Phosphosilicate-based bioactive material and preparation method thereof

Abstract

The invention belongs to the technical field of biomedical materials. Specifically, the invention discloses a phosphosilicate-based bioactive material and a preparation method thereof. The preparation method disclosed by the invention is based on an emulsification system regulation and control and dual-promotion reaction mechanism strategy, and is a preparation technology with simple process and low cost. According to the preparation method disclosed by the invention, an interface contact reaction is promoted particularly through emulsification, so that the application of a calcium source raw material with relatively low water solubility in the preparation process of the bioactive material can be realized, the dependence on a water-soluble calcium source which is easy to cause environmental pollution is reduced, the greenization of the preparation process is realized, and the preparation cost is reduced. And the phosphosilicate-based bioactive material prepared by the method disclosed by the invention has excellent biological activity.

Description

Technical Field

[0001] This invention belongs to the field of biomedical materials technology. Specifically, this invention discloses a phosphosilicate-based bioactive material and its preparation method. Background Technology

[0002] Phosphosilicate-based bioactive materials have attracted widespread attention in the field of bone tissue engineering repair due to their excellent biocompatibility, bioactivity, and osteoconductivity. Among these phosphosilicate-based bioactive materials, phosphorus and calcium-containing silicate materials, because their composition is similar to the inorganic components in human bone tissue, can better promote the proliferation and differentiation of osteocytes, accelerate bone-induced new bone formation, and exhibit excellent bone repair performance. Furthermore, because they can release active ions to promote cell proliferation and the scaffolds formed can promote cell migration and the repair of soft tissue injuries, they have broad application prospects.

[0003] Phosphosilicate-based bioactive materials in the prior art can be prepared by various methods; however, these methods still have many limitations, specifically in the following aspects: High-temperature melting method The principle of this method is to achieve atomic diffusion reactions by calcining solid raw materials (such as silica, calcium carbonate, calcium phosphate, and sodium carbonate) at high temperatures (typically from about 1300 to 1700°C). While this process is simple and easy to implement, the reaction may not proceed completely, leaving unreacted particles and resulting in uneven product composition. In particular, the addition of sodium-containing compounds to lower the melting point of the product can leave residues after the reaction, leading to increased pH and severe cytotoxicity. Furthermore, high-temperature sintering may coarsen the product grains (particle size may typically exceed about 10 μm), reducing the specific surface area and surface activity of the material, which is detrimental to its interaction with the biological environment. In addition, the sintering process can easily generate problems such as low porosity and high brittleness, making it difficult to meet the synergistic requirements of porous structure and mechanical properties for bone repair materials.

[0004] Sol-gel methodThe traditional sol-gel method works by hydrolyzing and condensing metal alkoxides to form a sol-gel network. While this method allows for precise control of the composition, the reaction system suffers from poor stability and is easily affected by environmental factors such as humidity and pH, leading to significant batch-to-batch variations in the product. Furthermore, the hydrolysis process is slow (typically requiring several days to weeks), and particle agglomeration due to colloidal aggregation is common in the later stages of the reaction. This necessitates the introduction of dispersants or complex surface modifications, increasing process complexity and production costs. Additionally, the sol-gel method requires the use of soluble calcium salts such as calcium nitrate / calcium chloride, necessitating heating to remove strong acid ions. This generates large amounts of highly polluting acidic gases, causing equipment corrosion and environmental damage.

[0005] Hydrothermal synthesis method This method relies on high temperature and high pressure (typically requiring temperatures of approximately 100 to 200°C and pressures of approximately 1 to 10 MPa) to promote the reaction, thus placing stringent requirements on the pressure resistance and sealing of the equipment. Furthermore, large-scale production using this method involves high energy consumption and significant safety risks; the temperature and pressure distribution within the reactor may be uneven, easily leading to a wide particle size distribution and imperfect crystal structure in the product. Therefore, multiple sieving or grinding processes are necessary to optimize product performance, which may further reduce material activity. Simultaneously, the phosphorus source (e.g., diammonium hydrogen phosphate) in the hydrothermal reaction is volatile, potentially causing the phosphorus content in the product to deviate from the design value, thereby affecting the stability of biological activity.

[0006] In addition, existing methods for preparing phosphosilicate-based bioactive materials also have the following problems: Inefficiency of the reaction mechanism In most of the preparation methods described, the reaction between calcium source (e.g., calcium nitrate, calcium chloride) and silicon source (e.g., tetraethyl orthosilicate) lacks a synergistic promoting mechanism. The calcium ion release rate does not match the silica intermediate formation rate, which may lead to insufficient precipitation reaction and low raw material utilization (e.g., possibly less than about 60%). At the same time, the introduction of phosphorus source (e.g., trimethyl phosphate) is mostly passive mixing, which makes it difficult to participate uniformly in the construction of silicate network. It often forms local phosphorus-rich or phosphorus-poor regions, thereby affecting the consistency of bioactivity of the material.

[0007] Environmental and cost issues Existing preparation methods typically require soluble calcium sources such as calcium nitrate or calcium chloride. Some methods also require the use of strong acids (e.g., nitric acid) to adjust the pH value or the introduction of toxic organic solvents. This not only corrodes equipment but also generates harmful waste liquids. Furthermore, the decomposition of calcium nitrate or calcium chloride during calcination produces large amounts of toxic nitrogen oxides or hydrogen chloride gases, causing serious environmental pollution and contradicting the concept of green preparation. In addition, complex post-processing steps further increase production costs, limiting their industrial application.

[0008] Therefore, there is a need in this field to develop a method for preparing phosphosilicate-based bioactive materials that is highly efficient, mild, produces stable products, and is environmentally friendly. This is key to overcoming existing technological bottlenecks and promoting their clinical translation. Summary of the Invention

[0009] Purpose of the invention In view of the problems existing in the prior art described in the background section above, the object of the present invention is to provide a phosphosilicate-based bioactive material and a method for preparing the same.

