with a higher enlargement (courtesy of D. Marchat; [225]); (i) Robocast scaffold ([157]; scale bar: 2 mm; courtesy of S. Heinemann,
INNOTERE GmbH, Germany).

grain growth. For most industrial applications, the residual poros- last part of this section is devoted to the evaporation of phosphate
ity should be minimized to maximize the mechanical properties species during sintering.
and provide nice esthetics (among others). Regarding mechanical
properties, the theoretical tensile strength of β -TCP lies between 1
5.1. Challenges in β -TCP sintering
and 10 GPa, i.e. 1–10% of the theoretical Young’s modulus value of
110 GPa [87,120]. However, due to the inherent brittleness of ce-
ramics, experimental tensile properties are much lower: Jarcho et
β -TCP sintering efficiency is limited by three aspects. First,
the β to α -TCP phase transition occurring at 1115–1150 °C
al. [50] reported a value of 154 MPa. For bone regeneration, poros-
[58,67,69,73–77] is characterized by a ≈7% increase of volume
ity and pores are beneficial. Indeed, pores, and in particular mi-
[69,244], which typically leads to crack formation once phase
cropores (0.1–100 μm), promote bone ingrowth [36,226,236], and
transition occurs [245–247]. Second, this phase transition occurs
may even confer osteoinductive properties to β -TCP [42,180]. Addi-
at a relatively low temperature (≈ 69% of the melting tempera-
tionally, high mechanical properties are not needed, because β -TCP
ture), which is detrimental to the achievement of high densities.
cannot be used in load-bearing applications due to its brittleness.
Third, sintering is poor in the presence of pyrophosphate impuri-
The mechanical stability should be just high enough to prevent
ties (= Ca/P molar ratio < 1.50). According to Descamps, “pyrophos-
mechanical deterioration during manufacturing, transport, clinical
phate phase seems to help the bridging and thus the enlargement
handling, and soft tissue displacements (e.g. in ectopic sites). Lim-
of the grain”. These difficulties imply that (i) β -TCP composition
ited hardness even improves clinical handling by allowing the sur-
should be kept at a Ca/P molar ratio slightly above 1.50 to pre-
geon to carve preformed implants with a scalpel to match the de-
vent the presence of pyrophosphate impurities [187], and that (ii)
fect shape. Clinically, mechanically unstable bone defects are stabi-
sintering should be performed below the β - to α -TCP phase tran-
lized with osteosynthesis plates and screws, and β -TCP bone sub-
sition temperature, i.e. 1100–1130 °C [85,187,215,248]. When ful-
stitutes are used as “spacer” or “filler”, generally in the form of
filling these conditions and maximizing the initial density of the
0.5–5.0 mm granules. The use of dense β -TCP ceramics is however
green body, it is possible to obtain > 98% dense β -TCP samples
of interest when studying β -TCP bone adhesion force [237–239] or
[85,187,244] (Fig. 6d). It is neither necessary to use hot isostatic
β -TCP cell response [240], for example to look at the formation of
pressing [248], nor to add elemental impurities like MgO [74,249],
resorption pits on polished β -TCP surfaces [85,97,241–243] (Fig. 6).
ZnO [247,249], MgO–ZnO [250], or pyrophosphate [245] to increase
The aim of this section is to review the challenges faced by those
the β to α -TCP phase transition temperature and sinter the sam-
attempting to sinter β -TCP and to modify their microstructure. The
ples at higher temperature. Champion [241] in fact stated that “op-

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M. Bohner, B.L.G. Santoni and N. Döbelin Acta Biomaterialia 113 (2020) 23–41

Fig. 6. (a) Dense BCP ceramic (courtesy of A. Wagoner Johnson; [311]); some grains are shown in red; (b) Micropores in BCP ceramic obtained by burning off PMMA
microparticles (courtesy of A. Wagoner Johnson; [311]); (c) Micropores in a CDHA samples sintered at 1250 °C and doped with Na2 HPO4 (courtesy of Geoff Richards, AO
Research Institute, Davos); (d,e) sintered β -TCP samples with Ca/P = 1.502; 100 ± 1% relative density; sintering temperature = 1100 °C; (g,h) sintered β -TCP samples with
Ca/P = 1.497; 97 ± 1% relative density; sintering temperature = 1100 °C; the arrows in (d) show pores; the surfaces are either (d,g) polished, or (e,h) unpolished. (f,i) Surface
of a dense and polished β -TCP platelets after osteoclastic resorption. (i) is an enlargement of the rectangular zone shown in (f). The insert in (i) shows the rectangular zone
in the center of (i). The typical needle-like structure seen after osteoclastic resorption is clearly visible. The needles are oriented along the c-axis [85]; the white arrows
show HA grains that have not been resorbed by osteoclasts; the black arrows show some grain boundaries that are preferentially attacked by osteoclasts.

