CALCIUM-DEFICIENT SILICATE-SUBSTITUTED CALCIUM PHOSPHATE APATITE COMPOSITIONS AND METHODS
20230270915 · 2023-08-31
Inventors
Cpc classification
A61L2430/02
HUMAN NECESSITIES
C01P2004/61
CHEMISTRY; METALLURGY
C01P2002/72
CHEMISTRY; METALLURGY
C01B33/36
CHEMISTRY; METALLURGY
International classification
Abstract
A calcium-deficient silicate-substituted calcium phosphate apatite composition comprises an apatite phase having a Ca/P molar ratio of from greater than 2.15 to 2.30, and a Ca/(P+Si) molar ratio of from 1.45 to 1.55. A method of producing a calcium-deficient silicate-substituted calcium phosphate apatite composition comprises contacting a silicate-substituted calcium phosphate apatite starting material with an acidic solution to produce the calcium-deficient silicate-substituted calcium phosphate apatite composition. The starting material comprises an apatite phase and up to 15 wt % total of a phase or phases other than the apatite phase, and has a Ca/P molar ratio of from 2.3 to 2.6, and a Ca/(P+Si) molar ratio of from 1.56 to 1.66, and the calcium-deficient silicate-substituted calcium phosphate apatite composition comprises an apatite phase having a Ca/P molar ratio lower than the Ca/P ratio of the starting material apatite phase.
Claims
1. A calcium-deficient silicate-substituted calcium phosphate apatite composition comprising an apatite phase having a Ca/P molar ratio of from greater than 2.15 to 2.30, and a Ca/(P+Si) molar ratio of from 1.45 to 1.55.
2. The composition according to claim 1, wherein the apatite phase has a Ca/P molar ratio of from greater than 2.15 to 2.28, from 2.20 to 2.30, or from 2.20 to 2.28.
3. The composition according to claim 1, wherein the apatite phase has a Ca/(P+Si) molar ratio of from 1.45 to 1.54, or from 1.45 to 1.52.
4. The composition according to claim 1, having a silicon content of 4 to 6 wt %.
5. The composition according to claim 1, densified by sintering at a temperature of from 1100 to 1300° C.
6. The composition according to claim 1, comprising up to 5 wt % total of a phase or phases other than the apatite phase, and the composition has Ca/P molar ratio of from greater than 2.15 to 2.35, and a Ca/(P+Si) molar ratio of from 1.45 to 1.60.
7. The composition according to claim 1, wherein the composition consists or consists essentially of the apatite phase.
8. A method of producing a calcium-deficient silicate-substituted calcium phosphate apatite composition, comprising contacting a silicate-substituted calcium phosphate apatite starting material with an acidic solution to produce the calcium-deficient silicate-substituted calcium phosphate apatite composition, wherein the starting material comprises an apatite phase and has a Ca/P molar ratio of from 2.3 to 2.6, and a Ca/(P+Si) molar ratio of from 1.56 to 1.66, and wherein the calcium-deficient silicate-substituted calcium phosphate apatite composition comprises an apatite phase having a Ca/P molar ratio which is lower than the Ca/P ratio of the starting material apatite phase before contact with the acidic solution.
9. A method according to claim 8, wherein the starting material comprises a silicon atom content of from 4 to 6 wt %.
10. A method according to claim 8, wherein the starting material comprises up to 15 wt % total of a phase or phases other than the apatite phase.
11. A method according to claim 8, wherein the starting material comprises a material according to formula (I):
Ca.sub.10-δ(PO.sub.4).sub.6-x(SiO.sub.4).sub.x(OH).sub.2-y (I) wherein 1.1≤x≤2.0, 1.0≤y 2.0, and δ represents a Ca deficiency.
12. A method according to claim 8, wherein the starting material is a powder with a specific surface area of from 10 to 90 m.sup.2/g.
13. A method according to claim 8, wherein the starting material is a powder with a D.sub.v50 less than 100 μm, or comprises granules having an average particle diameter D.sub.v50 greater than 100 μm.
