**5. Phase evolution during setting**

pH conditions, can be used as precursors for the DCPD- or DCP-forming cements. Although DCP is the more stable of the two phases, it is kinetically constrained to have a higher nucleation activation energy and can only form under certain conditions as explained earlier. After setting, the pH of the cement paste slowly changes towards the equilibrium pH [140]. Up to now, several formulations have been proposed, including β-TCP + MCPM, β-TCP + H<sup>3</sup>

The second type of setting reaction is defined as hydrolysis of a metastable calcium phosphate when the reactant and the product have the same Ca/P molar ratio. Typical examples are

+ H<sup>2</sup> O → Ca9(HPO4) (PO4)

6−x (OH)

5

, and anions: PO<sup>4</sup>

, Na3 Ca<sup>6</sup> (PO<sup>4</sup> ) 5

addition extended the initial setting times but significantly short-

4−. Therefore, mixed-type cements consisting of calcium phos-

5

OH + 3Ca (OH)

3−, HPO<sup>4</sup>

ACP, α-TCP, and TTCP which form CDHA upon contact with an aqueous solution:

2

KNa(PO<sup>4</sup>

small spheroidal crystals and in faster dissolution rates [42].

.nH<sup>2</sup> <sup>O</sup> <sup>+</sup> <sup>H</sup><sup>2</sup> <sup>O</sup> <sup>→</sup> Ca10−<sup>x</sup> (HPO4)<sup>x</sup> (PO4)

O + 3 H<sup>2</sup> O → Ca9(HPO4) (PO4)

, Sr2+, Si4+, Fe2+, Ag+

) 2

Chemical composition of calcium phosphate cements may include all ionic compounds of naturally occurring minerals in human body. The list of possible additives includes the follow-

phates and other calcium salts like gypsum, calcium sulfate hemihydrate, calcium pyrophosphate, calcium polyphosphates, calcium carbonate, calcium oxide, calcium hydroxide, calcium aluminate, calcium silicate, strontium phosphate, as well as cements made of ion substituted

, NaCaPO<sup>4</sup>

2− ions have the most significant effect on CPC microstructure such that incorporation of carbonate in the apatite cement causes a decrease in the precipitated crystallite size and reduces the setting rate as well as the attained compressive strength. According to the study

ened the final setting times of single component HA cement. Furthermore its accelerating effect was more pronounced at higher concentrations [137]. Morphological studies reveal that the size and shape of the crystallites change from long needles to smaller rods to tiny spheroids [18, 102]. Carbonate ions can incorporate into apatite and substitute for PO<sup>4</sup>

 in the apatite crystal structure and subsequently change its properties. It is reported that the supersaturation required for precipitation of slightly carbonated apatite was higher than that of apatite in simulated body fluid [143]. Carbonate ions disturb the crystallization of the growing apatite crystallites to such an extent that, depending upon the amount of carbonate added, the material may give an amorphous X-ray diffraction pattern. A submicron structure of interconnected microcrystals are responsible for the improved final mechanical properties of the cement formulation with addition of calcium carbonate. Moreover, carbonate ions cause the bonding in the apatite to become weaker and more isotropic, which results in the

calcium deficient hydroxyapatite (CDHA), strontium-substituted CDHA are possible [142].

and TTCP + MCPM + CaO [51, 99, 141].

3 α − Ca3 (PO4)

, K<sup>+</sup>

2−, HSO<sup>4</sup> − , Cl<sup>−</sup> , F<sup>−</sup> , SiO<sup>4</sup>

calcium phosphates such as Ca2

by Khairoun *et al*. CaCO<sup>3</sup>

2

, Mg2+, Ca2+, H<sup>+</sup>

Cax <sup>H</sup><sup>y</sup> (PO4)<sup>z</sup>

206 Cement Based Materials

3 Ca4 (PO4)

ing cations: Na+

HCO<sup>3</sup> − , SO<sup>4</sup>

CO<sup>3</sup>

OH−

PO<sup>4</sup> ,

<sup>2</sup>−<sup>x</sup> + nH<sup>2</sup> O (20)

