**3. Properties**

#### **3.1. Bioactivity**

As the chemical composition of the mammalian bone mineral is similar to ion-substituted, calcium-deficient hydroxyapatite (CDHA), apatite forming calcium phosphate cements have been more extensively investigated as bioactive implant materials than brushite forming CPCs. All apatite CPC formulations have precipitated hydroxyapatite (PHA) as the end-product of the reaction which has a much finer crystal structure than its sintered counterparts or other CPC setting products including brushite and monetite. High surface area and roughness are the physical requisites for osteoconduction as bone bonding is achieved by micro-mechanical interdigitation of the cement line (a thick apatite layer secreted by osteoblasts) with the material surface [22]. Also micro-topographically complex surfaces promote osteoconduction by both increasing the available surface area for fibrin attachment and providing surface features with which fibrin becomes entangled; and potentiating the activation of platelets, which produce density gradients of cytokines and growth factors that guide leukocytes and osteogenic cells during the healing process [23]. Furthermore Davies demonstrated that platelet activation on calcium phosphate surfaces is a function of the surface topography of the calcium phosphate, rather than the composition.

According to Davies, the formation of bone requires not only the recruitment and migration of a potentially osteogenic cell population but also the differentiation of this population into mature secretory cells [24]. The potentially osteogenic population migrates through the wound site and reaches the surface of bone fragments, or the implant within the wound site. This stage termed osteoconduction is the most important aspect of peri-implant healing. The implant surface design can have a profound influence on osteoconduction not only by modulating the levels of platelet activation, but also by maintaining the anchorage of the temporary scaffold of fibrin and proteins through which these cells reach the implant surface. Cells that reach the solid surface will initiate matrix synthesis by secreting the first collagenous matrix of the cement line directly on the implant surface. This new bone formation stage is generally considered as a separate and distinct phenomenon and is followed by remodeling of the bone. The bone bonding theory of Davies helps one understand how calcium phosphate and 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 bonding of the elaborated bone matrix to that surface.

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.

As the chemical composition of the mammalian bone mineral is similar to ion-substituted, calcium-deficient hydroxyapatite (CDHA), apatite forming calcium phosphate cements have been more extensively investigated as bioactive implant materials than brushite forming CPCs. All apatite CPC formulations have precipitated hydroxyapatite (PHA) as the end-product of the reaction which has a much finer crystal structure than its sintered counterparts or other CPC setting products including brushite and monetite. High surface area and roughness are the physical requisites for osteoconduction as bone bonding is achieved by micro-mechanical interdigitation of the cement line (a thick apatite layer secreted by osteoblasts) with the material surface [22]. Also micro-topographically complex surfaces promote osteoconduction by both increasing the available surface area for fibrin attachment and providing surface features with which fibrin becomes entangled; and potentiating the activation of platelets, which produce density gradients of cytokines and growth factors that guide leukocytes and osteogenic cells during the healing process [23]. Furthermore Davies demonstrated that platelet activation on calcium phosphate surfaces is a function of the surface topography of the calcium phosphate, rather than the composition. According to Davies, the formation of bone requires not only the recruitment and migration of a potentially osteogenic cell population but also the differentiation of this population into mature secretory cells [24]. The potentially osteogenic population migrates through the wound site and reaches the surface of bone fragments, or the implant within the wound site. This stage termed osteoconduction is the most important aspect of peri-implant healing. The implant surface design can have a profound influence on osteoconduction not only by modulating the levels of platelet activation, but also by maintaining the anchorage of the temporary scaffold of fibrin and proteins through which these cells reach the implant surface. Cells that reach the solid surface will initiate matrix synthesis by secreting the first collagenous matrix of the cement line directly on the implant surface. This new bone formation stage is generally considered as a separate and distinct phenomenon and is followed by remodeling of the bone. The bone bonding theory of Davies helps one understand how calcium phosphate and

**3. Properties**

194 Cement Based Materials

**3.1. Bioactivity**

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 the most efficient among them [36, 37]. CPCs are not generally considered to be osteoinductive. However their drug delivery capability has been effectively exploited to impart osteoinductivity to various CPC formulations [16, 38].

