**2. Applications**

Compared to sintered calcium phosphate ceramics which are the most commonly applied materials in orthopedic surgery, calcium phosphate cements have three major advantages. Firstly, CPCs are nanocrystalline and hence have a very high specific surface area. Values as high as 100 m2 /g can be reached. In comparison, sintered ceramics have surface areas close to or below 1 m2 /g. Secondly, CPCs enable the synthesis of granules and blocks of low-temperature calcium phosphates such as dicalcium phosphate dihydrate (DCPD), dicalcium phosphate anhydrate, octacalcium phosphate (OCP), or precipitated apatite (PHA) [4]. In addition, initial flowability of CPCs enable their convenient conveying to the surgical site by means of a pressurization equipment and easy shaping by hand to conform to the defect perfectly. Injectability and sufficient compressive strength of CPCs has expanded their use to minimally invasive surgeries like percutaneous vertebroplasty and balloon kyphoplasty where organic polymethylmethacrylate (PMMA) cements had previously been the only choice for the surgeon to fill bone defects or fix bulk implants to the defect site [5, 6]. Due to the superiority of CPCs to PMMA in many aspects including bioactivity [7–9], dimensional stability [10], and biomimetic hardening, these materials are gradually replacing the organic bone cements especially in minimally invasive operations.

zinc phosphate, zinc polycarboxylate, magnesium phosphate, calcium phosphate, calcium silicate and glass polyalkenoate cements all proved to be biocompatible and to some degree osteoconductive. Particularly the effectiveness of calcium phosphate cements (CPC) as biomaterials has been attributed largely to their similar composition to hard tissues, aqueous setting solutions and tailorable viscosity. In addition constant improvements in cement properties have been realized due to their biomimetic setting reactions at ambient conditions that enabled experimenting with a wide variety of chemical and biological additives. As a result, inorganic cements led in quantity by calcium phosphate cements have been applied as bulk materials to fill defects in bone and teeth, support, induce and conduct bone regeneration rather than just bind more effective biomaterials in isolation. As highlighted in the subsequent parts of this chapter, biological interaction of calcium phosphate cements with human cells have been tested extensively and provides the basis for various modification approaches to

extend their applications and facilitate their evolution toward the ideal biomaterial.

proposed, most of which are given in the following sections.

**2. Applications**

192 Cement Based Materials

100 m2

1 m2

Inherent solubility of most calcium compounds in water has been a major motivation for material scientists to research and discover novel cementitious systems of these materials. So was the discovery of the major class of inorganic biomedical cements, calcium phosphate cements, realized. CPCs were discovered by LeGeros, Brown and Chow in early 1980s as an alternative to bulky bone graft bioceramics to set in situ and fill bone or dental defects [1, 2]. According to Chow, the discovery of the first CPC was in fact a result of basic studies on calcium phosphate solubility behaviors for the purpose of development of a tooth remineralizing suspension similar to contemporary toothpaste formulations. Based on solubility phase diagrams, material scientists were aware of the fact that both tetracalcium phosphate (TTCP) and dicalcium phosphate anhydrate (DCP) are much more soluble than hydroxyapatite (HA) under neutral pH conditions. Further, a slurry containing appropriate amounts of these compounds can produce continuous HA precipitation while maintaining the solution composition relatively constant. Brown and Chow observed that some of the TTCP + DCP aqueous pastes became a hardened mass when left in test tubes for a few hours. Thus unaware of the beneficial biomedical consequences, they discovered a new type of bioactive, self-hardening cement that consisted of only calcium phosphates and formed HA as the product. Rigorous subsequent in vivo research on the same cement system led to the conclusion that implanted CPC was gradually replaced by new bone. This CPC composition received approval by the US Food and Drug Administration in 1996, thus becoming the first commercially available CPC for use in humans [3]. Since then, many compositions have been

Compared to sintered calcium phosphate ceramics which are the most commonly applied materials in orthopedic surgery, calcium phosphate cements have three major advantages. Firstly, CPCs are nanocrystalline and hence have a very high specific surface area. Values as high as

/g can be reached. In comparison, sintered ceramics have surface areas close to or below

/g. Secondly, CPCs enable the synthesis of granules and blocks of low-temperature calcium phosphates such as dicalcium phosphate dihydrate (DCPD), dicalcium phosphate anhydrate, Calcium phosphate bone cement pastes typically exhibit relatively low shear viscosity and elastic modulus, then gain elasticity and shear viscosity with time. The rates of growths of the elasticity and viscosity of calcium phosphate based cements are generally higher than those of conventional cements as a result of the rapid dissolution and crystallization of calcium phosphate particles in water. Their initial flowability and workability are exploited most commonly in biomedical applications for bone repair and regeneration due to their exceptional osteoconductivity especially following cancerous bone removal and for minimally invasive surgeries. The minimally invasive clinical applications of bone cement pastes include spinal fusion, vertebroplasty, khyphoplasty, cranioplasty and periodontal surgery. During surgical applications the precise placement of the bone cement paste by the surgeon is very important. Various means are available for the placement of the cement paste into the repair site. Generally a syringe with a needle can be used. Calcium phosphate cements must react slowly enough to provide enough time for the surgeon to inject and work the paste into the implantation site, and fast enough to prevent washing-out or delaying the wound closure. Also its setting time and extent of reaction should be balanced to impart strength to the final product. The initial setting time is critical as it should allow sufficient time for shaping and filling. After the filling, it is not advisable to disturb the set cement until its hardening because any mechanical strain during this period will produce cracks and adversely affect the strength. Therefore it requires the shortest possible final setting time so that the wound closure is not delayed. The initial setting time denotes the end of workability of the paste after wetting, and the final setting time indicates the hardening of the set mass [11]. An initial setting time of about 8 minutes and a final setting time of less than 15 minutes are recommended for orthopedic applications.

