Composite microsphere containing gallium biomimetic mineralized particles and polydopamine nanoparticles as well as preparation method and application of composite microsphere

Abstract

The invention provides a composite microsphere of gallium-containing biomimetic mineralized particles and polydopamine nanoparticles and a preparation method of the composite microsphere, the composite microsphere is formed by adsorbing and embedding the polydopamine nanoparticles into nano structures on the surfaces and inside the gallium-containing biomimetic mineralized particles, the polydopamine nano particles are distributed in the gallium element-containing biomimetic mineralization particles in an embedded and dispersed manner; according to the preparation method disclosed by the invention, the bionic mineralized particles containing the gallium element and the polymerized dopamine nanoparticles are integrated through an oxidation-reduction reaction and a self-polymerization reaction, so that not only is the anti-infection characteristic of the gallium-containing nano material remarkably improved, but also the advantages of polymerized dopamine can be utilized, osteogenic differentiation is remarkably promoted, and the biocompatibility and the stability of the composite material are improved.

Description

Technical Field

[0001] The present invention relates to the fields of nanomaterial technology, biomedical engineering and anti-infection treatment, and in particular to a composite microsphere containing gallium-containing bionic mineralized particles and polydopamine nanoparticles, and a preparation method and application thereof. Background Art

[0002] With the increasing severity of antibiotic resistance, the development of new anti-infection materials and treatment strategies has become a global challenge. Traditional antibiotic treatment is facing problems such as decreased antibacterial effect and increased side effects. Therefore, it is particularly important to find and develop new anti-infection methods. In recent years, the application of nanotechnology in the biomedical field has provided new ideas for anti-infection treatment. Among them, nanomaterials containing gallium have shown great potential in the field of anti-infection due to their unique physical and chemical properties. Gallium can interfere with the metabolic process of bacteria, thereby inhibiting bacterial growth. However, single gallium-containing nanomaterials still have limitations in practical applications, such as poor biocompatibility and insufficient stability.

[0003] Polymerized dopamine nanoparticles have been widely used in drug delivery, bioimaging and other fields due to their good biocompatibility, easy functionalization and excellent stability. The synthesis process of polymerized dopamine is simple and can be quickly prepared through the oxidative self-polymerization reaction of dopamine. The surface of polymerized dopamine is rich in phenolic hydroxyl groups, which is easy to further functionalize.

[0004] Therefore, in view of the problems in clinical treatment of infected bone defects such as lack of antibacterial properties, poor osteogenesis, antibiotic bone cement bead resistance, inability to absorb and poor osteogenesis in existing bone filling materials, it is necessary to develop new anti-infective composite microspheres, which is expected to provide an efficient and safe new strategy for anti-infection treatment. Summary of the invention

[0005] The purpose of the present invention is to provide a composite microsphere containing gallium biomimetic mineralized particles and polydopamine nanoparticles, and a preparation method and application thereof. The composite microsphere is efficient, safe, and easy to prepare. It is used for antibacterial treatment in the medical and health field, especially for the treatment of diseases such as orthopedic infected bone defects, and exhibits excellent broad-spectrum antibacterial effects and good biocompatibility.

[0006] In a first aspect of the present invention, a composite microsphere of gallium-containing biomimetic mineralized particles and polydopamine nanoparticles is provided, wherein the composite microsphere is composed of polydopamine nanoparticles adsorbed and embedded in the surface and internal nanostructures of gallium-containing biomimetic mineralized particles, wherein the polydopamine nanoparticles are distributed in an embedded and diffuse manner in the gallium-containing biomimetic mineralized particles;

[0007] The polydopamine nanoparticles are spherical nanoparticles;

[0008] The gallium-containing bionic mineralized particles are obtained by doping gallium ions into bionic mineralized particles, and the bionic mineralized particles are composed of the following substances in mass fractions: 1-80wt% carbonated hydroxyapatite, 2-90wt% hydroxyapatite, 0-60wt% white calcium phosphate, 0-40wt% amorphous calcium phosphate, and 0-50wt% tricalcium phosphate.

[0009] Furthermore, the diameter of the polydopamine nanoparticles is between 50-500 nm; the biomimetic mineralized particles are irregular nanoparticles, and the particle size distribution is between 200 nm and 5 μm.

