Progress in Biomaterials

, Volume 5, Issue 1, pp 9–70 | Cite as

Calcium orthophosphates (CaPO4): occurrence and properties

  • Sergey V. DorozhkinEmail author
Open Access
Review Paper


The present overview is intended to point the readers’ attention to the important subject of calcium orthophosphates (CaPO4). This type of materials is of the special significance for the human beings because they represent the inorganic part of major normal (bones, teeth and antlers) and pathological (i.e., those appearing due to various diseases) calcified tissues of mammals. For example, atherosclerosis results in blood vessel blockage caused by a solid composite of cholesterol with CaPO4, while dental caries and osteoporosis mean a partial decalcification of teeth and bones, respectively, that results in replacement of a less soluble and harder biological apatite by more soluble and softer calcium hydrogenorthophosphates. Therefore, the processes of both normal and pathological calcifications are just an in vivo crystallization of CaPO4. Similarly, dental caries and osteoporosis might be considered as in vivo dissolution of CaPO4. In addition, natural CaPO4 are the major source of phosphorus, which is used to produce agricultural fertilizers, detergents and various phosphorus-containing chemicals. Thus, there is a great significance of CaPO4 for the humankind and, in this paper, an overview on the current knowledge on this subject is provided.


Calcium orthophosphates Hydroxyapatite Fluorapatite Bones Teeth Antlers Calcification Crystallization Biomimetics 


Due to the abundance in nature (as phosphate ores) and presence in living organisms (as bones, teeth, deer antlers and the majority of various pathological calcifications), calcium phosphates are the inorganic compounds of a special interest for human being. They were discovered in 1769 and have been investigated since then (Dorozhkin 2012a, 2013a). According to the databases of scientific literature (Web of knowledge, Scopus, Medline, etc.), the total amount of currently available publications on the subject exceeds 40,000 with the annual increase for, at least, 2000 papers. This is a clear confirmation of the importance.

Briefly, by definition, all known calcium phosphates consist of three major chemical elements: calcium (oxidation state +2), phosphorus (oxidation state +5) and oxygen (reduction state −2), as a part of the phosphate anions. These three chemical elements are present in abundance on the surface of our planet: oxygen is the most widespread chemical element of the earth’s surface (~47 mass %), calcium occupies the fifth place (~3.3–3.4 mass %) and phosphorus (~0.08–0.12 mass%) is among the first 20 of the chemical elements most widespread on our planet (Lide 2005). In addition, the chemical composition of many calcium phosphates includes hydrogen, as an acidic orthophosphate anion (for example, HPO4 2− or H2PO4 ), hydroxide [for example, Ca10(PO4)6(OH)2] and/or incorporated water (for example, CaHPO4·2H2O). Regarding their chemical composition, diverse combinations of CaO and P2O5 oxides (both in the presence of water and without it) provide a large variety of calcium phosphates, which are differentiated by the type of the phosphate anion. Namely, ortho- (PO4 3−), meta- (PO3 ), pyro- (P2O7 4−) and poly- ((PO3) n n− ) phosphates are known. Furthermore, in the case of multi-charged anions (valid for orthophosphates and pyrophosphates), calcium phosphates are also differentiated by the number of hydrogen ions substituted by calcium ones. The examples comprise mono- (Ca(H2PO4)2), di- (CaHPO4), tri- (Ca3(PO4)2) and tetra- (Ca2P2O7) calcium phosphates (LeGeros 1991; Elliott 1994; Amjad 1997). However, to narrow the subject, calcium orthophosphates (abbreviated as CaPO4) will be considered and discussed only. Their names, standard abbreviations, chemical formulae and solubility values are listed in Table 1 (Dorozhkin 2011, b). Since all of them belong to CaPO4, strictly speaking, all abbreviations in Table 1 are incorrect; however, they have been extensively used in literature for decades and, to avoid confusion, there is no need to modify them.
Table 1

Existing calcium orthophosphates and their major properties (Dorozhkin 2011, 2012b)

Ca/P molar ratio



Solubility at 25 °C, −log(Ks)

Solubility at 25 °C (g/L)

pH stability range in aqueous solutions at 25 °C


Monocalcium phosphate monohydrate (MCPM)






Monocalcium phosphate anhydrous (MCPA or MCP)






Dicalcium phosphate dihydrate (DCPD), mineral brushite






Dicalcium phosphate anhydrous (DCPA or DCP), mineral monetite






Octacalcium phosphate (OCP)






α-Tricalcium phosphate (α-TCP)






β-Tricalcium phosphate (β-TCP)






Amorphous calcium phosphates (ACP)

Ca x H y (PO4) z ·nH2O, n = 3–4.5; 15–20 % H2O





Calcium-deficient hydroxyapatite (CDHA or Ca-def HA)e

C−x(HPO4) x (PO4)6−x (OH)2−x (0 < x < 1)





Hydroxyapatite (HA, HAp or OHAp)






Fluorapatite (FA or FAp)






Oxyapatite (OA, OAp or OXA)f, mineral voelckerite






Tetracalcium phosphate (TTCP or TetCP), mineral hilgenstockite





aThese compounds cannot be precipitated from aqueous solutions

bCannot be measured precisely. However, the following values were found: 25.7 ± 0.1 (pH = 7.40), 29.9 ± 0.1 (pH = 6.00), 32.7 ± 0.1 (pH = 5.28) (Ohura et al. 1996). The comparative extent of dissolution in acidic buffer is: ACP ≫ α-TCP ≫ β-TCP > CDHA ≫ HA > FA (Daculsi et al. 1997)

cStable at temperatures above 100 °C

dAlways metastable

eOccasionally, it is called “precipitated HA (PHA)”

fExistence of OA remains questionable

In general, the atomic arrangement of all CaPO4 is built up around a network of orthophosphate (PO4) groups, which stabilize the entire structure. Therefore, the majority of CaPO4 are sparingly soluble in water (Table 1); however, all of them are easily soluble in acids but insoluble in alkaline solutions. In addition, all chemically pure CaPO4 are colorless transparent crystals of moderate hardness but, as powders, they are of white color. Nevertheless, natural minerals of CaPO4 are always colored due the presence of impurities and dopants, such as ions of Fe, Mn and rare earth elements (Cantelar et al. 2001; Ribeiro et al. 2005). Biologically formed CaPO4 are the major component of all mammalian calcified tissues (Lowenstam and Weiner 1989), while the geologically formed ones are the major raw material to produce phosphorus-containing agricultural fertilizers, chemicals and detergents (McConnell 1973; Becker 1989; Rakovan and Pasteris 2015).

Geological and biological occurrences

Geologically, natural CaPO4 are found in different regions mostly as deposits of apatites, mainly as ion-substituted FA (igneous rocks), and phosphorites (sedimentary rocks) (Becker 1989; Rakovan and Pasteris 2015; Cook et al. 2005; Dumoulin et al. 2011). In addition, natural ion-substituted CDHA was also found (Mitchell et al. 1943) but it is a very rare mineral. Some types of sedimentary rocks can be formed by weathering of igneous rocks into smaller particles (Zhang et al. 2010a). Other types of sedimentary rocks can be composed of minerals precipitated from the dissolution products of igneous rocks or minerals produced by biomineralization (Fig. 1; Omelon and Grynpas 2008). Thus, due to a sedimentary origin, both a general appearance and a chemical composition of natural phosphorites vary a lot (Jarvis 1994; Glenn 1994). It is a common practice to consider francolite (or carbonate-hydroxyfluorapatite regarded as its synonym) as the basic phosphorite mineral (Cook et al. 2005; McClellan 1980; Mcarthur 1985; Zanin 2004; Lapin and Lyagushkin 2014). According to Henry (1850), the name francolite was given by Mr. Brooke and Mr. Nuttall to a mineral from Wheal Franco, Tavistock, Devon, some years prior to 1850. A cryptocrystalline (almost amorphous) variety of francolite (partly of a biological origin) is called collophane (synonyms: collophanit, collophanita, collophanite, grodnolite, kollophan), named in 1870 by Karl Ludwig Fridolin von Sandberger from the Greek roots κολλα (=glue) and φαινεσθαι (to appear) referring to the appearance of the mineral (Rogers 1922; Cao et al. 2013; Francolite is found in natural phosphorites predominantly as fossil bones and phosphatized microbial pseudomorphs: phosphatic crusts of chasmolithic biofilms (or microstromatolites) and globular clusters with intra-particular porosities (Elorza et al. 1999; Hubert et al. 2005; Xiao et al. 1998, 2000). Natural phosphorites (therefore, francolite and collophane as well) occur in various forms, such as nodules, crystals or masses. Occasionally, other types of natural CaPO4 are found as minerals, for example clinohydroxylapatite (Chakhmouradian and Medici 2006), staffelite (synonyms: staffelit, staffelita) belonging to carbonate-rich fluorapatites (chemical formula: Ca5[(F,O)(PO4,CO3)3]) (Mason et al. 2009; and DCPD (Klein 1901; Kaflak-Hachulska et al. 2000). Furthermore, CaPO4 were found in meteoric stones (Merrill 1917; McCubbin and Nekvasil 2008; McCubbin et al. 2014). The world deposits of natural CaPO4 are estimated to exceed 150 billion tons; from which approximately 85 % belong to phosphorites and the remaining ~15 % belong to apatites (Cook et al. 2005).
Fig. 1

A simplified schematic of the phosphorus cycle from apatitic igneous rock to phosphorite sedimentary rock through chemical or physical weathering. Life forms accumulate soluble phosphorus species and can produce apatite through biomineralization. Reprinted from Ref. (Omelon and Grynpas 2008) with permission

As minor constituents (<~5 %), natural CaPO4 (both apatites and phosphorites) occur in many geological environments. Concentrations sufficient for economic use (>15 %) are also available. Namely, the largest world deposits of natural apatites are located in Russia [the Khibiny and Kovdor massifs, Kola peninsula (Lapin and Lyagushkin 2014; Tyrrell 1938; Kogarko 1999)], Brazil and Zambia, while the largest world deposits of natural phosphorites are located in Morocco, Russia, Kazakhstan, USA (Florida, Tennessee), China and Australia (McConnell 1973; Becker 1989; Rakovan and Pasteris 2015; Cook et al. 2005). In addition, they are found at seabed and ocean floor (Baturin 2012). There is an opinion, that the marine phosphorites could be formed due to microbial activity (Schulz and Schulz 2005; Crosby and Bailey 2012). The majority of natural CaPO4 occur as small polycrystalline structures (spherulitic clusters). Larger crystals are rare (Ford 1917). They usually have the crystal structure of apatites (hexagonal system, space group P63/m). Giant crystals including “a solid but irregular mass of green crystalline apatite, 15 feet long and 9 feet wide” (Hogarth 1974) and a single euhedral crystal from the Aetna mine measuring 2.1 × 1.2 m with an estimated weight of 6 tons (van Velthuizen 1992) were found. None of them is a pure compound; they always contain dopants of other elements. For example, ions of orthophosphate may be partly replaced by AsO4 3−, CO3 2− and VO4 3− (Trueman 1966), ions of calcium might be partially replaced by Sr, Ba, Mg, Mn, K, Na, Fe, while ions of hydroxide, chloride, bromide, carbonate and oxide may to a certain extent substitute fluoride in the crystal lattice of natural apatites (Pan and Fleet 2002). Furthermore, organic compounds have been found in natural apatites (Gilinskaya 2010; Gilinskaya and Zanin 2012). In principle, the crystal structure of apatites can incorporate half the Periodic Chart of the elements in almost any valence state into its atomic arrangement. Namely, substituents such as the first row transition elements and the lanthanides (they act as activators and chromophores) impart colors and can lead to luminescence. Furthermore, crystal imperfections, such as site vacancies, vacancies with trapped electrons and point defect clusters, can likewise influence both color and luminescence (Rakovan and Pasteris 2015). The substitutions in apatites are usually in trace concentrations; however, for certain dopants (e.g., F and OH) large concentrations and even complete solid solutions exist. To make things even more complicated, some ions in the crystal structure may be missing, leaving the crystallographic defects, which leads to formation of non-stoichiometric compounds, such as CDHA. Due to their affinity for chromophoric substituents and propensity for other defects, natural apatites are found in just about all colors of the rainbow. Ease of atomic substitution for apatite leaves this mineral open to a wide array of compositions. This might be related to the fact that the apatite structure type displays porous properties (White et al. 2005). In medicine, this property might be used as an antidote for heavy metal intoxication (Sánchez-Salcedo et al. 2010). Figure 2 shows some examples of natural FA.
Fig. 2

Samples of natural FA: (a) polycrystalline, (b) single-crystalline and (c) a gem. The colors are due to incorporated ions of transition metals

Manufacturing of elementary phosphorus (white and red) (Jacob and Reynolds 1928; Emsley 2001), phosphoric acids (Becker 1989; Dorozhkin 1996, 1997, 1998; Gilmour 2014), various P-containing chemicals, agricultural fertilizers [namely, superphosphate (Copson et al. 1936; Newton and Copson 1936; Rossete et al. 2008), ammonium orthophosphates (Magda et al. 2008)] and detergents [principally sodium tripolyphosphate (Kijkowska et al. 2007)] are the major industrial applications of natural CaPO4. The annual consumption of a phosphate rock has approached ~150 million tons and about 95 % of this production is utilized in the fertilizer industry (Abouzeid 2007, 2008). However, the significance of CaPO4 to the society is by no means limited to their role as a source of phosphorus; all currently available applications have been summarized in Table 2 (Rakovan and Pasteris 2015).
Table 2

The principal technological and scientific uses of apatites and other calcium orthophosphates (Rakovan and Pasteris 2015)


Properties utilized


 Petrogenetic indicator

Major- and trace-element composition

 Geochronology (dating)

Radionuclide composition, fission tracks

 Ore of phosphorus and rare earth elements

Composition (P and rare earth elements)


 Heavy metal and phosphate sequestration

Elemental affinity, chemical stability, insolubility

 Solid nuclear waste form

Thermal and chemical stability, annealing temperature, elemental affinity

 Water treatment

Elemental affinity, deflocculant


Constituent phosphate



Natural constituent of bones


Natural constituent of teeth

 Nanoparticle drug delivery agent

Size, morphology, structure, solubility, biocompatibility

 Prosthetic coating, bone and tooth replacement media

Compositional and structural similarity to mineral in bones and teeth



Optical emission


Optical emission and lasing behavior


Color, diaphaneity, chatoyancy

In biological systems, many organisms, ranging from bacteria and isolated cells to invertebrates and vertebrates, synthesize CaPO4 (Omelon and Grynpas 2008). Formation of solid CaPO4 in primitive organisms is believed to enable the storage and regulation of essential elements such as calcium, phosphorus and, possibly, magnesium. The morphology of precipitates in these organisms (small intracellular nodules of ACP often located in mitochondria) complies with the necessities for rapid mobilization and intracellular control of the concentration of these elements (Rey et al. 2006). In vertebrates CaPO4 occur as the principal inorganic constituent of normal (bones, teeth, fish enameloid, deer antlers and some species of shells) and pathological (dental and urinary calculus and stones, atherosclerotic lesions, etc.) calcifications (Lowenstam and Weiner 1989; O’Neill 2007; LeGeros 2001; Wopenka and Pasteris 2005; Pasteris et al. 2008; Sun and Hanley 2007). In addition, they are found in ganoid fish scales (in alligator gar and Senegal bichir), turtle shells, as well as in armadillo and alligator osteoderms (Currey 2010). In minute quantities CaPO4 exist in the brain (brain sand), without significantly affecting its function (Bocchi and Valdre 1993). Therefore, the expression “having sand in the head” is not without a reason. Except for small portions of the inner ear, all hard tissues of the human body are formed of CaPO4. Structurally, they occur mainly in the form of poorly crystalline, non-stoichiometric, Na-, K-, Mg- and carbonate-containing CDHA (Young 1975; Danilchenko 2013). It is often called “biological apatite” (Young 1975; Danilchenko 2013; Nakano et al. 2002a; Grynpas and Omelon 2007; Bazin et al. 2014a) [which might be abbreviated as BAp (Lee et al. 2009; Basaruddin and Takano 2014)], bioapatite (Eagle et al. 2010; Cherkinsky et al. 2013; Šupová 2014) or dahllite (Lowenstam and Weiner 1985; Fernandez et al. 1998). The latter was named in 1888 by Brögger and Bäckström (1890) after the Swedish mineralogist brothers Tellef and Johan Martin Dahll.

The main constituents of human bones are CaPO4 (~60–70 wt%), collagen (~20–30 wt%) and water (up to 10 wt%) (Bocchi and Valdre 1993; Skinner 2005; Daculsi et al. 1997). An interesting cautionary tale on the knowledge development about the structurally incorporated water in bone apatite is available in literature (Pasteris 2012). The detailed information on the chemical composition of the most important human normal calcified tissues is comprised in Table 3. One should note that the values mentioned in Table 3 are approximate; the main constituents can vary by a percent or more (Driessens and Verbeeck 1990). Due to the aforementioned effect of lattice flexibility, bones act as both the mineral reservoir of the body and the storage for toxic elements, thus fulfilling two of its essential physiological roles.
Table 3

Comparative composition and structural parameters of inorganic phases of adult human calcified tissues







Composition (wt%)







 Phosphorus (as P)a






 Ca/P (molar ratio)a





















 Carbonate (as CO3 2−)b








Up to 0.9







 Pyrophosphate (as P2O7 4−)b





 Total inorganicb






 Total organicb










Crystallographic properties: lattice parameters (±0.003 Å)

 a-axis (Å)






 c-axis (Å)






 Crystallinity index (HA = 100)






 Typical crystal sizes (nm) (Lowenstam and Weiner 1989; Weiner and Wagner 1998)

100 µm × 50 × 50

35 × 25 × 4


50 × 25 × 4


 Ignition products (800 °C)

β-TCP + HA

β-TCP + HA

β-TCP + HA

β-TCP + HA


 Elastic modulus (GPa)


23.8 ± 3.7

15.0 ± 3.6



 Tensile strength (MPa)






Due to the considerable variation found in biological samples, typical values are given in these cases (LeGeros 1991; Daculsi et al. 1997)

aAshed samples

bUnashed samples

cNumerical values were not found in the literature but they should be similar to those for dentine

Finally, one should mention, that, in a dissolved state, CaPO4 are found in many biological liquids, such as blood serum (Floege et al. 2011), urine (Suller et al. 2005), sweat (Prompt et al. 1978), and milk (Holt 1982) (Lenton et al. 2015) and, therefore, in dairy products (Gaucheron 2012).

The members of CaPO4 family

In the ternary aqueous system Ca(OH)2–H3PO4–H2O (or CaO–P2O5–H2O) (Clark 1931; Brown 1992; Martin and Brown 1997), there are twelve known non-ion-substituted CaPO4 with the Ca/P molar ratio ranging between 0.5 and 2.0 (Table 1). An anhydrous phase diagram CaO–P2O5 at temperatures within 200–2200 °C is shown in Fig. 3 (Kreidler and Hummel 1967; Carayon and Lacout 2003). Table 4 comprises crystallographic data of the existing CaPO4 (Elliott 1994; White and Dong 2003; Mathew and Takagi 2001). The most important parameters of CaPO4 are the ionic Ca/P ratio, basicity/acidity and solubility. All these parameters strongly correlate with the solution pH. The lower the Ca/P molar ratio is, the more acidic and water-soluble the CaPO4 is (LeGeros 1991; Elliott 1994; Amjad 1997). Therefore, the Ca/P ratio can be used as a fingerprint of the CaPO4 phases. One can see that the solubility ranges from high values for acidic compounds, such as MCPM, to very low values for basic compounds, such as apatites, which allowing CaPO4 to be dissolved, transported from one place to another and precipitated, when necessary. Crystallization, dissolution and phase transformation processes of different CaPO4 under various experimental conditions have been reviewed (Wang and Nancollas 2008). Regarding applications, some of them might be used in food industry and, according to the European classification of food additives, CaPO4 of food grade quality are known as E341 additive.
Fig. 3

Phase diagram of the system CaO–P2O5 (C=CaO, P=P2O5) at elevated temperatures. Here: C7P5 means 7CaO·5P2O5; other abbreviations should be written out in the same manner. Reprinted from Refs. (Kreidler and Hummel 1967; Carayon and Lacout 2003) with permission

Table 4

Crystallographic data of calcium orthophosphates (Elliott 1994; White and Dong 2003; Mathew and Takagi 2001)


Space group

Unit cell parameters

Z a

Density (g cm−3)


Triclinic P \( \bar{1} \)

a = 5.6261 (5), b = 11.889 (2), c = 6.4731 (8) Å, α = 98.633 (6)º, β = 118.262 (6)º, γ = 83.344 (6)º




Triclinic P \( \bar{1} \)

a = 7.5577 (5), b = 8.2531 (6), c = 5.5504 (3) Å, α = 109.87 (1)º, β = 93.68 (1)º, γ = 109.15 (1)º




Monoclinic Ia

a = 5.812 (2), b = 15.180(3), c = 6.239 (2) Å, β = 116.42 (3)º




Triclinic P \( \bar{1} \)

a = 6.910 (1), b = 6.627 (2), c = 6.998 (2) Å, α = 96.34 (2)º, β = 103.82 (2)º, γ = 88.33 (2)º




Triclinic P \( \bar{1} \)

a = 19.692 (4), b = 9.523 (2), c = 6.835 (2) Å, α = 90.15 (2)º, β = 92.54 (2)º, γ = 108.65 (1)º




Monoclinic P21/a

a = 12.887 (2), b = 27.280 (4), c = 15.219 (2) Å, β = 126.20 (1)º




Rhombohedral R3cH

a = b = 10.4183 (5), c = 37.3464 (23) Å, γ = 120°




Monoclinic P21/b or hexagonal P63/m

a = 9.84214 (8), b = 2a, c = 6.8814 (7) Å, γ = 120° (monoclinic)

a = b = 9.4302 (5), c = 6.8911 (2) Å, γ = 120º (hexagonal)





Hexagonal P63/m

a = b = 9.367, c = 6.884 Å, γ = 120º




Hexagonal P \( \overline{6} \)

a = b = 9.432, c = 6.881 Å, α = 90.3°, β = 90.0°, γ = 119.9°




Monoclinic P21

a = 7.023 (1), b = 11.986 (4), c = 9.473 (2) Å, β = 90.90 (1)º



aNumber of formula units per unit cell

bPer the hexagonal unit cell

Due to the triprotic equilibrium that exists within orthophosphate-containing solutions, variations in pH alter the relative concentrations of the four types of anionic species of orthophosphoric acid (Fig. 4; Lynn and Bonfield 2005) and thus both the chemical composition (Fig. 5; León and Jansen 2009) and the amount of the CaPO4 that are formed by a direct precipitation. The solubility isotherms of different CaPO4 are shown in Fig. 6 (Elliott 1994; Amjad 1997; Brown 1992; Martin and Brown 1997; McDowell et al. 1977; Chow 2009; Ishikawa 2010). However, in 2009, the classic solubility data of CaPO4 (Elliott 1994; Amjad 1997; Brown 1992; Martin and Brown 1997; McDowell et al. 1977; Chow 2009; Ishikawa 2010) were mentioned to be inappropriate (Pan and Darvell 2009a). According to the authors of the latter study, all previous solubility calculations were based on simplifications, which were only crudely approximate. The problem lies in incongruent dissolution, leading to phase transformations and lack of the detailed solution equilibria. Using an absolute solid-titration approach, the true solubility isotherm of HA was found to lie substantially lower than previously reported. In addition, contrary to a wide belief, DCPD appeared not to be the most stable phase below pH ~4.2, where CDHA was less soluble (Pan and Darvell 2009a).
Fig. 4

pH variation of ionic concentrations in triprotic equilibrium for orthophosphoric acid solutions. Reprinted from Ref. (Lynn and Bonfield 2005) with permission

Fig. 5

Various types of CaPO4 obtained by neutralizing of orthophosphoric acid by calcium hydroxide. The Ca/P values of the known types of CaPO4 (Table 1) are reported in the figure. The solubility of CaPO4 in water decreases drastically from left to right, HA being the most insoluble and stable phase. Reprinted from Ref. (León and Jansen 2009) with permission

Fig. 6

Top: a 3D version of the classical solubility phase diagrams for the ternary system Ca(OH)2–H3PO4–H2O. Reprinted from Ref. (Chow 2009) with permission. Middle and bottom: solubility phase diagrams in two-dimensional graphs, showing two logarithms of the concentrations of (a) calcium and (b) orthophosphate ions as a function of the pH in solutions saturated with various salts. Reprinted from Ref. (Ishikawa 2010) with permission

A brief description of all known CaPO4 (Table 1) is given below.


Monocalcium phosphate monohydrate [Ca(H2PO4)2·H2O; the IUPAC name is calcium dihydrogen orthophosphate monohydrate] is both the most acidic and water-soluble CaPO4. Although acidic CaPO4 in general were known by 1795 as “super-phosphate of lime” (Fourcroy 1804), their differentiation started in 1800s. Namely, by 1807, researchers first prepared a calcium phosphate, which could be attributed to MCPM (Aikin and Aikin 1807).

MCPM crystallizes from aqueous solutions containing dissolved ions of H2PO4 and Ca2+ at the Ca/P ratio ~0.5 and solution pH below ~2.0. Besides, MCPM might be precipitated from aqueous solutions containing organic solvents (Boonchom 2009; Kongteweelert et al. 2013). At temperatures above ~100 °C, MCPM releases a molecule of water and transforms into MCPA but at temperatures >~500 °C MCPA further transforms into Ca(PO3)2 (Tynsuaadu 1990). The results of the spectroscopic investigations of MCPM are available in literature (Xu et al. 1998).

Due to high acidity and solubility, MCPM is never found in biological calcifications. Moreover, pure MCPM is not biocompatible with bones (Köster et al. 1977). However, in medicine MCPM is used as a component of several self-hardening CaPO4 formulations (Huan and Chang 2009; Dorozhkin 2013b). In addition, MCPM is used as a nutrient, acidulant and mineral supplement for food, feed and some beverages (Budavari et al. 1996; Stein et al. 2008). Coupled with NaHCO3, MCPM is used as a leavening agent for both dry baking powders and bakery dough. MCPM might be added to salt-curing preserves, pickled and marinated foods. In addition, MCPM might be added to tooth pastes and chewing gums (Dorozhkin 2013c). Besides, MCPM might be added to ceramics and glasses, while agriculture is the main consumer of a technical grade MCPM, where it is used as a fertilizer, triple superphosphate (Nasri et al. 2015).


Monocalcium phosphate anhydrous [Ca(H2PO4)2; the IUPAC name is calcium dihydrogen orthophosphate anhydrous] is the anhydrous form of MCPM. Although MCPM has been known since 1807 (Dorozhkin 2012a, 2013a), MCPA was differentiated as “tetra-hydrogen calcium phosphate, H4Ca(PO4)2” by 1879 (Roscoe and Schorlemmer 1879). It crystallizes under the same conditions as MCPM but at temperatures above ~100 °C (e.g., from concentrated hot mother liquors during fertilizer production). In addition, MCPA might be prepared from MCPM by dehydration. Furthermore, it might be also prepared at ambient temperatures by crystallization in water-restricted or non-aqueous systems. Like MCPM, MCPA never appears in calcified tissues and is not biocompatible due to its acidity. There is no current application of MCPA in medicine. Due to the similarity with MCPM, in many cases, MCPA might be used instead of MCPM; however, highly hydroscopic properties of MCPA reduce its commercial applications (Becker 1989; Budavari et al. 1996).


Dicalcium phosphate dihydrate [CaHPO4·2H2O; the IUPAC name is calcium hydrogen orthophosphate dihydrate; the mineral brushite] has been known since, at least, 1804 (Fourcroy 1804). As a mineral, brushite was first discovered in phosphatic guano from Avis Island (Caribbean) in 1865 (Moore 1865) and named to honor an American mineralogist Prof. George Jarvis Brush (1831–1912), Yale University, New Haven, Connecticut, USA.

DCPD can be easily crystallized from aqueous solutions containing dissolved ions of HPO4 2− and Ca2+ at the Ca/P ratio ~1 and solution pH within ~2.0 < pH < ~6.5 (Hamai et al. 2013). Other preparation techniques such as neutralization of H3PO4 and/or MCPM solutions by CaO, CaCO3 or more basic CaPO4 (α- or β-TCP, CDHA, HA, TTCP) are also known. Interestingly, that precipitation of DCPD by mixing a Ca(OH)2 suspension and a H3PO4 solution in the equimolar quantities was found to occur in five stages, being HA the first precipitated phase (Ferreira et al. 2003; Oliveira et al. 2007). Besides, DCPD might be prepared in gels (Sivkumar et al. 1997; Madhurambal et al. 2009). DCPD transforms into DCPA at temperatures above ~80 °C and this transformation is accompanied by ~11 % decrease in volume (MacDowell et al. 1971) and structural changes (Landin et al. 1994). The value for Δ r G° for DCPD → DCPA transformation is −1.032 kJ/mol (Landin et al. 1994). Briefly, DCPD crystals consist of CaPO4 chains arranged parallel to each other, while lattice water molecules are interlayered between them (Curry and Jones 1971). Liquid ordering at the {010} DCPD/water interface was determined (Arsic et al. 2004). In 2009, data on DCPD solubility were updated by solid titration technique (Pan and Darvell 2009b). The optical properties of DCPD were described (Lundager-Madsen 2008), while many additional data on DCPD including a good drawing of its atomic structure might be found in Ref. (Qiu and Orme 2008).

DCPD is of biological importance because it is often found in pathological calcifications (dental calculi, crystalluria, chondrocalcinosis and urinary stones) and some carious lesions (LeGeros 1991, 2001; O’Neill 2007). It was proposed as an intermediate in both bone mineralization and dissolution of enamel in acids (dental erosion) (LeGeros 1991, 2001; O’Neill 2007). In medicine, DCPD is used in self-setting CaPO4 formulations (Dorozhkin 2013b) and as an intermediate for tooth remineralization. DCPD is added to toothpaste both for caries protection (in this case, it is often coupled with F-containing compounds such as NaF and/or Na2PO3F) and as a gentle polishing agent (Dorozhkin 2013c). Other applications include a flame retardant (Mostashari et al. 2006), a slow release fertilizer, using in glass production, as well as calcium supplement in food, feed and cereals. In food industry, it serves as a texturizer, bakery improver and water retention additive. In diary industry, DCPD is used as a mineral supplement. In addition, plate-like crystals of DCPD might be used as a non-toxic, anticorrosive and passivating pigment for some ground coat paints (Budavari et al. 1996).


Dicalcium phosphate anhydrous (CaHPO4; the IUPAC name is calcium hydrogen orthophosphate anhydrate; the mineral monetite) is the anhydrous form of DCPD. Although DCPD has been known since, at least, 1804 (Dorozhkin 2012a, 2013a), DCPA was differentiated as “mono-hydrogen CaPO4, HCaPO4” by 1879 (Roscoe and Schorlemmer 1879). As a mineral, monetite was first described in 1882 in rock-phosphate deposits from the Moneta (now Monito) Island (archipelago of Puerto Rico), which contains a notable occurrence (Shepard 1882).

Due to the absence of water inclusions, DCPA is less soluble than DCPD (Table 1). Like DCPD, DCPA can be crystallized from aqueous solutions containing Ca/P ratio ~1 at solution pH within ~2.0 < pH < ~6.5 but at temperatures >~90 °C. In addition, DCPA might be prepared by dehydration of DCPD. Furthermore, it might be also prepared at ambient temperatures in water-restricted or non-aqueous systems, such as gels (Sivkumar et al. 1997), ethanol (Tas 2009), as well as in the oil-in-water and water-in-oil systems (Chen et al. 2005). DCPA is physically stable and resisted hydration even when dispersed in water for over 7 months in the temperature range of 4–50 °C (Miyazaki et al. 2009). A calcium-deficient DCPA was also prepared. It might be sintered at ~300 °C (Eshtiagh-Hosseini et al. 2008). Unlike DCPD, DCPA occurs in neither normal nor pathological calcifications. It is used in self-setting CaPO4 formulations (Dorozhkin 2013b). Besides, DCPA might be implanted as bioceramics (Tamimi et al. 2010). Other applications include using as a polishing agent, a source of calcium and phosphate in nutritional supplements (e.g., in prepared breakfast cereals, enriched flour and noodle products), a tableting aid (Takami et al. 1996) and a toothpaste component (Dorozhkin 2013c). In addition, it is used as a dough conditioner in food industry (Budavari et al. 1996). DCPA of a technical grade of purity might be used as a fertilizer (Habashi 2011).


Octacalcium phosphate [Ca8(HPO4)2(PO4)4·5H2O; the IUPAC name is tetracalcium hydrogen orthophosphate diorthophosphate pentahydrate, another name is octacalcium bis(hydrogenphosphate) tetrakis(phosphate) pentahydrate] is often found as an unstable transient intermediate during the precipitation of the thermodynamically more stable CaPO4 (e.g., CDHA) in aqueous solutions. To the best of my findings (Dorozhkin 2012a, 2013a), OCP has been known since, at least, 1843, when Percy published a paper (Percy 1843), in which he described formation of “a new hydrated phosphate of lime” with a chemical formula 2CaO + PO5 + 6HO, in which “1 equiv. water being basic and 5 constitutional”. However, according to Bjerrum (Bjerrum 1958), a CaPO4 with the OCP composition was first described by Berzelius in 1836.

The preparation techniques of OCP are available in literature (LeGeros 1985; Nakahira et al. 2001; Arellano-Jiménez et al. 2009; Suzuki 2010a). Briefly, to prepare OCP, Ca- and PO4-containing chemicals must be mixed to get the supersaturated aqueous solutions with the Ca/P ratio equal to 1.33. Typically, OCP crystals are smaller if compared to DCPD ones, extremely platy and almost invariably twinned. However, OCP might be non-stoichiometric and be either Ca-deficient (down to Ca/P = 1.26) or include excessive calcium (up to Ca/P = 1.48) in the structure (Suzuki 2010a). It has been proposed that the structure of a non-stoichiometric OCP contains an excess of hydrogen, resulting in a non-stoichiometric chemical formula Ca16H4+x (PO4)12(OH) x ·(10 − x)H2O, which resembles the structure of HA even more closely than previously anticipated (Mathew et al. 1988). Furthermore, a partially hydrolyzed form of OCP with Ca/P molar ratio of 1.37 might be prepared (Suzuki 2010a; Miyatake et al. 2009). At solution pH = 7.2 and temperature 60 °C, the full hydrolysis of OCP into CDHA occurs within ~6 h (Arellano-Jiménez et al. 2009). Ion-substituted OCP might be prepared as well (Matsunaga 2008a; Boanini et al. 2010a).

The triclinic structure of OCP displays apatitic layers (with atomic arrangements of calcium and orthophosphate ions similar to those of HA) separated by hydrated layers (with atomic arrangements of calcium and orthophosphate ions similar to those in DCPD) (LeGeros 1991; Elliott 1994; Amjad 1997; Suzuki 2010a). A similarity in crystal structure between OCP and HA (Brown 1962; Brown et al. 1962) is one reason that the epitaxial growth of these phases is observed. It is generally assumed that, in solutions, the hydrated layer of the (100) face is the layer most likely exposed to solution. The water content of OCP crystals is ~20 % that of DCPD and this is partly responsible for its lower solubility. The latest data on OCP structure (Davies et al. 2012) and solubility (Pan and Darvell 2009c) are available.

OCP is of a great biological importance because it is one of the stable components of human dental and urinary calculi (Chow and Eanes 2001; Kakei et al. 2009). OCP was first proposed by W. E. Brown to participate as the initial phase in enamel mineral formation and bone formation through subsequent precipitation and stepwise hydrolysis of OCP (Brown 1962, 1966; Brown et al. 1962). It plays an important role in formation of apatitic biominerals in vivo (Suzuki 2010b). A “central OCP inclusion” (also known as “central dark line”) is seen by transmission electron microscopy in many biological apatites and in synthetically precipitated CDHA (Iijima et al. 1996; Bodier-Houllé et al. 1998; Rodríguez-Hernández et al. 2005). Although OCP has not been observed in vascular calcifications, it has been strongly suggested as a precursor phase to biological apatite found in natural and prosthetic heart valves (Tomazic et al. 1994; Nancollas and Wu 2000). In surgery, OCP is used for implantation into bone defects (Suzuki et al. 2006; Kikawa et al. 2009; Murakami et al. 2010; Suzuki 2013). For the comprehensive information on OCP, the readers are referred to other reviews (Suzuki 2010a; Chow and Eanes 2001; Suzuki 2013).


β-tricalcium phosphate [β-Ca3(PO4)2; the IUPAC name is tricalcium diorthophosphate beta, other names are CaPO4 tribasic beta or tricalcium bis(orthophosphate) beta] is one of the polymorphs of TCP. Although CaPO4 with the composition close to that of TCP, CDHA and HA were known in 1770s (Dorozhkin 2012a, 2013a), α- and β-polymorphs of TCP were differentiated only by 1932 (Bredig et al. 1932; Trömel 1932).

β-TCP cannot be precipitated from aqueous solutions. It is a high-temperature phase, which can be prepared at temperatures above ~800 °C by thermal decomposition of CDHA or by solid-state interaction of acidic CaPO4, e.g., DCPA, with a base, e.g., CaO. In all cases, the chemicals must be mixed in the proportions to get the Ca/P ratio equal to 1.50. However, β-TCP can also be prepared at relatively low temperatures (~150 °C) by precipitation in water-free mediums, such as ethylene glycol (Tao et al. 2008, 2009). Apart from the chemical preparation routes, ion-substituted β-TCP can be prepared by calcining of bones (Hou et al. 2008; Santos et al. 2012): such type of CaPO4 is occasionally called “bone ash” (Lee et al. 2013). At temperatures above ~1125 °C, β-TCP is transformed into a high-temperature phase α-TCP. Being the stable phase at room temperature, β-TCP is less soluble in water than α-TCP (Table 1). Both ion-substituted (Ito and LeGeros 2008; Kannan et al. 2009, 2010; Quillard et al. 2012) and organically modified (Karlinsey and Mackey 2009; Karlinsey et al. 2010a, b) forms of β-TCP can be synthesized, as well. The modern structural data on β-TCP are available in Refs. (Yashima et al. 2003; Yin et al. 2003; Liang et al. 2010; Zhai and Wu 2010), Raman spectra of β-TCP might be found if Ref. (Zhai et al. 2015), while solubility data—in Ref. (Pan and Darvell 2009d). Furthermore, an ability of β-TCP to store an electrical charge by electrical polarization was studied and this material was found to have a suitable composition and structure for both ion conduction and charge storage (Wang et al. 2010).

Pure β-TCP never occurs in biological calcifications. Only a Mg-substituted form [β-TCMP—β-tricalcium magnesium phosphate, β-(Ca,Mg)3(PO4)2, which is often called whitlockite to honor Mr. Herbert Percy Whitlock (1868–1948), an American mineralogist, the curator of the American Museum of Natural History, New York City, New York, USA (Frondel 1941)] is found. Since β-TCMP is less soluble than β-TCP (Li et al. 2009a), it is formed instead of β-TCP in dental calculi and urinary stones, dentineal caries, salivary stones, arthritic cartilage, as well as in some soft-tissue deposits (LeGeros 1991, 2001; O’Neill 2007; Kodaka et al. 1988; Reid and Andersen 1993; Scotchford and Ali 1995; P’ng et al. 2008). However, it has not been observed in enamel, dentine or bone. In medicine, β-TCP is used in the self-setting CaPO4 formulations (Dorozhkin 2013b) and other types of bone grafts (Hou et al. 2008; Horch et al. 2006; Ogose et al. 2006; Kamitakahara et al. 2008; Liu et al. 2008; Epstein 2009; Liu and Lun 2012). Dental applications of β-TCP are also known. For example, β-TCP is added to some brands of toothpaste as a gentle polishing agent (Dorozhkin 2013c). Multivitamin complexes with CaPO4 are widely available in the market and β-TCP is used as the calcium phosphate there. In addition, β-TCP serves as a texturizer, bakery improver and anti-clumping agent for dry powdered food (flour, milk powder, dried cream, cocoa powder). Besides, β-TCP is added as a dietary or mineral supplement to food and feed (Güngörmüş et al. 2010). Occasionally, β-TCP might be used as inert filler in pelleted drugs. Other applications comprise porcelains, pottery, enamel, using as a component for mordants and ackey, as well as a polymer stabilizer (Budavari et al. 1996). β-TCP of a technical grade (as either calcined natural phosphorites or bone dust) is used as a slow release fertilizer for acidic soils (Becker 1989).

To conclude, one should briefly mention on an existence of γ-TCP polymorph, naturally known as tuite, which was named after Prof. Guangzhi Tu (born in 1920), a founding director of the Guangzhou Institute of Geochemistry, Chinese Academy of Sciences, Guangzhou, China. Tuite appears to be a high-pressure polymorph of whitlockite with an empirical formula \( {\text{Ca}}_{ 2. 5 1} {\text{Na}}_{0. 2 8} {\text{Mg}}_{0. 2 7} {\text{Fe}}_{0.02}^{2 + } \left( {{\text{PO}}_{ 4} } \right)_{ 2.0 2} \). Pure γ-TCP polymorph can be synthesized from β-TCP at pressures above ~4 GPa and temperatures above ~1000 °C (Murayama et al. 1986; Xie et al. 2003; Zhai et al. 2009, 2014).


