Calcium Orthophosphates: Applications in Nature, Biology, and Medicine Sergey Dorozhkin Copyright © 2012 Pan Stanford Publishing Pte. Ltd. ISBN 978-981-4316-62-0 (Hardcover), 978-981-4364-17-1 (eBook) www.panstanford.com
Brown and Chow [13-16] in the early 1980s. However, there is an opinion  that self-setting calcium orthophosphate formulations for orthopedic and dental restorative applications have first been described in the early 1970s by Driskell et al. . 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 ; thus, he appears to be the first (see Chapter 8). Leaving aside the priority topic, we 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 are also named as calcium phosphate bone cements (occasionally referred to as CPBC) . 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. The readers interested in formulations based on other types of calcium phosphates are requested to read the original publications . Due to a good bioresorbability, all self-setting calcium orthophosphate formulations belong to the second generation of bone-substituting biomaterials . These formulations are blends of amorphous and/or crystalline calcium orthophosphate powder(s) with an aqueous solution, which might be distilled water, phosphatebuffered saline (PBS), aqueous solutions of sodium orthophosphate (~ 0.25 M), orthophosphoric acid, citric acid (~ 0.5 M) , sodium silicate [24, 25], magnesium hydroorthophosphate , or even the revised simulated body fluid (rSBF) . 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
twentieth 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 . 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 . Such formulations provide surgeons with a unique ability of manufacturing, shaping, and implanting the bioactive bonesubstitute 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 biocompatibility, 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− . 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 , magnesium orthophosphate [74-78], magnesium oxide , Zn-containing compounds , 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 , as well as by treatment of calcium carbonates with orthophosphate solutions . 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 chapter. The purpose of this chapter is to review 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. 5.2 General Information and Data
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” . Thus, calcium orthophosphate cement appears to be a generic 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. The first self-setting calcium orthophosphate cement formulation consists of the equimolar mixture of TTCP and dicalcium phosphate (DCPA or DCPD)  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 1990s, 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  of a very high viscosity [122-125] are known as well. According to the classical solubility data of calcium orthophosphates (Fig. 1.6), 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  at pH > 4.2 and DCPD (also called “brushite” ) at pH < 4.2 . 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 1.1). The results of the only study on an ACP cement demonstrated that this end product was rapidly converted into CDHA ; 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 1980s  and early 1990s , in recent papers either simultaneous formation of OCP and CHDA has been detected  or no phase analysis has been performed . 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 . Thus, all existing formulations of calcium orthophosphate cements can be divided into two major groups: apatite cements and brushite cements . 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 1.1) 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 (precipitated HA) or DCPD with possible formation of intermediate precursor phases (e.g., ACP  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. 4.9). 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.