Tricalcium phosphate biological ceramic as well as preparation method and application thereof

Abstract

The invention provides a tricalcium phosphate biological ceramic as well as a preparation method and application thereof. The tricalcium phosphate biological ceramic is prepared by the following method: (1) reacting calcium nitrate tetrahydrate with diammonium hydrogen phosphate to generate a tricalcium phosphate precursor, and calcining and ball-milling to obtain beta-tricalcium phosphate powder; (2) uniformly mixing the beta-tricalcium phosphate powder and the binder solution so as to obtain slurry; (3) uniformly mixing the slurry and a pore-forming material, and drying to obtain a ceramic blank; and (4) sintering the ceramic blank and cooling to room temperature to obtain the tricalcium phosphate biological ceramic. The prepared tricalcium phosphate biological ceramic has better mechanical properties.

Description

Technical Field

[0001] The present invention relates to the field of biomedical technology, and particularly to a tricalcium phosphate bioceramic and its preparation method and application. Background Art

[0002] Calcium phosphate bioceramics are a class of materials with excellent biocompatibility and bioactivity, and are widely used in the fields of orthopedics and dentistry. Their main components include hydroxyapatite (HA, Ca / P atomic ratio of 1.67) and β-tricalcium phosphate (β-TCP, Ca / P atomic ratio of 1.5), or a biphasic composite (BCP) of both, which can form chemical bonds with natural bone and promote bone tissue regeneration. Such materials are biodegradable, and the degradation rate can be adjusted by the composition ratio, and are suitable for scenarios such as bone defect filling, dental implants, and drug sustained-release carriers. The vast majority of calcium phosphate bioceramics are composite materials composed of tricalcium phosphate and hydroxyapatite composites. Limited by processes and technologies, pure calcium phosphate bioceramics are not common.

[0003] Therefore, the preparation process of calcium phosphate bioceramics needs to be improved. Summary of the Invention

[0004] The present invention aims to solve at least one of the technical problems in the related art to a certain extent. The present invention provides a tricalcium phosphate bioceramic, which is prepared only by tricalcium phosphate, a binder, and a pore-forming agent; the prepared bioceramic has better mechanical properties.

[0005] In a first aspect of the present invention, a preparation method of a tricalcium phosphate bioceramic is provided, including:

[0006] (1) Reacting calcium nitrate tetrahydrate and diammonium hydrogen phosphate to generate a tricalcium phosphate precursor, and obtaining β-tricalcium phosphate powder through calcination and ball milling treatment;

[0007] (2) Mixing the β-tricalcium phosphate powder and a binder solution evenly to obtain a slurry;

[0008] (3) Mixing the slurry and a pore-forming material evenly and drying to obtain a ceramic green body;

[0009] (4) Sintering the ceramic green body and cooling it to room temperature to obtain the tricalcium phosphate bioceramic.

[0010] According to an embodiment of the present invention, the preparation method of the tricalcium phosphate bioceramic provided above may further include the following technical features:

[0011] According to an embodiment of the present invention, the binder solution is selected from a binder solution composed of at least one of aluminum oxide, magnesium oxide, phosphorus pentoxide, silicon oxide, sodium oxide, calcium oxide, aluminum phosphate, polyvinyl alcohol, or a ceramic binder.

[0012] According to an embodiment of the present invention, the mass ratio of the β-tricalcium phosphate powder to the binder in the binder solution is (40 - 70):(0.1 - 10).

[0013] According to an embodiment of the present invention, the pore-forming material is selected from at least one of polymethyl methacrylate, stearic acid, and polyurethane organic foam. According to an embodiment of the present invention, the particle size of the polymethyl methacrylate is 100 - 1000 microns.

[0014] According to an embodiment of the present invention, the mass ratio of the β-tricalcium phosphate powder to the pore-forming material is (2 - 3):1.

