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Nano size and nanocrystalline calcium orthophosphate

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https://www.eduzhai.net American Journal of Biomedical Engineering 2012,2(3): 48-97 DOI: 10. 5923/j.ajbe.20120203.01 Nanodimensional and Nanocrystalline Calcium Orthophosphates Sergey V. Dorozhkin Kudrinskaja sq. 1-155, Moscow 123242, Russia Abstract Nano-sized particles and crystals play an important role in the formation of calcified tissues of various ani- mals. For example, nano-sized and nanocrystalline calcium orthophosphates in the form of apatites of biological origin represent the basic inorganic building blocks of bones and teeth of mammals. Namely, according the recent developments in biomineralization, tens to hundreds nanodimensional crystals of a biological apatite are self-assembled into these complex structures. This process occurs under a strict control by bioorganic matrixes. Furthermore, both a greater viability and a better proliferation of various types of cells have been detected on smaller crystals of calcium orthophosphates. Thus, the nano-sized and nanocrystalline forms of calcium orthophosphates have a great potential to revolutionize the hard tissue-engineering field, starting from bone repair and augmentation to controlled drug delivery systems. This review reports on current state of the art and recent developments on the subject, starting from synthesis and characterization to biomedical and clinical applications. Furthermore, the review also discusses possible directions for future research and development. Keywords Calcium Orthophosphates, Hydroxyapatite, Nanodimensional, Nano-Sized, Nanocrystalline, Biomedical Applications, Bone Grafts, Tissue Engineering 1. Introduction Living organisms can create the amazing ways to produce various high-performance materials and over 60 different inorganic minerals of biological origin have already been revealed[1]. Among them, calcium orthophosphates are of a special importance since they are the most important inorganic constituents of hard tissues in vertebrates[2, 3]. In the form of a poor crystalline, non-stoichiometric, ion-substituted CDHA (commonly referred to as “biological apatite”), calcium orthophosphates are present in bones, teeth, deer antlers and tendons of mammals to give these organs stability, hardness and function[2, 4, 5]. Through we still do not exactly know why the highly intelligent animals use conformable calcium orthophosphates as their crucial biomineral for survival[6], current biomedical questions of persistent pathological and physiological mineralization in the body force people to focus on the processes, including the occurrence, formation and degradation of calcium orthophosphates in living organisms[7, 8, 9]. Biological mineralization (or biomineralization) is a process of in vivo formation of inorganic minerals[1, 2]. In the biomineralization processes, organized assemblies oforganic macromolecules regulate nucleation, growth, * Corresponding author: sedorozhkin@yandex.ru (Sergey V. Dorozhkin) Publíshed onlíne at https://www.eduzhaí.net Copyright © 2012 Scientific & Academic Publishing. All Rights Reserved morphology and assembly of inorganic crystals. Biologically formed calcium orthophosphates (biological apatite) are always nanodimensional and nanocrystalline, which have been formed in vivo under mild conditions. According to many reports, dimensions of biological apatite in the calcified tissues always possess a range of a few to hundreds of nanometers with the smallest building blocks on the nanometer size scale[2, 4, 5, 10, 11]. For example, tens to hundreds of nanometer-sized apatite crystals in a collagen matrix are combined into self-assembled structures during bone and teeth formation[2, 4, 5]. Recent advances suggest that this is a natural selection, since the nanostructured materials provide a better capability for the specific interactions with proteins[12]. Due to the aforementioned, nanodimensional and nanocrystalline forms of calcium orthophosphates are able to mimic both the composition and dimensions of constituent components of the calcified tissues. Thus, they can be utilized in biomineralization and as biomaterials due to the excellent biocompatibility[13, 14]. Further development of calcium orthophosphate-based biomaterials obviously will stand to benefit mostly from nanotechnology[15], which offers unique approaches to overcome shortcomings of many conventional materials. For example, nano-sized ceramics can exhibit significant ductility before failure contributed by the grain-boundary phase. Namely, already in 1987, Karch et al., reported that, with nanodimensional grains, a brittle ceramic could permit a large plastic strain American Journal of Biomedical Engineering 2012,2(3): 48-97 49 up to 100%[16]. In addition, nanostructured ceramics can be sintered at lower temperatures; thereby major problems associated with a high temperature sintering are also decreased. Thus, nanodimensional and nanocrystalline forms of bioceramics clearly represent a promising class of orthopedic and dental implant formulations with improved biological and biomechanical properties[17]. Many other advances have been made in biomaterial field due to a rapid growth of nanotechnology[18]. For example, a recent theory of “aggregation-based crystal growth”[19] and a new concept of “mesocrystals”[20, 21] highlighted the roles of nano-sized particles in biological crystal engineering. In this aspect, the study of calcium orthophosphates is a specific area in nanotechnology, because they might be applied readily to repair hard skeletal tissues of mammals[22-24]. Herein, an overview of nanodimensional and nanocrystalline apatites and other calcium orthophosphates in studies on biomineralization and biomaterials is given. The available calcium orthophosphates are listed in Table 1. To narrow the subject of this review, with a few important exceptions, undoped and un-substituted calcium orthophosphates are considered and discussed only. The readers interested in various nanodimensional and nanocrystalline ion-substituted calcium orthophosphates[25-63] are referred to the original publications. Furthermore, details on calcium orthophosphate-based nanodimensional biocomposites[64-85] or nanodimensional calcium orthophosphate-based biocomposites[86-104] are available in Refs.