Typically after setting of calcium phosphate cements, aqueous setting liquid is trapped in micro-reservoirs. The release of incorporated ions enable continuous hardening for days after setting. This reservoir effect is beneficial for many aqueous inorganic cements but especially for biomedical applications because of the contribution of the material to the dynamic tissue remodeling processes. Inorganic bone cements are required to provide a temporary support for the activity of the bone microenvironment consisting of cells, proteins, growth factors and ions while simultaneously facilitating the natural remodeling process by providing a preferentially alkaline environment and an abundance of relevant ions of calcium, phosphate, carbonate, etc. An excellent explanation of the bone remodeling process from a materials scientist's perspective by Driessens *et al*. is recommended for more information [12]. Exceptional bioactivity of apatite forming CPCs is due to the alkaline microenvironment rich in calcium and phosphate ions in ratio similar to those in the bone extracellular matrix. In addition, the inherent microporosity of these materials is beneficial for the release of drugs, and biomolecules that are proven to direct cellular activity so as to facilitate a wound healing and remodeling process close to natural as possible [13]. However macroporosity is also needed to be able to make use of these macromolecule osteoinductive factors like bone morphogenetic protein, transforming growth factor, platelet-derived growth factor, basic fibroblast growth factor and enable invasion of the material by osteoblasts [14]. Generally interconnected pores of sizes in excess of 300 μm are recommended to enhance new bone formation and the formation of capillaries [15]. Various macropore induction techniques have been applied to these biomimetically setting pastes with ease but those that work *in situ* are the most suitable for orthopedic applications [16–19]. Precise control on the porous architecture of calcium phosphate cement based scaffolds have been realized in a number of recent studies by indirect 3D printing techniques [20, 21]. The dimensional accuracy and bioactivity of such custom-fit forms of the material were found outstanding.

most other inorganic cements provide the advantages of accelerating early healing and bone bonding over most other biomaterials. Calcium phosphates are known to readily adsorb proteins to their surfaces. Potentiating protein adsorption on calcium phosphate surfaces can be expected to increase the binding of fibrinogen that may lead to increased platelet adhesion and, possibly result in increased platelet activation that may accelerate healing. Increasing protein adsorption can also include an improvement in fibrin binding to the implant surface resulting in an earlier establishment of the three-dimensional matrix through which osteogenic cells have to migrate to reach the implant surface. Therefore surface micro-topography and chemistry of calcium phosphates are critical for both the osteoconduction, and also the

Calcium Phosphate Bone Cements

195

http://dx.doi.org/10.5772/intechopen.74607

Aside from osteoconductivity, the most important requirement for a bone substitute implant material is biocompatibility. It is defined by Williams as [25]: "The ability of a biomaterial to perform its desired function with respect to a medical therapy, without eliciting any undesirable local or systemic effects in the recipient or beneficiary of that therapy, but generating the most appropriate beneficial cellular or tissue response in that specific situation, and optimizing the clinically relevant performance of that therapy." Orthopedic and maxillofacial implants are designed for non-sustained, short-term contact meaning that the implant should degrade in time. Therefore the implant material is required to have a level of degradability in the body in addition to the appropriate beneficial cellular response to be biocompatible. The physical presence of particulate or ionic degradation products are able to stimulate inflammatory cells, especially macrophages and giant cells that may elicit a systematic response and lead to a foreign body reaction to the biomaterial. Therefore biomaterial and its degradation products have to be devoid of any potential for mutagenicity, genotoxicity, carcinogenicity, reproductive toxicity and other adverse systematic effects in order to be considered biocompatible.

In this context apatite and brushite CPCs are biocompatible and osteoconductive. Calcium phosphate cements form an apatite layer on the surface shortly after implantation in bone. However, a unique feature of cements is that the particles are mixed with each other and the force linking them is weak; therefore, these particles can easily detach from the cement body, especially after some dissolution has occurred. When this happens, the particles are easily ingested by osteoclast-like cells or by giant cells [26]. However, inflammatory reactions and cytotoxicity have been reported when large brushite CPC volumes were used, primarily due to the transformation to precipitated HA and the resultant release of phosphoric acid [27, 28]. The transformation of DCPD into PHA can be prevented by adding magnesium ions to the cement paste [29] and converting brushite to the more stable anhydrous form, monetite [30]. The latter has been achieved by various techniques including heating [31], water deficient setting [32], acidic setting [33] and high ionic strength [34]. Some inflammatory reactions due to the initial acidity of brushite cement precursors may also apparently occur when the CPC does not set since the pH gradually increases close to the physiological level upon setting. The addition of collagen to brushite cement at different powder-to-liquid ratios resulted in an up to ninefold reduction in the amount of particles released from the cement when compared to the control cement without collagen. Collagen effectively prevented particle loss from the submerged cement paste during setting. In addition brushite-collagen cement composites had a three-fold increased cell adhesion capacity [35]. Numerous other in vivo and in vitro assessments have reported that calcium phosphates always support the attachment, differentiation, and proliferation of osteoblasts and mesenchymal cells, with hydroxyapatites being

bonding of the elaborated bone matrix to that surface.