[0015] According to an embodiment of the present invention, the sintering is carried out by a multi-stage sintering method or a one-step sintering method;

[0016] Wherein the multi-stage sintering method includes: heating to 260°C and holding for 320 min, 290°C and holding for 120 min, 400°C and holding for 300 min, 600°C and holding for 180 minutes respectively, then heating to 1150°C and holding for 180 minutes; finally cooling to 1000°C in 75 minutes and cooling to room temperature;

[0017] The one-step sintering method includes: heating from room temperature to 1150°C at a rate of 5°C / minute and holding for 180 minutes, then cooling to room temperature.

[0018] According to an embodiment of the present invention, step (1) includes:

[0019] Providing an aqueous solution of calcium nitrate tetrahydrate and an aqueous solution of diammonium hydrogen phosphate;

[0020] Dropping the aqueous solution of diammonium hydrogen phosphate into the continuously stirred aqueous solution of calcium nitrate tetrahydrate at a rate of 1 - 2 drops / second, and adjusting the pH to between 6.5 and 8.0 with ammonia water;

[0021] After the dropping is completed, continue to stir and react for 3 - 8 hours, and keep the pH at 6.5 - 8.0 to obtain a reaction solution;

[0022] Based on the reaction solution, a precipitate is obtained, washed and dried to obtain a dry powder;

[0023] The dry powder is calcined and ball-milled to obtain the β-tricalcium phosphate powder.

[0024] According to an embodiment of the present invention, the concentration of the calcium nitrate tetrahydrate aqueous solution is 0.6 mol / L; the concentration of the diammonium hydrogen phosphate solution is 0.4 mol / L.

[0025] According to an embodiment of the present invention, the volume ratio of the calcium nitrate tetrahydrate solution to the diammonium hydrogen phosphate solution is 1:0.6.

[0026] According to an embodiment of the present invention, the drying is carried out at a temperature of 80 - 90 °C for 48 hours;

[0027] The calcination is carried out by heating to 800 - 1000 °C at a rate of 5 °C per minute, calcining for 2 - 3 hours, and then cooling naturally;

[0028] The ball milling treatment is carried out at a rotational speed of 200 - 500 revolutions per minute for 2 - 4 hours.

[0029] A second aspect of the present invention provides a tricalcium phosphate bioceramic obtained according to the preparation method described in the first aspect.

[0030] A third aspect of the present invention provides the application of the tricalcium phosphate bioceramic described in the second aspect above in the preparation of tissue defect repair materials.

[0031] The beneficial effects achieved by the present invention are at least:

[0032] (1) The tricalcium phosphate bioceramic prepared by applying the method provided by the present invention has better mechanical properties;

[0033] (2) The tricalcium phosphate prepared by applying the method provided by the present invention has higher purity. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figure 1 is a schematic diagram of the appearance of the tricalcium phosphate bioceramic prepared according to Example 1 of the present invention.

[0035] Figure 2 is a scanning electron microscope image of the tricalcium phosphate bioceramic prepared according to Example 2 of the present invention. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0036] The embodiments of the present invention will be described in detail below. The examples of the embodiments are shown in the drawings. The embodiments described below with reference to the drawings are exemplary and are intended to explain the present invention and should not be construed as limiting the present invention.

[0037] The present invention provides a method for preparing a tricalcium phosphate bioceramic, including:

[0038] (1) React calcium nitrate tetrahydrate with diammonium hydrogen phosphate to generate a β-tricalcium phosphate precursor, and obtain β-tricalcium phosphate powder through calcination and ball milling;

[0039] (2) Mix the β-tricalcium phosphate powder evenly with the binder solution to obtain a slurry;

[0040] (3) Mix the slurry evenly with the pore-forming material and dry it to obtain a ceramic green body;

[0041] (4) Sinter the ceramic green body and cool it to room temperature to obtain β-tricalcium phosphate bioceramics.

[0042] The prepared β-tricalcium phosphate bioceramics have a porous surface and can be fabricated into various shapes, including one or any combination of regular geometric shapes and irregular geometric shapes. The regular geometric shapes include cylinders, cubes, cuboids, and spheres. The total porosity of the provided bioceramics is 40%-60%.