α-Tricalcium phosphate [α-Ca3(PO4)2; the IUPAC name is tricalcium diorthophosphate alpha, other names are CaPO4 tribasic alpha or tricalcium bis(orthophosphate) alpha] is another polymorph of TCP, which was differentiated by 1932 (Bredig et al. 1932; Trömel 1932). α-TCP is also a high-temperature phase; therefore, it cannot be precipitated from aqueous solutions either. Thus, α-TCP is usually prepared by the same techniques as β-TCP (see the previous section) but, since the β-TCP → α-TCP transition temperature is ~1125 °C (Welch and Gutt 1961), calcining is performed at temperatures above ~1200 °C (Jokic et al. 2007). Consequently, α-TCP is often considered as a high-temperature polymorph of β-TCP. However, data are available that α-TCP might be prepared at lower temperatures. Namely, at the turn of the millennium, the previously forgotten data that the presence of silicates stabilized α-TCP at temperatures of 800–1000 °C (Nurse et al. 1959) were rediscovered again. Such type of α-TCP is called “silica stabilized α-TCP” (Sayer et al. 2003; Reid et al. 2005, 2006). Furthermore, sometimes, α-TCP might be prepared at even lower temperatures (~700 °C) by a thermal decomposition of low-temperature ACPs (Kanazawa et al. 1982).

Although α-TCP and β-TCP have exactly the same chemical composition, they differ by the crystal structure (Table 4) and solubility (Table 1). In the absence of humidity, both polymorphs of TCP are stable at room temperatures; however, according to a density functional study, stability of β-TCP crystal lattice exceeds that of α-TCP (Yin et al. 2003). Therefore, of them, α-TCP is more reactive in aqueous systems, has a higher specific energy and in aqueous solutions it can be hydrolyzed to CDHA (TenHuisen and Brown 1998; Durucan and Brown 2000, 2002). Milling was found to increase the α-TCP reactivity even more (Camiré et al. 2005). Although, α-TCP never occurs in biological calcifications, in medicine, it is used as a component of self-setting CaPO4 formulations (Budavari et al. 1996). On the other hand, the chemically pure α-TCP has received not much interest in the biomedical field (Kamitakahara et al. 2008). The disadvantage for using α-TCP is its quick resorption rate (faster than formation of a new bone), which limits its application in this area. However, the silicon stabilized α-TCP (more precisely as a biphasic composite with HA) has been commercialized as a starting material to produce bioresorbable porous ceramic scaffolds to be used as artificial bone grafts (Sayer et al. 2003; Reid et al. 2005, 2006). Upon implantation, α-TCP tends to convert to CDHA, which drastically reduces further degradation rate. Theoretical insights into bone grafting properties of the silicon-stabilized α-TCP might be found in Ref. (Yin and Stott 2005). The structure of α-TCP is well described in literature (Yin et al. 2003; Liang et al. 2010), while the surface and adsorption properties are available in Ref. (Yin and Stott 2006). Similar to β-TCP, α-TCP of a technical grade might be used slow release fertilizer for acidic soils (Budavari et al. 1996).

To conclude, one should briefly mention on an existence of α′-TCP polymorph, which was discovered in 1959 (Nurse et al. 1959). However, this TCP polymorph lacks of any practical interest because it only exists at temperatures between ~1450 °C and its melting point (~1756 °C). It reverts to α-TCP polymorph by cooling below the transition temperature. Additional details on α-TCP are available in the topical review (Carrodeguas and de Aza 2011).


Amorphous calcium phosphates (ACPs) represent a special class of CaPO4 salts, having variable chemical but rather identical glass-like physical properties, in which there are neither translational nor orientational long-range orders of the atomic positions. To the best of my findings (Dorozhkin 2012a, 2013a), ACP was first prepared in 1845 (Jones 1845). Nevertheless, until recently (Dorozhkin 2012c), ACP has often been considered as an individual CaPO4 compound with a variable chemical composition, while, in reality, ACP is just an amorphous state of other CaPO4. Therefore, in principle, all compounds mentioned in Table 1 might be somehow fabricated in an amorphous state but, currently, only few of them (e.g., an amorphous TCP) are known (Dorozhkin 2012c). Thus, strictly speaking, ACP should be excluded from Table 1. Furthermore, since ACPs do not have the definite chemical composition, the IUPAC nomenclature is not applicable to describe them.

Depending on the production temperatures, all types of ACP are divided into two major groups: low-temperature ACPs (prepared in solutions, usually aqueous ones) and high-temperature ACPs (Dorozhkin 2012c). Low-temperature ACPs (described by the chemical formula Ca x H y (PO4) z ·nH2O, n = 3–4.5; 15–20 % H2O) are often encountered as a transient precursor phase during precipitation of other CaPO4 in aqueous systems. Usually, an ACP is the first phase precipitated from supersaturated solutions (the higher supersaturation, the better) prepared by rapid mixing of solutions containing ions of calcium and orthophosphate (Elliott 1994; Dorozhkin 2012c). Such ACP precipitates usually look like spherical particles with diameters in the range 200–1200 Å without a definite structure. Generally, the ACP particles are smaller if prepared under conditions of high supersaturation and/or high pH, while for a given pH, higher temperatures give larger particles (Blumenthal et al. 1972). The freshly precipitated ACPs contain 10–20 % by weight of tightly bound water, which is removed by vacuum drying at elevated temperature (Posner and Betts 1975). The amorphization degree of ACPs increases with the concentration increasing of Ca- and PO4-containing solutions, as well as at a high solution pH and a low crystallization temperature. A continuous gentle agitation of as precipitated ACPs in the mother solution, especially at elevated temperatures, results in a slow recrystallization and formation of better crystalline CaPO4, such as CDHA (LeGeros 1991; Elliott 1994). In addition, other production techniques of ACPs are known (Dorozhkin 2012c).

The lifetime of ACPs in aqueous solutions was reported to be a function of the presence of additive molecules and ions, pH, ionic strength and temperature. In addition, confinement was found to increase their lifetime (Wang et al. 2014a). Thus, ACPs may persist for appreciable periods and retain the amporphous state under some specific experimental conditions (Termine et al. 1970). The chemical composition of ACPs strongly depends on the solution pH and the concentrations of mixing solutions. For example, ACPs with Ca/P ratios in the range of 1.18 (precipitated at solution pH = 6.6) to 1.53 (precipitated at solution pH = 11.7) (Elliott 1994, 1998) and even to 2.5 (LeGeros 1991, 2001; O’Neill 2007) were described. In deed and not in name, these data mean that various types of CaPO4 were prepared in an amorphous state (Dorozhkin 2012c). It should be noted that unsubstituted ACPs are unstable in aqueous solutions and even when stored dry they tend to transform into more crystalline CaPO4, such as poorly crystalline CDHA. The presence of poly(ethylene glycol) (Li and Weng 2007), ions of pyrophosphate, carbonate and/or magnesium in solutions during the crystallization promotes formation of ACPs and slows down their further transformation, while the presence of fluoride has the opposite effect (LeGeros 1991; Elliott 1994; Amjad 1997; Daculsi et al. 1997; Tadic et al. 2002). In general, low-temperatures ACPs heated to ~550 °C (so that all volatiles have already escaped) remain amorphous, but further heating above ~650 °C causes their transformation into crystalline CaPO4, such as α- or β-TCP, HA, mixtures thereof, depending on the Ca/P ratio of the ACP heated.

High-temperature ACPs might be prepared using high energy processing at elevated temperatures (Dorozhkin 2012c). This method is based on a rapid quenching of melted CaPO4 occurring, e.g., during plasma spraying of HA (Carayon and Lacout 2003; Keller and Dollase 2000; Kumar et al. 2004). A plasma jet, possessing very high temperatures (~5000 to ~20,000 °C), partly decomposes HA, which results in formation of a complicated mixture of products, some of which would be ACPs. Obviously, all types of high-temperature ACPs are definitively anhydrous contrary to the precipitated ACPs. Unfortunately, no adequate chemical formula is available to describe the high-temperature ACPs.

In general, as all amorphous compounds are characterized by a lack of long-range order, it is problematic to discuss the structure of ACPs (they are X-ray amorphous). Concerning a short-range order (SRO) in ACPs, it exists, just due to the nature of chemical bonds. Unfortunately, in many cases, the SRO in ACPs is uncertain either, because it depends on many variables, such as Ca/P ratio, preparation conditions, storage and admixtures. Infrared spectra of ACPs show broad featureless phosphate absorption bands. Electron microscopy of freshly precipitated ACPs usually shows featureless nearly spherical particles with diameters in the range of 20–200 nm. However, there is a questionable opinion that ACPs might have an apatitic structure but with a crystal size so small, that they are X-ray amorphous. This is supported by X-ray absorption spectroscopic data (EXAFS) on biogenic and synthetic samples (Harries et al. 1986, 1987; Taylor et al. 1998; Peters et al. 2000). On the other hand, it was proposed that the basic structural unit of the precipitated ACPs is a 9.5 Å diameter, roughly spherical cluster of ions with the composition of Ca9(PO4)6 (Fig. 7; Elliott 1994, 1998; Posner et al. 1980; Boskey 1997). These clusters were found experimentally as first nuclei during the crystallization of CDHA and a model was developed to describe the crystallization of HA as a step-wise assembly of these units (Onuma and Ito 1998) [see “HA (or HAp, or OHAp)”]. Biologically, ion-substituted ACPs (always containing ions of Na, Mg, carbonate and pyrophosphate) are found in soft-tissue pathological calcifications (e.g., heart valve calcifications of uremic patients) (LeGeros 1991, 2001; O’Neill 2007).
Fig. 7

A model of ACP structure. Reprinted from Ref. (Posner et al. 1980) with permission

In medicine, ACPs are used in self-setting CaPO4 formulations (Dorozhkin 2013b). Bioactive composites of ACPs with polymers have properties suitable for use in dentistry (Dorozhkin 2012c, 2013c) and surgery (Dorozhkin 2012c; Tadic and Epple 2002). Due to a reasonable solubility and physiological pH of aqueous solutions, ACPs appeared to be consumable by some microorganisms and, due to this reason, it might be added as a mineral supplement to culture media. Non-biomedical applications of ACPs comprise their using as a component for mordants and ackey. In food industry, ACPs are used for syrup clearing. Occasionally, they might be used as inert filler in pelleted drugs. In addition, ACPs are used in glass and pottery production and as a raw material for production of some organic phosphates. To get further details on ACPs, the readers are referred to special reviews (Dorozhkin 2012c; Boskey 1997; Combes and Rey 2010).

CDHA (or Ca-def HA, or CDHAp)

Calcium-deficient hydroxyapatite [Ca10-x (HPO4) x (PO4)6-x (OH)2-x (0 < x < 1)] became known since the earliest experiments on establishing the chemical composition of bones performed in 1770s (Dorozhkin 2012a, 2013a). However, the first appropriate term “subphosphate of lime” appeared by 1819 (Bache 1819). Other chemical formulae such as Ca10-x (HPO4)2x (PO4)6−2x (OH)2 (0 < x < 2), Ca10−xy (HPO4) x (PO4)6-x (OH)2−x−2y (0 < x < 2 and y < x/2), Ca10−x (HPO4) x (PO4)6−x (OH)2−x (H2O) x (0 < x < 1), and Ca9−x (HPO4)1+2x (PO4)5−2x (OH) were also proposed to describe its variable composition (Elliott 1994). As seen from these formulae, Ca deficiency is always coupled with both OH deficiency and protonation of some PO4 groups with simultaneous formation of the ionic vacancies in the crystal structure (Wilson et al. 2005). In addition, CDHA often contains tightly bound water molecules, which might occupy some of these ionic vacancies. For example, there is an approach describing a lack of the hydroxide vacancies in CDHA: to perform the necessary charge compensation of the missing Ca2+ ions, a portion of OH anions is substituted by neutral water molecules (Zahn and Hochrein 2008). This water is removed by vacuum drying at elevated temperature. Concerning possible vacancies of orthophosphate ions, nothing is known about their presence in CDHA. It is just considered that a portion of PO4 3− ions is either protonated (as HPO4 2−) or substituted by other ions (e.g., CO3 2−) (Ivanova and Frank-Kamenetskaya 2001). Since CDHA does not have any definite chemical composition, the IUPAC nomenclature is not applicable to describe it.

CDHA can be easily prepared by simultaneous addition of Ca- and PO4-containing solutions in the proportions to get Ca/P ratio within 1.50–1.67 into boiling water followed by boiling the suspension for several hours (an aging stage). That is why, in literature, it might be called as “precipitated HA (PHA)” (Sinha et al. 2003; Mayer et al. 2003). Besides, it might be prepared by hydrolysis of α-TCP (TenHuisen and Brown 1998; Durucan and Brown 2000, 2002). Other preparation techniques of CDHA are known as well (Vallet-Regí et al. 1997; Siddharthan et al. 2004; Hutchens et al. 2006; Mochales et al. 2011). During aging, initially precipitated ACPs are restructured and transformed into CDHA. Therefore, there are many similarities in the structure, properties and application between the precipitated in alkaline solutions (pH > 8) ACPs and CDHA. Some data indicated on a presence of intermediate phases during further hydrolysis of CDHA to a more stable HA-like phase (Brès et al. 2005). In general, CDHA crystals are poorly crystalline and of submicron dimensions. They have a very large specific surface area, typically 25–100 m2/g. On heating above ~700 °C, CDHA with Ca/P = 1.5 converts to β-TCP and that with 1.5 < Ca/P < 1.67 converts into a biphasic composite of HA and β-TCP (see “Biphasic, triphasic and multiphasic CaPO4 formulations”) (Dorozhkin 2012d). A solid-state transformation mechanism of CDHA into HA + β-TCP biocomposite was proposed (Dorozhkina and Dorozhkin 2002a; Dorozhkin 2003).

The variability in Ca/P molar ratio of CDHA has been explained through different models: surface adsorption, lattice substitution and intercrystalline mixtures of HA and OCP (Rodríguez-Lorenzo 2005). Due to a lack of stoichiometry, CDHA is usually doped by other ions (Rey et al. 2006). The doping extent depends on the counter-ions of the chemicals used for CDHA preparation. Direct determinations of the CDHA structures are still missing and the unit cell parameters remain uncertain. However, unlike that in ACPs (see “ACP”), a long-range order exists in CDHA. Namely, the following lattice parameters were reported for CDHA with Ca/P = 1.5: a = 9.4418 (20) Å and c = 6.8745 (17) Å (Mochales et al. 2011).

Systematic studies of defect constellations in CDHA are available in literature (Zahn and Hochrein 2008; Liou et al. 2004). As a first approximation, CDHA may be considered as HA with some ions missing (ionic vacancies) (Brown and Martin 1999). The more amount of Ca is deficient, the more disorder, imperfections and vacancies are in the CDHA structure (Honghui et al. 2007). Furthermore, a direct correlation between the Ca deficiency and the mechanical properties of the crystals was found: calcium deficiency lead to an 80 % reduction in the hardness and elastic modulus and at least a 75 % reduction in toughness in plate-shaped HA crystals (Viswanath et al. 2010). More recently, using first-principles calculations, a reduction in the elastic constants and moduli of CDHA due to vacancies was reported (Sun et al. 2013; Bhat et al. 2014). Theoretical investigations of the defect formation mechanism relevant to non-stoichiometry in CDHA are available elsewhere (Matsunaga 2008b).

Undoped CDHA (i.e., that containing ions of Ca2+, PO4 3−, HPO4 2− and OH only) does not exist in biological systems. However, the ion-substituted CDHA: Na+, K+, Mg2+, Sr2+ for Ca2+; CO3 2− for PO4 3− or HPO4 2−; F, Cl, CO3 2− for OH, plus some water forms biological apatite—the main inorganic part of animal and human normal and pathological calcifications (LeGeros 1991; Rey et al. 2006; O’Neill 2007). Therefore, CDHA is a very promising compound for industrial manufacturing of artificial bone substitutes (Bourgeois et al. 2003), including drug delivery applications (Liu et al. 2005). Non-biomedical applications of CDHA are similar to those of ACP and HA. Interesting that CDHA was found to possess a catalytic activity to produce biogasoline (Tsuchida et al. 2008).

HA (or HAp, or OHAp)

Hydroxyapatite [Ca5(PO4)3(OH), but is usually written as Ca10(PO4)6(OH)2 to denote that the crystal unit cell comprises two molecules; the IUPAC name is pentacalcium hydroxide tris(orthophosphate)] is the second most stable and least soluble CaPO4 after FA. Apatites were recognized as calcium phosphates by, at least, 1789 (Dorozhkin 2012a, 2013a). Here, it is worth noting that hydroxylapatite would be a more accurate abbreviation expansion of HA (perhaps, hydroxideapatite would be even better because it relates to calcium hydroxide) while by both the medical and material communities HA is usually expanded as hydroxyapatite.

Chemically pure HA crystallizes in the monoclinic space group P21/b (Elliott et al. 1973). However, at temperatures above ~250 °C, there is a monoclinic to hexagonal phase transition in HA (space group P63/m) (Elliott 1994, 1998; Mathew and Takagi 2001; Rangavittal et al. 2000; Kim et al. 2000a). The structural difference between the two modifications represents the ordered, head-to-tail arrangement of OH groups located in the center of every other Ca2 triangle in the monoclinic low-temperature symmetry and the disordered arrangement of OH groups, where the head-to-tail and tail-to-head arrangements alternate throughout the channel in the hexagonal high-temperature symmetry. This induces strains that might be compensated by substitutions and/or ion vacancies. Some impurities, like partial substitution of hydroxide by fluoride or chloride, stabilize the hexagonal structure of HA at ambient temperature. Due to this reason, hexagonal HA is seldom the stoichiometric phase and very rare single crystals of natural HA always exhibit the hexagonal space group. The detailed description of the HA structure was first reported in 1964 (Kay et al. 1964) and its interpretation in terms of aggregation of Ca9(PO4)6 clusters, the so-called Posner’s clusters, has been widely used since publication of the article by Posner and Betts (Posner and Betts 1975).

Due to the exceptional importance of HA for the human beings, its properties have been thoroughly investigated by many research groups and further studies are kept going. Namely, the crystal structure of HA is well described elsewhere (Elliott 1994; White and Dong 2003; Mathew and Takagi 2001), the detailed analysis of the electronic structure, bonding, charge transfer, optical and elastic properties is also available (Calderin et al. 2003; Rulis et al. 2004; Snyders et al. 2007; Ching et al. 2009), while the readers interested in Posner’s clusters are referred to still other papers (Treboux et al. 2000; Yin and Stott 2003; Kanzaki et al. 2001). A shell model was developed to study the lattice dynamics of HA (Calderin et al. 2005), while a cluster growth model was created to illustrate its growth (Onuma and Ito 1998). Polarization characteristics (Tanaka et al. 2010a, b), pyroelectric (Tofail et al. 2009, 2015) and piezoelectric (Tofail et al. 2015; Bystrov 2015) properties of HA as well as diffusion of protons inside the HA crystal lattice (Yashima et al. 2014) were investigated. The thermodynamic properties of HA and other types of orthophosphate-based apatites were summarized (Drouet 2015). First-principles calculations for the elastic properties of doped HA (Kawabata and Yamamoto 2010) and vacancy formation in HA (Matsunaga and Kuwabara 2007) were performed. Other examples of the computer simulations of the structure and properties of HA are available elsewhere (de Leeuw 2010; Corno et al. 2010; Slepko and Demkov 2011; Aquilano et al. 2014, 2015). Finally, an attempt was performed to explain an array of the curious characteristics of HA by referring to the hydroxyl ion channels extending in the direction of the c-axis, through a crystallographic column created by the overlapping calcium ion triangles (Uskoković 2015).

Many techniques might be utilized for HA preparation; they can be divided into solid-state reactions and wet methods (Briak-Ben et al. 2008), which include precipitation, hydrothermal synthesis and hydrolysis of other CaPO4. However, in all cases, Ca- and PO4-containing chemicals must be mixed to get the Ca/P ratio strictly equal to 1.67. Nevertheless, even under the ideal stoichiometric conditions, the precipitates are generally non-stoichiometric, suggesting intermediate formation of precursor phases, such as ACP and CDHA. Usually, unsintered HA is poorly crystalline and often non-stoichiometric, resembling the aforementioned CDHA. However, well crystalline HA can be prepared from aqueous solutions at relatively high (10–11) pH and elevated (>90 °C) temperatures (Markovic et al. 2004). HA with the Ca/P ratio >1.67 (Ca-rich HA) might be prepared as well (Bonel et al. 1988). The detailed information on HA synthesis is available elsewhere (Narasaraju and Phebe 1996; Riman et al. 2002; Koutsopoulos 2002; Norton et al. 2006; Sadat-Shojai et al. 2013). In addition, there are good reviews on HA solubility, crystal growth and intermediate phases of HA crystallization (Rakovan 2002), as well as on HA dissolution (Dorozhkin 2012e).

Pure HA never occurs in biological systems. However, due to the chemical similarities to bone and teeth mineral (Table 3), HA is widely used as coatings on orthopedic (e.g., hip joint prosthesis) and dental implants (Dorozhkin 2013c; Suchanek and Yoshimura 1998; Sun et al. 2001; Ong and Chan 1999; Dey et al. 2009; Dorozhkin 2015a). HA bioceramics is very popular as well (Yuan et al. 2009; Engin and Tas 1999; Mangano et al. 2008). Due to a great similarity to biological apatite, over a long time HA has been used in liquid chromatography of nucleic acids, proteins and other biological compounds (Bernardi 1965; Brand et al. 2008; Hou et al. 2011; Hilbrig and Freitag 2012; Niimi et al. 2014; Pinto et al. 2014) and for drug delivery purposes (Uskoković and Uskoković 2011; Chen et al. 2011a; Li et al. 2013; Long et al. 2013; Feng et al. 2013a). Also, HA is added to some brands of toothpaste as a gentle polishing agent instead of calcium carbonate (Niwa et al. 2001; Kim et al. 2006). Non-biomedical applications of HA include its using as an environmental-friendly filler for elastomers (Pietrasik et al. 2008), a low-temperature sorbent (Bailliez et al. 2004; Corami et al. 2008) and/or stabilizer (Wang et al. 2014b) of poisonous chemical elements, a high-temperature sorbent for carbon dioxide (Landi et al. 2014), both a catalyst (Xu et al. 2010; Rodrigues et al. 2014) and a carrier for other catalysts (Domínguez et al. 2009; Sun et al. 2009; Vukomanović et al. 2012), a material for ultraviolet light protection (Holzmann et al. 2009) and sunscreen filter (Piccirillo et al. 2014), as well as a component of various sensors (Nagai et al. 1988; Petrucelli et al. 1996; Tagaya et al. 2010; Khairnar et al. 2011). Finally, highly flexible and nonflammable inorganic paper could be prepared from HA (Lu et al. 2014a).

FA (or FAp)

Fluorapatite [Ca5(PO4)3F, but is usually written as Ca10(PO4)6F2 to denote that the crystal unit cell comprises two molecules; the IUPAC name is pentacalcium fluoride tris(orthophosphate)] is the only ion-substituted CaPO4, considered in this review. Since the presence of 2.5 % of fluorides in natural apatites was established by 1798 (Dobson 1798), this date might be accepted as the earliest hearing of FA.

FA is the hardest (five according to the Mohs’ scale of mineral hardness), most stable and least soluble compound among all CaPO4 (Table 1). In addition, it is the most thermally stable CaPO4 with the melting point at ~1650 °C (Tõnsuaadu et al. 2012). Perhaps, such “extreme” properties of FA are related to the specific position of F ions in the center of Ca(2) triangles of the crystal structure (Elliott 1994; White and Dong 2003). Due to its properties, FA is the only CaPO4 that naturally forms large deposits suitable for the commercial use (McConnell 1973; Becker 1989; Rakovan and Pasteris 2015; see also Fig. 2). Preparation techniques of the chemically pure FA are similar to the aforementioned ones for HA but the synthesis must be performed in presence of the necessary amount of F ions (usually, NaF or NH4F is added). Under some special crystallization conditions (e.g., in presence of gelatin or citric acid), FA might form unusual dumbbell-like fractal morphology that finally are closed to spheres (Fig. 8; Busch et al. 1999; Wu et al. 2010). In addition, FA is the only CaPO4, which melts without decomposition; therefore, big (up to 30 cm long and, for shorter lengths, up to 1.9 cm wide) single FA crystals might be grown from FA melts (Mazelsky et al. 1968a; Loutts and Chai 1993). Similar to that for HA (see CDHA), an existence of CaF2-deficient FA was also detected but for the crystals grown from the FA melt only (Mazelsky et al. 1968a; Warren 1972). In addition, FA with an excess of CaF2 was prepared (Mann and Turner 1972). A hierarchical structure for FA was proposed (Dorozhkin 2007a). The crystal structure of FA for the first time was studied in 1930 (Mehmel 1930; Naray-Szabo 1930) and is well described elsewhere (Elliott 1994; White and Dong 2003; Mathew and Takagi 2001). Computer simulations of the FA structure were performed as well (Li et al. 2015). The detailed analysis of the electronic structure, bonding, charge transfer and optical properties of FA (Rulis et al. 2004), as well as its NMR study under pressure (Pavan et al. 2012) is available as well. In addition, there are reviews on FA solubility (Rakovan 2002) and the dissolution mechanism (Dorozhkin 2012e).
Fig. 8

A biomimetically grown aggregate of FA that was crystallized in a gelatin matrix. Its shape can be explained and simulated by a fractal growth mechanism. Scale bar 10 μm. Reprinted from Ref. (Busch et al. 1999) with permission

FA easily forms solid solutions with HA with any desired F/OH molar ratio. Such compounds are called fluorhydroxyapatites (FHA) (Nikcevic et al. 2004; Montazeri et al. 2010; Zhu et al. 2012) or hydroxyfluorapatites (HFA) (Rodríguez-Lorenzo et al. 2003; Azami et al. 2012) and described with a chemical formula Ca10(PO4)6(OH)2−x F x , where 0 < x < 2. If the F/OH ratio is either uncertain or not important, the chemical formula of FHA and HFA is often written as Ca10(PO4)6(F,OH)2. The lattice parameters, crystal structure, solubility and other properties of FHA and HFA lay in between of those for the chemically pure FA and HA. Namely, the substitution of F for OH results in a contraction in the a-axis with no significant change in the c-axis dimensions and greater resolution of the IR absorption spectra.

Similar to pure HA, pure FA never occurs in biological systems. Obviously, a lack of the necessary amount of toxic fluorides (the acute toxic dose of fluoride is ~5 mg/kg of body weight) in living organisms is the main reason of this fact (pure FA contains 3.7 % mass. F). Enameloid of shark teeth (Lowenstam and Weiner 1989; Daculsi et al. 1997; Prostak et al. 1993; Dahm and Risnes 1999; Carr et al. 2006; Enax et al. 2014) and some exoskeletons of mollusks (Leveque et al. 2004) seem to be the only exclusions because they contain substantial amounts of fluoride, with is presented there as ion-substituted, non-stoichiometric FHA or HFA. Among all normal calcified tissues of humans, the highest concentration of fluorides is found in dentine and cementum, while the lowest—in dental enamel (Table 3). Nevertheless, one should stress that the amount of fluorides on the very surface of dental enamel might be substantially increased using fluoride-containing toothpastes and mouthwashes (Schemehorn et al. 2011; Hattab 2013). However, in no case, the total amount of fluorides is enough to form pure FA.

Contrary to the initial expectations (Heling et al. 1981), chemically pure FA is not used for grafting purposes. Presumably, this is due to the lowest solubility, good chemical stability of FA and toxicity of high amounts of fluorides. However, attempts to test FA-containing formulations (Gineste et al. 1999; Agathopoulos et al. 2003; Yoon et al. 2005; Bogdanov et al. 2009; Nordquist et al. 2011), ion-substituted FA (Kheradmandfard et al. 2012; Sharifnabi et al. 2014), FHA (Savarino et al. 2003; Vitkovič et al. 2009) and porous FA bioceramics (Chaari et al. 2009) are kept performing. The effect of fluoride contents in FHA on both osteoblast behavior (Qu and Wei 2006; Bhadang et al. 2010) and leukemia cells proliferation (Theiszova et al. 2008) has been described. Non-biomedical applications of FA include luminescent light tubes (Davis et al. 1971) and thermometers (Fu et al. 2015), laser materials (Mazelsky et al. 1968b; Ohlmann et al. 1968) (in all these cases various dopants are necessary), as well as catalysts (An et al. 2009).

OA (or OAp, or OXA)

Oxyapatite [Ca10(PO4)6O; the IUPAC name is decacalcium oxide hexakis(phosphate), mineral voelckerite] is the least stable and, therefore, the least known CaPO4, which, probably, does not exist at all. Nevertheless, a name “voelckerite” was introduced in 1912 by A.F. Rogers (1887–1957) for a hypothetical mineral with the chemical composition of 3Ca3(PO4)2 + CaO (Rogers 1912, 1914), to honor an English agricultural chemist John Christopher Augustus Voelcker (1822–1884), who, in 1883, first showed an apparent halogen deficiency in some natural apatites (Voelcker 1883). Therefore, 1883 might be accepted as the earliest hearing on OA.

To the best of my findings, phase pure OA has never been obtained at room temperatures; therefore, its properties are not well established. Furthermore, still there are serious doubts that pure OA can exist. Since hydroxyl ions in HA appear to be the most mobile ones and upon exposure to high temperatures are the first to leave the lattice, a mixture (or a solid solution?) of OA and HA (so-called “oxy-HA”, chemical formula: Ca10(PO4)6(OH)2−2xOxVx, where V represents an OH vacancy) might be prepared by a partial dehydroxylation of HA at temperatures exceeding ~900 °C (e.g., during plasma spray of HA) strictly in the absence of water vapor (Gross et al. 1998; Hartmann et al. 2001; Alberius-Henning et al. 2001; Wang and Dorner-Reisel 2004; Liu and Shen 2012). It also might be crystallized in glass-ceramics (van’t Hoen et al. 2007). OA is very unstable and has no stability field in aqueous conditions (Duff 1972). Namely, data are available that oxy-HA containing less than 25 % HA (i.e., almost OA) during further dehydration decomposes to a mixture of α-TCP and TTCP. In addition, OA is very reactive and transforms to HA in contact with water vapor (HA reconstitution) (Gross et al. 1998). The largest impediment to active research in OA is the non-availability of a user-friendly approach to measure the concentration of hydroxyl ions (Gross and Pluduma 2012).

Therefore, computer-modeling techniques have been employed to qualitatively and quantitatively investigate the dehydration of HA to OA (de Leeuw et al. 2007). OA has the hexagonal space group symmetry P \( \overline{6} \) (174) of cesanite type (White and Dong 2003), while the space group symmetry for partially dehydrated HA was found to change from hexagonal P63/m to triclinic P \( \bar{1} \) when more than ca. 35 % of the structurally bound water had been removed (Alberius-Henning et al. 2001). On the c-axis, pure OA should have a divalent ion O2− coupled with a vacancy instead of two neighboring monovalent OH ions.

Due to the aforementioned problems with OA preparation, it cannot be found in biological systems. In addition, no information on the biomedical applications of OA is available either. Plasma-sprayed coatings of CaPO4, in which OA might be present as an admixture phase, seem to be the only exception (Dorozhkin 2015a).

To conclude, one should mention that various types of calcium peroxy-HA (oxygenated HA) could be prepared both in the presence of hydrogen peroxide (Rey et al. 1978) and by HA heating in an oxygen-rich atmosphere (Zhao et al. 2000; Yu et al. 2007). Similar to that for OA, none of them was ever prepared as a phase pure individual compound and no examples of the biomedical applications of such types of CaPO4 were found.

TTCP (or TetCP)

Tetracalcium phosphate or tetracalcium diorthophosphate monoxide (Ca4(PO4)2O; the IUPAC name is tetracalcium oxide bis(orthophosphate); the mineral hilgenstockite) is the most basic CaPO4, however, its solubility in water is higher than that of HA (Table 1). TTCP has been known since 1883 (Hilgenstock 1883), while the mineral hilgenstockite was named to honor a German metallurgist Gustav Hilgenstock (1844–1913), who first discovered it in Thomas slag from blast furnaces (Hilgenstock 1883, 1887). Its major industrial importance stems from the fact that it is formed by the reactions between orthophosphates and lime in the manufacture of iron, and through these reactions, TTCP has a significant role in controlling the properties of the metal.

TTCP cannot be precipitated from aqueous solutions. It can be prepared only under the anhydrous conditions by solid-state reactions at temperatures above ~1300 °C, e.g., by heating homogenized equimolar quantities of DCPA and CaCO3 in dry air, or in a flow of dry nitrogen (Elliott 1994, 1998; Kai et al. 2009). These reactions should be carried out in a dry atmosphere, in vacuum or with rapid cooling (to prevent uptake of water and formation of HA). Easily DCPA might be replaced by ammonium orthophosphates (Romeo and Fanovich 2008; Jalota et al. 2005), while calcium carbonate might be replaced by calcium acetate (Jalota et al. 2005); however, in all cases, Ca/P ratio must be equal to 2.00. Furthermore, TTCP often appears as an unwanted by-product in plasma-sprayed HA coatings, where it is formed as a result of the thermal decomposition of HA to a mixture of high-temperature phases of α-TCP, TTCP and CaO (Moseke and Gbureck 2010). Nevertheless, TTCP might be produced at 900 °C by calcining of a precipitated ACP with Ca/P = 2 in vacuum; the process is suggested to occur via a intermediate formation of a mixture of OA + CaO (Gross and Rozite 2015).

TTCP is metastable: in both wet environment and aqueous solutions it slowly hydrolyses to HA and calcium hydroxide (Elliott 1994, 1998; Martin and Brown 1993). Consequently, TTCP is never found in biological calcifications. In medicine, TTCP is widely used for preparation of various self-setting CaPO4 formulations (Dorozhkin 2013b; Moseke and Gbureck 2010); however, to the best of my knowledge, there is no commercial bone-substituting product consisting solely of TTCP. For the comprehensive information on TTCP, the readers are referred to a special review (Moseke and Gbureck 2010), while the spectra (Jillavenatesa and Condrate 1997) and solubility (Pan and Darvell 2009a) of TTCP are well described elsewhere.

To finalize the description of individual CaPO4, one should mention on an interesting opinion, that all types of CaPO4 listed in Table 1 might be classified into three major structural types (Mathew and Takagi 2001; Chow and Eanes 2001). They comprise: (1) the apatite type, Ca10(PO4)6X2, which includes HA, FA, OA, CDHA, OCP and TTCP; (2) the glaserite type, named after the mineral glaserite, K3Na(SO4)2, which includes all polymorphs of TCP and, perhaps, ACP; (3) the Ca-PO4 sheet-containing compounds, which include DCPD, DCPA, MCPM and MCPA. According to the authors, a closer examination of the structures revealed that all available CaPO4 could be included into distorted glaserite type structures, but with varying degrees of distortion (Mathew and Takagi 2001; Chow and Eanes 2001).

Biphasic, triphasic and multiphasic CaPO4 formulations

CaPO4 might form biphasic, triphasic and multiphasic (polyphasic) formulations, in which the individual components cannot be separated from each other. Presumably, the individual phases of such compositions are homogeneously “mixed” at a far submicron level (<0.1 μm) and strongly integrated with each other. Nevertheless, the presence of all individual phases is easily seen by X-ray diffraction technique (Dorozhkin 2012d).

The usual way to prepare multiphasic formulations consists of sintering non-stoichiometric compounds, such as ACP and CDHA, at temperatures above ~700 °C. Furthermore, a thermal decomposition of the stoichiometric CaPO4 at temperatures above ~1300 °C might be used as well; however, this approach often results in formation of complicated mixtures of various products including admixtures of CaO, calcium pyrophosphates, etc. (Dorozhkin 2012d; Nakano et al. 2002b). Namely, transformation of HA into polyphasic CaPO4 by annealing in a vacuum occurs as this: the outer part of HA is transformed into α-TCP and TTCP, while the α-TCP phase of the surface further transforms into CaO. Besides, in the boundary phase, HA is transformed into TTCP (Nakano et al. 2002b).

Historically, Nery and Lynch with co-workers first used the term biphasic calcium phosphate (BCP) in 1986 to describe a bioceramic that consisted of a mixture of HA and β-TCP (Ellinger et al. 1986). Based on the results of X-ray diffraction analysis, these authors found that the “tricalcium phosphate” preparation material used in their early publication (Nery et al. 1975) was in fact a mixture of ~20 % HA and ~80 % β-TCP. Currently, only biphasic and triphasic CaPO4 formulations are known; perhaps, more complicated formulations will be manufactured in future. Furthermore, nowadays, multiphasic and/or polyphasic compositions consisting of high-temperature phases of CaPO4, such as α-TCP, β-TCP, HA and, perhaps, high-temperature ACP, OA and TTCP, are known only. No precise information on multiphasic compositions, containing MCPM, MCPA, DCPD, DCPA, low-temperature ACP, OCP and CDHA has been found in literature (Dorozhkin 2012d). Perhaps, such formulations will be produced in future.

All BCP formulations might be subdivided into two major groups: those consisting of CaPO4 having either the same (e.g., α-TCP and β-TCP) or different (e.g., β-TCP and HA) molar Ca/P ratios. Among all known BCP formulations, BCP consisting of HA and β-TCP is both the most known and the best investigated (Dorozhkin 2012d). In 1986, LeGeros in USA and Daculsi in France initiated the basic studies on preparation of this type of BCP and its in vitro properties. This material is soluble and gradually dissolves in the body, seeding new bone formation as it releases calcium and orthophosphate ions into the biological medium. Presently, commercial BCP products of different or similar HA/β-TCP ratios are manufactured in many parts of the world as bone graft or bone substitute materials for orthopedic and dental applications under various trademarks and several manufacturers (Dorozhkin 2012d). A similar combination of α-TCP with HA forms BCP as well (Reid et al. 2005; Pan et al. 2006; Kui 2007; Li et al. 2009b).

Recently, the concept of BCP has been extended by preparation and characterization of biphasic TCP (BTCP), consisting of α-TCP and β-TCP phases (Wang et al. 2006a; Li et al. 2007, 2008a). It is usually prepared by heating ACP precursors (Wang et al. 2006a; Li et al. 2007, 2008a), in which the α-TCP/β-TCP ratio can be controlled by aging time and pH value during synthesis of the amorphous precursor (Li et al. 2007). Furthermore, triphasic formulations, consisting of HA, α-TCP and β-TCP (Vani et al. 2009) or HA, α-TCP and TTCP (Nakano et al. 2002b) have been prepared (Dorozhkin 2012d).

It is important to recognize, that the major biomedical properties (such as bioactivity, bioresorbability, osteoconductivity and osteoinductivity) of the multiphasic formulations might be adjusted by changing the ratios among the phases. When compared to both α- and β-TCP, HA is a more stable phase under the physiological conditions, as it has a lower solubility (Table 1) and, thus, slower resorption kinetics. Therefore, due to a higher biodegradability of the α- or β-TCP component, the reactivity of BCP increases with the TCP/HA ratio increasing. Thus, in vivo bioresorbability of BCP can be adjusted through the phase composition. Similar conclusions are also valid for both the biphasic TCP (in which α-TCP is a more soluble phase) and the triphasic (HA, α-TCP and β-TCP) formulations. Further details on this subject might be found in a topical review (Dorozhkin 2012d).

Ion-substituted CaPO4

Last, one should very briefly mention on existence of carbonated HA (Lafon et al. 2008; Tonegawa et al. 2010; Yahia and Jemal 2010; Silvester et al. 2014; Fleet 2015), chlorapatite (Kannan et al. 2007; García-Tuñón et al. 2012; Zhao et al. 2013), as well as on a great number of CaPO4 with various ionic substitutions (CaPO4 with dopants) (Pan and Fleet 2002; Rey et al. 2006; Kannan et al. 2008; Boanini et al. 2010b; Shepherd et al. 2012; Adzila et al. 2012; Grigg et al. 2014; Šupová 2015). In principle, any ion in CaPO4 might be substituted by other ion(s). Usually, the ion-substituted CaPO4 are of a non-stoichiometric nature with just a partial ionic substitution and there are too many of them to be described here. Currently, this is a hot investigation topic; therefore, the readers are referred to the special literature (Pan and Fleet 2002; Rey et al. 2006; Kannan et al. 2008; Boanini et al. 2010b; Shepherd et al. 2012; Adzila et al. 2012; Grigg et al. 2014; Šupová 2015). In addition, there is a very good review, in which the structures of more than 75 chemically different apatites have been discussed (White and Dong 2003).

To finalize this brief topic of ion-substituted CaPO4, it is important to note that chemical elements not found in natural bones can be intentionally incorporated into CaPO4 biomaterials to get special properties. For example, addition of Ag+ (Pushpakanth et al. 2008; Zhang et al. 2010b; Kim et al. 1998; Kolmas et al. 2014), Zn2+ (Kim et al. 1998; Kolmas et al. 2014; Stanić et al. 2010) and Cu2+ (Kim et al. 1998; Kolmas et al. 2014; Stanić et al. 2010; Li et al. 2010) was used for imparting antimicrobial effect, while radioactive isotopes of 90Y (Thomas et al. 2008), 153Sm (Chinol et al. 1993; Argüelles et al. 1999; O’Duffy et al. 1999) and 186Re (Chinol et al. 1993) were incorporated into HA bioceramics and injected into knee joints to treat rheumatoid joint synovitis (Thomas et al. 2008; Chinol et al. 1993; O’Duffy et al. 1999). More to the point, apatites were found to incorporate individual molecules, such as water, oxygen and carbon dioxide (Rey et al. 2006).

Finally, to conclude the description of the known CaPO4, one should mention that in spite of the well-defined crystallographic data (Table 4) and, therefore, the well-defined shapes of the single crystals, various types of CaPO4 can be prepared with the controllable sizes from nano- to macro-scale (up to centimeter size) and the diverse shapes including zero- (particles), one- (rods, fibers, wires and whiskers), two- (sheets, disks, plates, belts, ribbons and flakes) and three-dimensional morphologies (Sadat-Shojai et al. 2013; Lin et al. 2014). The latter might be of versatile morphologies and shapes (Fig. 8 is an example), including porous and hollow structures.

