review REVIEW Biomatter 1:2, 121-164; October/November/December 2011; © 2011 Landes Bioscience Calcium orthophosphates Occurrence, properties, biomineralization, pathological calcification and biomimetic applications Sergey V. Dorozhkin Kudrinskaja sq. 1-155; Moscow, Russia Key words: calcium orthophosphates, hydroxyapatite, fluorapatite, bones, teeth, antlers, calcification, crystallization, biomimetics The present overview is intended to point the readers’ attention 1873,5 while the crystallographic faces of a natural calcium apa- to the important subject of calcium orthophosphates. tite were described in 1883.6 Furthermore, a paper on a behavior This type of materials is of special significance for human of an undisclosed calcium orthophosphate in organisms of carni- beings, because they represent the inorganic part of vores was published in 1883.7 Further, the quantitative analysis major normal (bones, teeth and antlers) and pathological 8 (i.e., those appearing due to various diseases) calcified tissues of a calcium orthophosphate was performed in 1884, followed 9 of mammals. For example, atherosclerosis results in blood by remarks by C. Glaser in 1885. In the 1880s, occurrence of 10 11-13 vessel blockage caused by a solid composite of cholesterol a calcium apatite and another calcium orthophosphate in a with calcium orthophosphates, while dental caries and metallurgical slag was discovered. Chemical reactions between osteoporosis mean a partial decalcification of teeth and bones, calcium orthophosphates and other chemicals were investigated respectively, that results in replacement of a less soluble and in 1891.14 Research papers on bone repairing are known since at harder biological apatite by more soluble and softer calcium least 1892,15 while the earliest well-documented systematic stud- hydrogenphosphates. Therefore, the processes of both normal ies of calcium orthophosphates were performed at the beginning ©2011 Landes Bioscience. and pathological calcificationsLandes are ©2011 just an in vivo crystallization of the 20th century by F.K. Cameron with coworkers16-20 and of calcium orthophosphates. Similarly, dental caries and H. Bassett.21-24 The majority of the aforementioned researchers osteoporosis might be considered an in vivo dissolution of Do not distribute. not Do already operated with individual chemical compounds. calcium orthophosphates. Thus, calcium orthophosphates hold a great significance for humankind, and in this paper an By definition, all calcium orthophosphates consist of three overview on the current knowledge on this subject is provided. major chemical elements, calcium (oxidation state +2), phos- phorus (oxidation state +5) and oxygen (reduction state -2), as a part of orthophosphate anions. These three chemical elements are present in abundance on the surface of our planet: oxygen Introduction is the most widespread chemical element of the Earth’s sur- face (~47 mass%), calcium occupies the fifth place (~3.3–3.4 Due to their abundance in nature and presence in living organ- mass%) and phosphorus (~0.08–0.12 mass%) is among the first isms, calcium apatites[a] and other calcium orthophosphates 20 of the chemical elements most widespread on our planet.25 remain the chemical compounds of a special interest in many In addition, the chemical composition of many calcium ortho- fields of science, including geology, chemistry, biology and medi- phosphates includes hydrogen, as an acidic orthophosphate 2- - cine. Due to big problems with access to the scientific literature anion (for example, HPO4 or H2PO4 ); hydroxide [for exam- published in the 19th century and before, a historical descrip- ple, Ca10(PO4)6(OH)2] and/or incorporated water (for example, tion of the subject appears to be very brief. Namely, according to CaHPO4·2H2O). Diverse combinations of CaO and P2O5 (both the accessible literature,1 as early as the end of the 18th century, in the presence of water and without it) provide a large variety French chemist Joseph-Louis Proust (1754–1826) and German of calcium phosphates, which are distinguished by the type of 3- - 4- chemist Martin Klaproth (1743–1817) proposed that calcium the phosphate anion: ortho-(PO4 ), meta-(PO3 ), pyro-(P2O7 ) n- apatite was the major inorganic component of bones. In the and poly-[(PO3)n ]. In the case of multi-charged anions (ortho- middle of the 19th century, attempts to establish the chemical phosphates and pyrophosphates), calcium phosphates are also composition of calcium apatites and other calcium orthophos- differentiated by the number of hydrogen ions attached to the 2 3 phates were performed by J. Berzelius, R. Warington Jr. and R. anion. Examples include mono-[Ca(H2PO4)2], di-(CaHPO4), 4 Fresenius. The chemical formula of perfectly transparent crys- tri-[Ca3(PO4)2] and tetra-(Ca2P2O7) calcium phosphates (here, tals of natural fluorapatite (FA) as Ca5(PO4)3F was established in prefixes “mono,” “di,” “tri” and “tetra” are related to the amount of hydrogen ions replaced by calcium).26-28 