14. A method according to claim 8, wherein the acidic solution is an aqueous acidic solution.
15. A method according to claim 8, wherein the acidic solution comprises an acid component and a liquid vehicle, wherein the acid component is an acid having a pKa of greater than −1.73.
16. A method according to claim 8, wherein the acidic solution comprises or consists of an aqueous ammonium chloride solution.
17. A method according to claim 16, wherein the aqueous ammonium chloride solution has an ammonium chloride concentration of from 0.01% w/v to 15% w/v.
18. A method according to claim 8, comprising mixing the acidic solution and the starting material in a weight ratio of at least 5:1.
19. A method according to claim 8, comprising incubating the mixture of the starting material and the acidic solution for a predetermined period of time.
20. A method according to claim 19, wherein incubating the mixture comprises heating the incubation mixture to a temperature T.sub.1 and allowing the incubation mixture to remain at temperature T.sub.1 for a time t.sub.1, wherein T.sub.1 is at least 30° C. and t.sub.1 is at least 10 mins.
21. A method according to claim 8, comprising separating the calcium-deficient silicate-substituted calcium phosphate apatite composition from the acidic solution.
22. A method according to claim 8, further comprising one or more steps of sintering the calcium-deficient silicate-substituted calcium phosphate apatite composition at a temperature of at least 100° C.
23. A method according to claim 8, wherein the calcium-deficient silicate-substituted calcium phosphate apatite composition comprises a Ca/(P+Si) molar ratio which is lower than the Ca/(P+Si) ratio of the starting material before contact with the acidic solution.
24. A method according to claim 8, wherein the calcium-deficient silicate-substituted calcium phosphate apatite composition comprises a Ca/P molar ratio of from greater than 2.15 to 2.35 and a Ca/(P+Si) molar ratio of from 1.45 to 1.60.
25. A method according to claim 8, wherein the calcium-deficient silicate-substituted calcium phosphate apatite composition comprises a silicon atom content of from 4 to 6 wt %.
26. A method according to claim 8, wherein the calcium-deficient silicate-substituted calcium phosphate apatite composition comprises an apatite phase having a Ca/P molar ratio of from greater than 2.15 to 2.30, and a Ca/(P+Si) molar ratio of from 1.45 to 1.55.
27. A calcium-deficient silicate-substituted calcium phosphate apatite composition obtained or obtainable by a method according to claim 8.
28.-29. (canceled)
30. A medical device comprising a coating which includes a calcium-deficient silicate-substituted calcium phosphate apatite composition according to claim 1.
31. A macroporous ceramic bone graft substitute comprising a calcium-deficient silicate-substituted calcium phosphate apatite composition according to claim 1.
32. (canceled)
33. A method of treating a disease or disorder requiring the replacement of bone tissue, comprising replacing bone tissue with a calcium-deficient silicate-substituted calcium phosphate apatite composition according to claim 1.
34. A method according to claim 8, wherein the acidic solution improves the thermal stability of the calcium-deficient silicate-substituted calcium phosphate apatite phase.
Description
DESCRIPTION OF THE DRAWINGS
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EXAMPLES
[0132] Aspects and embodiments of the present invention will now be discussed in the following examples. Further aspects and embodiments will be apparent to those skilled in the art. All documents mentioned in this text are incorporated herein by reference.
Example 1—Conversion of Calcined Silicate-Substituted Hydroxyapatite Granules in 5% NH.SUB.4.Cl to Form Non-Sintered New Composition Material
[0133] Granules of silicated calcium phosphate, nominally with x=2.0 in the idealised composition Ca.sub.10(PO.sub.4).sub.6-x(SiO.sub.4).sub.x(OH).sub.2-x, were produced by methods described in U.S. Pat. Nos. 8,545,895 and 9,492,585 (the contents of which are incorporated herein by reference in their entirety) as the starting material. Briefly, for the purpose of this example, this involved the dropwise addition of phosphoric acid solution to a calcium hydroxide suspension containing tetraethyl orthosilicate (TEOS), with a Ca/P molar ratio of 2.45 and a Ca/(P+Si) molar ratio of 1.64, maintaining a pH of between 10 and 11. After ageing overnight, the suspension was filtered to remove water and the collected precipitate was dried overnight in an oven at approximately 80° C. The dried filter cake was then broken into small granules and for the purpose of this example a size fraction of granules with dimensions between 1 and 2 mm was collected by sieving, and calcined in a furnace at 900° C. A sample of this calcined material was taken and denoted Comparative Composition 1.