One of the main reasons for the weakness of CPCs is their inherent microporosity, which makes it easier for micro- and macro-cracks to run throughout the mass [14]. The pores that typically account for about 40% of hardened cement volume, originate from water reservoirs that form due to packing imperfections, shrinkage, drying and water consuming setting reaction. Porosity may be controlled to a certain extent by precompaction [52], adjusting the particle size [53, 54] and the powder/liquid (P/L) ratio [46], addition of porogens [55] and rheology enhancing chemical [56]. Combination of precompaction with citric acid due to its liquefying effect results in outstanding strength values. Unusually high strengths can also be obtained when cement P/L ratio is maximized to the limiting level of insufficient wetting. This is possible by either efficient dispersion of particle agglomerates through a liquefying effect due to electrostatic repulsion of particles or by using bimodal particle size distribution in the setting cement. Various organic and inorganic chemicals including alphahydroxylic acids (a.k.a. carboxylic acids), and vinylic superplasticizers have been utilized for increasing the surface charge by binding to the active surface sites [56, 57]. Bimodal particle size distributions have been shown to decrease the water demand in an α-tricalcium phosphate (α-TCP) single-component, HA-forming system where the addition of an CaCO<sup>3</sup>

of much smaller particle size enabled higher workable P/L [58]. In the case of macropore introduction to the cement matrix by incorporation of porogens, the microporosity is simply decreased because the sample contains less CPC per unit volume due to more macroporosity. Although this is beneficial for the resorbability of the cement, mechanical properties of macroporous cement are greatly reduced compared to macropore free cements. According to Rice, strength of ceramics vary as an exponential function of porosity as given below and

*σ* = *σ*<sup>0</sup> *exp*(−*KP*) (1)

*σ* = (*E*<sup>0</sup> *R*/(*c*))0.5 exp(−*KP*) (2)

Fiber reinforcement is one of the most convenient methods to compensate for the induced macroporosity in CPCs [61, 62]. Certain fibers like aramid have the property of bonding with hydroxyapatite and providing nucleation sites for set crystals. This property of aramid was made use of in the study by Xu *et al*. where fiber reinforcement imparted a substantial improvement of mechanical properties over those of fiber free porous cement, with strength increasing 3–7 times and toughness by 2 orders of magnitude [55]. The porosity values of the fiber composites were slightly less than those without fibers because the 6% mass imparted by

Other factors affecting strength are the materials used in the solid phase, incorporation and particle size/shape of filler materials in the solid phase. Several researchers attempted to add

is modified by Le Huec to take pore size into account accordingly [60]:

is the strength of the material with zero porosity and *K* is a constant. This equation

is the modulus of zero porosity, *c* is the average pore size and *R* is fracture surface

so does the strength of CPCs [59]:

the reinforcing fibers was fully dense.

where *σ<sup>0</sup>*

where *E0*

energy.

filler

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#### **3.2. Mechanical properties**

The mechanical properties of calcium phosphate cements depend on two conditions: (a) the precipitate should grow in the form of clusters of crystals which have a high degree of rigidity, (b) the morphology of the crystals should enable entanglement of the clusters. In Driessen's study of 450 different CPC formulations, about 40% set in a time shorter than 60 minutes [39]. However, only part of these formulations led to cement bodies having a considerable strength. It was found that both compressive and diametral tensile strength were maximum for stoichiometric compositions with respect to the reaction products. Strength is also related to pore structure due to the size distribution of all the particles and the pressure applied to compact the particle network. Thus, the early compressive strength of the cement is mainly dependent on the quantity of the hydration products, the amount of contact points among hydrated grains, and the volume proportion of hydration product crystals [40]. In addition to the above-mentioned factors, the final compressive strength is obviously dependent on the degree of dissolution, recrystallization, growth and intergrowth of cement precursor and product crystals [41].