However, only cal- Correspondence to: Sergey V. Dorozhkin; Email: [email protected] cium orthophosphates will be considered and discussed in this Submitted: 07/13/11; Revised: 11/10/11; Accepted: 11/16/11 review. The names, standard abbreviations, chemical formulae http://dx.doi.org/10.4161/biom.1.2.18790 and solubility values are listed in Table 1.29,30 Since all of them www.landesbioscience.com Biomatter 121 Table 1. Existing calcium orthophosphates and their major properties30,31 pH stability range Ca/P molar Solubility at Solubility at Compound Formula in aqueous ratio 25°C, -log(K ) 25°C, g/L s solutions at 25°C Monocalcium phosphate monohydrate 0.5 Ca(H PO ) ·H O 1.14 ~18 0.0–2.0 (MCPM) 2 4 2 2 Monocalcium phosphate anhydrous (MCPA 0.5 Ca(H PO ) 1.14 ~17 c or MCP) 2 4 2 Dicalcium phosphate dihydrate (DCPD), 1.0 CaHPO ·2H O 6.59 ~0.088 2.0–6.0 mineral brushite 4 2 Dicalcium phosphate anhydrous (DCPA or 1.0 CaHPO 6.90 ~0.048 c DCP), mineral monetite 4 1.33 Octacalcium phosphate (OCP) Ca8(HPO4)2(PO4)4·5H2O 96.6 ~0.0081 5.5–7.0 a 1.5 α-Tricalcium phosphate (α-TCP) α-Ca3(PO4)2 25.5 ~0.0025 a 1.5 β-Tricalcium phosphate (β-TCP) β-Ca3(PO4)2 28.9 ~0.0005 Ca H (PO ) ·nH O, n = 3 - 4.5; 1.2–2.2 Amorphous calcium phosphates (ACP) x y 4 z 2 b b ~5–12d 15 - 20% H2O Calcium-deficient hydroxyapatite (CDHA or Ca (HPO ) (PO ) (OH) (0 1.5–1.67 10-x 4 x 4 6-x 2-x ~85 ~0.0094 6.5–9.5 Ca-def HA)e < x < 1) 1.67 Hydroxyapatite (HA, HAp or OHAp) Ca10(PO4)6(OH)2 116.8 ~0.0003 9.5–12 1.67 Fluorapatite (FA or FAp) Ca10(PO4)6F2 120.0 ~0.0002 7–12 f a 1.67 Oxyapatite (OA, OAp or OXA) Ca10(PO4)6O ~69 ~0.087 Tetracalcium phosphate (TTCP or TetCP), 2.0 Ca (PO ) O 38–44 ~0.0007 a mineral hilgenstockite 4 4 2 ©2011 Landes Bioscience. aThese compounds cannotLandes be precipitated©2011 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).236 The comparative extent of dissolution in acidic buffer is: ACP >> α-TCP >> β-TCP > CDHA >> HA > FA.107 cStable at temperatures above 100°C. dAlways metastable. eOccasionally, it is called “precipitated HA (PHA).” fExistence of OA remains questionable. distribute. not Do belong to calcium orthophosphates, strictly speaking, all abbre- produced by biomineralization (Fig. 1).42 Thus, due to a sedi- viations in Table 1 are incorrect; however, they are extensively mentary origin, both the general appearance and the chemical used in the literature, and there is no need to modify them. composition of natural phosphorites vary a great deal.43,44 It is The atomic arrangement of calcium orthophosphates is built common practice to consider francolite (or carbonate-hydroxy- up around a network of orthophosphate (PO4) groups, which fluorapatite regarded as its synonym) as the basic phosphorite gives stability to the entire structure. The majority of calcium mineral.40,45-49 A cryptocrystalline (almost amorphous) variety orthophosphates are sparingly soluble in water; however, all of of francolite (partly of a biological origin) is called collophane them are easily soluble in acids but insoluble in alkaline solutions. (synonyms: collophanit, collophanita, collophanite, grodnolite, All chemically pure calcium orthophosphates are crystals of white kollophan).50-52 It occurs in natural phosphorites predominantly color and moderate hardness. However, natural minerals of cal- as fossil bones and phosphatized microbial pseudomorphs: cium orthophosphates are always colored due to impurities, the phosphatic crusts of chasmolithic biofilms (or microstromato- most widespread of which are ions of Fe, Mn and rare earth ele- lites) and globular clusters with intra-particular porosities.53-56 ments.33,34 Biologically formed calcium orthophosphates are the Natural phosphorites (therefore, francolite and collophane as major component of all mammalian calcified tissues,35 while the well) occur in various forms, such as nodules, crystals or masses. natural ones are the major raw material to produce phosphorus- Occasionally, other types of natural calcium orthophosphates are containing fertilizers.36-39 found as minerals, for example, clinohydroxylapatite,57 staffelite (synonyms: staffelit, staffelita) belonging to carbonate-rich flu- 4,58 Geological and Biological Occurrences orapatites (chemical formula: Ca5[(F,O)(PO4,CO3)3]) and DCPD.59 Furthermore, calcium orthophosphates were found in Geologically, natural calcium orthophosphates are found in meteoric stones.60 The world deposits of natural calcium ortho- different regions mostly as deposits of apatites (belong to igne- phosphates are estimated to exceed 150 billion tons, out of which ous rocks), mainly as natural FA or phosphorites (a sedimen- approximately 85% belong to phosphorites and the remaining tary rock).37-40 Some types of sedimentary rocks can be formed ~15% belong to apatites.40 by weathering of igneous rocks into smaller particles.41 Other Natural calcium orthophosphates occur in most geo- types of sedimentary rocks can be composed of minerals precipi- logical environments, usually as accessory minerals (<5%).