[0134] Four identical solutions of aqueous ammonium chloride (NH.sub.4Cl) with concentration of 5% were prepared by adding a defined mass (50 g) of NH.sub.4Cl powder to 1000 mL of water in a volumetric flask and mixing until dissolved; these were referred to as Immersion Solutions A, B, C and D. The pH of the immersion solutions were measured with a calibrated pH meter and recorded.
[0135] Granules of Comparative Composition 1 were mixed with each 5% ammonium chloride (NH.sub.4Cl) solution at a ratio of 1:60 (15 g of granules in 900 mL of NH.sub.4Cl solution) and incubated at 37° C. for defined time periods as follows:
TABLE-US-00001 Solution A B C D Incubation time/hours 1 24 72 120
[0136] After incubation, granules from each solution were filtered under vacuum using a Buchner funnel and grade 3 filter paper. The pH of incubation filtrates was recorded and used to calculate the variation of pH relative to the starting pH using Equation 1 below.
Relative pH change=[([pH.sub.f]−[pH.sub.0])/pH.sub.0]×100% Equation 1
where pH.sub.0 and pH.sub.f are the pH values measured from the NH.sub.4Cl solution before granules were added, and post incubation, respectively.
[0137] The granules were then rinsed with distilled water and dried to a constant mass in a drying oven at a temperature of between 60° C. and 80° C. After the drying step, the mass loss of granules was recorded and used to calculate the relative % mass loss using Equation 2.
Relative mass loss=(M.sub.0−M.sub.f)/M.sub.0×100% Equation 2
where M.sub.0 and M.sub.f are the masses of granules before and after incubation, respectively.
[0138] The compositions obtained from this process were denoted Composition 1 (1 h incubation), Composition 2 (24 h incubation), Composition 3 (72 h incubation) and Composition 4 (120 h incubation).
[0139] Samples of the non-sintered new composition granules of Compositions 1-4 were then characterised with X-ray diffraction (XRD) and X-ray fluorescence spectroscopy (XRF), to assess phase purity and composition, and elemental composition, respectively.
[0140] Mass losses from the granules after incubation in the immersion solution ranged from 5 to 8% and showed a trend of increasing mass loss with increased immersion time. The pH of the immersion solution increased after each of the immersion times, reaching a final pH of between 7 and 8, Table 1.
TABLE-US-00002 TABLE 1 pH values of solutions before and after granules were incubated in 5% NH.sub.4Cl solutions. pH of solution pH of solution pH Incubation time before after variation (hours) incubation, pH.sub.0 incubation, pH.sub.f (%) 1 h (solution A) 4.66 7.40 59 24 h (solution B) 4.82 7.44 54 72 h (solution C) 4.63 7.95 72 120 h (solution D) 4.73 7.66 62
[0141] The X-ray diffraction patterns of the non-sintered new composition granules of Compositions 1-4 showed comparable diffraction patterns for the granules before immersion and after each of the immersion times; diffraction patterns showed broad diffraction peaks, indicative of a nano-crystalline material, that matched the reference pattern of hydroxyapatite (ICDD 09-432).
[0142] Elemental composition (Ca/P, Ca/(P+Si) ratios and wt % Si) obtained from XRF analysis performed on samples incubated in 5% NH.sub.4Cl solutions at various time points are summarised in Table 2 below. The composition of the starting material pre-incubation (Comparative Composition 1) is provided for comparison.