<sup>2</sup> (22)

PO4−, CO<sup>3</sup>

2−,

3− or

OH (21)

2−, H<sup>2</sup>

, magnesium-substituted

The powder of the original calcium phosphate cement formulation proposed by Brown and Chow consists of an equimolar mixture of TTCP and DCP. The setting reaction of calcium phosphate cements starts with ordered dissolution of the salts in the aqueous system. This supplies Ca2+ and PO<sup>4</sup> 3− ions, which precipitate in the form of HA. Epitaxial enlargement of petal or needle-like crystals after initial setting is responsible for the adherence and interlocking of the crystalline grains, which result in hardening [26]. Detailed investigations of the setting of various CPC formulation using various molar ratios, particle sizes, P/L ratios reveal that the reaction proceeds by complete dissolution of the acidic phases DCP or MCPM and partial dissolution of the basic TTCP or β-TCP particles. The specific surface area and the resulting solubility of the basic phase has a much greater effect on the setting rate as increasing its specific surface area leads to an increase in pH, and results in a sharp rise in the solubility of the acidic particles and the supersaturation of HA in the solution [40]. For apatite cement setting is controlled by the dissolution of reactant particles in the first 4-h period, and since the rate of dissolution is proportional to the surface area of the particles which is basically constant in CPC specimens in the earlier stage, the precipitation rate of HA is linear with time. HA forms among the reactant particles which enhances the joint of solids, or around the particles which reduces the distance between grains [42]. Setting is controlled by diffusion through the HA layer at later stages. At 24 hours, the crystals are completely formed, being highly compacted in some areas of high density and well separated in areas with more porosity. Precipitated HA either in stoichiometric or calcium deficient form, nucleate and grow on TTCP particles, thereby reducing their dissolution rate at the final stages [145]. When such a shell is formed around the reactants, the rate of HA formation is controlled by the transport of water and ions through the shell and decrease with an increase of its thickness. Since the densities of DCP and HA are different, the hydration of the residual DCP engulfed by the shell to HA leads to volume expansion and internal stress which is harmful to the compressive strength.

Liu *et al*. describes the thermodynamics of apatite cement setting clearly [118]. Calcium phosphate cement setting reactions are generally exothermic reactions consisting of several steps. In the short initiating period, water is absorbed and wets the surface of the grains upon mixing calcium phosphate powder with water. This is a physical exothermic process. In the inducing period or latency, the particle dissolution which is also exothermic contributes to a rise in concentration of the calcium and phosphate ions in the solution. With the different dissolution rates of the basic and acidic precursors and the latter being faster, initially acidic pH translates toward the neutral or basic region until the solution is supersaturated, and then DCPD or HA crystallizes from the solution. The accelerating period is a fast, reaction controlled region. In the decelerating period, setting reaction decreases and the reaction process converts from surface reaction-controlled to diffusion-controlled after the setting product grows around the particle surface of the raw materials. Finally, the precipitate product layer may be destroyed by osmotic pressure and crystallization interior stress, which may lead to the increase of the reaction rate and another slight exothermic peak.

