Composite microspheres of gallium-containing biomimetic mineralized particles and polydopamine nanoparticles, and preparation method and application thereof

Abstract

This invention provides a composite microsphere of gallium-containing biomimetic mineralization particles and polydopamine nanoparticles, and its preparation method. The composite microsphere is composed of polydopamine nanoparticles adsorbed and embedded in the nanostructure of the gallium-containing biomimetic mineralization particles on the surface and inside. The polydopamine nanoparticles are distributed in an embedded and dispersed manner within the gallium-containing biomimetic mineralization particles. This invention integrates gallium-containing biomimetic mineralization particles and polydopamine nanoparticles through redox reactions and self-polymerization reactions. This not only significantly increases the anti-infection properties of gallium-containing nanomaterials, but also utilizes the advantages of polydopamine to significantly promote osteogenic differentiation and improve the biocompatibility and stability of the composite material.

Description

Technical Field

[0001] This invention relates to the fields of nanomaterials technology, biomedical engineering, and anti-infective therapy, and particularly to a composite microsphere containing gallium-inspired biomimetic mineral particles and polydopamine nanoparticles, its preparation method, and its application. Background Technology

[0002] With the increasing prevalence of antibiotic resistance, the development of novel anti-infective materials and treatment strategies has become a global challenge. Traditional antibiotic treatments are facing problems such as declining antibacterial efficacy and increased side effects; therefore, finding and developing new anti-infective methods is particularly important. In recent years, the application of nanotechnology in the biomedical field has provided new ideas for anti-infective therapy. Among them, gallium-containing nanomaterials have shown great potential in the field of anti-infectives due to their unique physical and chemical properties. Gallium can interfere with bacterial metabolic processes, thereby inhibiting bacterial growth. However, single gallium-containing nanomaterials still have limitations in practical applications, such as poor biocompatibility and insufficient stability.

[0003] Polymeric dopamine nanoparticles have been widely used in drug delivery, bioimaging, and other fields due to their good biocompatibility, ease of functionalization, and excellent stability. The synthesis of polymeric dopamine is simple and can be rapidly prepared through the oxidative self-polymerization of dopamine. Furthermore, the surface of polymeric dopamine is rich in phenolic hydroxyl groups, making it easy to further functionalize.

[0004] Therefore, in the clinical treatment of infectious bone defects, existing bone filling materials lack antibacterial properties, have poor osteogenic properties, are resistant to antibiotic bone cement beads, are non-absorbable, and have poor osteogenic effects. It is necessary to develop novel anti-infective composite microspheres, which are expected to provide a new, efficient, and safe strategy for anti-infective treatment. Summary of the Invention

[0005] The purpose of this invention is to provide a composite microsphere containing gallium-inspired biomimetic mineral particles and polydopamine nanoparticles, its preparation method and application. This composite microsphere is highly efficient, safe and easy to prepare, and can be used for antibacterial treatment in the medical and health field, especially for the treatment of diseases such as infectious bone defects in orthopedics, exhibiting excellent broad-spectrum antibacterial effects and good biocompatibility.

[0006] In a first aspect of the present invention, a composite microsphere of gallium-containing biomimetic mineralization particles and polydopamine nanoparticles is provided. The composite microsphere is composed of polydopamine nanoparticles adsorbed and embedded in the nanostructures on the surface and inside of the gallium-containing biomimetic mineralization particles, wherein the polydopamine nanoparticles are distributed in an embedded and dispersed manner in the gallium-containing biomimetic mineralization particles.

[0007] The polydopamine nanoparticles are spherical nanoparticles;

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

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

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

[0011] A gallium-containing solution was added to the simulated body fluid to obtain a modified simulated body fluid.

[0012] The modified simulated body fluid was reacted under high temperature and high pressure, and then naturally cooled, filtered, and dried to obtain gallium-containing biomimetic mineralized particles.

[0013] Dopamine hydrochloride was dissolved in water, then an initiator was added, the pH was adjusted, and the mixture was heated and stirred to react. After centrifugation, washing, and drying, polydopamine nanoparticles were obtained.

[0014] By integrating the gallium-containing biomimetic mineralized particles with the polymeric dopamine nanoparticles, composite microspheres containing gallium-containing biomimetic mineralized particles and polydopamine nanoparticles are obtained.

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

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

[0017] This invention integrates gallium-containing biomimetic mineralized particles with polymeric dopamine nanoparticles through redox and self-polymerization reactions. This not only leverages the anti-infective properties of gallium-containing nanomaterials but also utilizes the advantages of polymeric dopamine to improve the biocompatibility and stability of the composite material. Specifically, it offers the following effects:

[0018] (1) Highly effective antibacterial properties: This invention utilizes the excellent antibacterial properties of gallium and combines it with polydopamine nanoparticles through a biomimetic mineralization process. The resulting composite microspheres have significant broad-spectrum antibacterial effects against a variety of bacteria, effectively inhibiting and killing pathogens and reducing the risk of infection.

[0019] (2) Good biocompatibility: Polydopamine nanoparticles have good biocompatibility, which makes the composite microspheres of the present invention safer to use 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 and mild, requiring no complex equipment, which facilitates large-scale production and application, and helps to reduce production costs and promote its use.