TABLE-US-00003 TABLE 2 Ca/P, Ca/(P + Si) molar ratios and wt % Si of samples incubated in 5% NH.sub.4Cl solutions for various time points. Composition Ca/P Ca/(P + Si) wt % Si Comparative 2.43 1.63 5.71 Composition 1 Composition 1 2.34 1.58 5.76 Composition 2 2.32 1.56 5.73 Composition 3 2.28 1.54 5.76 Composition 4 2.25 1.52 5.76
[0143] Immersion of the starting material granules in the 5% NH.sub.4Cl immersion solution resulted in a significant change in the chemical composition of the starting material. Although the silicon (wt % Si) content of the granules remains relatively unchanged, the Ca/P and the Ca/(P+Si) molar ratios decreased significantly with increased immersion time, achieving a Ca/(P+Si) molar ratio of close to 1.5 after 120 hours (Composition 4). The immersion process has an effect of decreasing the relative calcium content of the granules, with a Ca/(P+Si) molar ratio of 1.52-1.56 after 24 hours (Composition 2) that is far from the Ca/(P+Si) molar ratio that is typical for a silicate-substituted hydroxyapatite of 1.63-1.68.
[0144] The non-sintered new composition granules produced by this immersion process can be described as a nano-crystalline silicated calcium-deficient hydroxyapatite. This Example shows that the final composition of the material can be controlled by the incubation time in the immersion solution.
Example 2—Conversion of Calcined Silicate-Substituted Hydroxyapatite Granules in 5% NH.SUB.4.Cl to Form Sintered New Composition Material
[0145] In this Example Compositions 1-4 produced in Example 1 were subjected to a sintering treatment by heating samples in a furnace at temperatures between 900 and 1250° C. Sintering these new compositions will not affect the chemical compositions described in Table 1, but will affect the phase composition. Sintered Compositions 1S, 2S, 3S and 4S were prepared by sintering Compositions 1, 2, 3 and 4 respectively at 1250° C. X-ray diffraction patterns of Compositions 1S, 2S, 3S and 4S are shown in
[0146] The sintered new composition granules of Compositions 1S, 2S, 3S and 4S produced by this immersion process can be described as a crystalline silicated calcium-deficient hydroxyapatite. The final composition, specifically the conditions to produce a single phase hydroxyapatite-like phase, can be controlled by the incubation time in the immersion solution.
Example 3—Conversion of Non-Calcined Silicate-Substituted Hydroxyapatite Granules in 5% NH.SUB.4.Cl to Form Non-Sintered or Sintered New Composition Material
[0147] Granules were produced in a similar way to those described in Example 1, but the granules were not calcined prior to incubating in the immersion solution (i.e. the step of calcining the granules at 900° C. was omitted). Non-calcined granules were incubated in 5% NH.sub.4Cl immersion solution for 120 hours, then samples were collected by filtration, washed with water then dried in an oven at a temperature of between 60° C. and 80° C., to provide a composition which was denoted Composition 5. Elemental composition (Ca/P, Ca/(P+Si) ratios and wt % Si) obtained from XRF analysis and phase composition analysis by XRD of Composition 5 showed a similar phase composition and chemical composition to that observed in Compositions 1-4. Composition 5 was then sintered at 1250° C. to provide sintered granules denoted Composition 5S; XRD analysis showed that the same single phase hydroxyapatite-like composition was formed in Composition 5S as was observed in Compositions 3S and 4S of Example 2.
[0148] The results showed that the initial calcination of the starting material before incubation did not significantly affect the chemical and phase composition of the new composition after incubation in the 5% NH.sub.4Cl immersion solution for 120 hours, both non-sintered or after sintering at 1250° C.