[0010] In a second aspect of the present invention, a method for preparing composite microspheres containing gallium-containing biomimetic mineralized particles and polydopamine nanoparticles is provided, the method comprising:

[0011] A solution containing gallium is added to the simulated body fluid to obtain an improved simulated body fluid;

[0012] reacting the modified simulated body fluid under high temperature and high pressure, and then naturally cooling, filtering, and drying to obtain bionic mineralized particles containing gallium elements;

[0013] Dopamine hydrochloride is dissolved in water, and then an initiator is added, the pH value is adjusted, heated and stirred for reaction, and then centrifuged, washed and dried to obtain polydopamine nanoparticles;

[0014] The bionic mineralized particles containing gallium element and the polymerized dopamine nanoparticles are integrated to obtain composite microspheres of bionic mineralized particles containing gallium element and polydopamine nanoparticles.

[0015] In the third aspect of the present invention, there is provided the use of the composite microspheres of the gallium-containing biomimetic mineralized particles and polydopamine nanoparticles in the preparation of anti-infective drugs.

[0016] One or more technical solutions in the embodiments of the present invention have at least the following technical effects or advantages:

[0017] The present invention integrates gallium-containing bionic mineralized particles and polymerized dopamine nanoparticles through redox reaction and self-polymerization reaction, which can not only give full play to the anti-infection properties of gallium-containing nanomaterials, but also utilize the advantages of polymerized dopamine to improve the biocompatibility and stability of the composite material. Specifically, it has the following effects:

[0018] (1) Highly effective antibacterial property: The present invention utilizes the excellent antibacterial properties of gallium and combines it with polydopamine nanoparticles through a biomimetic mineralization process. The prepared composite microspheres have significant broad-spectrum antibacterial effects against a variety of bacteria, can effectively inhibit and kill pathogens, and reduce the risk of infection.

[0019] (2) Good biocompatibility: Polydopamine nanoparticles have good biocompatibility, which makes the composite microspheres of the present invention safer when used in vivo, reduces stimulation and inflammatory response to host tissues, and is suitable for medical applications that directly contact sensitive tissues.

[0020] (3) Simple preparation method: The preparation process of the present invention is simple, the conditions are mild, and no complicated equipment is required, which is convenient for large-scale production and application, and helps to reduce production costs and promote use.

[0021] (4) Strong controllability: By adjusting the ratio of polydopamine nanoparticles and gallium-containing mineralized particles, reaction conditions, etc., the size, morphology and antibacterial properties of the composite microspheres can be controlled to meet the needs of different application scenarios.

[0022] (5) The anti-infection composite microspheres can be widely used in existing fields, such as artificial joints, dental implants, orthopedic fixation devices, etc., effectively improving the biocompatibility, bone integration speed and anti-infection ability of the composite microspheres, thereby improving the treatment effect and the quality of life of patients. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] In order to more clearly illustrate the technical solutions in the embodiments of the present invention, the accompanying drawings required for use in the description of the embodiments will be briefly introduced below. Obviously, the accompanying drawings in the following description are some embodiments of the present invention. For ordinary technicians in this field, other accompanying drawings can be obtained based on these accompanying drawings without paying creative work.

[0024] Figure 1 The SEM morphology of polydopamine nanoparticles at different magnifications.

[0025] Figure 2 TEM morphologies of gallium-containing bionic mineralized microspheres prepared in the present invention at different magnifications of the transmission electron microscope.

[0026] Figure 3 This is the release curve of gallium in the composite microspheres over time.

[0027] Figure 4 The colony counts were obtained after culturing the composite microspheres mixed with bacterial colonies for 24 hours. Left: Inoculated with Staphylococcus aureus (S. aureus) solution only, without composite microspheres; Right: Inoculated with a mixed solution of S. aureus and composite microspheres.

[0028] Figure 5 The antibacterial rates of polydopamine nanoparticles, gallium-containing mineralized particles and composite microspheres against S. aureus at 1 hour, 3 hours, 6 hours and 18 hours.

[0029] Figure 6Comparison of the antibacterial rates of polydopamine nanoparticles, gallium-containing mineralized particles and composite microspheres against Escherichia coli (E. coli) at 1 hour, 3 hours, 6 hours and 18 hours.

[0030] Figure 7 Micro-CT representation of the osteogenesis of polydopamine nanoparticles, gallium-containing mineralized particles and composite microspheres in the skull defect of one-month-old rats.