The phase evolution of brushite forming β-TCP—MCPM system has been monitored by various techniques including FTIR spectroscopy [146], DS calorimetry [117], pH-stat base titration [33, 34] and small amplitude oscillatory rheometry [44]. The observations confirm the above-mentioned general thermodynamic changes in the state of the CPC. Upon mixing the cement precursors with excess setting liquid, MCPM instantly dissolves and supplies H<sup>2</sup> PO<sup>4</sup> − and Ca2+ ions to the solution. A small fraction of H<sup>2</sup> PO<sup>4</sup> − is expected to dissociate into H<sup>+</sup> and HPO<sup>4</sup> 2− ions due to its relative stability among phosphoric acid species in water at room temperature [83]. β-TCP dissolves simultaneously to release 3Ca2+ and 2PO<sup>4</sup> 3− that can form brushite CaHPO<sup>4</sup> ·2H<sup>2</sup> O provided that stoichiometric H<sup>+</sup> ions are removed from the solution to first form HPO<sup>4</sup> 2−groups, resulting in an initial rise in solution pH that is an indication of supersaturation build-up. At this stage cement injectability is maximum. Subsequent to this period, the injectability of CPC gradually diminishes as crystal domains start to expand and intergrow with increasing β-TCP dissolution. Built-up supersaturation can quickly relax by crystal growth in the presence of brushite seeds. As crystals intergrow into small domains, cements gain dough consistency and elasticity develops as seen in **Figure 3**. With increasing intergrowth of the crystalline phase the suspension becomes thicker, i.e., more viscous and more elastic as defined by the increases of the storage modulus, G′ and the magnitude of complex viscosity, η\* occurring between the dough time and the initial setting time. CPC is workable by hand prior to the dough time as it lacks stiffness and rigidity. Subsequent precipitation and β-TCP dissolution act to balance the supersaturation and pH until the rate of one weakens relative to the other [147]. This interplay between dissolution and precipitation continues indefinitely until the consumption of precursors.

viscous to elastic flow behavior and elasticity increases at a decreasing rate as a function of the dissolution rate which depends on the β-TCP and water content. Flow instabilities naturally build pressure drop up constantly beyond that point as a result of which injection becomes

**Figure 3.** Schematics of calcium phosphate cement setting as represented by the dynamic rheological properties (Şahin

Calcium Phosphate Bone Cements

209

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

A recent development on improvement of injectability or extrudability of calcium phosphate cements was introduced by our research group so that the inherent injectability problem can be solved by conditioning the cement prior to injection by preshearing. [44]. Our observation that application of oscillatory and steady shear strains i.e. preshearing alters both the setting kinetics and the microstructure, enables tailoring of the cement viscosity and the injection, working and setting periods. The rheology of fast-setting brushite cement was also characterized (**Figure 3**) including the linear viscoelastic strain limit which was characterized for inorganic cements as a function of setting time for the first time. A preshearing apparatus akin to a syringe with the capability to not only pressurize but also mix, preshear and dispense cements *in situ* is designed to facilitate their effective handling and injection. This novel mechanical modification technique is applicable to most inorganic cements and opens an avenue for further research on modification of cement properties, especially rheology without resorting to chemical additives that may compromise the bioactivity and other favorable properties. The beneficial effects of preshearing on workability and extrudability of inorganic cements promise exciting new applications for them such as direct 3D printing of micro- and

impractical.

and Kalyon [44]).

macroporous scaffolds for bone regeneration.

After the working period a particle to particle network develops and the injectability of the doughy cement suspension becomes modestly more difficult as the initial setting time is approached [148]. Bone cements with various solid contents have been reported to be injectable well beyond their dough time [67] which is most likely due to the active wall-slip mechanism that enables stable flow of doughy pastes. Cement suspension can be shaped by hand at this working period when it has a dough consistency and does not stick to surgical gloves. At the initial setting time a solid network structure or gelling starts to develop in cement microstructure when elasticity and viscosity starts to overshoot asymptotically. The viscoelastic properties change abruptly during this setting period with a sudden transition from

period or latency, the particle dissolution which is also exothermic contributes to a rise in concentration of the calcium and phosphate ions in the solution. With the different dissolution rates of the basic and acidic precursors and the latter being faster, initially acidic pH translates toward the neutral or basic region until the solution is supersaturated, and then DCPD or HA crystallizes from the solution. The accelerating period is a fast, reaction controlled region. In the decelerating period, setting reaction decreases and the reaction process converts from surface reaction-controlled to diffusion-controlled after the setting product grows around the particle surface of the raw materials. Finally, the precipitate product layer may be destroyed by osmotic pressure and crystallization interior stress, which may lead to the increase of the