[0043] The binders used include one or more of the following: aluminum oxide Al2O3, magnesium oxide MgO, phosphorus pentoxide P2O5, silicon dioxide SiO2, sodium oxide Na2O, calcium oxide CaO, aluminum phosphate AlPO4, polyvinyl alcohol (PVA), and ceramic binders.

[0044] According to the preferred embodiment, the binders used are polyvinyl alcohol and ceramic binders, etc., which are safer than phosphorus pentoxide or sodium oxide.

[0045] According to the specific embodiment, the mass ratio of the β-tricalcium phosphate powder to the binder solution is (40-70):(0.1-10). During the research process, it was found that if too much binder is added, resulting in uneven mixing, it will affect the mechanical properties of the prepared β-tricalcium phosphate bioceramics; if too little binder is added, the bonding effect is poor and the mechanical properties of the ceramics are not good.

[0046] In step (2), after mixing the β-tricalcium phosphate powder with the binder solution, stir for 2-3 h or ball mill for 1 h until the powder is evenly dispersed to obtain a slurry with appropriate viscosity and no bubbles in the dispersion system.

[0047] The obtained slurry is mixed evenly with the pore-forming material and dried at 60-80 °C for 1-2 h, and stirred every 10-20 min to make the slurry coating evenly mixed with the pore-forming material to obtain a ceramic green body. The obtained ceramic green body is first placed in an oven at 80 °C and dried overnight, and then sintered and cooled to room temperature.

[0048] The pore-forming materials used include one or more of the following: polymethyl methacrylate (PMMA), stearic acid, and polyurethane organic foam. According to a specific embodiment, the particle size of the PMMA is 100-1000 microns.

[0049] If polyurethane organic foam is used as the pore-forming material, the polyurethane organic foam can be immersed in the slurry with no excessive extra slurry. If PMMA is used as the pore-forming material, the mass ratio of the β-tricalcium phosphate powder to the pore-forming material is (2-3):1. During the research process, it was found that if the addition amount of the pore-forming material is too small, the prepared tricalcium phosphate bioceramics have fewer pores; if the addition amount of the pore-forming material is too large, the mechanical properties of the prepared tricalcium phosphate bioceramics are poor.

[0050] The sintering is carried out by a multi-stage sintering method or a one-step sintering method; for the multi-stage sintering method, the temperature is raised to 260°C and held for 320 min, 290°C and held for 120 min, 400°C and held for 300 min, 600°C and held for 180 minutes, then the temperature is raised to 1150°C and held for 180 minutes. Finally, the temperature is lowered to 1000°C in 75 minutes and cooled naturally in the furnace to room temperature. For the one-step sintering method, it is to raise the temperature from room temperature to 1150°C at a rate of 5°C / minute and hold for 180 minutes, and finally cool naturally in the furnace to room temperature. During the research process, it was found that if the sintering temperature is not appropriate, it may cause the pore-forming material such as PMMA to rapidly disintegrate during sintering, thus affecting the mechanical properties of the tricalcium phosphate bioceramics. The tricalcium phosphate content in the provided tricalcium phosphate bioceramics is as high as 98% or even more than 99%, with very high purity, showing many advantages. The provided tricalcium phosphate bioceramics can be used in orthopedics, ophthalmology, and stomatology for the repair of tissue defects.

[0051] For example, the degradation rate of tricalcium phosphate in the body is relatively fast, and it can release calcium and phosphate ions faster. These ions can participate in the physiological metabolic process in the body and promote the formation of new bone tissue, showing high biological activity. Moreover, the biocompatibility is better. β-tricalcium phosphate has good biocompatibility, can interact well with human tissues, and rarely causes immune reactions or inflammatory reactions. It can be gradually absorbed in the body, while guiding tissue regeneration, and is finally completely replaced by the newly formed bone tissue. Good processability: Tricalcium phosphate bioceramics are relatively easy to process and form, and can be made into implants of various shapes and sizes to meet the repair needs of different bone defect sites. For example, according to the specific situation of the patient's bone defect, β-TCP can be made into customized block, granular or porous scaffold forms, which are convenient for surgical implantation operations.