[0031] Figure 8 A schematic flow chart of a method for preparing composite microspheres of gallium-containing biomimetic mineralized particles and polydopamine nanoparticles provided in an embodiment of the present invention. DETAILED DESCRIPTION

[0032] The present invention will be described in detail below in conjunction with specific implementations and examples, and the advantages and various effects of the present invention will be more clearly presented. It should be understood by those skilled in the art that these specific implementations and examples are used to illustrate the present invention, rather than to limit the present invention.

[0033] Throughout the specification, unless otherwise specifically stated, the terms used herein should be understood as meanings commonly used in the art. Therefore, unless otherwise defined, all technical and scientific terms used herein have the same meanings as those generally understood by those skilled in the art to which the present invention belongs. In the event of a conflict, the present specification takes precedence.

[0034] Unless otherwise specified, various raw materials, reagents, instruments and equipment used in the present invention can be purchased from the market or obtained by existing methods.

[0035] The general idea of ​​the present invention is as follows:

[0036] According to a typical embodiment of the present invention, a composite microsphere of gallium-containing biomimetic mineralized particles and polydopamine nanoparticles is provided, wherein the composite microsphere is composed of polydopamine nanoparticles adsorbed and embedded in the nanostructure on the surface and inside of gallium-containing biomimetic mineralized particles, wherein the polydopamine nanoparticles are distributed in an embedded and diffuse manner in the gallium-containing biomimetic mineralized particles;

[0037] The polydopamine nanoparticles are spherical nanoparticles;

[0038] The gallium-containing bionic mineralized particles are obtained by doping gallium ions into bionic mineralized particles, and the bionic mineralized particles are composed of the following substances in mass fractions: 1-80wt% carbonated hydroxyapatite, 2-90wt% hydroxyapatite, 0-60wt% white calcium phosphate, 0-40wt% amorphous calcium phosphate, and 0-50wt% tricalcium phosphate.

[0039] The inventors of this application discovered that:

[0040] The antibacterial effect and the ability to promote osteogenic differentiation of the composite microspheres obtained by combining the bionic mineralized particles containing gallium elements with the polymerized dopamine nanoparticles in the present invention are significantly stronger than those of the single polydopamine nanoparticles and the single bionic mineralized particles containing gallium elements, and have an unexpected technical effect of 1+1>2.

[0041] According to another typical embodiment of the present invention, a method for preparing composite microspheres of gallium-containing biomimetic mineralized particles and polydopamine nanoparticles is provided, the method comprising:

[0042] Step S1, adding a solution containing gallium element to the simulated body fluid to obtain improved simulated body fluid;

[0043] In step S1, when preparing the simulated body fluid (mSBF for short), a solution containing calcium ions, phosphate ions and gallium ions is first prepared. Common calcium sources and phosphorus sources include calcium chloride (CaCl2) and sodium phosphate (Na3PO4), and the gallium source can be gallium nitrate (Ga(NO3)3) and the like. The pH value of the solution is adjusted and maintained by adding a buffer (such as HEPES). The mSBF contains an appropriate amount of mineralization inducers, such as polyacrylic acid (PAA), polyaspartic acid (PASP), and the like.

[0044] As a specific embodiment, the formula composition of the simulated body fluid is: Na + 142mmol / L, Mg 2+ 1.5mmol / L, Ca 2+ 2.5-5.0mmol / L, K + 5.0mmol / L, (HPO4) 2- 1.0-2.0mmol / L, Cl - 147.8mmol / L, (HCO3) - 4.2mmol / L, (SO4) 2- 0.5mmol / L, polycarboxylate 1μmol / L, the solvent is ultrapure water; the polycarboxylate is one of polyacrylic acid and polyaspartic acid or a mixture of the two in any proportion.

[0045] The solution containing gallium element includes one or more of gallium salt solution, such as gallium chloride solution and gallium nitrate solution;

[0046] The volume ratio of the simulated body fluid to the solution containing the gallium element is in the range of 100:1-10000:1;

[0047] Step S2, reacting the modified simulated body fluid under high temperature and high pressure, and then naturally cooling, filtering, and drying to obtain bionic mineralized particles containing gallium elements;

[0048] In the step S2,

[0049] The high temperature and high pressure conditions include: a temperature range of 60 to 220° C., a pressure range of 63.4 kPa to 205.8 kPa, and a pH of about 7.3 to 7.4.