[105, 106]. This review is organized into several sections. After a brief introduction (current section), general information on “nano” is provided in the second section. The third section briefly compares the micron-sized and nanodimensional calcium orthophosphates. The forth section briefly discusses the presence of nano-sized and nanocrystalline calcium orthophosphates in normal calcified tissues of mammals. The structure of nano-sized and nanocrystalline apatites is described in the fifth section. Synthesis of nanodimensional and nanocrystalline calcium orthophosphates of various dimensions and shapes is reviewed in the sixth section, while the biomedical applications are examined in the seventh section. Finally, the summary and reasonable future perspectives in this active research area are given in the last section. Table 1. Existing calcium orthophosphates and their major properties[204, 205]. Ca/P molar ratio 0.5 0.5 1.0 1.0 Compound Monocalcium phosphate monohydrate (MCPM) Monocalcium phosphate anhydrous (MCPA or MCP) Dicalcium phosphate dihydrate (DCPD), mineral brushite Dicalcium phosphate anhydrous (DCPA or DCP), min- eral monetite Formula Ca(H2PO4)2·H2O Ca(H2PO4)2 CaHPO4·2H2O CaHPO4 Solubility at 25 ºC, -log(Ks) 1.14 1.14 6.59 6.90 Solubility at 25 ºC, g/L ~ 18 ~ 17 ~ 0.088 ~ 0.048 pH stability range in aqueous solutions at 25°C 0.0 – 2.0 [c] 2.0 – 6.0 [c] 1.33 Octacalcium phosphate (OCP) Ca8(HPO4)2(PO4)4·5H2O 96.6 ~ 0.0081 5.5 – 7.0 1.5 1.5 1.2 – 2.2 1.5 – 1.67 1.67 α-Tricalcium phosphate (α-TCP) β-Tricalcium phosphate (β-TCP) Amorphous calcium phosphates (ACP) Calcium-deficient hydroxyapatite (CDHA or Ca-def HA)[e] Hydroxyapatite (HA, HAp or OHAp) α-Ca3(PO4)2 β-Ca3(PO4)2 CaxHy(PO4)z·nH2O, n = 3 – 4.5; 15 – 20% H2O Ca10-x(HPO4)x(PO4)6-x(OH)2-x (0> α-TCP >> β-TCP > CDHA >> HA > FA[126]. [c] Stable at temperatures above 100°C. [d] Always metastable. [e] Occasionally, it is called “precipitated HA (PHA)”. [f] Existence of OA remains questionable. 50 Sergey V. Dorozhkin: Nanodimensional and Nanocrystalline Calcium Orthophosphates 2. General Information on “Nano” The prefix “nano” specifically means a measure of 10-9 units. Although it is widely accepted that the prefix “nano” specifically refers to 10-9 units, in the context of nano-sized and nanocrystalline materials, the units should only be those of dimensions, rather than of any other unit of the scientific measurements. Besides, for practical purposes, it appears to be unrealistic to consider the prefix “nano” to solely and precisely refer to 10-9 m, just as it is not considered that “micro” specifically and solely concerns something with a dimension of precisely 10-6 m[107]. Currently, there is a general agreement that the subject of nanoscience and nanotechnology started after the famous talk: “There’s plenty of room at the bottom” given by the Nobel Prize winner in physics Prof. Richard P. Feynman on December 26, 1959 at the annual meeting of the American Physical Society held at California Institute of Technology. This well-known talk has been widely published in various media (e.g.,[108]). In a recent extensive discussion about a framework for definitions presented to the European Commission, the nano-scale has been defined as being of the order of 100 nm or less. Similarly, a nanomaterial has been defined as “any form of a material that is composed of discrete functional parts, many of which have one or more dimensions of the order of 100 nm or less”[109]. Other definitions logically follow this approach such as: a nanocrystalline material is “a material that is comprised of many crystals, the majority of which have one or more dimensions of the order of 100 nm or less” (normally, with presence of neither the micron-sized crystals nor an intergranular amorphous phase) and a nanocomposite is a “multi-phase material in which the majority of the dispersed phase components have one or more dimensions of the order of 100 nm or less”[107]. Similarly, nanostructured materials are defined as the materials containing structural elements (e.g., clusters, crystallites or molecules) with dimensions in the 1 to 100 nm range[110], nanocoatings represent individual layers or multilayer surface coatings of 1 – 100 nm thick, nanopowders are extremely fine powders with an average particle size in the range of 1 – 100 nm and nanofibers are the fibers with a diameter within 1 – 100 nm[111, 112]. It also has been proposed to extend the lower size limit to 0.1 nm[113], which would include all existing organic molecules, allowing chemists to rightly claim they have been working on nanotechnology for very many years[114]. Strictly speaking, there are serious doubts that the term “nanomaterial” has a reasonable meaning. For example, let me cite Prof. David F. Williams, the Editor-in-Chief of Biomaterials: “… some words which have no rational basis whatsoever become part of everyday language so rapidly, even if so illogically, that it is impossible to reverse the process and their common use has to be accepted, or perhaps, accommodated. Nanomaterial is one such word, where I have argued that it should not exist, but accept that it does through common usage and have to recognise its existence[107]. The discussion about nanomaterial provides a hint of the analysis of a biomaterial that follows, since a prefix, which is an indicator of scale, cannot specify the integer that follows (in this case a material) unless that integer can be qualified by that scale. In other words, it is very clear what a nanometre is because nano – means 10-9 and a metre is a measure of length. In the case of nanomaterial, what is it about the material that is 10-9. Is it the dimension of a crystal within the material, or of a grain boundary, a domain, or a molecule, or is it a parameter of a surface feature of the sample, or perhaps of the resistivity or thermal conductivity of the material. Clearly this is nonsense, but one has to accept that nanomaterials are here to stay, with even some journal titles containing the word.”