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Self curing calcium orthophosphate formula: cement, concrete, paste and putty

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https://www.eduzhai.net International Journal of Materials and Chemistry 2011; 1(1): 1-48 DOI: 10.5923/j.ijmc.20110101.01 Self-Setting Calcium Orthophosphate Formulations: Cements, Concretes, Pastes and Putties Sergey V. Dorozhkin Kudrinskaja sq. 1-155, Moscow, 123242, Russia Abstract In early 1980s, researchers discovered self-setting calcium orthophosphate cements, which are a bioactive and biodegradable grafting material in the form of a powder and a liquid. Both phases after mixing form a viscous paste that after being implanted sets and hardens within the body as either a non-stoichiometric calcium deficient hydroxyapatite (CDHA) or brushite, sometimes blended with un-reacted particles and other phases. As both CDHA and brushite are remarkably biocompartible and bioresorbable (therefore, in vivo they can be replaced with a newly forming bone), self-setting calcium orthophosphate cements represent a good correction technique of non-weight-bearing bone fractures or defects and appear to be very promising materials for bone grafting applications. Besides, these cements possess an excellent osteoconductivity, molding capabilities, and easy manipulation. Nearly perfect adaptation to the tissue surfaces in bone defects and a gradual bioresorption followed by new bone formation are additional distinctive advantages of calcium orthophosphate cements. Besides, reinforced formulations are available; those are described as calcium orthophosphate concretes. Furthermore, formulations with high viscosity, such as pastes and putties are also known. The discovery of self-setting formulations has opened up a new era in the medical application of calcium orthophosphates; several commercial compositions have already been introduced as a result. Many more formulations are in experimental stages. In this review, an insight into the self-setting calcium orthophosphate formulations, as excellent biomaterials suitable for both dental and bone grafting applications, has been provided. Keywords Calcium Orthophosphates, Hydroxyapatite, Cements, Concretes, Pastes, Putties, Self-Setting, Bioceramics, Biomaterials, Grafts, Biomedical Applications, Tissue Engineering 1. Introduction Calcium orthophosphates have been studied as bone repair materials for the last 80 years. The first in vivo use of calcium orthophosphates was performed in 1920; that time the researchers implanted tricalcium phosphate (TCP) into animals to test its efficacy as a bone substitute[1]. In the following years, some other calcium orthophosphates were tested on animals to investigate their effect on the healing of nonunions[2]. However, it was 1951, when for the first time hydroxyapatite (HA) was implanted in rats and guinea pigs[3]. Those attempts might be characterized as initial medical trials with the first generation of bone substituting biomaterials. However, it was already the 1970-s, when other calcium orthophosphates were synthesized, characterized, investigated and tried in medicine[4-10]. The list of known calcium orthophosphates, including their standard abbreviations and the major properties, is shown in Table 1[11]. * Corresponding author: sedorozhkin@yandex.ru (Sergey V. Dorozhkin) Públíshed oñlíñe at https://www.edúzhaí.ñet Copyright © 2011 Scientific & Academic Publishing. All Rights Reserved It is generally considered, that the possibility to obtain a monolithic calcium orthophosphate bioceramics at ambient or body temperature via a cementation reaction was put forward by the scientists at the American Dental Association LeGeros et al.,[12] and Brown and Chow[13-16] in the early 1980-s. However, there is an opinion[17] that self-setting calcium orthophosphate formulations for orthopedic and dental restorative applications have first been described in the early 1970-s by Driskell et al.,[18]. More to the point, there are researchers, who worked with similar reactions even earlier. Namely, in 1950, Kingery investigated chemical interactions among oxides and/or hydroxides of various metals (including CaO) with H3PO4 and discovered several self-hardening formulations[19]; thus, he appears to be the first. Leaving aside the priority topic, we will further discuss the material subject, which currently is known as calcium phosphate cements (commonly referred to as CPC), and, due to their suitability for repair, augmentation and regeneration of bones, these biomaterials also named as calcium phosphate bone cements (occasionally referred to as CPBC)[20]. In order to stress the fact, that these cements consist either entirely or essentially from calcium orthophosphates, this review is limited to consideration of calcium orthophosphate-based formulations only. 2 Sergey V. Dorozhkin: Self-Setting Calcium Orthophosphate Formulations: Cements, Concretes, Pastes and Putties The readers interested in formulations based on other types of calcium phosphates are requested to read the original publications[21]. Due to a good bioresorbability, all self-setting calcium orthophosphate formulations belong to the second generation of bone substituting biomaterials[22]. These formulations are blends of amorphous and/or crystalline calcium orthophosphate powder(s) with an aqueous solution, which might be distilled water, phosphate-buffered saline (PBS), aqueous solutions of sodium orthophosphate (~ 0.25 M), orthophosphoric acid, citric acid (~ 0.5 M)[23], sodium silicate[24,25], magnesium hydroorthophosphate[26] or even the revised simulated body fluid (rSBF)[27]. After the calcium orthophosphate powder(s) and the solution are mixed together, a viscous and moldable paste is formed that sets to a firm mass within a few minutes. When the paste becomes sufficiently stiff, it can be placed into a defect as a substitute for the damaged part of bone, where it hardens in situ within the operating theatre. The proportion of solid to liquid or the powder-to-liquid (P/L) ratio is a very important characteristic because it determines both bioresorbability and rheological properties. As the paste is set and hardened at room or body temperature, direct application in healing of bone defects became a new and innovative treatment modality by the end of