[0010] Technical solution To achieve the above objectives, the present invention adopts the following technical solution: Option 1: A method for preparing a phosphosilicate-based bioactive material, wherein the method includes the following steps: Step 1: Provide an aqueous phase solution containing an emulsifier, wherein the concentration of the emulsifier in the aqueous phase solution is in the range of about 0.5% to about 10% by weight; Step 2: Provide an oil phase solution containing a liquid silicate substance, wherein the concentration of the liquid silicate substance in the oil phase solution is in the range of about 15 to about 60% by volume, and the solvent of the oil phase solution is a water-soluble organic solvent; Step 3: At a temperature of about 20 to about 30°C, the oil phase solution obtained in step 2 is slowly added dropwise to the aqueous phase solution obtained in step 1 under stirring, wherein the weight ratio of the aqueous phase solution to the total volume of the added oil phase solution is in the range of about 0.7 g / mL to about 3 g / mL, thereby forming a stable oil-in-water emulsion system. Step 4: Add a calcium source material, including calcium hydroxide and optional clean calcium source material, to the emulsion system obtained from Step 3 under stirring, and add an organophosphorus source material, and continue stirring until uniformly mixed, wherein the molar ratio of phosphorus in the added organophosphorus source material to silicon in the silicate ester material is in the range of about (0.1-1):1, and the molar ratio of calcium in the calcium source material to silicon in the silicate ester material is in the range of about (0.1-2):1; Step 5: The mixture obtained from Step 4 is reacted at a temperature of about 20 to about 80°C for about 2 to about 24 hours to form a suspension containing phosphosilicate precursor solids. Step 6: Separate the phosphosilicate precursor solid obtained from Step 5 from the suspension, and after optional washing and drying, calcine it at a calcination temperature of about 500 to about 900°C for about 2 to about 6 hours to obtain the phosphosilicate-based bioactive material.

[0011] Option 2: According to the preparation method described in Option 1 above, wherein in step 1, the emulsifier comprises one or more of Tween 80, Span 80, sodium dodecyl sulfate and polyether F68.

[0012] Option 3: According to the preparation method described in Option 1 or 2 above, wherein in step 2, the liquid silicate ester material comprises one or more of methyl orthosilicate, ethyl orthosilicate and butyl orthosilicate.

[0013] Option 4: The preparation method according to any one of Options 1 to 3 above, wherein in step 2, the water-soluble organic solvent comprises an alcohol organic solvent.

[0014] Option 5: The preparation method according to any one of Options 1 to 4 above, wherein in step 2, the water-soluble organic solvent comprises one or more of ethanol, propanol and isopropanol.

[0015] Option 6: The preparation method according to any one of Options 1 to 5 above, wherein step 3 further includes slowly adding the oil phase solution obtained from step 2 to the aqueous phase solution obtained from step 1, stirring the obtained mixture at a stirring speed of about 300 to about 800 rpm for about 10 to about 30 minutes, and then homogenizing and emulsifying at a homogenization speed of about 3000 to about 6000 rpm for about 2 to about 5 minutes, thereby forming a stable oil-in-water emulsion system.

[0016] Option 7: The preparation method according to any one of Options 1 to 6 above, wherein the calcium source material added in step 4 includes added calcium hydroxide and clean calcium source material, and the ratio of calcium element in the calcium hydroxide and the clean calcium source material is in the range of about (2.5-5.5):1.

[0017] Option 8: The preparation method according to any one of Options 1 to 7 above, wherein in step 4, the clean calcium source material includes a water-slightly soluble calcium source.

[0018] Option 9: The preparation method according to any one of Options 1 to 8 above, wherein in step 4, the clean calcium source material includes one or more of calcium dihydrogen phosphate and calcium acetate.

[0019] Scheme 10: The preparation method according to any one of Schemes 1 to 9 above, wherein in step 4, the organophosphorus source includes one or more of triethyl phosphate, inositol hexaphosphate, and glycerophosphate.

[0020] Scheme 11: The preparation method according to any one of Schemes 1 to 10 above, wherein in step 4, other metal source substances are added to the emulsion system obtained from step 3 while adding calcium source substances and / or organophosphorus source substances.

[0021] Option 12: The preparation method according to Option 11 above, wherein the other metal source material includes compounds containing sodium, magnesium and / or strontium.

[0022] Option 13: According to the preparation method described in Option 11 or 12 above, the molar ratio of the metal cation in the other metal salt substance to the silicon element in the silicate ester substance is in the range of about (0-0.6):1.

[0023] Option 14: The preparation method according to any one of Options 1 to 13 above, wherein in step 6, the separation process includes centrifuging the suspension containing the phosphosilicate precursor solid at a speed of about 3000 to about 8000 rpm for about 5 to about 15 minutes, thereby separating the phosphosilicate precursor solid from the suspension.

[0024] Scheme 15: The preparation method according to any one of Schemes 1 to 14 above, wherein in step 6, the washing process includes washing the separated phosphosilicate precursor solid with deionized water and ethanol alternately 3 to 5 times.

[0025] Scheme 16: The preparation method according to any one of Schemes 1 to 15 above, wherein in step 6, the drying process includes drying the separated phosphosilicate precursor solid at a temperature of about 60 to about 100°C for about 6 to about 24 hours.

[0026] Scheme 17: The preparation method according to any one of Schemes 1 to 16 above, wherein in step 6, before the calcination, the phosphosilicate precursor solid is heated to the calcination temperature at a heating rate of about 2 to about 10 °C / min.

[0027] Scheme 18: Phosphosilicate-based bioactive material prepared by any one of Schemes 1 to 17 above.

[0028] Option 19: The phosphosilicate-based bioactive material according to Option 18 above, wherein the phosphosilicate-based bioactive material has one or more of the following properties: The phosphosilicate-based bioactive material is a porous particle composed of particles with a primary particle size in the range of about 50 to about 100 nm. The phosphosilicate-based bioactive material has at least approximately 100 μm 2 The specific surface area per g is preferably at least about 113.3 m².2 Specific surface area per g; The phosphosilicate-based bioactive material has D 50 Not exceeding about 7 μm, preferably not exceeding about 6.86 μm, and / or D 98 The particle size should not exceed about 17 μm, preferably not exceed about 16.24 μm.

[0029] Technical effect To overcome the shortcomings of existing preparation methods, this invention provides a simple, low-cost, and bioactive phosphosilicate-based bioactive material preparation technology based on emulsification system regulation and a dual-promotion reaction mechanism. The preparation method of this invention, in particular, promotes interfacial contact reactions through emulsification, enabling the application of calcium source materials with low water solubility in the preparation process of such bioactive materials. This reduces dependence on soluble calcium sources that easily cause environmental pollution, thus achieving a green preparation process.