[0050] The reaction under high temperature and pressure is a biomimetic mineralization reaction: under the above conditions, calcium, phosphorus and gallium ions will gradually combine in the solution to form calcium phosphate microsphere particles containing gallium. This process may take several hours to several days, depending on the desired microsphere size and structure.

[0051] The biomimetic mineralization reaction: After the mineralization is completed, the formed calcium phosphate microspheres are collected by centrifugation, filtration, etc., and washed with water or a suitable solvent to remove unreacted ions and impurities. The microspheres are then dried for further use or analysis.

[0052] Characterization of the nanoparticles obtained by the bionic mineralization reaction: The structure and composition of the prepared bionic mineralized calcium phosphate microspheres containing gallium are analyzed by scanning electron microscopy (SEM), X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR) and other techniques to confirm that they meet the expected requirements.

[0053] Step S3, dissolving dopamine hydrochloride in water, then adding an initiator, adjusting the pH value, heating and stirring for reaction, then centrifuging, washing, and drying to obtain polydopamine nanoparticles;

[0054] In step S3, the dopamine solution is prepared by dissolving dopamine powder in a Tris-HCl buffer solution (pH 8.5) to prepare a solution of appropriate concentration (concentration range is 1wt%-10wt%). The concentration of dopamine will directly affect the size and yield of the polymerized dopamine nanoparticles finally formed.

[0055] Furthermore, the pH value of the solution is adjusted: sodium hydroxide (NaOH) or hydrochloric acid (HCl) is used to adjust the pH value of the solution to alkaline, usually between 8.0 and 9.0, to promote the oxidative polymerization reaction of dopamine. The heated stirring reaction: under continuous stirring, dopamine begins oxidative polymerization in the presence of oxygen (oxygen in the air). This process can be carried out at room temperature, but the reaction can also be accelerated by heating to 35-50°C. The reaction time is from several hours to one day, and the specific time depends on the size and degree of polymerization of the desired nanoparticles.

[0056] The high-speed centrifugation, washing, and drying: After the polymerization reaction is completed, the polymerized dopamine nanoparticles are separated by centrifugation and washed with water or a suitable solvent to remove unreacted dopamine and by-products. Then, the nanoparticles are redispersed in water or a desired solvent, or freeze-dried to obtain a powdered product.

[0057] Characterization of the obtained polydopamine nanoparticles: The structure and properties of the prepared polymerized dopamine nanoparticles were characterized by dynamic light scattering (DLS), transmission electron microscopy (TEM), Fourier transform infrared spectroscopy (FTIR) and other techniques to confirm that they met the expected requirements.

[0058] Step S4, integrating the bionic mineralized particles containing gallium element and the polymerized dopamine nanoparticles to obtain composite microspheres of bionic mineralized particles containing gallium element and polydopamine nanoparticles.

[0059] Furthermore, the mass ratio of the gallium-containing bionic mineralized particles to the polymerized dopamine nanoparticles is in the range of 1:10-10:1. If the mass ratio is less than 1:10, it is not conducive to the integration of the composite microspheres. At the same time, the osteogenic efficiency after the composite is greatly weakened, which is not conducive to osteogenic differentiation. If it is greater than 10:1, it is also not conducive to the integration of the composite microspheres. At the same time, too high gallium elements lead to reduced biocompatibility of the composite microspheres.

[0060] Furthermore, the bionic mineralized particles of the gallium element are specifically mixed with the polymerized dopamine nanoparticles and the pH is adjusted to the range of 7-7.8. If the pH value is too small, the bionic mineralized particles will decompose and the structure and composition will change. If the pH value is too high, the polydopamine nanoparticles will become unstable and the integration of the composite microspheres will be difficult.

[0061] Preparation of the composite microspheres: The biomimetic mineralized microsphere solution containing gallium and the polymerized dopamine nanoparticle solution are mixed and stirred, and the polymerized dopamine nanoparticle layer is formed on the surface and in the pores of the biomimetic mineralized microspheres by utilizing the adhesion and reducibility of dopamine. This can not only enhance the stability of the composite microspheres, but also further enhance the antibacterial bone integration performance of the composite microspheres.

