Ceramic artificial bone material and method for preparing the same

Abstract

The application discloses a kind of ceramic artificial bone materials and preparation method thereof, belong to ceramic material preparation technical field.The method is constructed amphiphilic micellar system by PEG-PLA block copolymer, first preparation micellar solution, then it is used for precursor slurry preparation and PLGA pore former pretreatment (solve compatibility and agglomeration problem) in stages, after forming and drying, by gradient sintering (low temperature to aid agent, high temperature promotes densification) obtain product.The application solves the problem that pore former and precursor are compatible in traditional process, powder agglomeration, pore structure is uneven, and the obtained material has three-dimensional connected and uniformly distributed micropore structure, and uniform composition.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of ceramic material preparation, and particularly relates to a ceramic artificial bone material and a preparation method thereof. BACKGROUND

[0002] Hydroxyapatite (HA) ceramics have excellent biocompatibility, bone conduction and biodegradability due to the high matching of chemical composition and crystal structure with the inorganic components of human bone tissue, and are clinically used artificial bone repair materials. Among them, multi-doped hydroxyapatite (such as Sr 2+ , Mg 2+ , Si 4+ doped HA) can regulate the degradation rate and bone induction activity of the material through ion synergistic effect, match the human bone healing period, and become a research hotspot in the field of biomedical materials in recent years.

[0003] However, the hydroxyapatite ceramics prepared by the traditional method have dense structure, generally low porosity, and mainly isolated closed pores with poor connectivity, which cannot provide three-dimensional space for the growth of new bone cells, and is difficult to realize the transmission of nutrients and the discharge of metabolic products, resulting in low bone integration efficiency of the material and limiting its application in key scenes such as weight-bearing bone defect repair.

[0004] Large-pore structures are usually obtained through porous scaffold molds, but although large pores can enhance the growth and bone integration capacity of bone inwards after implantation, large pores also bring problems such as too fast degradation speed and new bone generation unable to replace in time, and too fast mechanical performance decline due to the appearance of material structure vacancies.

[0005] Therefore, micropores (pore size < 10 µm) also play an important role in bone regeneration and the existence of cells or nutrients, and micropores will provide a larger surface area. In the existing pore-forming technology, common pore-forming agents include ammonium bicarbonate, polymethyl methacrylate (PMMA) microspheres, etc.: ammonium bicarbonate is easy to produce local intense gas production by thermal decomposition, resulting in uneven pore size and easy formation of penetrating cracks, which reduces the mechanical strength of the material; PMMA microspheres can form regular pores, but the surface of the microspheres is strongly hydrophobic, and has poor compatibility with the hydroxyapatite precursor slurry (hydrophilic), which is easy to cause microsphere aggregation and sedimentation, resulting in irregular pore distribution and inability to construct a connected porous structure matching the human bone trabecula. At the same time, the hydroxyapatite powder and doping ions in the precursor slurry are easy to aggregate due to local concentration difference, which affects the uniformity of the material composition and the stability of the mechanical properties, and is difficult to meet the clinical bone repair requirements. SUMMARY

[0006] The application provides a ceramic artificial bone material and a preparation method thereof. By introducing an amphiphilic micelle system to regulate the dispersion of pore-forming agents and the growth environment of powders, and combining with precise process design, the problems of poor compatibility of pore-forming agents and precursors, powder agglomeration and uneven pore structure are solved, and finally the ceramic artificial bone material with microporous structure, high porosity and good connectivity is obtained.

[0007] To achieve the above object, the application provides the following technical scheme.