[0030] The preparation method of this invention uses silicate esters as silicon sources, calcium hydroxide combined with calcium hydrogen phosphate and calcium acetate as calcium sources and catalysts, and phosphate esters and phosphoric acid as mixed phosphorus sources. An oil-in-water emulsion system is constructed using an emulsifier to promote the hydrolysis reaction of silicate esters. The hydrolysis intermediates combine with calcium ions to form precipitates, and the reduced calcium ion concentration further promotes the dissolution of slightly soluble calcium sources such as calcium hydroxide, forming a double-promoting reaction cycle. At the same time, phosphorus sources and substances containing metal elements such as sodium, magnesium, and strontium are introduced to participate in the reaction, and finally, phosphosilicate bioactive materials with excellent biological activity, such as calcium phosphosilicate and sodium calcium phosphosilicate, are prepared.

[0031] The method for preparing phosphosilicate-based bioactive materials provided by this invention uses slightly soluble clean calcium sources such as dicalcium phosphate, calcium hydroxide, and calcium acetate to replace water-soluble calcium sources such as calcium nitrate and calcium chloride, which may cause pollution. By constructing an emulsion system of silicate esters and slightly soluble calcium source suspensions, not only is the contact area between the slightly soluble clean calcium source and tetraethyl orthosilicate increased, but the alkaline catalytic hydrolysis of calcium hydroxide is also used to promote the reaction. The hydrolysis intermediates combine with calcium ions to precipitate, resulting in a decrease in calcium ion concentration. The slightly soluble clean calcium source is further dissolved to replenish the calcium source, forming a double-promoting cycle reaction of "hydrolysis-precipitation-dissolution". The double-promoting reaction mechanism improves the reaction efficiency and product performance. It has the advantages of simple process, mild reaction conditions, stable product performance, and high bioactivity, and has broad application prospects in the fields of tissue engineering repair.

[0032] In addition, the method for preparing phosphosilicate-based bioactive materials provided by the present invention is a widely applicable preparation technology. When using this technology to prepare phosphosilicate-based bioactive materials, active substances such as sodium-containing, magnesium-containing, and strontium-containing compounds can be added to the calcium-containing compounds to synthesize a variety of bioactive materials such as calcium phosphosilicate, sodium calcium phosphosilicate, and strontium-containing phosphosilicates.

[0033] Specifically, compared with the prior art, the preparation method of the present invention has the following beneficial effects: (1) The preparation method of the present invention uses an emulsifier to construct an oil-in-water emulsion system, which increases the contact area between the oily silicate esters and the aqueous phase, realizes the contact reaction between the oily substances and the aqueous substances through the interface, significantly promotes the hydrolysis reaction of the silicate esters, and improves the reaction rate and raw material utilization. (2) The preparation method of the present invention utilizes calcium hydroxide as both a calcium source and a catalyst to construct a micro-nano reactor. During the reaction process, a double-promoting reaction cycle is formed, which combines the hydrolysis intermediate with calcium ion precipitation and calcium hydroxide dissolution, so that the reaction can proceed continuously and efficiently and the composition of the product is more uniform. (3) The preparation method of the present invention achieves the purpose of preparing bioactive silicates using slightly soluble calcium sources such as calcium hydroxide and calcium hydrogen phosphate through the above process; it breaks the dependence of the synthesis process of this type of material on soluble calcium sources such as calcium nitrate, and reduces the risks and environmental pollution caused by using this type of calcium source; (4) The preparation method of the present invention is simple, the reaction conditions are mild, no high temperature and high pressure equipment is required, the production cost is low, and it is easy to industrialize. (5) The calcium phosphosilicate bioactive silicate prepared by the preparation method of the present invention has excellent bioactivity and bone induction properties, and has broad application prospects in the field of bone tissue engineering repair. Attached Figure Description

[0034] To more clearly illustrate the specific embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the specific embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are some embodiments of the present invention. For those skilled in the art, other drawings can be obtained from these drawings without creative effort.

[0035] Figure 1 To show the SEM image (magnification of 100,000) of the primary particle size of the phosphosilicate-based bioactive material particles prepared in Example 1 of the present invention. Figure 2 To show the SEM image (magnification of 10000x) of the porous particles formed by the accumulation of phosphosilicate-based bioactive material particles prepared in Example 1 of the present invention. Figure 3 This is a particle size distribution diagram of porous particles formed by the accumulation of phosphosilicate-based bioactive materials prepared in Example 3 of the present invention. Figure 4 The image shows the scanning electron microscope energy dispersive spectroscopy (SEM) spectrum of the phosphosilicate-based bioactive material prepared in Example 2 of this invention. Figure 5 The infrared spectrum of the phosphosilicate-based bioactive material prepared in Example 2 of this invention; Figure 6 This is a differential scanning calorimetry (DSC) spectrum of the phosphosilicate-based bioactive material prepared in Example 2 of this invention. Figure 7 X-ray diffraction patterns of the phosphosilicate-based bioactive materials prepared in Examples 1 and 4 of the present invention before and after mineralization treatment; Figure 8 This is an X-ray diffraction pattern of a commercially available bioactive material (bioactive glass) after mineralization treatment. Detailed Implementation

[0036] To make the objectives, technical solutions, and advantages of this invention clearer, the technical solutions of this invention will be clearly and completely described below in conjunction with the embodiments of this invention. Those skilled in the art should understand that the embodiments described are merely for the purpose of aiding understanding of this invention and should not be considered as specific limitations on this invention. Based on the embodiments of this invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of this invention. Process parameters in the following embodiments that are not specifically specified are generally performed under conventional conditions.

[0037] The endpoints and any values ​​of the ranges disclosed in this invention are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. The term "about" as used in this invention means that the number it modifies may fluctuate within ±20%, ±15%, ±10%, ±5%, or ±2% of that number. For numerical ranges, the endpoint values ​​of the various ranges, the endpoint values ​​of the various ranges and the individual point values ​​contained within them, and the individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed in this invention.

[0038] According to a first aspect of the present invention, a method for preparing a phosphosilicate-based bioactive material is provided. The preparation method according to the first aspect of the present invention includes steps 1 to 6.