the XX-th century. Moreover, calcium orthophosphate cements can be injected directly into the fractures and bone defects, where they intimately adapt to the bone cavity regardless its shape. More to the point, they were found to promote development of osteoconductive pathways, possess sufficient compressive strengths, be non-cytotoxic, create chemical bonds to the host bones, restore contour and have both the chemical composition and X-ray diffraction patterns similar to those of bone[28]. Finally but yet importantly, they are osteotransductive, i.e., after implantation, calcium orthophosphate cements are replaced by a new bone tissue[29-31]. The aim of biomimetic bone cements is to disturb bone functions and properties as little as possible and, until a new bone has been grown, to behave temporary in a manner similar to that of bone. From a biological point of view, this term defines cements that can reproduce the composition, structure, morphology and crystallinity of bone crystals [32,33]. Therefore, the discovery of self-setting calcium orthophosphate formulations was a significant step forward in the field of bioceramics for bone regeneration, since it established good prospects for minimally invasive surgical techniques that were less aggressive than the classical surgical methods[34]. Such formulations provide surgeons with a unique ability of manufacturing, shaping and implanting the bioactive bone substitute materials on a patient-specific base in real time in the surgery room. Implanted bone tissues also take benefits from initial setting characteristics of the cements that give, in an acceptable clinical time, a suitable mechanical strength for a shorter tissue functional recovery. The major advantages of the self-setting calcium orthophosphate formulations include a fast setting time, excellent moldability, outstanding bio- compatibility and easy manipulation; therefore, they are more versatile in handling characteristics than prefabricated calcium orthophosphate granules or blocks. Besides, like any other type of calcium orthophosphate bioceramics, the self-setting formulations provide with the opportunity for bone grafting using alloplastic materials, which are unlimited in quantity and provide no risk of infectious diseases [35-37]. Since self-setting calcium orthophosphate formulations are intended for using as implanted biomaterials for parenteral application, for their chemical composition one might employ all ionic compounds of oligoelements occurring naturally in a human body. The list of possible additives includes (but is not limited to) the following cations: Na+, K+, Mg2+, Ca2+, Sr2+, H+ and anions: PO43−, HPO42−, H2PO4−, P2O74−, CO32−, HCO3−, SO42−, HSO4−, Cl−, OH−, F−, SiO44−[29]. Therefore, mixed-type self-setting formulations consisting of calcium orthophosphates and other calcium salts (e.g., calcium sulfates[38-47], calcium pyrophosphate[48-50], calcium polyphosphates[51,52], calcium carbonates[33, 53-55], calcium oxide[56-61], calcium hydroxide[62-64], calcium aluminate[26,65,66], calcium silicates[67-71], etc.), strontium orthophosphate[72-74], magnesium orthophosphate[74-78], magnesium oxide[79], Zn-containing compounds[80], as well as cements made of various ion substituted calcium orthophosphates (e.g., Ca2KNa(PO4)2, NaCaPO4, Na3Ca6(PO4)5, magnesium substituted CDHA, strontium substituted CDHA, etc.)[81-90] are available. Furthermore, self-setting formulations might be prepared in the reaction-setting mixture of Ca(OH)2 – KH2PO4 system[91], as well as by treatment of calcium carbonates with orthophosphate solutions[92]. More to the point, self-setting formulations possessing magnetic properties due to incorporation of iron oxides have been developed as well[93,94]. However, with a few important exceptions, such ion-substituted formulations have not been considered in this review. The purpose of this review is to evaluate the chemistry, physical and mechanical properties of the available self-setting calcium orthophosphate formulations with the specific reference to their biomedical applications in dentistry and surgery. 2. General Information and Data This According to Wikipedia, the free encyclopedia: “In the most general sense of the word, cement is a binder, a substance that sets and hardens independently and can bind other materials together. The name “cement” goes back to the Romans who used the term “opus caementitium” to describe masonry, which resembled concrete and was made from crushed rock with burnt lime as binder. The volcanic ash and pulverized brick additives, which were added to the burnt lime to obtain a hydraulic binder, were later referred to as cementum, cimentum, cäment and cement”[95]. Thus, calcium orthophosphate cement appears to be a generic International Journal of Materials and Chemistry 2011; 1(1): 1-48 3 term to describe chemical formulations in the ternary system Ca(OH)2 – H3PO4 – H2O which can experience a transformation from a liquid or pasty state to a solid state and in which the end-product of the chemical reactions is a calcium orthophosphate. Figure 1. Top: a 3D version of the classical solubility phase diagrams for the ternary system Ca(OH)2 – H3PO4 – H2O. Reprinted from Ref. [621] 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. [622] with permission The first self-setting calcium orthophosphate cement formulation consists of the equimolar mixture of TTCP and dicalcium phosphate (DCPA or DCPD)[96] which is mixed with water at a P/L ratio of 4:1; the paste hardened in about 30 min and formed CDHA[97,98]. This highly viscous, non-injectable paste can be molded and, therefore, is used mainly as a contouring material in craniofacial surgery. In 1990-s, it was established that there were about 15 different binary combinations of calcium orthophosphates, which gave pastes upon mixing with water or aqueous solutions, so that the pastes set at room or body temperature into a solid cement. The list of these combinations is available in literature[99-101]. From these basic systems, secondary formulations could be derived containing additional or even non-reactive compounds but still setting like cements[29,58,99,102-116]. Concerning their viscosity, both pasty cement formulations[117-120] and putties[121] of a very high viscosity[122-125] are known as well. According to the classical solubility