[0008] A preparation method of a ceramic artificial bone material, comprising the following steps:

[0009] S1, micelle solution preparation: 0.8-1.2g of polyethylene glycol-poly-lactic acid (PEG-PLA) block copolymer is dissolved in 15-20mL of dichloromethane, and stirred uniformly; 8%-12% of an ethanol aqueous solution is mixed with the dichloromethane solution of PEG-PLA in a volume ratio of 5:1, and stirring is continuously carried out at 300-400r / min during the dropping process, and after the dropping is completed, stirring is continuously carried out for 30-60min, dichloromethane is removed by volatilization, a stable PEG-PLA micelle system is formed, and a micelle solution is obtained;

[0010] S2, precursor slurry preparation: 8-10g of hydroxyapatite powder, 0.3-0.5mmol of strontium nitrate (Sr(NO3)2), 0.1-0.2mmol of magnesium nitrate (Mg(NO3)2·6H2O), 0.2-0.4mmol of tetraethyl orthosilicate (TEOS) and citric acid are added to 2 / 3 of the micelle solution in S1; wherein the molar ratio of citric acid to total metal ions (Sr 2+ , Mg 2+ ) is 1.3-1.7:1, and 30-40mL of deionized water is added at the same time; stirring is carried out at 25-30℃ and 200-300r / min for 30-40min, and a uniform precursor slurry is obtained;

[0011] S3, pore-forming agent pretreatment and addition: according to the mass of the hydroxyapatite powder in S2, PLGA microspheres are weighed in a mass ratio of 0.3-0.5:1, added to 1 / 3 of the micelle solution reserved in S1, and ultrasonically dispersed for 50-70min to obtain a PLGA microsphere suspension; after the precursor slurry is stirred, the stirring state is maintained at 200r / min, the PLGA microsphere suspension is added at a rate of 2-4 drops per second, and stirring is continuously carried out for 25-35min to form a composite slurry;

[0012] S4, molding and drying: the composite slurry is injected into a polyethylene mold, dried in a vacuum drying oven at 40-50℃ for 12-16h to remove free water, and a green body is obtained;

[0013] S5, gradient sintering: the green body is placed in a high-temperature sintering furnace, first heated to 500-600 DEG C at a rate of 3-5 DEG C / min, and kept for 2-3 h to remove the pore-forming agent, micelles and organic additives; then heated to 750-850 DEG C at a rate of 2-3 DEG C / min, and kept for 4-5 h to promote crystal densification; finally, the furnace is cooled to room temperature, and a ceramic artificial bone material is obtained.

[0014] The core innovation of the application specifically includes:

[0015] The micellar double-effect regulation mechanism: the amphiphilic micellar system formed by the PEG-PLA block copolymer plays a double role: on the one hand, the hydrophilic PEG segment is compatible with the precursor slurry, and the hydrophobic PLA segment is combined with the PLGA microspheres to build an interface bridge, cooperate with ultrasonic dispersion to break the van der Waals force between the microspheres, and solve the compatibility problem of the pore-forming agent and the slurry; on the other hand, the micelles can wrap hydroxyapatite powder and doped ions, inhibit particle agglomeration through steric hindrance effect, and at the same time make the ions uniformly distributed in the system, ensuring the uniformity of the material composition.

[0016] The micellar solution is first used to prepare the precursor slurry to ensure uniform dispersion of the powder and ions; then it is used to disperse the pore-forming agent, and precise dropwise addition is carried out after the viscosity of the precursor system is stable, so as to avoid competition between the powder and the microspheres for dispersion, prevent the microspheres from settling, realize ordered distribution of pores, and achieve the advantages of pore structure regulation similar to the colloidal crystal template method.

[0017] The pore-forming agent and micelles are slowly removed at a low temperature stage to avoid structure damage caused by violent gas production; the crystal ordered growth is promoted at a high temperature stage to ensure high porosity while improving mechanical properties, and the balance problem between the strength and structure of the porous material is solved.

[0018] The beneficial effects of the application compared with the prior art

[0019] (1) Through the PEG-PLA micellar regulation and the multi-stage process, a three-dimensionally interconnected and uniformly distributed microporous structure (pore size is adapted to cell growth and material transport) is constructed, which not only solves the problem of "no growth space" of traditional dense HA ceramics, but also avoids the defect of "degradation faster than bone formation" of simple macroporous structure.