[115, p. 5898, left column]. Following this logic, such terms as “nanocomposite”, “nanocoatings”, “nanopowders”, “nanofibers” and “nanocrystals” are senseless either and should be replaced, for example, by “composites with nano-sized (or nanodimensional) dispersed phase(s)”, “coatings of nano-sized (or nanodimensional) thickness”, “nano-sized (or nanodimensional) powders”, “fibers of nano-sized (or nanodimensional) thickness” and “nano-sized (or nanodimensional) crystals”, respectively. At least, this has been done in this review. According to their geometry, all nanodimensional materials can be divided into three major categories: equiaxed, one dimensional (or fibrous) and two dimensional (or lamellar) forms. Selected examples and typical applications of each category of nanodimensional materials and their use in biomedical applications are available in literature[116]. It is important to note, that in literature on calcium orthophosphates there are cases, when the prefix “nano” has been applied for the structures, with the minimum dimensions exceeding 100 nm[44, 83, 117-133]. As a rule, nanodimensional materials can be manufactured from nearly any substance. Of crucial importance, there are two major characteristics conferring the special properties of any nanodimensional material. These are the quantum effects associated with the very small dimensions (currently, this is not applicable to the biomaterials field) and a large surface-to-volume ratio that is encountered at these dimensions. For instance, specific surface areas for submicron-sized particles are typically 60 – 80 m2/g, while decreasing particle diameter to tens of nanometers increases the specific surface area up to 5 times more – an amazing amount of surface area per mass! Furthermore, all nanophase materials have the unique surface properties, such as an increased number of grain boundaries and defects on the surface, huge surface area and altered electronic structure, if compared to the micron-sized materials[107, 134]. While less than ~ 1 % of a micron-sized particle’s atoms occupy the surface positions, over a tenth of the atoms in a 10-nm diameter particle reside on its surface and ~ 60 % in a 2-nm particle[135]. This very high surface-to-volume ratio of nanodimensional materials provides a tremendous driving American Journal of Biomedical Engineering 2012,2(3): 48-97 51 force for diffusion, especially at elevated temperatures, as well as causes a self-aggregation into larger particles. Besides, solubility of many substances increases with particle size decreasing[136, 137]. What’s more, nanophase materials could have surface features (e.g., a higher amount of nano-scale pores) to influence the type and amount of adsorption of selective proteins that could enhance specific osteoblast adhesion[138]. Finally and yet importantly, the nanodimensional and nanocrystalline materials have different mechanical, electrical, magnetic and optical properties if compared to the larger grained materials of the same chemical composition[139-142]. The nanostructured materials can take the form of powders, dispersions, coatings or bulk materials. In general, nanostructured materials contain a large volume fraction (greater than 50 %) of defects such as grain boundaries, interphase boundaries and dislocations, which strongly influences their chemical and physical properties. The great advantages of nanostructuring were first understood in electronic industry with the advent of thin film deposition processes. Other application areas have followed. For example, nanostructured bioceramics was found to improve friction and wear problems associated with joint replacement components because it was tougher and stronger than coarser-grained bioceramics[143]. Furthermore, nanostructuring has allowed chemical homogeneity and structural uniformity to an extent, which was once thought to impossible to achieve[110]. In calcium orthophosphate bioceramics, the major target of nanostructuring is to mimic the architecture of bones and teeth[144, 145]. 3. Micron- and Submicron-Sized Calcium Orthophosphates versus The Nanodimensional Ones The micron-sized calcium orthophosphate-based bioceramic powders suffer from poor sinterability, mainly due to a low surface area (typically 2 – 5 m2/g), while the specific surface area of nanodimensional calcium orthophosphates exceeds 100 m2/g[146]. In addition, the resorption process of synthetic micron-sized calcium orthophosphates was found to be quite different from that of bone mineral[147]. Although the nanodimensional and nanocrystalline features of natural calcium orthophosphates of bones and teeth had been known earlier[2, 148-153], the history of the systematic investigations of this field has started only in 1994. Namely, a careful search in scientific databases using various combinations of keywords “nano” + “calcium phosphate”, “nano” + “apatite”, “nano” + “hydroxyapatite”, etc. in the article title revealed 5 papers published in 1994[154-158]. No papers published before 1994 with the aforementioned keywords in the title have been found. Nanodimensional (size ~ 67 nm) HA was found to have a higher surface roughness of 17 nm if compared to 10 nm for the submicron-sized (~ 180 nm) HA, while the contact angles (a quantitative measure of the wetting of a solid by a liquid) were significantly lower for nano-sized HA (6.1) if compared to the submicron-sized HA (11.51). Additionally, the diameter of individual pores in nanodimensional HA compacts is several times smaller (pore diameter ~ 6.6 Å) than that in the submicron grain-sized HA compacts (pore diameter within 19.8 – 31.0 Å)[159]. A surface roughness is known to enhance the osteoblast functions while a porous structure improves the osteoinduction compared with smooth surfaces and nonporpous structure, respectively[138]. Furthermore, nanophase HA appeared to have ~ 11% more proteins of fetal bovine serum adsorbed per 1 cm2 than submicron-sized HA[160]. Interfacial interactions between calcined HA nano-sized crystals and various substrates were studied and a bonding strength appeared to be influenced not only by the nature of functional groups on the substrate but also by matching of surface roughness between the nano-sized crystals and the substrate[161]. More to the point, incorporating of nanodimensional particles of HA into polyacrylonitrile fibers were found to result in their crystallinity degree rising by about 5%[162]. In a comparative study on the influence of incorporated micron-sized and nano-sized HA particles into poly-L-lactide matrixes, addition of nano-sized HA was found to influence both thermal and dynamic mechanical properties in greater extents[163]. In general, nanostructured biomaterials[164] offer much improved performances than their larger particle sized counterparts due to their huge