Both the extent of CPC conversion and the compressive strength of the cement increase drastically with time in the form of a sigmoidal function [42, 43]. In common practice, the observation of the initial plateau strength values is prevented by the requirement of sample rigidity and the finite time period of strength measurements, so that an exponential rise with time and an end plateau is reported in mechanical characterization results. The complete variation of cement strength and modulus as a function setting time can be conveniently observed using a mechanical spectrometer that is able to probe the viscoelastic character of the cement suspension [44, 45]. The compressive strength is highly correlated with the extent of conversion of the reactants to the products. After setting, CPCs can reach mechanical properties comparable to those of calcium phosphate blocks with the same porosity. Having the ceramic origin, the set products of all calcium orthophosphate cements are brittle, have both a low impact resistance and a low tensile strength within 1–10 MPa, whereas the compressive strength varies within 10–100 MPa. Brushite cements are slightly weaker than apatite cements. However their innovative modification methods result in exceptional strength because of the water consuming setting reaction of brushite cements [46]. Unlike apatite cements, which consume little (1 mole per 3 moles of powder reactant in β-tricalcium phosphate (β-TCP) systems) or no water (TTCP/DCP systems) during setting, the brushite cement system consumes a lot of water during setting reaction (up to 6 moles per 1 mole of powder reactant), theoretically allowing for the formation of cements with low or almost zero porosities. Some excellent reviews on the mechanical properties of both apatite and brushite cements are recommended for additional information [26, 47, 48]. In macroporous form apatite cement has adequate strength to replace trabecular bone. In vivo, the mechanical properties of apatite cements were found to increase, whereas those of brushite cements decreased [49, 50]. This is generally attributed to a higher bioresorbability of DCPD when compared with that of CDHA which not only depends on the inherent solubility but also on various physiological processes occurring around the implant site [51].

One of the main reasons for the weakness of CPCs is their inherent microporosity, which makes it easier for micro- and macro-cracks to run throughout the mass [14]. The pores that typically account for about 40% of hardened cement volume, originate from water reservoirs that form due to packing imperfections, shrinkage, drying and water consuming setting reaction. Porosity may be controlled to a certain extent by precompaction [52], adjusting the particle size [53, 54] and the powder/liquid (P/L) ratio [46], addition of porogens [55] and rheology enhancing chemical [56]. Combination of precompaction with citric acid due to its liquefying effect results in outstanding strength values. Unusually high strengths can also be obtained when cement P/L ratio is maximized to the limiting level of insufficient wetting. This is possible by either efficient dispersion of particle agglomerates through a liquefying effect due to electrostatic repulsion of particles or by using bimodal particle size distribution in the setting cement. Various organic and inorganic chemicals including alphahydroxylic acids (a.k.a. carboxylic acids), and vinylic superplasticizers have been utilized for increasing the surface charge by binding to the active surface sites [56, 57]. Bimodal particle size distributions have been shown to decrease the water demand in an α-tricalcium phosphate (α-TCP) single-component, HA-forming system where the addition of an CaCO<sup>3</sup> filler of much smaller particle size enabled higher workable P/L [58]. In the case of macropore introduction to the cement matrix by incorporation of porogens, the microporosity is simply decreased because the sample contains less CPC per unit volume due to more macroporosity. Although this is beneficial for the resorbability of the cement, mechanical properties of macroporous cement are greatly reduced compared to macropore free cements. According to Rice, strength of ceramics vary as an exponential function of porosity as given below and so does the strength of CPCs [59]:

the most efficient among them [36, 37]. CPCs are not generally considered to be osteoinductive. However their drug delivery capability has been effectively exploited to impart osteoin-

The mechanical properties of calcium phosphate cements depend on two conditions: (a) the precipitate should grow in the form of clusters of crystals which have a high degree of rigidity, (b) the morphology of the crystals should enable entanglement of the clusters. In Driessen's study of 450 different CPC formulations, about 40% set in a time shorter than 60 minutes [39]. However, only part of these formulations led to cement bodies having a considerable strength. It was found that both compressive and diametral tensile strength were maximum for stoichiometric compositions with respect to the reaction products. Strength is also related to pore structure due to the size distribution of all the particles and the pressure applied to compact the particle network. Thus, the early compressive strength of the cement is mainly dependent on the quantity of the hydration products, the amount of contact points among hydrated grains, and the volume proportion of hydration product crystals [40]. In addition to the above-mentioned factors, the final compressive strength is obviously dependent on the degree of dissolution, recrystallization, growth and intergrowth of cement precursor and product crystals [41]. Both the extent of CPC conversion and the compressive strength of the cement increase drastically with time in the form of a sigmoidal function [42, 43]. In common practice, the observation of the initial plateau strength values is prevented by the requirement of sample rigidity and the finite time period of strength measurements, so that an exponential rise with time and an end plateau is reported in mechanical characterization results. The complete variation of cement strength and modulus as a function setting time can be conveniently observed using a mechanical spectrometer that is able to probe the viscoelastic character of the cement suspension [44, 45]. The compressive strength is highly correlated with the extent of conversion of the reactants to the products. After setting, CPCs can reach mechanical properties comparable to those of calcium phosphate blocks with the same porosity. Having the ceramic origin, the set products of all calcium orthophosphate cements are brittle, have both a low impact resistance and a low tensile strength within 1–10 MPa, whereas the compressive strength varies within 10–100 MPa. Brushite cements are slightly weaker than apatite cements. However their innovative modification methods result in exceptional strength because of the water consuming setting reaction of brushite cements [46]. Unlike apatite cements, which consume little (1 mole per 3 moles of powder reactant in β-tricalcium phosphate (β-TCP) systems) or no water (TTCP/DCP systems) during setting, the brushite cement system consumes a lot of water during setting reaction (up to 6 moles per 1 mole of powder reactant), theoretically allowing for the formation of cements with low or almost zero porosities. Some excellent reviews on the mechanical properties of both apatite and brushite cements are recommended for additional information [26, 47, 48]. In macroporous form apatite cement has adequate strength to replace trabecular bone. In vivo, the mechanical properties of apatite cements were found to increase, whereas those of brushite cements decreased [49, 50]. This is generally attributed to a higher bioresorbability of DCPD when compared with that of CDHA which not only depends on the inherent solubility but also