timized pressureless sintering (…) remains the most useful and the tained by Mazaheri et al. [255] was only slightly smaller than the
reference technique for producing dense calcium phosphate ceramics grain size of HA ceramics produced by (optimized) conventional
with a fine microstructure”. Nevertheless, transparent β -TCP require sintering. The efforts of the authors to produce dense β -TCP sam-
the use of hot isostatic pressing [240,248,251]. ples by two-step sintering have brought limited results so far (10–
20% reduction in grain size).
5.2. Control of grain size
5.3. Evaporation of phosphate species
β -TCP bone graft substitutes are polycrystalline materials, i.e.
they are made of a 3D assembly of randomly-oriented single crys- As discussed herein, phosphate species may evaporate from
tals. In first approximation, these single crystals can be consid- the surface of calcium phosphate ceramics during sintering
ered to be grains (Fig. 6a, e, and h). These grains are bound to- [109,158,159,162], which may affect the chemical, physical, and bi-
gether by the so-called grain boundaries that have a thickness of a ological properties of β -TCP [59,163,164]. Nevertheless, very little
few atomic layers and may have a different composition and ther- is known on the link between the sintering atmosphere and β -
modynamic state than the rest of the ceramic / β -TCP (so-called TCP surface properties. In fact, β -TCP sintering atmosphere is often
“complexions”) [252]. Since resorption occurs first at grain bound- not mentioned in scientific articles and β -TCP surface is practically
aries [85,97], it is relevant to consider ways to vary the grain size never analyzed. Phosphate evaporation apparently leads to the for-
of dense β -TCP ceramics. Unfortunately, the freedom to operate is mation of Ca-rich basic surface species, most likely calcium oxide
limited due to the relatively low β to α -TCP phase conversion tem- [162], which may readily transform into calcium hydroxide or cal-
perature (1125 °C) [77], as discussed above. Two main approaches cium carbonate upon contact with air [161]. Varma et al. [257] re-
can be considered. First, the sintering time can be increased to fa- ported a difference of β -TCP grain orientation between the surface
vor grain growth, but the effects remain moderate. Second, a re- and the bulk.
duction of β -TCP grain size can be achieved by the two-step sinter-
ing approach [253,254], which consists in first densifying ceramic 6. Biological response to β-TCP
green bodies to a point where pores become unstable (> 75%,
[254]) and then lowering the temperature to further densify the β -TCP has emerged in recent years as one of the most attractive
ceramic without grain growth. Mazaheri et al. [255] observed a bone graft substitutes due to its synthetic nature, osteoconduction,
nine fold grain size reduction of HA sintered ceramics using this osteoinduction, and cell-mediated resorption. It has been proposed
approach. Lukic et al. [256] reported similar results with BCP. How- as carrier for local administration of drugs (bone morphogenic pro-
ever, as pointed out by Champion [241], the final grain size ob- teins, antibiotics) at the defect site, and has been widely used in

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M. Bohner, B.L.G. Santoni and N. Döbelin Acta Biomaterialia 113 (2020) 23–41

Fig. 7. (a) β -TCP scaffold after 6 weeks of implantation in a sheep model (sample ‘A’) [312]; Toluidine blue staining. Dark blue: bone; light blue: ceramic remnants, free
of bone; yellowish gray: soft tissue; The newly-formed trabecular structure, still containing ceramic remnants, is indicated with arrows. (b) Same as (a) but β -TCP scaffold
with larger macropores (reproduced from [36]); The newly-formed trabecular structure goes through the ceramic (arrows); (c) SEM-BSE image of a zone containing lots of
resorption pits and tunnels (arrows); the approximative edges of the macropores are highlighted with red lines; bone inside the ceramic is shown with “x” (reproduced from
[36])) (d) Histological section of a β -TCP porous scaffold after 6-month implantation in a baboon (courtesy of Prof Olah, University of Berne; reproduced from [313] and
[98]); the purple zone corresponds to the ceramic. The two white arrows show some TRAP positive multi-nucleated giant cells (“bone resorbing cells”) present at the ceramic
surface. The central “hole” is a ceramic pore (roughly 30 0–50 0 μm in diameter). (e) Same as (d) at a different enlargement. The two white arrows show two TRAP positive
multi-nucleated giant cells. Ingested particles can been seen inside the cells (black arrow); (f) Same as (d) and (e); the ceramic (in black) macropores (roughly 30 0–50 0 μm
in diameter) are filled with new bone (in pink) (courtesy of Prof Olah, University of Berne); (g) Interface between β -TCP and bone (courtesy of A. Bernstein); (h) bone (“x”)
within the micropores of β -TCP (“o”) [36]; (i) multinucleated giant cell ingesting β -TCP debris at the β -TCP surface, as seen under SEM. The insert shows some of the debris
[36].