[0039] Step 1, provide an aqueous solution: Step 1 includes providing an aqueous solution containing an emulsifier, wherein the concentration of the emulsifier in the aqueous solution is in the range of about 0.5% to about 10% by weight.

[0040] Step 1 may include, for example, mixing the emulsifier with deionized water and stirring at a temperature of about 20 to about 30°C for about 10 to about 20 minutes until the emulsifier is completely dissolved in the deionized water, thereby obtaining an aqueous solution of the emulsifier.

[0041] In step 1, the selected emulsifier is one that enables the mixture of the aqueous and oil phase solutions to form a stable oil-in-water emulsion system in the subsequent emulsification step 3.

[0042] Specifically, in some exemplary preferred embodiments of the present invention, the emulsifier may comprise one or more of Tween 80, Span 80, sodium dodecyl sulfate, and polyether F68.

[0043] Furthermore, the concentration of the emulsifier in the aqueous solution should be in the range of about 0.5% to about 10% by weight, for example, about 1% by weight, about 3% by weight, about 5% by weight, about 7% by weight, or about 9% by weight. Here, the concentration of the emulsifier should not be too high, for example, it should not exceed about 10% by weight, otherwise it may not only cause material waste, but also make it difficult to remove the emulsifier after the reaction is complete; the concentration of the emulsifier should also not be too low, for example, it should not be lower than about 0.5% by weight, otherwise the emulsification effect may not be achieved.

[0044] Step 2, provide the oil phase solution: Step 2 includes providing an oil phase solution containing a liquid silicate ester, wherein the concentration of the liquid silicate ester in the oil phase solution is in the range of about 15 to about 60% by volume, and the solvent of the oil phase solution is a water-soluble organic solvent.

[0045] Step 2 may include, for example, mixing the liquid silicate with a water-soluble organic solvent and stirring at a temperature of about 20 to about 30°C for about 5 to about 10 minutes until the liquid silicate is miscible in the water-soluble organic solvent, thereby obtaining an oil phase solution of the silicate.

[0046] In step 2, the liquid silicate ester refers to a silicate ester that is in liquid form at the temperature at which the oil phase solution is prepared and at the temperature of the subsequent emulsification process in step 3 (e.g., at room temperature of 20 to 30°C), including but not limited to one or more of methyl orthosilicate, ethyl orthosilicate and butyl orthosilicate.

[0047] In addition, in step 2, the solvent in the oil phase solution needs to be a water-soluble organic solvent, preferably including alcohol organic solvents, such as one or more of ethanol, propanol and isopropanol.

[0048] Furthermore, the concentration of the liquid silicate ester in the oil phase solution is required to be in the range of approximately 15% to approximately 60% by volume, for example, approximately 20% by volume, approximately 30% by volume, approximately 40% by volume, or approximately 50% by volume. Here, the concentration of the silicate ester in the oil phase solution should not be too high, for example, not exceeding approximately 60% by volume, otherwise it may lead to excessively high reactant concentrations, excessively large particle sizes, and uneven elemental distribution; nor should it be too low, for example, not below approximately 15% by volume, otherwise it may lead to an excessively slow reaction, which is detrimental to material forming.

[0049] Step 3, Emulsification process: Step 3 includes slowly adding the oil phase solution obtained in step 2 dropwise to the aqueous phase solution obtained in step 1 under stirring at room temperature, for example at a temperature of about 20 to about 30°C, wherein the weight ratio of the aqueous phase solution to the total volume of the oil phase solution added is in the range of about 0.7 g / mL to about 3 g / mL, thereby forming a stable oil-in-water emulsion system.

[0050] The emulsification process can increase the contact area between the oil phase and the water phase, thereby promoting the hydrolysis reaction of silicate esters.

[0051] During the emulsification process in step 3, the emulsification temperature should be at room temperature, for example, about 20°C, about 25°C, or about 30°C. The emulsification temperature should not be too high, for example, it should not exceed about 30°C, otherwise it may cause hydrolysis reaction before emulsification is completed, resulting in uneven element distribution and larger particle size in the obtained material; it should also not be too low, for example, it should not be below about 20°C, otherwise it may affect the solubility of the emulsifier.

[0052] Furthermore, in step 3, the weight-to-volume ratio of the aqueous solution to the total volume of the added oil solution should be in the range of approximately 0.7 g / mL to approximately 3 g / mL, for example, approximately 1 g / mL, approximately 1.5 g / mL, approximately 2 g / mL, or approximately 2.5 g / mL. Here, the weight-to-volume ratio of the aqueous solution to the oil solution should not be too large, for example, not exceeding approximately 3 g / mL, otherwise it may result in a low concentration of reactants in the system and a slow reaction; nor should it be too small, for example, not less than approximately 0.7 g / mL, otherwise it may result in insufficient aqueous phase, failing to adequately encapsulate the oil phase and failing to fully form an emulsion system.

[0053] In addition, in order to better form a stable oil-in-water emulsion system, step 3 may further include slowly adding the oil phase solution obtained in step 2 to the aqueous phase solution obtained in step 1, and then continuing to stir the resulting mixture at a stirring speed of about 300 to about 800 rpm (e.g., about 400 rpm, about 500 rpm, about 600 rpm or about 700 rpm) for about 10 to about 30 minutes (e.g., about 20 minutes), and then homogenizing and emulsifying at a homogenization speed of about 3000 to about 6000 rpm (e.g., about 4000 rpm or about 5000 rpm) for about 2 to about 5 minutes (e.g., about 3 minutes or about 4 minutes).

[0054] Step 4, construct the reaction system: Step 4 includes adding a calcium source, including calcium hydroxide and optionally a clean calcium source, to the emulsion system obtained from step 3 under stirring, and adding an organophosphorus source, and continuing stirring (e.g., stirring for about 10 to about 20 minutes) until homogeneous, wherein the molar ratio of phosphorus in the added organophosphorus source to silicon in the silicate ester is in the range of about (0.1-1):1, and the molar ratio of calcium in the calcium source to silicon in the silicate ester is in the range of about (0.1-2):1.

