Materials Science and Engineering C 33 (2013) 475–481

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Magnesium substitution in brushite cements Mohammad Hamdan Alkhraisat a,⁎, Jatsue Cabrejos-Azama a, b, Carmen Rueda Rodríguez a, Luis Blanco Jerez b, Enrique López Cabarcos a a b

Departamento de Química-Física II, Facultad de Farmacia, UCM, 28040 Madrid, Spain Departamento de Estomatología III, Facultad de Odontología, UCM, 28040 Madrid, Spain

a r t i c l e

i n f o

Article history: Received 12 July 2011 Received in revised form 12 August 2012 Accepted 25 September 2012 Available online 29 September 2012 Keywords: Calcium phosphate cement Magnesium Brushite Newberyite Ionic substitution

a b s t r a c t The use of magnesium-doped ceramics has been described to modify brushite cements and improve their biological behavior. However, few studies have analyzed the efficiency of this approach to induce magnesium substitution in brushite crystals. Mg-doped ceramics composed of Mg-substituted β-TCP, stanfieldite and/or farringtonite were reacted with primary monocalcium phosphate (MCP) in the presence of water. The cement setting reaction has resulted in the formation of brushite and newberyite within the cement matrix. Interestingly, the combination of SAED and EDX analyses of single crystal has indicated the occurrence of magnesium substitution within brushite crystals. Moreover, the effect of magnesium ions on the structure, and mechanical and setting properties of the new cements was characterized as well as the release of Ca2+ and Mg 2+ ions. Further research would enhance the efficiency of the system to incorporate larger amounts of magnesium ions within brushite crystals. © 2012 Elsevier B.V. All rights reserved.

1. Introduction Calcium phosphates are proved to be biocompatible and effective in bone regeneration such that all bone substitutes contain calcium and/or phosphate ions. Still, intense research is dedicated to obtain a biomaterial that is better than or as efficient as autologous bone to achieve osseous tissue regeneration. Often, researchers employ growth factors to achieve such task; however, this approach will significantly increase costs and should comply with a more restrictive legislation. Another approach is based on ionic substitution of calcium ions within calcium phosphates by cations of biological importance like strontium, magnesium and zinc [1–3]. Magnesium is involved in various biological processes like cellular proliferation and differentiation, cell–matrix interaction and the normal functionality of organs [4–9]. Such that magnesium deficiency adversely affects all stages of skeletal metabolism, causing cessation of bone growth, decrease of osteoblastic and osteoclastic activities, osteopenia and bone fragility and thus, is proposed as a potential risk factor for osteoporosis [10]. Patients with postmenopausal osteoporosis showed increased bone mass after receiving magnesium [11]. Several studies have discussed the cation incorporation into various calcium phosphates. The stability of amorphous calcium phosphate (ACP) in aqueous solution is enhanced [12,13] and the structure of β-TCP is stabilized by lattice inclusion of Mg2+ ions. Thus, phase transformation to α-TCP is shifted to higher temperature improving the ⁎ Corresponding author. Tel.: +34 91 3941751. E-mail address: [email protected] (M.H. Alkhraisat). 0928-4931/$ – see front matter © 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.msec.2012.09.017

sintering of the β form [14]. Li et al. explained the decrease in the solubility of Mg substituted β-TCP by the increased structural stability and the possible formation of a whitlockite-type phase on the surface [15]. In contrast, Mg-substitution enhances the solubility and improved the osteoconductivity and resorption of HA granules [16]. Salimi et al. have reported that Mg 2+ has no effect on the rate of brushite formation [17], but, inhibits brushite dissolution [18]. Brushite is metastable under physiological conditions and undergoes phase transformation to HA [19,20]. The use of poorly-soluble Mg salts in brushite cement was advocated to prevent brushite transformation to hydroxyapatite (HA) as Mg2+ ions bind to mineral nucleating sites preventing their growth [21]. Different systems have been developed to incorporate magnesium ions in brushite cements. One system was developed by mixing Mg-substituted α-TCP with different setting liquids [22]. The phase analysis of the cement produced with 10 wt.% PEG+ 20 wt.% citric acid as the setting liquid resulted in a matrix predominantly composed of Mg-substituted α-TCP (62%), brushite (23%) and β-TCP (15%). Lilly et al. have reacted Mg-substituted HA with phosphoric acid [23] and reported Mg 2+ ions to be incorporated in brushite lattice as evidenced by the increase in the crystal lattice parameters. The cement matrix was composed of brushite, monetite and unreacted HA. In a previous study, we have proved the efficiency of using β-TCP to induce ionic substitution in brushite cements [24]. This approach was recently employed to develop calcium magnesium phosphate cement [25]. The use of citric acid and powder milling were necessary to develop cytocompatible cement with adequate setting time and compressive strength. This could be related to the reduced reactivity of Mg doped β-TCP [26].