[0052] According to a specific embodiment, the β-tricalcium phosphate powder used can be prepared by the following steps:

[0053] Prepare a 0.6 mol / L aqueous solution of calcium nitrate tetrahydrate as the Ca solution; a 0.4 mol / L solution of diammonium hydrogen phosphate as the P solution;

[0054] Drop the P solution into the continuously stirred Ca solution at a rate of 1 - 2 drops per second; adjust the pH to between 6.5 and 8.0 with ammonia water. After the addition of the P solution is complete, continue to stir the reaction solution for 3 - 8 hours and always keep the pH within this range; the volume ratio of the Ca solution to the P solution is 1:0.6;

[0055] Centrifuge or filter the obtained reaction solution to obtain a white precipitate, then wash it three times with purified water to remove impurity ions, and finally dehydrate and wash it three times with absolute ethanol. Dry the washed precipitate in an oven at 80 - 90 °C for 48 hours;

[0056] Place the dried powder obtained in the above steps in a muffle furnace and calcine it at a temperature of 800 - 1000 °C for 2 - 3 hours with a heating rate of 5 °C per minute, and then cool it naturally with the furnace; use a ball mill to mill the prepared calcium phosphate powder for 2 hours at a ball mill rotation speed of 200 - 500 revolutions per minute, and finally obtain calcium phosphate powder with uniform particle size.

[0057] The technical solution of the present invention will be described below through specific examples. It should be noted that these examples are only for the convenience of those skilled in the art to understand and should not be regarded as a limitation of the protection scope of the present invention. Unless otherwise specified, the reagents used in the examples can be obtained through commercial purchase.

[0058] Example 1

[0059] β - tricalcium phosphate powder was prepared in Example 1 by the following method.

[0060] First, prepare β - tricalcium phosphate powder through the following steps:

[0061] Prepare 1 L of a 0.6 mol / L aqueous solution of calcium nitrate tetrahydrate (Ca solution), and stir the Ca solution until the particles are completely dissolved; prepare 600 mL of a 0.4 mol / L solution of diammonium hydrogen phosphate (P solution), and stir the P solution until the particles are completely dissolved;

[0062] Drop the P solution into the continuously stirred Ca solution at a rate of 1 - 2 drops per second; adjust the pH to 7.5 ± 0.1 with ammonia water. After the addition of the P solution is complete, continue to stir the reaction solution for 3 hours and always keep the pH within this range to obtain a reaction solution;

[0063] Centrifuge the obtained reaction solution to obtain a white precipitate, then wash it three times with purified water to remove impurity ions, and finally dehydrate and wash it three times with absolute ethanol. Dry the washed precipitate in an oven at 90 °C for 48 hours to obtain a dried powder;

[0064] The obtained dry powder was placed in a muffle furnace and calcined at 900 °C for 2 hours, with a heating rate of 5 °C / minute, and then cooled naturally with the furnace; the prepared calcium phosphate powder was ball-milled for 2 hours using a ball mill at a ball-milling speed of 300 revolutions per minute, and finally β-tricalcium phosphate powder with uniform particle size (all of which can pass through a 60-mesh sieve) was obtained.

[0065] Then, using the prepared β-tricalcium phosphate powder, tricalcium phosphate bioceramics were prepared by the following method:

[0066] 1) Prepare the binder solution: Weigh 0.8 g of Al2O3, 0.9 g of MgO, and 6.6 g of P2O5; slowly add 160 mL of purified water, and stir for 3 hours to obtain the binder solution for standby.

[0067] 2) Weigh 6 g of β-tricalcium phosphate powder, add 9 mL of the binder solution, and add 1 - 2 mL of purified water, and stir for 2 h until the powder is uniformly dispersed to obtain a slurry without bubbles;

[0068] 3) Take an appropriate amount of the above slurry and mix it with the polyurethane foam cut to the appropriate size, with the density of the polyurethane foam being 30 ppi - 60 ppi. Dry it at 70 °C for 1 - 2 h, and turn the polyurethane foam over every 10 min to prevent the slurry from depositing at the bottom to obtain a ceramic blank. Place it in an oven at 80 °C and dry it overnight.