[0055] In a preferred embodiment, the calcium source material added in step 4 includes both calcium hydroxide and a clean calcium source material, and the ratio of calcium in the calcium hydroxide and the clean calcium source material is preferably in the range of about (2.5-5.5):1, for example, about 3:1, about 3.5:1, about 4:1, about 4.5:1, or about 5:1. Here, the ratio of calcium in the calcium hydroxide and the clean calcium source material should not be too high, for example, not exceeding about 5.5:1, because calcium hydroxide acts as both a calcium source and a catalyst. If the proportion of calcium hydroxide is too high, the system will be highly alkaline, which may lead to a slightly faster reaction rate, which is not conducive to uniform element distribution and particle size control; nor should it be too low, for example, not less than about 2.5:1, otherwise the reaction system will be too weakly alkaline, and the reaction may be too slow or even fail to initiate in time.

[0056] In step 4, the clean calcium source material refers to a calcium source material that, unlike calcium nitrate and calcium chloride, does not produce harmful substances (such as nitrogen oxides or hydrogen chloride) during calcination. For example, in some preferred embodiments of the present invention, one or more of calcium dihydrogen phosphate and calcium acetate can be used as the clean calcium source material.

[0057] Furthermore, the clean calcium source is preferably also slightly soluble in the emulsion system, rather than requiring the use of water-soluble calcium sources (such as calcium nitrate and calcium chloride) as in existing methods. The solubility of the slightly soluble clean calcium source can be, for example, less than about 5 g / 100 mL of water, such as less than about 1 g / 100 mL of water or less than about 0.5 g / 100 mL of water, but should not be less than about 0.01 g / 100 mL of water.

[0058] In addition, the organophosphorus source may include phosphate esters or salts, such as one or more of triethyl phosphate, inositol hexaphosphate, and glycerophosphate.

[0059] In step 4, the molar ratio of phosphorus in the added organophosphorus source to silicon in the silicate ester is in the range of approximately (0.1-1):1, for example, approximately 0.2:1, approximately 0.3:1, approximately 0.4:1, approximately 0.5:1, approximately 0.6:1, approximately 0.7:1, approximately 0.8:1, or approximately 0.9:1. Here, the molar ratio of phosphorus to silicon should not be too high, for example, not exceeding approximately 1:1, otherwise the excessive phosphorus content may cause the prepared material to lose its biological activity; nor should it be too low, for example, not lower than approximately 0.1:1, otherwise the excessively low phosphorus content may also cause the prepared material to lose its biological activity.

[0060] Furthermore, in step 4, the molar ratio of calcium in the calcium source material to silicon in the silicate ester material should be within the range of approximately (0.1-2):1, for example, approximately 0.2:1, approximately 0.4:1, approximately 0.6:1, approximately 0.8:1, approximately 1:1, approximately 1.2:1, approximately 1.4:1, approximately 1.6:1, or approximately 1.8:1. Here, the molar ratio of calcium to silicon should not be too large, for example, not exceeding approximately 2:1, otherwise the silicon content will be too low, which may cause the silicon-oxygen network of the prepared material to collapse, resulting in the material not forming properly; nor should it be too small, for example, not lower than approximately 0.1:1, otherwise the calcium content will be too low, which may cause the material to lose its biological activity.

[0061] In addition, in step 4, other metal source substances may be added to the emulsion system obtained from step 3 along with the addition of calcium source substances and / or organophosphorus source substances. These other metal source substances preferably include compounds containing sodium, magnesium, and / or strontium to introduce corresponding active metal elements into the formed bioactive material. For example, to form sodium calcium phosphosilicate bioactive material, disodium hydrogen phosphate or similar substances may be introduced as other metal source substances in step 4.

[0062] In some further preferred embodiments, the molar ratio of the metal cation in the other metal salt to the silicon in the silicate ester can be in the range of about (0-0.6):1, for example, about 0.1:1, about 0.2:1, about 0.3:1, about 0.4:1, or about 0.5:1. Here, the molar ratio of the metal cation in the other metal salt to the silicon in the silicate ester should not be too high, for example, it should not exceed about 0.6:1, otherwise the material may be difficult to form.

[0063] Step 5, reaction process: Step 5 involves reacting the mixture obtained from step 4 at a temperature of about 20 to about 80°C for about 2 to about 24 hours to form a suspension containing a phosphosilicate precursor solid.

[0064] Step 5 may include, for example, placing the mixture in a constant-temperature water bath at a temperature of approximately 20 to approximately 80°C for reaction. During the reaction, silicate esters undergo hydrolysis under the catalysis of alkaline substances such as calcium hydroxide to generate silicic acid intermediates. These silicic acid intermediates further combine with metal ions such as calcium ions in the system to form precipitates. As the concentration of calcium ions in the system decreases, slightly soluble calcium hydroxide and other clean calcium source substances further dissolve and release calcium ions, forming a double-promoting reaction cycle. Simultaneously, they also combine with hydrolysis intermediates of phosphate esters in the system, ultimately forming phosphosilicate precursors.

[0065] In step 5, the reaction temperature should be in the range of approximately 20 to approximately 80°C, for example, approximately 30°C, approximately 40°C, approximately 50°C, approximately 60°C, or approximately 70°C. Within this temperature range, the reaction rate is moderate, which is conducive to the full progress of the reaction and the formation of products. Here, the reaction temperature should not be too high, for example, it should not exceed approximately 80°C, because the boiling point of silicate esters is usually around 80°C. Excessive temperature will lead to the volatilization and loss of reactants, and may also cause the reaction rate to be too fast, resulting in uneven distribution of material elements; nor should it be too low, for example, it should not be below approximately 20°C, otherwise the reaction rate may be too slow or the reaction may not even be initiated.

[0066] Furthermore, in step 5, the reaction time should be in the range of approximately 2 to approximately 24 hours, for example, approximately 6 hours, approximately 10 hours, approximately 14 hours, approximately 18 hours, or approximately 22 hours. Here, the reaction time should not be too long, for example, it should not exceed approximately 24 hours; otherwise, on the one hand, continuing the reaction after it is complete is meaningless and may also lead to product aggregation; on the other hand, it should not be too short, for example, it should not be less than approximately 2 hours; otherwise, the reaction may be incomplete.

[0067] Step 6, Post-processing: Step 6 includes separating the phosphosilicate precursor solid obtained from step 5 from the suspension, optionally washing and drying it, and then calcining it at a calcination temperature of about 500 to about 900°C for about 2 to about 6 hours to obtain the phosphosilicate-based bioactive material.