Biological hard tissues of CaPO4

Biological mineralization (or biomineralization) is the process of in vivo formation of inorganic minerals (so-called, biominerals). One should stress that the term “biomineral” refers not only to a mineral produced by organisms but also to the fact that almost all of these mineralized products are composite materials comprised both inorganic and bioorganic components. Furthermore, having formed in vivo under well-controlled conditions, the biomineral phases often have properties, such as shape, size, crystallinity, isotopic and trace element compositions, quite unlike its inorganically formed counterpart (please, compare Figs. 2, 8, 10 and 15 bottom). Thus, the term “biomineral” reflects all this complexity (Lowenstam and Weiner 1989).

As shown in Table 3 and discussed above, in the body of mammals, the vast majority of both normal and pathological calcifications consist of non-stoichiometric and ion-doped CaPO4, mainly of apatitic structure (Pasteris et al. 2008; Palmer et al. 2008). At the atomic scale, nano-sized crystals bone apatite exhibit a variety of substitutions and vacancies that make the Ca/P molar ratio distinct from the stoichiometric HA ratio of 1.67. Their chemical composition is complicated and varies in relatively wide ranges. This depends on what the animal has ingested (Grynpas et al. 1993). Occasionally, attempts are performed to compose chemical formulas of biological apatites. For example, the following formula Ca8.856Mg0.088Na0.292K0.010(PO4)5.312(HPO4)0.280(CO3)0.407(OH)0.702Cl0.078(CO3)0.050 was proposed to describe the chemical composition of the inorganic part of dental enamel (Elliott 2002).

The presence of impurities in the biological apatite of calcified tissues introduces significant stresses into the crystal structure, which make it less stable and more reactive. Among all substituting ions, the presence of 4–8 % of carbonates instead of orthophosphate anions (so-called, B-type substitution (LeGeros 1991; Elliott 1994; Amjad 1997; Lafon et al. 2008)) and of 0.5–1.5 % of Mg is of the special importance because it leads to large lattice strain and significantly increases the solubility (Palmer et al. 2008; Elliott 2002; Boskey 2006). Higher concentrations of Mg and carbonates in bone or dentine compared to those in enamel (Table 3) may explain a higher solubility, a lower crystallinity and smaller crystal dimensions of bone or dentine compared to enamel.

In addition, the crystals of biological apatite are always very small which also increases its solubility when compared with that for the chemically pure HA and even CDHA (Rey et al. 2006). However, biologic apatites of enamel have considerably larger both crystal sizes (about 2000 nm) and crystallite dimensions compared to those of either bone or dentine apatite. The substantial differences in crystallite dimensions of biological apatites of different origin are clearly seen as the well-defined X-ray diffraction peaks of enamel apatite and much broader diffraction peaks of either bone or dentine apatites (Fig. 9, center). Small dimensions and a low crystallinity are two distinct features of biological apatites, which, combined with their non-stoichiometric composition, inner crystalline disorder and presence of other ions in the crystal lattice, allow explaining their special behavior. For example, the small crystal size means that a large percentage of the atoms are on the surface of the crystals, providing a large specific surface area for sorption of ions, proteins and drugs (Boskey 2006; Vallet-Regí and González-Calbet 2004). The major physical properties of biological apatite are summarized in Fig. 9. It is interesting to note, that the solubility and equilibrium phenomena of CaPO4 related to the calcification process have been studied, at least, since 1925 (Holt et al. 1925a, b).
Fig. 9

Left crystal structure of a biological apatite. Powder X-ray diffraction patterns (center) and infrared spectra (right) of human enamel, dentine and bone. Reprinted from Ref. (Vallet-Regí and González-Calbet 2004) with permission

To the best of my findings (Dorozhkin 2012a, 2013a), the first attempts to mimic the CaPO4 nature of bones were performed in 1913 (Gassmann 1913). This discovery was clarified afterwards, suggesting that the bone mineral could be carbonated apatite (de Jong 1926; Bredig 1933). Further optical and X-ray analysis of bones and other mineralized tissues matched analyses of two apatites: FA and dahllite (Taylor and Sheard 1929). Additional historical data on this point are available in literature (Dorozhkin 2012a, 2013a). In 1998, Weiner and Wagner wrote the following: “the term bone refers to a family of materials, all of which are built up of mineralized collagen fibrils” (Weiner and Wagner 1998; Weiner et al. 1999). Therefore, for mammals, this family of materials includes dentine—the material that constitutes the inner layers of teeth, cementum—the thin layer that binds the roots of teeth to the jaw, deer antlers and some other materials. It is worth noting, that bones and teeth contain almost 99 % of the total body calcium and about 85 % of the total body phosphorus that amounts to a combined mass of approximately 2 kg in an average person. In addition, it is important to recognize that CaPO4 of bones are by no means inert; they play an important role in the metabolic functions of the body. The data on the physico-chemical and crystallographic study of biological apatite are available elsewhere (Elliott 2002).


Bone, also called osseous tissue (Latin: os), is a type of hard endoskeletal connective tissue found in many vertebrate animals. All bones of a single animal are, collectively, known as the skeleton. True bones are present in bony fish (osteichthyes) and all tetrapods. Bones support body structures, protect internal organs and, in conjunction with muscles, facilitate movement (Loveridge 1999). In addition, bones are also involved with blood cell formation, calcium metabolism and act for mineral storage. For a material scientist, bone is a dynamic, highly vascularized solid tissue that is formed from a complicated biocomposite containing both inorganic (Table 3) and bioorganic (chiefly, collagen) compounds, in which nanodimensional crystals of the inorganic phases are dispersed in the meshes of the bioorganic ones (Palmer et al. 2008; Nightingale and Lewis 1971; Currey 2002; Rho et al. 1998; Tzaphlidou 2008). More than 20 types of collagen have been reported in the human body, among which type I collagen is the most abundant protein and provides much of the structural integrity for connective tissue, particularly in bones, tendons and ligaments. Furthermore, for a physiologist, bone is a living organ populated by living cells (mainly, osteoblasts, osteoclasts and osteocytes); however, that is another story. The inorganic to bioorganic ratio is approximately 75–25 % by dry weight and about 65–35 % by volume. This ratio not only differs among animals, among bones in the same animal and over time in the same animal but also it exerts a major control on the material properties of bone, such as its toughness, ultimate strength and stiffness. In general, load-bearing ability of bones depends on not only architectural properties, such as cortical thickness and bone diameter, but also intrinsic, size-independent, material properties such as porosity, level of mineralization, crystal size and properties derived from the organic phase of bone (Davison et al. 2006). A higher mineral to collagen ratio typically yields stronger, but more brittle, bones (Turner and Burr 1993; Currey 2004; Currey et al. 2004). For example, bones from the leg of a cow have a relatively high concentration of CaPO4 (for support), whereas bones from the antler of a deer have a relatively high concentration of collagen (for flexibility) (Pan and Darvell 2009a). It is interesting to note that bones exhibit several physical properties such as piezoelectricity (Anderson and Eriksson 1970) and pyroelectricity (Lang 1966).

Stability of the mineral composition of bones has a very long history: CaPO4 were found in dinosaur fossils (Elorza et al. 1999; Eagle et al. 2010; Haynes 1968; Rensberger and Watabe 2000; Kolodny et al. 1996; Trueman and Tuross 2002). Therefore, organisms have had a great deal of time to exploit the feedback between composition and structure in apatite, on the one hand, and benefit from its biological functionality, on the other. Bones of the modern animals are a relatively hard and lightweight porous composite material, formed mostly of biological apatite (i.e., poorly crystalline CDHA with ionic substitutions). It has relatively high compressive strength but poor tensile strength (Currey and Brear 1990). While bones are essentially brittle, they have a degree of significant plasticity contributed by their bioorganic components.

The distribution of the inorganic and bioorganic phases depends on a highly complex process that takes place during bone formation. Each of these components may be assembled in different proportions creating two different architectural structures depending on the bone type and function. They are characterized by different structural features that strongly correlate with the mechanical performance of the tissue. These two types of bones are: the cortical bones (or compact bones) which are dense and the cancellous bones (also known as trabecular or spongious bones) which are less dense and less stiff than the compact ones. Usually, bones are composed of a relatively dense outer layer of cortical bone covering an internal mesh-like structure (average porosity of 75–95 %) of cancellous bone, the density of which is about 0.2 g/cm3 but it may vary at different points (Fig. 10). Cortical bones make up a large portion of the skeletal mass; they have a high density (~1.80 g/cm3) and a low surface area. Cancellous bones have an open meshwork or honeycomb-like structure. They have a relatively high surface area but form a smaller portion of the skeleton. Bones are a porous material with the pore sizes ranging from 1 to 100 μm in normal cortical bones and 200–400 μm in trabecular ones. 55–70 % of the pores in trabecular bones are interconnected. The porosity reduces the strength of bones but also reduces their weight (LeGeros 1991, 2001; Lowenstam and Weiner 1989; O’Neill 2007; Skinner 2005; Daculsi et al. 1997; Weiner and Wagner 1998; Currey 2002; Rho et al. 1998; Rey et al. 2009; Lerebours et al. 2015).
Fig. 10

General structure of a mammalian bone. Other very good graphical sketches of the mammalian bone structure are available in Refs. (Pasteris et al. 2008; Vallet-Regí and González-Calbet 2004)

Bones can be either woven or lamellar. The fibers of woven bones are randomly aligned and as the result have a low strength. In contrast, lamellar bones have parallel fibers and are much stronger. Woven bones are put down rapidly during growth or repair (Watt 1925) but as growth continues, they are often replaced by lamellar bones. The replacement process is called “secondary bone formation” and described in details elsewhere (Olszta et al. 2007). In addition, bones might be long, short, flat, sutural, sesamoid and irregular (Fig. 11). The sizes and shapes of bones reflect their function. Namely, broad and flat bones, such as scapulae, anchor large muscle masses, flat skull bones protect the brain, ribs protect the lungs, pelvis protects other internal organs, short tubular bones in the digits of hands and feet provide specific grasping functions, hollow and thick-walled tubular bones, such as femur or radius, support weight and long bones enable locomotion (Boskey 2007; Glimcher 2006). Long bones are tubular in structure (e.g., the tibia). The central shaft of a long bone is called the diaphysis and has a medullar cavity filled with bone marrow (Fig. 10). Surrounding the medullar cavity is a thin layer of cancellous bone that also contains marrow. The extremities of the bone are called the epiphyses and are mostly cancellous bone covered by a relatively thin layer of compact bone. Short bones (e.g., finger bones) have a similar structure to long bones, except that they have no medullar cavity. Flat bones (e.g., the skull and ribs) consist of two layers of compact bone with a zone of cancellous bone sandwiched between them. Irregular bones (e.g., vertebrae) do not conform to any of the previous forms. Thus, bones are shaped in such a manner that strength is provided only where it is needed. All bones contain living cells embedded in a mineralized organic matrix that makes up the main bone material (Boskey 2007; Glimcher 2006; Boskey and Roy 2008). The structure of bones is most easily understood by differentiating between seven levels of organization because bones exhibit a strongly hierarchical structure (Palmer et al. 2008; Weiner and Wagner 1998; Nightingale and Lewis 1971; Currey 2002, 2005; Rho et al. 1998; Rensberger and Watabe 2000; Cui et al. 2007; Fratzl and Weinkamer 2007; Boskey and Coleman 2010; Meyers et al. 2008; Reznikov et al. 2014a, b). One should stress that, taking into account the presence of ordered and disordered materials, nine hierarchical levels for lamellar bones have been differentiated (Fig. 12; Reznikov et al. 2014b).
Fig. 11

Classification of bones by shape

Fig. 12

A schematic illustration of the hierarchical organization of bones. Up to level V, the hierarchical levels can be divided into the ordered material (green) and the disordered material (blue). At level VI, these two materials combine in lamellar bone and parallel fibered bone. Other members of the bone family still need to be investigated with respect to the presence of both material types; hence, they are depicted in a box without color. Level VII depicts the lamellar packets that make up trabecular bone material and the cylindrically shaped lamellar bone that makes up osteonal bone. The fibrolamellar unit comprises the primary hypercalcified layer, parallel fibered bone and lamellar bone. c-HAP carbonated HA, GAGs glycosaminoglycans, NCPs non-collagenous proteins. Reprinted from Ref. (Reznikov et al. 2014b) with permission. Other good graphical sketches of the hierarchical structure of bones are available in Refs. (Weiner and Wagner 1998; Cui et al. 2007; Boskey and Coleman 2010; Meyers et al. 2008)

The mechanical properties of bones reconcile high stiffness and high elasticity in a manner that is not yet possible with synthetic materials (Meyers et al. 2008). Cortical bone specimens have been found to have tensile strength in the range of 79–151 MPa in longitudinal direction and 51–56 MPa in transversal direction. Bone’s elasticity is also important for its function giving the ability to the skeleton to withstand impact. Estimates of modulus of elasticity of bone samples are of the order of 17–20 GPa in longitudinal direction and of 6–13 GPa in the transversal direction (Athanasiou et al. 2000). The elastic properties of bone were successfully modeled at the level of mineralized collagen fibrils via step-by-step homogenization from the staggered arrangement of collagen molecules up to an array of parallel mineralized fibrils (Nikolov and Raabe 2008). The investigations revealed that bone deformation was not homogeneous but distributed between a tensile deformation of the fibrils and a shearing in the interfibrillar matrix between them (Gupta et al. 2005; Peterlik et al. 2006). Readers, who are interested in further details, are addressed to a good review on the effects of the microscopic and nano-scale structure on bone fragility (Ruppel et al. 2008).

The smallest level of the bone hierarchy consists of the molecular components: water, biological apatite, collagen and other proteins (Fig. 13; Duer 2015). The second smallest hierarchical level is formed by mineralization of collagen fibrils, which are of 80–100 nm thickness and a length of a few to tens of microns (Fig. 12). Thus, biocomposites of biological apatite and molecules of type I collagen are formed (Pasteris et al. 2008; Weiner and Wagner 1998; Nightingale and Lewis 1971; Tzaphlidou 2008; Fratzl et al. 2004). Some evidences for direct physical bonding between the collagen fibers and apatite crystals in bone were found (Marino and Becker 1967). Atomic force microscopy was used to measure the crystals of biological apatite in mature cow bones (Eppell et al. 2001). The crystals are always platelet like (elongated along the crystallographic c-axis) and very thin (Wopenka and Pasteris 2005; Clark and Iball 1954; Rubin et al. 2003; Su et al. 2003), with remarkably uniform thicknesses (determined in transmission electron microscopy) of 2–4 nm (i.e., just a few unit cells thick—see Table 3). They exist in bones not as discrete aggregates but rather as a continuous phase, which is indirectly evidenced by a very good strength of bones. This results in a very large surface area facing extracellular fluids, which is critically important for the rapid exchange of ions with these fluids. The nano-sized crystals of biological apatite are inserted in a nearly parallel way into the collagen fibrils, while the latter are formed by self-assembly of collagen triple helices (Weiner and Wagner 1998; Nightingale and Lewis 1971; Cui et al. 2007; Landis et al. 1996; Rosen et al. 2002) using the self-organization mechanism (Sato 2006; Hartgerink et al. 2001). In addition, experimental data from electron diffraction studies revealed that that the mineral plates of biological apatite are not quite as ordered as previously assumed (Olszta et al. 2007). This imperfect arrangement of nearly parallel crystals has been supported by SAXS and transmission electron microscopy studies (Burger et al. 2008). According to the latest data, water, which always present in bone mineral, appears to glue the mineral platelets together in a way akin to how water sticks two glass plates together—it provides firm binding between the plates, but at the same time allows slippage between them—flexibility for a stack of mineral platelets held together in this way (Duer 2015).
Fig. 13

a A schematic view of the current model of the organic–inorganic composite nanostructure of bone. Polycrystalline particles of biological apatite, consisting of stacks of (single crystal) mineral platelets are sandwiched into the space between collagen fibrils. The large platelet (100) faces are parallel to each other and the platelet c-axis is strongly ordered with the collagen fibril axis. b A schematic view of the structure of a single mineral platelet, with an atomically ordered core resembling the CDHA structure (with substitutions) surrounded by a surface layer of disordered, hydrated mineral ions. c A schematic view of the detailed structural model of bone mineral showing how citrate anions and water bind the mineral platelets together. Reprinted from Ref. (Duer 2015) with permission

The lowest level of hierarchical organization of bone has successfully been simulated by CDHA precipitation on peptide-amphiphile nanodimensional fibers (Hartgerink et al. 2001). However, apatite platelets nucleating on the surface of peptide tubules are not similar to the nanostructure of bone and they are only an example of surface induced nucleation (and not accurately characterized either), while the nanostructure of bone consists of intra-fibrillar platelets intercalated within the collagen fibrils. However, the interface between collagen and biological apatite is still poorly understood; for the available details, the readers are referred to a review devoted to the structure and mechanical quality of the collagen/mineral nanodimensional biocomposite of bones (Fratzl et al. 2004). There is still no clear idea why the crystals of biological apatite are platelet shaped even though dahllite has hexagonal crystal symmetry (Weiner and Wagner 1998; Currey 2002; Rho et al. 1998; Rey et al. 2009). One possible reason is that they grow via an OCP transition phase, in which crystals are plate-shaped (Weiner and Wagner 1998). Another explanation involves the presence of citrates, which strongly bound to (10Ī0) surface of biological apatite because of space matching (Hu et al. 2010; Xie and Nancollas 2010). Therefore, the crystal growth in the [10Ī0] direction becomes inhibited, while the citrate effect on other crystal surfaces of biological apatite appears to be very small owing to poor space matching. Thus, after crystal growth, the (10Ī0) crystal face becomes predominant resulting in plate-like morphology of biological apatite (Xie and Nancollas 2010).

The processes of bone formation (ossification) and growth are very complicated ones and it is difficult to describe them without making a deep invasion into biology. It has been studied for decades (Watt 1925) but still there are missing points. From the standpoint of chemists, formation of bones could be considered as calcification (i.e., deposition or precipitation of CaPO4) within the bioorganic matrix of connective tissues (mainly cartilage), resulting in formation of biocomposites (Palmer et al. 2008; Olszta et al. 2007). Cartilage is composed of collagen fibers, cells (chondrocytes and their precursor forms known as chondroblasts) and extracellular matrix (proteoglycans, which are a special class of heavily glycosylated glycoproteins). Very briefly, the initial stage of ossification involves synthesis and extracellular assembly of the collagen matrix framework of fibrils. At the second stage, chondrocytes calcify the matrix before undergoing the programmed cell death (apoptosis). At this point, blood vessels penetrate this calcified matrix, bringing in osteoblasts (they are mononuclear cells primarily responsible for bone formation), which use the calcified cartilage matrix as a template to build bone, and ions of calcium and orthophosphate to be deposited in the ossifying tissue (Hall 2015). Therefore, the role of collagen in the nucleation, growth, structure and orientation of apatite crystals appears to be predominant (Wang et al. 2012). The biomineralization process is controlled to some extent by cells and the organic matrices made by those cells facilitate the deposition of crystals (Boskey and Roy 2008). As bone crystals grow, there is greater association with proteins, such as osteocalcin, that regulate remodeling (George and Veis 2008). Thus, in vivo formation of hard tissues always occurs by mineral reinforcement of the previously formed network of soft tissues (Palmer et al. 2008; Olszta et al. 2007; Boskey 2007; Glimcher 2006; Cui et al. 2007).

Since the bioorganic matrix has control over the size and orientation of CaPO4 crystals, the latter grow with a specific crystalline orientation—the c-axes of the crystals are roughly parallel to the long axes of the collagen fibrils within which they are deposited (Palmer et al. 2008; Grynpas et al. 1993; Weiner and Wagner 1998; Currey 2002; Rho et al. 1998; Tzaphlidou 2008; Olszta et al. 2007). Earlier, it was believed that this process occurred via epitaxial growth mechanism (Marino and Becker 1970). The same was suggested for dentine and enamel (Jodaikin et al. 1988; Fincham et al. 1995) (see “Teeth”), as well as for more primitive living organisms. For example, in the shell of the fossil marine animal Lingula brachiopod unguis that consists of a biological apatite, the crystal c-axes are oriented parallel to the β-chitin fibrils (Leveque et al. 2004; Williams et al. 1998; Rohanizadeh and LeGeros 2007; Neary et al. 2011). Therefore, the orientation of biological apatite crystals parallel to the long axes of the organic framework could be a general feature of the CaPO4 biomineralization. However, the degree of the crystal orientation appears to be a useful parameter to evaluate an in vivo stress distribution, a nano-scale microstructure and a related mechanical function, a regenerative process of the healed bone, as well as to diagnose bone diseases such as osteoarthritis (Nakano et al. 2007, 2008). It is interesting to note that contrary to what might be expected in accordance with possible processes of dissolution, formation and remineralization of hard tissues, no changes in phase composition of mineral part, crystal sizes (length, width and thickness) and arrangement of crystals on collagen fibers were detected in abnormal (osteoporotic) human bones compared to the normal ones (Suvorova et al. 2007).

Some animals, such as newts, are able to regenerate amputated limbs. This is, of course, of a high interest for the regenerative medicine. Therefore, bone regeneration in the forelimbs of mature newts was studied by noninvasive X-ray microtomography to image regenerating limbs from 37 to 85 days. The missing limb skeletal elements were restored in a proximal-to-distal direction, which reiterated the developmental patterning program. However, in contrast to this proximal–distal sequence, the portion of the humerus distal to the amputation site was found to fail to ossify in synchrony with the regenerating radius and ulna. This finding suggests that the replacement of cartilage with mineralized bone close to the amputation site is delayed with respect to other regenerating skeletal elements (Stock et al. 2003).

Unlike other mineralized tissues, bone continuously undergoes a remodeling process, as it is resorbed by specialized cells called osteoclasts and formed by another type of cells called osteoblasts (so-called “bone lining cells”) in a delicate equilibrium to ensure that there are major net changes in neither bone mass nor its mechanical strength (Palmer et al. 2008; Olszta et al. 2007; Boskey and Roy 2008; Teitelbaum 2000; Rodan and Martin 2000). The purpose of remodeling is the release of calcium and the repair of micro-damaged bones from everyday stress. Osteoblasts are mononuclear cells primarily responsible for bone formation. They contain alkaline phosphatase, which enzymatically produces orthophosphate anions needed for the mineralization. In addition, there is one more type of the cells called osteocytes that originate from osteoblasts, which have migrated into, become trapped and surrounded by bone matrix, which they themselves produce (Palmer et al. 2008; Currey 2002; Olszta et al. 2007; Boskey 2007; Glimcher 2006; Boskey and Roy 2008; Weiner et al. 2005).

If osteoblasts are bone-forming cells, osteoclasts are multinuclear, macrophage-like cells, which can be described as bone-destroying cells because they mature and migrate to discrete bone surfaces (Boskey and Roy 2008; Teitelbaum 2000; Rodan and Martin 2000). Upon arrival, active enzymes, such as acid phosphatase, are secreted to produce lactic acid that causes dissolution of biological apatite. This process, called bone resorption, allows stored calcium to be released into systemic circulation and is an important process in regulating calcium balance (Teitelbaum 2000; Rodan and Martin 2000). The iteration of remodeling events at the cellular level is influential on shaping and sculpting the skeleton both during growth and afterwards. That is why, mature bones always consist of a very complex mesh of bone patches, each of which has both a slightly different structure and a different age (Palmer et al. 2008; Grynpas et al. 1993; Elliott 2002; Weiner and Wagner 1998; Currey 2002; Rho et al. 1998; Olszta et al. 2007). The interested readers are suggested to read a review on the interaction between biomaterials and osteoclasts (Schilling et al. 2006).

Still there is no general agreement on the chemical mechanism of bone formation. It is clear that the inorganic part of bone consists of biological apatite, i.e., CDHA with ionic substitutions but without the detectable amounts of hydroxide (Rey et al. 1995a; Loong et al. 2000; Seo et al. 2007). However, the results of solid-state nuclear magnetic resonance on fresh-frozen and ground whole bones of several mammalian species revealed that the bone crystal OH was readily detectable; a rough estimate yielded an OH content of human cortical bone of about 20 % of the amount expected in stoichiometric HA (Cho et al. 2003). Various in vitro experiments on precipitation of CDHA and HA revealed that none of these compounds is directly precipitated from supersaturated aqueous solutions containing calcium and orthophosphate ions: some intermediate phases (precursors) are always involved (LeGeros 1991, 2001; Elliott 1994; O’Neill 2007; Iijima et al. 1996; Bodier-Houllé et al. 1998; Rodríguez-Hernández et al. 2005; Tomazic et al. 1994; Nancollas and Wu 2000; Dorozhkin 2012c). Depending on both the solution pH and crystallization conditions, three types of CaPO4 compounds (DCPD, ACP and OCP) have been discussed as possible precursors of CDHA precipitation in vitro. Due to this reason, the same CaPO4 are suggested as possible precursors of biological apatite formation in vivo.

The transient nature of the precursor phase of bone, if it exists at all, makes it very difficult to detect, especially in vivo (Grynpas and Omelon 2007). However, in 1966 Brown proposed that OCP was the initial precipitate that then acted as a template upon which biological apatite nucleates (Brown 1966). This idea was extended in his further investigations (Tung and Brown 1983, 1985; Brown et al. 1987; Siew et al. 1992). The principal support for this concept derived from the following: (1) the close structural similarity of OCP and HA (Brown 1962; Brown et al. 1962); (2) formation of interlayered single crystals of OCP and HA (pseudomorphs of OCP); (3) the easier precipitation of OCP compared with HA; (4) the apparent plate- or lath-like habit of biological apatites that does not conform to hexagonal symmetry, but looks like a pseudomorph of triclinic OCP; (5) the presence of HPO4 2− in bone mineral, particularly in newly formed bones (Elliott 2002). Some evidences supporting this idea were found using high-resolution transmission electron microscopy: computer-simulated lattice images of the “central dark line” in mineralized tissues revealed that it consisted of OCP (Brown 1966; Bodier-Houllé et al. 1998; Rodríguez-Hernández et al. 2005). In addition, Raman spectroscopic indications for an OCP precursor phase were found during intra-membranous bone formation (Crane et al. 2006). Other evidences of OCP to HA transformation, including a mechanistic model for the central dark line formation, might be found in literature (Tseng et al. 2006).

Simultaneously with Brown, the research group led by Posner proposed that ACP was the initially precipitated phase of bone and dentine mineral formation in vivo, thus explaining the non-stoichiometric Ca/P ratio in bones and teeth (Eanes et al. 1965; Termine and Posner 1966a, b). This conclusion was drawn from the following facts: (1) when CaPO4 are prepared by rapid precipitation from aqueous solutions containing ions of calcium and orthophosphate at pH > 8.5, the initial solid phase is amorphous; (2) mature bone mineral is composed of a mixture of ion-substituted ACP and poorly crystallized ion-substituted CDHA; (3) early bone mineral has a lower crystallinity than mature bone and the observed improvement in crystallinity with the age of the bone mineral is a result of a progressive reduction in the ACP content (Elliott 2002; Eanes et al. 1965; Termine and Posner 1966a, b; Harper and Posner 1966; Posner 1969, 1973, 1978; Boskey and Posner 1976; Glimcher et al. 1981). Interestingly, thermodynamic data prove that the transition of freshly precipitated ACP into CDHA involves intermediate formation of OCP (Meyer and Eanes 1978a, b). However, the discovery of a stable amorphous calcium carbonate in sea urchin spines (Politi et al. 2004) reawakened the suggestion that a transient amorphous phase might also exist in bones (Olszta et al. 2007; Weiner et al. 2005, 2009; Weiner 2006; Pekounov and Petrov 2008; Gower 2008). Afterwards, evidences of an abundant ACP phase in the continuously forming fin bones of zebrafish were found (Mahamid et al. 2008, 2010). The new bone mineral was found to be delivered and deposited as packages of nanodimensional spheres of ACP, which further transformed into platelets of crystalline apatite within the collagen matrix (Mahamid et al. 2010).

Furthermore, to investigate how apatite crystals form inside collagen fibrils, researchers carried out a time-resolved study starting from the earliest stages of mineral formation (Nudelman et al. 2010). After 24 h of mineralization, CaPO4 particles were found outside the fibril, associated with the overlap region, in close proximity to the gap zone. Cryogenic energy-dispersive X-ray spectroscopy confirmed that these precipitates were composed of CaPO4, while a low-dose selected-area electron diffraction technique showed a diffuse band characteristic of ACP. After 48 h, CDHA crystals started to develop within a bed of ACP and after 72 h, elongated electron-dense crystals were abundant within the fibril, in many cases still embedded within a less dense matrix. A low-dose selected-area electron diffraction technique demonstrated that the mineral phase consisted of both ACP and oriented apatite, the latter identical to bone apatite (Nudelman et al. 2010). This process is schematically shown in Fig. 14 (Cölfen 2010). Further details on the bone formation mechanisms are available in literature (Olszta et al. 2007; Hall 2015; Driessens et al. 2012; Boonrungsiman et al. 2012), where the interested readers are referred.
Fig. 14

A schematic illustration of in vivo mineralization of a collagen fibril: top layer—CaPO4 clusters (green) form complexes with biopolymers (orange line), forming stable mineral droplets; second top layer—mineral droplets bind to a distinct region on the collagen fibers and enter the fibril; second bottom layer—once inside the collagen, the mineral in a liquid state diffuses through the interior of the fibril and solidifies into a disordered phase of ACP (black); bottom layer—finally, directed by the collagen, ACP is transformed into oriented crystals of biological apatite (yellow). Reprinted from Ref. (Cölfen 2010) with permission

In spite of the century-plus long studies (Dorozhkin 2012a, 2013a), the maturation mechanism of bone minerals remains to be not well established, mainly due to the difficulties involved in the nanostructural analyses (Olszta et al. 2007; Sahar et al. 2005). Still, indirect evidences for the in vivo bone mineral maturation are available only. For example, X-ray diffraction patterns of bones from animals of different age show that the reflections become sharper with age increasing (Meneghini et al. 2003; Bilezikian et al. 2008). This effect is more pronounced in the crystallographic a-axis [(310) reflections] as compared to the c-axis [(002) reflections] (Burnell et al. 1980; Weiner and Traub 1986). The most comprehensive report describing how normal human bone mineral changes in composition and crystal size as a function of age was based on X-ray diffraction analyses by Hanschin and Stern (Hanschin and Stern 1995), who examined 117 homogenized iliac crest biopsies from patients aged 0–95 years. They found that the bone mineral crystal size and perfection increased during the first 25–30 years and then decreased thereafter, slightly increasing in the oldest individuals. The same 117 homogenized biopsy samples were analyzed by wavelength-dispersive X-ray fluorescence to quantify the carbonate substitution in biological apatite as a function of age. Although the changes observed in carbonate substitution were relatively slight (at most 10 %), there was a general increase from 0 to 90 years that is distinct from the absence of a change in crystallinity after age 30 in these samples (Boskey and Coleman 2010). In addition, other changes, like an increase of Ca2+ content and a decrease of HPO4 2−, occur in bone mineral with age (Verdelis et al. 2007; Yerramshetty et al. 2006; Kuhn et al. 2008; Donnelly et al. 2009; Li and Pasteris 2014; Lowenstam 1981; Lowenstam and Weiner 1983; Plate et al. 1996; Stratmann et al. 1996; Jahnen-Dechent et al. 1997, 2001; Schinke et al. 1999; Savelle and Habu 2004; Chen et al. 2011b; Delloye et al. 2007; Araújo et al. 2009; Koussoulakou et al. 2009; Jones 2001; Avery 2001; Nanci 2012; Xue et al. 2008; Gaft et al. 1996; Huang et al. 2007; Yin et al. 2013; Ho et al. 2009a). Both the crystal sizes and carbonate content were found to increase during aging in rats and cows (LeGeros et al. 1987; Rey et al. 1995b). The increase in carbonate content with age was also reported in other studies (Yerramshetty et al. 2006; Kuhn et al. 2008; Donnelly et al. 2009; Li and Pasteris 2014). Simultaneously with carbonate content increasing, the content of sodium increased as well (Li and Pasteris 2014). From a chemical point of view, these changes indicate to a slow transformation of poorly crystallized non-apatitic CaPO4 into a better-crystallized ion-substituted carbonate-containing CDHA. In addition, during aging, edge areas of bones were found to become less porous, whereas the concentration of organics in the edges was reduced (Li and Pasteris 2014). While there are still many gaps in our knowledge, the researchers seem to be comfortable in stating that in all but the youngest bone and dentine, the only phase present is a highly disordered, highly substituted biological apatite.

In general, the biomineralization process (therefore, bone formation) can happen in two basic ways: either the mineral phase is developed from the ambient environment as it would from a supersaturated solution of the requisite ions, but just requires the living system to nucleate and localize mineral deposition, or the mineral phase is developed under the direct regulatory control of the organism, so that the mineral deposits are not only localized but may be directed to form unique crystal habits not normally developed by a saturated solution of the requisite ions. In a very famous paper (Lowenstam 1981) and two extended elaborations (Lowenstam and Weiner 1983, 1989), the first type of biomineralization was called “biologically induced” mineralization and the second “(organic) matrix-mediated” biomineralization. In some papers, the former process is called “passive” and the latter one—“active” biomineralization (Lowenstam and Weiner 1989). Briefly, an “active process” means an assembly of nano-sized crystals of biological apatite into bones due to an activity of the suitable cells (e.g., osteoblasts), i.e., within a matrix vesicle. Such structures have been discovered by transmission electron microscopy for bone and teeth formation (Plate et al. 1996; Stratmann et al. 1996). A “passive process” does not require involvement of cells and means mineralization from supersaturated solutions with respect to the precipitation of biological apatite. In the latter case, thermodynamically, biomineralization might occur at any suitable nucleus. The collagen fibrils have a specific structure with a 67 nm periodicity and 35–40 nm gaps or holes between the ends of the collagen molecules where bone mineral is incorporated in the mineralized fibril (Weiner and Wagner 1998; Weiner et al. 1999; Tzaphlidou 2008; Boskey 2007; Glimcher 2006). Such a nucleation within these holes would lead to discrete crystals with a size related to the nucleating cavity in the collagen fibril (Fig. 12). It was proposed that a temporary absence of the specific inhibitors might regulate the process of bone formation (Jahnen-Dechent et al. 1997, 2001; Schinke et al. 1999).

To conclude the bone subject, let me briefly mention on the practical application of bones. In the Stone Age, bones were used to manufacture art, weapons, needles, catchers, amulets, pendants, headdresses, etc. In the coastal regions, big bones of whales were used to construct houses (Savelle and Habu 2004). Nowadays, cut and polished bones from a variety of animals are sometimes used as a starting material for jewelry and other crafts. Ground cattle bones are used as a fertilizer (Chen et al. 2011b). Furthermore, in medicine, bones are used for bone graft substitutes, such allografts from cadavers (Delloye et al. 2007) and xenografts (Araújo et al. 2009). However, since recently, bone-derived biomaterials are attempting to avoid due to serious concerns about bovine spongiform encephalopathy (“mad cow disease”) and other possible diseases that might be transmitted even by heated bones.


Teeth (singular: tooth) are dense mineralized hard tissues found in the jaws, mouth and/or pharynx of many vertebrates (Koussoulakou et al. 2009). They have various structures to allow them to fulfill their different purposes. The primary function of teeth is to tear and chew food, while for carnivores it is also a weapon. Therefore, teeth have to withstand a range of physical and chemical processes, including compressive forces (up to ~700 N), abrasion and chemical attack due to acidic foods or products of bacterial metabolism (Jones 2001). The roots of teeth are covered by gums. From the surface teeth are covered by enamel of up to ~2 mm thick at the cutting edges of the teeth, which helps to prevent cavities on the teeth. The biggest teeth of some gigantic animals (elephants, hippopotamuses, walruses, mammoths, narwhals, etc.) are known as tusks or ivory.

Similar to the various types of bones, there are various types of teeth. The shape of the teeth is related to the animal’s food, as well as its evolutionary descent. For example, plants are hard to digest, so herbivores have many molars for chewing. Carnivores need canines to kill and tear and since meat is easy to digest, they can swallow without the need for molars to chew the food well. Thus, the following types of teeth are known: molars (used for grinding up food), carnassials (used for slicing food), premolars (small molars), canines (used for tearing apart food) and incisors (used for cutting food). While humans only have two sets of teeth, some animals have many more: for example, sharks grow a new set of teeth every 2 weeks. Some other animals grow just one set during the life, while teeth of rodents grow and wear away continually through the animal gnawing, maintaining constant length (Avery 2001; Nanci 2012).

Similar to bones, the inorganic part of teeth also consist of biological apatite (Xue et al. 2008). The stability of the mineral composition of teeth also has a very long history: namely, CaPO4 were found in fossil fish teeth (Gaft et al. 1996). Similarly, investigations of biological apatite from fossil human and animal teeth revealed its similarity to the modem biological apatite (Huang et al. 2007). The same was found for modern and fossil (mammoth) elephant ivories (Yin et al. 2013).

The structure of teeth (Fig. 15 top) appears to be even more complicated than that of bones. Unlike bones, teeth consist of at least two different CaPO4 materials: enamel, which is a rigid, inert and acellular outer layer, and dentine, which is a bone-like Mg-rich hard tissue that forms the bulk of vertebrate teeth. In addition, there is cementum, which is a thin layer of a bone-like calcified tissue that covers dentine at the roots of teeth and anchors them to the jaw (Ho et al. 2009a, b; Bosshardt and Selvig 2000; Yamamoto et al. 2010). Finally, there is the core called pulp (commonly called “the nerve”)—it is a remnant of the embryologic organ for tooth development and contains nerves and blood vessels necessary for tooth function. All these tissues form a highly organized and complex structure (Fig. 15 top) with ideal functional and structural capabilities, which assist in sustaining mastication-induced mechanical loading and preventing their mechanical failures during function (Boskey 2007; Glimcher 2006; Avery 2001; Nanci 2012). It is interesting to note that the structure of teeth is common to the most species. Namely, fish, reptiles and mammals share the same architecture of a harder external layer and a tougher core.
Fig. 15

Top a schematic drawing of a tooth. Other very good graphical sketches of the mammalian tooth structure, including the hierarchical levels, are available in Refs. (Palmer et al. 2008; Meyers et al. 2008). Bottom a scanning electron micrograph of the forming enamel of a continuously growing rat incisor showing ordered rods of CaPO4. Scale bar 10 μm. Reprinted from Ref. (Lowenstam and Weiner 1989) with permission

Both dentine and cementum are mineralized connective tissues with an organic matrix of collagenous proteins, while the inorganic component of them consists of biological apatite. As shown in Table 3, dentine, cementum and bone are quite similar and for general purposes of material scientists they are regarded as being essentially the same material (Elliott 2002; Weiner and Wagner 1998; Currey 2002; Rho et al. 1998; Fratzl et al. 2004; Rubin et al. 2003; Su et al. 2003; Pellegrino and Blitz 1972; LeGeros et al. 1987; Jones 2001). However, strictly speaking, there are some differences among them. For example, the hardness of live dentine is less than that of enamel but is greater than that of bone or cementum (Ho et al. 2009a). When pulp of the tooth dies or is removed by a dentist, the properties of dentine change: it becomes brittle, liable to fracture and looses a reparative capability. In addition, unlike bones, both dentine and cementum lack vascularization. In spite of these minor differences, let us consider that the majority of the statements made in the previous section for bones are also valid for dentine and cementum.

Dental enamel is the outermost layer of teeth. It is white and translucent and its true color might be observed at the cutting edges of the teeth only. Enamel is highly mineralized and acellular, so it is not a living tissue. Nevertheless, it is sufficiently porous for diffusion and chemical reactions to occur within its structure, particularly acidic dissolution (dental caries) and remineralization from saliva (possible healing of caries lesions). Therefore, it acts as a selectively permeable membrane, allowing water and certain ions to pass via osmosis (Avery 2001; Nanci 2012).

Enamel is the hardest substance in the body and forms a solid, tough and wear-resistant surface for malaxation (Chai et al. 2009). In the mature state, it contains up to 98 % of inorganic phase (Table 3). Other components of enamel include remnants of the organic matrix and loosely bound water molecules. Interestingly, from the mechanical point of view, dental enamel was found to be a “metallic-like” deformable biocomposite, because enamel was found to have a similar stress–strain response to that of cast alloy and gold alloy, all of which showed work-hardening effect (He and Swain 2007). The crystals of biological apatite of enamel are much larger as evidenced by higher crystallinity (reflecting greater crystal size and perfection) demonstrated in their X-ray diffraction patterns than those of bone and dentine. Besides, enamel apatite has fewer ionic substitutions than bone or dentine mineral and more closely approximates the stoichiometric HA (Boskey 2007). The organic phase of enamel does not contain collagen. Instead, enamel has two unique classes of proteins called amelogenins and enamelins. While the role of these proteins is not fully understood yet, it is believed that both classes of proteins aid in the enamel development by serving as a framework support (Avery 2001; Nanci 2012; Margolis et al. 2006). The large amount of minerals in enamel accounts not only for its strength but also for its brittleness. Dentine, which is less mineralized and less brittle, compensates for enamel and is necessary as a support (Avery 2001; Nanci 2012). Shark enameloid is an intermediate form bridging enamel and dentine. It has enamel-like crystals of fluoridated biological apatite associated with collagen fibrils (Lowenstam and Weiner 1989; Rey et al. 2006; Prostak et al. 1993; Dahm and Risnes 1999; Carr et al. 2006; Enax et al. 2014). Due to the presence of fluorides, biological apatite of shark enameloid shows both higher crystal sizes and a more regular hexagonal symmetry if compared to non-fluoridated biological apatite of bones and teeth (Daculsi et al. 1997). Similar correlation between the presence of fluorides and crystal dimensions was found for enamel (Vieira et al. 2003).