on various physiological processes occurring around the implant site [51].

ductivity to various CPC formulations [16, 38].

**3.2. Mechanical properties**

196 Cement Based Materials

$$
\sigma = \sigma\_0 \exp(-\text{KP}) \tag{1}
$$

where *σ<sup>0</sup>* is the strength of the material with zero porosity and *K* is a constant. This equation is modified by Le Huec to take pore size into account accordingly [60]:

$$
\sigma = \left(\mathbb{E}\_0 \,\mathbb{R}/(\pi c)\right)^{0.5} \exp(-KP) \tag{2}
$$

where *E0* is the modulus of zero porosity, *c* is the average pore size and *R* is fracture surface energy.

Fiber reinforcement is one of the most convenient methods to compensate for the induced macroporosity in CPCs [61, 62]. Certain fibers like aramid have the property of bonding with hydroxyapatite and providing nucleation sites for set crystals. This property of aramid was made use of in the study by Xu *et al*. where fiber reinforcement imparted a substantial improvement of mechanical properties over those of fiber free porous cement, with strength increasing 3–7 times and toughness by 2 orders of magnitude [55]. The porosity values of the fiber composites were slightly less than those without fibers because the 6% mass imparted by the reinforcing fibers was fully dense.

Other factors affecting strength are the materials used in the solid phase, incorporation and particle size/shape of filler materials in the solid phase. Several researchers attempted to add filler materials to increase the mechanical properties as in a composite matrix [63, 64]. The idea behind the use of filler particles is that if a tough filler is present in the matrix, it may stop crack Propagation. However by adding fillers porosity decreases, as does the ability of the material to allow bone ingrowth into the pores. Using bioresorbable polymers as fillers provides an effective solution to this problem [65, 66].

The Zeta potential is an important property of cement particles influencing not just particle coagulation but also ion exchange between the hydrate layer around the ceramic particle and

CPC injectability depends on many factors and may be quite poor in certain cases which results in liquid-solid phase separation called filter-pressing. Their capillary flow has been analyzed extensively in order to understand their injectability behavior [70, 71]. The common observation has been the overshot pressure that is needed to extrude the whole cement sample out, in other words clogging. Highly filled suspensions stably flowing inside a barrel exhibit a constant pressure vs. time curve as seen in **Figure 1a**. Binder phase migrates toward

termed mat behind as shown in **Figure 1b**. Filtration of the low viscosity binder is caused by weak adhesion between the particles and the binder that may originate from improper dispersion in addition to low binder viscosity, low particle surface area and high difference between the densities of the two phases [72]. Further increasing the pressure either thickens the mat layer or discharges it (**Figure 1c**) depending on the propensity of the system to wallslip [73–76]. The viscoplasticity of complex fluids, including gels and concentrated suspensions and cements is always accompanied by slip at the wall [77–81]. The wall-slip behavior of concentrated suspensions always occurs on the basis of the apparent slip behavior which is generated by the formation of a slip layer consisting of pure binder (which is typically 1/16th to 1/8th of particle diameter) [82–84]: Understanding the conditions necessary for the development of a contiguous slip layer at the wall is the key to prevent mat layer formation and the resulting flow instabilities including filter-pressing and clogging [85]. The development of the apparent slip layer as well as the shear viscosity of the suspension as a function of time is affected by the role that entrained air plays. Wall-slip and shear viscosity of the suspension are both intimately linked to the amount of air that is entrained during mixing and processing [86–90]. Another important factor which affects the flow and deformation behavior of concentrated suspensions is linked directly to the efficacy of the distributive and dispersive mixing of the ingredients of the formulation and the possible shear-induced migration of particles