surface-to-volume ratio and unusual chemical synergistic effects. Such nanostructured systems constitute a bridge between single molecules and bulk material systems[165]. For instance, powders of nanocrystalline apatites[166-172] and β-TCP[173] were found to exhibit an improved sinterability and enhanced densification due to a greater surface area. This is explained by the fact that the distances of material transport during the sintering becomes shorter for ultrafine powders with a high specific surface area, resulting in a densification at a low temperature. Therefore, due to low grain growth rates, a low-temperature sintering appears to be effective to produce fine-grained apatite bioceramics[174]. Furthermore, the mechanical properties (namely, hardness and toughness) of HA bioceramics appeared to increase as the grain size decreased from sub-micrometers to nanometers[175]. More to the point, nano-sized HA is also expected to have a better bioactivity than coarser crystals[176-178]. Namely, Kim et al., found that osteoblasts (bone-forming cells) attached to the nano-sized HA/gelatin biocomposites to a significantly higher degree than to micrometer size analog did[179]. An increased osteoblast and decreased fibroblast (fibrous tissue-forming cells) adhesion on nanophase ceramics[180-184], as well as on nanocrystalline HA coatings on titanium, if compared to traditionally used plasma-sprayed HA coatings, was also discovered by other researchers[185-187]. Scientists also observed enhanced osteoclast (bone-resorbing cells) functions to show healthy remodeling of bone at the simulated implant surface[177]. Besides, the proliferation and osteogenic differentiation of periodontal ligament cells were found to be promoted when 52 Sergey V. Dorozhkin: Nanodimensional and Nanocrystalline Calcium Orthophosphates a nanophase HA was used, if compared to dense HA bioceramics[188]. Thus, the underlying material property, responsible for this enhanced osteoblast function, is the surface roughness of the nanostructured surface[18]. Interestingly, but an increased osteoblast adhesion was discovered on nano-sized calcium orthophosphate powders with higher Ca/P ratios[189], which points out to some advantages of apatites over other calcium orthophosphates. Furthermore, a histological analysis revealed a superior biocompatibility and osteointegration of bone graft substitutes when nano-sized HA was employed in biocomposites[190-192]. However, data are available that nano-sized HA could inhibit growth of osteoblasts in a dose-dependent manner[193]. Furthermore, a cellular activity appeared to be affected by the shape and dimensions of nano-sized HA. Namely, the cellular activity of L929 mouse fibroblasts on nano-sized fibers with a diameter within 50 – 100 nm was significantly enhanced relative to that on a flat HA surface, while nanodimensional HA needles and sheets with a diameter/thickness of less than 30 nm inhibited cellular adhesion and/or subsequent activity because cells could not form focal adhesions of sufficient size[194]. Obviously, the volume fraction of grain boundaries in nanodimensional calcium orthophosphates is increased significantly leading to improved osteoblast adhesion, proliferation and mineralization. Therefore, a composition of these biomaterials at the nano-scale emulates the bone’s hierarchic organization, to initiate the growth of an apatite layer and to allow for the cellular and tissue response of bone remodeling. These examples emphasize that nanophase materials deserve more attention in improving orthopedic implant failure rates. However, to reduce surface energy, all nano-sized materials tend to agglomerate and, to avoid self-aggregation of calcium orthophosphate nano-sized particles[195-198], special precautions might be necessary[54, 60, 120, 199-202]. Finally yet importantly, nano-sized crystals of CDHA obtained by precipitation methods in aqueous solutions were shown to exhibit physico-chemical characteristics rather similar to those of bone apatite[203]. In particular, their chemical composition departs from stoichiometry by calcium and hydroxide ions deficiency, leading to an increased solubility, and in turn bioresorption rate in vivo[148, 204-206]. The nano-sized crystals of CDHA have also a property to evolve in solution (maturation) like bone crystals. Namely, freshly precipitated CDHA has been shown to be analogous to embryonic bone mineral crystals whereas aged precipitates resemble bone crystals of old vertebrates[203]. 4. Nanodimensional and Nanocrystalline Calcium Orthophosphates in Calcified Tissues of Mammals 4.1. Bones Figure 1. The seven hierarchical levels of organization of the zebrafish skeleton bone. Level 1: Isolated crystals and part of a collagen fibril with the triple helix structure. Level 2: Mineralized collagen fibrils. Level 3: The array of mineralized collagen fibrils with a cross-striation periodicity of nearly 60-70 nm. Level 4: Two fibril array patterns of organization as found in the zebrafish skeleton bone. Level 5: The lamellar structure in one vertebra. Level 6: A vertebra. Level 7: Skeleton bone. Reprinted from Ref.[208] with permission Bone is the most typical calcified tissue of mammals and it comes in all sorts of shapes and sizes in order to achieve various functions of protection and mechanical support for the body. The major inorganic component of bone mineral is a biological apatite, which might be defined as a poorly crystalline, non-stoichiometric and ion substituted CDHA[2-5, 204-207]. From the material point of view, bone can be considered as an assembly of distinct levels of seven hierarchical structural units from macro- to micro- and to nano-scale (Fig. 1) to meet numerous functions[2, 5, 134, 208-210]. Furthermore, all these levels of bones permanently interact with cells and biological macromolecules. At the nanostructural level, tiny plate-like crystals of biological apatite in bone occur within the discrete spaces within the collagen fibrils and grow with specific crystalline orientation along the c-axes, which are roughly parallel to the long axes of the collagen fibrils[211]. Type I collagen molecules are self-assembled into fibrils with a periodicity of ~ 67 nm and ~ 40 nm gaps between the ends of their molecules, into which the apatite nano-sized crystals are placed. A biocomposite of these two constituents forms mineralized fibers. The fibers also may be