Like that for bones, seven levels of structural hierarchy have been also discovered in human enamel; moreover, the analysis of the enamel and bone hierarchical structure suggests similarities of the scale distribution at each level (Palmer et al. 2008; Athanasiou et al. 2000; Cui and Ge 2007). On the mesoscale level, there are three main structural components: a rod, an interrod and aprismatic enamel. Among them, the enamel rod (formerly called an enamel prism) is the basic unit of enamel. It is a tightly packed mass of biological apatite in an organized pattern. Each rod traverses uninterrupted through the thickness of enamel. They number 5–12 million rods per crown. The rods increase in diameter (4 up to 8 microns) as they flare outward from the dentine-enamel junction (DEJ). Needle-like enamel rods might be tens of microns long (up to 100 µm) but sometimes only 50 nm wide and 30 nm thick (Fig. 15 bottom; Avery 2001; Nanci 2012; Jandt 2006; Chen et al. 2004; Rönnholm 1962; Nylen et al. 1963; Miake et al. 1993; Daculsi et al. 1984; Jodaikin et al. 1984; Bres and Hutchison 2002). They are quite different from the much smaller crystals of dentine and bone (Table 3), but all of them consist of biological apatite (Schroeder and Frank 1985; Brès et al. 1990). In cross section, an enamel rod is best compared to a keyhole, with the top, or head, oriented toward the crown of the tooth and the bottom, or tail, oriented toward the root of the tooth.

The arrangement of the crystals of biological apatite within each enamel rod is highly complex. Enamel crystals in the head of the enamel rod are oriented parallel to the long axis of the rod. When found in the tail of the enamel rod, the crystals’ orientation diverges slightly from the long axis (Avery 2001; Nanci 2012). The arrangement of the enamel rods is understood more clearly than their internal structure. Enamel rods are found in rows along the tooth (Fig. 15 bottom) and, within each row, the long axis of the enamel rod is generally perpendicular to the underlying dentine (Avery 2001; Nanci 2012; Jandt 2006; Chen et al. 2004; Rönnholm 1962; Nylen et al. 1963; Miake et al. 1993). An AFM study indicated that apatite crystals in enamel exhibited regular sub-domains or subunits with distinct chemical properties related to topographical features and gave rise to patterned behavior in terms of the crystal surface itself and the manner in which it responded to low pH (Robinson et al. 2004). In addition, the results of the investigations of human single apatite crystals of both enamel and dentine revealed an absence of the mirror plane perpendicular to the c-axis leading to the P63 space group (Mugnaioli et al. 2014) instead of the P63/m space group typical for HA and FA (Table 4).

The second structural component of the enamel matrix is the interrod (or interprismatic) enamel, which surrounds and packs between the rods. The difference between the rod and the interrod is the orientation of apatite crystals; the rod contains aligned crystallites, whereas the mineral in the interrod is less ordered. These structures coalesce to form the tough tissue of enamel, which can withstand high forces and resist damage by crack deflection. The third structure, aprismatic enamel, refers to the structures containing apatite crystals that show no meso-scale or macro-scale alignment (Palmer et al. 2008).

The in vivo formation and development of teeth appears to be even more complicated when compared with the aforedescribed process of bone formation. It is a very complex biological process, by which teeth are formed from embryonic cells, grow and erupt into the mouth (Boskey and Roy 2008). For human teeth enamel, dentine and cementum must all be developed during the appropriate stages of fetal development. Primary (baby) teeth start to form between the sixth and eighth weeks in utero, while the permanent teeth begin to form in the twentieth week in utero (Avery 2001; Nanci 2012). Experimental data confirmed the necessity of CaPO4 in the diet of pregnant and nursing mother to prevent early childhood dental caries (Warf and Watson 2008).

As teeth consist of at least two materials with different properties (enamel and dentine), the tooth bud (sometimes called “the tooth germ”—that is an aggregation of cells that eventually forms a tooth) is organized into three parts: the enamel organ, the dental papilla and the dental follicle. The enamel organ is composed of at least four other groups of cells [for the biological details see Refs. (Avery 2001; Nanci 2012)]. Altogether, these groups of cells give rise to ameloblasts, which secret enamel matrix proteins. The protein gel adjacent to ameloblasts is supersaturated with CaPO4, which leads to the precipitation of biological apatite. Similarly, the dental papilla contains cells that develop into odontoblasts, which are dentine-forming cells. The dental follicle gives rise to three important entities: cementoblasts, osteoblasts and fibroblasts. Cementoblasts form the cementum of a tooth (Bosshardt and Selvig 2000). Osteoblasts give rise to the alveolar bone around the roots of teeth (see bone formation above). Fibroblasts develop the periodontal ligaments that connect teeth to the alveolar bone through cementum (Boskey 2007; Glimcher 2006; Boskey and Roy 2008; Hall 2015; Avery 2001; Nanci 2012).

The first detectable crystals in enamel formation are flat thin ribbons (Rönnholm 1962; Nylen et al. 1963; Miake et al. 1993) that were reported to be OCP (Brown and Chow 1976; Simmer and Fincham 1995; Diekwisch et al. 1995; Aoba 1996), β-(Ca,Mg)3(PO4)2 (Diekwisch et al. 1995), DCPD (Rey et al. 1995a; Bonar et al. 1991) or ACP (Beniash et al. 2009). The formation process of enamel is different from that for bone or dentine: amelogenin being hydrophobic self-assembles into nano-sized spheres that guide the growth of the ribbon-like dental enamel crystals. During maturation of enamel, the mineral content increases from initially ~45 wt.% up to ~98–99 wt.% (Avery 2001; Nanci 2012; Bonar et al. 1991). The enamel crystal rods widen and thicken by additional growth (Rey et al. 1995b; Bonar et al. 1991; Smith 1998) with a simultaneous increase of the Ca/P molar ratio (Smith 1998) and a decrease in carbonate content (Sydney-Zax et al. 1991; Rey et al. 1991; Takagi et al. 1998), finally resulting in the most highly mineralized and hardest substance produced by vertebrates. It is interesting to note that in the radular teeth of chitons, ACP was found to be the first-formed CaPO4 mineral, which over a period of weeks was transformed to dahllite (Lowenstam and Weiner 1985).

The crystal faces expressed in enamel are always (100) face and at the ends presumably (001) (Selvig 1970, 1973), which are the ones usually found in HA. The centers of enamel crystals contain a linear structure known as the “central dark line” (this line was also observed in bone and dentine), which consists of OCP (Iijima et al. 1996; Bodier-Houllé et al. 1998; Rodríguez-Hernández et al. 2005; Tseng et al. 2006). However, data are available that the “central dark line” appears to be the calcium richest part of the human tooth enamel crystallites (Gasga et al. 2008). As described above for bones, X-ray diffraction studies revealed that the biological apatite of younger teeth was less crystalline than that of more mature ones, while the maximum crystallinity was found for teeth belonged to people of 31–40 years old (Pankaew et al. 2012). Therefore, maturation of teeth also means a slow transformation (re-crystallization?) of biological CaPO4 from ion-substituted ACP to a better-crystallized ion-substituted CDHA. However, crystallinity of teeth belonged to older people (41–50 and 51–60 years old) was found to decrease with age. Simultaneously, thermogravimetric studies revealed bigger weight loss for teeth of the older people (Pankaew et al. 2012), which could be due to a greater amount of carbonates.

The development of individual enamel and dentine crystals was studied by high-resolution transmission electron microscopy. Both processes appear to be roughly comparable and were described in a four-step process. The first two steps include the initial nucleation and formation of nano-sized particles of biological apatite. They are followed by ribbon-like crystal formation, which until recently was considered as the first step of biological crystal formation (Cuisinier et al. 1993; Houllé et al. 1997). These complicated processes, starting with the heterogeneous nucleation of inorganic CaPO4 on an organic extracellular matrix, are controlled in both tissues by the organic matrix and are under cellular control (Bodier-Houllé et al. 1998; Mann 1993). To complicate the process even further, regular and discrete domains of various charges or charge densities on the surface of apatite crystals derived from the maturation stage of enamel development were discovered by a combination of atomic and chemical force microscopy (Kirkham et al. 2000). Binding of organic molecules (e.g., amelogenin (Kirkham et al. 2000)) at physiological solution pH appears to occur on the charged surface domains of apatite. The recent visions on dental tissue research are available elsewhere (Smith and Tafforeau 2008).

As teeth consist of several materials, there are mutual junctions among them. For example, a dentine–enamel junction (DEJ) is a thin [2.0 ± 1.1 μm (Habelitz et al. 2001)] but gradual interface with characteristics transiting from those of dentine to those of enamel. Namely, the collagen fibers in dentine were found to enter into the enamel side of DEJ and terminate in a region in which crystals of biological apatite begin to show enamel characteristics (Chan et al. 2011). In addition, the average contents of organic matrix and carbonate ions were found to increase in the order: enamel < DEJ < dentin. Furthermore, HPO4 2− ions were not detected in the DEJ, while in dentin their content was higher than in enamel (Kolmas et al. 2010). Comparable results were obtained in another study (Desoutter et al. 2014). Besides, both chemical and molecular structure of DEJ appeared to be dependent on the intratooth location (Xu et al. 2009). Genetically, it is a remnant of the onset of enamel formation because enamel grows outwards from this junction (Nanci 2012). Mechanically, DEJ plays an important role in preventing crack propagation from enamel into dentine (Imbeni et al. 2005). Hierarchically, DEJ has a three-level structure: 25–100 μm scallops with their convexities directed toward the dentin and concavities toward the enamel, 2–5 μm microscallops and a smaller scale structure (Marshall et al. 2003). Therefore, high-resolution elastic modulus mapping has indicated that the DEJ is a band with a graded mechanical property rather than a discrete interface (Sui et al. 2014). The major steps of enamel crystal growth at the junction have been described above but the mechanism of the junction formation is still debatable. Some authors claim that enamel crystals grow epitaxially on the pre-existing dentine crystals because of a high continuity between enamel and dentine crystals (Arsenault and Robinson 1989; Hayashi 1992, 1993). Others have shown that enamel crystals are formed at a given distance from the dentine surface (Simmer and Fincham 1995; Diekwisch et al. 1995; Aoba 1996; Bodier-Houllé et al. 2000) and could either reach dentine crystals by a subsequent growth (Takano et al. 1996) or remain distant (Bodier-Houllé et al. 2000; Dong and Warshawsky 1996). In addition, there are both a cementum–enamel junction (CEJ) (Wang et al. 2006b), which is quite similar to DEJ, and a cementum–dentine junction (CDJ) (Ho et al. 2004, 2005; Jang et al. 2014).

Enamel formation, or amelogenesis, is a highly regulated process involving precise genetic control as well as protein–protein interactions, protein–mineral interactions and interactions involving the cell membrane. Much is still unknown about the interactions among proteins present in enamel matrix and the final crystalline phase of biological apatite (Palmer et al. 2008; Paine et al. 2001). At some point before a tooth erupts into the mouth, the ameloblasts are broken down. Consequently, unlike bones, enamel has no way to regenerate itself using the process of “active mineralization” (see bone formation) because there is no biological process that repairs degraded or damaged enamel (Avery 2001; Nanci 2012). In addition, certain bacteria in the mouth feed on the remains of foods, especially sugars. They produce lactic acid, which dissolves the biological apatite of enamel in a process known as enamel demineralization that takes place below the critical pH of about 5.5. Similar process called enamel erosion occurs when a person consumes acid-containing (citric, lactic, phosphoric, etc.) soft drinks (Jandt 2006; Barbour and Rees 2004; Low and Alhuthali 2008; White et al. 2010). Evidences exist that there is a preferential loss of carbonates and Mg during acidic dissolution of mineral in dental caries. Luckily, saliva gradually neutralizes the acids that cause pH on teeth surface to rise above the critical pH. This might cause partial enamel remineralization, i.e., a return of the dissolved CaPO4 to the enamel surface. Until recently, it was generally agreed that if there was sufficient time between the intake of foods (generally, 2–3 h) plus a damage was very limited, teeth could repair themselves by the “passive mineralization” process (LeGeros 1999). Data on increased remineralization of dental enamel by CaPO4-containing compounds (Cochrane et al. 2008; Langhorst et al. 2009; Weir et al. 2012) are in support of this hypothesis.

However, studies performed using atomic force microscopy nano-indentation technique revealed that previously demineralized samples of dental enamel further exposed to remineralizing solutions did show a dense crystalline layer of CaPO4 formed on their surface. Unfortunately, the re-precipitated deposits of CaPO4 always consisted of loosely packed crystals and did not protect the underlying enamel from a subsequent acid attack. Furthermore, these surface deposits were completely removed by either a toothbrush or a short exposure to an erosive acidic solution (Jandt 2006; Lippert et al. 2004a, b, c). In this context, it should be emphasized that the term “remineralization”, which is often misused in the literature, should imply the process of mineral growth that goes hand in hand with a strengthening effect of the weakened enamel surface. Since no strengthening of an exposure to remineralizing solutions was observed, it might be considered that no “passive mineralization” was found (in spite of the real evidence of the re-precipitated surface deposits of CaPO4) (Jandt 2006; Lippert et al. 2004b, c).

An interesting hypothesis that nano-sized apatite crystallites occur in the oral cavity during extensive physiological wear of the hierarchical structured enamel surface due to dental abrasion and attrition has been published (Hannig and Hannig 2010). These nano-scaled apatite enamel crystallites might promote remineralization at the tooth surface. However, this idea should be verified experimentally. Thus, according to the current knowledge, the enamel self-repairing ability by a passive remineralization appears to be doubtful, while an active remineralization is impossible. Nevertheless, investigations in this field keep going (Karlinsey and Mackey 2009; Karlinsey et al. 2010a, b; Busch 2004; Onuma et al. 2005; He and Feng 2007; Li et al. 2008b, 2014a; Wang et al. 2009; Roveri et al. 2009a, b; Peters et al. 2010; Orsini et al. 2010; Uysal et al. 2010; Niu et al. 2014). For example, ACP-containing orthodontic biocomposite resins might reduce the enamel decalcification found in patients with poor oral hygiene (Uysal et al. 2010). Further details on CaPO4 application in dentistry are available in a topical review (Dorozhkin 2013c).

A content of fluoride added to either toothpaste or mouthwash lowers the solubility of CaPO4 (by formation of FHA on the surface) and therefore improves the acid resistance of dental enamel (Schemehorn et al. 2011; Hattab 2013; Driessens 1973; Moreno et al. 1974; McClendon 1966). Furthermore, fluorides also reduce production of acids by bacteria in the mouth by reducing their ability to metabolize sugars. However, dental treatment by fluorides must be used with care because an improper treatment results in formation of CaF2 globules deposited on the enamel surface (Wang et al. 2008a).

To conclude the teeth subject, let me briefly mention on the practical application of teeth. Due to relatively small dimensions of normal teeth, only tusks and ivory of giant animals are widely used. For example, both the Greek and Roman civilizations used large quantities of ivory to make high value works of art, precious religious objects and decorative boxes for costly objects. Ivory was often used to form the whites of the eyes of statues. Prior to introduction of plastics, it was used for billiard balls, piano keys, buttons and ornamental items. The examples of modern carved ivory objects are small statuary, netsukes, jewelry, flatware handles and furniture inlays.


Deer antlers (Fig. 16 top) are unique biological structures since their growth rate is without parallel in vertebrates and because they are the only bony appendages in mammals capable of complete regeneration. This allows for basic research in bone biology without the interference of surgical procedures and their adverse effects in animals where samples are obtained. In addition, antlers also allow for the gathering of a large amount of samples from different populations to assess nutritional and ecological effects on bone composition and structure (Yue et al. 2005; Zhao et al. 2006; Landete-Castilleijos et al. 2007a). They are costly sexual secondary characters of male deer and constitute 1–5 % of the body weight (Huxley 1931). Recent studies suggest that antler regeneration is a stem cell-based process and that these stem cells are located in the pedicle periosteum (Kierdorf et al. 2009; Kierdorf and Kierdorf 2011).
Fig. 16

Top red deer stag at velvet shedding. The bare bone of the hard antlers is exposed. Reprinted from Ref. (Kierdorf and Kierdorf 2011) with permission. A good cross-sectional image of a deer antler is available in Ref. (Meyers et al. 2008). Bottom fallen antlers used to make a chandelier

Antlers are not true horns; they are a simple extension of bone. Both antlers and bones utilize the same basic building blocks, namely the type I collagen in the protein phase and the carbonated CDHA in the mineral phase, which was verified by amino acid analysis, X-ray diffraction and TEM observations (Chen et al. 2009). Antlers are large and complex horn-like appendages of deer consisting of bony outgrowths from the head with no covering of keratin as found in true horns. Usually, they begin growing in March and reach maturity in August. In winter, antlers fall off; this is known as shedding. Similar to bones, antlers contain pores and can withstand applied stresses of over 300 MPa (Landete-Castilleijos et al. 2007b; Evans et al. 2005; Akhtar et al. 2008; Currey et al. 2009), which is even higher than that of bones (Table 3). Therefore, antlers are occasionally considered an almost unbreakable bone (Currey et al. 2004). However, there are several distinct differences between them. Namely, antlers and skeletal bones have different functions. The primary functions of antlers are social display, defense against predators and combat between male species. Skeletal bones contain bone marrow, whereas antlers have no marrow. There exists a transition zone between cortical and cancellous bones in antlers, whereas there is no such transition zone in skeletal bones. The cancellous bone is well aligned and uniformly distributed through the entire antler. In bovine femur, the cancellous bone is mainly located in the femur head and its density decreases progressively toward the central region of the femur, which correlates to the external loading conditions. In addition, antlers have a lower mineral content and consequently lowest elastic modulus among mineralized calcified tissues with a mineral content of ~50 wt% (or ~30 vol. %). Interesting that antlers may act as large hearing aids; namely, moose with antlers have far more sensitive hearing than moose without them (Bubenik and Bubenik 2008).

Since antlers are accessible, shed after mating season and cast every year, they appear to be a good model to study bone biology (Price et al. 2005; Landete-Castilleijos et al. 2007c; Li et al. 2014b). Each antler grows from an attachment point on the skull called a pedicle. While an antler is growing, it is covered with highly vascular skin called velvet, which supplies oxygen and nutrients to the growing bone. Antlers bud and branch as they grow. Once they have achieved the proper dimensions, the velvet starts to dry out, cracks and breaks off, while the antler’s bone dies. Therefore, fully developed antlers consist of dead bone only (Kierdorf and Kierdorf 2000, 2005; Pathak et al. 2001; Yuxia et al. 2002; Li et al. 2005). However, the formation and mineralization process of antlers is still not fully understood. To clarify this, researchers used oxytetracycline injections to label different stages of bone formation in antlers of 14 red deer between days 28 and 156 of antler growth. The results revealed that initially a trabecular scaffold of woven bone was formed which largely replaced a pre-existing scaffold of mineralized cartilage. Lamellar bone was then deposited and from about day 70 onwards, primary osteons filled in the longitudinal tubes lined by the scaffold in a proximal to distal sequence (Gomez et al. 2013). In addition, it was found that food processing cannot supply the mineral needs required for antler growth and thus, male deer must temporarily resorb CaPO4 minerals from their own skeleton for antler growth (Meister 1956; Muir et al. 1987; Baxter et al. 1999). Detailed studies revealed that daily food intake provided between 25 and 40 % of calcium needed for antler mineralization, which resulted in a temporary skeleton demineralization (Muir et al. 1987; Baxter et al. 1999).

One should note that people seldom come across the antlers in the woods. Rabbits and rodents such as mice and chipmunks eat antlers (and bones of wild animals after they die) for calcium. Rodents and rabbits also gnaw bones and antlers to sharpen their incisors. Due to an extremely high growth rate, which can achieve 2–4 cm per day, combined with a very fast biomineralization, these unique appendages might be a well-suited animal model for studying the disturbances of bone formation induced by additives (e.g., by excess of fluoride) (Kierdorf and Kierdorf 2005). Antler size and external characteristics were found to be influenced by nutrition, climatic variability and other factors. Thus, since antlers are periodically replaced, the analysis of naturally cast antlers offers the opportunity for a continuous and a noninvasive monitoring of the environmental pollution by these additives (Kierdorf and Kierdorf 2005).

To conclude this part, let me briefly mention on the practical application of antlers. Associated with aristocracy, antlers have adorned European castles and hunting lodges for centuries. Today, furnishings and accessories made from antlers are featured in fine homes throughout the world and are a reflection of grace and elegance (Fig. 16 bottom). Concerning biomedical applications, the initial attempts to evaluate a potential use of deer antlers as xenogenic bone grafts have been already performed (Baciut et al. 2007; Hasan et al. 2012; Zhang et al. 2012, 2013).

Pathological calcification of CaPO4

In the body of mammals, osteoblasts and odontoblasts fix ions of calcium and orthophosphate and then precipitate biological apatite onto an organic matrix. This is the process of physiological biomineralization that is restricted to the specific sites in skeletal tissues, including growth plate cartilage, bones, teeth and antlers (Lowenstam and Weiner 1989; Daculsi et al. 1997). Normally, mammals are supposed to die with CaPO4 located in bones and teeth (and antlers for male deer) only and nowhere else, because under the normal conditions soft tissues are not mineralized. Unfortunately, owing to aging, various diseases and under certain pathological conditions blood vessels, muscles, extracellular matrix of articular cartilaginous tissues of the joints and some internal organs are calcified as well. This process is called pathological calcification or ectopic (bio)mineralization and leads to a morbidity and a mortality (Lowenstam and Weiner 1989; Daculsi et al. 1997; Block et al. 1998). In general, any type of abnormal accumulation of CaPO4 in wrong places is accounted for by a disruption of systemic defense mechanism against calcification (Kazama et al. 2006).

To the best of my findings (Dorozhkin 2012a, 2013a), the earliest paper on a negative influence of unwanted depositions of CaPO4 in the body was published as early as in 1798 (Pearson 1798). According to the data available (Poloni and Ward 2014), the unwanted depositions could consist of many substances and all of them always lead to various diseases. Regarding the unwanted depositions of CaPO4, they are found in soft tissue calcification (in damaged joints, blood vessels, dysfunctional areas in the brain, diseased organs, scleroderma, prostate stones) (Reid and Andersen 1993; Scotchford and Ali 1995; P’ng et al. 2008; Brancaccio and Cozzolino 2005; Goff and Reichard 2006; Bittmann et al. 2003; Molloy and McCarthy 2006; Giachelli 2004; Kazama et al. 2007), kidney (Giannossi and Summa 2012; Mukherjee 2014) and urinary (Zhu et al. 2014; Huo et al. 2015; Selvaraju et al. 2015) stones, dental pulp stones and dental calculus (Kakei et al. 2009; Kodaka et al. 1988, 1998; Çiftçioglu et al. 1998; Hayashizaki et al. 2008), salivary stones (Zelentsov et al. 2001; Luers et al. 2014), gall stones (Qiao et al. 2013; Hussain and Al-Jashamy 2013), pineal gland calcifications (Güney et al. 2013), atherosclerotic arteries and veins (Ortlepp et al. 2004; Tomazic 2001; Marra et al. 2006; Kurabayashi 2013), coronary calcification (Fitzpatrick et al. 2003; Matsui et al. 2015), damaged cardiac valves (Suvorova and Buffat 2005), calcification on artificial heart valves (Giachelli 2001; Pettenazzo et al. 2001; Schoen and Levy 2005; Delogne et al. 2007), carpal tunnel (Sensui et al. 2003; Namba et al. 2008) and tumoral (Namba et al. 2008; Carlson et al. 2007; Sprecher 2010; Slavin et al. 2012; Kim et al. 2013; Burns et al. 2013) calcifications, cataracts (Kim and Choi 2007; Koinzer et al. 2009), malacoplakia (Ho 1989), calcified menisci (Katsamenis et al. 2012; Dessombz et al. 2013), dermatomyositis (Stock et al. 2004; Pachman and Boskey 2006) and still other places (Daculsi et al. 1997; Bazin et al. 2014b). In addition, there is a metastatic calcification of non-osseous viable tissue occurring throughout the body (Hale 2003; Alkan et al. 2009), but it primarily affects the interstitial tissue of the blood vessels, kidney, lungs and gastric mucosa. A metastatic calcification is defined as a deposition of CaPO4 in previously normal tissue due to an abnormal biochemistry with disturbances in the calcium or phosphorus metabolism (Grech et al. 1998). Common causes of the metastatic calcification include hyperparathyroidism, chronic renal disease, massive bone destruction in widespread bone metastases and increased intestinal calcium absorption. One author has mentioned on “apatite diseases” which are characterized by the appearance of needle-like crystals comparable to those of bone apatite in the fibrous connective tissue (Mohr 2003). All these cases are examples of a calcinosis (Sprecher 2010; Slavin et al. 2012; Kim et al. 2013; Burns et al. 2013), which might be described as a formation of undesired CaPO4 deposits in any soft tissue. In dentistry, a calculus or a tartar refers to a hardened plaque on the teeth, formed by the presence of saliva, debris and minerals (White 1997). Its rough surface provides the ideal medium for bacterial growth, threatening the health of the gums and absorbing unaesthetic stains far more easily than natural teeth (LeGeros 1991).

Calcifying nanodimensional particles are the first CaPO4-containing particles isolated from human blood and were detected in numerous pathologic calcification related diseases (Ciftçioğlu and McKay 2010). Interestingly, contrary to the mineral phases of normal calcifications (bone, dentine, enamel, cementum, antlers), which consist of only one type of CaPO4 (namely, biological apatite), the mineral phases of abnormal and/or pathological calcifications are found to occur as single or mixed phases of other types of CaPO4 (ACP, DCPD, OCP, β-(Ca,Mg)3(PO4)2) and/or other phosphate and non-phosphate compounds (e.g., magnesium orthophosphates, calcium pyrophosphates, calcium oxalates, etc.) in addition to or in place of biological apatite (Table 5; LeGeros 1991, 2001; Amjad 1997; Daculsi et al. 1997; Qiu and Orme 2008; Kodaka et al. 1988; Reid and Andersen 1993; Scotchford and Ali 1995; P’ng et al. 2008; Bazin et al. 2014b; Lee et al. 2006; Rosenthal 2007; Lagier and Baud 2003; Wesson and Ward 2007). However, precipitation of biological apatite in wrong places is also possible; this is the so-called “HA deposition disease” (Burns et al. 2013; Hayes and Conway 1990; Best et al. 1997; Garcia et al. 2003; Melrose et al. 2009).
Table 5

Occurrence of calcium phosphates in biological systems (human) (LeGeros 2001)

Calcium phosphate


Biological apatite

Enamel, dentine, bone, dental calculi, stones, urinary stones, soft-tissue deposits


Dental calculi and urinary stones


Dental calculi, crystalluria, chondrocalcinosis, in some carious lesions


Dental calculi, salivary stones, arthritic cartilage, soft-tissue deposits


Pseudo-gout deposits in synovium fluids


Heart calcifications in uremic patients, kidney stones

Occurrence of non-apatite phases in the pathological calcifications may indicate that they were crystallized under the conditions different from homeostasis or crystallization of the apatite structures was inhibited and less stable phases crystallized instead, without further change to the more stable one. Furthermore, in the places of pathological calcifications the solution pH is often relatively low. Given that nucleation and crystal growth is not a highly regulated process in any pathological deposits, there is not likely just one fundamental formation mechanism for all possible calcification types. Furthermore, various bioorganic impurities in the local environment undoubtedly influence the crystallization process, resulting in a great variety of pathological deposits. Thus, it is a highly complex problem. In some cases, the chemical composition of an unwanted inorganic phase might depend on the age of the pathological calcification and its location. For example, DCPD is more frequently found in young (3 months or younger) calculus, biological apatite is present in all ages of calculus, while β-(Ca,Mg)3(PO4)2 occurs more frequently in sub-gingival calculus. In mature calculus, the relative abundance of OCP, β-(Ca,Mg)3(PO4)2 and biological apatite also differ between the inner and outer layers (LeGeros 2001). It is interesting to note that the mineral phases of animal calculus (e.g., from dog) was found to consist of calcium carbonate and biological apatite, while human calculi do not contain calcium carbonate (LeGeros 2001; LeGeros et al. 1988).

The nucleation process is the main step in both normal and pathological calcifications. In vitro experiments performed to simulate the formation of sedimentary urinary stones demonstrated that in the absence of organic matter no CaPO4 crystallized in cavities with scarce liquid renovation, but regular CDHA layers appeared on the wall around the cavity (Grases and Llobera 1998). Visible deposits of calcified organic materials (mixtures of organic matter and spherulites of CDHA) were formed when a glycoprotein (mucin) was present. In this case, the walls of the cavity as well as the glycoproteins had the capacity to act as heterogeneous nucleators of CaPO4. CDHA microcrystal nucleation on the surface of epithelial cells can be a critical step in the formation of kidney stones (Lieske et al. 1997) and identical mechanisms can be thought for unwanted calcifications in other soft tissues of the body, such as cardiac valves or vascular ducts. Monolayers of CDHA crystals can bind to epithelial cells. A large amount of kidney stones contains CDHA as the crystallization nuclei.

In general, formation of crystals in pathological mineralizations follows the same principles as normal calcifications (Kirsch 2006, 2007). Namely, local conditions for nucleation require a certain degree of local supersaturation induced by biochemical processes, which can be promoted by deficiency of inhibitors (like diphosphate, Mg2+ or even citrate ions) and/or the presence of matrix of a bioorganic material (such as cholesterol) or other crystals of different solids, those might act as heterogeneous nuclei. In addition, other regulators (activators and inhibitors) of physiological biomineralization have been identified and characterized (Kirsch 2006, 2007; Speer and Giachelli 2004; Giachelli 2005; Giachelli et al. 2005; Schmitt et al. 2006; Azari et al. 2008). What is more, the biological fluids (e.g., serum, saliva, synovial fluids) are normally supersaturated with respect to biological apatite precipitation (LeGeros 1991, 2001; Lowenstam and Weiner 1989); therefore, in principle, calcification is thermodynamically feasible in any part of the body. However, normally it is not the case. Therefore, in the healthy body, the appropriate inhibitory mechanisms must be at work to prevent a superfluous calcification of soft tissues. These inhibition mechanisms are a hot research topic in molecular medicine but this subject is beyond the scope of current review.

In 2010, an arachidic acid Langmuir monolayer system was reported as a model for pathological mineralization of ion-substituted carbonate apatites from simulated body fluid (Dey et al. 2010). The authors demonstrated that the surface-induced formation of carbonateapatite started from aggregation of pre-nucleation clusters of yet unknown CaPO4 leading to nucleation of ACP before further development of oriented apatite crystals. This process is schematically shown in Fig. 17 (Cölfen 2010; Dey et al. 2010).
Fig. 17

A schematic representation of the different stages of a surface-directed mineralization of CaPO4. In stage 1, aggregates of pre-nucleation clusters are in equilibrium with ions in solution. The clusters approach a surface with chemical functionality. In stage 2, pre-nucleation clusters aggregate near the surface, with loose aggregates still in solution. In stage 3, further aggregation causes densification near the surface. In stage 4, nucleation of spherical particles of ACP occurs at the surface only. In stage 5, crystallization occurs in the region of the ACP particles directed by the surface. Reprinted from Refs. (Cölfen 2010; Dey et al. 2010) with permission

To conclude this part, it is worth reminding that CaPO4 of the biological origin are sparingly soluble in aqueous solutions. Therefore, removing them from the places of unwanted deposition would be an equivalent of bone demineralization; that is a challenge. Thus, the majority of therapeutic approaches are directed at preventing the progression of pathological calcifications. Among them, a chelation therapy might be of some interest to chemists and materials researchers because it deals with chemical processes (Lamas and Ackermann 2000; Knudtson et al. 2002). The general principles of demineralization and decalcification (i.e., removing the mineral Ca-containing compounds (phosphates and carbonates) from the bioorganic matrix) have been extensively reviewed (Ehrlich et al. 2008, 2009), where the interested readers are referred to.

Biomimetic crystallization of CaPO4

The term “biomimetics” (“the mimicry of life”) was coined by an American inventor, engineer and biophysicist Otto Herbert Schmitt (1913–1998) in the 1950s. Biomimetics (also known as bionics, biognosis and/or biomimicry) might be defined as application of the methods and systems found in nature to the study, design and construction of new engineering systems, materials, chemical compounds and modern technology. Another definition describes biomimetics as a micro-structural process that mimics or inspires the biological mechanism, in part or as a whole (Green et al. 2002). This biological process generates highly ordered materials with a hybrid composition, a complex texture and ultra-fine crystallites through a hierarchical self-assembly and begins by designing and synthesizing molecules that have an ability to self-assemble or self-organize spontaneously to higher order structures.

Biomimetism of synthetic materials for biomedical applications can be carried out at different levels in view of composition, structure, morphology, bulk and surface chemical-physical properties. Chemists, biologists, physicists and engineers interested in material science are amazed by the high degree of sophistication, miniaturization, hierarchical organization, hybridizing, reliability, efficiency, resistance and adaptability characterizing the natural materials. These properties, which biogenic materials have achieved through specific building principles selected by evolution, can be only partially obtained in manmade materials by present synthetic processes. For this reason, Nature is a school for material science. Biomimetism and bioinspiration represent important tools for the design and the synthesis of innovative materials and devices (Roveri et al. 2009b).

Historically, the biomimetic concept is very old (e.g., the Chinese wanted to make artificial silk ~3000 years ago; Daedalus’ wings was one of the early design failure), but the implementation is gathering momentum only in the 20th century. The first papers with the term “biomimetics” in the title were published in 1972 (Burke et al. 1972; Breslow 1972). In spite of the tremendous achievements of modern science and technology, the nature’s ability to assemble inorganic compounds into hard tissues (shells, spicules, teeth, bones, antlers, skeletons, etc.) is still not achievable by the synthetic procedures. This is not surprising—designs found in nature are the result of millions of years of evolution and competition for survival. The models that failed are fossils; those that survived are the success (Benyus 1997). In the frames of this review, biomimetics is considered as mimicking natural manufacturing methods to generate artificial calcified tissues (grafts, implants, prostheses) those might be used as temporary or permanent replacements of the missing, lost, injured or damaged bones and teeth. It is important to notice that precipitation of CaPO4 and calcium carbonates has been considered to correlate with bone formation, at least, since 1923 (Watt 1923).

A key step in the biomimetic bone graft production is attributed to the crystal growth of apatite phase onto a collagen matrix. Therefore, the matter of choosing the correct experimental conditions and well-mimicking solutions is of the primary importance. The easiest way to perform the crystallization would be mixing of aqueous solutions containing the ions of calcium and orthophosphate (LeGeros 1991; Elliott 1994; Amjad 1997). Unfortunately, such type of crystallization provides precipitates with the properties (chemical composition, Ca/P ratio, crystallinity level, particle size distribution, etc.) far different from those of biological apatite. This can be explained by the following paramount differences between the in vivo biological and in vitro chemical crystallization conditions (Dorozhkin et al. 2004):
  1. 1.

    In vitro crystallization normally occurs at permanently depleting concentrations of calcium and orthophosphate ions, while the concentrations of all ions and molecules are kept strictly constant during biological mineralization (the same is valid for the solution pH);

  2. 2.

    Chemical crystallization is a fast process (time scale of minutes to days), while the biological process is a slow one (time scale of weeks to years);

  3. 3.

    Many inorganic, bioorganic, biological and polymeric compounds are present in biological liquids (blood plasma, serum, saliva). Each of these compounds might act as an inhibitor, promoter, nucleator or even as a template for the growth of biological apatite. In addition, each of them somehow influences the crystallization kinetics and might be either incorporated into the solid structure or co-precipitated with CaPO4 (Jahromi et al. 2013).

  4. 4.

    Chemical crystallization is, by all means, a “passive” process, while the biological mineralization is strongly influenced by cells and occurs by the self-organization mechanisms (Boskey and Roy 2008; Sato 2006; Hartgerink et al. 2001). Still there are no good ways to overcome this difference.


The first and the second differences might be overcome using the appropriate crystallization techniques. The details are available elsewhere (Dorozhkin et al. 2004) but, briefly, the first problem might be overcome by either a continuous flow of a supersaturated solution (Izquierdo-Barba et al. 2000; Vallet-Regí et al. 2000) or using a constant-composition (CC) technique (Nancollas and Wu 2000; Koutsoukos et al. 1980; Tomson and Nancollas 1978). The second difference might be surpassed by a restrained diffusion of calcium and orthophosphate ions from the opposite directions in, for example, a double-diffusion (DD) crystallization device or in viscous gels (Busch et al. 1999; Manjubala et al. 2006; Cai et al. 2010; Yokoi et al. 2010; Sadjadi et al. 2010). The CC and DD techniques have been combined into a single constant-composition double-diffusion (CCDD) device, which currently seems to be the most advanced experimental tool to perform biomimetic crystallization (Dorozhkin et al. 2003, 2004; Dorozhkin and Dorozhkina 2003, 2005; Dorozhkina and Dorozhkin 2003a; Dorozhkin 2007b). However, in no case, the CCDD device should be considered as the final construction; it still has much room for further improvement, e.g., by upgrading the design of the crystallization chamber (Becker and Epple 2005). Other constructions, e.g., to study calcification of biological heart valve prostheses (Krings et al. 2006), are also possible. In addition, one should keep in mind that the potential of the standard CC technique has not reached its limit yet: for example, a good mimicking of the self-organized microstructure of tooth enamel has been achieved (Wang et al. 2008b).

The third major difference between the in vivo and in vitro crystallization conditions might be overcome using the appropriate crystallization solutions (Dorozhkin et al. 2004). To the best of my findings (Dorozhkin 2012a, 2013a), the presence of calcium and orthophosphate ions in the biological fluids (blood, saliva, lymph, etc.) has been known since, at least, 1804 (Fourcroy 1804). Therefore, the best way would be to perform experiments using these natural liquids, but this is not easy due to both a great variability of their chemical and biochemical compositions and problems with their collection and storage. As stated before, using supersaturated aqueous solutions containing only the ions of calcium and orthophosphate appears to be unable to mimic the crystallization of biological apatite; therefore, more advanced solutions have been elaborated. According to the topical review on the subject (Tas 2014), a formulation developed by Tyrode in 1910 (Tyrode 1910) was the first simulating medium, containing dissolved ions of calcium and orthophosphate together with other inorganic ions; however, no information was found on applicability of that solution for CaPO4 crystallization. Therefore, the earliest solution, suitable for CaPO4 crystallization was introduced 1943 by Earle (Earle 1943) and called Earle’s balanced salt solution (EBSS). EBSS contains inorganic salts (NaCl, KCl, CaCl2, MgSO4, NaHCO3, NaH2PO4) and was successfully used for CaPO4 crystallization (Termine and Eanes 1974). Other popular physiological solutions comprise Hanks’ balanced salt solution (HBSS), which contains almost similar inorganic salts and glucose (Hanks and Wallace 1949; Shibata et al. 2004; Marques et al. 2003a; Mareci et al. 2010), Eagle’s minimum essential medium (MEM) and its variation Dulbecco’s modified Eagle’s medium (DMEM), which contain numerous bioorganic (alanine, aspartic acid, glycine, biotin, vitamin C, folic acid, riboflavin) and inorganic (CaCl2, KCl, NaCl, NaH2PO4) components (Meuleman et al. 2006; Touny et al. 2011; Coelho et al. 2000; Mandel and Tas 2010; Rohanová et al. 2014), phosphate-buffered saline (PBS) that contains only inorganic (CaCl2, MgCl2, KCl, KH2PO4, NaCl, NaH2PO4) components (Gao et al. 2006; Lichtenauer et al. 2011). Furthermore, artificial saliva (Sato et al. 2006; Ionta et al. 2014; Okulus et al. 2014), synthetic urine (Assimos 2013; Dbira et al. 2015) and simulated milk ultrafiltrate (SMUF) (Jenness and Koops 1962; Spanos et al. 2007; Gao et al. 2010a, b) solutions are available. They contain both bioorganic (e.g., xanthan gum or sodium carboxymethylcellulose, sorbitol, etc.) and inorganic (e.g., CaCl2, MgCl2, KCl, KH2PO4, NaCl, KH2PO4) compounds. Additional information on the media and physiological solutions used for mineralization studies is available elsewhere (Boskey and Roy 2008; Tas 2014). The majority of the aforementioned simulating solutions are commercially available.

However, the most popular biomimetic solution is a protein-free acellular simulated body fluid (SBF). It was introduced in 1990 by Kokubo et al., (Kokubo et al. 1990) and occasionally named as Kokubo’s SBF. It is a metastable aqueous solution with pH ~ 7.40, supersaturated with respect to the precipitation of OCP, β-TCP, CDHA and HA (Lu and Leng 2005), containing only inorganic ions in concentrations nearly equal to those in human blood plasma. However, the standard SBF formulation, first, contains the tris/HCl buffer, and, second, the concentration of hydrogencarbonate (4.2 mM) is only a fraction of that in blood plasma (27 mM) (Kokubo et al. 1990). The problem of a low concentration of hydrogencarbonate ions has been overcome by first introducing a “synthetic body fluid” (Tas 2000; Landi et al. 2005; Jalota et al. 2008) and later a revised SBF (rSBF) (Kim et al. 2001; Oyane et al. 2003). Due to the chemical similarity with human blood plasma, rSBF currently seems to be the best simulating solution. However, it contains Hepes buffer, loses CO2 in open vessels and does not contain any organic and/or biological molecules (Kim et al. 2001; Oyane et al. 2003). Other types of SBF are also available (Müller and Müller 2006; Hu et al. 2006; Wen et al. 2009; Gemelli et al. 2010) and the interested readers are referred to a leading opinion co-authored by the SBF inventor (Kokubo and Takadama 2006), where the entire history and the preparation techniques of various SBF formulations are well described. Later, another leading opinion on the suitability of SBF for the in vitro bioactivity tests was published (Bohner and Lemaitre 2009). The authors demonstrated that (1) there is presently no enough scientific data to support the SBF suitability and (2) even though bioactivity tests with SBFs are valid, the way the tests are generally conducted leaves room for further improvements. In addition, the preparation protocol of SBF solutions was reconsidered and a new procedure was suggested to improve the reproducibility of bioactivity tests (Bohner and Lemaitre 2009). However, the situation with SBF appears to be not so straightforward. Namely, further studies revealed that the actual behavior of osteoblasts was likely to provide the primary measures of biocompatibility and bioactivity, rather than oversimplified and essentially irrelevant tests with SBF (Pan et al. 2010), while the in vitro bioactivity experiments performed with SBF did not always predict the relative in vivo performance of the same implants (Zadpoor 2014).