The phase evolution of brushite forming β-TCP—MCPM system has been monitored by various techniques including FTIR spectroscopy [146], DS calorimetry [117], pH-stat base titration [33, 34] and small amplitude oscillatory rheometry [44]. The observations confirm the above-mentioned general thermodynamic changes in the state of the CPC. Upon mixing the cement precursors with excess setting liquid, MCPM instantly dissolves and

and Ca2+ ions to the solution. A small fraction of H<sup>2</sup>

cies in water at room temperature [83]. β-TCP dissolves simultaneously to release 3Ca2+

·2H<sup>2</sup>

tion pH that is an indication of supersaturation build-up. At this stage cement injectability is maximum. Subsequent to this period, the injectability of CPC gradually diminishes as crystal domains start to expand and intergrow with increasing β-TCP dissolution. Built-up supersaturation can quickly relax by crystal growth in the presence of brushite seeds. As crystals intergrow into small domains, cements gain dough consistency and elasticity develops as seen in **Figure 3**. With increasing intergrowth of the crystalline phase the suspension becomes thicker, i.e., more viscous and more elastic as defined by the increases of the storage modulus, G′ and the magnitude of complex viscosity, η\* occurring between the dough time and the initial setting time. CPC is workable by hand prior to the dough time as it lacks stiffness and rigidity. Subsequent precipitation and β-TCP dissolution act to balance the supersaturation and pH until the rate of one weakens relative to the other [147]. This interplay between dissolution and precipitation continues indefinitely until the

After the working period a particle to particle network develops and the injectability of the doughy cement suspension becomes modestly more difficult as the initial setting time is approached [148]. Bone cements with various solid contents have been reported to be injectable well beyond their dough time [67] which is most likely due to the active wall-slip mechanism that enables stable flow of doughy pastes. Cement suspension can be shaped by hand at this working period when it has a dough consistency and does not stick to surgical gloves. At the initial setting time a solid network structure or gelling starts to develop in cement microstructure when elasticity and viscosity starts to overshoot asymptotically. The viscoelastic properties change abruptly during this setting period with a sudden transition from

PO<sup>4</sup> −

2− ions due to its relative stability among phosphoric acid spe-

O provided that stoichiometric H<sup>+</sup>

2−groups, resulting in an initial rise in solu-

is expected to

ions are

reaction rate and another slight exothermic peak.

and HPO<sup>4</sup>

removed from the solution to first form HPO<sup>4</sup>

3− that can form brushite CaHPO<sup>4</sup>

supplies H<sup>2</sup>

208 Cement Based Materials

and 2PO<sup>4</sup>

dissociate into H<sup>+</sup>

PO<sup>4</sup> −

consumption of precursors.

**Figure 3.** Schematics of calcium phosphate cement setting as represented by the dynamic rheological properties (Şahin and Kalyon [44]).

viscous to elastic flow behavior and elasticity increases at a decreasing rate as a function of the dissolution rate which depends on the β-TCP and water content. Flow instabilities naturally build pressure drop up constantly beyond that point as a result of which injection becomes impractical.

A recent development on improvement of injectability or extrudability of calcium phosphate cements was introduced by our research group so that the inherent injectability problem can be solved by conditioning the cement prior to injection by preshearing. [44]. Our observation that application of oscillatory and steady shear strains i.e. preshearing alters both the setting kinetics and the microstructure, enables tailoring of the cement viscosity and the injection, working and setting periods. The rheology of fast-setting brushite cement was also characterized (**Figure 3**) including the linear viscoelastic strain limit which was characterized for inorganic cements as a function of setting time for the first time. A preshearing apparatus akin to a syringe with the capability to not only pressurize but also mix, preshear and dispense cements *in situ* is designed to facilitate their effective handling and injection. This novel mechanical modification technique is applicable to most inorganic cements and opens an avenue for further research on modification of cement properties, especially rheology without resorting to chemical additives that may compromise the bioactivity and other favorable properties. The beneficial effects of preshearing on workability and extrudability of inorganic cements promise exciting new applications for them such as direct 3D printing of micro- and macroporous scaffolds for bone regeneration.