cross-linked, which provides a highly dynamic system capable of modification through the selec- American Journal of Biomedical Engineering 2012,2(3): 48-97 53 tion of different amino acids to allow for different mechanical properties for different biomaterial applications[212]. This is why bone is usually termed a fiber-reinforced composite of a biological origin, in which nanometer-sized hard inclusions are embedded into a soft protein matrix[213]. Though dimensions of biological apatite crystals reported in the literature vary due to different treatment methods and analytical techniques, it is generally around the nanometric level with values in the ranges of 30 – 50 nm (length), 15 – 30 nm (width) and 2 – 10 nm (thickness)[214]. Some details on the stability reasons of nanodimensional apatites in bones are available in literature[215, 216]. Why does the nanometer scale appear to be so important to bones? It was recently demonstrated that natural biocomposites exhibit a generic mechanical structure in which the nanometer sizes of mineral particles are used to ensure the optimum strength and maximum tolerance of flaws[217, 218]. Furthermore, nanodimensional apatite has another crucial function for organisms. It is a huge reservoir of calcium and orthophosphate ions necessary for a wide variety of metabolic functions, which offer or consume calcium and orthophosphate ions through a so-called “remodeling” process because of a continuous resorption and formation of nanodimensional apatite by osteoclasts and osteoblasts, respectively, in a delicate equilibrium[2, 5]. Additional details on the structure, properties and composition of bones might be found in special literature[5, 207, 219]. 4.2. Teeth Teeth are another normal calcium orthophosphate-based calcified tissue of vertebrates. Unlike bone, teeth consist of at least two different biominerals: enamel (a crown, the part above the gum line) and dentin (root, the part below the gum line)[220]. Dental enamel contains up to 98% of biological apatite, ~ 1% of bioorganic compounds and up to 2% of water. Typical rods in enamel are composed of rod-like apatite crystals measuring 25 – 100 nm and an undetermined length of 100 nm to 100 μm or longer along the c-axis[221-223]. However, the apatite crystals in enamel were found to exhibit regular sub-domains or subunits with distinct chemical properties[224]. This subunit structure reflects an assembly mechanism for such biological crystals[225, 226]. Like that for bones (Fig. 1), seven levels of structural hierarchy have been also discovered in human enamel; moreover, the analysis of the enamel and bone hierarchical structures suggests similarities of the scale distribution at each level[227]. In enamel, nano-sized crystals of biological apatite at first form mineral nanodimensional fibrils; the latter always align lengthways, aggregating into fibrils and afterwards into thicker fibers; further, prism/interprism continua are formed from the fibers. At the micro-scale, prisms are assembled into prism bands, which present different arrangements across the thickness of the enamel layer. These compositional and structural characteristics endow enamel special properties such as anisotropic elastic modulus, effective viscoelastic properties, much higher fracture toughness and stress-strain relationships more similar to metals than ceramics[228]. Dentin contains ~ 50% of biological apatite, ~ 30% of bioorganic compounds and ~ 20% of water. In dentin, the nanodimensional building blocks (~ 25 nm width, ~ 4 nm thickness and ~ 35 nm length) of biological apatite are smaller than those of enamel. Dentin is analogous to bone in many aspects, for example, it has a similar composition and a hierarchical structure up to the level of the bone lamellae[204, 205]. Additional details on the structure, properties and composition of teeth might be found in special literature[229]. 5. The structure of the Nanodimensional and Nanocrystalline Apatites Due to the apatitic structure on natural calcified tissues, apatites appear to be the best investigated compounds among the available calcium orthophosphates (Table 1). Thus, nanodimensional and nanocrystalline apatites have been extensively studied by various physico-chemical techniques and chemical analysis methods[197, 230-242] with a special attention to the “nano” effect (i.e., an enhanced contribution of the surface against the volume). Unfortunately, no publications on the structure of other nanodimensional and/or nanocrystalline calcium orthophosphates were found in the available literature. Due to a nanocrystalline nature, various diffraction techniques have not yet given much information on the fine structural details related to apatite nano-sized crystals (assemblies of nano-sized particles give only broad diffraction patterns, similar to ones from an amorphous material)[230, 231]. Nevertheless, the diffraction studies with electron microprobes of 35 ± 10 nm in diameter clearly indicated a crystalline character of the nano-sized particles in these assemblies. Furthermore, high-resolution transmission electron microscopy results revealed that nano-sized particles of HA behaved a fine monocrystalline grain structure[197, 230]. Therefore, a recent progress on the structure of nanodimensional and nanocrystalline apatites has relied mainly on diverse spectroscopic methods, which are sensitive to disturbances of the closest environments of various ions. Namely, the structure analysis revealed an existence of structural disorder at the particle surface, which was explained by chemical interactions between the orthophosphate groups and either adsorbed water molecules or hydroxyl groups located at the surface of nano-sized apatites[232]. More to the point, infrared (FTIR) spectra of nanocrystalline apatites, in the ν4 PO4 domain, revealed the existence of additional bands of orthophosphate ions which could not be assigned to an apatitic environment and which were not present in well-crystallized apatites (Fig. 2). These bands were assigned to non-apatitic environments of PO43and HPO42- ions of the nano-sized crystals. Thus, FTIR 54 Sergey V. Dorozhkin: Nanodimensional and Nanocrystalline Calcium Orthophosphates spectra can be used to provide a sufficiently accurate evaluation of the amounts of such environments. Furthermore, the non-apatitic environments were found to correspond to hydrated domains of the nano-sized crystals, which