[0020] (2) The amphiphilic PEG-PLA micelles act as an "interface bridge", the hydrophilic segment is compatible with the hydrophilic precursor slurry, and the hydrophobic segment is combined with the PLGA pore-forming agent, which cooperates with ultrasonic dispersion to completely eliminate the agglomeration of the pore-forming agent; at the same time, the micelles wrap HA powder and doped ions (Sr 2+ , Mg 2+ , Si 4+ ) through steric hindrance, ensuring uniform material composition and avoiding the problem of unstable mechanical properties caused by traditional process of disordered pores and local composition imbalance. BRIEF DESCRIPTION OF DRAWINGS

[0021] Figure 1 is a Fourier infrared spectrum of the ceramic artificial bone material prepared in Example 1~3 and Comparative Example 1;

[0022] Figure 2 is a high-power microscope photograph of the ceramic artificial bone material prepared in Example 1;

[0023] Figure 3 is a low-power microscope photograph of the ceramic artificial bone material prepared in Example 1;

[0024] Figure 4 is a photograph of the ceramic artificial bone material prepared in Example 1;

[0025] Figure 5 is a microscope photograph of the ceramic artificial bone material prepared in Comparative Example 1. DETAILED DESCRIPTION

[0026] In order to make the above objectives, features and advantages of the present application more apparent, specific embodiments of the present application are described in detail below. The following content is merely an example and illustration of the concept of the present application, and various modifications or supplements or similar ways are adopted by those skilled in the art to the described specific embodiments, as long as they do not deviate from the concept of the present application, which shall belong to the protection scope of the present application.

[0027] The above preparation method of the present application is described below through specific examples and comparative examples.

[0028] Example 1

[0029] A preparation method of a ceramic artificial bone material, comprising the following steps:

[0030] S1, micelle solution preparation: 0.8g PEG-PLA is dissolved in 15mL dichloromethane and stirred uniformly; 8% by mass fraction of an ethanol aqueous solution is mixed with the above-mentioned PEG-PLA dichloromethane solution in a volume ratio of 5:1, and stirring is continuously carried out at 300r / min during the dropping process, and stirring is continuously carried out for 30min after the dropping is completed, dichloromethane is removed by volatilization, a stable PEG-PLA micelle system is formed, and a micelle solution is obtained;

[0031] S2, precursor slurry preparation: 8g hydroxyapatite powder, 0.3mmol Sr(NO3)2, 0.1mmol Mg(NO3)2·6H2O, 0.2mmol TEOS and citric acid are added into 2 / 3 of the micelle solution in S1; wherein, the mass ratio of citric acid to total metal ions (Sr 2+ , Mg 2+The molar ratio of the hydroxylapatite powder to the total metal ions (Sr

[0032] S3, pore-forming agent pretreatment and addition: according to the mass of the hydroxylapatite powder in S2, PLGA microspheres were weighed according to a mass ratio of 0.3:1 of the hydroxylapatite powder to the PLGA microspheres, and were added to 1 / 3 of the micellar solution reserved in S1, and were ultrasonically dispersed for 50 min to obtain a PLGA microsphere suspension; after the stirring of the precursor slurry was completed, the PLGA microsphere suspension was added dropwise at a rate of 2 drops per second while keeping the stirring at 200 r / min, and the stirring was continued for 25-35 min to form a composite slurry;

[0033] S4, molding and drying: the composite slurry was injected into a polyethylene mold, and was dried in a vacuum drying oven at 40℃ for 12 h to remove free water to obtain a green body;

[0034] S5, gradient sintering: the green body was placed in a high-temperature sintering furnace, was first heated to 500℃ at a rate of 3℃ / min, was kept at 500℃ for 2 h to remove the pore-forming agent, the micelles and the organic additives, was then heated to 750℃ at a rate of 2℃ / min, was kept at 750℃ for 4 h to promote the densification of the crystals, and was finally cooled to room temperature with the furnace to obtain a ceramic artificial bone material.