Table 4.
Non-exhaustive list of surgical indications of β -TCP.

Field Indication References

Dental Periodontal defects [333,334]

applications Apical closure [45]
Filling of extraction socket [335]
Reconstructive surgery of the jaw [336]
Sinus lift / floor augmentation [5–7,337–340]
Orthopedic Cyst/tumor filling [34,301,341–344]
applications Acetabulum / revision fracture [304]
Spinal fusion [309,345–351]
Spine posterolateral fusion [352–354]
Tibial osteotomy [8–10,355–357]
Subchondral tibial defects /tibia plateau [3,206,207,304,358,359]
Tibia (shaft) defects [47]
Tibia pilon [304]
ACL fixation [205,360]
Distal radius fracture [4,304,361]
Graft extender [353,362,363]
Drug Growth factors [269,364–367]
delivery Antibiotics [368–372]

dental and orthopedic applications for bone regeneration (Table 4). 6.1. Cell-mediated resorption
However, β -TCP has also been reported to present an inconsistent
biological behavior. The aim of this section is to address these as- Physiological fluids present in the human body are gen-
pects and propose in particular potential avenues of explanation erally considered to be in equilibrium with OCP [258,259]
for these inconsistencies. or DCPD [38]. Since β -TCP is less soluble than these two
phases [260,261], β -TCP is insoluble in physiological condi-

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M. Bohner, B.L.G. Santoni and N. Döbelin Acta Biomaterialia 113 (2020) 23–41