were distinct from the apatite domains[234]. Hence, precipitated crystals of nano-sized apatite appeared to have a hydrated surface layer containing labile ionic species, which easily and rapidly could be exchanged by ions and/or macromolecules from the surrounding fluids[233, 232, 241]. For the as-precipitated apatites, such a layer appears to constitute mainly by water molecules coordinated to surface Ca2+ ions, approximately in the 1 : 1 ratio, while the OH groups account only for ~ 20% of the surface hydration species. The FTIR data indicated that water molecules, located on the surface of nanodimensional apatites, are coordinated to surface cations and experience hydrogen bonding significantly stronger than that in liquid water[240]. The surface hydrated layer is very delicate and becomes progressively transformed into a more stable apatitic lattice upon ageing in aqueous media. Furthermore, it irreversibly altered upon drying[234]. Outgassing at increasing temperatures up to ~ 300 °C resulted in a complete surface dehydration, accompanied by a decrease of the capability to re-adsorb water. Combination of these data with rehydration tests suggested that a significant part of the surface Ca2+ ions, once dehydrated, could undergo a relaxation inward the surface, more irreversibly as the outgassing temperature increased[239]. In another study, elongated nano-sized crystals of CDHA of ~ 10 nm thick and of ~ 30 – 50 nm length were synthesized followed by investigations with X-ray diffraction and nuclear magnetic resonance techniques. The nano-sized crystals of CDHA were shown to consist of a crystalline core with the composition close to the stoichiometric HA and a disordered (amorphous) surface layer of 1 – 2 nm thick[238, 239] with the composition close to DCPD[237]. Based on the total Ca/P ratio, on the one hand, and the crystal shape, on another hand, a thickness of the DCPD surface layer along the main crystal axis was estimated to be ~ 1 nm[237], which is close to dimensions of the unit-cells (Table 2). A similar structure of a crystalline core with the composition of the stoichiometric HA and a disordered (amorphous) surface layer was found by other researchers[243]; however, in yet another study devoted to nanodimensional carbonateapatites[244], the model of a crystalline core and an outer amorphous layer was not confirmed. Perhaps, this discrepancy could be explained by the presence of carbonates. A lack of hydroxide in nanodimensional apatites was detected; an extreme nanocrystallinity was found to place an upper bound on OH- possible in apatites[245]. Figure 2. FTIR spectra of poorly crystalline apatites showing the non-apatitic environments of the orthophosphate ions (bold lines with peaks at 617 and 534 cm-1) and the apatitic PO43- (thin lines with peaks at 600, 575 and 560 cm-1) and HPO42- (thin line with peak at 550 cm-1) in the ν4 PO4 domain. Reprinted from Ref.[234] with permission Table 2. Crystallographic data of calcium orthophosphates[206]. Compound MCPM MCPA Space group triclinic P 1 triclinic P 1 Unit cell parameters 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 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 Z[a] Density, g/cm3 2 2.23 2 2.58 DCPD monoclinic Ia a = 5.812(2), b = 15.180(3), c = 6.239(2) Å, β = 116.42(3)º 4 2.32 DCPA triclinic P 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 4 2.89 OCP triclinic P 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 1 2.61 α-TCP monoclinic P21/a a = 12.887(2), b = 27.280(4), c = 15.219(2) Å, β = 126.20(1)º 24 2.86 β-TCP rhombohedral R3cH a = b = 10.4183(5), c = 37.3464(23) Å, γ = 120° 21[b] 3.08 HA monoclinic P21/b a = 9.84214(8), b = 2a, c = 6.8814(7) Å, γ = 120° (monoclinic) or hexagonal P63/m a = b = 9.4302(5), c = 6.8911(2) Å, γ = 120º (hexagonal) 4 2 3.16 FA hexagonal P63/m a = b = 9.367, c = 6.884 Å, γ = 120º 2 3.20 OA hexagonal P 6 a = b = 9.432, c = 6.881 Å, α = 90.3°, β = 90.0°, γ = 119.9° 1 ~ 3.2 TTCP monoclinic P21 a = 7.023(1), b = 11.986(4), c = 9.473(2) Å, β = 90.90(1)º 4 3.05 [a] Number of formula units per unit cell. [b] Per the hexagonal unit cell. American Journal of Biomedical Engineering 2012,2(3): 48-97 55 However, it is possible to address the structure of surface terminations of HA nano-sized particles to be amorphous or crystalline by properly selecting the preparation parameters and, in particular, the temperature; thus, nanodimensional HA without the amorphous layer on the surface has been prepared[246]. The two types of surfaces (amorphous or crystalline) of nanodimensional HA appeared to be quite similar in terms of their first hydration layer, as well as Lewis acid strength of exposed Ca2+ ions. Both features have a strong dependence on the local structure of surface sites (well probed by small molecules, such as H2O and CO) that appeared essentially unaffected by the organization at a longer range. Interestingly, but once treated at 573 K, the crystalline surfaces of nanodimensional HA was found to adsorb multilayers of water in a larger extent than the amorphous ones[246]. Nevertheless, after summarizing the available data, the following statements on the structure of nano-sized crystals of apatites have been made: (1) they involve non-apatitic anionic and cationic chemical environments (in another study, the researchers mentioned on “ordered and disordered HA”[238]), (2) at least part of these environments are located on the surface of the nano-sized crystals and are in strong interaction with hydrated domains, (3) immature samples show FTIR band fine substructure that is altered upon drying without leading to long-range order (LRO) modifications, (4) this fine substructure shows striking similarities with the FTIR spectrum of OCP[235]. All these elements favor a model in which nano-sized crystals of apatites are covered with a rather fragile but structured surface hydrated layer containing relatively mobile ions (mainly, bivalent anions and cations: Ca2+, HPO42-, CO32-) in “non-apatitic” sites (Fig. 3), which is supposed to be of either OCP or DCPD structure. Unfortunately, both the exact structure and the chemical composition of this hydrated layer are still uncertain (regrettably, as the hydrated layer cannot be isolated, it is not possible to standardize the methods for detailed studies)[235, 237-239]. Nevertheless, it is known that the surface layer might adsorb considerable amounts of foreign compounds (molecules and ions) in the percent mass range[247]. Strictly speaking, all the aforementioned apply to both biological apatite of calcified tissues[248] and micron-sized apatites as well[249]; nonetheless, in nano-sized crystals, the composition of the hydrated surface layer contributes to the global composition for a non-negligible proportion. The results of electron states spectroscopy of nanostructural HA bioceramics are available elsewhere[250, 251]. The hydrated surface layer confers unexpected properties to nano-sized apatite, is responsible for most of the properties of apatites, and, for example, can help to explain the regulation by biological apatites of the concentration in mineral ions in body fluids (homeostasis). These properties are important for living organisms; therefore, they need to be used in both material science and biotechnology[234]. The consideration of this type of surface state can help understanding and explaining the behavior of biological apatites in participating in homeostasis due to a very high specific surface area of bone crystals and in constituting an important ion reservoir with an availability that depends on the maturation state. The important consequences are that the surface of nanodimensional apatites has nothing in common with the bulk composition and that the chemistry of such materials (e.g., binding of protein molecules) must be reconsidered[235, 237]. Interestingly, but, in response to an electrical potential, the surface of nano-sized HA bioceramics was found to exhibit dynamic changes in interfacial properties, such as wettability. The wettability modification enabled both a sharp switching from hydrophilic to hydrophobic states and a microscopic wettability patterning of the HA surface, which may be used for fabrication of spatially arrayed HA for biological cells immobilization or gene transfer[252]. Figure 3. A schematic representation of the “surface hydrated layer model” for poorly crystalline apatite nanocrystals. Reprinted from Ref.[235] with permission Furthermore, dry powders of nanodimensional HA were found to contain an X-ray amorphous portion with an unspecified location[253]. After mixing of an initial nano-sized HA powder with a physiological solution (aqueous isotonic 0.9 % NaCl solution for injections), this amorphous portion was fully converted into the crystalline phase of HA. The initial crystallite average size (~ 35 nm) was enlarged by a factor of about 4 within the first 100 min after mixing the powder with the physiological solution and no more structural changes were detected during the following period[253]. In the light of the aforementioned studies, presumably, the discovered X-ray amorphous component of the initial powder was located on the surface of nanodimensional HA. 6. Synthesis of the Nanodimensional and Nanocrystalline Calcium Orthophosphates 6.1. General Nanotechnological Approaches The synthesis of nano-scale materials has received con- siderable attention and their novel properties can find numerous applications, for example, in the biomedical field. This has encouraged the invention of chemical, physical and biomimetic methods by which such nano-sized materials can 56 Sergey V. Dorozhkin: Nanodimensional and Nanocrystalline Calcium Orthophosphates be obtained[134]. Generally, all approaches for preparation of nanodimensional and nanocrystalline materials can be categorized as “bottom-up” and “top-down” ones[142, 254]. The bottom-up approach refers to the build up of a material from the bottom, i.e., atom by atom, molecule by molecule or cluster by cluster and then assembles them into the final nanostructured material. An example is production of a nano-sized powder and its compaction into the final product (e.g., hot-pressed or sintered nanostructured ceramics). The top-down approach starts from a bulk material and then, via different dimension decreasing techniques, such as milling, slicing or successive cutting, leads to the formation of nanodimensional materials[134]. Using this approach, a novel 2-dimensional carbon material graphene of just 1 atom thick has been prepared from bulk graphite. Furthermore, environmentally friendly methodologies of nanostructure synthesis have been summarized into a special review[255]. Concerning calcium orthophosphates, presumably, all of them (see Table 1) might be manufactured in a nanodimensional and/or a nanocrystalline state; however, not all of them (especially those with low Ca/P ionic ratios) have been prepared yet. The details on the available preparation techniques are given below. stress that in the vast majority of the available literature on apatites, the authors do not tell the difference between CDHA and HA. Therefore, getting through scientific papers, an attentive reader often finds statements, as: “Because natural bone is composed of both organic components (mainly type I collagen) and inorganic components (HA), …”[116, p. 357], “The HA nanorods are synthesized via a wet precipitation process …”[167, p. 2364], “… (TTCP) has been shown previously to be an essential component of self-setting calcium phosphate cements that form hydroxyapatite (HA) as the only end-product. …”[287, abstract], etc. The matter with distinguishing between CDHA and HA becomes even much more complicated, when researchers deal with nanodimensional and/or nanocrystalline apatites because the assemblies of nano-sized particles give only broad diffraction patterns, similar to ones from an amorphous material[230, 231]. While composing this review, I always tried to specify whether each cited study dealt with CDHA or HA; unfortunately, the necessary data were found in just a few papers. Therefore, in many cases, I was forced to mention just “apatites” without a further clarification. Thus, the readers are requested to be understandable on this uncertainty. 