The solid mat layer in a cement is thickened as filtration progresses, setting continues, the liquid content decreases or the solid packing increases, as a result of which the pressure required

**Figure 1.** Stable flow (a), destabilized flow due to mat formation (b), stabilized flow due to mat formation (c) in capillary and the associated variation in the pressure drop (adapted with permission from Kalyon and Aktas et al. [72]).

and leaves a percolated particle network

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the particle surface itself as well as the net precipitation of new material [69].

the direction of applied pressure starting at time t0

during flow [91–95].

#### **3.3. Injectability**

Injectability of CPCs is of crucial importance for surgical procedures utilizing minimally invasive procedures such as in vertebraplasty and kyphoplasty or for delivery of the cement into a very narrow space as in root canal obturation. During the injection of the cement paste a pressure drop of the ceramic paste is developed as the paste flows out of the syringe and the needle and as it is forced into the treatment site. This pressure drop represents the bottle neck to injection and is overcome by the surgeon applying a higher pressure on the ram of the syringe that holds the cement. The applicability and the injectability of the cement suspension are governed by the time-dependent shear viscosity and elasticity of the ceramic paste (functions of all parameters affecting the setting kinetics). Once the ceramic suspension attains certain upper thresholds of viscosity and elasticity the injection of the cement paste to the treatment site is no longer possible. A rapid increase in the shear viscosity of the cement paste (transition from flowable suspension to a gel and then to a rigid solid) that is associated with the cement reaching its setting time, restricts the duration of time that the cement remains viable for injection during surgery. Usual practice for the orthopedic surgeon is to change cement formulations that include various setting retarder or promoter chemicals in addition to the setting precursors, according to the time limitations of the task. Alternatively, the setting time and flowability of calcium phosphate cements are adjustable *in situ* by the novel preshearing technology through application of oscillatory and torsional shear strains prior to pressurization and delivery to the surgical site which gives the surgeon freedom to use a wide range of cement formulations that set at various times [44].

At the initial period after mixing with the setting liquid, cements consist of dissolving particles in an aqueous solution that is gradually enriching in precursor ions. This dynamic microstructure with constantly changing maximum packing ratio and solid content typically exhibits concomitant slow alterations in the cement flow behavior according to the Krieger-Dougherty model:

$$\eta^{\prime} = \left(\mathbf{1} - \frac{\phi}{\phi\_{mm}}\right)^{-n} \tag{3}$$

where *η<sup>r</sup>* is the relative viscosity (the ratio between the cement and the setting liquid viscosities), *φ* and *φ*max are the volume fraction of particles in suspension and the volume fraction at which viscosity approaches infinity, respectively, and *n* is the intrinsic viscosity, an experimentally determinable constant (2.5 for spherical particles). Calcium phosphate cements show a shear-thinning behavior by a significant yield stress that increases with time. They are viscoplastic and can be described as Herschel-Bulkley fluids at any instant but lose their plasticity with time [67]. Furthermore, these materials are thixotropic [68]. The rheological behavior of the cement pastes are strongly influenced by the change of the surface charge during setting. The formation of agglomerates upon mixing the cement powder with the setting liquid can be minimized by taking advantage of the electrostatic repulsion between highly charged surfaces. The Zeta potential is an important property of cement particles influencing not just particle coagulation but also ion exchange between the hydrate layer around the ceramic particle and the particle surface itself as well as the net precipitation of new material [69].

filler materials to increase the mechanical properties as in a composite matrix [63, 64]. The idea behind the use of filler particles is that if a tough filler is present in the matrix, it may stop crack Propagation. However by adding fillers porosity decreases, as does the ability of the material to allow bone ingrowth into the pores. Using bioresorbable polymers as fillers