[0068] The calcination in step 6 can remove the organic components in the phosphosilicate precursor solid, promote the dehydration and bonding of calcium hydroxide and silanol groups, and improve the stability of the product.

[0069] In step 6, the separation process is not particularly limited and can employ methods such as filtration, vacuum filtration, or centrifugation. For example, in some preferred embodiments of the present invention, the separation process may include centrifuging the reaction product at a speed of about 3000 to about 8000 rpm for about 5 to about 15 minutes, thereby effectively separating the phosphosilicate precursor solid from the suspension.

[0070] In step 6, the optional washing process may include washing the separated phosphosilicate precursor solid with deionized water and ethanol alternately 3, 4 or 5 times to remove impurities and unreacted raw materials adsorbed on the precipitate surface.

[0071] In step 6, the optional drying process is not particularly limited, and may include air drying, vacuum drying, freeze drying, and oven drying. For example, in some preferred embodiments of the invention, the drying process may include drying the separated phosphosilicate precursor solid at a temperature of about 60 to about 100°C for about 6 to about 24 hours, thereby sufficiently removing moisture and organic solvents from the precipitate.

[0072] Furthermore, in step 6, it is preferable to heat the phosphosilicate precursor solid to the calcination temperature at a heating rate of about 2 to about 10 °C / min after washing and drying. Here, the heating rate should not be too fast, for example, not exceeding about 10 °C / min, otherwise the organic matter may not be fully decomposed, leading to carbonization and material denaturation; nor should it be too slow, for example, not below about 2 °C / min, otherwise the material preparation efficiency may be reduced.

[0073] The calcination process can be carried out, for example, in a muffle furnace. The calcination temperature should be in the range of about 500 to about 900°C, for example, about 600°C, about 700°C, or about 800°C. Here, the calcination temperature should not be too high, for example, it should not exceed about 900°C, otherwise it may cause the material to crystallize, thereby causing the material to lose its activity; nor should it be too low, for example, it should not be lower than about 500°C, otherwise it may cause the material to be difficult to form.

[0074] The calcination process should last for approximately 2 to 6 hours, for example, approximately 3 hours, approximately 4 hours, or approximately 5 hours. The calcination time should not be too long, for example, not exceeding approximately 6 hours, otherwise it would result in unnecessary waste of time and energy if the reaction were already complete; nor should it be too short, for example, not less than approximately 2 hours, otherwise it might lead to incomplete reaction.

[0075] After calcination, the obtained phosphosilicate-based bioactive material can be naturally cooled to room temperature, for example.

[0076] According to a second aspect of the present invention, the present invention provides a phosphosilicate-based bioactive material prepared by the preparation method according to the first aspect of the present invention. The phosphosilicate-based bioactive material according to the second aspect of the present invention preferably possesses one or more of the following properties: The phosphosilicate-based bioactive material is a porous particle composed of particles with a primary particle size in the range of about 50 to about 100 nm. The phosphosilicate-based bioactive material has at least approximately 100 μm 2 The specific surface area per g is preferably at least about 113.3 m². 2 Specific surface area per g; The phosphosilicate-based bioactive material has D 50 Not exceeding about 7 μm, preferably not exceeding about 6.86 μm, and / or D 98 The particle size should not exceed about 17 μm, preferably not exceed about 16.24 μm.

[0077] Example: The present invention will now be described in further detail with reference to specific embodiments.

[0078] All chemical substances used in the following examples are commercially available analytical grade chemicals.

[0079] Examples 1 to 4: Preparation of Phosphosilicate-based Bioactive Materials Step 1: Preparation of aqueous solution: Mix the amount of emulsifier shown in Table 1 with about 50 g of deionized water, stir at the temperature shown in Table 1 for the time shown in Table 1, so that the emulsifier is completely dissolved, and obtain an aqueous solution of emulsifier as the aqueous solution containing emulsifier. Step 2: Preparation of oil phase solution: Add about 10 mL of tetraethyl orthosilicate to about 50 mL of water-soluble organic solvent and stir for the time shown in Table 1 to make the mixture homogeneous, thereby obtaining an organic solution of tetraethyl orthosilicate as the oil phase solution containing liquid silicate esters. Step 3: Preparation of emulsion system: The oil phase solution obtained from step 2 is slowly added dropwise to the aqueous phase solution obtained from step 1 under stirring, and then stirred for a period of time at the emulsification stirring speed to form a stable oil-in-water emulsion system. The emulsification stirring speed and emulsification stirring time are shown in Table 1. Step 4: Construction of the reaction system: Add the amounts of calcium source and optional other metal source as shown in Table 1, and the amounts of organophosphorus source as shown in Table 1, to the emulsion system obtained from Step 3 under stirring, and continue stirring for the stirring time shown in Table 1 to make the mixture homogeneous. Step 5: Reaction process: The mixture obtained from Step 4 is kept in a constant temperature water bath at the temperatures shown in Table 1 for the reaction times shown in Table 1 to carry out the reaction and form a suspension containing phosphosilicate precursor solids. Step 6: Post-processing: After the reaction in step 5 is completed, the suspension of the reaction product is centrifuged under the conditions shown in Table 1 to collect the precipitate; the precipitate is then washed several times alternately with deionized water and ethanol; the washed precipitate is thoroughly dried at the temperature and time shown in Table 1, placed in a muffle furnace, heated to the temperature shown in Table 1 at the heating rate shown in Table 1, calcined for the calcination time shown in Table 1, and finally naturally cooled to room temperature to obtain the phosphosilicate-based bioactive material.

[0080] Table 1

[0081] Test case The phosphosilicate-based bioactive materials prepared in Examples 1 to 4 above were subjected to morphological and performance tests, including testing the physical properties such as morphology, particle size, and specific surface area. Compositional characterization was performed using scanning electron microscopy-energy dispersive spectroscopy (SEM-EDS), inductively coupled plasma optical emission spectroscopy (ICP-OES), Fourier transform infrared spectroscopy (FT-IR), and differential thermal analysis (DTA). Their bioactivity was characterized by comparing X-ray diffraction before and after mineralization. Details are shown below.