[0035] Example 2

[0036] A method for preparing a ceramic artificial bone material, comprising the following steps:

[0037] S1, preparation of a micellar solution: 1.0 g of PEG-PLA was dissolved in 18 mL of dichloromethane and was stirred uniformly; a 10% ethanol aqueous solution was mixed with the PEG-PLA dichloromethane solution in a volume ratio of 5:1, the stirring was continued at 350 r / min during the dropwise addition, and the stirring was continued for 40 min after the dropwise addition was completed, dichloromethane was removed by volatilization, a stable PEG-PLA micellar system was formed, and a micellar solution was obtained;

[0038] S2, preparation of a precursor slurry: 9 g of hydroxylapatite powder, 0.4 mmol of Sr(NO3)2, 0.15 mmol of Mg(NO3)2·6H2O, 0.3 mmol of TEOS and citric acid were added to 2 / 3 of the micellar solution in S1; the molar ratio of the citric acid to the total metal ions (Sr 2+ , Mg 2+ ) was 1.5:1, and 35 mL of deionized water was added; the stirring was performed at 28℃ and 300 r / min for 35 min to obtain a uniform precursor slurry;

[0039] S3, pore-forming agent pretreatment and addition: according to the mass of the hydroxyapatite powder in S2, PLGA microspheres were weighed at a mass ratio of 0.4:1 and added to 1 / 3 of the micellar solution reserved in S1, and ultrasonic dispersion was performed for 60 min to obtain a PLGA microsphere suspension; after the stirring of the precursor slurry was completed, the PLGA microsphere suspension was added dropwise at a rate of 3 drops per second while maintaining a stirring state of 200 r / min, and stirring was continued for 30 min to form a composite slurry;

[0040] S4, forming and drying: the composite slurry was injected into a polyethylene mold and dried in a 45°C vacuum drying oven for 14 h to remove free water, thereby obtaining a green body;

[0041] S5, gradient sintering: the green body was placed in a high-temperature sintering furnace, first heated to 550°C at a rate of 4°C / min, and held for 2.5 h to remove the pore-forming agent, micelles, and organic additives; then heated to 800°C at a rate of 2°C / min, and held for 4 h to promote crystal densification; finally, the furnace was cooled to room temperature, thereby obtaining a ceramic artificial bone material.

[0042] Example 3

[0043] A method for preparing a ceramic artificial bone material, comprising the following steps:

[0044] S1, micellar solution preparation: 1.2 g of PEG-PLA was dissolved in 20 mL of dichloromethane and stirred uniformly; a 12% mass fraction of an ethanol aqueous solution was mixed with the PEG-PLA dichloromethane solution in a volume ratio of 5:1, and stirring was continued at 400 r / min during the dropwise addition process; after the dropwise addition was completed, stirring was continued for 60 min; dichloromethane was removed by volatilization to form a stable PEG-PLA micellar system, thereby obtaining a micellar solution;

[0045] S2, precursor slurry preparation: 10 g of hydroxyapatite powder, 0.5 mmol of Sr(NO3)2, 0.2 mmol of Mg(NO3)2·6H2O, 0.4 mmol of TEOS, and citric acid were added to 2 / 3 of the micellar solution in S1; the molar ratio of citric acid to total metal ions (Sr 2+ , Mg 2+ ) was 1.7:1, and 40 mL of deionized water was added at the same time; stirring was performed at 30°C and 300 r / min for 40 min to obtain a uniform precursor slurry;

[0046] S3, pore-forming agent pretreatment and addition: according to the mass of the hydroxyapatite powder in S2, PLGA microspheres were weighed at a mass ratio of 0.5:1 and added to 1 / 3 of the micellar solution reserved in S1, and ultrasonic dispersion was performed for 70 min to obtain a PLGA microsphere suspension; after the completion of stirring of the precursor slurry, the PLGA microsphere suspension was added at a rate of 4 drops per second while maintaining the stirring state at 200 r / min, and stirring was continued for 35 min to form a composite slurry;