data of calcium orthophosphates (Fig. 1), depending upon the pH value of a cement paste, after setting all calcium orthophosphate cements can form only two major end-products: a precipitated poorly crystalline HA or CDHA[126] at pH > 4.2 and DCPD (also called “brushite”[127]) at pH < 4.2[128]. However, the pH-border of 4.2 is shifted to a higher value of pH in the real cement formulations. Namely, DCPD might be formed at pH up to ~ 6, while CDHA normally is not formed at pH below 6.5 – 7 (Table 1). The results of the only study on an ACP cement demonstrated that this end-product was rapidly converted into CDHA[113]; thus, it also belongs to apatite-forming formulations. Besides, there are some papers devoted to OCP-forming cements[129-132]; however, contrary to the reports of late 1980-s[129] and early 1990-s[130], in recent papers either simultaneous formation of OCP and CHDA has been detected[132] or no phase analysis has been performed[131]. Strong experimental evidences of the existence of a transient OCP phase during cement setting were found in still another study; however, after a few hours, the OCP phase disappeared giving rise to the final CDHA phase[25]. Thus, all existing formulations of calcium orthophosphate cements can be divided into two major groups: apatite cements and brushite cements[133]. The final hardened product of the cements is of the paramount importance because it determines the solubility and, therefore, in vivo bioresorbability. Since the chemical composition of mammalian bones is similar to an ion-substituted CDHA, apatite- forming cement formulations have been more extensively investigated. Nevertheless, many research papers on brushite cements have been published as well. All self-setting calcium orthophosphate formulations are made of an aqueous solution and fine powders of one or several calcium orthophosphate(s). Here, dissolution of the initial calcium orthophosphate(s) (quickly or slowly depending on the chemical composition and solution pH) and mass transport appear to be the primary functions of an aqueous environment, in which the dissolved reactants form a supersaturated (very far away from the equilibrium) microenvironment with regard to precipitation of the final product(s)[135,136]. The relative stability and solubility of various calcium orthophosphates (see Table 1) is the major driving force for setting reactions that occur in these cements. Therefore, mixing of a dry powder with an aqueous solution induces various chemical transformations, where crystals of the initial calcium orthophosphate(s) rapidly dissolve(s) and precipitate(s) into crystals of CDHA (preci- 4 Sergey V. Dorozhkin: Self-Setting Calcium Orthophosphate Formulations: Cements, Concretes, Pastes and Putties pitated HA) or DCPD with possible formation of intermediate precursor phases (e.g., ACP[113] and OCP[25,129132]). During precipitation, the newly formed crystals grow and form a web of intermingling microneedles or microplatelets of the final products, thus provide a mechanical rigidity to the hardened cements. In other words, entanglement of the newly formed crystals is the major reason of setting (Fig. 2). For the majority of apatite cements, water is not a reactant in the setting reaction. Therefore, the quantity of water, actually needed for setting of apatite cements, is very small[22,135,137]. However, for brushite cements, water always participates in the chemical transformations because it is necessary for DCPD formation. Due to this reason, brushite cements are always hydraulic, while usually this term is not associated with apatite cements. Figure 2. A typical microstructure of calcium orthophosphate cement after hardening. The mechanical stability is provided by the physical entanglement of crystals. Reprinted from Ref. [623] with permission Setting of calcium orthophosphate cements is a continuous process that always starts with dissolution of the initial compounds in an aqueous system. This process supplies ions of calcium and orthophosphate into the solution, where they chemically interact and precipitate in the form of either the end-products or precursor phases, which causes the cement setting[138-140]. This was confirmed by Ishikawa and Asaoka, who showed that when TTCP and DCPA powders were mixed in double-distilled water, both powders were dissolved. The dissolved calcium and orthophosphate ions in the solution were then precipitated in the form of CDHA on the surface of the powders[141]. The precipitate can be either a gel or a conglomerate of crystals. Therefore, the hardening mechanism is either a sol-gel transition of ACP [113] or entanglement of the precipitated crystals of other calcium orthophosphates (Fig. 2)[29]. For example, for the classical Brown-Chow cement formulation, after the initial setting, petal or needle-like crystals enlarge epitaxially and are responsible for the adherence and interlocking of the crystalline grains, which result in hardening. After ~ 2 hours, the newly formed crystals become rod-like, resulting from higher crystallinity with the observation of more material at the inter-particle spaces. During this period, the cement setting reaction proceeded at a near-constant rate, suggest- ing that the reaction rate was limited by factors that are un- related to the amounts of the starting materials and the reac- tion products present in the system. Such factors could be related to the surface area of DCPA or TTCP or to the diffusion distances over which the calcium and orthophosphate ions migrate in order to form CDHA[142-144]. At ~ 24 hours, the crystals are completely formed, being very compacted in some areas of high density, and well separated in areas with more porosity[106,111,112]. The chemical reactions occurring during setting of calcium orthophosphate cements depend on their chemical composition. However, it can be stated that only two major chemical types of the setting reaction are possible. The first type occurs according to the classical rules of the acid-base interaction, i.e. a relatively acidic calcium orthophosphate reacts with a relatively basic one to produce a relatively neutral compound. The first cement by Brown and Chow is a typical example of this type because TTCP (basic) reacts with DCPA (slightly acidic) in an aqueous suspension to form a poorly crystalline precipitated