[0082] Test Example 1: Microstructure Testing of Phosphosilicate-Based Bioactive Material Particles Scanning electron microscopy (SEM) analysis of samples of phosphosilicate-based bioactive materials prepared in Examples 1 to 4 revealed that the samples consisted of particles with a primary particle size ranging from approximately 50 to approximately 100 nm (see attached specification). Figure 1 Porous particles formed by accumulation (see instruction manual appendix) Figure 2 ).

[0083] Test Example 2: Specific Surface Area Test of Phosphosilicate-Based Bioactive Materials To further characterize the microstructure of the phosphosilicate-based bioactive materials prepared in the embodiments of the present invention, the specific surface area of ​​the phosphosilicate-based bioactive materials prepared in Examples 1 to 4 was tested using the nitrogen adsorption method. The test results are shown in Table 2 below. Table 2

[0084] As can be seen from the results in Table 2 above, the phosphosilicate-based bioactive materials obtained in Examples 1 to 4 of the present invention all have at least approximately 100 μm 2 The specific surface area is / g, and in Example 2 it can even reach about 200 m². 2 Specific surface area above / g.

[0085] Test Example 3: Particle Size Testing of Phosphosilicate-Based Bioactive Materials The particle size of the phosphosilicate-based bioactive materials prepared in Examples 1 to 4 was tested, specifically using a laser particle size analyzer with water as the dispersion medium. The test results are shown in Table 3 below. Table 3:

[0086] The particle size distribution of the phosphosilicate-based bioactive material particles obtained in Example 3 is shown in... Figure 3 As shown in Table 3 and Figure 3 The particle size distribution results show that the phosphosilicate-based bioactive materials obtained in Examples 1 to 4 of this invention all have D 50 No more than approximately 6.86 μm and D 98 Particle size not exceeding approximately 16.24 μm.

[0087] Test Example 4: Scanning Electron Microscopy Energy Dispersive Spectroscopy The phosphosilicate-based bioactive materials prepared in Examples 1-4 were sputter-coated with gold and placed in a scanning electron microscope at an appropriate magnification. They were then analyzed using energy dispersive spectroscopy (EDS) three times via a spot scan method. The EDS spectrum of the phosphosilicate-based bioactive material from Example 2 is exemplarily shown in [example image / image / image]. Figure 4 It is displayed in the middle.

[0088] The energy dispersive spectroscopy (EDS) quantitative elemental qualitative and semi-quantitative results of the phosphosilicate-based bioactive materials in Example 2 are shown in Table 4 below: Table 4:

[0089] As can be seen from the analysis results in Table 4, the phosphosilicate-based bioactive material prepared in Example 2 of the present invention is composed of calcium, silicon, phosphorus and oxygen, and the carbon may be carbon dioxide adsorbed on the surface of the material.

[0090] Test Example 5: Elemental Content Analysis The phosphosilicate-based bioactive materials prepared in Examples 1-4 were subjected to quantitative elemental analysis using inductively coupled plasma optical emission spectroscopy (ICP-OES). The detection results of the phosphosilicate-based bioactive materials obtained in Example 2 are exemplarily shown in Table 5 below: Table 5:

[0091] Test Example 6: Infrared Spectroscopy Analysis The phosphosilicate-based bioactive materials prepared in Examples 1-4 were pressed into tablets with potassium bromide and then subjected to infrared spectroscopy analysis using an infrared spectrometer. The infrared spectral results of the phosphosilicate-based bioactive material obtained in Example 2 are exemplarily provided in the appendix to the specification. Figure 5 It is displayed in the middle.

[0092] The infrared spectral results of the phosphosilicate-based bioactive material obtained in Example 2 show that: ~1630 cm⁻¹ -1 and ~3440 cm -1 The nearby absorption peaks are the bending vibration peaks of HOH and the stretching vibration peaks of OH, respectively, at ~1400-1500 cm⁻¹. -1 The absorption peak may be due to carbonate vibration caused by CO2 adsorption in the environment, ~1000-1100 cm⁻¹ -1 The absorption peak (a very strong and broad peak) is the asymmetric stretching vibration peak of Si-O-Si, which is the main peak of the silicate network and is usually very broad and strong, ~560 cm⁻¹. -1 and ~600 cm -1 The absorption peak is the bending vibration peak of PO, which is the peak of the phosphate group PO4. 3- Characteristic peak, ~460-480 cm⁻¹ -1 The absorption peak is the bending vibration peak of Si-O-Si.

[0093] Test Example 7: Differential Scanning Calorimetry (DSC) Analysis The phosphosilicate-based bioactive materials prepared in Examples 1-4 were placed in a crucible and heated from room temperature to approximately 700°C at a rate of approximately 10°C / min using a differential scanning calorimeter. The differential scanning calorimetry spectrum of the phosphosilicate-based bioactive material obtained in Example 2 is exemplarily shown in the appendix to the specification. Figure 6 It is displayed in the middle.

[0094] Depend on Figure 6The results show that there is a peak between approximately 47.0℃ and approximately 76.7℃, which is an endothermic peak produced by water. The baseline is stable thereafter, indicating that the sample has good thermal stability. Within the tested temperature range, the sample did not decompose or oxidize, proving that there are no organic components in the composition. This confirms that the surface carbon element in the energy dispersive spectroscopy analysis is carbon dioxide adsorbed by the sample.

[0095] Test Example 8: Bioactivity Testing of Phosphosilicate-Based Bioactive Materials According to Appendix C, "Test Method for In Vitro Deposition of Hydroxyapatite," of the Chinese pharmaceutical industry standard YY / T 0964-2014 "Surgical Implant Bio-glass and Glass-Ceramic Materials," the phosphosilicate-based bioactive materials prepared in Examples 1 to 4 were subjected to in vitro mineralization experiments to verify their bioactivity. Specifically, the bioactivity of the phosphosilicate-based bioactive material samples prepared in Examples 1 to 4 was tested according to the following implementation methods: A glass conical flask or a polyethylene plastic bottle was used as the reaction vessel. The material was placed in the reaction vessel, and approximately 200.0 mL of SBF simulated body fluid was added for every 0.3 g of material powder. After mixing, the vessel was placed in a water bath shaker at approximately 37°C and shaken at approximately 175 rpm to conduct the mineralization experiment. After soaking the sample for approximately 48 hours, the mineralized sample was separated and rinsed with deionized water and acetone solution, respectively, and then air-dried at room temperature. The sample was then subjected to X-ray diffraction (XRD) and scanning electron microscopy (SEM) tests.