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However, detailed structural analysis of brushite crystals to confirm that Mg 2+ substitution occurred in brushite crystals is lacking. For this, we designed this study and employed Mg-substituted TCP powder (Ca3 − xMgx(PO4)2) to induce magnesium substitution in brushite cement. Water instead of acidic solutions was employed as the cement liquid phase so that the only variable parameter would be the magnesium content. The effect of magnesium ions on the structure, and mechanical and setting properties of the new cements was characterized and Ca 2 + and Mg 2+ ion release was studied. We also probed the inclusion of Mg 2+ ions within β-TCP and brushite crystals.

ceramics (Mg-substituted β-TCP, stanfieldite and farringtonite) that could be distinguished according to the Mg/(Ca + Mg) ratio. Scanning electron microscopy (SEM; JSM6400) was employed for morphological analysis of the cement fractural surfaces after DTS testing. The porosity and the distribution of cement pore diameter were determined using high-pressure mercury porosimetry (Micrometrics 9420, UK) and the cement specific surface area (SSA) was determined using the Brunauer–Emmett–Teller method (BET; GEMINI, Micrometrics, USA).

2. Materials and methods

2.4. Mg-doped cement as a matrix for ion release

2.1. Synthesis of Mg doped biomaterials The as purchased (CaHPO4.2H2O, Sigma-Aldrich) and CaCO3 (Sigma-Aldrich) powders were mixed in a molar ratio of 2:1 and thoroughly homogenized in a mortar with a pestle. β-TCP was prepared by sintering the mixture at 1000 °C for 12 h. Mg-substituted β-TCP was produced by replacing brushite with newberyite (MgHPO4.3H2O, Sigma-Aldrich) resulting in a molar Mg/(Mg + Ca) ratio of the reactants between 0 and 66.67%. The (Mg + Ca)/P ratio was maintained constant at 1.5. Thereafter, the sintered ceramics were crushed and sieved with 200 μm pore size-mesh. The as-prepared powder was mixed at an equimolar ratio with MCPM (Sigma-Aldrich) in a mortar with pestle and reacted with water at a powder to liquid ratio (PLR) of 3.0 g.ml −1. Cement samples (10 mm in Φ, 5 mm thick) were produced using rubber silicon molds. 2.2. Handling properties of Mg doped cements For each Mg content, wet diametral tensile strength (DTS) was measured on Pharma Test PTB 311 and calculated from the failure load applied along the diametral plane of samples (n = 5) previously aged in 10 ml of double-distilled water at 37 °C for 24 h. The final setting time of the cement was measured (n = 3) in normal laboratory atmosphere conditions (20–23 °C and 50–60% humidity) using the Vicat needle test with a needle of 1 mm diameter and loaded with 400 g according to international standard ISO 1566 for dental zinc phosphate cement.

Ca 2+ and Mg 2+ ion release from set cement samples (n = 3) was measured daily following immersion of one sample (10 mm in Φ and 5 mm height) into 5 ml deionized water at 37 °C renewing the immersion liquid after every measurement. The Ca 2+ and Mg 2+ concentrations were determined using inductively coupled plasma optical emission spectrometry (ICP-OES) against standard solutions of Ca 2 + and Mg 2+ ions obtained from Merck.