HA (slightly basic) [14,15]: 2Ca4(PO4)2O + 2CaHPO4 → Ca10(PO4)6(OH)2 (1) Earlier, it was believed that DCPA and TTCP reacted upon mixing with water to form the stoichiometric HA[13-16]. However, further investigations have shown that only the first nuclei consist of a nearly stoichiometric HA, whereas further growth of these nuclei occurs in the form of CDHA[145]. Besides, there is a study demonstrating that the initially formed stoichiometric HA further interacts with remaining DCPD to form CDHA[146]. According to equation (1), formation of HA releases neither acidic nor basic by-products. Thus, the liquid phase of the cement remains at a near constant pH of ~ 7.5 for the TTCP + DCPD and ~ 8.0 for the TTCP + DCPA formulations, respectively[142-144]. Various deviations from the stoichiometry of chemical equation (1) were studied in de- tails and various apatitic calcium orthophosphates with Ca/P ionic ratio within 1.5 – 1.67 were found as the end-product[147]. The effect of mixing ratio and pH on the reaction between TTCP and DCPA is well described else- where[148]. Furthermore, the influence of Ca/P ionic ratio of TTCP on the properties of the TTCP + DCPD cement was studied as well[149]. A blend proposed by Lemaître et al.,[150,151] is another example of the acid-base interaction where β-TCP (almost neutral) reacts with MCPM (acidic) to form DCPD (slightly acidic): β-Ca3(PO4)2 + Ca(H2PO4)2·H2O + 7H2O → 4CaHPO4·2H2O (2) In chemical equation (2) MCPM might easily be substi- tuted by orthophosphoric acid[152-155] or MCPA, while β-TCP might be replaced by either α-TCP[156,157], CDHA[158,159] or HA[160]. For example: Ca9(HPO4)(PO4)5(OH)+3H3PO4+17H2O → 9CaHPO4·2H2O (3) International Journal of Materials and Chemistry 2011; 1(1): 1-48 5 Furthermore, self-setting formulations based on mixtures of ACP + α-TCP[161], ACP + DCPD[162,163], DCPA + α-TCP[157], OCP + TTCP[164], OCP + α-TCP[165,166] and partially crystallized calcium orthophosphate + DCPA [167] as the initial reagents, are also available. The second type of the setting reaction might be defined as hydrolysis of a metastable calcium orthophosphate in aqueous media. As the result, both the initial and final compounds have the same Ca/P ionic ratio. Due to the fact, that only one calcium orthophosphate is used; the solid part of such formulations might be called as a single-phase (or single-component) cement powder[168]. Cements made of ACP + an aqueous solution[169,170], α-TCP + an aqueous solution[171-178], β-TCP + an aqueous solution[175,179], DCPA + an aqueous solution[24], CDHA + an aqueous solution[25], TTCP + an aqueous solution[26,180,181] or γ-radiated TTCP + an aqueous solution[182-184] are the typical examples; the majority of them are re-crystallized to CDHA during setting: CaxHy(PO4)z·nH2O + H2O → Ca10-x(HPO4)x(PO4)6-x(OH)2-x + nH2O (4) 3(α- or β-)Ca3(PO4)2 + H2O → Ca9(HPO4)(PO4)5(OH) (5) 3Ca4(PO4)2O + 3H2O → Ca9(HPO4)(PO4)5(OH) + 3Ca(OH)2 (6) Table 1. Existing calcium orthophosphates and their major properties[11] Ca/P molar ratio Compound Formula 0.5 0.5 1.0 1.0 1.33 1.5 1.5 1.2 – 2.2 1.5 – 1.67 1.67 1.67 1.67 2.0 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) Calcium-deficient hydroxyapatite (CDHA or Ca-def HA)[e] Hydroxyapatite (HA, HAp or OHAp) Fluorapatite (FA or FAp) Oxyapatite (OA, OAp or OXA)[f] Tetracalcium phosphate (TTCP or TetCP), mineral hilgenstockite Ca(H2PO4)2·H2O Ca(H2PO4)2 CaHPO4·2H2O CaHPO4 Ca8(HPO4)2(PO4)4·5H2O 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. [c] Stable at temperatures above 100°C. [d] Always metastable. [e] Occasionally, it is called “precipitated HA (PHA)”. [f] Existence of OA remains questionable. Table 2. Some self-setting calcium orthophosphate cement formulations having the 510(k) clearance from the FDA[20,137,202]. The technical data on these cements might be found in literature[22] Product* Manufacturer Applications* BoneSourceTM** α-Bone Substitute Material (α-BSM®)*** Skeletal Repair Systems (SRS®) Striker Howmedica Osteonics (Rutherford, NJ) Etex Corporation (Cambridge, MA) Norian Corporation (Cupertino, CA) Craniofacial Filling of bone defects and voids, dental, craniofacial Skeletal distal radius fractures, craniofacial * In Europe, other applications may apply, and the materials may be sold with a different commercial name. ** BoneSourceTM is the original formulation of calcium orthophosphate cement developed by Brown and Chow. *** In Europe, it is distributed by Biomet Merck (Zwijndrecht, The Netherlands) as Biobon®[137], while in North America it is marketed by Walter Lorenz Surgical (Jacksonville, FL) as Embarc®[22]. 6 Sergey V. Dorozhkin: Self-Setting Calcium Orthophosphate Formulations: Cements, Concretes, Pastes and Putties The experimental details on TTCP hydrolysis under a near-constant composition condition might be found elsewhere[185]. The details on α-TCP hydrolysis are also available. The results indicated that setting of α-TCP was initially controlled by surface dissolution; therefore, it depended on the surface area of the reactants[186-189]. Hydrolysis of DCPD to CDHA was studied as well[190]. Addition of ~ 2 wt. % of a precipitated poorly crystalline HA (i.e., CDHA) as a seed to α-TCP powder phase might be useful to accelerate the kinetics of reaction (5)[191]. Further, there is a single-phase cement powder consisting of K- and Na- containing CDHA (with the Ca/P ionic ratio of 1.64 ± 0.02) that sets and hardens after mixing with an aqueous solution of sodium citrate and sodium orthophosphate[17]. After setting, this formulation gives rise to formation of a weak cement (the compressive strength of 15 ± 3 MPa) consisting of the ion-substituted CDHA again (presumably, with another Ca/P ionic ratio), mimicking the bone mineral. Unfortunately, neither the setting reaction nor the setting mechanism of this cement has been disclosed in literature[17]. What’s more, a self-setting cement might be prepared from the thermal decomposition product of HA[192]. The hydration process of calcium orthophosphate cements is slightly exothermic (which is beneficial for biomedical applications) and undergoes five periods: initiating period, induction period, accelerating period, decelerating period and terminating period[193]. For the classical Brown-Chow cement formulation, the activation energy of the hydration reaction is 176 