[0096] For example, the X-ray diffraction patterns of the samples from Examples 1 and 4 before and after mineralization treatment are shown in the appendix to the specification. Figure 7 .from Figure 7 As can be seen, obvious characteristic peaks of carbonate hydroxyapatite (HA) were formed after mineralization treatment; thus, it is shown that the phosphosilicate-based bioactive materials prepared by Examples 1 and 4 of the present invention have bioactivity.

[0097] Using commercially available bioactive materials (bioactive glass), the same method described above was used to test for "in vitro deposited hydroxyapatite." The characteristic peaks of hydroxyapatite could only be detected by X-ray diffraction (XRD) after the sample had been immersed for approximately 120 hours. The test spectrum is shown in the attached instruction manual. Figure 8 As shown. From Figure 7 and Figure 8 The comparison shows that the bioactivity of the phosphosilicate-based bioactive materials prepared in the embodiments of the present invention is even better than that of commercially available similar materials.

[0098] The results obtained from the above embodiments and test examples show that: the synthesis process of the phosphosilicate-based bioactive materials prepared in the embodiments of the present invention is mild and produces no pollutants; the prepared phosphosilicate-based bioactive materials have a uniform porous structure; after immersion in simulated body fluid, a bone-like apatite layer can be rapidly formed on the surface, showing excellent bioactivity, thereby achieving the purpose of the present invention.

[0099] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some or all of the technical features therein; and these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions claimed by the present invention.

Claims

1. A method for preparing a phosphosilicate-based bioactive material, characterized in that, The method includes the following steps: Step 1: Provide an aqueous solution containing an emulsifier, wherein the concentration of the emulsifier in the aqueous solution is in the range of 0.5% to 10% by weight; Step 2: Provide an oil phase solution containing liquid silicate esters, wherein the concentration of the liquid silicate esters in the oil phase solution is in the range of 15 to 60% by volume, and the solvent of the oil phase solution is a water-soluble organic solvent; Step 3: At a temperature of 20 to 30°C, the oil phase solution obtained in Step 2 is slowly added dropwise to the aqueous phase solution obtained in Step 1 under stirring, wherein the weight ratio of the aqueous phase solution to the total volume of the added oil phase solution is in the range of 0.7 g / mL to 3 g / mL, thereby forming a stable oil-in-water emulsion system. Step 4: Add a calcium source material, including calcium hydroxide and optional clean calcium source material, to the emulsion system obtained from Step 3 under stirring, and add an organophosphorus source material. Continue stirring until the mixture is homogeneous, wherein the molar ratio of phosphorus in the added organophosphorus source material to silicon in the silicate ester material is in the range of (0.1-1):1, and the molar ratio of calcium in the calcium source material to silicon in the silicate ester material is in the range of (0.1-2):

1. Step 5: React the mixture obtained from Step 4 at a temperature of 20 to 80°C for 2 to 24 hours to form a suspension containing phosphosilicate precursor solids; Step 6: Separate the phosphosilicate precursor solid obtained from Step 5 from the suspension, and after optional washing and drying, calcine it at a calcination temperature of 500 to 900°C for 2 to 6 hours to obtain the phosphosilicate-based bioactive material.

2. The preparation method according to claim 1, characterized in that, In step 1, the emulsifier comprises one or more of Tween 80, Span 80, sodium dodecyl sulfate, and polyether F68.

3. The preparation method according to claim 1, characterized in that, In step 2, The liquid silicate ester contains one or more of methyl orthosilicate, ethyl orthosilicate, and butyl orthosilicate; and / or The water-soluble organic solvent includes alcoholic organic solvents, preferably one or more of ethanol, propanol, and isopropanol.

4. The preparation method according to claim 1, characterized in that, Step 3 further includes slowly adding the oil phase solution obtained in step 2 to the aqueous phase solution obtained in step 1, stirring the resulting mixture at a stirring speed of 300 to 800 rpm for 10 to 30 minutes, and then homogenizing and emulsifying it at a homogenization speed of 3000 to 6000 rpm for 2 to 5 minutes to form a stable oil-in-water emulsion system.

5. The preparation method according to claim 1, characterized in that, In step 4, The added calcium source includes calcium hydroxide and a clean calcium source, and the ratio of calcium element in the calcium hydroxide and the clean calcium source is in the range of (2.5-5.5):1; and / or The clean calcium source material includes a water-slightly soluble calcium source, and / or The clean calcium source material includes one or more of calcium dihydrogen phosphate and calcium acetate; and / or The organophosphate source includes one or more of triethyl phosphate, inositol hexaphosphate, and glycerophosphate.

6. The preparation method according to claim 1, characterized in that, In step 4, other metal sources are added to the emulsion system obtained from step 3, along with calcium and / or organophosphorus sources.

7. The preparation method according to claim 6, characterized in that, The other metal source substances include compounds containing sodium, magnesium, and / or strontium; and / or The molar ratio of the metal cations in the other metal salts to the silicon in the silicate esters is in the range of (0-0.6):

1.

8. The preparation method according to any one of claims 1 to 7, characterized in that, In step 6, The separation process includes centrifuging the suspension containing the phosphosilicate precursor solids at a speed of 3000 to 8000 rpm for 5 to 15 minutes, thereby separating the phosphosilicate precursor solids from the suspension; and / or The washing process includes washing the separated phosphosilicate precursor solids alternately with deionized water and ethanol 3 to 5 times; and / or The drying process includes drying the separated phosphosilicate precursor solids at a temperature of 60 to 100°C for 6 to 24 hours; and / or Prior to the calcination, the phosphosilicate precursor solid is heated to the calcination temperature at a heating rate of 2 to 10 °C / min.

9. Phosphosilicate-based bioactive materials prepared by the preparation method according to any one of claims 1 to 8.

10. The phosphosilicate-based bioactive material according to claim 9, characterized in that, The phosphosilicate-based bioactive material has one or more of the following properties: The phosphosilicate-based bioactive material is a porous particle composed of particles with a primary particle size in the range of 50 to 100 nm. The phosphosilicate-based bioactive material has at least 100 μm 2 Specific surface area per g; The phosphosilicate-based bioactive material has D 50 Not exceeding 7 μm and / or D 98 Particle size not exceeding 17 μm.

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