[0062] Characterization of the obtained composite microspheres: The structure and composition of the composite microspheres were analyzed using scanning electron microscopy (SEM), X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR) and other techniques.

[0063] Through the above steps, composite microspheres containing gallium-containing biomimetic mineralized microspheres that are antibacterial and promote bone integration, and polymerized DOPA nanoparticles that enhance adhesion and functionality can be constructed. The composite microspheres can effectively inhibit bacterial infection while improving osteogenic differentiation.

[0064] The present application will be described in detail below with reference to embodiments and experimental data.

[0065] Example 1

[0066] A method for preparing anti-infection composite microspheres containing gallium-containing biomimetic mineralized particles and polydopamine nanoparticles comprises the following steps:

[0067] 1. Weigh 500 mg of dopamine hydrochloride and dissolve it in 100 mL of 0.05 M Tris-HCl buffer solution (pH 8.5) to prepare a 5 mg / mL dopamine solution.

[0068] 2. At room temperature, place the prepared dopamine solution on a magnetic stirrer and start stirring at 500 rpm. At the same time, slowly add 100 mg of ammonium persulfate (APS) as an initiator to the solution and continue stirring to ensure that APS is completely dissolved.

[0069] 3. Maintain stirring reaction for 24 hours to promote oxidative polymerization of dopamine to form polydopamine nanoparticles. The obtained polydopamine nanoparticles are as follows Figure 1 shown.

[0070] 4. After the reaction is completed, the polymerized dopamine nanoparticles are collected by centrifugation, washed several times with deionized water, and finally dispersed in water for later use.

[0071] 5. Prepare mSBF solution: Mix appropriate amount of calcium ion source (such as calcium nitrate Ca(NO3)2), phosphate source (such as diammonium phosphate (NH4)2HPO4), and appropriate amount of KCl, NaHCO3, MgCl2, NaSO4, and stir to dissolve with deionized water as solvent. Then add appropriate amount of Ga(NO3)2, stir, and adjust the composition of mSBF to: Na + 142mmol / L, Mg 2+ 1.5mmol / L, K + 5.0mmol / L, Ca 2+

[0072] 5.0mmol / L, Cl - 147.8mmol / L, (HCO3) - 4.2mmol / L, (HPO4) 2- 2.0mmol / L, (SO4) 2- 0.5mmol / L, Ca 2+ 0.5mmol / L Add appropriate amount of polyaspartic acid to 0.2mmol / L and adjust the pH to 7.3.

[0073] 6. Add the mSBF solution into a glass bottle, loosen the bottle cap, react in a high pressure steam sterilizer at 120°C for 6 hours, take it out, cool it naturally, filter it with filter paper, and dry it to obtain the gallium-containing bionic mineralized particles for use; the TEM structure of the obtained gallium-containing bionic mineralized particles is as follows: Figure 2 shown.

[0074] 7. Collect the bionic mineralized particles containing gallium by centrifugation, wash them with deionized water for several times, and finally disperse them in water for later use.

[0075] 8. Take 50 mL of the polydopamine nanoparticle solution (5 mg / mL) prepared in step 4. Make sure the solution is fully stirred before mixing to ensure that the polydopamine nanoparticles are evenly dispersed.

[0076] 9. Under continuous stirring, slowly pour 50 mL of polydopamine nanoparticle solution into 50 mL of biomimetic mineralized microsphere (2 mg / mL) solution prepared in step 6. The pouring speed is controlled at 2 drops per second to avoid aggregation caused by excessive local concentration.

[0077] 10. Maintain stirring at 300 rpm for 3 hours to allow the polydopamine nanoparticles to be fully adsorbed on the surface of the biomimetic mineralized microspheres.

[0078] 11. The solvent is removed by rotary evaporation or freeze drying to obtain anti-infection composite microspheres containing gallium-containing bionic mineralized particles and polymerized dopamine nanoparticles.

[0079] Comparative Example 1

[0080] This comparative example is bionic mineralized particles containing gallium element, and the preparation steps are the same as those of Example 1.

[0081] Comparative Example 2

[0082] This comparative example is polydopamine nanoparticles, and the preparation steps are the same as those in Example 1.