The application of SBF for the surface mineralization of various materials in vitro has been reviewed (Kim 2003), while the theoretical analysis of CaPO4 precipitation (the driving force and the nucleation rate based on the classical crystallization theory) in SBF is also available (Lu and Leng 2005). It is important to note that nanometer-sized pre-nucleation clusters in SBF solutions have been discovered (Dey et al. 2010); those clusters are believed to be the initial building blocks of crystallized CaPO4 [e.g., CDHA (Onuma and Ito 1998)], while the crystallization process itself occurs via intermediate formation of ACP (Fig. 17).

Further attempts to improve the biomimetic properties of SBF and rSBF have been performed (Kokubo and Takadama 2006; Bohner and Lemaitre 2009). Efforts were made to replace artificial buffers (tris/HCl, Hepes) with simultaneously increasing the concentration of hydrogencarbonates for SBF (Marques et al. 2003b, 2004; Dorozhkina and Dorozhkin 2002b) or avoiding losses of CO2 from open vessels for rSBF (Dorozhkin et al. 2003, 2004; Dorozhkin and Dorozhkina 2003, 2005; Dorozhkina and Dorozhkin 2003a; Dorozhkin 2007b) by means of permanent bubbling of gaseous CO2 through the solutions. Addition of the most important organic and biological compounds like glucose (Dorozhkin et al. 2003), albumin (Dorozhkin and Dorozhkina 2003; Marques et al. 2004), lactates (Pasinli et al. 2010) and collagen (Sun and Wang 2010) is another direction to improve biomimetic properties of various types of SBF. Once a cow milk-based rSBF has been prepared (Dorozhkin and Dorozhkina 2007). Further improvements of all biomimetic solutions are to be made in future. Occasionally, condensed solutions of SBF [e.g., 1.5-fold, twofold (Sun and Wang 2010; Miyaji et al. 1999; Kim et al. 2000b), fivefold (Barrere et al. 2002a, b) and even tenfold (Tas and Bhaduri 2004; Demirtaş et al. 2015)] are used to accelerate precipitation and increase the amount of precipitates. However, whenever possible this should be avoided because the application of condensed solutions of SBF leads to changes in the chemical composition of the precipitates; namely, the concentration of carbonates increases, while the concentration of orthophosphates decreases (Dorozhkina and Dorozhkin 2003b).

To conclude this part, one should note on the difficulties in mimicking the calcification process that occurs in bones and teeth. A reasonable mechanism of the induction of CDHA nucleation and crystallization by carboxylate groups on the bioorganic matrices looks as this. At first, calcium and orthophosphate ions are combined with carboxylate groups. By using this as seeds, CDHA crystals then grow to generate interfaces that contain the most stable structure of the {100} faces. Such a crystallization mechanism explains why the c-axes of biological apatite are parallel to the organic matrices. Collagen fibers can be regarded as axis-like organic matrices: when CDHA is formed on the surface of collagen fibers parallel to the c-axes, the c-axes are oriented parallel to the fiber orientation (Sato 2007). A step further would be to perform the precipitation from the simulating solutions on templates of biomineralization proteins for the control of crystal organization and properties. For example, there are successful attempts to crystallize CaPO4 on collagen to obtain bone-like composites (Nassif et al. 2010; Li et al. 2011; Xia et al. 2012, 2013, 2014; Antebi et al. 2013). Such collagen/CaPO4 biocomposites are currently under investigation for clinical use. Other popular matrixes to perform biomimetic CaPO4 crystallization comprise gelatin (Busch et al. 1999; Rosseeva et al. 2008; Liu et al. 2009; Raz et al. 2014), chitosan (Raz et al. 2014; Wang et al. 2011; Lu et al. 2014b), the surface of metals and alloys (Wang et al. 2004; Bigi et al. 2005; Liu et al. 2010, 2013; Dorozhkin 2014), polymers (Iwatsubo et al. 2006), cellulose (Bodin et al. 2006), self-assembled monolayers (Toworfe et al. 2006) and many other materials. Such biomimetically prepared CaPO4 precipitates are occasionally called “organoapatites” (Spoerke and Stupp 2003; Storrie and Stupp 2005).

Conclusions and outlook

By the end of the XX-th century, it became clear that CaPO4-based biomaterials and bioceramics by themselves could not give a complete response to the clinical needs for artificial implants. Biomaterials with more demanding properties were required. Namely, in 1998, Prof. Larry L. Hench published a forecast for the future of biomaterials development (Hench 1998), where he noted that available that time bioactive materials (CaPO4, bioactive glasses and glass ceramics) had already improved prostheses lifetime but, unfortunately, any type of prosthesis had mechanical limitations. As the solution, he proposed that biomaterial researchers would need to focus on tissue regeneration instead of tissue replacement. A working hypothesis was announced: “Long-term survivability of prosthesis will be increased by the use of biomaterials that enhance the regeneration of natural tissues” (Hench 1998). One path to follow is the regeneration of bone using CaPO4-based scaffolds that mimic the structure of biological apatite, bond to bone and in some cases activate the genes within bone cells to stimulate new bone growth (Jones and Hench 2003; Griffith and Naughton 2002; Hench and Polak 2002). Thus, in 2002, Hench predicted a rapid development of tissue engineering field, where CaPO4 play an auxiliary role. The practice reveals that tissue engineering, indeed, is a very rapidly developed field of science and research (Ratner and Bryant 2004).

However, what can be said about CaPO4 themselves? The major questions on chemistry, crystallization, ion-substitution, crystallography, thermodynamics and phase relationships for the chemically pure CaPO4 have been answered in the XXth century. Some important topics for DCPD and CDHA have been additionally investigated in the field of self-setting CaPO4 formulations (Dorozhkin 2013b). Conversely, CaPO4 of biological origin, including the control of their morphology and interaction of CaPO4-based bioceramics with various bioorganic compounds are not well investigated yet. The same is valid for the nanocrystalline and amorphous samples of CaPO4. Small amounts of bone-like apatite might be easily prepared by crystallization from simulating solutions, such as SBF and rSBF, but what can be said about larger quantities? A standard way of the concentration increasing causes chemical changes in the precipitates (Dorozhkina and Dorozhkin 2003b). After a necessary technology is developed, one will have to think on scaffold preparation from this material, keeping in mind that any thermal treatment would destroy this material. A spark plasma sintering approach based on the use of pulsed current and enabling very fast heating and cooling rates seemed to be a first hint to achieve this goal (Zhang et al. 2008; Grossin et al. 2010). However, a rapid development of the self-setting CaPO4 formulations, which can be easily doped by the necessary chemical elements, seems to be a better solution of this problem (Dorozhkin 2013b). Furthermore, the existence of OA remains to be questionable, as well as the bioactivity mechanism of CaPO4 requires better understanding.

To date, although CaPO4-based biomaterials and bioceramics have been extensively studied for over 50 years, their ability to trigger bone formation is still incomparable with other biomaterials. Nowadays, the biomaterials’ field is shifting towards biologically active systems to improve their performance and to expand their use (Kolk et al. 2012; Garg and Goyal 2014; Tang and Diehl 2014). Therefore, tissue engineering is the strongest direction of current research, which, in the case of CaPO4, means fabrication of proper substrates and/or scaffolds to carry cells, hormones and biochemical factors to be further used in surgery and medicine (Zhou and Lee 2011; Zakaria et al. 2013; Shao et al. 2015). Presumably, a synthesis of various types of CaPO4-based biocomposites and hybrid biomaterials occupies the second important place (Dorozhkin 2015b). The third important place is occupied by investigations devoted to the synthesis and characterization of various nano-sized particles and nanodimensional crystals of CaPO4 (Dorozhkin 2013d), ACP (Dorozhkin 2012c), as well as CaPO4 with controlled particle geometry and shapes (Lin et al. 2014; Galea et al. 2013; Kalia et al. 2014). In general, the geometry of crystal phases can be varied by controlling the precipitation conditions, such as temperature, solution pH, concentration of the reagents, hydrodynamics, presence of various admixtures, inhibitors or promoters and ultrasonication. All these approaches might be useful in preparation of CaPO4 fibers, whiskers, hollow microspheres, etc. In addition, a great attention is paid to manufacturing of the self-setting CaPO4 formulations (Dorozhkin 2013b) and multiphase formulations (Dorozhkin 2012d) mimicking as closely as possible the mineral component of biological apatite. A work along the ecological ways of synthesis of CaPO4 might be of a great importance as well (Dorozhkin 2008). A deeper study of the fascinating growth rate of deer antlers and the ability of some animals, such as newts, to regenerate amputated limbs might provide new and unexpected approaches to the bone-healing concept, as well as this will be important for further development of both biomimetics and biomineralization fields. Unfortunately, no currently available grafting biomaterials can substitute the bones’ mechanical function, illustrating yet unmet medical need that would entirely substitute and regenerate a damaged tissue or organ. In a close future, the foreseeable application of CaPO4 will be as an integrated component of the third generation of biomaterials (Hench 1998; Hench and Polak 2002), where they will support cells and/or other biologically active substances (peptides, growth factors, hormones, drugs, etc.) to guide regeneration of hard tissues (Daculsi et al. 2013; Feng et al. 2013b; Miura et al. 2013; Wang et al. 2014c).

To finalize this review, one should note that in spite of almost the 250-year long history of the CaPO4 research (Dorozhkin 2012a, 2013a) and many important discoveries, still many gaps remain in our knowledge to be investigated in future.


Compliance with ethical standards

Conflict of interest

The author declares that he has no conflict of interest.


This study was not funded.

Ethical approval

This review article does not contain any studies with human participants or animals performed by any of the authors.