Injectability of CPCs is of crucial importance for surgical procedures utilizing minimally invasive procedures such as in vertebraplasty and kyphoplasty or for delivery of the cement into a very narrow space as in root canal obturation. During the injection of the cement paste a pressure drop of the ceramic paste is developed as the paste flows out of the syringe and the needle and as it is forced into the treatment site. This pressure drop represents the bottle neck to injection and is overcome by the surgeon applying a higher pressure on the ram of the syringe that holds the cement. The applicability and the injectability of the cement suspension are governed by the time-dependent shear viscosity and elasticity of the ceramic paste (functions of all parameters affecting the setting kinetics). Once the ceramic suspension attains certain upper thresholds of viscosity and elasticity the injection of the cement paste to the treatment site is no longer possible. A rapid increase in the shear viscosity of the cement paste (transition from flowable suspension to a gel and then to a rigid solid) that is associated with the cement reaching its setting time, restricts the duration of time that the cement remains viable for injection during surgery. Usual practice for the orthopedic surgeon is to change cement formulations that include various setting retarder or promoter chemicals in addition to the setting precursors, according to the time limitations of the task. Alternatively, the setting time and flowability of calcium phosphate cements are adjustable *in situ* by the novel preshearing technology through application of oscillatory and torsional shear strains prior to pressurization and delivery to the surgical site which gives the surgeon freedom to use a wide

At the initial period after mixing with the setting liquid, cements consist of dissolving particles in an aqueous solution that is gradually enriching in precursor ions. This dynamic microstructure with constantly changing maximum packing ratio and solid content typically exhibits concomitant slow alterations in the cement flow behavior according to the Krieger-Dougherty model:

> *φmax*) −*n*

is the relative viscosity (the ratio between the cement and the setting liquid viscosi-

ties), *φ* and *φ*max are the volume fraction of particles in suspension and the volume fraction at which viscosity approaches infinity, respectively, and *n* is the intrinsic viscosity, an experimentally determinable constant (2.5 for spherical particles). Calcium phosphate cements show a shear-thinning behavior by a significant yield stress that increases with time. They are viscoplastic and can be described as Herschel-Bulkley fluids at any instant but lose their plasticity with time [67]. Furthermore, these materials are thixotropic [68]. The rheological behavior of the cement pastes are strongly influenced by the change of the surface charge during setting. The formation of agglomerates upon mixing the cement powder with the setting liquid can be minimized by taking advantage of the electrostatic repulsion between highly charged surfaces.

(3)

provides an effective solution to this problem [65, 66].

range of cement formulations that set at various times [44].

*<sup>η</sup><sup>r</sup>* <sup>=</sup> (<sup>1</sup> <sup>−</sup> *<sup>φ</sup>*\_\_\_\_

**3.3. Injectability**

198 Cement Based Materials

where *η<sup>r</sup>*

CPC injectability depends on many factors and may be quite poor in certain cases which results in liquid-solid phase separation called filter-pressing. Their capillary flow has been analyzed extensively in order to understand their injectability behavior [70, 71]. The common observation has been the overshot pressure that is needed to extrude the whole cement sample out, in other words clogging. Highly filled suspensions stably flowing inside a barrel exhibit a constant pressure vs. time curve as seen in **Figure 1a**. Binder phase migrates toward the direction of applied pressure starting at time t0 and leaves a percolated particle network termed mat behind as shown in **Figure 1b**. Filtration of the low viscosity binder is caused by weak adhesion between the particles and the binder that may originate from improper dispersion in addition to low binder viscosity, low particle surface area and high difference between the densities of the two phases [72]. Further increasing the pressure either thickens the mat layer or discharges it (**Figure 1c**) depending on the propensity of the system to wallslip [73–76]. The viscoplasticity of complex fluids, including gels and concentrated suspensions and cements is always accompanied by slip at the wall [77–81]. The wall-slip behavior of concentrated suspensions always occurs on the basis of the apparent slip behavior which is generated by the formation of a slip layer consisting of pure binder (which is typically 1/16th to 1/8th of particle diameter) [82–84]: Understanding the conditions necessary for the development of a contiguous slip layer at the wall is the key to prevent mat layer formation and the resulting flow instabilities including filter-pressing and clogging [85]. The development of the apparent slip layer as well as the shear viscosity of the suspension as a function of time is affected by the role that entrained air plays. Wall-slip and shear viscosity of the suspension are both intimately linked to the amount of air that is entrained during mixing and processing [86–90]. Another important factor which affects the flow and deformation behavior of concentrated suspensions is linked directly to the efficacy of the distributive and dispersive mixing of the ingredients of the formulation and the possible shear-induced migration of particles during flow [91–95].