[0083] Example 2

[0084] The preparation method of the composite microspheres of gallium-containing biomimetic mineralized particles and polydopamine nanoparticles in this embodiment is the same as that in Example 1, except that the reaction conditions of the simulated body fluid under high temperature and high pressure are changed to "reacting under high pressure steam sterilization pot at 100°C for 8 hours and then taking out", and the gallium-containing biomimetic mineralized particles and the polymerized dopamine nanoparticles are mixed in a 1:2 ratio by wt%, and the other steps are as follows:

[0085] 1. Prepare mSBF solution: Mix appropriate amount of calcium ion source (such as calcium nitrate Ca(NO3)2), phosphate source (such as ammonium dihydrogen phosphate (NH4)2HPO4), and appropriate amount of KCl, NaHCO3, MgCl2, NaSO4, and stir to dissolve with deionized water as solvent. Then add appropriate amount of Ga(NO3)2 and stir, and adjust the composition of mSBF to: Na + 142mmol / L, Mg 2+ 1.5mmol / L, K + 5.0mmol / L, Ca 2+

[0086] 5.0mmol / L, Cl - 147.8mmol / L, (HCO3) - 4.2mmol / L, (HPO4) 2- 2.0mmol / L, (SO4) 2- 0.5mmol / L, Ca 2+ 0.5mmol / L Add appropriate amount of polyaspartic acid to 0.2mmol / L and adjust the pH to 7.3.

[0087] 2. Add the mSBF solution into a glass bottle, loosen the bottle cap, react in a high pressure steam sterilizer at 120°C for 6 hours, take it out, cool it naturally, filter it with filter paper, and dry it to obtain the gallium-containing bionic mineralized particles for use;

[0088] 3. Collect the bionic mineralized particles containing gallium by centrifugation, wash them with deionized water for several times, and finally disperse them in water for later use.

[0089] 4. Dissolve an appropriate amount of dopamine hydrochloride in 0.05M Tris-HCl buffer solution to prepare 1L of 0.1M dopamine hydrochloride solution and adjust the solution pH to 8.5.

[0090] 5. Add 100 mL of 0.01 M ammonium persulfate as an initiator to the solution under stirring and react for 12 hours.

[0091] 6. After the reaction is completed, the polymerized dopamine nanoparticles are collected by centrifugation, washed several times with deionized water, and finally dispersed in water for later use.

[0092] 7. The gallium-containing biomimetic mineralized particles prepared in step 3 and the polymerized dopamine nanoparticles prepared in step 6 are mixed in a ratio of 1:2. Under stirring conditions, the pH of the mixed solution is adjusted to 7.4 to promote the integration of the two.

[0093] 8. The solvent is removed by rotary evaporation or freeze drying to obtain anti-infection composite microspheres containing gallium-containing biomimetic mineralized particles and polymerized dopamine nanoparticles.

[0094] Experimental Example 1: Application Experiment

[0095] The anti-infection effect of the anti-infection composite microspheres (Example 1) and the single polydopamine nanoparticles (Comparative Example 1) and the single biomimetic mineralized particles containing gallium (Comparative Example 2) were evaluated by comparative experiments.

[0096] a. The anti-infection composite microspheres prepared in Example 1 were dispersed in physiological saline to simulate the body fluid environment. The release curve of the gallium element is as follows: Figure 3 shown.

[0097] b. Inoculate bacteria (Staphylococcus aureus) into the solution containing anti-infection composite microspheres, and observe and record the growth of bacteria. The colony count effect of bacterial culture in composite microspheres is as follows: Figure 4 shown.

[0098] c. Inoculate bacteria (Staphylococcus aureus) into the polydopamine nanoparticles prepared in step 4, and observe and record the growth of the bacteria.

[0099] d. Inoculate bacteria (Staphylococcus aureus) into the biomimetic mineralized particles containing gallium prepared in step 7, and observe and record the growth of the bacteria.

[0100] e. The anti-infection effect of the anti-infection composite microspheres (Example 1) and the single polydopamine nanoparticles (Comparative Example 1) and the single biomimetic mineralized particles containing gallium (Comparative Example 2) are as follows Figure 5 , Figure 6 As shown, for Staphylococcus aureus and Escherichia coli, the antibacterial effect of the composite microspheres was significantly stronger than that of the single polydopamine nanoparticles and the single gallium-containing biomimetic mineralized particles.