tions (pH 7.4). The solubility constant for the reaction: β - The combination of an osteoclast-mediated resorption and osteo-
Ca3 (PO4 )2 + 4H+ → 3Ca2+ #x002B; 2H2 PO4 − is pKs = 10.18 [262]. conduction allows a remarkably fast osteotransduction from a β -
In vitro results demonstrate indeed that β -TCP is insoluble in sim- TCP scaffold structure to a trabecular structure (Fig. 7a–c), where
ulated body fluid (SBF) at pH 7.4 [38,263], and possibly also at “unnecessary” β -TCP material is rapidly removed by MNGCs in
pH 6.0 [237]. Accordingly, β -TCP does not spontaneously dissolve a “tunnel-like” fashion (Fig. 7c) [36]. In [36], bone ingrowth was
upon implantation, but is resorbed by a cell-mediated process in- found to be linear in time and close to 89 μm/day, which means
volving macrophages and multinucleated giant cells (MNGCs) (Fig. that a ø 8mm cylinder was invaded by bone within 40 0 0/90 = 45
6f and i; Fig. 7d and e) [30,32,97,234,264–267]. MNGCs adhere days. For comparison, the linear β -TCP resorption rate (perpendic-
to β -TCP surface, open their membrane at the cell-material in- ular to β -TCP surface) of the same samples was estimated to be in
terface, and secrete acidic species that lower the local pH value the range of 2–10 μm/week [281]. However, the latter study con-
of 3-4 [268]. Since β -TCP solubility increases rapidly with a de- sidered an instantaneous homogeneous surface resorption rather
crease of pH [260], β -TCP is dissolved locally (Figs. 6 and 7). This is than a “tunnel-like” distance-delayed resorption. Accordingly, re-
part of the so-called cell-mediated resorption. These MNGCs do not sorption rate must occur much faster under the action of MNGCs.
only attack β -TCP at its surface, but ingest and phagocytose β -TCP In fact, ø 8 mm L 13 mm cylinders were almost fully resorbed
grains dislodged during that process (Fig. 7e and i) [36,266,269]. within 24 weeks [36,264].
Etched grains present a pillar-like topography (Fig. 6i) [85,97,98],
where the pillars are crystallographically aligned along the c-axis 6.4. Osteoinduction
[85]. The fact that the areas between the pillars, which are very
deep compared to the pillar diameters, are dissolved faster than Some β -TCP materials have been shown to be osteoinduc-
the pillar tips suggests that β -TCP is heterogeneous (see also the tive [42,282–290]. However, not all β -TCP materials implanted ec-
discussion about the crystallographic structure). In that respect, it topically induce bone formation [223,291,292]. Bohner and Miron
is interesting to point out that β -TCP dissolution stops in under- [180] presented recently a mechanism for material-induced het-
saturated conditions [105,270] for a reason that is still debated, but erotopic ossification in which the material “bioactivity” (ability to
that could be related to the difficulty to nucleate “critical size de- spontaneously mineralize in physiological conditions) is a prereq-
fects” [271]. Since doping agents, such as Mg and Zn, modify β -TCP uisite for heterotopic ossification to occur. In detail, since phys-
solubility [272,273], it is likely that they also modify cell-mediated iological fluids are supersaturated at pH 7.4 towards hydroxyap-
resorption, as shown by Gallo et al. with Mg [85]. atite [38,293], any implantation of a foreign material (like β -TCP)
may trigger the heterogeneous nucleation of apatite crystals on
the material surface, thus reducing very locally the calcium and
6.2. Grain boundaries
phosphate concentrations. If this reaction occurs in a large vol-
ume and at high rate, Bohner and Miron [294] postulated that
Grain boundaries are typically a few atomic layers thick and can
calcium and phosphate concentrations could be lowered over vol-
be treated as thermodynamically stable interfacial states [252]. It
umes large enough to affect cells present in these volumes (Fig.
means that grain boundary composition and solubility may differ
8). Accordingly, they attributed the inconsistent osteoinductive po-
from those of β -TCP. Indeed, despite the fact that β -TCP is insol-
tential of β -TCP to an inconsistent “bioactivity”. To support their
uble in physiological conditions, a number of results suggest that
claim, these authors mentioned that β -TCP apatite-forming abil-
grain boundaries are sometimes soluble. For example, Bhatt and
ity is triggered by autoclaving [177] and that most osteoinductive
Kalita [249] demonstrated experimentally that β -TCP lost weight
β -TCP materials have been autoclaved [282–287]. For comparison,
in SBF solution, i.e. in a liquid in which β -TCP is thermodynam-
Barba et al. [223] sterilized their (non-osteoinductive) β -TCP sam-
ically insoluble. Also, grain boundaries are preferentially dissolved
ples by gamma-irradiation and Tang et al. [292] by dry heat.
upon resorption [85,97,274]. In addition, grain boundaries are likely
It is important to point out that β -TCP autoclaving is expected
to accommodate elemental impurities, particularly those acting on
to trigger the formation of an apatite layer on top of the β -TCP
β -TCP sintering, such as Na [235] or pyrophosphates (Ca/P mo-
surface since HA is thermodynamically more stable than β -TCP.
lar ratio < 1.50) [187,244]. Considering the involvement of grain
This apatite layer can then grow right after implantation. In the
boundaries in the in vivo response of calcium phosphates, it is
absence of autoclaving, an apatite layer can also form on β -TCP,
very likely that β -TCP biological response is not only affected by
but it needs first to nucleate, which typically takes time and is ki-
its bulk composition, but also by a change of surface composition
netically driven. An apatite layer is chemically so similar to β -TCP
(see above) and grain boundary composition. Currently, this field
and most likely so thin that it cannot be detected by most meth-
of research is practically unexplored.
ods, like thin-film XRD [177], SEM [237,239], or possibly even TEM
[238].
6.3. Osteoconduction
6.5. Inconsistent biological behavior
β -TCP is osteoconductive [37,41,237,238,275], but does not fit
in the “bioactivity” concept of T. Kokubo [38,276], since no ap- In 1996, Hollinger et al. [295] mentioned that β -TCP has “an
atite layer was detected between β -TCP and bone [237,238,275]. unpredictable biodegradation profile” and that “β -TCP biodegradation
β -TCP is osteoconductive as underlined by the study of Kitsugi within bone defects routinely was not accompanied by bone forma-
et al. [275], who measured a significantly higher bone bonding tion”. Even though neither results nor references were provided to
strength for β -TCP than for HA at 10 weeks of implantation. Also, support these statements, the “too fast dissolution rate” of β -TCP
β -TCP is even invaded by bone at the microscale [36] (Fig. 7a, b, c, is regularly used as rationale for the design of BCPs [39,296] or
and h). Since most bone is produced in the form of lamellar bone the incorporation of stabilizing dopants [85,250,297–299]. Contrar-
[36], which is a process activated by osteoclasts [277,278], there ily, some authors have underlined the very slow resorption of β -
is more bone formed when osteoclastic resorption is more intense TCP [300–303]. Altermatt et al. [300] mentioned that “even 7 years
[279]. It may explain why β -TCP, when implanted in a fully ortho- after implantation, the radiographic evaluation showed no evidence of
topic site, generates more bone [34,37] and is often better invaded biodegradation”. These inconsistencies also mirror the inconsistent
by bone tissue than HA [34,37]. Interestingly, part of the calcium osteoinductive behavior of β -TCP mentioned herein. Potential ex-
ions released during resorption is used for bone formation [280]. planations for inconsistent results are numerous, such as the pres-