  1. Abouzeid AZM (2007) Upgrading of phosphate ores—a review. Powder Handl Process 19:92–109Google Scholar
  2. Abouzeid AZM (2008) Physical and thermal treatment of phosphate ores—an overview. Int J Miner Process 85:59–84CrossRefGoogle Scholar
  3. Adzila S, Murad MC, Sopyan I (2012) Doping metal into calcium phosphate phase for better performance of bone implant materials. Rec Pat Mater Sci 5:18–47CrossRefGoogle Scholar
  4. Agathopoulos S, Tulyaganov DU, Marques PAAP, Ferro MC, Fernandes MH, Correia RN (2003) The fluorapatite—anorthite system in biomedicine. Biomaterials 24:1317–1331CrossRefGoogle Scholar
  5. Aikin A, Aikin CR (1807) A dictionary of chemistry and mineralogy, with an account of the processes employed in many of the most important chemical manufactures. To which are added a description of chemical apparatus, and various useful tables of weights and measures, chemical instruments, &c. &c. Illustrated with fifteen engravings, vol II. John and Arthur Arch, Couninll; and William Phillips, George Yard, Lombard Street, London, p 176Google Scholar
  6. Akhtar R, Daymond MR, Almer JD, Mummery PM (2008) Elastic strains in antler trabecular bone determined by synchrotron X-ray diffraction. Acta Biomater 4:1677–1687CrossRefGoogle Scholar
  7. Alberius-Henning P, Adolfsson E, Grins J, Fitch A (2001) Triclinic oxy-hydroxyapatite. J Mater Sci 36:663–668CrossRefGoogle Scholar
  8. Alkan O, Tokmak N, Demir S, Yildirim T (2009) Metastatic pulmonary calcification in a patient with chronic renal failure. J Radiol Case Rep 3:14–17Google Scholar
  9. Amjad Z (ed) (1997) Calcium phosphates in biological and industrial systems. Kluwer Academic Publishers, Boston, p 529Google Scholar
  10. An L, Zhang L, Zou J (2009) Fluorapatite: an effective solid base catalyst for Michael addition of indole/pyrrole to nitroalkenes under solventless condition. Chin J Chem 27:2223–2228CrossRefGoogle Scholar
  11. Anderson JC, Eriksson C (1970) Piezoelectric properties of dry and wet bone. Nature 227:491–492CrossRefGoogle Scholar
  12. Antebi B, Cheng X, Harris JN, Gower LB, Chen XD, Ling J (2013) Biomimetic collagen-hydroxyapatite composite fabricated via a novel perfusion-flow mineralization technique. Tissue Eng C 19:487–496CrossRefGoogle Scholar
  13. Aoba T (1996) Recent observations on enamel crystal formation during mammalian amelogenesis. Anat Rec 245:208–218CrossRefGoogle Scholar
  14. Aquilano D, Bruno M, Rubbo M, Massaro FR, Pastero L (2014) Low symmetry polymorph of hydroxyapatite. Theoretical equilibrium morphology of the monoclinic Ca5(OH)(PO4)3. Cryst Growth Des 14:2846–2852CrossRefGoogle Scholar
  15. Aquilano D, Bruno M, Rubbo M, Pastero L, Massaro FR (2015) Twin laws and energy in monoclinic hydroxyapatite, Ca5(OH)(PO4)3. Cryst Growth Des 15:411–418CrossRefGoogle Scholar
  16. Araújo M, Linder E, Lindhe J (2009) Effect of a xenograft on early bone formation in extraction sockets: an experimental study in dog. Clin Oral Implan Res 20:1–6CrossRefGoogle Scholar
  17. Arellano-Jiménez MJ, García-García R, Reyes-Gasga J (2009) Synthesis and hydrolysis of octacalcium phosphate and its characterization by electron microscopy and X-ray diffraction. J Phys Chem Solids 70:390–395CrossRefGoogle Scholar
  18. Argüelles MG, Berlanga ISL, Torres EA (1999) Preparation of 153Sm-particles for radiosynovectomy. J Radioanal Nucl Chem 240:509–511CrossRefGoogle Scholar
  19. Arsenault AL, Robinson BW (1989) The dentino-enamel junction: a structural and microanalytical study of early mineralization. Calcif Tissue Int 45:111–121CrossRefGoogle Scholar
  20. Arsic J, Kaminski D, Poodt P, Vlieg E (2004) Liquid ordering at the brushite—{010}—water interface. Phys Rev B 69(245406):4Google Scholar
  21. Assimos D (2013) Rapid oxalate determination in blood and synthetic urine using a newly developed oxometer. J Urol 189:575–576Google Scholar
  22. Athanasiou KA, Zhu C, Lanctot DR, Agrawal CM, Wang X (2000) Fundamentals of biomechanics in tissue engineering of bone. Tissue Eng 6:361–381CrossRefGoogle Scholar
  23. Avery JK (2001) Oral development and histology, 3rd edn. Thieme Medical Publishers Inc., New York, p 435Google Scholar
  24. Azami M, Jalilifiroozinezhad S, Mozafari M (2012) Calcium fluoride/hydroxyfluorapatite nanocrystals as novel biphasic solid solution for tooth tissue engineering and regenerative dentistry. Key Eng Mater 493–494:626–631Google Scholar
  25. Azari F, Vali H, Guerquin-Kern JL, Wu TD, Croisy A, Sears SK, Tabrizian M, McKee MD (2008) Intracellular precipitation of hydroxyapatite mineral and implications for pathologic calcification. J Struct Biol 162:468–479CrossRefGoogle Scholar
  26. Bache F (1819) A system of chemistry for the use of students of medicine. William Fry, Philadelphia, p 624Google Scholar
  27. Baciut M, Baciut G, Simon V, Albon C, Coman V, Prodan P, Florian S, Bran S (2007) Investigation of deer antler as a potential bone regenerating biomaterial. J Optoelectron Adv Mater 9:2547–2550Google Scholar
  28. Bailliez S, Nzihou A, Bèche E, Flamant G (2004) Removal of lead (Pb) by hydroxyapatite sorbent. Process Saf Environ 82:175–180CrossRefGoogle Scholar
  29. Barbour ME, Rees JS (2004) The laboratory assessment of enamel erosion: a review. J Dent 32:591–602CrossRefGoogle Scholar
  30. Barrere F, van Blitterswijk CA, de Groot K, Layrolle P (2002a) Influence of ionic strength and carbonate on the Ca-P coating formation from SBF × 5 solution. Biomaterials 23:1921–1930CrossRefGoogle Scholar
  31. Barrere F, van Blitterswijk CA, de Groot K, Layrolle P (2002b) Nucleation of biomimetic Ca-P coatings on Ti6Al4 V from a SBF × 5 solution: influence of magnesium. Biomaterials 23:2211–2220CrossRefGoogle Scholar
  32. Basaruddin KS, Takano N (2014) Estimation of apparent elastic moduli of trabecular bone considering biological apatite (BAp) crystallite orientation in tissue modulus. Adv Mater Res 894:167–171CrossRefGoogle Scholar
  33. Baturin GN (2012) Phosphorites of the sea of Japan. Oceanology 52:666–676CrossRefGoogle Scholar
  34. Baxter BJ, Andrews RN, Barrell GK (1999) Bone turnover associated with antler growth in red deer (Cervus elaphus). Anat Rec 256:14–19CrossRefGoogle Scholar
  35. Bazin D, Dessombz A, Nguyen C, Ea HK, Lioté F, Rehr J, Chappard C, Rouzière S, Thiaudière D, Reguer S, Daudon M (2014a) The status of strontium in biological apatites: an XANES/EXAFS investigation. J Synchrotron Radiat 21:136–142CrossRefGoogle Scholar
  36. Bazin D, Haymann JP, Letavernier E, Rode J, Daudon M (2014b) Calcifications pathologiques: un diagnostic médical basé sur leurs parameters physicochimiques. Presse Med 43:135–148CrossRefGoogle Scholar
  37. Becker P (1989) Phosphates and phosphoric acid: raw materials technology and economics of the wet process, 2nd Ed. In: Fertilizer science and technology series. Marcel Dekker, New York, p 760Google Scholar
  38. Becker A, Epple M (2005) A high-throughput crystallisation device to study biomineralisation in vitro. Mater Res Soc Symp Proc 873E:K12.1.1–K12.1.10Google Scholar
  39. Beniash E, Metzler RA, Lam RSK, Gilbert PUPA (2009) Transient amorphous calcium phosphate in forming enamel. J Struct Biol 166:133–143 (corrigendum ibid . 167, p 95) Google Scholar
  40. Benyus JM (1997) Biomimicry: innovation inspired by nature. William Morrow, New York, p 308Google Scholar
  41. Bernardi G (1965) Chromatography of nucleic acids on hydroxyapatite. Nature 206:779–783CrossRefGoogle Scholar
  42. Best JA, Shapiro RD, Kalmar J, Westsson PL (1997) Hydroxyapatite deposition disease of the temporomandibular joint in a patient with renal failure. J Oral Maxillofac Surg 55:1316–1322CrossRefGoogle Scholar
  43. Bhadang KA, Holding CA, Thissen H, McLean KM, Forsythe JS, Haynes DR (2010) Biological responses of human osteoblasts and osteoclasts to flame-sprayed coatings of hydroxyapatite and fluorapatite blends. Acta Biomater 6:1575–1583CrossRefGoogle Scholar
  44. Bhat SS, Waghmare UV, Ramamurty U (2014) First-principles study of structure, vibrational, and elastic properties of stoichiometric and calcium-deficient hydroxyapatite. Cryst Growth Des 14:3131–3141CrossRefGoogle Scholar
  45. Bigi A, Boanini E, Bracci B, Facchini A, Panzavolta S, Segatti F, Sturba L (2005) Nanocrystalline hydroxyapatite coatings on titanium: a new fast biomimetic method. Biomaterials 26:4085–4089CrossRefGoogle Scholar
  46. Bilezikian JP, Raisz LG, Martin TJ (2008) Principles of bone biology, 3rd edn. Academic Press, New York, p 1900Google Scholar
  47. Bittmann S, Gunther MW, Ulus H (2003) Tumoral calcinosis of the gluteal region in a child: case report with overview of different soft-tissue calcifications. J Pediatr Surg 38:E4–E7CrossRefGoogle Scholar
  48. Bjerrum N (1958) Calciumorthophosphate. I. Die Festen Calciumorthophosphate. II. Komplexbildung in Lösung von Calcium-und Phosphate-Ionen. Math Fys Medd Dan Vid Selsk 31:1–79Google Scholar
  49. Block GA, Hulbert-Shearon TE, Levin NW, Port FK (1998) Association of serum phosphorus and calcium x phosphate product with mortality risk in chronic hemodialysis patients: a national study. Am J Kidney Dis 31:607–617CrossRefGoogle Scholar
  50. Blumenthal NC, Posner AS, Holmes JM (1972) Effect of preparation conditions on the properties and transformation of amorphous calcium phosphate. Mater Res Bull 7:1181–1190CrossRefGoogle Scholar
  51. Boanini E, Gazzano M, Rubini K, Bigi A (2010a) Collapsed octacalcium phosphate stabilized by ionic substitutions. Cryst Growth Des 10:3612–3617CrossRefGoogle Scholar
  52. Boanini E, Gazzano M, Bigi A (2010b) Ionic substitutions in calcium phosphates synthesized at low temperature. Acta Biomater 6:1882–1894CrossRefGoogle Scholar
  53. Bocchi G, Valdre G (1993) Physical, chemical, and mineralogical characterization of carbonate-hydroxyapatite concretions of the human pineal gland. J Inorg Biochem 49:209–220CrossRefGoogle Scholar
  54. Bodier-Houllé P, Steuer P, Voegel JC, Cuisinier FJG (1998) First experimental evidence for human dentine crystal formation involving conversion of octacalcium phosphate to hydroxyapatite. Acta Crystallogr D Biol Crystallogr 54:1377–1381CrossRefGoogle Scholar
  55. Bodier-Houllé P, Steuer P, Meyer JM, Bigeard L, Cuisinier FJG (2000) High-resolution electron-microscopic study of the relationship between human enamel and dentin crystals at the dentinoenamel junction. Cell Tissue Res 301:389–395CrossRefGoogle Scholar
  56. Bodin A, Gustafsson L, Gatenholm P (2006) Surface-engineered bacterial cellulose as template for crystallization of calcium phosphate. J Biomater Sci Polym Ed 17:435–447CrossRefGoogle Scholar
  57. Bogdanov BI, Pashev PS, Hristov JH, Markovska IG (2009) Bioactive fluorapatite-containing glass ceramics. Ceram Int 35:1651–1655CrossRefGoogle Scholar
  58. Bohner M, Lemaitre J (2009) Can bioactivity be tested in vitro with SBF solution? Biomaterials 30:2175–2179CrossRefGoogle Scholar
  59. Bonar LC, Shimizu M, Roberts JE, Griffin RG, Glimcher MJ (1991) Structural and composition studies on the mineral of newly formed dental enamel: a chemical, X-ray diffraction, and 31P and proton nuclear magnetic resonance study. J Bone Miner Res 6:1167–1176CrossRefGoogle Scholar
  60. Bonel G, Heughebaert JC, Heughebaert M, Lacout JL, Lebugle A (1988) Apatitic calcium orthophosphates and related compounds for biomaterials preparation. Ann NY Acad Sci 523:115–130CrossRefGoogle Scholar
  61. Boonchom B (2009) Parallelogram-like microparticles of calcium dihydrogen phosphate monohydrate (Ca(H2PO4)2·H2O) obtained by a rapid precipitation route in aqueous and acetone media. J Alloy Compd 482:199–202CrossRefGoogle Scholar
  62. Boonrungsiman S, Gentleman E, Carzaniga R, Evans ND, McComb DW, Porter AE, Stevens MM (2012) The role of intracellular calcium phosphate in osteoblast-mediated bone apatite formation. Proc Natl Acad Sci USA 109:14170–14175CrossRefGoogle Scholar
  63. Boskey AL (1997) Amorphous calcium phosphate: the contention of bone. J Dent Res 76:1433–1436CrossRefGoogle Scholar
  64. Boskey AL (2006) Assessment of bone mineral and matrix using backscatter electron imaging and FTIR imaging. Curr Osteoporos Rep 4:71–75CrossRefGoogle Scholar
  65. Boskey AL (2007) Mineralization of bones and teeth. Elements 3:385–391CrossRefGoogle Scholar
  66. Boskey AL, Coleman R (2010) Aging and bone. J Dent Res 89:1333–1348CrossRefGoogle Scholar
  67. Boskey AL, Posner AS (1976) Formation of hydroxyapatite at low supersaturation. J Phys Chem 80:40–44CrossRefGoogle Scholar
  68. Boskey AL, Roy R (2008) Cell culture systems for studies of bone and tooth mineralization. Chem Rev 108:4716–4733CrossRefGoogle Scholar
  69. Bosshardt DD, Selvig KA (2000) Dental cementum: the dynamic tissue covering of the root. Periodontol 1997(14):41–75Google Scholar
  70. Bourgeois B, Laboux O, Obadia L, Gauthier O, Betti E, Aguado E, Daculsi G, Bouler JM (2003) Calcium-deficient apatite: a first in vivo study concerning bone ingrowth. J Biomed Mater Res A 65A:402–408CrossRefGoogle Scholar
  71. Brancaccio D, Cozzolino M (2005) The mechanism of calcium deposition in soft tissues. Contrib Nephrol 149:279–286CrossRefGoogle Scholar
  72. Brand M, Rampalli S, Chaturvedi CP, Dilworth FJ (2008) Analysis of epigenetic modifications of chromatin at specific gene loci by native chromatin immunoprecipitation of nucleosomes isolated using hydroxyapatite chromatography. Nat Protoc 3:398–409CrossRefGoogle Scholar
  73. Bredig MA (1933) Zur Apatitstruktur der anorganischen Knochen- und Zahnsubstanz. H.-S. Z. Physiol. Chem. 216:239–243CrossRefGoogle Scholar
  74. Bredig MA, Franck HH, Fülnder H (1932) Beiträge zur Kenntnis der Kalk-Phosphorsäure-Verbindungen. II. Z Elktrochem Angew P 38:158–164Google Scholar
  75. Bres EF, Hutchison JL (2002) Surface structure study of biological calcium phosphate apatite crystals from human tooth enamel. J Biomed Mater Res 63:433–440CrossRefGoogle Scholar
  76. Brès EF, Voegel JC, Frank RM (1990) High-resolution electron microscopy of human enamel crystals. J Microsc 160:183–201CrossRefGoogle Scholar
  77. Brès EF, Duhoo T, Leroy N, Lemaitre J (2005) Evidence of a transient phase during the hydrolysis of calcium-deficient hydroxyapatite. Z Metallkd/Mater Res Adv Tech 96:503–506Google Scholar
  78. Breslow R (1972) Centenary lecture: biomimetic chemistry. Chem Soc Rev 1:553–580CrossRefGoogle Scholar
  79. Briak-Ben E, Abdeslam H, Ginebra MP, Vert M, Boudeville P (2008) Wet or dry mechanochemical synthesis of calcium phosphates? Influence of the water content on DCPD–CaO reaction kinetics. Acta Biomater 4:378–386CrossRefGoogle Scholar
  80. Brögger WC, Bäckström H (1890) Über den Dahllit, ein neues Mineral von Ödegärden, Bamle, Norwegen. Neues Jb Miner Geol Paläont 223–224Google Scholar
  81. Brown WE (1962) Octacalcium phosphate and hydroxyapatite: crystal structure of octacalcium phosphate. Nature 196:1048–1050CrossRefGoogle Scholar
  82. Brown WE (1966) Crystal growth of bone mineral. Clin Orthop Relat Res 44:205–220CrossRefGoogle Scholar
  83. Brown PW (1992) Phase relationships in the ternary system CaO–P2O5–H2O at 25°C. J Am Ceram Soc 75:17–22CrossRefGoogle Scholar
  84. Brown WE, Chow LC (1976) Chemical properties of bone mineral. Ann Rev Mater Sci 6:213–236CrossRefGoogle Scholar
  85. Brown PW, Martin RI (1999) An analysis of hydroxyapatite surface layer formation. J Phys Chem B 103:1671–1675CrossRefGoogle Scholar
  86. Brown WE, Smith JP, Lehr JR, Frazier AW (1962) Octacalcium phosphate and hydroxyapatite: crystallographic and chemical relations between octacalcium phosphate and hydroxyapatite. Nature 196:1050–1055CrossRefGoogle Scholar
  87. Brown WE, Eidelman N, Tomazic BB (1987) Octacalcium phosphate as a precursor in biomineral formation. Adv Dent Res 1:306–313Google Scholar
  88. Bubenik GA, Bubenik PG (2008) Palmated antlers of moose may serve as a parabolic reflector of sounds. Eur J Wildl Res 54:533–535CrossRefGoogle Scholar
  89. Budavari S, O’Neil MJ, Smith A, Heckelman PE, Kinneary JF (eds) (1996) The Merck Index: an encyclopedia of chemicals, drugs, and biologicals, 12th edn. Chapman & Hall, USA, p 1741Google Scholar
  90. Burger C, Zhou H, Wang H, Sics I, Hsiao BS, Chu B, Graham L, Glimcher M (2008) Lateral packing of mineral crystals in bone collagen fibrils. Biophys J 95:1985–1992CrossRefGoogle Scholar
  91. Burke DE, de Markey CA, le Quesne PW, Cook JM (1972) Biomimetic synthesis of the bis-indole alkaloid macralstonine. J Chem Soc Chem Commun 1346–1347Google Scholar
  92. Burnell JM, Teubner EJ, Miller AG (1980) Normal maturational changes in bone matrix, mineral, and crystal size in the rat. Calcif Tissue Int 31:13–19CrossRefGoogle Scholar
  93. Burns RE, Bicknese EJ, Westropp JL, Shiraki R, Stalis IH (2013) Tumoral calcinosis form of hydroxyapatite deposition disease in related red-bellied short-necked turtles, Emydura subglobosa. Vet Pathol 50:443–450CrossRefGoogle Scholar
  94. Busch S (2004) Regeneration of human tooth enamel. Angew Chem Int Ed Engl 43:1428–1431CrossRefGoogle Scholar
  95. Busch S, Dolhaine H, Duchesne A, Heinz S, Hochrein O, Laeri F, Podebrad O, Vietze U, Weiland T, Kniep R (1999) Biomimetic morphogenesis of fluorapatite-gelatin composites: fractal growth, the question of intrinsic electric fields, core/shell assemblies, hollow spheres and reorganization of denatured collagen. Eur J Inorg Chem 1643–1653Google Scholar
  96. Bystrov VS (2015) Piezoelectricity in the ordered monoclinic hydroxyapatite. Ferroelectrics 475:148–153CrossRefGoogle Scholar
  97. Cai HQ, Li QL, Zhou J, Tang J, Chen H (2010) Biomimetic synthesis and cytocompatibility of agar-hydroxyapatite composites. J Clin Rehabil Tissue Eng Res 14:410–414Google Scholar
  98. Calderin L, Stott MJ, Rubio A (2003) Electronic and crystallographic structure of apatites. Phys Rev B 67(134106):6Google Scholar
  99. Calderin L, Dunfield D, Stott MJ (2005) Shell-model study of the lattice dynamics of hydroxyapatite. Phys Rev B 72(224304):12Google Scholar
  100. Camiré CL, Gbureck U, Hirsiger W, Bohner M (2005) Correlating crystallinity and reactivity in an α-tricalcium phosphate. Biomaterials 26:2787–2794CrossRefGoogle Scholar
  101. Cantelar E, Lifante G, Calderón T, Meléndrez R, Millán A, Alvarez MA, Barboza-Flores M (2001) Optical characterisation of rare earths in natural fluorapatite. J Alloy Compd 323–324:851–854CrossRefGoogle Scholar
  102. Cao Q, Wen S, Li C, Bai S, Liu D (2013) Investigation on beneficiation strategy for collophane. Adv Mater Res 634–638:3404–3411CrossRefGoogle Scholar
  103. Carayon MT, Lacout JL (2003) Study of the Ca/P atomic ratio of the amorphous phase in plasma-sprayed hydroxyapatite coatings. J Solid State Chem 172:339–350CrossRefGoogle Scholar
  104. Carlson AP, Yonas HM, Turner PT (2007) Disorders of tumoral calcification of the spine: illustrative case study and review of the literature. J Spinal Disord Technol 20:97–103CrossRefGoogle Scholar
  105. Carr A, Kemp A, Tibbetts I, Truss R, Drennan J (2006) Microstructure of pharyngeal tooth enameloid in the parrotfish Scarus rivulatus (Pisces: Scaridae). J Microsc 221:8–16CrossRefGoogle Scholar
  106. Carrodeguas RG, de Aza S (2011) α-Tricalcium phosphate: synthesis, properties and biomedical applications. Acta Biomater 7:3536–3546CrossRefGoogle Scholar
  107. Chaari K, Ayed FB, Bouaziz J, Bouzouita K (2009) Elaboration and characterization of fluorapatite ceramic with controlled porosity. Mater Chem Phys 113:219–226CrossRefGoogle Scholar
  108. Chai H, Lee JJW, Constantino PJ, Lucas PW, Lawn BR (2009) Remarkable resilience of teeth. Proc Natl Acad Sci USA 106:7289–7293CrossRefGoogle Scholar
  109. Chakhmouradian AR, Medici L (2006) Clinohydroxylapatite: a new apatite-group mineral from northwestern Ontario (Canada), and new data on the extent of Na-S substitution in natural apatites. Eur J Miner 18:105–112CrossRefGoogle Scholar
  110. Chan YL, Ngan AHW, King NM (2011) Nano-scale structure and mechanical properties of the human dentine-enamel junction. J Mech Behav Biomed Mater 4:785–795CrossRefGoogle Scholar
  111. Chen H, Chen Y, Orr BG, Banaszak-Holl M, Majoros I, Clarkson BH (2004) Nanoscale probing of the enamel nanorod surface using polyamidoamine dendrimers. Langmuir 20:4168–4171CrossRefGoogle Scholar
  112. Chen GG, Luo GS, Yang LM, Xu JH, Sun Y, Wang JD (2005) Synthesis and size control of CaHPO4 particles in a two-liquid phase micro-mixing process. J Cryst Growth 279:501–507CrossRefGoogle Scholar
  113. Chen PY, Stokes AG, McKittrick J (2009) Comparison of the structure and mechanical properties of bovine femur bone and antler of the North American elk (Cervus elaphus canadensis). Acta Biomater 5:693–706CrossRefGoogle Scholar
  114. Chen F, Huang P, Zhu YJ, Wu J, Zhang CL, Cui DX (2011a) The photoluminescence, drug delivery and imaging properties of multifunctional Eu3+/Gd3+ dual-doped hydroxyapatite nanorods. Biomaterials 32:9031–9039CrossRefGoogle Scholar
  115. Chen L, Kivelä J, Helenius J, Kangas A (2011b) Meat bone meal as fertiliser for barley and oat. Agric Food Sci 20:235–244CrossRefGoogle Scholar
  116. Cherkinsky A, Dantas MAT, Cozzuol MA (2013) Bioapatite 14C age of giant mammals from Brazil. Radiocarbon 55:464–471Google Scholar
  117. Ching WY, Rulis P, Misra A (2009) Ab initio elastic properties and tensile strength of crystalline hydroxyapatite. Acta Biomater 5:3067–3075CrossRefGoogle Scholar
  118. Chinol M, Vallabhajosula S, Goldsmith SJ, Klein MJ, Deutsch KF, Chinen LK, Brodack JW, Deutsch EA, Watson BA, Tofe AJ (1993) Chemistry and biological behavior of samarium-153 and rhenium-186-labeled hydroxyapatite particles: potential radiopharmaceuticals for radiation synovectomy. J Nucl Med 34:1536–1542Google Scholar
  119. Cho G, Wu Y, Ackerman JL (2003) Detection of hydroxyl ions in bone mineral by solid-state NMR spectroscopy. Science 300:1123–1127CrossRefGoogle Scholar
  120. Chow LC (2009) Next generation calcium phosphate-based biomaterials. Dent Mater J 28:1–10CrossRefGoogle Scholar
  121. Chow LC, Eanes ED (eds) (2001) Octacalcium phosphate. Monographs in oral science, vol 18. Karger, Basel, p 167Google Scholar
  122. Ciftçioğlu N, McKay DS (2010) Pathological calcification and replicating calcifying-nanoparticles: general approach and correlation. Pediatr Res 67:490–499CrossRefGoogle Scholar
  123. Çiftçioglu N, Çiftçioglu V, Vali H, Turcott E, Kajander EO (1998) Sedimentary rocks in our mouth: dental pulp stones made by nanobacteria. P SPIE 3441:130–137CrossRefGoogle Scholar
  124. Clark NA (1931) The system P2O5–CaO–H2O and the recrystallization of monocalcium phosphate. J Phys Chem 35:1232–1238CrossRefGoogle Scholar
  125. Clark SM, Iball J (1954) Orientation of apatite crystals in bone. Nature 174:399–400CrossRefGoogle Scholar
  126. Cochrane NJ, Saranathan S, Cai F, Cross KJ, Reynolds EC (2008) Enamel subsurface lesion remineralisation with casein phosphopeptide stabilised solutions of calcium, phosphate and fluoride. Caries Res 42:88–97CrossRefGoogle Scholar
  127. Coelho MJ, Cabral AT, Fernandes MH (2000) Human bone cell cultures in biocompatibility testing. Part I: osteoblastic differentiation of serially passaged human bone marrow cells cultured in α-MEM and in DMEM. Biomaterials 21:1087–1094CrossRefGoogle Scholar
  128. Cölfen H (2010) A crystal-clear view. Nature Mater 9:960–961CrossRefGoogle Scholar
  129. Combes C, Rey C (2010) Amorphous calcium phosphates: synthesis, properties and uses in biomaterials. Acta Biomater 6:3362–3378CrossRefGoogle Scholar
  130. Cook PJ, Shergold JH, Davidson DF (eds) (2005) Phosphate deposits of the world: phosphate rock resources, vol 2. Cambridge University Press, Cambridge, p 600Google Scholar
  131. Copson RL, Newton RH, Lindsay JD (1936) Superphosphate manufacture—mixing phosphate rook with concentrated phosphoric acid. Ind Eng Chem 28:923–927CrossRefGoogle Scholar
  132. Corami A, Mignardi S, Ferrini V (2008) Cadmium removal from single- and multi-metal (Cd plus Pb plus Zn plus Cu) solutions by sorption on hydroxyapatite. J Colloid Interf Sci 317:402–408CrossRefGoogle Scholar
  133. Corno M, Rimola A, Bolis V, Ugliengo P (2010) Hydroxyapatite as a key biomaterial: quantum-mechanical simulation of its surfaces in interaction with biomolecules. Phys Chem Chem Phys 12:6309–6329CrossRefGoogle Scholar
  134. Crane NJ, Popescu V, Morris MD, Steenhuis P, Ignelzi JMA (2006) Raman spectroscopic evidence for octacalcium phosphate and other transient mineral species deposited during intramembranous mineralization. Bone 39:434–442CrossRefGoogle Scholar
  135. Crosby CH, Bailey JV (2012) The role of microbes in the formation of modern and ancient phosphatic mineral deposits. Front Microbiol 3(241):6Google Scholar
  136. Cui FZ, Ge J (2007) New observations of the hierarchical structure of human enamel, from nanoscale to microscale. J Tissue Eng Regener Med 1:185–191CrossRefGoogle Scholar
  137. Cui FZ, Li Y, Ge J (2007) Self-assembly of mineralized collagen composites. Mater Sci Eng, R 57:1–27CrossRefGoogle Scholar
  138. Cuisinier FJG, Steuer P, Senger B, Voegel JC, Frank RM (1993) Human amelogenesis: high resolution electron microscopy of nanometer-sized particles. Cell Tissue Res 273:175–182CrossRefGoogle Scholar
  139. Currey JD (2002) Bones: structure and mechanics. Princeton Univercity Press: Princeton, p 456Google Scholar
  140. Currey JD (2004) Tensile yield in compact bone is determined by strain, post-yield behaviour by mineral content. J Biomech 37:549–556CrossRefGoogle Scholar
  141. Currey JD (2005) Hierarchies in biomineral structures. Science 309:253–254CrossRefGoogle Scholar
  142. Currey JD (2010) Mechanical properties and adaptations of some less familiar bony tissues. J Mech Behav Biomed Mater 3:357–572CrossRefGoogle Scholar
  143. Currey JD, Brear K (1990) Hardness, Young’s modulus and yield stress in mammalian mineralized tissues. J Mater Sci Mater Med 1:14–20CrossRefGoogle Scholar
  144. Currey JD, Brear K, Zioupos P (2004) Notch sensitivity of mammalian mineralized tissues in impact. Proc R Soc Lond B 217:517–522CrossRefGoogle Scholar
  145. Currey JD, Landete-Castillejos T, Estevez J, Ceacero F, Olguin A, Garcia A, Gallego L (2009) The mechanical properties of red deer antler bone when used in fighting. J Exp Biol 212:3985–3993CrossRefGoogle Scholar
  146. Curry NA, Jones DW (1971) Crystal structure of brushite, calcium hydrogen orthophosphate dihydrate: a neutron-diffraction investigation. J Chem Soc A Inorg Phys Theoret Chem 3725–3729Google Scholar
  147. Daculsi G, Menanteau J, Kerebel LM, Mitre D (1984) Length and shape of enamel crystals. Calcif Tissue Int 36:550–555CrossRefGoogle Scholar
  148. Daculsi G, Bouler JM, LeGeros RZ (1997) Adaptive crystal formation in normal and pathological calcifications in synthetic calcium phosphate and related biomaterials. Int Rev Cytol 172:129–191CrossRefGoogle Scholar
  149. Daculsi G, Miramond T, Borget P, Baroth S (2013) Smart calcium phosphate bioceramic scaffold for bone tissue engineering. Key Eng Mater 529–530:19–23Google Scholar
  150. Dahm S, Risnes S (1999) A comparative infrared spectroscopic study of hydroxide and carbonate absorption bands in spectra of shark enameloid, shark dentine, and a geological apatite. Calcif Tissue Int 65:459–465CrossRefGoogle Scholar
  151. Danilchenko SN (2013) The approach for determination of concentration and location of major impurities (Mg, Na, K) in biological apatite of mineralized tissues. J Nano-Electron Phys 5(03043):5Google Scholar
  152. Davies E, Duer MJ, Ashbrook SE, Griffin JM (2012) Applications of NMR crystallography to problems in biomineralization: refinement of the crystal structure and 31P solid-state NMR spectral assignment of octacalcium phosphate. J Am Chem Soc 134:12508–12515CrossRefGoogle Scholar
  153. Davis TS, Kreidler ER, Parodi JA, Soules TF (1971) The luminescent properties of antimony in calcium halophosphates. J Lumin 4:48–62CrossRefGoogle Scholar
  154. Davison KS, Siminoski K, Adachi JD, Hanley DA, Goltzman D, Hodsman AB, Josse R, Kaiser S, Olszynski WP, Papaioannou A, Ste-Marie LG, Kendler DL, Tenenhouse A, Brown JP (2006) Bone strength: the whole is greater than the sum of its parts. Semin Arthritis Rheum 36:22–31CrossRefGoogle Scholar
  155. Dbira S, Bensalah N, Bedoui A, Cañizares P, Rodrigo MA (2015) Treatment of synthetic urine by electrochemical oxidation using conductive-diamond anodes. Environ Sci Pollut Res 22:6176–6184CrossRefGoogle Scholar
  156. de Jong WF (1926) La substance minérale dans les os. Recl Trav Chim Pays-Bas 45:445–448CrossRefGoogle Scholar
  157. de Leeuw NH (2010) Computer simulations of structures and properties of the biomaterial hydroxyapatite. J Mater Chem 20:5376–5389CrossRefGoogle Scholar
  158. de Leeuw NH, Bowe JR, Rabone JAL (2007) A computational investigation of stoichiometric and calcium-deficient oxy- and hydroxy-apatites. Faraday Disc 134:195–214CrossRefGoogle Scholar
  159. Delloye C, Cornu O, Druez V, Barbier O (2007) Bone allografts. What they can offer and what they cannot. J Bone Joint Surg Br 89:574–579CrossRefGoogle Scholar
  160. Delogne C, Lawford PV, Habesch SM, Carolan VA (2007) Characterization of the calcification of cardiac valve bioprostheses by environmental scanning electron microscopy and vibrational spectroscopy. J Microsc 228:62–77CrossRefGoogle Scholar
  161. Demirtaş TT, Kaynak G, Gümüşderelioğlu M (2015) Bone-like hydroxyapatite precipitated from 10 × SBF-like solution by microwave irradiation. Mater Sci Eng C 49:713–719CrossRefGoogle Scholar
  162. Desoutter A, Salehi H, Slimani A, Marquet P, Jacquot B, Tassery H, Cuisinier FJG (2014) Structure and chemical composition of the dentin-enamel junction analyzed by confocal Raman microscopy. In: Proc SPIE, 8929, Lasers in Dentistry XX, 892907Google Scholar
  163. Dessombz A, Nguyen C, Ea HK, Rouzière S, Foy E, Hannouche D, Réguer S, Picca FE, Thiaudière D, Lioté F, Daudon M, Bazin D (2013) Combining μX-ray fluorescence, μXANES and μXRD to shed light on Zn2+ cations in cartilage and meniscus calcifications. J Trace Elem Med Bio 27:326–333CrossRefGoogle Scholar
  164. Dey A, Mukhopadhyay AK, Gangadharan S, Sinha MK, Basu D (2009) Characterization of microplasma sprayed hydroxyapatite coating. J Therm Spray Technol 18:578–592CrossRefGoogle Scholar
  165. Dey A, Bomans PHH, Müller FA, Will J, Frederik PM, de With G, Sommerdijk NAJM (2010) The role of prenucleation clusters in surface-induced calcium phosphate crystallization. Nature Mater. 9:1010–1014CrossRefGoogle Scholar
  166. Diekwisch TG, Berman BJ, Genters S, Slavkin HC (1995) Initial enamel crystals are not spatially associated with mineralized dentine. Cell Tissue Res 279:149–167CrossRefGoogle Scholar
  167. Dobson T (1798) Encyclopaedia; or, a dictionary of arts, sciences, and miscellaneous literature; Conſtructed on a Plan, by which the different sciences and arts are digeſted into the Form of diſtinct treatises or systems, comprihending the history, theory, and practice, of each, According to the Lateſt Diſcoveries and Improvements; and full explanations given of the various detached parts of knowledge, where relating to Natural and Artificial Objects, or to Matters Ecclesiastical, Civil, Military, Commercial, &c. Including Elucidations of the moſt important Topics relative to Religion, Morals, Manners, and the Oeconomy of Life. Together with A Description of all the Countries, Cities, principle Mountains, Seas, Rivers, &c. throughout the World; A General History, Ancient and Modern, of the different Empires, Kingdoms, and States; and An Account of the Lives of the moſt Eminent Perſons in every Nation, from the earliest ages down to the preſent times. The first American edition, in eighteen volumes, greatly improved, vol. XIV. PAS–PLA. Stone-house, Philadelphia, p 797Google Scholar
  168. Domínguez MI, Romero-Sarria F, Centeno MA, Odriozola JA (2009) Gold/hydroxyapatite catalysts. Synthesis, characterization and catalytic activity to CO oxidation. Appl Catalysis B 87:245–251Google Scholar
  169. Dong W, Warshawsky H (1996) Lattice fringe continuity in the absence of crystal continuity in enamel. Adv Dent Res 10:232–237CrossRefGoogle Scholar
  170. Donnelly E, Boskey AL, Baker SP, van der Meulen MC (2009) Effects of tissue age on bone tissue material composition and nanomechanical properties in the rat cortex. J Biomed Mater Res A 92A:1048–1056Google Scholar
  171. Dorozhkin SV (1996) Fundamentals of the wet-process phosphoric acid production. 1. Kinetics and mechanism of the phosphate rock dissolution. Ind Eng Chem Res 35:4328–4335CrossRefGoogle Scholar
  172. Dorozhkin SV (1997) Fundamentals of the wet-process phosphoric acid production. 2. kinetics and mechanism of CaSO4·0.5H2O surface crystallization and coating formation. Ind Eng Chem Res 36:467–473CrossRefGoogle Scholar
  173. Dorozhkin SV (1998) Ecological principles of wet-process phosphoric acid technology. J Chem Technol Biotechnol 71:227–233CrossRefGoogle Scholar
  174. Dorozhkin SV (2003) Mechanism of solid-state conversion of non-stoichiometric hydroxyapatite to diphase calcium phosphate. Russ Chem Bull (Int Ed) 52:2369–2375Google Scholar
  175. Dorozhkin SV (2007a) A hierarchical structure for apatite crystals. J Mater Sci Mater Med 18:363–366CrossRefGoogle Scholar
  176. Dorozhkin SV (2007b) In vitro mineralization of silicon containing calcium phosphate bioceramics. J Am Ceram Soc 90:244–249CrossRefGoogle Scholar
  177. Dorozhkin SV (2008) Green chemical synthesis of calcium phosphate bioceramics. J Appl Biomater Biomech 6:104–109Google Scholar
  178. Dorozhkin SV (2011) Calcium orthophosphates: occurrence, properties, biomineralization, pathological calcification and biomimetic applications. Biomatter 1:121–164CrossRefGoogle Scholar
  179. Dorozhkin SV (2012a) Calcium orthophosphates and human beings. A historical perspective from the 1770s until 1940. Biomatter 2:53–70CrossRefGoogle Scholar
  180. Dorozhkin SV (2012b) Calcium orthophosphates: applications in nature, biology, and medicine. Pan Stanford, Singapore, p 854CrossRefGoogle Scholar
  181. Dorozhkin SV (2012c) Amorphous calcium orthophosphates: nature, chemistry and biomedical applications. Int J Mater Chem 2:19–46CrossRefGoogle Scholar
  182. Dorozhkin SV (2012d) Biphasic, triphasic and multiphasic calcium orthophosphates. Acta Biomater 8:963–977CrossRefGoogle Scholar
  183. Dorozhkin SV (2012e) Dissolution mechanism of calcium apatites in acids: a review of literature. World J Methodol 2:1–17CrossRefGoogle Scholar
  184. Dorozhkin SV (2013a) A detailed history of calcium orthophosphates from 1770s till 1950. Mater Sci Eng C 33:3085–3110CrossRefGoogle Scholar
  185. Dorozhkin SV (2013b) Self-setting calcium orthophosphate formulations. J Funct Biomater 4:209–311CrossRefGoogle Scholar
  186. Dorozhkin SV (2013c) Calcium orthophosphates in dentistry. J Mater Sci Mater Med 24:1335–1363CrossRefGoogle Scholar
  187. Dorozhkin SV (2013d) Nanodimensional and nanocrystalline calcium orthophosphates. Int J Chem Mater Sci 1:105–174Google Scholar
  188. Dorozhkin SV (2014) Calcium orthophosphate coatings on magnesium and its biodegradable alloys. Acta Biomater 10:2919–2934CrossRefGoogle Scholar
  189. Dorozhkin SV (2015a) Calcium orthophosphate deposits: preparation, properties and biomedical applications. Mater Sci Eng C 55:272–326CrossRefGoogle Scholar
  190. Dorozhkin SV (2015b) Calcium orthophosphate-containing biocomposites and hybrid biomaterials for biomedical applications. J Funct Biomater 6:708–832CrossRefGoogle Scholar
  191. Dorozhkin SV, Dorozhkina EI (2003) The influence of bovine serum albumin on the crystallization of calcium phosphates from a revised simulated body fluid. Colloid Surf A 215:191–199CrossRefGoogle Scholar
  192. Dorozhkin SV, Dorozhkina EI (2005) In vitro simulation of vascular calcification by the controlled crystallization of amorphous calcium phosphates onto porous cholesterol. J Mater Sci 40:6417–6422CrossRefGoogle Scholar
  193. Dorozhkin SV, Dorozhkina EI (2007) Crystallization from a milk-based revised simulated body fluid. Biomed Mater 2:87–92CrossRefGoogle Scholar
  194. Dorozhkin SV, Dorozhkina EI, Epple M (2003) Precipitation of carbonateapatite from a revised simulated body fluid in the presence of glucose. J Appl Biomater Biomech 1:200–208Google Scholar
  195. Dorozhkin SV, Dorozhkina EI, Epple M (2004) A model system to provide a good in vitro simulation of biological mineralization. Cryst Growth Des 4:389–395CrossRefGoogle Scholar
  196. Dorozhkina EI, Dorozhkin SV (2002a) Mechanism of the solid-state transformation of a calcium-deficient hydroxyapatite (CDHA) into biphasic calcium phosphate (BCP) at elevated temperatures. Chem Mater 14:4267–4272CrossRefGoogle Scholar
  197. Dorozhkina EI, Dorozhkin SV (2002b) Surface mineralisation of hydroxyapatite in modified simulated body fluid (mSBF) with higher amounts of hydrogencarbonate ions. Colloid Surf A 210:41–48CrossRefGoogle Scholar
  198. Dorozhkina EI, Dorozhkin SV (2003a) In vitro crystallization of carbonateapatite on cholesterol from a modified simulated body fluid. Colloid Surf A 223:231–237CrossRefGoogle Scholar
  199. Dorozhkina EI, Dorozhkin SV (2003b) Structure and properties of the precipitates formed from condensed solutions of the revised simulated body fluid. J Biomed Mater Res A 67A:578–581CrossRefGoogle Scholar
  200. Driessens FCM (1973) Relation between apatite solubility and anti-cariogenic effect of fluoride. Nature 243:420–421CrossRefGoogle Scholar
  201. Driessens FCM, Verbeeck RMH (1990) Biominerals. CRC Press, Boca Raton, p 440Google Scholar
  202. Driessens FCM, Wolke JGC, Jansen JA (2012) A new theoretical approach to calcium phosphates, aqueous solutions and bone remodeling. J Aust Ceram Soc 48:144–149Google Scholar
  203. Drouet C (2015) A comprehensive guide to experimental and predicted thermodynamic properties of phosphate apatite minerals in view of applicative purposes. J. Chem. Thermodyn 81:143–159CrossRefGoogle Scholar
  204. Duer MJ (2015) The contribution of solid-state NMR spectroscopy to understanding biomineralization: atomic and molecular structure of bone. J Magn Reson 253:98–110CrossRefGoogle Scholar
  205. Duff EJ (1972) Orthophosphates—VII. Thermodynamical considerations concerning the stability of oxyapatite, Ca10O(PO4)6, in aqueous media. J Inorg Nuclear Chem 34:853–857Google Scholar
  206. Dumoulin JA, Slack JF, Whalen MT, Harris AG (2011) Depositional setting and geochemistry of phosphorites and metalliferous black shales in the carboniferous-permian lisburne group, northern Alaska. US Geological Survey Professional Paper, 1776 C, pp 1–30Google Scholar
  207. Durucan C, Brown PW (2000) α-tricalcium phosphate hydrolysis to hydroxyapatite at and near physiological temperature. J Mater Sci Mater Med 11:365–371CrossRefGoogle Scholar
  208. Durucan C, Brown PW (2002) Kinetic model for α-tricalcium phosphate hydrolysis. J Am Ceram Soc 85:2013–2018CrossRefGoogle Scholar
  209. Eagle RA, Schauble EA, Tripati AK, Tütken T, Hulbert RC, Eiler JM (2010) Body temperatures of modern and extinct vertebrates from 13C-18O bond abundances in bioapatite. Proc Natl Acad Sci USA 107:10377–10382CrossRefGoogle Scholar
  210. Eanes ED, Gillessen IH, Posner AS (1965) Intermediate states in the precipitation of hydroxyapatite. Nature 208:365–367CrossRefGoogle Scholar
  211. Earle WR (1943) Production of malignancy in vitro. IV. The mouse fibroblast cultures and changes seen in the living cells. J Nat Cancer Inst 4:165–212Google Scholar
  212. Ehrlich H, Koutsoukos PG, Demadis KD, Pokrovsky OS (2008) Principles of demineralization: modern strategies for the isolation of organic frameworks. Part I. common definitions and history. Micron 39:1062–1091CrossRefGoogle Scholar
  213. Ehrlich H, Koutsoukos PG, Demadis KD, Pokrovsky OS (2009) Principles of demineralization: modern strategies for the isolation of organic frameworks.Part II. Decalcification. Micron 40:169–193CrossRefGoogle Scholar
  214. Ellinger RF, Nery EB, Lynch KL (1986) Histological assessment of periodontal osseous defects following implantation of hydroxyapatite and biphasic calcium phosphate ceramics: a case report. Int J Periodont Restor Dent 3:22–33Google Scholar
  215. Elliott JC (1994) Structure and chemistry of the apatites and other calcium orthophosphates. In: Studies in inorganic chemistry, vol 18. Elsevier, Amsterdam, p 389Google Scholar
  216. Elliott JC (1998) Recent studies of apatites and other calcium orthophosphates. In: Les matériaux en phosphate de calcium. Aspects fondamentaux./Calcium phosphate materials. In: Brès E, Hardouin P (eds) Fundamentals. Sauramps Medical, Montpellier, pp 25–66Google Scholar
  217. Elliott JC (2002) Calcium phosphate biominerals. In: Hughes JM, Kohn M, Rakovan J (eds) Phosphates: geochemical, geobiological and materials importance. Series: reviews in mineralogy and geochemistry, vol 48. Mineralogical Society of America: Washington, D.C., pp 13–49Google Scholar
  218. Elliott JC, Mackie PE, Young RA (1973) Monoclinic hydroxyapatite. Science 180:1055–1057CrossRefGoogle Scholar
  219. Elorza J, Astibia H, Murelaga X, Pereda-Suberbiola X (1999) Francolite as a diagenetic mineral in dinosaur and other upper cretaceous reptile bones (Lano, Iberian peninsula): microstructural, petrological and geochemical features. Cretac Res 20:169–187CrossRefGoogle Scholar
  220. Emsley J (2001) The shocking history of phosphorus: a biography of the devil’s element. Pan Books, Macmillan, p 336Google Scholar
  221. Enax J, Janus AM, Raabe D, Epple M, Fabritius HO (2014) Ultrastructural organization and micromechanical properties of shark tooth enameloid. Acta Biomater 10:3959–3968CrossRefGoogle Scholar
  222. Engin NO, Tas AC (1999) Manufacture of macroporous calcium hydroxyapatite bioceramics. J Eur Ceram Soc 19:2569–2572CrossRefGoogle Scholar
  223. Eppell SJ, Tong W, Katz JL, Kuhn L, Glimcher MJ (2001) Shape and size of isolated bone mineralites measured using atomic force microscopy. J Orthoporos Res 19:1027–1034CrossRefGoogle Scholar
  224. Epstein NE (2009) Beta tricalcium phosphate: observation of use in 100 posterolateral lumbar instrumented fusions. Spine J 9:630–638CrossRefGoogle Scholar
  225. Eshtiagh-Hosseini H, Houssaindokht MR, Chahkandhi M, Youssefi A (2008) Preparation of anhydrous dicalcium phosphate, DCPA, through sol-gel process, identification and phase transformation evaluation. J Non-Cryst Solids 354:3854–3857CrossRefGoogle Scholar
  226. Evans LA, McCutcheon AL, Dennis GR, Mulley RC, Wilson MA (2005) Pore size analysis of fallow deer (Dama dama) antler bone. J Mater Sci 40:5733–5739CrossRefGoogle Scholar
  227. Feng D, Shi J, Wang X, Zhang L, Cao S (2013a) Hollow hybrid hydroxyapatite microparticles with sustained and pH-responsive drug delivery properties. RSC Adv 3:24975–24982CrossRefGoogle Scholar
  228. Feng J, Chong M, Chan J, Zhang ZY, Teoh SH, Thian ES (2013b) Apatite-based microcarriers for bone tissue engineering. Key Eng Mater 529–530:34–39CrossRefGoogle Scholar
  229. Fernandez E, Planell JA, Best SM, Bonfield W (1998) Synthesis of dahllite through a cement setting reaction. J Mater Sci Mater Med 9:789–792CrossRefGoogle Scholar
  230. Ferreira A, Oliveira C, Rocha F (2003) The different phases in the precipitation of dicalcium phosphate dihydrate. J Cryst Growth 252:599–611CrossRefGoogle Scholar
  231. Fincham AG, Moradian-Oldak J, Diekwisch TGH, Lyaruu DM, Wright JT, Bringas P, Slavkin HC (1995) Evidence for amelogenin “nanospheres” as functional components of secretory-stage enamel matrix. J Struct Biol 115:50–59CrossRefGoogle Scholar
  232. Fitzpatrick LA, Turner RT, Ritman ER (2003) Endochondral bone formation in the heart: a possible mechanism of coronary calcification. Endocrinology 144:2214–2219CrossRefGoogle Scholar
  233. Fleet M (2015) Carbonated hydroxyapatite: materials, synthesis, and applications. Pan Stanford, Singapore, p 278Google Scholar
  234. Floege J, Kim J, Ireland E, Chazot C, Drueke T, de Francisco A, Kronenberg F, Marcelli D, Passlick-Deetjen J, Schernthaner G, Fouqueray B, Wheeler DC (2011) Serum iPTH, calcium and phosphate, and the risk of mortality in a European haemodialysis population. Nephrol Dial Transpl 26:1948–1955CrossRefGoogle Scholar
  235. Ford AK (1917) A remarkable crystal of apatite from Mt. Apatite, Auburn, Maine. Am J Sci 44:245–246CrossRefGoogle Scholar
  236. Fourcroy AF (1804) A general system of chemical knowledge; and its application to the phenomena of nature and art. In eleven volumes. Translated from the original French by William Nicholson. vol. III. Cadell and Davies, Strand; Longman and Rees, G. and J. Robinson, and J. Walker, Paternoster-row; Vernor and Hood, Poultry; Clarke and sons, Portugal-street; Cuthell and Martin, and Ogilvy and son, Holborn; and S. Bagster, Strand, London, p 472Google Scholar