3. Results and discussion 3.1. Composition of Mg-substituted ceramics The analysis of X-ray diffraction patterns of Mg-substituted β-TCP reveals a shift toward higher diffraction angles indicating a decrease in the unit cell volume of β-TCP (Fig. 1). These changes indicate that Mg2+ ions were successfully introduced into the lattice of β-TCP. The diffraction pattern of β-TCP prepared at Mg/[Ca+ Mg] ratio of 6.67% could be assigned to Ca2.71Mg0.29(PO4)2 and to Ca2.589Mg0.41(PO4)2 when prepared at higher substitution ratio (Fig. 1). The ceramic of 13.33%Mg-TCP is only composed of Ca2.589Mg0.41(PO4)2. This would suggest that the maximum degree of magnesium substitution is 13.3% as new calcium magnesium phosphates (farringtonite and stanfieldite) started to appear at higher magnesium content. Magnesium substitution in β-TCP is reported to have a value of 13.7% [27]. The Rietveld refinement of β-TCP showed an almost linear decrease in the cell unit parameters a and c that resulted in a decrease in the cell unit volume, a symptom for Mg 2+ ion inclusion in the crystal lattice of β-TCP (Fig. 2).

2.3. Composition and structure of Mg-doped biomaterials X-ray diffraction patterns were recorded on a Philips X'pert diffractometer (Cu-Ka radiation, 45 kV, 40 mA). Data were collected from 2θ = 10–40° with a step size of 0.02° and a normalized count time of 1 s/step. The mineral composition of TCP powder was checked using structural model files of β-TCP (JCPDS PDF-ref 70–2065), Ca2.71 Mg0.29(PO4)2 (JCPDS PDF-ref 70–682), Ca2.589Mg0.41(PO4)2 (JCPDS PDF-ref 87–1582), Farringtonite (Mg3(PO4)2; JCPDS PDF-ref 33–876) and Stanfieldite (JCPDS PDF-ref 73–1182). Whereas, cement composition was checked using the anterior structural model files in addition to brushite (JCPDS PDF-ref 72–713), monetite (JCPDS PDF-ref 71–1760), and newberyite (JCPDS PDF-ref 35–780). Changes of the lattice parameters of Mg-substituted β-TCP and brushite were determined by Rietveld refinement analysis. Furthermore, transmission electron microscopy (TEM) was employed to perform specific area electron diffraction (SAED) and energy-dispersive X-ray (EDX) analyses of single crystals to sense the presence of Mg ions. The combined use of SAED and EDX analyses was determinant to identify the crystal phase. Thus, the crystals of (Ca + Mg)/P close to 1 where the Ca or Mg content was almost zero could be assigned to either brushite or newberyite, respectively. Otherwise, the mineral could be identified as Mg-substituted brushite. Higher (Ca + Mg)/P ratio could be assigned to calcium magnesium phosphate

Fig. 1. X-ray diffraction patterns of Mg-substituted β-TCP. The most prominent peaks of β-TCP (•), Ca2.71Mg0.29(PO4)2 (#), Ca2.589Mg0.41(PO4)2 (*), stanfieldite (+) and farringtonite (°) are marked.

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Fig. 2. The effect of Mg substitution on β-TCP unit cell parameters and volume.

3.2. Composition of Mg-substituted cements The diffraction patterns of cements prepared are displayed in Fig. 3. These cements are mainly composed of brushite and the increase in Mg content (≥40%) provoked the precipitation of a new magnesium phosphate phase (newberyite; MgHPO4.3H2O). Moreover, the rest of the unreacted Mg-substituted β-TCP could be identified (Fig. 3A). Rietveld refinement of crystal unit cell dimensions is widely used as a probe of ionic substitution in calcium phosphates. Unfortunately, the changes in brushite unit cell volume do not follow a certain tendency and failed to clearly indicate the possible Mg incorporation in

brushite crystals (Table 1). For this, we performed SAED and EDX of single crystals to identify brushite and newberyite crystals. The first EDX analysis showed the presence of a single crystal from cement prepared with 6.67%Mg-TCP where [Ca + Mg]/P is equal to 1. As neither calcium nor Mg content is close to zero the crystal could be assigned to brushite (Mg content of 95%) or newberyite (calcium content of 5%). Although XRD of 6.67%Mg cement showed the cement to be mostly composed of brushite, the SAED analysis increases the probability of the crystal identification as newberyite with calcium content of 5%. Fig. 4 and Table 2 showed the identification of brushite crystals where almost 3% of Ca 2+ ions were substituted by Mg 2+ ions. This is indicative of Mg 2+ ion inclusion within the crystal lattice of brushite. 3.3. Structure of Mg-substituted cements SEM analysis has shown cements prepared with Mg- doped β-TCP to be composed of round like crystals rather than plate-like crystals commonly observed for brushite cements (crystal size 2.5 ± 0.4 μm) (Fig. 5). These crystals have two main diameters of 2.2 ± 0.3 and 17 ± 2 μm (Fig. 5B and 5C). These large round-like crystals within

Table 1 Porosity and lattice parameters of brushite crystals of Mg-substituted cements. CPC made with

Fig. 3. X-ray diffraction patterns of CPCs prepared with Mg-substituted β-TCP. The most prominent peaks of brushite (*), newberyite (+) and Mg-substituted β-TCP (°) are marked.