kJ/mol[194]. The rate of heat liberation during the solidification of calcium orthophosphate cements is low. The results of adiabatic experiments showed that the temperature rise arrived at the highest value of 37℃ 3 h later, which would cause no harm to surrounding tissues[193]. The results show that the hardening process of this cement is initially controlled by dissolution of the reactants in a 4 h period and subsequently by diffusion through the product layer of CDHA around the grains [112]. In general, setting of calcium orthophosphate cements occurs mostly within the initial ~ 6 hours, yielding an ~ 80 % conversion to the final products. The volume of the cements stays almost constant during setting. However, after hardening, calcium orthophosphate cements always form brittle ceramics with the tensile strength of 5 to 20 times lower than the compression strength[195,196]. Since this material is weak under tensile forces, these cements can only be used either in combination with metal implants or in non-load bearing (e.g., craniofacial) applications[137,197199]. This is confirmed by the mechanical characterization of a bone defect model filled with ceramic cements[200]. To conclude this part, one must stress, that chemical equations (1) – (6) of the cement setting are valid for the in vitro conditions only. There are evidences that samples of calcium orthophosphate cement retrieved 12 h after hardening in vivo already contained carbonateapatite, even though the initial cement mixture did not contain carbonate as one of the solid components[201]. The mass fraction of carbonate in the 12 h samples was about 1 %. The results suggest that under the in vivo conditions, carbonate is readily available and this allows formation of carbonateapatite in favor of carbonate-free CDHA[201]. The United States Food and Drug Administration (FDA) has approved several cement formulations for clinical use[22,202]. Some examples are given in Table 2. The same formulations have also received a Conformite Europene (CE) mark for certain maxillofacial indications and for use as a bone-void filler in the specific non-load-bearing orthopedic indications[137]. The major properties of these formulations are available in literature[22]. An extended list of the cement formulations is presented in Table 3[125]. Other lists of the commercially available injectable bone cements with their chemical composition (when obtainable) might be found elsewhere[34,144,203,204], while various types of bone cements and fillers are listed in still another review[198]. A general appearance of two randomly chosen commercial calcium orthophosphate cements is shown in Fig. 3. Besides, even more cement formulations are in experimental stages. Figure 3. A presentation of two randomly chosen commercial calcium orthophosphate cements 3. Two Major Types of Calcium Orthophosphate Cements 3.1. Apatite Cements Typically, apatite cement formulations have a precipitated poorly crystalline HA and/or CDHA as the end product of the setting reaction (see chemical equations (1), (4) – (6)), although traces of the unreacted starting materials can be present[106]. A FA-forming cement is also known; it might be prepared by the same way but in the presence of F—ions [205]. Due to the initial presence of carbonates, such commercial formulations as Norian SRS® and Biocement D® form a non-stoichiometric carbonatapatite or dahllite (Ca8.8(HPO4)0.7(PO4)4.5(CO3)0.7(OH)1.3) as the end-product [53,206]. As both CDHA and carbonateapatite are formed in an aqueous environment and have a low crystallinity, they appear to be similar to biological apatite of bones and teeth. These properties are believed to be responsible for their excellent in vivo resorption characteristics. Conventional apatite cements contain TCP and/or TTCP phases in their International Journal of Materials and Chemistry 2011; 1(1): 1-48 7 powder components[34], while a single component cement powder consisting of K- and Na- containing CDHA is also available[17]. The reactivity of TCP-based apatite cements varies as a function of TCP crystal phase, crystallinity and particle size[207,208]. Generally, a higher reactivity is observed with a thermodynamically less stable phase (from β-TCP to α-TCP and further to ACP) and with a smaller particle size[175]. Nominally, it might be stated that formation of apatites through a cementation reaction is a sort of a biomimetic process because it occurs in physiological en- vironment and at body temperature[37]; however, both the crystallization kinetics and a driving force are very far away from the biomimeticity. A unique feature of the hardened apatite cements is that the force linking the newly formed crystals (of both CDHA and carbonatapatite) is weak; therefore, the crystals can be easily detached from the bulk of hardened cement, especially after dissolution has partly occurred. When this happens, osteoclasts and other cells can easily ingest the apatite crystals[209]. Table 3. A list of the commercial self-setting calcium orthophosphate formulations with the producer, product name, composition (when available) and main end-product. The main end-product of the reaction can be either an apatite (CDHA, carbonateapatite, etc…) or brushite (= DCPD)[125] Producer Commercial name Composition Berkeley Advanced Biomaterials (US) Biomatlante (FR) Biomet (US) Interpore (US) Walter Lorenz Surgical (GER) Calcitec (US) ETEX (US) Graftys (FR) Kasios (FR) Kyphon (US) Mitsubishi Materials (J) Produits Dentaires SA (CH) CalciphOs (CH) Cem-Ostetic™ Tri-Ostetic™ MCPC Calcibon® Mimix™ Quick Set Mimix™ Osteofix α-BSM®; Embarc; Biobon β-BSM® γ-BSM® OssiPro CarriGen Graftys® HBS Graftys® Quickset Jectos Eurobone® Jectos+ KyphOs™ Biopex® Biopex®-R VitalOs4 Powder: calcium orthophosphates (details unknown); Solution: Sterile water Powder: calcium orthophosphates (details unknown); Solution: Sterile water Powder: mainly α-TCP, ACP, BCP (HA + β-TCP); Solution: phosphate buffered solution Powder: α-TCP (61%), DCPA (26%), CaCO3 (10%), CDHA (3%); Solution: H2O, Na2HPO4 Powder: TTCP, α-TCP, trisodium citrate; Solution: citric acid aqueous solution Powder: Calcium orthophosphate powders, trisodium citrate; Solution: citric acid aqueous solution Powder: calcium orthophosphate and calcium oxide powders; Solution: phosphate buffer Powder: ACP (50%), DCPD (50%); Solution: Un-buffered aqueous saline solution Composition: could not be found (it has apparently a higher compressive strength and better injectability than α-BSM®) Composition: could not be found (putty consistency) Composition: could not be found; the cement is claimed to be macroporous after hardening Composition: synthetic calcium orthophosphate, sodium carboxymethylcellulose, sodium bicarbonate and sodium carbonate Powder: mainly β-TCP, ACP, BCP (HA + β-TCP); Solution: phosphate buffered solution Composition: calcium orthophosphate salts, hydroxypropylmethylcellulose and orthophosphate-based aqueous solution Powder: β-TCP (98%), Na2P2O7 (2%); Solution: H2O, H3PO4 (3.0M), H2SO4 (0.1M) Composition: could not be found (likely to be close to that of Jectos) Powder: β-TCP (77%), Mg3(PO4)2 (14%), MgHPO4 (4.8%), SrCO3 (3.6%); Solution: H2O, (NH4)2HPO4 (3.5M) Powder: α-TCP (75%), TTCP (20-18%), DCPD (5%), HA (0-2%) Solution: H2O, Na succinate (12-13%), Na chondroitin sulfate (5-5.4%) Powder: α-TCP, TTCP, DCPD, HA, Mg3(PO4)2, NaHSO3; Solution: H2O, Na succinate, Na chondroitin sulfate Solution 1: β-TCP (1.34g), Na2H2P2O7 (0.025g), H2O, salts (0.05M PBS solution, pH 7.4); Solution 2: MCPM (0.78g), CaSO4·2H2O (0.39g), H2O, H3PO4 (0.05M) Shanghai Rebone Biomaterials Co (CN) Skeletal Kinetics (US) Rebone Callos™ Powder: TTCP, DCPA; Solution: H2O Composition: α-TCP, CaCO3, MCPM; Solution: sodium silicate Product apatite apatite apatite apatite apatite apatite apatite apatite apatite apatite apatite apatite apatite apatite brushite brushite apatite apatite apatite brushite apatite apatite 8 Sergey V. Dorozhkin: Self-Setting Calcium Orthophosphate Formulations: Cements, Concretes, Pastes and Putties Stryker (US) Leibinger (GER) Stryker (US) Synthes (US) Teknimed (FR) Callos Inject™ OsteoVation EX Inject BoneSource™ HydroSet™ Norian® SRS Norian® CRS Norian® SRS Fast Set Putty Norian® CRS Fast Set Putty Norian Drillable chronOS™ Inject Cementek® Cementek® LV Composition: α-TCP and unknown compounds (likely to be close to that of Callos™) Probably similar to Callos Inject™ (Product produced by S.K. but sold by OsteoMed) Powder: TTCP (73%), DCPD (27%); Solution: H2O, mixture of Na2HPO4 and NaH2PO4 Powder: TTCP, DCPD, trisodium citrate; Solution: H2O, polyvynilpyrrolidone, Na orthophosphate Powder: α-TCP (85%), CaCO3 (12%), MCPM (3%); Solution: H2O, Na2HPO4 Composition: could not be found (likely to be close to that of Norian SRS/CRS) Composition: calcium orthophosphate powder, bioresorbable fibers and Na hyaluronate solution Powder: β-TCP (73%), MCPM (21%), MgHPO4·3H2O (5%), MgSO4 (<1%), Na2H2P2O7 (<1%); Solution: H2O, Na hyaluronate (0.5%) Powder: α-TCP, TTCP, Na glycerophosphate; Solution: H2O, Ca(OH)2, H3PO4 Powder: α-TCP, TTCP, Na glycerophosphate, dimethylsiloxane; Solution: H2O, Ca(OH)2, H3PO4 apatite apatite apatite apatite apatite apatite apatite brushite apatite apatite Immediately after implantation, any cement becomes exposed to blood and other tissue fluids that delays the setting time. Intrinsic setting time for apatite cements has been extensively studied and it appeares to be rather long. For example, for the original formulation by Brown and Chow it ranges from 15 to 22 min[14,15]. This may result in procedural complications. To remedy this, the amount of liquid might be reduced to a possible minimum. Therefore, all apatite cements look like viscous and easily moldable pastes which tend to be difficult to inject. Besides playing with the P/L ratio, the setting time can also be reduced by using additives to the liquid phase (which is distilled water in the Brown-Chow formulation[14,15]). The list of additives includes phosphoric acid, MCPM and other soluble orthophosphates. These additives promote dissolution of the initial solids by lowering the solution pH. In such cases, a setting time in the range of 10 – 15 minutes can be obtained[169,171-177,210]. The influence of soluble orthophosphates (e.g., Na2HPO4 or NaH2PO4) on the setting time of apatite cements is explained by the fact that dissolution of DCPA and formation of CDHA during setting occur in a linear fashion, thus avoiding early formation of CDHA. This is important because too early formation of CDHA might engulf un-reacted DCPA, which slows down DCPA dissolution and thus the setting kinetics becomes slower, while the presence of sodium orthophosphates prevents DCPA particles from being isolated[211]. Particle size[191,212,213], temperature of the liquid phase and initial presence of HA as a seed in the solid phase are other factors that influence the setting time[14,15,37,207,208]; however, in vitro studies demonstrated that these parameters did not affect significantly[106]. On the other hand, a reduction in particle size was found to result in a significant decrease in both initial and final setting times[191,212,213], an acceleration of the hardening rate[191] and hydration kinetics of the hardening cement[213]. Besides, the crystallite sizes of the final product can be strongly reduced by increasing the specific surface of the starting powder, which allows developing calcium orthophosphate cements with tailored structures at the micro and nano-scale levels[191]. Unfortunately, an unclear correlation was found between the particle dimensions of the initial calcium orthophosphates and mechanical properties of the hardened cements: namely, a significant increase in compressive strength and storage modulus was reported for some formulations[212,213] but a minor effect on compressive strength was discovered for other ones[191]. This inconsistence is not surprising because the manufacturing method used to produce test samples varies from one author to the other. Therefore, the only remaining fact is that calcium orthophosphate cements are brittle and hence worthless for load-bearing applications[197,198]. Setting process of the most types of apatite cements occurs according to just one chemical reaction (see chemical equations (1), (4) – (6)) and at near the physiological pH. The latter may additionally contribute to the high biocompatibility observed for these materials[142-144]. For the classical formulation by Brown and Chow, the transmission electron microscopy results suggested the process for early-stage apatite formation as follows: when TTCP and DCPA powders were mixed in an