[0047] S4, molding and drying: the composite slurry was injected into a polyethylene mold, and dried in a vacuum drying oven at 50°C for 16 h to remove free water, thereby obtaining a green body;

[0048] S5, gradient sintering: the green body was placed in a high-temperature sintering furnace, first heated to 600°C at a rate of 5°C / min, and held for 3 h to remove the pore-forming agent, micelles and organic additives; then heated to 850°C at a rate of 3°C / min, and held for 5 h to promote crystal densification; finally, the furnace was cooled to room temperature to obtain a ceramic artificial bone material.

[0049] Comparative Example 1

[0050] A method for preparing a ceramic artificial bone material, comprising the following steps:

[0051] S1, preparation of precursor slurry: 8 g of hydroxyapatite powder, 0.3 mmol of Sr(NO3)2, 0.1 mmol of Mg(NO3)2·6H2O, 0.2 mmol of TEOS and citric acid were added to 30 mL of deionized water; stirring was performed at 25°C and 200 r / min for 30 min to obtain a uniform precursor slurry;

[0052] S2, pore-forming agent pretreatment and addition: according to the mass of the hydroxyapatite powder in S1, PLGA microspheres were weighed at a mass ratio of 0.3:1 of hydroxyapatite powder:PLGA microspheres, added to 30 mL of a 12% mass fraction ethanol aqueous solution, and ultrasonic dispersion was performed for 50 min to obtain a PLGA microsphere suspension; after the completion of stirring of the precursor slurry, the PLGA microsphere suspension was added at a rate of 2 drops per second while maintaining the stirring state at 200 r / min, and stirring was continued for 25-35 min to form a composite slurry;

[0053] S3, molding and drying: the composite slurry was injected into a polyethylene mold, and dried in a vacuum drying oven at 40°C for 12 h to remove free water, thereby obtaining a green body;

[0054] S4, Gradient sintering: the green body was placed in a high-temperature sintering furnace, first heated to 500℃ at a rate of 3℃ / min, and kept for 2h; then heated to 750℃ at a rate of 2℃ / min, and kept for 4h to promote crystal densification; finally, the furnace was cooled to room temperature, and a ceramic artificial bone material was obtained.

[0055] Figure 1 is the Fourier infrared spectrum of the ceramic artificial bone material prepared in Examples 1-3 and Comparative Example 1; the characteristic peaks of hydroxyapatite (HA) in the spectra of Examples 1-3 and Comparative Example 1.

[0056] Figure 2 is a high-power microscope photograph of the ceramic artificial bone material prepared in Example 1; the microscope photograph is used for direct observation of the micro-pore morphology of the material, and a large number of micro-pores with a pore size <10μm can be seen in the photograph, and the pores are three-dimensionally networked and connected, with uniform sizes (no obvious size difference), and no isolated closed pores or local pore density / void phenomena. This is because the hydrophilic segment of the PEG-PLA micelle is compatible with the precursor, and the hydrophobic segment is combined with the PLGA pore-forming agent, and the ultrasonic dispersion breaks the microsphere aggregation, so that the pore-forming agent is uniformly distributed; on the other hand, the micelle disperses the powder and ions first, and then disperses the pore-forming agent, avoiding the microsphere sedimentation caused by the competition between the two, and finally forming an ordered and connected micro-pore structure.

[0057] Figure 3 is a low-power microscope photograph of the ceramic artificial bone material prepared in Example 1; it can be seen that there are no obvious cracks on the surface of the artificial bone material in a large area.

[0058] Figure 4 is a photograph of the ceramic artificial bone material prepared in Example 1; the surface of the material has no obvious cracks or deformation, and the color is uniform.