6.67%Mg-TCP 13.33%Mg-TCP 26.67%Mg-TCP 40%Mg-TCP 53.33%Mg-TCP 66.67%Mg-TCP

Porosity

57% 42% 45% 38% 27% 27%

Lattice parameters a (Å)

b (Å)

c (Å)

β (°)

Volume (Å3)

6.363 6.362 6.362 6.364 6.365 6.364

15.183 15.178 15.177 15.194 15.188 15.179

5.809 5.812 5.812 5.809 5.814 5.813

118.503 118.492 118.542 118.449 118.532 118.524

493.213 493.269 493.041 492.720 493.792 493.345

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Fig. 4. TEM images and SAED patterns of single crystals in brushite cements prepared with 6.67%Mg-TCP, 26.67%Mg-TCP, and 66.67%Mg-TCP (in a downward order).

Table 2 Results of SAED and EDX analyses of single crystals in cements prepared with Mg-doped ceramics. SAED analysis

EDX analysis

Measured d (Å)

hkl

Ca

5.26316 4.34783 3.47826 3.44444 2.18579 7.40741 4.34783 2.94118 2.61438 7.54717 4.76190 4.21053 1.66667

020 102 221 122 214 020 12-1 12-1 150 020 110 12-1 25-3

Mg

P

(Ca + Mg)/P

(Mg/Ca + Mg)%

Mineral

2.43

47.63

49.94

1.0024

95.1%

Newberyite

46.81

1.50

51.68

0,9348

3.1%

Brushite

45.95

1.36

52.69

0,8979

2.9%

Brushite

the matrix of CPC prepared with 53.33%Mg-β-TCP have an average diameter of 11 ± 1 μm. Similar results were explained by the increase of instability of platelet morphology caused by Mg 2+ ion incorporation inducing the acquisition of round-like morphology [28]. Furthermore, we observed a compact surface morphology of cement prepared with 53.33%Mg-β-TCP due to a dense and solid network that fills the cement micropores (Fig. 5D). Furthermore, Hg porosity of brushite cement was 44% with an average pore size of 0.63 μm and 81% of the pores have a diameter lower than 1 μm. This porosity for Mg-substituted cements was increased to 57% for CPC prepared with 6.67% Mg-TCP (Table 1). Interestingly, the increase in Mg content resulted in more dense cements as indicated by the almost linear decrease in porosity to a value of 27% for CPC prepared with 53.33% and 66.67%MgTCP (Table 1). Moreover, the differences in pore diameter distribution are significantly evidenced by the shift toward higher pore diameter for Mg-substituted CPCs (Fig. 6). Brushite cement has a bimodal pore diameter distribution with peaks at 0.22 μm and 0.44 μm. CPC prepared with 6.67%Mg-TCP has also a bimodal distribution with peaks

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Fig. 5. SEM images of the fracture surfaces of CPC recovered from DTS test and prepared with 6.67%Mg-β-TCP (A), 26.67%Mg-β-TCP (B and C), and 53.33%Mg-β-TCP (D).

at 0.82 μm and 1.27 μm where 40% of the pores have a diameter b1 μm. Whereas, CPC prepared with 26.67%Mg-TCP has peaks at 0.82 μm and 1.40 μm with 23% of the pores being smaller than 1 μm. A new peak appeared at 2.20 μm for CPC prepared with 40%Mg-TCP with 17% of the pores b1 μm. This new peak appeared at 1.74 μm for CPC prepared with 53.33%Mg-TCP and 27% of the pores b1 μm (Fig. 6). For CPCs prepared with Mg substitution ≤ 53.33%, 98% of pores have a diameter b 10 μm. Pore diameter distribution of 66.67%Mg-TCP has peaks at 0.82, 1.23, 55 and 216 μm. Interestingly, 5% of pores have a diameter ≥ 10 μm and 39% b 1 μm. The results of SSA measurements pointed out that only CPC prepared with 26.67% had higher SSA (5.85 ± 0.02% m 2.g −1) than brushite cement (5.10 ± 0.01 m 2.g −1). SSA tends to decrease with the increase of Mg content. SSA of 2.441 ± 0.003, 1.80 ± 0.01 and

Fig. 6. Pore diameter distribution of CPC prepared with β-TCP at different degrees of Mg substitution.