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M. Bohner, B.L.G. Santoni and N. Döbelin Acta Biomaterialia 113 (2020) 23–41

fully orthotopic defect should be rapidly invaded by soft tissue and

resorbed in the zones in apposition with soft tissue, as seen for
onlay grafts [307] and when implanted ectopically [223]. Clearly,
an osteoinductive β -TCP material would perform very differently
in these conditions by promoting bone formation throughout the
graft. Lin et al. [305] observed more inflammation around β -TCP
implants when the calcium pyrophosphate (CPP) content was in-
creased (Ca/P molar ratio decreasing from 1.50 to 1.45). These au-
thors associated the inflammation to the release of particles at
high CPP content. They concluded that the CPP impurity content
should be kept below 0.5%. Currently, authorities consider a β -TCP
bone substitute to be pure if the β -TCP content is larger than 95%
[308]. Wang et al. [309] found that 60% porous β -TCP granules
achieved a higher bone fusion rate than 75% porous β -TCP gran-
ules, suggesting that a too high porosity is deleterious for β -TCP
bone regenerative properties. The controversial discussion of the
biological behavior of β -TCP implants shows that the phase com-
position is only one aspect among many controlling the in vivo re-
sponse to the bone graft substitute. Elemental impurities, calcium
phosphate phase impurities, surface composition, as well as vari-
ous topological features (micro-, macro-porosity, grain size, perme-
ability) must be controlled meticulously to achieve consistent and
optimum biological properties.

7. Conclusion

The present review has documented the richness, breadth, and

interest of the research devoted to β -TCP. More than 200 arti-
cles are published yearly. β -TCP is synthetic, osteoconductive, os-
teoinductive, and its resorption is cell-mediated, thus making it
one of, or if not, the most potent bone graft substitutes. β -TCP
is widely used in the clinics. β -TCP can be readily doped with
ions, which may provide functionalities like bactericidal activity or
luminescence. This review has also revealed a surprisingly large
number of unknown aspects in β -TCP research: what is the ex-
act β -TCP crystallographic structure? What is the surface and grain
boundary composition of (sintered) β -TCP? What is the effect of a
low (< 1.50) or a high (> 1.50) Ca/P molar ratio on β -TCP sin-
tering, crystallography, surface and grain boundary composition?
What is the link between β -TCP physico-chemical properties (Ca/P
molar ratio, surface and grain boundary composition) and biolog-
ical properties? The current developments in the production of
pure and doped β -TCP, as well as the access to powerful char-
acterization tools, such as magic angle spinning nuclear magnetic
resonance, high-resolution transmission electron microscopy, and
atom-probe tomography, will most certainly allow to answer some
of these questions in a near future, and thereby make β -TCP an
even more attractive research subject and bone graft substitute.

Declaration of Competing Interest

Fig. 8. Schematic representation of blood vessel ingrowth and heterotopic bone for-
mation in non-bioactive, poorly bioactive, and highly bioactive granular bone sub-
None.
stitutes. The effect of a difference of porosity is also displayed. A higher osteoinduc-
tion is expected when the material bioactivity is increased and when the material
porosity is reduced (provided blood vessel ingrowth is still possible). (reproduced Acknowledgments
from [180]).
Gabrielle A. Sblendorio, Duncan T.L. Alexander and Paul Bowen
for fruitful discussions. Baptiste Charbonnier and David Marchat for
proofreading the manuscript and for providing pertinent sugges-
ence of large amounts of HA in β -TCP (a typical raw-material re-
tions. Bastien Le Gars Santoni thanks the Swiss National Science
lated problem in the early days of calcium phosphate bone graft
Foundation for his doctoral scholarship (Grant no. 20 0 021_169027).
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