6.2. Nanodimensional and Nanocrystalline Apatites First of all, one should stress that the stoichiometric HA with well resolved X-ray diffraction patterns might be prepared mostly at temperatures exceeding ~ 700 ºC either by calcining of CDHA with the Ca/P molar ratio very close to 1.67 or by solid-state reactions of other calcium orthophosphates with various chemicals (e.g., DCPA + CaO). Thus, with the exception of a hydrothermal synthesis[256-258], in aqueous solutions only CDHA might be prepared[148, 204-206, 259-263]. As apatites (CDHA, HA and FA) belong to the sparingly soluble compounds (Table 1), simple mixing of calcium- and orthophosphate-containing aqueous solutions at pH > 9 results in formation of extremely supersaturated solutions and, therefore, a very fast precipitation of the tremendous amounts of very fine crystals[264], initially of ACP, those afterwards are re-crystallized into apatites[204-206, 265-268]. The dimensions of the precipitated nano-sized crystals might be slightly increased by the Ostwald ripening approach (maturation), that is, by boiling and/or ambient aging in the mother liquid (Fig. 4)[156, 169, 203, 235, 257, 267-272]. Heat treatment of ACP might be applied as well[273]. Therefore, preparation of nanodimensional and/or nanocrystalline apatites is not a problem at all and has been known for many years[156, 157, 274-276]; however, prefix “nano” had not been used before 1994. On the contrary, with the exception of a thermally stable FA (thus, big crystals of FA might be produced by a melt-growth process[277, 278]), manufacturing of big crystals of both CDHA and HA still is a challenge. Many different methodologies have been proposed to prepare nanodimensional and/or nanocrystalline structures[279-286]. Prior to describing them, it is important to Figure 4. Variation of nanocrystalline apatite dimensions with maturation time. Reprinted from Ref.[235] with permission The greater part of the published reports on synthesizing of nanodimensional and/or nanocrystalline apatites is focused on the bottom-up approach. Among the available preparation techniques, a wet chemical precipitation is the most popular one[74, 86, 88, 103, 119, 121, 167-169, 172, 178, 201, 203, 265, 274, 288-332]. Various authors discussed the effects of synthesis parameters, such as temperature[300-303, 322], time[301], calcium ion concentration[303], presents of surfactants[306-308], calcination[301] and the use of different reagents on the morphological properties of nanodimensional apatites. In general, the shape, stoichiometry, dimensions and specific surface area of nano-sized apatites appeared to be very sensitive to both the reaction temperature (Fig. 5) and the reactant addition rate[300, 315, 322]. Namely, particle sizes of nanodimensional apatites were observed to increase in a linear correlation with temperature[302, 322], which is a good indication that sizes of nanodimensional apatites can possibly be tailored. Furthermore, the initial pH values and reaction temperatures both play important roles in the morphology of the precipitated apatites, as well as on the phase formation and American Journal of Biomedical Engineering 2012,2(3): 48-97 57 degree of crystallinity[326]. For example, significant differences in the chemical composition, morphology and amorphous character of nano-sized CDHA produced through the reaction between aqueous solutions of Ca(NO3)2 and (NH4)2HPO4 can be induced, simply by changing the pH of the reactant hydrogen phosphate solution[327]. Thus, the solvent systems, dispersant species and drying methods appear to have effects on the particle size and dispersibility. However, some conflicting results have been obtained on how certain synthesis parameters can affect the morphological properties of these nano-sized particles. Nevertheless, it was commonly observed that nano-sized crystals of apatites synthesized through the chemical precipitation were often highly agglomerated; however, these agglomerates could be clusters of ultra-fine primary particles[304]. The prepared nanodimensional apatites might be consolidated to transparent bioceramics[330]. Figure 6. A variety of nano-scale calcium orthophosphates with different structures and morphologies synthesized by: (A and B) sol-gel processing, (C) co-precipitation, (D) emulsion technique, (E) hydrothermal process, (F) ultrasonic technique, (G) mechano-chemical method, (H – L) template method, (M) microwave processing, (N) emulsion-hydrothermal combination, (O) microwave-hydrothermal combination. Reprinted from Ref.[452] with permission Figure 5. The influence of the reaction temperature on the crystal dimensions of precipitated CDHA: a – 25 ºC, b – 37 ºC, c – 55 ºC, d – 75 ºC A hydrothermal synthesis[69, 72, 156, 157, 257, 258, 288, 322, 323, 333-357] seems to be the second most popular preparation technique of the nanodimensional and/or nanocrystalline apatites. The term “hydrothermal” refers to a chemical reaction of substances in a sealed heated solution above ambient temperature and pressure[358] and this process allows synthesis of highly pure fine-grained single crystals, with controlled morphology and narrow size distribution[333]. Extraneous additives, such as EDTA[351], surfactants[352, 359], anionic starburst dendrimer[353] etc., might be utilized to modify the morphology of nanodimensional and/or nanocrystalline apatites during the synthesis. Most of these techniques produced rod-like crystals or whiskers, while plate-like shapes were obtained in just a few studies[335, 345, 347]. Other preparation methods of nanodimensional and/or nanocrystalline apatites of various states, shapes and sizes include sol-gel[30, 188, 231, 232, 270, 328, 360-376], co-precipitation[271, 333, 334, 377-380], mechanochemical approach[65, 250, 343, 348, 381-387], mechanical alloying[388, 389], ball milling[348, 383, 390-392], radio frequency induction plasma[393, 394], vibro-milling of bones[395], flame spray pyrolysis[396], liquid-solid-solution synthesis[397], electro-crystallization[158, 398, 399], electrochemical deposition[400], microwave processing[32, 69, 288, 333, 334, 342, 356, 401-415], hydrolysis of other calcium orthophosphates[416-418], double step stirring[419], emulsion-based[310, 349, 420-433], steam-assistant[434], sonochemical[435] and solvothermal[436] syntheses. However, still other preparation techniques are also known[31, 45, 147, 154, 275, 355, 437-457]. Continuous preparation procedures are also available[200, 458]. Application of both ultrasound[362, 459-461] and viscous systems[462] might be helpful. Furthermore, nanodimensional HA might be manufactured by a laser-induced fragmentation of HA targets in water[463-467] and in solvent-containing aqueous solutions[344, 371, 468], while dense nanocrystalline HA films might be produced by radio frequency magnetron sputtering[469, 470]. An interesting approach using sitting drop vapor diffusion technique should

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