  237. Fratzl P, Weinkamer R (2007) Nature’s hierarchical materials. Prog Mater Sci 52:1263–1334CrossRefGoogle Scholar
  238. Fratzl P, Gupta HS, Paschalis EP, Roschger P (2004) Structure and mechanical quality of the collagen-mineral nano-composite in bone. J Mater Chem 14:2115–2123CrossRefGoogle Scholar
  239. Frondel C (1941) Whitlockite: a new calcium phosphate, Ca3(PO4)2. Am Miner 26:145–152Google Scholar
  240. Fu L, Fu Z, Yu Y, Wu Z, Jeong JH (2015) An Eu/Tb-codoped inorganic apatite Ca5(PO4)3F luminescent thermometer. Ceram Int 41:7010–7016CrossRefGoogle Scholar
  241. Gaft M, Shoval S, Panczer G, Nathan Y, Champagnon B, Garapon C (1996) Luminescence of uranium and rare-earth elements in apatite of fossil fish teeth. Palaeogeogr Palaeocl 126:187–193CrossRefGoogle Scholar
  242. Galea L, Bohner M, Thuering J, Doebelin N, Aneziris CG, Graule T (2013) Control of the size, shape and composition of highly uniform, non-agglomerated, sub-micrometer β-tricalcium phosphate and dicalcium phosphate platelets. Biomaterials 34:6388–6401CrossRefGoogle Scholar
  243. Gao YB, Weng WJ, Deng XL, Cheng K, Liu XG, Du PY, Shen G, Han GR (2006) Surface morphology variations of porous nano-calcium phosphate/poly(L-lactic acid) composites in PBS. Key Eng Mater 309–311:569–572CrossRefGoogle Scholar
  244. Gao R, van Halsema FED, Temminghoff EJM, van Leeuwen HP, van Valenberg HJF, Eisner MD, Giesbers M, van Boekel MAJS (2010a) Modelling ion composition in simulated milk ultrafiltrate (SMUF). I: influence of calcium phosphate precipitation. Food Chem 122:700–709CrossRefGoogle Scholar
  245. Gao R, van Halsema FED, Temminghoff EJM, van Leeuwen HP, van Valenberg HJF, Eisner MD, van Boekel MAJS (2010b) Modelling ion composition in simulated milk ultrafiltrate (SMUF). II. Influence of pH, ionic strength and polyphosphates. Food Chem 122:710–715CrossRefGoogle Scholar
  246. Garcia GM, McCord GC, Kumar R (2003) Hydroxyapatite crystal deposition disease. Semin Musculoskelet Radiol 7:187–193CrossRefGoogle Scholar
  247. García-Tuñón E, Couceiro R, Franco J, Saiz E, Guitián F (2012) Synthesis and characterisation of large chlorapatite single-crystals with controlled morphology and surface roughness. J Mater Sci Mater Med 23:2471–2482CrossRefGoogle Scholar
  248. Garg T, Goyal AK (2014) Biomaterial-based scaffolds—current status and future directions. Expert Opin Drug Deliv 11:767–789CrossRefGoogle Scholar
  249. Gasga JR, Carbajal-De-La-Torre G, Bres E, Gil-Chavarria IM, Rodríguez-Hernández AG, Garcia-Garcia R (2008) STEM-HAADF electron microscopy analysis of the central dark line defect of human tooth enamel crystallites. J Mater Sci Mater Med 19:877–882CrossRefGoogle Scholar
  250. Gassmann T (1913) The preparation of a complex salt corresponding to apatite-typhus and its relations to the constitution of bones. H -S Z Physiol Chem 83:403–408CrossRefGoogle Scholar
  251. Gaucheron F (2012) Calcium phosphates in dairy products. In: Heimann RB (ed) Calcium phosphates: structure, synthesis, properties, and applications. Nova Science Publishers, New York, pp 381–397Google Scholar
  252. Gemelli E, Resende CX, de Soares GDA (2010) Nucleation and growth of octacalcium phosphate on treated titanium by immersion in a simplified simulated body fluid. J Mater Sci Mater Med 21:2035–2047CrossRefGoogle Scholar
  253. George A, Veis A (2008) Phosphorylated proteins and control over apatite nucleation, crystal growth, and inhibition. Chem Rev 108:4670–4693CrossRefGoogle Scholar
  254. Giachelli C (2001) Ectopic calcification: new concepts in cellular regulation. Z Kardiol 90(Suppl 3):III31–III37Google Scholar
  255. Giachelli CM (2004) Vascular calcification mechanisms. J Am Soc Nephrol 15:2959–2964CrossRefGoogle Scholar
  256. Giachelli CM (2005) Inducers and inhibitors of biomineralization: lessons from pathological calcification. Orthod Craniofac Res 8:229–231CrossRefGoogle Scholar
  257. Giachelli CM, Speer MY, Li X, Rajachar RM, Yang H (2005) Regulation of vascular calcification: roles of phosphate and osteopontin. Circ Res 96:717–722CrossRefGoogle Scholar
  258. Giannossi ML, Summa V (2012) Calcium phosphate urinary stones: prevalence, composition and management. In: Heimann RB (ed) Calcium phosphates: structure, synthesis, properties, and applications. Nova Science Publishers, New York, pp 343–361Google Scholar
  259. Gilinskaya LG (2010) Organic radicals in natural apatites according to EPR data: potential genetic and paleoclimatic indicators. J Struct Chem 51:471–481CrossRefGoogle Scholar
  260. Gilinskaya LG, Zanin YN (2012) Geochemistry of organic matter in natural apatites of phosphorites according to EPR spectra of free radicals. Geochem Int 50:1007–1025CrossRefGoogle Scholar
  261. Gilmour R (2014) Phosphoric acid: purification, uses, technology, and economics. CRC Press, Boca Raton, p 354Google Scholar
  262. Gineste L, Gineste M, Ranz X, Ellefterion A, Guilhem A, Rouquet N, Frayssinet P (1999) Degradation of hydroxylapatite, fluorapatite and fluorhydroxyapatite coatings of dental implants in dogs. J Biomed Mater Res 48:224–234CrossRefGoogle Scholar
  263. Glenn CR (1994) Phosphorus and phosphorites: sedimentology and environments of formation. Eclogae Geol Helv 87:747–788Google Scholar
  264. Glimcher MJ (2006) Bone: nature of the calcium phosphate crystals and cellular, structural and physical chemical mechanisms in their formation. In: Sahai N, Schoonen MAA (eds) Medical mineralogy and geochemistry, series: reviews in mineralogy and geochemistry, vol 64. Mineralogical Society of America, Washington, D.C., pp 223–282Google Scholar
  265. Glimcher MJ, Bonar LC, Grynpas MD, Landis WJ, Roufosse AH (1981) Recent studies of bone mineral: is the amorphous calcium phosphate theory valid? J Cryst Growth 53:100–119CrossRefGoogle Scholar
  266. Goff AK, Reichard R (2006) A soft-tissue calcification: differential diagnosis and pathogenesis. J Forensic Sci 51:493–497CrossRefGoogle Scholar
  267. Gomez S, Garcia AJ, Luna S, Kierdorf U, Kierdorf H, Gallego L, Landete-Castillejos T (2013) Labeling studies on cortical bone formation in the antlers of red deer (Cervus elaphus). Bone 52:506–515CrossRefGoogle Scholar
  268. Gower LB (2008) Biomimetic model systems for investigating the amorphous precursor pathway and its role in biomineralization. Chem Rev 108:4551–4627CrossRefGoogle Scholar
  269. Grases F, Llobera A (1998) Experimental model to study sedimentary kidney stones. Micron 29:105–111CrossRefGoogle Scholar
  270. Grech P, Ell PJ, Martin TJ, Barrington NA, Martin TJ (1998) Diagnosis in metabolic bone disease. Hodder Arnold H&S, USA, p 300Google Scholar
  271. Green D, Walsh D, Mann S, Oreffo ROC (2002) The potential of biomimesis in bone tissue engineering: lessons from the design and synthesis of invertebrate skeletons. Bone 30:810–815CrossRefGoogle Scholar
  272. Griffith LG, Naughton G (2002) Tissue engineering—current challenges and expanding opportunities. Science 295:1009–1014CrossRefGoogle Scholar
  273. Grigg AT, Mee M, Mallinson PM, Fong SK, Gan Z, Dupree R, Holland D (2014) Cation substitution in β-tricalcium phosphate investigated using multi-nuclear, solid-state NMR. J Solid State Chem 212:227–236CrossRefGoogle Scholar
  274. Gross KA, Pluduma L (2012) Putting oxyhydroxyapatite into perspective: a pathway to oxyapatite and its applications. In: Heimann RB (ed) Calcium phosphates: structure, synthesis, properties, and applications. Nova Science Publishers, New York, pp 95–120Google Scholar
  275. Gross KA, Rozite E (2015) Synthesis of tetracalcium phosphate at reduced temperatures. Key Eng Mater 631:93–98CrossRefGoogle Scholar
  276. Gross KA, Berndt CC, Dinnebier R, Stephens P (1998) Oxyapatite in hydroxyapatite coatings. J Mater Sci Mater Med 33:3985–3991CrossRefGoogle Scholar
  277. Grossin D, Rollin-Martinet S, Estournès C, Rossignol F, Champion E, Combes C, Rey C, Geoffroy C, Drouet C (2010) Biomimetic apatite sintered at very low temperature by spark plasma sintering: physico-chemistry and microstructure aspects. Acta Biomater 6:577–585CrossRefGoogle Scholar
  278. Grynpas MD, Omelon S (2007) Transient precursor strategy or very small biological apatite crystals? Bone 41:162–164CrossRefGoogle Scholar
  279. Grynpas MD, Hancock RG, Greenwood C, Turnquist J, Kessler MJ (1993) The effects of diet, age, and sex on the mineral content of primate bones. Calcif Tissue Int 52:399–405CrossRefGoogle Scholar
  280. Güney M, Ayranci E, Kaplan S (2013) Development and histology of the pineal gland in animals. In: Turgut M (ed) Step by step experimental pinealectomy techniques in animals for researchers. Nova Science Publishers, New York, pp 33–52Google Scholar
  281. Güngörmüş C, Kiliç A, Akay MT, Kolankaya D (2010) The effects of maternal exposure to food additive E341 (tricalcium phosphate) on foetal development of rats. Environ Toxicol Pharmacol 29:111–116CrossRefGoogle Scholar
  282. Gupta HS, Wagermaier W, Zickler GA, Aroush DRB, Funari SS, Roschger P, Wagner HD, Fratzl P (2005) Nanoscale deformation mechanisms in bone. Nano Lett 5:2108–2111CrossRefGoogle Scholar
  283. Habashi F (2011) The future of dicalcium phosphate. In: SME annual meeting and exhibit and CMA 113th national western mining conference 2011, pp 327–330Google Scholar
  284. Habelitz S, Marshall SJ, Marshall GW Jr, Balooch M (2001) The functional width of the dentino-enamel junction determined by AFM-based nanoscratching. J Struct Biol 135:294–301CrossRefGoogle Scholar
  285. Hale EK (2003) Metastatic calcification. Dermatology Online J 9:2. ( Accessed June 2015
  286. Hall BK (2015) Bones and cartilage: developmental skeletal biology, 2nd edn. Academic Press, New York, p 920Google Scholar
  287. Hamai R, Toshima T, Tafu M, Masutani T, Chohji T (2013) Effect of anions on morphology control of brushite particles. Key Eng Mater 529–530:55–60Google Scholar
  288. Hanks JH, Wallace RE (1949) Relation of oxygen and temperature in the preservation of tissues by refrigeration. Proc Soc Exp Biol Med 71:196–200CrossRefGoogle Scholar
  289. Hannig C, Hannig M (2010) Natural enamel wear—a physiological source of hydroxylapatite nanoparticles for biofilm management and tooth repair? Med Hypotheses 74:670–672CrossRefGoogle Scholar
  290. Hanschin RG, Stern WB (1995) X-ray diffraction studies on the lattice perfection of human bone apatite (Crista iliaca). Bone 16(Suppl 4):355S–363SCrossRefGoogle Scholar
  291. Harper RA, Posner AS (1966) Measurement of non-crystalline calcium phosphate in bone mineral. Proc Soc Exptl Biol Med 122:137–142CrossRefGoogle Scholar
  292. Harries JE, Hukins DWL, Hasnain SS (1986) Analysis of the EXAFS spectrum of hydroxyapatite. J Phys C Solid State Phys 19:6859–6872CrossRefGoogle Scholar
  293. Harries JE, Hukins DWL, Holt C, Hasnain SS (1987) Conversion of amorphous calcium phosphate into hydroxyapatite investigated by EXAFS spectroscopy. J Cryst Growth 84:563–570CrossRefGoogle Scholar
  294. Hartgerink JD, Beniash E, Stupp SI (2001) Self-assembly and mineralization of peptide-amphiphile nanofibers. Science 294:1684–1688CrossRefGoogle Scholar
  295. Hartmann P, Jäger C, Barth S, Vogel J, Meyer K (2001) Solid state NMR, X-ray diffraction, and infrared characterization of local structure in heat-treated oxyhydroxyapatite microcrystals: an analog of the thermal decomposition of hydroxyapatite during plasma-spray procedure. J Solid State Chem 160:460–468CrossRefGoogle Scholar
  296. Hasan I, Keilig L, Reimann S, Rahimi A, Wahl G, Bourauel C (2012) Material parameters of the reindeer antler for use in dental implant biomechanics. Ann Anat 194:518–523CrossRefGoogle Scholar
  297. Hattab FN (2013) Remineralisation of carious lesions and fluoride uptake by enamel exposed to various fluoride dentifrices in vitro. Oral Health Prev Dent 11(3):281–290Google Scholar
  298. Hayashi Y (1992) High resolution electron microscopy in the dentino-enamel junction. J Electron Microsc (Tokyo) 41:387–391Google Scholar
  299. Hayashi Y (1993) High resolution electron microscopic study on the human dentine crystal. J Electron Microsc (Tokyo) 42:141–146Google Scholar
  300. Hayashizaki J, Ban S, Nakagaki H, Okumura A, Yoshii S, Robinson C (2008) Site specific mineral composition and microstructure of human supra-gingival dental calculus. Arch Oral Biol 53:168–174CrossRefGoogle Scholar
  301. Hayes CW, Conway WF (1990) Calcium hydroxyapatite deposition disease. Radiogr Rev Publ Radiol Soc N Am Inc. 10:1031–1048Google Scholar
  302. Haynes V (1968) Radiocarbon: analysis of inorganic carbon of fossil bone and enamel. Science 161:687–688CrossRefGoogle Scholar
  303. He L, Feng Z (2007) Preparation and characterization of dicalcium phosphate dihydrate coating on enamel. Mater Lett 61:3923–3926CrossRefGoogle Scholar
  304. He LH, Swain MV (2007) Enamel—a ‘metallic-like’ deformable biocomposite. J Dent 35:431–437CrossRefGoogle Scholar
  305. Heling L, Heindel R, Merin B (1981) Calcium-fluorapatite. A new material for bone implants. J Oral Implantol 9:548–555Google Scholar
  306. Hench LL (1998) Biomaterials: a forecast for the future. Biomaterials 19:1419–1423CrossRefGoogle Scholar
  307. Hench LL, Polak JM (2002) Third-generation biomedical materials. Science 295:1014–1017CrossRefGoogle Scholar
  308. Henry TH (1850) On francolite, a supposed new mineral. Phil Mag 36:134–135Google Scholar
  309. Hilbrig F, Freitag R (2012) Isolation and purification of recombinant proteins, antibodies and plasmid DNA with hydroxyapatite chromatography. Biotechnol J 7:90–102CrossRefGoogle Scholar
  310. Hilgenstock G (1883) Eine neue Verbindung von P2O5 und CaO. Stahl Eisen 3:498Google Scholar
  311. Hilgenstock G (1887) Das vierbasische Kalkphosphat und die Basicitätsstufe des Silicats in der Thomas-Schlacxke. Stahl Eisen 7:557–560Google Scholar
  312. Ho KL (1989) Morphogenesis of Michaelis-Gutmann bodies in cerebral malacoplakia. An ultrastructural study. Arch Pathol Lab Med 113:874–879Google Scholar
  313. Ho SP, Balooch M, Goodis HE, Marshall GW, Marshall SJ (2004) Ultrastructure and nanomechanical properties of cementum dentin junction. J Biomed Mater Res A 68A:343–351CrossRefGoogle Scholar
  314. Ho SP, Sulyanto RM, Marshall SJ, Marshall GW (2005) The cementum-dentin junction also contains glycosaminoglycans and collagen fibrils. J Struct Biol 151:69–78CrossRefGoogle Scholar
  315. Ho SP, Yu B, Yun W, Marshall GW, Ryder MI, Marshall SJ (2009a) Structure, chemical composition and mechanical properties of human and rat cementum and its interface with root dentine. Acta Biomater 5:707–718CrossRefGoogle Scholar
  316. Ho SP, Senkyrikova P, Marshall GW, Yun W, Wang Y, Karan K, Li C, Marshall SJ (2009b) Structure, chemical composition and mechanical properties of coronal cementum in human deciduous molars. Dent Mater 25:1195–1204CrossRefGoogle Scholar
  317. Hogarth DD (1974) The discovery of apatite on the Lievre River,Quebec. Miner Rec 5:178–182Google Scholar
  318. Holt C (1982) Inorganic constituents of milk. III. The colloidal calcium phosphate of cow’s milk. J Dairy Res 49:29–38CrossRefGoogle Scholar
  319. Holt LE, la Mer VK, Chown HB (1925a) Studies in calcification. I. The solubility product of secondary and tertiary calcium phosphate under various conditions. J Biol Chem 64:509–565Google Scholar
  320. Holt LE, la Mer VK, Chown HB (1925b) Studies in calcification. II. Delayed equilibrium between the calcium phosphates and its biological significance. J Biol Chem 64:567–578Google Scholar
  321. Holzmann D, Holzinger D, Hesser G, Schmidt T, Knör G (2009) Hydroxyapatite nanoparticles as novel low-refractive index additives for the long-term UV-photoprotection of transparent composite materials. J Mater Chem 19:8102–8106CrossRefGoogle Scholar
  322. Honghui Z, Hui L, Linghong G (2007) Molecular and crystal structure characterization of calcium-deficient apatite. Key Eng Mater 330–332:119–122Google Scholar
  323. Horch HH, Sader R, Pautke C, Neff A, Deppe H, Kolk A (2006) Synthetic, pure-phase beta-tricalcium phosphate ceramic granules (Cerasorb®) for bone regeneration in the reconstructive surgery of the jaws. Int J Oral Maxillofac Surg 35:708–713CrossRefGoogle Scholar
  324. Hou XJ, Mao KY, Chen DF (2008) Bone formation performance of beta-tricalcium phosphate sintered bone. J Clin Rehabil Tiss Eng Res 12:9627–9630Google Scholar
  325. Hou Y, Morrison CJ, Cramer SM (2011) Classification of protein binding in hydroxyapatite chromatography: synergistic interactions on the molecular scale. Anal Chem 83:3709–3716CrossRefGoogle Scholar
  326. Houllé P, Voegel JC, Schultz P, Steuer P, Cuisinier FJG (1997) High resolution electron microscopy: structure and growth mechanisms of human dentine crystals. J Dent Res 76:895–904CrossRefGoogle Scholar
  327. Hu K, Yang XJ, Cai YL, Cui ZD, Wei Q (2006) Preparation of bone-like composite coating using a modified simulated body fluid with high Ca and P concentrations. Surf Coat Technol 201:1902–1906CrossRefGoogle Scholar
  328. Hu YY, Rawal A, Schmidt-Rohr K (2010) Strongly bound citrate stabilizes the apatite nanocrystals in bone. Proc Natl Acad Sci USA 107:22425–22429CrossRefGoogle Scholar
  329. Huan Z, Chang J (2009) Novel bioactive composite bone cements based on the β-tricalcium phosphate–monocalcium phosphate monohydrate composite cement system. Acta Biomater 5:1253–1264CrossRefGoogle Scholar
  330. Huang CM, Zhang Q, Bai S, Wang CS (2007) FTIR and XRD analysis of hydroxyapatite from fossil human and animal teeth in Jinsha Relict, Chengdu. Spectrosc Spect Anal 27:2448–2452Google Scholar
  331. Hubert B, Álvaro JJ, Chen JY (2005) Microbially mediated phosphatization in the Neoproterozoic Doushantuo Lagerstätte, South China. Bull Soc Géol Fr 176:355–361CrossRefGoogle Scholar
  332. Huo J, Liu ZY, Wang KF, Xu ZQ (2015) In vivo evaluation of chemical composition of eight types of urinary calculi using spiral computerized tomography in a Chinese population. J Clin Labor Anal 29:370–374CrossRefGoogle Scholar
  333. Hussain SM, Al-Jashamy KA (2013) Determination of chemical composition of gallbladder stones and their association with induction of cholangiocarcinoma. Asian Pac J Cancer Prev 14:6257–6260CrossRefGoogle Scholar
  334. Hutchens SA, Benson RS, Evans BR, O’Neill HM, Rawn CJ (2006) Biomimetic synthesis of calcium-deficient hydroxyapatite in a natural hydrogel. Biomaterials 27:4661–4670CrossRefGoogle Scholar
  335. Huxley J (1931) The relative size of antlers of deer. Proc Zool Soc Lond 72:819–864Google Scholar
  336. Iijima M, Nelson DGA, Pan Y, Kreinbrink AT, Adachi M, Goto T, Moriwaki Y (1996) Fluoride analysis of apatite crystals with a central planar OCP inclusion: concerning the role of F ions on apatite/OCP/apatite structure formation. Calcif Tissue Int 59:377–384CrossRefGoogle Scholar
  337. Imbeni V, Kruzic JJ, Marshall GW, Marshall SJ, Ritchie RO (2005) The dentin-enamel junction and the fracture of human teeth. Nature Mater 4:229–232CrossRefGoogle Scholar
  338. Ionta FQ, Mendonça FL, de Oliveira GC, de Alencar CRB, Honório HM, Magalhães AC, Rios D (2014) In vitro assessment of artificial saliva formulations on initial enamel erosion remineralization. J Dent 42:175–179CrossRefGoogle Scholar
  339. Ishikawa K (2010) Bone substitute fabrication based on dissolution-precipitation reactions. Materials 3:1138–1155CrossRefGoogle Scholar
  340. Ito A, LeGeros RZ (2008) Magnesium- and zinc-substituted beta-tricalcium phosphates as potential bone substitute biomaterials. Key Eng Mater 377:85–98CrossRefGoogle Scholar
  341. Ivanova TI, Frank-Kamenetskaya OV (2001) Kol’tsov, A.B., Ugolkov, V.L. Crystal structure of calcium-deficient carbonated hydroxyapatite thermal decomposition. J Solid State Chem 160:340–349CrossRefGoogle Scholar
  342. Iwatsubo T, Kusumocahyo SP, Kanamori T, Shinbo T (2006) Mineralization of hydroxyapatite on a polymer substrate in a solution supersaturated by polyelectrolyte. J Appl Polym Sci 100:1465–1470CrossRefGoogle Scholar
  343. Izquierdo-Barba I, Salinas AJ, Vallet-Regí M (2000) Effect of the continuous solution exchange on the in vitro reactivity of a CaO–SiO2 sol-gel glass. J Biomed Mater Res 51:191–199CrossRefGoogle Scholar
  344. Jacob KD, Reynolds DS (1928) Reduction of tricalcium phosphate by carbon. Ind Eng Chem 20:1204–1210CrossRefGoogle Scholar
  345. Jahnen-Dechent W, Schinke T, Trindl A, Muller-Esterl W, Sablitzky F, Kaiser S, Blessing M (1997) Cloning and targeted deletion of the mouse fetuin gene. J Biol Chem 272:31496–31503CrossRefGoogle Scholar
  346. Jahnen-Dechent W, Schäfer G, Heiss A, Grötzinger J (2001) Systemic inhibition of spontaneous calcification by the serum protein a2-HS glycoprotein/fetuin. Z Kardiol 90(Suppl 3):III/47–III/56Google Scholar
  347. Jahromi MT, Yao G, Cerruti M (2013) The importance of amino acid interactions in the crystallization of hydroxyapatite. J R Soc Interface 10(20120906):14Google Scholar
  348. Jalota S, Tas AC, Bhaduri SB (2005) Synthesis of HA-seeded TTCP (Ca4(PO4)2O) powders at 1230 °C from Ca(CH3COO)2·H2O and NH4H2PO4. J Am Ceram Soc 88:3353–3360CrossRefGoogle Scholar
  349. Jalota S, Bhaduri SB, Tas AC (2008) Using a synthetic body fluid (SBF) solution of 27 mM HCO3 to make bone substitutes more osteointegrative. Mater Sci Eng C 28:129–140CrossRefGoogle Scholar
  350. Jandt KD (2006) Probing the future in functional soft drinks on the nanometre scale—towards tooth friendly soft drinks. Trends Food Sci Technol 17:263–271CrossRefGoogle Scholar
  351. Jang AT, Lin JD, Choi RM, Seto ML, Ryder MI, Gansky SA, Curtis DA, Ho SP (2014) Adaptive properties of human cementum and cementum dentin junction with age. J Mech Behav Biomed Mater 39:184–196CrossRefGoogle Scholar
  352. Jarvis I (1994) Phosphorite geochemistry: state-of-the-art and environmental concerns. Eclogae Geol Helv 87:643–700Google Scholar
  353. Jenness R, Koops J (1962) Preparation and properties of a salt solution which simulates milk ultrafiltrate. Neth Milk Dairy J 16:153–164Google Scholar
  354. Jillavenatesa A, Condrate RA Sr (1997) The infrared and Raman spectra of tetracalcium phosphate (Ca4(PO4)2O). Spectrosc Lett 30:1561–1570CrossRefGoogle Scholar
  355. Jodaikin A, Traub W, Weiner S (1984) Enamel rod relations in the developing rat incisor. J Ultrastruct Res 89:324–332CrossRefGoogle Scholar
  356. Jodaikin A, Weiner S, Talmon Y, Grossman E, Traub W (1988) Mineral-organic matrix relations in tooth enamel. Int J Biol Macromol 10:349–352CrossRefGoogle Scholar
  357. Jokic B, Jankovic-Castvan I, Veljovic DJ, Bucevac D, Obradovic-Djuricic K, Petrovic R, Janackovic DJ (2007) Synthesis and settings behavior of α-TCP from calcium deficient hydroxyapatite obtained by hydrothermal method. J Optoelectron Adv Mater 9:1904–1910Google Scholar
  358. Jones HB (1845) Contributions to the chemistry of the urine. On the variations in the alkaline and earthy phosphates in the healthy state, and on the alkalescence of the urine from fixed alkalies. Philos Trans R Soc Lond 135:335–349Google Scholar
  359. Jones FH (2001) Teeth and bones: application of surface science to dental materials and related biomaterials. Surf Sci Rep 42:75–205CrossRefGoogle Scholar
  360. Jones JR, Hench LL (2003) Regeneration of trabecular bone using porous ceramics. Curr Opin Solid State Mater Sci 7:301–307CrossRefGoogle Scholar
  361. Kaflak-Hachulska A, Slosarczyk A, Kolodziejski W (2000) Kinetics of NMR cross-polarization from protons to phosphorus-31 in natural brushite. Solid State Nucl Mag 15:237–238CrossRefGoogle Scholar
  362. Kai D, Fan H, Li D, Zhu X, Zhang X (2009) Preparation of tetracalcium phosphate and the effect on the properties of calcium phosphate cement. Mater Sci Forum 610–613:1356–1359CrossRefGoogle Scholar
  363. Kakei M, Sakae T, Yoshikawa M (2009) Electron microscopy of octacalcium phosphate in the dental calculus. J Electron Microsc 58:393–398CrossRefGoogle Scholar
  364. Kalia P, Vizcay-Barrena G, Fan JP, Warley A, di Silvio L, Huang J (2014) Nanohydroxyapatite shape and its potential role in bone formation: an analytical study. J R Soc Interface 11(20140004):11Google Scholar
  365. Kamitakahara M, Ohtsuki C, Miyazaki T (2008) Review paper: behavior of ceramic biomaterials derived from tricalcium phosphate in physiological condition. J Biomater Appl 23:197–212CrossRefGoogle Scholar
  366. Kanazawa T, Umegaki T, Uchiyama N (1982) Thermal crystallisation of amorphous calcium phosphate to α-tricalcium phosphate. J Chem Tech Biotechnol 32:399–406CrossRefGoogle Scholar
  367. Kannan S, Rebelo A, Lemos AF, Barba A, Ferreira JMF (2007) Synthesis and mechanical behaviour of chlorapatite and chlorapatite/β-TCP composites. J Eur Ceram Soc 27:2287–2294CrossRefGoogle Scholar
  368. Kannan S, Goetz-Neunhoeffer F, Neubauer J, Ferreira JMF (2008) Ionic substitutions in biphasic hydroxyapatite and β-tricalcium phosphate mixtures: structural analysis by Rietveld refinement. J Am Ceram Soc 91:1–12CrossRefGoogle Scholar
  369. Kannan S, Goetz-Neunhoeffer F, Neubauer J, Ferreira JMF (2009) Synthesis and structure refinement of zinc-doped β-tricalcium phosphate powders. J Am Ceram Soc 92:1592–1595CrossRefGoogle Scholar
  370. Kannan S, Goetz-Neunhoeffer F, Neubauer J, Pina S, Torres PMC, Ferreira JMF (2010) Synthesis and structural characterization of strontium- and magnesium-co-substituted β-tricalcium phosphate. Acta Biomater 6:571–576CrossRefGoogle Scholar
  371. Kanzaki N, Treboux G, Onuma K, Tsutsumi S, Ito A (2001) Calcium phosphate clusters. Biomaterials 22:2921–2929CrossRefGoogle Scholar
  372. Karlinsey RL, Mackey AC (2009) Solid-state preparation and dental application of an organically modified calcium phosphate. J Mater Sci 44:346–349CrossRefGoogle Scholar
  373. Karlinsey RL, Mackey AC, Walker ER, Frederick KE (2010a) Preparation, characterization and in vitro efficacy of an acid-modified β-TCP material for dental hard-tissue remineralization. Acta Biomater 6:969–978CrossRefGoogle Scholar
  374. Karlinsey RL, Mackey AC, Walker ER, Frederick KE (2010b) Surfactant-modified β-TCP: structure, properties, and in vitro remineralization of subsurface enamel lesions. J Mater Sci Mater Med 21:2009–2020CrossRefGoogle Scholar
  375. Katsamenis OL, Karoutsos V, Kontostanos K, Panagiotopoulos EC, Papadaki H, Bouropoulos N (2012) Microstructural characterization of CPPD and hydroxyapatite crystal depositions on human menisci. Cryst Res Technol 47:1201–1209CrossRefGoogle Scholar
  376. Kawabata K, Yamamoto T (2010) First-principles calculations of the elastic properties of hydroxyapatite doped with divalent ions. J Ceram Soc Jpn 118:548–549CrossRefGoogle Scholar
  377. Kay MI, Young RA, Posner AS (1964) Crystal structure of hydroxyapatite. Nature 204:1050–1052CrossRefGoogle Scholar
  378. Kazama JJ, Amizuka N, Fukagawa M (2006) Ectopic calcification as abnormal biomineralization. Ther Apher Dial 10(Suppl 1):S34–S38CrossRefGoogle Scholar
  379. Kazama JJ, Amizuka N, Fukagawa M (2007) The making of a bone in blood vessels: from the soft shell to the hard bone. Kidney Int 72:533–534CrossRefGoogle Scholar
  380. Keller L, Dollase WA (2000) X-ray determination of crystalline hydroxyapatite to amorphous calcium-phosphate ratio in plasma sprayed coatings. J Biomed Mater Res 49:244–249CrossRefGoogle Scholar
  381. Khairnar RS, Mene RU, Munde SG, Mahabole MP (2011) Nano-hydroxyapatite thick film gas sensors. AIP Conf Proc 1415:189–192CrossRefGoogle Scholar
  382. Kheradmandfard M, Fathi MH, Ahangarian M, Zahrani EM (2012) In vitro bioactivity evaluation of magnesium-substituted fluorapatite nanopowders. Ceram Int 38:169–175CrossRefGoogle Scholar
  383. Kierdorf U, Kierdorf H (2000) The fluoride content of antlers as an indicator of fluoride exposure in red deer (Cervus elaphus): a historical biomonitoring study. Fluoride 33:92–94Google Scholar
  384. Kierdorf U, Kierdorf H (2005) Antlers as biomonitors of environmental pollution by lead and fluoride: a review. Eur J Wildl Res 51:137–150CrossRefGoogle Scholar
  385. Kierdorf U, Kierdorf H (2011) Deer antlers—a model of mammalian appendage regeneration: an extensive review. Gerontology 57:53–65CrossRefGoogle Scholar
  386. Kierdorf U, Li C, Price JS (2009) Improbable appendages: deer antler renewal as a unique case of mammalian regeneration. Semin Cell Dev Biol 20:535–542CrossRefGoogle Scholar
  387. Kijkowska R, Kowalski Z, Pawlowska-Kozinska D, Wzorek Z, Gorazda K (2007) Effect of purification from sulfates on phase composition of sodium tripolyphosphate obtained from wet-process phosphoric acid derived from Kola apatite. Phosphorus Sulfur 182:2667–2683CrossRefGoogle Scholar
  388. Kikawa T, Kashimoto O, Imaizumi H, Kokubun S, Suzuki O (2009) Intramembranous bone tissue response to biodegradable octacalcium phosphate implant. Acta Biomater 5:1756–1766CrossRefGoogle Scholar
  389. Kim HM (2003) Ceramic bioactivity and related biomimetic strategy. Curr Opin Solid State Mater Sci 7:289–299CrossRefGoogle Scholar
  390. Kim CJ, Choi SK (2007) Analysis of aqueous humor calcium and phosphate from cataract eyes with and without diabetes mellitus. KJO 21:90–94Google Scholar
  391. Kim TN, Feng QL, Kim JO, Wu J, Wang H, Chen GC, Cui FZ (1998) Antimicrobial effects of metal ions (Ag+, Cu2+, Zn2+) in hydroxyapatite. J Mater Sci Mater Med 9:129–134CrossRefGoogle Scholar
  392. Kim JY, Fenton RR, Hunter BA, Kennedy BJ (2000a) Powder diffraction studies of synthetic calcium and lead apatites. Aust J Chem 53:679–686CrossRefGoogle Scholar
  393. Kim HM, Kishimoto K, Miyaji F, Kokubo T, Yao T, Suetsugu Y, Tanaka J, Nakamura T (2000b) Composition and structure of apatite formed on organic polymer in simulated body fluid with a high content of carbonate ion. J Mater Sci Mater Med 11:421–426CrossRefGoogle Scholar
  394. Kim HM, Miyazaki T, Kokubo T, Nakamura T (2001) Revised simulated body fluid. In: Giannini S, Moroni A (eds) Bioceramics 13, vol 192–195. Trans Tech Publ, Switzerland, pp 47–50Google Scholar
  395. Kim BI, Jeong SH, Jang SO, Kim KN, Kwon HK, Park YD (2006) Tooth whitening effect of toothpastes containing nano-hydroxyapatite. Key Eng Mater 309–311:541–544Google Scholar
  396. Kim SW, Kwon YH, Park CK, Kim YH (2013) Tumoral calcinosis in the nose in a patient with scleroderma: an unusual site for a rare tumor. J Craniofac Surg 24:1483–1484CrossRefGoogle Scholar
  397. Kirkham J, Zhang J, Brookes SJ, Shore RC, Wood SR, Smith DA, Wallwork ML, Ryu OH, Robinson C (2000) Evidence for charge domains on developing enamel crystal surfaces. J Dent Res 79:1943–1947CrossRefGoogle Scholar
  398. Kirsch T (2006) Determinants of pathological mineralization. Curr Opin Rheumatol 18:174–180CrossRefGoogle Scholar
  399. Kirsch T (2007) Physiological and pathological mineralization: a complex multifactorial process. Curr Opin Orthop 18:425–427CrossRefGoogle Scholar
  400. Klein C (1901) Brushite from the island of Mona (between Haiti and Puerto Rico). Sitzber K Preuss Aka 720–725Google Scholar
  401. Knudtson ML, Wyse DG, Galbraith PD, Brant R, Hildebrand K, Paterson D, Richardson D, Burkart C, Burgess E (2002) Chelation therapy for ischemic heart disease: a randomized controlled trial. JAMA 287:481–486CrossRefGoogle Scholar
  402. Kodaka T, Debari K, Higashi S (1988) Magnesium-containing crystals in human dental calculus. J Electron Microsc (Tokyo) 37:73–80Google Scholar
  403. Kodaka T, Hirayama A, Mori R, Sano T (1998) Spherulitic brushite stones in the dental pulp of a cow. J Electron Microsc 47:57–65CrossRefGoogle Scholar
  404. Kogarko LN (1999) Problems of the genesis of giant apatite and rare metal deposits of the Kola Peninsula, Russia. Geol Ore Depos 41:351–366Google Scholar
  405. Koinzer S, Scharpenack P, Katzke H, Leuschner I, Roider J (2009) Cataracta ossea—ultrastructural and specimen analysis. Ann Anat 191:563–567CrossRefGoogle Scholar
  406. Kokubo T, Takadama H (2006) How useful is SBF in predicting in vivo bone bioactivity? Biomaterials 27:2907–2915CrossRefGoogle Scholar
  407. Kokubo T, Kushitani H, Sakka S, Kitsugi T, Yamamuro T (1990) Solutions able to reproduce in vivo surface-structure changes in bioactive glass-ceramic A-W3. J Biomed Mater Res 24:721–734CrossRefGoogle Scholar
  408. Kolk A, Handschel J, Drescher W, Rothamel D, Kloss F, Blessmann M, Heiland M, Wolff KD, Smeets R (2012) Current trends and future perspectives of bone substitute materials—from space holders to innovative biomaterials. J Cran Maxillofac Surg 40:706–718CrossRefGoogle Scholar
  409. Kolmas J, Kalinowski E, Wojtowicz A, Kolodziejski W (2010) Mid-infrared reflectance microspectroscopy of human molars: chemical comparison of the dentin-enamel junction with the adjacent tissues. J Mol Struct 966:113–121CrossRefGoogle Scholar
  410. Kolmas J, Groszyk E, Kwiatkowska-Róhycka D (2014) Substituted hydroxyapatites with antibacterial properties. BioMed Res Int 2014(178123):15Google Scholar
  411. Kolodny Y, Luz B, Sander M, Clemens WA (1996) Dinosaur bones: fossils or pseudomorphs? The pitfalls of physiology reconstruction from apatitic fossils. Palaeo 126:161–171CrossRefGoogle Scholar
  412. Kongteweelert S, Ruttanapun C, Thongkam M, Chaiyasith P, Woramongkonchai S, Boonchom AB (2013) Facile, alternative synthesis of spherical-like Ca(H2PO4)2·H2O nanoparticle by aqueous-methanol media. Adv Mater Res 717:49–53CrossRefGoogle Scholar
  413. Köster K, Heide H, König R (1977) Resorbierbare Calciumphosphatkeramik im Tierexperiment unter Belastung. Langenbecks Arch Chir 343:173–181CrossRefGoogle Scholar
  414. Koussoulakou DS, Margaritis LH, Koussoulakos SL (2009) A curriculum vitae of teeth: evolution, generation, regeneration. Int J Biol Sci 5:226–243CrossRefGoogle Scholar
  415. Koutsopoulos S (2002) Synthesis and characterization of hydroxyapatite crystals: a review study on the analytical methods. J Biomed Mater Res 62:600–612CrossRefGoogle Scholar
  416. Koutsoukos P, Amjad Z, Tomson MB, Nancollas GH (1980) Crystallization of calcium phosphates: a constant composition study. J Am Chem Soc 102:1553–1557CrossRefGoogle Scholar
  417. Kreidler ER, Hummel FA (1967) Phase relationships in the system SrO–P2O5 and the influence of water vapor on the formation of Sr4P2O9. Inorg Chem 6:884–891CrossRefGoogle Scholar
  418. Krings M, Kanellopoulou D, Mavrilas D, Glasmacher B (2006) In vitro pH-controlled calcification of biological heart valve prostheses. Mat.-Wiss u Werkstofftech 37:432–435CrossRefGoogle Scholar
  419. Kuhn LT, Grynpas MD, Rey C, Wu Y, Ackerman JL, Glimcher MJ (2008) A comparison of the physical and chemical differences between cancellous and cortical bovine bone mineral at two ages. Calcif Tissue Int 83:146–154CrossRefGoogle Scholar
  420. Kui C (2007) Slip casting derived α-TCP/HA biphasic ceramics. Key Eng Mater 330–332:51–54Google Scholar
  421. Kumar R, Cheang P, Khor KA (2004) Phase composition and heat of crystallization of amorphous calcium phosphate in ultra-fine radio frequency suspension plasma sprayed hydroxyapatite powders. Acta Mater 52:1171–1181CrossRefGoogle Scholar
  422. Kurabayashi M (2013) Role of calcium and phosphate in atherosclerosis and vascular calcification. Clin Calcium 23:489–496Google Scholar
  423. Lafon JP, Champion E, Bernache-Assollant D (2008) Processing of AB-type carbonated hydroxyapatite Ca10-x(PO4)(6-x)(CO3)(x)(OH)(2-x-2y)(CO3)(y) ceramics with controlled composition. J Eur Ceram Soc 28:139–147CrossRefGoogle Scholar
  424. Lagier R, Baud CA (2003) Magnesium whitlockite, a calcium phosphate crystal of special interest in pathology. Pathol Res Pract 199:329–335CrossRefGoogle Scholar
  425. Lamas GA, Ackermann A (2000) Clinical evaluation of chelation therapy: is there any wheat amidst the chaff? Am Heart J 140:4–5CrossRefGoogle Scholar
  426. Landete-Castilleijos T, Garcia A, Gallego L (2007a) Body weight, early growth and antler size influence antler bone mineral composition of Iberian Red Deer (Cervus elaphus hispanicus). Bone 40:230–235CrossRefGoogle Scholar
  427. Landete-Castilleijos T, Currey JD, Estevez JA, Gaspar-Lopez E, Garcia A, Gallego L (2007b) Influence of physiological effort of growth and chemical composition on antler bone mechanical properties. Bone 41:794–803CrossRefGoogle Scholar
  428. Landete-Castilleijos T, Estevez JA, Martinez A, Ceacero F, Garcia A, Gallego L (2007c) Does chemical composition of antler bone reflect the physiological effort made to grow it? Bone 40:1095–1102CrossRefGoogle Scholar
  429. Landi E, Tampieri A, Celotti G, Langenati R, Sandri M, Sprio S (2005) Nucleation of biomimetic apatite in synthetic body fluids: dense and porous scaffold development. Biomaterials 26:2835–2845CrossRefGoogle Scholar
  430. Landi E, Riccobelli S, Sangiorgi N, Sanson A, Doghieri F, Miccio F (2014) Porous apatites as novel high temperature sorbents for carbon dioxide. Chem Eng J 254:586–596CrossRefGoogle Scholar
  431. Landin M, Rowe RC, York P (1994) Structural changes during the dehydration of dicalcium phosphate dihydrate. Eur J Pharmac Sci 2:245–252CrossRefGoogle Scholar
  432. Landis WJ, Hodgens KJ, Arena J, Song MJ, McEwen BF (1996) Structural relations between collagen and mineral in bone as determined by high voltage electron microscopic tomography. Microsc Res Tech 33:192–202CrossRefGoogle Scholar
  433. Lang SB (1966) Pyroelectric effect in bone and tendon. Nature 212:704–705CrossRefGoogle Scholar
  434. Langhorst SE, O’Donnell JNR, Skrtic D (2009) In vitro remineralization of enamel by polymeric amorphous calcium phosphate composite: quantitative microradiographic study. Dent Mater 25:884–891CrossRefGoogle Scholar
  435. Lapin AV, Lyagushkin AP (2014) The Kovdor apatite-francolite deposit as a prospective source of phosphate ore. Geol Ore Depos 56:61–80CrossRefGoogle Scholar
  436. Lee RS, Kayser MV, Ali SY (2006) Calcium phosphate microcrystal deposition in the human intervertebral disc. J Anat 208:13–19CrossRefGoogle Scholar
  437. Lee JW, Sasaki K, Ferrara JD, Akiyama K, Sasaki T, Nakano T (2009) Evaluation of preferential alignment of biological apatite (BAp) crystallites in bone using transmission X-ray diffraction optics. J Jpn Ins Metal 73:786–793CrossRefGoogle Scholar
  438. Lee NH, Hwang KH, Lee JK (2013) Fabrication of biphasic calcium phosphate bioceramics from the recycling of bone ash. Adv Mater Res 610–613:2328–2331Google Scholar
  439. LeGeros RZ (1985) Preparation of octacalcium phosphate (OCP): a direct fast method. Calcif Tissue Int 37:194–197CrossRefGoogle Scholar
  440. LeGeros RZ (1991) Calcium phosphates in oral biology and medicine. In: Monographs in oral science, vol 15. Karger, Basel, p 201Google Scholar
  441. LeGeros RZ (1999) Calcium phosphates in demineralization and remineralization processes. J Clin Dent 10:65–73Google Scholar
  442. LeGeros RZ (2001) Formation and transformation of calcium phosphates: relevance to vascular calcification. Z Kardiol 90(Suppl 3):III116–III125Google Scholar
  443. LeGeros RZ, Balmain N, Bonel G (1987) Age-related changes in mineral of rat and bovine cortical bone. Calcif Tissue Int 41:137–144CrossRefGoogle Scholar
  444. LeGeros RZ, Orly I, LeGeros JP, Gomez C, Kazimiroff J, Tarpley T, Kerebel B (1988) Scanning electron microscopy and electron probe microanalyses of the crystalline components of human and animal dental calculi. Scan Microsc 2:345–356Google Scholar
  445. Lenton S, Nylander T, Teixeira SCM, Holt C (2015) A review of the biology of calcium phosphate sequestration with special reference to milk. Dairy Sci Technol 95:3–14CrossRefGoogle Scholar
  446. León B, Jansen JJ (eds) (2009) Thin calcium phosphate coatings for medical implants. Springer, New York, p 326Google Scholar
  447. Lerebours C, Thomas CDL, Clement JG, Buenzli PR, Pivonka P (2015) The relationship between porosity and specific surface in human cortical bone is subject specific. Bone 72:109–117CrossRefGoogle Scholar
  448. Leveque I, Cusack M, Davis SA, Mann S (2004) Promotion of fluorapatite crystallization by soluble-matrix proteins from Lingula Anatina shells. Angew Chem Int Ed Engl 43:885–888CrossRefGoogle Scholar
  449. Li Z, Pasteris JD (2014) Tracing the pathway of compositional changes in bone mineral with age: preliminary study of bioapatite aging in hypermineralized dolphin’s bulla. Biochim Biophys Acta 40:2331–2339CrossRefGoogle Scholar
  450. Li Y, Weng W (2007) In vitro synthesis and characterization of amorphous calcium phosphates with various Ca/P atomic ratios. J Mater Sci Mater Med 18:2303–2308CrossRefGoogle Scholar
  451. Li C, Suttie JM, Clarck DE (2005) Histological examination of antler regeneration in red deer (Cervus elaphus). Anat Rec 282A:163–174CrossRefGoogle Scholar
  452. Li Y, Weng W, Tam KC (2007) Novel highly biodegradable biphasic tricalcium phosphates composed of α-tricalcium phosphate and β-tricalcium phosphate. Acta Biomater 3:251–254CrossRefGoogle Scholar
  453. Li Y, Li D, Weng W (2008a) In vitro dissolution behavior of biphasic tricalcium phosphate composite powders composed of α-tricalcium phosphate and β-tricalcium phosphate. Key Eng Mater 368–372:1206–1208CrossRefGoogle Scholar
  454. Li L, Pan H, Tao J, Xu X, Mao C, Gu X, Tang R (2008b) Repair of enamel by using hydroxyapatite nanoparticles as the building blocks. J Mater Chem 18:4079–4084CrossRefGoogle Scholar
  455. Li X, Ito A, Sogo Y, Wang X, LeGeros RZ (2009a) Solubility of Mg-containing β-tricalcium phosphate at 25 & #xB0;C. Acta Biomater 5:508–517CrossRefGoogle Scholar
  456. Li Y, Kong F, Weng W (2009) Preparation and characterization of novel biphasic calcium phosphate powders (α-TCP/HA) derived from carbonated amorphous calcium phosphates. J Biomed Mater Res B (Appl Biomater) 89B:508–517Google Scholar
  457. Li Y, Ho J, Ooi CP (2010) Antibacterial efficacy and cytotoxicity studies of copper (II) and titanium (IV) substituted hydroxyapatite nanoparticles. Mater Sci Eng C 30:1137–1144CrossRefGoogle Scholar
  458. Li H, Guo Z, Xue B, Zhang Y, Huang W (2011) Collagen modulating crystallization of apatite in a biomimetic gel system. Ceram Int 37:2305–2310CrossRefGoogle Scholar
  459. Li D, Liang Z, Chen J, Yu J, Xu R (2013) AIE luminogen bridged hollow hydroxyapatite nanocapsules for drug delivery. Dalton Transact 42:9877–9883CrossRefGoogle Scholar
  460. Li X, Wang J, Joiner A, Chang J (2014a) The remineralisation of enamel: a review of the literature. J Dent 42(Suppl. 1):S12–S20CrossRefGoogle Scholar
  461. Li C, Zhao H, Liu Z, McMahon C (2014b) Deer antler—a novel model for studying organ regeneration in mammals. Int J Biochem Cell Biol 56:111–122CrossRefGoogle Scholar
  462. Li CX, Duan YH, Hu WC (2015) Electronic structure, elastic anisotropy, thermal conductivity and optical properties of calcium apatite Ca5(PO4)3X (X = F, Cl or Br). J Alloy Compd 619:66–77CrossRefGoogle Scholar
  463. Liang L, Rulis P, Ching WY (2010) Mechanical properties, electronic structure and bonding of α- and β-tricalcium phosphates with surface characterization. Acta Biomater 6:3763–3771CrossRefGoogle Scholar
  464. Lichtenauer M, Nickl S, Hoetzenecker K, Mangold A, Mitterbauer A, Hacker S, Zimmermann M, Ankersmit HJ (2011) Effect of PBS solutions on chemokine secretion of human peripheral blood mononuclear cells. Am Lab 43:30–33Google Scholar
  465. Lide DR (2005) The CRC handbook of chemistry and physics, 86th edn. CRC Press, Boca Raton, p 2544Google Scholar
  466. Lieske JC, Norris R, Toback FG (1997) Adhesion of hydroxyapatite crystals to anionic sites on the surface of renal epithelial cells. Am J Physiol 273:F224–F233Google Scholar
  467. Lin K, Wu C, Chang J (2014) Advances in synthesis of calcium phosphate crystals with controlled size and shape. Acta Biomater 10:4071–4102CrossRefGoogle Scholar
  468. Liou SC, Chen SY, Lee HY, Bow JS (2004) Structural characterization of nano-sized calcium deficient apatite powders. Biomaterials 25:189–196CrossRefGoogle Scholar
  469. Lippert F, Parker DM, Jandt KD (2004a) In situ remineralisation of surface softened human enamel studied with AFM nanoindentation. Surf Sci 553:105–114CrossRefGoogle Scholar
  470. Lippert F, Parker DM, Jandt KD (2004b) In vitro demineralization/remineralization cycles at human tooth enamel surfaces investigated by AFM and nanoindentation. J Colloid Interf Sci 280:442–448CrossRefGoogle Scholar
  471. Lippert F, Parker DM, Jandt KD (2004c) Toothbrush abrasion of surface softened enamel studied with tapping mode AFM and AFM nanoindentation. Caries Res 38:464–472CrossRefGoogle Scholar
  472. Liu B, Lun DX (2012) Current application of β-tricalcium phosphate composites in orthopaedics. Orthop Surg 4:139–144CrossRefGoogle Scholar