[0101] f. SD rats were selected to construct a skull defect model. Equal amounts of polydopamine nanoparticles, biomimetic mineralized particles containing gallium, and composite microspheres were added to the skull defect of the rats. The osteogenesis of the skull was observed after the rats were cultured for 1 month. Figure 7 As shown in the figure, Micro-CT of skull defects in the composite microsphere group showed that the new bone almost completely filled the skull defects. However, rats in the polydopamine nanoparticle and gallium-containing biomimetic mineralized particle groups still had a large number of skull defects and poor osteogenesis. This shows that the composite microspheres are significantly more effective in promoting osteogenic differentiation than the individual gallium-containing mineralized particles and polydopamine nanoparticles.

[0102] Finally, it should be noted that the terms "comprises," "includes," or any other variations thereof are intended to cover non-exclusive inclusion, such that a process, method, article, or apparatus that includes a series of elements includes not only those elements, but also other elements not explicitly listed, or also includes elements that are inherent to such process, method, article, or apparatus.

[0103] Although the preferred embodiments of the present invention have been described, those skilled in the art may make other changes and modifications to these embodiments once they have learned the basic creative concept. Therefore, the appended claims are intended to be interpreted as including the preferred embodiments and all changes and modifications that fall within the scope of the present invention.

[0104] Obviously, those skilled in the art can make various changes and modifications to the present invention without departing from the spirit and scope of the present invention. Thus, if these modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalents, the present invention is also intended to include these modifications and variations.

Claims

1. A composite microsphere containing gallium-containing biomimetic mineralized particles and polydopamine nanoparticles, characterized in that: The composite microspheres are composed of polydopamine nanoparticles adsorbed and embedded in the surface and internal nanostructures of gallium-containing biomimetic mineralized particles, wherein the polydopamine nanoparticles are distributed in an embedded and diffuse manner in the gallium-containing biomimetic mineralized particles; The polydopamine nanoparticles are spherical nanoparticles; The gallium-containing bionic mineralized particles are obtained by doping gallium ions into bionic mineralized particles, and the bionic mineralized particles are composed of the following substances in mass fractions: 1-80wt% carbonated hydroxyapatite, 2-90wt% hydroxyapatite, 0-60wt% white calcium phosphate, 0-40wt% amorphous calcium phosphate, and 0-50wt% tricalcium phosphate.

2. The composite microspheres of gallium-containing biomimetic mineralized particles and polydopamine nanoparticles according to claim 1, characterized in that: The diameter of the polydopamine nanoparticles is between 50-500nm; the bionic mineralized particles are irregular nanoparticles, and the particle size distribution is between 200nm-5μm.

3. A method for preparing composite microspheres containing gallium-containing biomimetic mineralized particles and polydopamine nanoparticles, characterized in that: The method comprises: A solution containing gallium is added to the simulated body fluid to obtain an improved simulated body fluid; reacting the modified simulated body fluid under high temperature and high pressure, and then naturally cooling, filtering, and drying to obtain bionic mineralized particles containing gallium elements; Dopamine hydrochloride is dissolved in water, and then an initiator is added, the pH value is adjusted, heated and stirred for reaction, and then centrifuged, washed and dried to obtain polydopamine nanoparticles; The bionic mineralized particles containing gallium element and the polymerized dopamine nanoparticles are integrated to obtain composite microspheres of bionic mineralized particles containing gallium element and polydopamine nanoparticles.

4. The preparation method according to claim 3, characterized in that: The solution containing gallium element is a gallate solution.

5. The preparation method according to claim 3, characterized in that: The high temperature and high pressure conditions include: a temperature range of 60-220° C. and a pressure range of 63.4 kPa-205.8 kPa.

6. The preparation method according to claim 3, characterized in that: The initiator includes one or more of ammonium persulfate, potassium persulfate, nitrogen-nitrogen tetramethylethylenediamine, and azobisisobutyronitrile. The addition ratio of the initiator to the dopamine hydrochloride is in the range of 0.1wt%-5wt%, and the pH value is in the range of 7.3-7.

4.

7. The preparation method according to claim 3, characterized in that: The mass ratio of the bionic mineralized particles containing gallium elements to the polymerized dopamine nanoparticles is in the range of 1:10-10:

1.

8. Use of the composite microspheres of gallium-containing biomimetic mineralized particles and polydopamine nanoparticles according to any one of claims 1 to 2 in the preparation of anti-infective drugs.

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