orthophosphate-containing solution, TTCP powder quickly dissolved due to its higher solubility in acidic media. Then the dissolved ions of calcium and orthophosphate, along with ions already existing in the solution, were precipitated predominantly onto the surface of DCPA particles. Few apatite crystals were observed on the surface of TTCP powder. At a later stage of the reaction, an extensive growth of apatite crystals or whiskers effectively linked DCPA particles together and bridged the larger TTCP International Journal of Materials and Chemistry 2011; 1(1): 1-48 9 particles causing the cement setting[214]. However, Norian SRS® and Cementek® were found to set according to two chemical reactions: precipitation of DCPD, followed by precipitation of either CDHA or carbonatapatite: α-Ca3(PO4)2 + Ca(H2PO4)2·H2O + 7H2O → 4CaHPO4·2H2O (7) 5.2CaHPO4·2H2O + 3.6CaCO3 → Ca8.8(HPO4)0.7(PO4)4.5(CO3)0.7(OH)1.3 + 2.9CO2 + 12H2O (8) The initial chemical reaction (7) was very fast and pro- voked DCPD formation and setting of the cement pastes within seconds. The second step was slower: DCPD reacted completely within several hours with remaining α-Ca3(PO4)2 and CaCO3 forming carbonatapatite according to equation (8). The latter step caused the cement hardening. A similar two-step hardening mechanism was established for a cement consisting of MCPM and CaO: in the first step, during the mixing time, MCPM reacted with CaO immediately to give DCPD, which, in the second step, reacted more slowly with the remaining CaO to give CDHA[58]. In addition, the setting mechanism of an apatite cement was investigated in details for a three component mixture of TTCP, β-TCP and MCPM dry powders in convenient proportions and with the overall atomic Ca/P ratio equal to 1.67. Two liquid phases in a raw were used to damp the cement powder, initially it was water + ethanol (ethanol was added to slow down the hardening) and afterwards orthophosphoric acid and sodium glycerophosphate were added to water to prepare a reactive liquid[135]. At the very beginning, DCPD was found to form according to two chemical reactions: Ca(H2PO4)2·H2O + β-Ca3(PO4)2 + 7H2O → 4CaHPO4·2H2O (9) Ca4(PO4)2O + 2H3PO4 + 7H2O → 4CaHPO4·2H2O (10) The formation reactions of DCPD were fast and corresponded to the setting stage. Afterwards, TTCP reacted with the previously formed DCPD and with β-TCP to give CDHA according to the reactions: 2Ca4(PO4)2O + 2CaHPO4·2H2O → Ca10-x(HPO4)x(PO4)6-x(OH)2-x + xCa(OH)2 + (4–x)H2O (11) 2Ca4(PO4)2O + 4β-Ca3(PO4)2 + (2+2x)H2O → 2Ca10-x(HPO4)x(PO4)6-x(OH)2-x + 2xCa(OH)2 (12) The formation reactions of the CDHA phase were quite slow and corresponded to the hardening stage. Although OCP was not detected in that study, its formation as an intermediate phase was postulated for this formulation[135]. A similar suggestion on the intermediate formation of OCP was made for the setting mechanism of Brown-Chow classical cement formulation[101,106]; however, a reliable evidence for its presence is still lacking[172,215]. In both cases, OCP was suggested to appear as an intermediate because it was a faster forming phase than CDHA. This hypothesis is based upon the classical studies performed by Prof. W. E. Brown et al., about the precursor phase formation during chemical crystallization of apatites in aqueous solutions[216-218]. Solubility of the hardened apatite cements in aqueous solutions is expected to be rather similar to that of bone mineral. This means that they are relatively insoluble at neutral pH and increasingly soluble as pH drops down; this is an important characteristic of normal bone mineral that facilitates controlled dissolution by osteoclasts[206]. To conclude this part, one should mention, that in 2000 the US bone substitute market for Norian SRS® accounted for ~ 15 % of the total sales, followed by BoneSourceTM at ~ 13 %, and α-BSM® at ~ 8.5 %[137]. 3.2. Brushite Cements As indicated by its name, DCPD is the major end-product of the setting reaction of brushite cements (chemical equations (2) and (3)). Mirtchi and Lemaître[150] and independently Bajpai et al.,[151] introduced this type of the cements in 1987. Up to now, several formulations have been already proposed, e.g., β-TCP + MCPM[150,152], β-TCP + H3PO4 [151,153,154] and TTCP + MCPM + CaO[219]. All brushite cements are set by the acid-base interaction only. As DCPD can only precipitate at the solution pH < 6, the paste of brushite cement is always acidic during setting[153,220]. For example, during setting of a β-TCP + MCPM formulation, the cement pH varies from very acidic pH values of ~ 2.5, to almost neutral pH values of ~ 6.0[153]. Replacing MCPM by orthophosphoric acid renders the cement paste very acidic for the initial ~ 30 s but then the pH profile follows that obtained with MCPM. It is important to notice, that β-TCP + H3PO4 formulations have several advantages over β-TCP + MCPM formulations, namely: (i) easier and faster preparation, (ii) a better control of the chemical composition and reactivity, (iii) improved physico-chemical properties, such as longer setting times and larger tensile strengths due to a higher homogeneity. However, the use of orthophosphoric acid might impair the biocompatibility of the cement formulation, due to low pH values during setting[153]. If a cement formulation contains an excess of a basic phase, the equilibrium pH will be given by the intersection of the solubility isotherms of the basic phase with that of DCPD. For example, the equilibrium pH values of β-TCP + MCPM, HA + MCPM and TTCP + MCPM mixtures are 5.9, 4.2 and 7.6, respectively[197,198]. As the solubility of calcium orthophosphates decreases with increasing of their basicity (Table 1 and Fig. 1), the setting time of brushite cements much depends on the solubility of a basic phase: the higher its solubility, the faster the setting time. Therefore, the setting time of the cements made of MCPM + a basic calcium orthophosphate increases in the order: HA > β-TCP > α-TCP[197,198]. For example, HA + MCPM mixtures have a setting time of several minutes, β-TCP + MCPM mixtures – of 30 to 60 seconds and α-TCP + MCPM mixtures – of a few seconds[150,151]. Follow-up of the chemical composition by 31P solid state NMR enabled to show that the chemical setting process for β-TCP + MCPM formulation appeared to reach an end after ~ 20 min[221]. Nevertheless, despite