Example 4—Effect of the Form of the Starting Material on the Conversion of Calcined Silicate-Substituted Hydroxyapatite Granules in 5% NH.SUB.4.Cl to Form Non-Sintered or Sintered New Composition Material
[0149] Filter cake was produced as described in Example 1, but it was not granulated, rather it was calcined at 900° C. as a monolith filter cake. Calcined filter cake was then incubated in 5% NH.sub.4Cl immersion solution for 120 hours and compared to the incubated calcined granules from Example 1 (Composition 4). Samples were collected by filtration, washed with water then dried in an oven at a temperature of between 60° C. and 80° C. Elemental composition (Ca/P, Ca/(P+Si) ratios and wt % Si) obtained from XRF analysis performed on samples incubated in 5% NH.sub.4Cl solutions at various time points are summarised in Table 3 below.
TABLE-US-00004 TABLE 3 Ca/P, Ca/(P + Si) molar ratios and wt % Si of samples with starting material in the form of calcined granules or calcined filtercake incubated in 5% NH.sub.4Cl solution for 120 hours. Form of the starting material Ca/P Ca/(P + Si) wt % Si Granules 2.25 1.52 5.76 (Composition 4) Filtercake 2.25 1.52 5.90
[0150] The form that the starting material was in did not significantly affect the new composition after incubation in the 5% NH.sub.4Cl immersion solution for 120 hours.
Example 5—Effect of NH.SUB.4.Cl Immersion Solution Concentration on the Conversion of Non-Calcined Silicate Substituted HA Granules to Form Non-Sintered or Sintered New Composition Material
[0151] The effect of the concentration of the NH.sub.4Cl immersion solution on the conversion of calcined silicate-substituted HA granules to form new composition material was studied using an incubation time of 24 hours. Calcined starting material granules were incubated in NH.sub.4Cl immersion solutions as described in Example 1, with a range of NH.sub.4Cl solution concentrations from 0 (water), 0.01%, 1%, 5% and 10%, for a period of 24 hours. Granules were collected by filtration, washed with water, then dried in an oven at a temperature of between 60° C. and 80° C.
[0152] The compositions obtained by this process were denoted Comparative Composition 2 (incubation in water alone), Composition 6 (incubation in 0.01% NH.sub.4Cl solution), Composition 7 (incubation in 1% NH.sub.4Cl solution), Composition 8 (incubation in 5% NH.sub.4Cl solution) and Composition 9 (incubation in 10% NH.sub.4Cl solution).
[0153] The chemical composition of the material was then determined by XRF analysis; the results presented as Ca/P, Ca/(P+Si) molar ratios and wt % Si are presented in Table 4. As for the effect of incubation time in Example 1, the silicon content (wt % Si) of the new composition materials was not significantly affected by the concentration of the NH.sub.4Cl immersion solution. The Ca/P and the Ca/(P+Si) molar ratios decreased significantly with increased concentration of the NH.sub.4Cl immersion solution, although a concentration of 1% was required to result in a significant decrease in the Ca/P molar ratio (Composition 7) and concentration of 5% was required to result in a significant decrease in the Ca/(P+Si) molar ratio (Composition 8). The concentration of the NH.sub.4Cl immersion solution has an effect of decreasing the relative calcium content of the granules, with a Ca/(P+Si) molar ratio of 1.50-1.56 after 24 hours for 5 and 10% NH.sub.4Cl immersion solution (Compositions 8 and 9) that is far from the Ca/(P+Si) molar ratio that is typical for a silicate-substituted hydroxyapatite of 1.63-1.68.
TABLE-US-00005 TABLE 4 Ca/P, Ca/(P + Si) molar ratios and wt % Si of samples incubated for 24 hours in 0.01, 1, 5, 10% NH.sub.4Cl solutions. Composition Ca/P Ca/(P + Si) wt % Si Comparative 2.43 1.63 5.71 Composition 1 Comparative 2.41 1.61 5.71 Composition 2 (immersion in water) Composition 6 2.40 1.60 5.72 Composition 7 2.35 1.59 5.67 Composition 8 2.32 1.56 5.73 Composition 9 2.22 1.50 5.76
[0154] The non-sintered new composition granules of Compositions 6-9 produced by this immersion process can be described as a nano-crystalline silicated calcium-deficient hydroxyapatite. This Example shows that the final composition can be controlled by the concentration of acid in the immersion solution and/or the incubation time. For example, Composition 9, treated with 10% ammonium chloride for 24 hours and resulting in a chemical composition with Ca/P=2.22 and Ca/(P+Si)=1.50, was comparable with Composition 4 from Example 1, treated with 5% ammonium chloride for 120 hours and resulting in a chemical composition with Ca/P=2.25 and Ca/(P+Si)=1.52. Both treatments provided a calcium-deficient silicate-substituted calcium phosphate composition.