[0069] 4) Sinter the blank from the previous step at 1000 °C for 3 h, and finally cool it naturally with the furnace to room temperature. The obtained sample is as Figure 1 shown.

[0070] A comparative test of the mechanical properties was carried out with the reference sample (commercially available product), and the test results are as follows, and the test was determined five times.

[0071] Table 1 Mechanical Property Test

[0072]

[0073]

[0074] At the same time, the following physicochemical characterizations were carried out, and items 1 - 5 in Table 2 refer to the test standard of YY / T 0683 - 2008.

[0075] Table 2 Physicochemical Property Test

[0076]

[0077] Example 2

[0078] Tricalcium phosphate bioceramics were prepared in Example 1 by the following method.

[0079] First, prepare β-tricalcium phosphate powder through the following steps:

[0080] Prepare 1 L of 0.6 mol / L calcium nitrate tetrahydrate aqueous solution (Ca solution), and stir the Ca solution until the particles are completely dissolved; prepare 600 mL of 0.4 mol / L diammonium hydrogen phosphate solution (P solution), and stir the P solution until the particles are completely dissolved;

[0081] Drop the P solution into the continuously stirred Ca solution at a rate of 1 - 2 drops per second; adjust the pH to 6.5 ± 0.1 with ammonia water. After the addition of the P solution is complete, continue to stir the reaction solution for 6 hours and always keep the pH within this range to obtain the reaction solution;

[0082] Centrifuge the obtained reaction solution to obtain a white precipitate, then wash it three times with purified water to remove impurity ions, and finally dehydrate and wash it three times with absolute ethanol. Dry the washed precipitate in an oven at 90 °C for 48 hours;

[0083] Place the obtained dried powder in a muffle furnace and calcine it at 1000 °C for 3 hours with a heating rate of 5 °C per minute, and then cool it naturally with the furnace; use a ball mill to mill the prepared calcium phosphate powder for 1 hour at a ball mill rotation speed of 300 revolutions per minute, and finally obtain β-tricalcium phosphate powder with uniform particle size.

[0084] Then, use the prepared β-tricalcium phosphate powder to prepare tricalcium phosphate bioceramics according to the following method:

[0085] 1) Prepare the binder solution: Weigh 1 g of polyvinyl alcohol; slowly add 50 mL of purified water, and stir at 80 °C until completely dissolved to obtain the binder solution for standby.

[0086] 2) Weigh 7 g of β-tricalcium phosphate powder, add 10 mL of the binder solution, and stir for 2 h until the powder is uniformly dispersed to obtain a bubble-free slurry;

[0087] 3) Take an appropriate amount of the above slurry, mix it with PMMA microspheres of 300 - 700 microns, dry it at 70 °C to a certain extent and then perform tabletting to obtain a ceramic green body. Place it in an oven at 80 °C and dry it overnight.

[0088] 4) Sinter the green body obtained in the previous step at 1000 °C for 3 h, and finally cool it naturally with the furnace to room temperature.

[0089] The scanning electron microscope image of the tricalcium phosphate bioceramics prepared in Example 2 is as shown in Figure 2 shown. Then, perform characterization according to the method of Example 1, and the characterization results are shown in Table 3 below:

[0090] Table 3 Physical and chemical properties

[0091]

[0092] As can be seen from the above embodiments, the mechanical properties of the tricalcium phosphate bioceramics prepared by the present invention are more excellent. Moreover, the content of tricalcium phosphate is as high as 98%, or even more than 99%. The contents of trace elements and heavy metals are very low, and it can be used for the repair of tissue defects.

[0093] In the description of this specification, the description with reference to terms such as "one embodiment", "some embodiments", "example", "specific implementation manner", or "some examples", etc. means that the specific features, structures, materials, or characteristics described in connection with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials, or characteristics described can be combined in any one or more embodiments or examples in a suitable manner. Although the embodiments of the present invention have been shown and described above, it can be understood that the above embodiments are exemplary and should not be construed as limiting the present invention. Those of ordinary skill in the art can make changes, modifications, substitutions, and variations to the above embodiments within the scope of the present invention.