[0059] Figure 5 is a microscope photograph of the ceramic artificial bone material prepared in Comparative Example 1, which is used as a blank control; it can be seen that the artificial bone material is difficult to form, which is due to the uneven internal stress caused by aggregation during heating.

Claims

1. A method for preparing a ceramic artificial bone material, characterized in that, Includes the following steps: S1. Preparation of micelle solution: Dissolve PEG-PLA block copolymer in dichloromethane and stir until homogeneous; separately, mix aqueous ethanol solution with the above PEG-PLA dichloromethane solution at a volume ratio of 5:1, and continue stirring during the dropwise addition. After the dropwise addition is complete, continue stirring to remove dichloromethane by evaporation, forming a stable PEG-PLA micelle system and obtaining a micelle solution. S2, Preparation of precursor slurry: Hydroxyapatite powder, Sr(NO3)2, Mg(NO3)2·6H2O, TEOS, and citric acid are added to 2 / 3 of the micelle solution in S1; wherein, citric acid and total metal ions Sr 2+ Mg 2+ The molar ratio is 1.3-1.7:1, and deionized water is added simultaneously; the mixture is stirred at 25-30℃ to obtain a uniform precursor slurry; S3. Pretreatment and addition of pore-forming agent: Based on the mass of hydroxyapatite powder in S2, weigh PLGA microspheres at a mass ratio of 0.3-0.5:1, add them to the 1 / 3 micelle solution reserved in S1, and disperse them by ultrasonication to obtain a PLGA microsphere suspension; after the precursor slurry is stirred, keep stirring and add the PLGA microsphere suspension dropwise, continue stirring to form a composite slurry; S4. Molding and Drying: The composite slurry is injected into a polyethylene mold and dried in a vacuum drying oven to remove free moisture and obtain a green body; S5. Gradient sintering: The green body is placed in a high-temperature sintering furnace, first heated to 500-600℃ and held; then heated to 750-850℃ and held; finally cooled to room temperature with the furnace to obtain ceramic artificial bone material.

2. The method for preparing ceramic artificial bone material according to claim 1, characterized in that, The amount of PEG-PLA block copolymer added in S1 is 0.8~1.2g, the amount of dichloromethane is 15~20mL, the mass fraction of ethanol aqueous solution is 8%-12%, the stirring rate during the dropwise addition process is 300-400r / min, and the stirring time after dropwise addition is 30-60min.

3. The method for preparing ceramic artificial bone material according to claim 1, characterized in that, The amount of hydroxyapatite powder added in S2 is 8-10g, the amount of Sr(NO3)2 added is 0.3-0.5mmol, the amount of Mg(NO3)2·6H2O added is 0.1-0.2mmol, the amount of TEOS added is 0.2-0.4mmol, and the amount of deionized water is 30-40mL.

4. The method for preparing ceramic artificial bone material according to claim 1, characterized in that, As described in S2, stirring is carried out at 25-30℃, with a stirring rate of 200-300 r / min and a stirring time of 30-40 min.

5. The method for preparing ceramic artificial bone material according to claim 1, characterized in that, The ultrasonic dispersion time described in S3 is 50-70 min, the stirring rate of the precursor slurry is maintained at 200 r / min, the dropping acceleration rate of the PLGA microsphere suspension is 2-4 drops / second, and the stirring time after dropping is 25-35 min.

6. The method for preparing ceramic artificial bone material according to claim 1, characterized in that, The temperature of the vacuum drying oven described in S4 is 40-50℃, and the drying time is 12-16h.

7. The method for preparing ceramic artificial bone material according to claim 1, characterized in that, The heating rate to 500-600℃ described in S5 is 3-5℃ / min, and the holding time is 2-3h; the heating rate to 750-850℃ is 2-3℃ / min, and the holding time is 4-5h.

8. A ceramic artificial bone material obtained by any one of the preparation methods described in claims 1-7.

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