Example 6—Effect of the Chemical Composition of the Starting Material on the Conversion to a New Composition Material by Incubating in an Immersion Solution
[0155] The effect of the composition of the starting material used on the composition of the material after incubation in the immersion solution was studied by incubating starting materials with various values of x (0, 0.3, 1.4 and 2) in the idealised composition Ca.sub.10(PO.sub.4).sub.6-x(SiO.sub.4).sub.x(OH).sub.2-x in 5% NH.sub.4Cl immersion solution for 120 hours. Each of the starting material compositions were synthesised using a similar process to that described in Example 1, except the relative amounts of reagents were varied in accordance with the final desired composition. Samples of the compositions after calcination at 900° C. but before immersion in any solution were also taken and analysed; these were denoted Comparative Composition 3A (x=0), Comparative Composition 4A (x=0.3), Comparative Composition 5A (x=1.4). Comparative Composition 1 from Example 1 was used for the x=2.0 pre-immersion sample.
[0156] Starting material granules that had been calcined at 900° C. were incubated in 5% NH.sub.4Cl immersion solutions as described in Example 1, for a period of 120 hours. Granules were collected by filtration, washed with water, then dried in an oven at a temperature of between 60° C. and 80° C.
[0157] Composition 4 prepared in Example 1 was used as the x=2.0 sample. The new compositions prepared in the present Example were denoted Comparative Composition 3B (x=0), Comparative Composition 4B (x=0.3) and Comparative Composition 5B (x=1.4).
[0158] The chemical composition of the materials were then determined by XRF analysis; the results presented as Ca/P, Ca/(P+Si) molar ratios and wt % Si are presented in Table 5.
[0159] Of note, the compositions with no silicon in the starting material (Comparative Composition 3A) or a low level of silicon (x=0.3, or approximately 0.8 wt % Si; Comparative Composition 4A) were unaffected by the immersion process. This is important as Comparative Composition 3A corresponds to hydroxyapatite which has been studied for over 40 years as a bone replacement material, and Comparative Composition 4A corresponds to a silicate-substituted hydroxyapatite composition that has been studied as a bone replacement material for over 20 years. The immersion process described here clearly does not have a significant effect on the chemical composition of these two starting materials.
[0160] For a starting material with a composition of x=1.4 (Comparative Composition 5A), the immersion process in 5% NH.sub.4Cl for 120 hours had a similar effect to the starting material with a composition of x=2.0 (Comparative Composition 1), with a decrease in the Ca/P and the Ca/(P+Si) molar ratios, resulting in a new composition (Comparative Composition 5B), although the Ca/(P+Si) molar ratio does not approach a value close to 1.5 as was observed with x=2.0 for incubation times of 72-120 hours for 5% NH.sub.4Cl (Compositions 3 and 4, Example 1), or 24 hours for 10% NH.sub.4Cl (Composition 9, Example 5).