0.554 ± 0.004 m 2.g −1 were determined for CPC prepared with 6.67%, 40% and 66.67% Mg-TCP, respectively. These changes could be related to the more compacted morphology and the appearance of large crystals with a diameter of ca. 17 μm within the Mg-substituted cement matrix compared with smaller crystals (ca. 2.5 μm) for brushite cement (Fig. 5).

3.4. Handling properties of Mg-substituted cements The final setting time of brushite cements was significantly increased by Mg substitution in TCP powder (Fig. 7A). This time reached a maximum (> 90 min) for the cement prepared with 13.3%Mg-TCP but decreased to approximately 30 min for CPC prepared with 40% and 53.33%Mg-TCP. The FST was approximately 60 min for CPC prepared with 66.67%Mg-TCP. This increase in the FST could be related to the increase of stability of β-TCP by Mg 2+ ions explained by the formation of whitlockite-type layer on the β-TCP surface [15]. However, the precipitation of newberyite at higher Mg content has resulted in the relative decrease of the cement FST (Fig. 7A). Moreover, the DTS of Mg substituted cements prepared at PLR ratio of 3 g.ml −1 was measured after aging in water (Fig. 7B). The results indicate deterioration in the cement mechanical properties at lower Mg content. Interestingly, the Mg-substituted cements recover the DTS of control brushite cements (1.2 ± 0.2 MPa) at higher Mg content (Fig. 7B). The decrease in the cement DTS due to the incorporation of Mg 2+ ions (Fig. 7B) was also reported by Lilley et al. [23]. This was related to formation of crystal defects that could decrease the microhardness of brushite [29] and to brushite transformation to denser monetite [23]. We also relate this deterioration in the mechanical properties to the increase in cement porosity (Table 1). Herein, we improved this deterioration by the increase of the Mg content in TCP powder until the recovery of DTS of approximately 1.2 MPa (Fig. 7B). We relate this enhancement to the precipitation of newberyite within the cement

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Fig. 7. A: Final setting time (FST) and B: wet diametral tensile strength (DTS) of cements prepared with Mg-substituted β-TCP at PLR ratio of 3 g.ml−1.

Fig. 8. Ca2+ and Mg2+ ion release from CPCs prepared with β-TCP, 26.67%Mg-TCP and 66.67%Mg-TCP.

matrix leading to the formation of a denser cement matrix with a more compacted morphology (Fig. 5D, Table 1). 3.5. Ion release from Mg-substituted cements We have also studied these cements as substrates to release Ca 2+ and Mg 2 + ions by aging in water for 7 days. The ion release from cement samples was significantly affected by the Mg substitution in brushite cements. The Ca 2+ ion release was lowered by the increase in the Mg content while Mg 2+ ion release was higher for CPC prepared with 26.67%-Mg-TCP (Fig. 8). This decrease in Ca 2+ ion release with the increase in Mg content owes to Mg 2+ inhibition of brushite dissolution [18] and the decrease in cement SSA to 0.55 m 2.g −1 for CPC prepared with 66.67%Mg-TCP. The ionic release profile of unsubstituted CPC and CPC prepared with 26.67%-Mg-TCP consisted of an initial burst that switched to a constant rate after 2 days of incubation. Interestingly, CPC prepared with 66.67%Mg-TCP released Ca 2+ (approx. 13 ppm/day) and Mg 2+ ions (approx. 60 ppm/day) at a constant rate over the whole observation period indicating a zero-order release kinetic (Fig. 8). 4. Conclusions Magnesium substituted ceramics are successful to induce the cation substitution of calcium ions in brushite crystals. The presence of magnesium ions significantly inhibits the setting reaction of brushite cements and does not improve the cement diametral tensile strength. Furthermore, the resultant cement is an efficient substrate to release Ca and Mg ions with zero order kinetics. Further research would

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Magnesium substitution in brushite cements.

The use of magnesium-doped ceramics has been described to modify brushite cements and improve their biological behavior. However, few studies have ana...
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