Claims

1. A method for preparing a tricalcium phosphate bioceramic, characterized in that, Comprising: (1) Reacting calcium nitrate tetrahydrate and diammonium hydrogen phosphate to generate a β-tricalcium phosphate precursor, and obtaining β-tricalcium phosphate powder through calcination and ball milling; (2) Mixing the β-tricalcium phosphate powder and a binder solution evenly to obtain a slurry; (3) Mixing the slurry and a pore-forming material evenly, and drying to obtain a ceramic green body; (4) Sintering the ceramic green body and cooling it to room temperature to obtain the tricalcium phosphate bioceramic.

2. The preparation method according to claim 1, wherein The binder solution is selected from a binder solution composed of at least one of aluminum oxide, magnesium oxide, phosphorus pentoxide, silicon oxide, sodium oxide, calcium oxide, aluminum phosphate, polyvinyl alcohol or a ceramic binder.

3. The preparation method according to claim 1, characterized in that, The mass ratio of the binder in the β-tricalcium phosphate powder and the binder solution is (40 - 70):(0.1 - 10).

4. The preparation method according to claim 1, characterized in that, The pore-forming material is selected from at least one of polymethyl methacrylate, stearic acid, and polyurethane foam; Optionally, the particle size of the polymethyl methacrylate is 100 - 1000 microns; Optionally, the mass ratio of the β-tricalcium phosphate powder and the pore-forming material is (2 - 3):

1.

5. The preparation method according to claim 1, wherein The sintering is carried out by a multi-stage sintering method or a one-step sintering method; Wherein the multi-stage sintering method includes: heating to 260°C and holding for 320 min, 290°C and holding for 120 min, 400°C and holding for 300 min, 600°C and holding for 180 minutes respectively, then heating to 1150°C and holding for 180 minutes; finally cooling to 1000°C in 75 minutes and naturally cooling to room temperature with the furnace; The one-step sintering method includes: heating from room temperature to 1150°C at a rate of 5°C / minute and holding for 180 minutes, and finally naturally cooling to room temperature with the furnace.

6. The preparation method according to claim 1, characterized in that, Step (1) includes: Providing an aqueous solution of calcium nitrate tetrahydrate and an aqueous solution of diammonium hydrogen phosphate; Dropping the diammonium hydrogen phosphate solution into the continuously stirred aqueous solution of calcium nitrate tetrahydrate, controlling the dropping rate at 1 - 2 drops / second, and adjusting the pH to between 6.5 and 8.0 with ammonia water; After the dropping is completed, continue to stir and react for 3 - 8 hours, and keep the pH at 6.5 - 8.0 to obtain a reaction solution; Obtaining a precipitate based on the reaction solution, washing and drying to obtain a dried powder; Calcining and ball milling the dried powder to obtain the β-tricalcium phosphate powder.

7. The preparation method according to claim 6, wherein The concentration of the aqueous solution of calcium nitrate tetrahydrate is 0.6 mol / L; the concentration of the aqueous solution of diammonium hydrogen phosphate is 0.4 mol / L; Optionally, the volume ratio of the aqueous solution of calcium nitrate tetrahydrate and the aqueous solution of diammonium hydrogen phosphate is 1:0.

6.

8. The preparation method according to claim 6, characterized in that, The drying is carried out at a temperature of 80 - 90°C for 48 hours; The calcination is carried out by heating to 800 - 1000°C at a rate of 5°C / minute, calcining for 2 - 3 hours, and naturally cooling; The ball milling is carried out at a rotation speed of 200 - 500 revolutions per minute for 2 - 4 hours.

9. A tricalcium phosphate bioceramic, characterized in that, Obtained according to the preparation method described in any one of claims 1 - 8.

10. Use of the tricalcium phosphate bioceramic according to claim 9 in the preparation of a tissue defect repair material.

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