TABLE-US-00006 TABLE 5 Ca/P, Ca/(P + Si) molar ratios and wt % Si of samples incubated for 120 hours in 5% NH.sub.4Cl solution, produced with starting materials of different composition; the value of x was varied from 0 to 2 in the idealised composition Ca.sub.10(PO.sub.4).sub.6−x(SiO.sub.4).sub.x(OH).sub.2−x Value of x in Ca/ wt % Composition Ca.sub.10(PO.sub.4).sub.6−x(SiO.sub.4).sub.x(OH).sub.2−x] Ca/P (P + Si) Si Comparative Composition 3A 0 1.69 1.69 0 (starting material) Comparative Composition 3B 0 1.70 1.70 0 (incubated) Comparative Composition 4A 0.3 1.74 1.66 0.74 (starting material) Comparative Composition 4B 0.3 1.74 1.67 0.71 (incubated) Comparative Composition 5A 1.4 2.15 1.65 3.98 (starting material) Comparative Composition 5B 1.4 2.03 1.60 3.67 (incubated) Comparative Composition 1 2.0 2.43 1.63 5.71 Composition 4 2.0 2.25 1.52 5.76 (incubated)
[0161] The effect of the starting material composition on the phase composition of the material produced after the immersion process was negligible, with the diffraction patterns of Comparative Compositions 3B, 4B, 5B and 4 and Comparative Composition 1 showing no significant difference in the patterns.
[0162] The new composition granules produced by this immersion process can be described as a nano-crystalline silicated calcium-deficient hydroxyapatite. The final composition of the new composition granules can be controlled by the chemical composition of the starting material subjected to the immersion process for certain compositions, whereas some starting material composition, such as x=0 or x=0.3, are largely unaffected by the immersion process.
[0163] Comparative Composition 3B, Comparative Composition 4B and Comparative Composition 5B were then sintered at 1250° C. to prepare Comparative Composition 3S, Comparative Composition 4S and Comparative Composition 5S respectively. These sintered compositions and sintered Composition 4S from Example 2 were studied with XRD. Sintering the various compositions at 1250° C. after the immersion treatment had a notable effect on some compositions. For the two compositions with no silicon in the starting material (Comparative Composition 3B) or a low level of silicon (Comparative Composition 4B), the phase composition and diffraction peak shape remained unchanged after sintering at 1250° C., with Comparative Compositions 3S and 4S showing sharp diffraction peaks that matched the reference pattern of hydroxyapatite (ICDD 09-432),
[0164] This data confirms that the immersion process has little effect on starting materials with no or only small amounts of silicon substitution (x=0 and x=0.3), but for higher levels of silicon substitution (x=2.0), the immersion process changes the chemical composition significantly and results in the high thermal stability of a hydroxyapatite-like phase after sintering at 1250° C. Intermediate compositions, such as x=1.4, do undergo a change in chemical composition after the immersion process but the phase composition after sintering at 1250° C. does not produce a hydroxyapatite-like phase, but rather results in the formation of the phase silicocamotite.
Example 7—Effect of the Phase Composition of the Starting Material on the Conversion to a New Composition Material by Incubating in an Immersion Solution
[0165] Synthesis of calcium phosphates by methods such as aqueous precipitation sometimes results in products that contain small amounts of impurity phases which may affect the properties of the target phase composition. The feasibility of using starting material that contains a small amount of phase impurities, that could be considered as “out of specification” batches by conventional hydroxyapatite standards, to form the new composition product, was assessed. Two compositions similar to that described in Example 1 were prepared, but with a deficiency (Composition 11) and an excess (Composition 12) of calcium in the reaction mixture, respectively. The precipitated suspension was processed to calcined granules in a similar manner to the granules in Example 1, resulting in impurity phases of tricalcium phosphate or calcium oxide for the deficiency or excess of calcium in the reaction mixture, respectively. Samples of the materials were taken after initial calcination but before immersion in NH.sub.4Cl solution, as Comparative Composition 11 (calcium deficiency) and Comparative Composition 12 (calcium excess).
[0166] The granules were then incubated in 5% NH.sub.4Cl immersion solution for 120 hours in a similar manner. Samples were collected by filtration, washed with water then dried in an oven at a temperature of between 60° C. and 80° C. to provide Compositions 11 and 12. Elemental composition (Ca/P, Ca/(P+Si) ratios and wt % Si) obtained from XRF analysis are summarised in Table 6 below.