  473. Liu Y, Shen Z (2012) Dehydroxylation of hydroxyapatite in dense bulk ceramics sintered by spark plasma sintering. J Eur Ceram Soc 32:2691–2696CrossRefGoogle Scholar
  474. Liu TY, Chen SY, Liu DM, Liou SC (2005) On the study of BSA-loaded calcium-deficient hydroxyapatite nano-carriers for controlled drug delivery. J Control Release 107:112–121CrossRefGoogle Scholar
  475. Liu Y, Pei GX, Shan J, Ren GH (2008) New porous beta-tricalcium phosphate as a scaffold for bone tissue engineering. J Clin Rehabil Tiss Eng Res 12:4563–4567Google Scholar
  476. Liu X, Smith LA, Hu J, Ma PX (2009) Biomimetic nanofibrous gelatin/apatite composite scaffolds for bone tissue engineering. Biomaterials 30:2252–2258CrossRefGoogle Scholar
  477. Liu F, Xu J, Wang F, Zhao L, Shimizu T (2010) Biomimetic deposition of apatite coatings on micro-arc oxidation treated biomedical NiTi alloy. Surf Coat Technol 204:3294–3299CrossRefGoogle Scholar
  478. Liu F, Qiu W, Wang HR, Song Y, Wang FP (2013) Biomimetic deposition of apatite coatings on biomedical NiTi alloy coated with amorphous titanium oxide by microarc oxidation. Mater Sci Technol 29:749–753CrossRefGoogle Scholar
  479. Long T, Guo YP, Liu YZ, Zhu ZA (2013) Hierarchically nanostructured mesoporous carbonated hydroxyapatite microspheres for drug delivery systems with high drug-loading capacity. RSC Adv 3:24169–24176CrossRefGoogle Scholar
  480. Loong CK, Rey C, Kuhn LT, Combes C, Wu Y, Chen SH, Glimcher MJ (2000) Evidence of hydroxyl-ion deficiency in bone apatites: an inelastic neutron scattering study. Bone 26:599–602CrossRefGoogle Scholar
  481. Loutts GB, Chai BHT (1993) Growth of high-quality single crystals of FAP (Ca5(PO4)3F) and its isomorphs. Proc SPIE Int Soc Optical Eng 1863:31–34Google Scholar
  482. Loveridge N (1999) Bone: more than a stick. J Anim Sci 77(Suppl 2):190–196Google Scholar
  483. Low IM, Alhuthali A (2008) In-situ monitoring of dental erosion in tooth enamel when exposed to soft drinks. Mater Sci Eng C 28:1322–1325CrossRefGoogle Scholar
  484. Lowenstam HA (1981) Minerals formed by organisms. Science 211:1126–1131CrossRefGoogle Scholar
  485. Lowenstam HA, Weiner S (1983) Mineralization by organisms and the evolution of biomineralization. In: Westbroek P, de Jong EW (eds) Biomineralization and biological metal accumulation. D. Reidel Pub. Co., Dordrecht, pp 191–203CrossRefGoogle Scholar
  486. Lowenstam HA, Weiner S (1985) Transformation of amorphous calcium phosphate to crystalline dahllite in the radular teeth of chitons. Science 227:51–53CrossRefGoogle Scholar
  487. Lowenstam HA, Weiner S (1989) On biomineralization. Oxford University Press, Oxford, p 324Google Scholar
  488. Lu X, Leng Y (2005) Theoretical analysis of calcium phosphate precipitation in simulated body fluid. Biomaterials 26:1097–1108CrossRefGoogle Scholar
  489. Lu BQ, Zhu YJ, Chen F (2014a) Highly flexible and nonflammable inorganic hydroxyapatite paper. Chem Eur J 20:1242–1246CrossRefGoogle Scholar
  490. Lu ZH, Yin CG, Zhao DM (2014b) Biomimetic scaffolds containing chitosan and hydroxyapatite for bone tissue engineering. Adv Mater Res 971–973:21–25CrossRefGoogle Scholar
  491. Luers JC, Petry-Schmelzer JN, Hein WG, Gostian AO, Hüttenbrink KB, Beutner D (2014) Fragmentation of salivary stones with a 980 nm diode laser. Auris Nasus Larynx 41:76–80CrossRefGoogle Scholar
  492. Lundager-Madsen HE (2008) Optical properties of synthetic crystals of brushite (CaHPO4·2H2O). J Cryst Growth 310:617–623CrossRefGoogle Scholar
  493. Lynn AK, Bonfield W (2005) A novel method for the simultaneous, titrant-free control of pH and calcium phosphate mass yield. Acc Chem Res 38:202–207CrossRefGoogle Scholar
  494. MacDowell H, Brown WE, Sutter JR (1971) Solubility study of calcium hydrogenphosphate.Ion pair formation. Inorg Chem 10:1638–1643CrossRefGoogle Scholar
  495. Madhurambal G, Subha R, Mojumdar SC (2009) Crystallization and thermal characterization of calcium hydrogen phosphate dihydrate crystals. J Therm Anal Calorim 96:73–76CrossRefGoogle Scholar
  496. Magda A, Pode V, Niculescu M, Muntean C, Bandur G, Iovi A (2008) Studies on process of obtaining the fertilizers based on ammonium phosphates with addition of boric acid. Rev Chim Buchar 59:1340–1344Google Scholar
  497. Mahamid J, Sharir A, Addadi L, Weiner S (2008) Amorphous calcium phosphate is a major component of the forming fin bones of zebrafish: indications for an amorphous precursor phase. Proc Natl Acad Sci USA 105:12748–12753CrossRefGoogle Scholar
  498. Mahamid J, Aichmayer B, Shimoni E, Ziblat R, Li C, Siegel S, Paris O, Fratzl P, Weiner S, Addadi L (2010) Mapping amorphous calcium phosphate transformation into crystalline mineral from the cell to the bone in zebrafish fin rays. Proc Natl Acad Sci USA 107:6316–6321CrossRefGoogle Scholar
  499. Mandel S, Tas AC (2010) Brushite (CaHPO4·2H2O) to octacalcium phosphate (Ca8(HPO4)2(PO4)4·5H2O) transformation in DMEM solutions at 36.5 & #xB0;C. Mater Sci Eng C 30:245–254CrossRefGoogle Scholar
  500. Mangano C, Piattelli A, Perrotti V, Iezzi G (2008) Dense hydroxyapatite inserted into postextraction sockets: a histologic and histomorphometric 20-year case report. J Periodontol 79:929–933CrossRefGoogle Scholar
  501. Manjubala I, Scheler S, Bössert J, Jandt KD (2006) Mineralisation of chitosan scaffolds with nano-apatite formation by double diffusion technique. Acta Biomater 2:75–84CrossRefGoogle Scholar
  502. Mann S (1993) Molecular tectonics in biomineralization and biomimetic materials chemistry. Nature 365:499–505CrossRefGoogle Scholar
  503. Mann AW, Turner AG (1972) Excess calcium fluoride in fluorapatite. Aust J Chem 25:2701–2703CrossRefGoogle Scholar
  504. Mareci D, Chelariu R, Ciurescu G, Sutiman D, Gloriant T (2010) Electrochemical aspects of Ti-Ta alloys in HBSS. Mater Corros 61:768–774CrossRefGoogle Scholar
  505. Margolis HC, Beniash E, Fowler CE (2006) Role of macromolecular assembly of enamel matrix proteins in enamel formation. J Dent Res 86:775–793CrossRefGoogle Scholar
  506. Marino AA, Becker RO (1967) Evidence for direct physical bonding between the collagen fibres and apatite crystals in bone. Nature 213:697–698CrossRefGoogle Scholar
  507. Marino AA, Becker RO (1970) Evidence for epitaxy in the formation of collagen and apatite. Nature 226:652–653CrossRefGoogle Scholar
  508. Markovic M, Fowler BO, Tung MS (2004) Preparation and comprehensive characterization of a calcium hydroxyapatite reference material. J Res Natl Inst Stand Technol 109:553–568CrossRefGoogle Scholar
  509. Marques PAAP, Serro AP, Saramago BJ, Fernandes AC, Magalhães MCF, Correia RN (2003a) Mineralisation of two phosphate ceramics in HBSS: role of albumin. Biomaterials 24:451–460CrossRefGoogle Scholar
  510. Marques PAAP, Magalhães MCF, Correia RN (2003b) Inorganic plasma with physiological CO2/HCO3 buffer. Biomaterials 24:1541–1548CrossRefGoogle Scholar
  511. Marques PAAP, Cachinho SCP, Magalhães MCF, Correia RN, Fernandes MHV (2004) Mineralization of bioceramics in simulated plasma with physiological CO2/HCO3 buffer and albumin. J Mater Chem 14:1861–1866CrossRefGoogle Scholar
  512. Marra SP, Daghlian CP, Fillinger MF, Kennedy FE (2006) Elemental composition, morphology and mechanical properties of calcified deposits obtained from abdominal aortic aneurysms. Acta Biomater 2:515–520CrossRefGoogle Scholar
  513. Marshall SJ, Balooch M, Habelitz S, Balooch G, Gallagher R, Marshall GW (2003) The dentin-enamel junction—a natural, multilevel interface. J Eur Ceram Soc 23:2897–2904CrossRefGoogle Scholar
  514. Martin I, Brown PW (1993) Hydration of tetracalcium phosphate. Adv Chem Res 5:115–125Google Scholar
  515. Martin RI, Brown PW (1997) Phase equilibria among acid calcium phosphates. J Am Ceram Soc 80:1263–1266CrossRefGoogle Scholar
  516. Mason HE, Mccubbin FM, Smirnov AE, Phillips BL (2009) Solid-state NMR and IR spectroscopic investigation of the role of structural water and F in carbonate-rich fuorapatite. Am Miner 94:507–516CrossRefGoogle Scholar
  517. Mathew M, Takagi S (2001) Structures of biological minerals in dental research. J Res Natl Inst Stand Technol 106:1035–1044CrossRefGoogle Scholar
  518. Mathew M, Brown WE, Schroeder LW, Dickens B (1988) Crystal structure of octacalcium bis(hydrogenphosphate) tetrakis(phosphate)pentahydrate, Ca8(HPO4)2(PO4)4·5H2O. J Crystallogr Spectrosc Res 18:235–250CrossRefGoogle Scholar
  519. Matsui K, Machida H, Mitsuhashi T, Omori H, Nakaoka T, Sakura H, Ueno E (2015) Analysis of coronary arterial calcification components with coronary CT angiography using single-source dual-energy CT with fast tube voltage switching. Int J Cardiovasc Imaging 31:639–647CrossRefGoogle Scholar
  520. Matsunaga K (2008a) First-principles study of substitutional magnesium and zinc in hydroxyapatite and octacalcium phosphate. J Chem Phys 128:245101CrossRefGoogle Scholar
  521. Matsunaga K (2008) Theoretical investigation of the defect formation mechanism relevant to nonstoichiometry in hydroxyapatite. Phys Rev B 77(104106):14Google Scholar
  522. Matsunaga K, Kuwabara A (2007) First-principles study of vacancy formation in hydroxyapatite. Phys Rev B 75(014102):9Google Scholar
  523. Mayer I, Jacobsohn O, Niazov T, Werckmann J, Iliescu M, Richard-Plouet M, Burghaus O, Reinen D (2003) Manganese in precipitated hydroxyapatites. Eur J Inorg Chem 1445–1451Google Scholar
  524. Mazelsky R, Hopkins RH, Kramer WE (1968a) Czochralski-growth of calcium fluorophosphates. J Cryst Growth 3–4:260–264CrossRefGoogle Scholar
  525. Mazelsky R, Ohlmann RC, Steinbruegge K (1968b) Crystal growth of a new laser material, fluorapatite. J Electrochem Soc Solid State Sci 115:68–70Google Scholar
  526. Mcarthur JM (1985) Francolite geochemistry-compositional controls during formation, diagenesis, metamorphism and weathering. Geochim Cosmochim Acta 49:23–35CrossRefGoogle Scholar
  527. McClellan GH (1980) Mineralogy of carbonate fluorapatites (Francolites). J Geol Soc 137:675–681CrossRefGoogle Scholar
  528. McClendon JF (1966) Fluorapatite and teeth. Science 151:151CrossRefGoogle Scholar
  529. McConnell D (1973) Apatite: its crystal chemistry, mineralogy, utilization, and geologic and biologic occurrences. In: Applied mineralogy, vol 5. Springer, Vienna, p 111Google Scholar
  530. McCubbin FM, Nekvasil H (2008) Maskelynite-hosted apatite in the Chassigny meteorite: insights into late-stage magmatic volatile evolution in Martian magmas. Am Miner 93:676–684CrossRefGoogle Scholar
  531. McCubbin FM, Shearer CK, Burger PV, Hauri EH, Wang J, Elardo SM, Papike JJ (2014) Volatile abundances of coexisting merrillite and apatite in the Martian meteorite shergotty: implications for merrillite in hydrous magmas. Am Miner 99:1347–1354CrossRefGoogle Scholar
  532. McDowell H, Gregory TM, Brown WE (1977) Solubility of Ca5(PO4)3OH in the system Ca(OH)2–H3PO4–H2O at 5, 15, 25, and 37 degree C. J Res Natl Bur Stand Sect A Phys Chem 81A:273–281Google Scholar
  533. Mehmel M (1930) On the structure of apatite. I Z Kristallogr 75:323–331Google Scholar
  534. Meister W (1956) Changes in biological structure of the long bones of white-tailed deer during the growth of antlers. Anat Rec 124:709–721CrossRefGoogle Scholar
  535. Melrose J, Burkhardt D, Taylor TKF, Dillon CT, Read R, Cake M, Little CB (2009) Calcification in the ovine intervertebral disc: a model of hydroxyapatite deposition disease. Eur Spine J 18:479–489CrossRefGoogle Scholar
  536. Meneghini C, Dalconi MC, Nuzzo S, Mobilio S, Wenk RH (2003) Rietveld refinement on X-ray diffraction patterns of bioapatite in human fetal bones. Biophys J 84:2021–2029CrossRefGoogle Scholar
  537. Merrill GP (1917) On the calcium phosphate in meteoric stones. Am J Sci 43:322–324CrossRefGoogle Scholar
  538. Meuleman N, Tondreau T, Delforge A, Dejeneffe M, Massy M, Libertalis M, Bron D, Lagneaux L (2006) Human marrow mesenchymal stem cell culture: serum-free medium allows better expansion than classical α-MEM medium. Eur J Haematol 76:309–316CrossRefGoogle Scholar
  539. Meyer JL, Eanes ED (1978a) A thermodynamic analysis of the amorphous to crystalline calcium phosphate transformation. Calcif Tissue Res 25:59–68CrossRefGoogle Scholar
  540. Meyer JL, Eanes ED (1978b) A thermodynamic analysis of the secondary transition in the spontaneous precipitation of calcium phosphate. Calcif Tissue Res 28:209–216CrossRefGoogle Scholar
  541. Meyers MA, Chen PY, Lin AYM, Seki Y (2008) Biological materials: structure and mechanical properties. Prog Mater Sci 53:1–206CrossRefGoogle Scholar
  542. Miake Y, Shimoda S, Fukae M, Aoba T (1993) Epitaxial overgrowth of apatite crystals on the thin-ribbon precursor at early stages of porcine enamel mineralization. Calcif Tissue Int 53:249–256CrossRefGoogle Scholar
  543. Mitchell L, Faust GT, Hendricks SB, Reynolds DS (1943) The mineralogy and genesis of hydroxylapatite. Am Miner 28:356–371Google Scholar
  544. Miura M, Fukasawa J, Yasutomi Y, Maehashi H, Matsuura T, Aizawa M (2013) Reconstruction of tissue-engineered bone using an apatite-fiber scaffold, rat bone marrow cells and radial-flow bioreactor: optimization of flow rate in circulating medium. Key Eng Mater 529–530:397–401Google Scholar
  545. Miyaji F, Kim HM, Handa S, Kokubo T, Nakamura T (1999) Bonelike apatite coating on organic polymers: novel nucleation process using sodium silicate solution. Biomaterials 20:913–919CrossRefGoogle Scholar
  546. Miyatake N, Kishimoto KN, Anada T, Imaizumi H, Itoi E, Suzuki O (2009) Effect of partial hydrolysis of octacalcium phosphate on its osteoconductive characteristics. Biomaterials 30:1005–1014CrossRefGoogle Scholar
  547. Miyazaki T, Sivaprakasam K, Tantry J, Suryanarayanan R (2009) Physical characterization of dibasic calcium phosphate dihydrate and anhydrate. J Pharmac Sci 98:905–916CrossRefGoogle Scholar
  548. Mochales C, Wilson RM, Dowker SEP, Ginebra MP (2011) Dry mechanosynthesis of nanocrystalline calcium deficient hydroxyapatite: structural characterization. J Alloy Compd 509:7389–7394CrossRefGoogle Scholar
  549. Mohr W (2003) Apatitkrankheiten. Ihr pathohistologisches substrat in abhängigkeit von der gewebsaufbereitung und erörterungen zur pathogenese. Aktuel. Rheumatol 28:53–58Google Scholar
  550. Molloy ES, McCarthy GM (2006) Basic calcium phosphate crystals: pathways to joint degeneration. Curr Opin Rheumatol 18:187–192CrossRefGoogle Scholar
  551. Montazeri L, Javadpour J, Shokrgozar MA, Bonakdar S, Javadian S (2010) Hydrothermal synthesis and characterization of hydroxyapatite and fluorhydroxyapatite nano-size powders. Biomed Mater 5:045004CrossRefGoogle Scholar
  552. Moore GE (1865) On brushite, a new mineral occurring in phosphatic guano. Am J Sci 39:43–44CrossRefGoogle Scholar
  553. Moreno EC, Kresak M, Zahradnik RT (1974) Fluoridated hydroxyapatite solubility and caries formation. Nature 247:64–65CrossRefGoogle Scholar
  554. Moseke C, Gbureck U (2010) Tetracalcium phosphate: synthesis, properties and biomedical applications. Acta Biomater 6:3815–3823CrossRefGoogle Scholar
  555. Mostashari SM, Haddadi H, Hashempoor Z (2006) Effect of deposited calcium hydrogen phosphate dihydrate on the flame retardancy imparted to cotton fabric. Asian J Chem 18:2388–2390Google Scholar
  556. Mugnaioli E, Reyes-Gasga J, Kolb U, Hemmerlé J, Brès É (2014) Evidence of noncentrosymmetry of human tooth hydroxyapatite crystals. Chem Eur J 20:6849–6852CrossRefGoogle Scholar
  557. Muir PD, Sykes AR, Barrell GK (1987) Calcium metabolism in red deer (Cervus elaphus) offered herbages during antlerogenesis: kinetic and stable balance studies. J Agric Sci Camb 109:357–364CrossRefGoogle Scholar
  558. Mukherjee AK (2014) Human kidney stone analysis using X-ray powder diffraction. J Indian Inst Sci 94:35–44Google Scholar
  559. Müller L, Müller FA (2006) Preparation of SBF with different HCO3 content and its influence on the composition of biomimetic apatites. Acta Biomater 2:181–189CrossRefGoogle Scholar
  560. Murakami Y, Honda Y, Anada T, Shimauchi H, Suzuki O (2010) Comparative study on bone regeneration by synthetic octacalcium phosphate with various granule sizes. Acta Biomater 6:1542–1548CrossRefGoogle Scholar
  561. Murayama JK, Nakai S, Kato M, Kumazawa M (1986) A dense polymorph of Ca3(PO4)2: a high pressure phase of apatite decomposition and its geochemical significance. Phys Earth Planet Inter 44:293–303CrossRefGoogle Scholar
  562. Nagai M, Nishino T, Saeki T (1988) A new type of CO2 gas sensor comprising porous hydroxyapatite ceramics. Sens Actuator 15:145–151CrossRefGoogle Scholar
  563. Nakahira A, Aoki S, Sakamoto K, Yamaguchi S (2001) Synthesis and evaluation of various layered octacalcium phosphates by wet-chemical processing. J Mater Sci Mater Med 12:793–800CrossRefGoogle Scholar
  564. Nakano T, Kaibara K, Tabata Y, Nagata N, Enomoto S, Marukawa E, Umakoshi Y (2002a) Unique alignment and texture of biological apatite crystallites in typical calcified tissues analyzed by microbeam X-ray diffractometer system. Bone 31:479–487CrossRefGoogle Scholar
  565. Nakano T, Kaibara K, Umakoshi Y, Imazato S, Ogata K, Ehara A, Ebisu S, Okazaki M (2002b) Change in microstructure and solubility improvement of HAp ceramics by heat-treatment in a vacuum. Mater Transact 43:3105–3111CrossRefGoogle Scholar
  566. Nakano T, Ishimoto T, Umakoshi Y, Tabata Y (2007) Variation in bone quality during regenerative process. Mater Sci Forum 539–543:675–680CrossRefGoogle Scholar
  567. Nakano T, Ishimoto T, Lee JW, Umakoshi Y (2008) Preferential orientation of biological apatite crystallite in original, regenerated and diseased cortical bones. J Ceram Soc Jpn 116:313–315CrossRefGoogle Scholar
  568. Namba J, Murase T, Moritomo H, Denno K, Henmi S, Yoshikawa H (2008) Tumorous calcification causing carpal tunnel syndrome. Handchir Mikrochir Plast Chir 40:294–298CrossRefGoogle Scholar
  569. Nanci A (2012) Ten Cate’s oral histology: development, structure, and function, 8th edn. Mosby-Year Book, Saint Louis, p 400Google Scholar
  570. Nancollas GH, Wu W (2000) Biomineralization mechanisms: a kinetics and interfacial energy approach. J Cryst Growth 211:137–142CrossRefGoogle Scholar
  571. Narasaraju TSB, Phebe DE (1996) Some physico-chemical aspects of hydroxylapatite. J Mater Sci 31:1–21CrossRefGoogle Scholar
  572. Naray-Szabo S (1930) The structure of apatite (CaF)Ca4(PO4)3. Z Kristallogr 75:387–398Google Scholar
  573. Nasri K, El Feki H, Sharrock P, Fiallo M, Nzihou A (2015) Spray-dried monocalcium phosphate monohydrate for soluble phosphate fertilizer. Ind Eng Chem Res 54:8043–8047CrossRefGoogle Scholar
  574. Nassif N, Gobeaux F, Seto J, Belamie E, Davidson P, Panine P, Mosser G, Fratzl P (2010) Giraud Guille, M.M. Self-assembled collagen-apatite matrix with bone-like hierarchy. Chem Mater 22:3307–3309CrossRefGoogle Scholar
  575. Neary MT, Reid DG, Mason MJ, Friščić T, Duer MJ, Cusack M (2011) Contrasts between organic participation in apatite biomineralization in brachiopod shell and vertebrate bone identified by nuclear magnetic resonance spectroscopy. J R Soc Interface 8:282–288CrossRefGoogle Scholar
  576. Nery EB, Lynch KL, Hirthe WM, Mueller KH (1975) Bioceramic implants in surgically produced infrabony defects. J Periodontol 46:328–347CrossRefGoogle Scholar
  577. Newton RH, Copson RL (1936) Superphosphate manufacture—composition of superphosphate made from phosphate rock and concentrated phosphoric acid. Ind Eng Chem 28:1182–1186CrossRefGoogle Scholar
  578. Nightingale JP, Lewis D (1971) Pole figures of the orientation of apatite in bones. Nature 232:334–335CrossRefGoogle Scholar
  579. Niimi M, Masuda T, Kaihatsu K, Kato N, Nakamura S, Nakaya T, Arai F (2014) Virus purification and enrichment by hydroxyapatite chromatography on a chip. Sens Actuators B 201:185–190CrossRefGoogle Scholar
  580. Nikcevic I, Jokanovic V, Mitric M, Nedic Z, Makovec D, Uskokovic D (2004) Mechanochemical synthesis of nanostructured fluorapatite/fluorhydroxyapatite and carbonated fluorapatite/fluorhydroxyapatite. J Solid State Chem 177:2565–2574CrossRefGoogle Scholar
  581. Nikolov S, Raabe D (2008) Hierarchical modeling of the elastic properties of bone at submicron scales: the role of extrafibrillar mineralization. Biophys J 94:4220–4232CrossRefGoogle Scholar
  582. Niu LN, Zhang W, Pashley DH, Breschi L, Mao J, Chen JH, Tay FR (2014) Biomimetic remineralization of dentin. Dent Mater 30:77–96CrossRefGoogle Scholar
  583. Niwa M, Sato T, Li W, Aoki H, Aoki H, Daisaku T (2001) Polishing and whitening properties of toothpaste containing hydroxyapatite. J Mater Sci Mater Med 12:277–281CrossRefGoogle Scholar
  584. Nordquist WD, Okudera H, Kitamura Y, Kimoto K, Okudera T, Krutchkoff DJ (2011) Part II: crystalline fluorapatite-coated hydroxyapatite implant material: a dog study with histologic comparison of osteogenesis seen with FA-coated HA grafting material versus HA controls: potential bacteriostatic effect of fluoridated HA. J Oral Implant 37:35–42CrossRefGoogle Scholar
  585. Norton J, Malik KR, Darr JA, Rehman IU (2006) Recent developments in processing and surface modification of hydroxyapatite. Adv Appl Ceram 105:113–139CrossRefGoogle Scholar
  586. Nudelman F, Pieterse K, George A, Bomans PHH, Friedrich H, Brylka LJ, Hilbers PAJ, de With G, Sommerdijk NAJM (2010) The role of collagen in bone apatite formation in the presence of hydroxyapatite nucleation inhibitors. Nature Mater 9:1004–1009CrossRefGoogle Scholar
  587. Nurse RW, Welch JB, Gun W (1959) High-temperature phase equilibria in the system dicalcium silicate—tricalcium phosphate. J Chem Soc 1077–1083Google Scholar
  588. Nylen MU, Evans ED, Omnel KA (1963) Crystal growth in rat enamel. J Cell Biol 18:109–123CrossRefGoogle Scholar
  589. O’Duffy E, Clunie G, Lui D, Edwards J, Ell P (1999) Double blind glucocorticoid controlled trial of samarium-153 particulate hydroxyapatite radiation synovectomy for chronic knee synovitis. Ann Rheum Dis 58:554–558CrossRefGoogle Scholar
  590. O’Neill WC (2007) The fallacy of the calcium–phosphorus product. Kidney Int 72:792–796CrossRefGoogle Scholar
  591. Ogose A, Kondo N, Umezu H, Hotta T, Kawashima H, Tokunaga K, Ito T, Kudo N, Hoshino M, Gu W, Endo N (2006) Histological assessment in grafts of highly purified beta-tricalcium phosphate (OSferion®) in human bones. Biomaterials 27:1542–1549CrossRefGoogle Scholar
  592. Ohlmann RC, Steinbruegge KB, Mazelsky R (1968) Spectroscopic and laser characteristics of neodymium-doped calcium fluorophosphate. Appl Opt 7:905–914CrossRefGoogle Scholar
  593. Ohura K, Bohner M, Hardouin P, Lemaître J, Pasquier G, Flautre B (1996) Resorption of, and bone formation from, new β-tricalcium phosphate-monocalcium phosphate cements: an in vivo study. J Biomed Mater Res 30:193–200CrossRefGoogle Scholar
  594. Okulus Z, Héberger K, Voelkel A (2014) Sorption, solubility, and mass changes of hydroxyapatite-containing composites in artificial saliva, food simulating solutions, tea, and coffee. J Appl Polym Sci 131:39856CrossRefGoogle Scholar
  595. Oliveira C, Ferreira A, Rocha F (2007) Dicalcium phosphate dihydrate precipitation: characterization and crystal growth. Chem Eng Res Des 85:1655–1661Google Scholar
  596. Olszta MJ, Cheng X, Jee SS, Kumar R, Kim YY, Kaufman MJ, Douglas EP, Gower LB (2007) Bone structure and formation: a new perspective. Mater Sci Eng R 58:77–116CrossRefGoogle Scholar
  597. Omelon SJ, Grynpas MD (2008) Relationships between polyphosphate chemistry, biochemistry and apatite biomineralization. Chem Rev 108:4694–4715CrossRefGoogle Scholar
  598. Ong JL, Chan DCN (1999) Hydroxyapatites and their use as coatings in dental implants: a review. Crit Rev Biomed Eng 28:667–707CrossRefGoogle Scholar
  599. Onuma K, Ito A (1998) Cluster growth model for hydroxyapatite. Chem Mater 10:3346–3351CrossRefGoogle Scholar
  600. Onuma K, Yamagishi K, Oyane A (2005) Nucleation and growth of hydroxyapatite nanocrystals for nondestructive repair of early caries lesions. J Cryst Growth 282:199–207CrossRefGoogle Scholar
  601. Orsini G, Procaccini M, Manzoli L, Giuliodori F, Lorenzini A, Putignano A (2010) A double-blind randomized-controlled trial comparing the desensitizing efficacy of a new dentifrice containing carbonate/hydroxyapatite nanocrystals and a sodium fluoride/potassium nitrate dentifrice. J Clin Periodontol 37:510–517CrossRefGoogle Scholar
  602. Ortlepp JR, Schmitz F, Mevissen V, Weiß S, Huster J, Dronskowski R, Langebartels G, Autschbach R, Zerres K, Weber C, Hanrath P, Hoffmann R (2004) The amount of calcium-deficient hexagonal hydroxyapatite in aortic valves is influenced by gender and associated with genetic polymorphisms in patients with severe calcific aortic stenosis. Eur Heart J 25:514–522CrossRefGoogle Scholar
  603. Oyane A, Kim HM, Furuya T, Kokubo T, Miyazaki T, Nakamura T (2003) Preparation and assessment of revised simulated body fluids. J Biomed Mater Res A 65A:188–195CrossRefGoogle Scholar
  604. P’ng CH, Boadle R, Horton M, Bilous M, Bonar F (2008) Magnesium whitlockite of the aorta. Pathology 40:539–540Google Scholar
  605. Pachman LM, Boskey AL (2006) Clinical manifestations and pathogenesis of hydroxyapatite crystal deposition in juvenile dermatomyositis. Curr Rheumatol Rep 8:236–243CrossRefGoogle Scholar
  606. Paine ML, White SN, Luo W, Fong H, Sarikaya M, Snead ML (2001) Regulated gene expression dictates enamel structure and tooth function. Matrix Biol 20:273–292CrossRefGoogle Scholar
  607. Palmer LC, Newcomb CJ, Kaltz SR, Spoerke ED, Stupp SI (2008) Biomimetic systems for hydroxyapatite mineralization inspired by bone and enamel. Chem Rev 108:4754–4783CrossRefGoogle Scholar
  608. Pan HB, Darvell BW (2009a) Calcium phosphate solubility: the need for re-evaluation. Cryst Growth Des 9:639–645CrossRefGoogle Scholar
  609. Pan HB, Darvell BW (2009b) Solubility of dicalcium phosphate dihydrate by solid titration. Caries Res 43:254–260CrossRefGoogle Scholar
  610. Pan HB, Darvell BW (2009c) Solid titration of octacalcium phosphate. Caries Res 43:322–330CrossRefGoogle Scholar
  611. Pan HB, Darvell BW (2009d) Solubility of TTCP and β-TCP by solid titration. Arch Oral Biol 54:671–677CrossRefGoogle Scholar
  612. Pan Y, Fleet ME (2002) Compositions of the apatite-group minerals: substitution mechanisms and controlling factors. In: Hughes JM, Kohn M, Rakovan J (eds) Phosphates: geochemical, geobiological and materials importance. Series: reviews in mineralogy and geochemistry, vol 48. Mineralogical Society of America, Washington, D.C., pp 13–49Google Scholar
  613. Pan L, Li Y, Weng W, Cheng K, Song C, Du P, Zhao G, Shen G, Wang J, Han G (2006) Preparation of submicron biphasic α-TCP/HA powders. Key Eng Mater 309–311:219–222CrossRefGoogle Scholar
  614. Pan H, Zhao X, Darvell BW, Lu WW (2010) Apatite-formation ability—predictor of “bioactivity”? Acta Biomater 6:4181–4188CrossRefGoogle Scholar
  615. Pankaew P, Hoonnivathana E, Sujinnapram S, Thamaphat K, Limsuwan P, Naemchanthara K (2012) Characterization of apatite from human teeth via XRD, FT-IR and TGA techniques. Adv Mater Res 506:90–93CrossRefGoogle Scholar
  616. Pasinli A, Yuksel M, Celik E, Sener S, Tas AC (2010) A new approach in biomimetic synthesis of calcium phosphate coatings using lactic acid—Na lactate buffered body fluid solution. Acta Biomater 6:2282–2288CrossRefGoogle Scholar
  617. Pasteris JD (2012) Structurally incorporated water in bone apatite: a cautionary tale. In: Heimann RB (ed) Calcium phosphates: structure, synthesis, properties, and applications. Nova Science Publishers, New York, pp 63–94Google Scholar
  618. Pasteris JD, Wopenka B, Valsami-Jones E (2008) Bone and tooth mineralization: why apatite? Elements 4:97–104CrossRefGoogle Scholar
  619. Pathak NN, Pattanaik AK, Patra RC, Arora BM (2001) Mineral composition of antlers of three deer species reared in captivity. Small Rumin Res 42:61–65CrossRefGoogle Scholar
  620. Pavan B, Ceresoli D, Tecklenburg MMJ, Fornari M (2012) First principles NMR study of fluorapatite under pressure. Solid State Nucl Mag 45–46:59–65CrossRefGoogle Scholar
  621. Pearson G (1798) Experiments and observations, tending to show the composition and properties of urinary concretions. Phil Trans R Soc Lond 88:15–46Google Scholar
  622. Pekounov Y, Petrov OE (2008) Bone resembling apatite by amorphous-to-crystalline transition driven self-organisation. J Mater Sci Mater Med 19:753–759CrossRefGoogle Scholar
  623. Pellegrino ED, Blitz RM (1972) Mineralization in the chick embryo I. Monohydrogen phosphate and carbonate relationships during maturation of the bone crystal complex. Calcif Tissue Res 10:128–135Google Scholar
  624. Percy J (1843) Notice of a new hydrated phosphate of lime. Mem. Proc. Chem. Soc. 2:222–223CrossRefGoogle Scholar
  625. Peterlik H, Roschger P, Klaushofer K, Fratzl P (2006) From brittle to ductile fracture of bone. Nature Mater 5:52–55CrossRefGoogle Scholar
  626. Peters F, Schwarz K, Epple M (2000) The structure of bone studied with synchrotron X-ray diffraction, X-ray absorption spectroscopy and thermal analysis. Thermochim Acta 361:131–138CrossRefGoogle Scholar
  627. Peters MC, Bresciani E, Barata TJE, Fagundes TC, Navarro RL, Navarro MFL, Dickens SH (2010) In vivo dentine remineralization by calcium-phosphate cement. J Dent Res 89:286–291CrossRefGoogle Scholar
  628. Petrucelli GC, Kawachi EY, Kubota LT, Bertran CA (1996) Hydroxyapatite-based electrode: a new sensor for phosphate. Anal Commun 33:227–229CrossRefGoogle Scholar
  629. Pettenazzo E, Deiwick M, Thiene G, Molin G, Glasmacher B, Martignago F, Bottio T, Reul H, Valente M (2001) Dynamic in vitro calcification of bioprosthetic porcine valves: evidence of apatite crystallization. J Thorac Cardiovasc Surg 121:500–509CrossRefGoogle Scholar
  630. Piccirillo C, Rocha C, Tobaldi DM, Pullar RC, Labrincha JA, Ferreira MO, Castro PML, Pintado MME (2014) A hydroxyapatite-Fe2O3 based material of natural origin as an active sunscreen filter. J Mater Chem B 2:5999–6009CrossRefGoogle Scholar
  631. Pietrasik J, Szustakiewicz K, Zaborski M, Haberko K (2008) Hydroxyapatite: an environmentally friendly filler for elastomers. Mol Cryst Liq Cryst 483:172–178CrossRefGoogle Scholar
  632. Pinto G, Caira S, Mamone G, Ferranti P, Addeo F, Picariello G (2014) Fractionation of complex lipid mixtures by hydroxyapatite chromatography for lipidomic purposes. J Chromatogr A 1360:82–92CrossRefGoogle Scholar
  633. Plate U, Tkotz T, Wiesmann HP, Stratmann U, Joos U, Höhling HJ (1996) Early mineralization of matrix vesicles in the epiphyseal growth plate. J Microsc 183:102–107CrossRefGoogle Scholar
  634. Politi Y, Arad T, Klein E, Weiner S, Addadi L (2004) Sea urchin spine calcite forms via a transient amorphous calcium carbonate phase. Science 306:1161–1164CrossRefGoogle Scholar
  635. Poloni LN, Ward MD (2014) The materials science of pathological crystals. Chem Mater 26:477–495CrossRefGoogle Scholar
  636. Posner AS (1969) Crystal chemistry of bone mineral. Physiol Rev 49:760–792Google Scholar
  637. Posner AS (1973) Bone mineral on the molecular level. Fed Proc 32:1933–1937Google Scholar
  638. Posner AS (1978) The chemistry of bone mineral. Bull Hosp Joint Dis 39:126–144Google Scholar
  639. Posner AS, Betts F (1975) Synthetic amorphous calcium phosphate and its relation to bone mineral structure. Acc Chem Res 8:273–281CrossRefGoogle Scholar
  640. Posner AS, Betts F, Blumenthal NC (1980) Formation and structure of synthetic and bone hydroxyapatite. Progr Cryst Growth Char 3:49–64CrossRefGoogle Scholar
  641. Price J, Faucheux C, Allen S (2005) Deer antlers as a model of mammalian regeneration. Curr Top Dev Biol 67:2–49Google Scholar
  642. Prompt CA, Quinton PM, Kleeman CR (1978) High concentrations of sweat calcium, magnesium and phosphate in chronic renal failure. Nephron 20:4–9CrossRefGoogle Scholar
  643. Prostak KS, Seifert P, Skobe Z (1993) Enameloid formation in two tetraodontiform fish species with high and low fluoride contents in enameloid. Arch Oral Biol 38:1031–1044CrossRefGoogle Scholar
  644. Pushpakanth S, Srinivasan B, Sastry TP, Mandal AB (2008) Biocompatible and antibacterial properties of silver-doped hydroxyapatite. J Biomed Nanotechnol 4:62–66Google Scholar
  645. Qiao T, Ma RH, Luo XB, Luo ZL, Zheng PM, Yang LQ (2013) A microstructural study of gallbladder stones using scanning electron microscopy. Microsc Res Tech 76:443–452CrossRefGoogle Scholar
  646. Qiu SR, Orme CA (2008) Dynamics of biomineral formation at the near-molecular level. Chem Rev 108:4784–4822CrossRefGoogle Scholar
  647. Qu H, Wei M (2006) The effect of fluoride contents in fluoridated hydroxyapatite on osteoblast behavior. Acta Biomater 2:113–119CrossRefGoogle Scholar
  648. Quillard S, Mellier C, Gildenhaar R, Hervelin J, Deniard P, Berger G, Bouler JM (2012) Raman and infrared studies of substituted β-TCP. Key Eng Mater 493–494:225–230Google Scholar
  649. Rakovan J (2002) Growth and surface properties of apatite. In: Hughes JM, Kohn M, Rakovan J (eds) Phosphates: geochemical, geobiological and materials importance. Series: reviews in mineralogy and geochemistry, vol 48. Mineralogical Society of America, Washington, D.C., pp 51–86Google Scholar
  650. Rakovan JF, Pasteris JD (2015) A technological gem: materials, medical, and environmental mineralogy of apatite. Elements 11:195–200CrossRefGoogle Scholar
  651. Rangavittal N, Landa-Cánovas AR, González-Calbet JM, Vallet-Regí M (2000) Structural study and stability of hydroxyapatite and β-tricalcium phosphate: two important bioceramics. J Biomed Mater Res 51:660–668CrossRefGoogle Scholar
  652. Ratner BD, Bryant SJ (2004) Biomaterials: where we have been and where we are going. Ann Rev Biomed Eng 6:41–75CrossRefGoogle Scholar
  653. Raz M, Moztarzadeh F, Shokrgoza MA, Azami M, Tahriri M (2014) Development of biomimetic gelatin-chitosan/hydroxyapatite nanocomposite via double diffusion method for biomedical applications. Int J Mater Res 105:493–501CrossRefGoogle Scholar
  654. Reid JD, Andersen ME (1993) Medial calcification (whitlockite) in the aorta. Atherosclerosis 101:213–224CrossRefGoogle Scholar
  655. Reid JW, Pietak AM, Sayer M, Dunfield D, Smith TJN (2005) Phase formation and evolution in the silicon substituted tricalcium phosphate/apatite system. Biomaterials 26:2887–2897CrossRefGoogle Scholar
  656. Reid JW, Tuck L, Sayer M, Fargo K, Hendry JA (2006) Synthesis and characterization of single-phase silicon substituted α-tricalcium phosphate. Biomaterials 27:2916–2925CrossRefGoogle Scholar
  657. Rensberger JM, Watabe M (2000) Fine structure of bone in dinosaurs, birds and mammals. Nature 406:619–622CrossRefGoogle Scholar
  658. Rey C, Trombe JC, Montel G (1978) Some features of the incorporation of oxygen in different oxidation states in the apatitic lattice—III synthesis and properties of some oxygenated apatites. J Inorg Nucl Chem 40:27–30CrossRefGoogle Scholar
  659. Rey C, Renugopalakrishnan V, Shimizu M, Collins B, Glimcher MJ (1991) A resolution-enhanced Fourier transform infrared spectroscopic study of the environment of the CO3 2− ion in the mineral phase of enamel during its formation and maturation. Calcif Tissue Int 49:259–268CrossRefGoogle Scholar
  660. Rey C, Miquel JL, Facchini L, Legrand AP, Glimcher MJ (1995a) Hydroxyl groups in bone mineral. Bone 16:583–586CrossRefGoogle Scholar
  661. Rey C, Hina A, Tofighi A, Glimcher MJ (1995b) Maturation of poorly crystalline apatites: chemical and structural aspect in vivo and in vitro behavior. Cell Mater 5:345–356Google Scholar
  662. Rey C, Combes C, Drouet C, Sfihi H (2006) Chemical diversity of apatites. Adv Sci Technol 49:27–36CrossRefGoogle Scholar
  663. Rey C, Combes C, Drouet C, Glimcher MJ (2009) Bone mineral: update on chemical composition and structure. Osteoporos Int 20:1013–1021 (Erratum: ibid . p. 2155) Google Scholar
  664. Reznikov N, Shahar R, Weiner S (2014a) Three-dimensional structure of human lamellar bone: the presence of two different materials and new insights into the hierarchical organization. Bone 59:93–104CrossRefGoogle Scholar
  665. Reznikov N, Shahar R, Weiner S (2014b) Bone hierarchical structure in three dimensions. Acta Biomater 10:3815–3826CrossRefGoogle Scholar
  666. Rho JY, Kuhn-Spearing L, Zioupos P (1998) Mechanical properties and the hierarchical structure of bone. Med Eng Phys 20:92–102CrossRefGoogle Scholar
  667. Ribeiro HB, Guedes KJ, Pinheiro MVB, Greulich-Weber S, Krambrock K (2005) About the blue and green colours in natural fluorapatite. Phys Status Solidi C 2:720–723CrossRefGoogle Scholar
  668. Riman RE, Suchanek WL, Byrappa K, Chen CW, Shuk P, Oakes CS (2002) Solution synthesis of hydroxyapatite designer particulates. Solid State Ion 151:393–402CrossRefGoogle Scholar
  669. Robinson C, Connell S, Kirkham J, Shore R, Smith A (2004) Dental enamel—a biological ceramic: regular substructures in enamel hydroxyapatite crystals revealed by atomic force microscopy. J Mater Chem 14:2242–2248CrossRefGoogle Scholar
  670. Rodan GA, Martin TJ (2000) Therapeutic approaches to bone diseases. Science 289:1508–1514CrossRefGoogle Scholar
  671. Rodrigues EG, Keller TC, Mitchell S, Pérez-Ramírez J (2014) Hydroxyapatite, an exceptional catalyst for the gas-phase deoxygenation of bio-oil by aldol condensation. Green Chem 16:4870–4874CrossRefGoogle Scholar
  672. Rodríguez-Hernández AG, Fernández ME, Carbajal-de-la-Torre G, García-García R, Reyes-Gasga J (2005) Electron microscopy analysis of the central dark line defect of the human tooth enamel. Mater Res Soc Symp Proc 839:157–162Google Scholar
  673. Rodríguez-Lorenzo L (2005) Studies on calcium deficient apatites structure by means of MAS-NMR spectroscopy. J Mater Sci Mater Med 16:393–398CrossRefGoogle Scholar
  674. Rodríguez-Lorenzo LM, Hart JN, Gross KA (2003) Structural and chemical analysis of well-crystallized hydroxyfluorapatites. J Phys Chem B 107:8316–8320CrossRefGoogle Scholar
  675. Rogers AF (1912) Dahllite (podolite) from Tonopah, Nevada: voelckerite, a new basic calcium phosphate; remarks on the chemical composition of apatite and phosphate rock. Am J Sci Ser 4 33:475–482Google Scholar
  676. Rogers AF (1914) A new locality for voelckerite and the validity of voelckerite as a mineral species. Miner Mag 17:155–162CrossRefGoogle Scholar
  677. Rogers AF (1922) Collophane, a much neglected mineral. Am J Sci 3:269–276CrossRefGoogle Scholar
  678. Rohanizadeh R, LeGeros RZ (2007) Mineral phase in linguloid brachiopod shell: Lingula adamsi. Lethaia 40:61–68CrossRefGoogle Scholar
  679. Rohanová D, Boccaccini AR, Horkavcová D, Bozděchová P, Bezdička P, Častorálová M (2014) Is non-buffered DMEM solution a suitable medium for in vitro bioactivity tests? J Mater Chem B 2:5068–5076CrossRefGoogle Scholar
  680. Romeo HE, Fanovich MA (2008) Synthesis of tetracalcium phosphate from mechanochemically activated reactants and assessment as a component of bone cements. J Mater Sci Mater Med 19:2751–2760CrossRefGoogle Scholar
  681. Rönnholm E (1962) The amelogenesis of human teeth as revealed by electron microscopy. II. The development of the enamel crystallites. J Ultrastruct Res 6:249–303CrossRefGoogle Scholar
  682. Roscoe HE, Schorlemmer C (1879) A treatise on chemistry. Volume II: metals. Part 1. Macmillan and Co., London, p 504Google Scholar
  683. Rosen VB, Hobbs LW, Spector M (2002) The ultrastructure of anorganic bovine bone and selected synthetic hyroxyapatites used as bone graft substitute materials. Biomaterials 23:921–928CrossRefGoogle Scholar
  684. Rosenthal AK (2007) Update in calcium deposition diseases. Curr Opin Rheumatol 19:158–162CrossRefGoogle Scholar
  685. Rosseeva EV, Buder J, Simon P, Schwarz U, Frank-Kamenetskaya OV, Kniep R (2008) Synthesis, characterization, and morphogenesis of carbonated fluorapatite-gelatine nanocomposites: a complex biomimetic approach toward the mineralization of hard tissues. Chem Mater 20:6003–6013CrossRefGoogle Scholar
  686. Rossete ALRM, Carneiro JMT, Bendassolli JA, Tavares CRO, Sant’Ana Filho CR (2008) Production of single superphosphate labeled with 34S. Scientia Agricola 65:91–94CrossRefGoogle Scholar
  687. Roveri N, Battistella E, Bianchi CL, Foltran I, Foresti E, Iafisco M, Lelli M, Naldoni A, Palazzo B, Rimondini L (2009) Surface enamel remineralization: biomimetic apatite nanocrystals and fluoride ions different effects. J Nanomater 2009(746383):9Google Scholar
  688. Roveri N, Foresti E, Lelli M, Lesci IG (2009b) Recent advancements in preventing teeth health hazard: the daily use of hydroxyapatite instead of fluoride. Rec Pat Biomed Eng 2:197–215CrossRefGoogle Scholar
  689. Rubin MA, Jasiuk I, Taylor J, Rubin J, Ganey T, Apkarian RP (2003) TEM analysis of the nanostructure of normal and osteoporotic human trabecular bone. Bone 33:270–282CrossRefGoogle Scholar
  690. Rulis P, Ouyang L, Ching WY (2004) Electronic structure and bonding in calcium apatite crystals: hydroxyapatite, fluorapatite, chlorapatite and bromapatite. Phys Rev B 70(155104):8Google Scholar
  691. Ruppel ME, Miller LM, Burr DB (2008) The effect of the microscopic and nanoscale structure on bone fragility. Osteoporos Int 19:1251–1265CrossRefGoogle Scholar
  692. Sadat-Shojai M, Khorasani MT, Dinpanah-Khoshdargi E, Jamshidi A (2013) Synthesis methods for nanosized hydroxyapatite with diverse structures. Acta Biomater 9:7591–7621CrossRefGoogle Scholar
  693. Sadjadi MS, Meskinfam M, Sadeghi B, Jazdarreh H, Zare K (2010) In situ biomimetic synthesis, characterization and in vitro investigation of bone-like nanohydroxyapatite in starch matrix. Mater Chem Phys 124:217–222CrossRefGoogle Scholar
  694. Sahar ND, Hong SI, Kohn DH (2005) Micro- and nano-structural analyses of damage in bone. Micron 36:617–629CrossRefGoogle Scholar
  695. Sánchez-Salcedo S, Vila M, Izquierdo-Barba I, Cicuéndez M, Vallet-Regí M (2010) Biopolymer-coated hydroxyapatite foams: a new antidote for heavy metal intoxication. J Mater Chem 20:6956–6961CrossRefGoogle Scholar
  696. Santos CFL, Silva AP, Lopes L, Pires I, Correia IJ (2012) Design and production of sintered β-tricalcium phosphate 3D scaffolds for bone tissue regeneration. Mater Sci Eng C 32:1293–1298CrossRefGoogle Scholar
  697. Sato K (2006) Inorganic–organic interfacial interactions in hydroxyapatite mineralization processes. Topics Curr Chem 270:127–153CrossRefGoogle Scholar
  698. Sato K (2007) Mechanism of hydroxyapatite mineralization in biological systems. J Ceram Soc Jpn 115:124–130CrossRefGoogle Scholar
  699. Sato Y, Sato T, Niwa M, Aoki H (2006) Precipitation of octacalcium phosphates on artificial enamel in artificial saliva. J Mater Sci Mater Med 17:1173–1177CrossRefGoogle Scholar
  700. Savarino L, Fini M, Ciapetti G, Cenni E, Granchi D, Baldini N, Greco M, Rizzi G, Giardino R, Giunti A (2003) Biologic effects of surface roughness and fluorhydroxyapatite coating on osteointegration in external fixation systems: an in vivo experimental study. J Biomed Mater Res A 66A:652–661CrossRefGoogle Scholar
  701. Savelle JM, Habu J (2004) A processual investigation of a Thule whale bone house, Somerset Island,Arctic Canada. Arct Anthropol 41:204–221CrossRefGoogle Scholar
  702. Sayer M, Stratilatov AD, Reid JW, Calderin L, Stott MJ, Yin X, MacKenzie M, Smith TJN, Hendry JA, Langstaff SD (2003) Structure and composition of silicon-stabilized tricalcium phosphate. Biomaterials 24:369–382CrossRefGoogle Scholar
  703. Schemehorn BR, Wood GD, McHale W, Winston AE (2011) Comparison of fluoride uptake into tooth enamel from two fluoride varnishes containing different calcium phosphate sources. J Clin Dent 22:51–54Google Scholar
  704. Schilling AF, Filke S, Brink S, Korbmacher H, Amling M, Rueger JM (2006) Osteoclasts and biomaterials. Eur J Trauma 32:107–113CrossRefGoogle Scholar
  705. Schinke T, McKnee MD, Karsenty G (1999) Extracellular matrix calcification: where is the action? Nat Genet 21:150–151CrossRefGoogle Scholar
  706. Schmitt CP, Odenwald T, Ritz E (2006) Calcium, calcium regulatory hormones, and calcimimetics: impact on cardiovascular mortality. J Am Soc Nephrol 17:78–80CrossRefGoogle Scholar
  707. Schoen FJ, Levy RJ (2005) Calcification of tissue heart valve substitutes: progress toward understanding and prevention. Ann Thorac Surg 79:1072–1080CrossRefGoogle Scholar
  708. Schroeder I, Frank RM (1985) High-resolution transmission electron microscopy of adult human peritubular dentine. Cell Tissue Res 242:449–451CrossRefGoogle Scholar
  709. Schulz HN, Schulz HD (2005) Large sulfur bacteria and the formation of phosphorite. Science 307:416–418CrossRefGoogle Scholar
  710. Scotchford CA, Ali SY (1995) Magnesium whitlockite deposition in articular cartilage: a study of 80 specimens from 70 patients. Ann Rheum Dis 54:339–344