The solid mat layer in a cement is thickened as filtration progresses, setting continues, the liquid content decreases or the solid packing increases, as a result of which the pressure required

**Figure 1.** Stable flow (a), destabilized flow due to mat formation (b), stabilized flow due to mat formation (c) in capillary and the associated variation in the pressure drop (adapted with permission from Kalyon and Aktas et al. [72]).

to induce both liquid flow and mat discharge increases. This self-feeding loop gradually transforms the suspension to a packed bed at an increasing rate as evidenced by the exponential nature of the pressure vs. time curves of unstably flowing suspensions. Empirical attempts to tackle the filter-pressing issue shows that the injectability of CPCs is generally improved by decreasing the P/L ratio, the use of finer, round particles, the addition of electrically stabilizing groups, and the addition of viscous polymer solutions [96–101]. In addition to a large number of parameters relating to CPC composition, the injectability of a setting cement depends strongly on the post-mixing time interval relative to the cement setting time. In this regard, premixed CPCs that do not harden until being placed into the defect constitutes an advantage in that the viscoelastic properties are independent of time prior to injection [102].

efforts have been performed. Due to these reasons osteoclastic cells are able to degrade the hardened cements layer-by-layer only, starting at the bone cement interface. This is the main drawback of the classical cement formulations without controlled macroporous architecture. Bone substitution rate also depends on the anatomic site, age, sex, and general metabolic health of the recipient. Considering these factors, it may take 3–36 months for the cement to be completely resorbed and replaced by bone [26]. A linear degradation rate of 0.25 mm/week

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Various ions of zinc, magnesium, fluoride and pyrophosphate have been observed to inhibit β-TCP and HA dissolution [105–107]. HA dissolution is also inhibited by the presence of compounds such as bisphosphonates, polyphosphates or pyrophosphoric acid [108]. Bisphosphonates which are metabolically stable analogs of pyrophosphate, bind strongly to hydroxyapatite crystals and suppress osteoclast-mediated bone resorption and crystal growth. The oxygen atom that binds the two phosphate groups of pyrophosphate (P▬O▬P) is substituted by a carbon atom (P▬C▬P) in bisphosphonates. Bisphosphonates are characterized by the two covalently bonded sidechains attached to the central carbon atom, termed R1 and R2. Binding to bone is enhanced when R1 is a hydroxyl group, whereas the R2 side group has some effect on binding but predominantly determines the antiresorptive potency of the bisphosphonates. Bisphosphonates with an R2 side chain containing a basic primary nitrogen atom in an alkyl chain like pamidronate and alendronate are more potent antiresorptive agents than either etidronate or clodronate, whereas compounds with more highly substituted nitrogen moieties in R2 such as ibandronate can display further increases in anti-

Resorption of calcium phosphate cements is not desired at the onset of hardening in vivo due to washout of loose calcium phosphate particles by the surrounding body fluid before maintaining mechanical rigidity. The implant should be placed into the wound site between the initial and final setting times therefore washout constitutes a problem for the cement formulations with long setting time. Besides improving the setting times, it is possible to have a coherent cement prior to implantation that sets in contact with body fluids. These are called premixed cements and are essentially pastes formed by calcium phosphate particles mixed with non-aqueous but water-miscible liquids like glycerol [100]. Also several studies show that incorporation of a gelling agent such as hydroxypropyl methylcellulose, carboxymethyl cellulose, alginate, chitosan, into CPC provides good washout resistance [110, 111]. However, generally premixed CPC have lower mechanical properties probably related to the volume

Dissolution of the initial calcium phosphates and mass transport are the primary functions of the aqueous CPC setting solution, in which the dissolved reactants form a supersaturated microenvironment with regard to precipitation of the final product. The relative stability and solubility of various calcium phosphates is the major driving force for the setting reactions that occur in various cement formulations. Mixing of calcium phosphate precursors with aqueous setting solution induces various chemical transformations, where crystals of the initial

has been reported in literature [104].

resorptive potency [109].

initially taken up by the non-aqueous liquid [3].