TABLE-US-00007 TABLE 6 Ca/P, Ca/(P + Si) molar ratios and wt % Si of samples from starting materials with different phase compositions before incubation and after incubation in 5% NH.sub.4Cl solutions for 120 hours. Ca/(P + Composition Ca/P Si) wt % Si Comparative Composition 1 2.43 1.63 5.71 (Example 1) Composition 4 (Example 1) 2.25 1.52 5.76 Ca-deficient compositions Comparative 2.38 1.60 5.76 Composition 11 Composition 11 2.24 1.52 5.69 Ca-rich compositions Comparative 2.49 1.65 5.77 Composition 12 Composition 12 2.28 1.53 5.84
[0167] The Ca/P and Ca/(P+Si) molar ratios of the starting material before incubation from Example 1 (Comparative Composition 1) falls between the values for the Ca-deficient composition (Comparative Composition 11) and the Ca-rich composition (Comparative Composition 12), whereas the silicon contents (wt % Si) were comparable. Incubation in the 5% NH.sub.4Cl immersion solution for 120 hours resulted in a decrease in the Ca/P and Ca/(P+Si) molar ratios of all the products to very comparable values. This shows that the immersion process can utilise starting materials that contain an excess or a deficiency of calcium but that after the incubation in the immersion solution, a similar chemical composition can be obtained. This was confirmed by XRD analysis of the compositions produced by the immersion process and sintered to 1250° C., where diffraction patterns of a single phase hydroxyapatite-like phase similar to that in
Example 8—Effect of Properties of Material after Conversion and Heat Treatment—Surface Area and Porosity and Osteoinductivity
[0168] The microstructure of the granules of Composition 4S produced in Example 2 was analysed using SEM. The surface area of the granules was measured by nitrogen gas adsorption using the BET Method (ASTM C1274-12(2020), Standard Test Method for Advanced Ceramic Specific Surface Area by Physical Adsorption). The microstructure shows fused/sintered granules approximately 1-2 μm in size, with significant porosity between areas of fused granules; some regions of more densely sintered granules were evident,
[0169] To assess the ability of the new composition to induce the formation of bone in vivo (osteoinduction), 1 cc of the granules of Composition 4S were implanted into muscle defects in sheep. After 12 weeks the explants were fixed, decalcified, embedded in paraffin, and cut into histological sections and stained using a tetrachrome stain that stains new bone/osteoid as a deep blue colour. A representative histology section is shown in
[0170] The features disclosed in the foregoing description, or in the following claims, or in the accompanying drawings, expressed in their specific forms or in terms of a means for performing the disclosed function, or a method or process for obtaining the disclosed results, as appropriate, may, separately, or in any combination of such features, be utilised for realising the invention in diverse forms thereof.
[0171] While the invention has been described in conjunction with the exemplary embodiments described above, many equivalent modifications and variations will be apparent to those skilled in the art when given this disclosure. Accordingly, the exemplary embodiments of the invention set forth above are considered to be illustrative and not limiting. Various changes to the described embodiments may be made without departing from the spirit and scope of the invention.
[0172] For the avoidance of any doubt, any theoretical explanations provided herein are provided for the purposes of improving the understanding of a reader. The inventors do not wish to be bound by any of these theoretical explanations.
[0173] Any section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.
[0174] Throughout this specification, including the claims which follow, unless the context requires otherwise, the words “have”, “comprise”, and “include”, and variations such as “having”, “comprises”, “comprising”, and “including” will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.
[0175] It must be noted that, as used in the specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Ranges may be expressed herein as from “about” one particular value, and/or to “about” another particular value. When such a range is expressed, another embodiment includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by the use of the antecedent “about,” it will be understood that the particular value forms another embodiment. The term “about” in relation to a numerical value is optional and means, for example, +/−10%.
[0176] The words “preferred” and “preferably” are used herein refer to embodiments of the invention that may provide certain benefits under some circumstances. It is to be appreciated, however, that other embodiments may also be preferred under the same or different circumstances. The recitation of one or more preferred embodiments therefore does not mean or imply that other embodiments are not useful, and is not intended to exclude other embodiments from the scope of the disclosure, or from the scope of the claims.