this initial high reactivity, the hardening reaction of brushite cements typically lasts one day until 10 Sergey V. Dorozhkin: Self-Setting Calcium Orthophosphate Formulations: Cements, Concretes, Pastes and Putties completion[207,208]. Additives that inhibit the crystal growth of DCPD have successfully been used to increase the setting time of β-TCP + MCPM mixtures[222]. In contrast to apatite cements, the brushite cements can be initially liquid and still set within a short period of time[197,198]. By itself, brushite is remarkably biocompatible and bioresorbable[220]. Due to both a better solubility of DCPD if compared to that of CDHA (Table 1 and Fig. 1) and metastability of DCPD under physiological conditions[223], after implantation brushite cements are faster degradable than apatite ones[224-226]. They are quickly resorbed in vivo and suffered from a rapid decrease in strength (although the mechanical properties of the healing bone increase as bone ingrowth occurs[35]). Short setting times, low mechanical strength and limited injectability seem to prevent brushite cements from a broader clinical application. However, the major reason why brushite cements are not more widespread is probably not related to the mechanical issues but just to a later arrival on the market. Use of sodium citrate or citric acid as setting retardants is an option to get more workable and less viscous pastes of brushite cements[23,227-230]. Similar effect might be achieved by addition of chondroitin 4-sulfate[231] and glycolic acid[232]. For the cement for- mulations with orthophosphoric acid as the initial reactant (see chemical equation (3)), acid deficient formulations were also found to improve the workability. In this case, the set- ting reaction might be described by the following chemical equation[230]: 3.7β-Ca3(PO4)2 + H3PO4 + 27.8H2O → 3CaHPO4·2H2O + 2.7β-Ca3(PO4)2 + 21H2O (13) Although, several studies revealed that too much of DCPD in a given volume was not detrimental to the biological properties of brushite cements[35,206,219], occasionally, when large quantities of brushite cements were used, a cer- tain degree of tissue inflammation during the first weeks of in vivo implantation were reported[226,230,233]. Further investigations indicated that the inflammatory could be due to a partial transformation of DCPD into CDHA with release of orthophosphoric acid[234]: (10–x)CaHPO4·2H2O → Ca10-x(HPO4)x(PO4)6-x(OH)2-x + (4–x)H3PO4 + (18–x)H2O (14) Transformation of DCPD into CDHA occurs via two successive processes: dissolution and precipitation[235] and can be retarded by adding magnesium ions to the cement paste, thus reducing the possibility of inflammation[197, 198]. The aforementioned case of acid deficient formulations of brushite cements (chemical equation (13)) is an alternative, because it reduces the amount of unreacted acid in the ce- ment[230] with an option to consume liberating in chemical equation (14) orthophosphoric acid by the excess of β-TCP. Implantation of previously set brushite cement might be the third option, because a solid material was found to be better tolerated than paste implants. Besides, more bone was formed at the solid implant contact and the solid material degraded not so rapidly[236]. For brushite cements, a linear degradation rate of 0.25 mm/week was reported[237]. This rapid degradation rate might lead to formation of an immature bone. Adding β-TCP granules to the cement paste could solve this problem because β-TCP granules might act as bone anchors and encourage formation of a mature bone[237, 238]. 4. Various Properties 4.1. Setting and Hardening Generally, self-setting calcium orthophosphate formulations must set slowly enough to provide sufficient time to a surgeon to perform implantation but fast enough to prevent delaying the operation. Ideally, good mechanical properties should be reached within minutes after initial setting. Two main experimental approaches are used to study the cement setting process: a batch approach and a continuous approach. In the batch approach, the setting reaction is stopped at various times and the resulting samples are analyzed to determine e.g., the composition and compressive strength of the samples[207, 208]. There are currently two standardized methods to apply this approach, namely, Gillmore needles method (ASTM C266-89)[239] and Vicat needle method (ASTM C191-92)[240]. The idea of both methods is to examine visually the surface of cement samples to decide whether the cement has already set, i.e. if no mark can be seen on the surface after indentation. Besides, the setting process might be monitored in real time by non-destructive methods (the continuous approach), e.g., pulse-echo ultrasound technique[241,242], isothermal differential scanning calorimetry[174,175,243-248] and alternating current (AC) impedance spectroscopy[249]. For example, calorimetry measurements suggested that in equation (2) the endothermic MCPM dissolution and the highly exothermic β-TCP dissolution occurred simultaneously, followed by the exothermic crystallization of DCPD[247]. Moreover, acid-base reactions (1) – (3) can be and have been analyzed by measuring the pH evolution of a diluted cement paste[207]. Finally yet importantly, methods of Fourier-transform infrared spectroscopy[24-26,248,250], solid state NMR[221], X-ray diffraction[24,26,50,156,251] and energy dispersive X-ray diffraction[24-26,252,253] might be applied as well. The latter techniques proved to be powerful even though they have limitations such as the time required for each measurement (250 s for an X-ray diffraction scan is a problem for fast setting reactions); besides the analysis is located at the surface of the sample where evaporation and thermal effects can modify the reaction rate of the surface compared to that of the bulk. Furthermore, the continuous approach is an indirect one, which markedly complicates an interpretation of the collected data, particularly in complex cement formulations[207]. A way to assess the rate of a cement hardening is to measure its setting time, which means the time required to reach a certain compressive strength, generally close to 1 MPa. The most straightforward approach is to prepare cement samples with a well-controlled geometry (e.g., cylind-

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