**4. Thermochemistry and setting kinetics**

#### **3.4. Bioresorbability**

Calcium phosphate cements are able to provide short-term biologically desirable properties and then be replaced by a new bone. In order to achieve optimum clinical results, an appropriate CPC resorption rate is an important parameter that may vary with the intended clinical applications. For critical applications close to vital organs like cranioplasty, rapid implant resorption and replacement by bone may not be an as important factor as implant stability and integrity, and even may not be desirable due to the sensitivity of the brain to local ionic concentration gradients. For other applications, such as periodontal bone defect repairs or sinus lift, the ability of the implant cement to be replaced quickly by bone is highly desirable. Studies on the in vivo evaluation of macroporous calcium phosphate cements revealed a higher bioresorption rate due to both a higher contact with body fluids and enhanced cellular activity due to particle degradation. When the bioresorbability of dense and macroporous α-tricalcium phosphate cement were compared, it was seen that pores formed by albumin foaming promoted bone ingrowth and replacement [103]. Introduction of macroporosity to the CPC causes a trade-off between strength and bioresorbability which should be compensated by some means of strength reinforcement such as incorporation of polymeric fibers.

The overall bioresorption behavior of calcium phosphate cement is a combination of a solution-mediated passive resorption process and a cell-mediated active resorption process. The resorption properties of bioceramics are generally believed to relate to the solubility of their constitutive phases. The much higher (3 orders of magnitude) solubility of brushite compared to hydroxyapatite translates as the much quicker resorption of brushite cements. An important in vivo characteristic of HA-forming CPC is that it does not dissolve spontaneously in a normal physiological fluid environment, yet is resorbable under cell-mediated acidic conditions. Although brushite is soluble in normal physiological fluids, studies have shown that resorption of brushite CPC was also essentially cell-mediated [3]. Phase changes often occur in brushite cements in vivo by a dissolution-reprecipitation reaction, which results in stable phases with lower solubility, thus slowing down degradation and hence bone regeneration kinetics. The kinetics of passive resorption depends on porosity of the samples, ionic substitutions, Ca:P ratio, crystallinity and pH of the cement-tissue interface. The active resorption is due to cellular activity; however, it is also related to the passive one. Serum pH near macrophages and osteoclasts can drop to 5 by the excretion of lactic acid, whereas near osteoblasts pH can become as high as 8.5 by the excretion of ammonia [12]. The micropores in hardened cements do not allow fast bone ingrowth and they are not interconnected unless special efforts have been performed. Due to these reasons osteoclastic cells are able to degrade the hardened cements layer-by-layer only, starting at the bone cement interface. This is the main drawback of the classical cement formulations without controlled macroporous architecture. Bone substitution rate also depends on the anatomic site, age, sex, and general metabolic health of the recipient. Considering these factors, it may take 3–36 months for the cement to be completely resorbed and replaced by bone [26]. A linear degradation rate of 0.25 mm/week has been reported in literature [104].

Various ions of zinc, magnesium, fluoride and pyrophosphate have been observed to inhibit β-TCP and HA dissolution [105–107]. HA dissolution is also inhibited by the presence of compounds such as bisphosphonates, polyphosphates or pyrophosphoric acid [108]. Bisphosphonates which are metabolically stable analogs of pyrophosphate, bind strongly to hydroxyapatite crystals and suppress osteoclast-mediated bone resorption and crystal growth. The oxygen atom that binds the two phosphate groups of pyrophosphate (P▬O▬P) is substituted by a carbon atom (P▬C▬P) in bisphosphonates. Bisphosphonates are characterized by the two covalently bonded sidechains attached to the central carbon atom, termed R1 and R2. Binding to bone is enhanced when R1 is a hydroxyl group, whereas the R2 side group has some effect on binding but predominantly determines the antiresorptive potency of the bisphosphonates. Bisphosphonates with an R2 side chain containing a basic primary nitrogen atom in an alkyl chain like pamidronate and alendronate are more potent antiresorptive agents than either etidronate or clodronate, whereas compounds with more highly substituted nitrogen moieties in R2 such as ibandronate can display further increases in antiresorptive potency [109].

Resorption of calcium phosphate cements is not desired at the onset of hardening in vivo due to washout of loose calcium phosphate particles by the surrounding body fluid before maintaining mechanical rigidity. The implant should be placed into the wound site between the initial and final setting times therefore washout constitutes a problem for the cement formulations with long setting time. Besides improving the setting times, it is possible to have a coherent cement prior to implantation that sets in contact with body fluids. These are called premixed cements and are essentially pastes formed by calcium phosphate particles mixed with non-aqueous but water-miscible liquids like glycerol [100]. Also several studies show that incorporation of a gelling agent such as hydroxypropyl methylcellulose, carboxymethyl cellulose, alginate, chitosan, into CPC provides good washout resistance [110, 111]. However, generally premixed CPC have lower mechanical properties probably related to the volume initially taken up by the non-aqueous liquid [3].