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

[0022] (5) The anti-infective 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-infective ability of the composite microspheres, thereby improving the treatment effect and the patient's quality of life. Attached Figure Description

[0023] To more clearly illustrate the technical solutions in the embodiments of the present invention, the accompanying drawings used in the description of the embodiments will be briefly introduced below. Obviously, the accompanying drawings described below are some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

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

[0025] Figure 2 The TEM morphology of the gallium-containing biomimetic mineralized microspheres prepared in this invention at different magnifications.

[0026] Figure 3 The curves show the release of gallium from the composite microspheres over time.

[0027] Figure 4 Colony counting results were obtained after 24 hours of incubation of the mixed bacterial colonies with composite microspheres. Left image: Inoculated with only Staphylococcus aureus solution, without composite microspheres; Right image: Inoculated with a mixed solution of S. aureus and composite microspheres.

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

[0030] Figure 7 Micro-CT images of the osteogenic effects of polydopamine nanoparticles, gallium-containing mineralized particles, and composite microspheres in 1-month-old rats with skull defects.

[0031] Figure 8 This is a schematic flowchart illustrating the preparation method of composite microspheres containing gallium-containing biomimetic mineralized particles and polydopamine nanoparticles provided in an embodiment of the present invention. Detailed Implementation

[0032] The present invention will be described in detail below with reference to specific embodiments and examples, thereby making the advantages and various effects of the present invention more clearly apparent. Those skilled in the art should understand that these specific embodiments and examples are for illustrative purposes only and are not intended to limit the present invention.

[0033] Throughout this specification, unless otherwise specified, the terminology used herein should be understood as having the meaning commonly used in the art. Therefore, unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. In the event of any conflict, this specification shall prevail.

[0034] Unless otherwise specified, all raw materials, reagents, instruments and equipment used in this invention can be obtained by purchasing them from the market or by existing methods.

[0035] The overall concept of this invention is as follows:

[0036] According to a typical embodiment of the present invention, a composite microsphere of gallium-containing biomimetic mineralization particles and polydopamine nanoparticles is provided. The composite microsphere is composed of polydopamine nanoparticles adsorbed and embedded in the nanostructures on the surface and inside of the gallium-containing biomimetic mineralization particles. The polydopamine nanoparticles are distributed in an embedded and dispersed manner in the gallium-containing biomimetic mineralization particles.

[0037] The polydopamine nanoparticles are spherical nanoparticles;

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

[0039] The inventors of this application discovered that:

[0040] The composite microspheres obtained by combining gallium-containing biomimetic mineralized particles with polymeric dopamine nanoparticles have significantly stronger antibacterial effects and osteogenic differentiation-promoting efficacy than either polydopamine nanoparticles alone or gallium-containing biomimetic mineralized particles alone, resulting in an unexpected technical effect of 1+1>2.

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

[0042] Step S1: Add a gallium-containing solution to the simulated body fluid to obtain a modified simulated body fluid;

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

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

[0045] The gallium-containing solution includes one or more gallate solutions, such as gallium chloride solution and gallium nitrate solution;

[0046] The volume ratio of the simulated body fluid to the gallium-containing solution ranges from 100:1 to 10000:1.

[0047] Step S2: The modified simulated body fluid is reacted under high temperature and high pressure, then naturally cooled, filtered, and dried to obtain gallium-containing biomimetic mineralized particles.

[0048] In step S2

[0049] The conditions for high temperature and high pressure include: a temperature range of 60 to 220°C, a pressure range of 63.4 kPa to 205.8 kPa, and a pH range of approximately 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 gallium-containing calcium phosphate microspheres. This process may take from several hours to several days, depending on the required microsphere size and structure.

[0051] The biomimetic mineralization reaction involves collecting the formed calcium phosphate microspheres after mineralization by centrifugation and filtration, and washing them 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 from the biomimetic mineralization reaction: The structure and composition of the prepared gallium-containing biomimetic mineralized calcium phosphate microspheres were analyzed by scanning electron microscopy (SEM), X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR) to confirm that they meet the expected requirements.

[0053] Step S3: Dissolve dopamine hydrochloride in water, then add an initiator, adjust the pH value, heat and stir to react, then centrifuge, wash and dry 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 a suitable concentration (range 1 wt%-10 wt%). The concentration of dopamine directly affects the size and yield of the final polymerized dopamine nanoparticles.

[0055] Furthermore, the pH of the solution is adjusted: the pH of the solution is adjusted to alkalinity using sodium hydroxide (NaOH) or hydrochloric acid (HCl), typically between 8.0 and 9.0, to promote the oxidative polymerization of dopamine. The heating and stirring reaction: under continuous stirring, dopamine begins to oxidatively polymerize in the presence of oxygen (oxygen from the air is sufficient). This process can be carried out at room temperature, but can also be accelerated by heating to 35-50°C. The reaction time ranges from several hours to a day, depending on the desired nanoparticle size and degree of polymerization.

[0056] The high-speed centrifugation, washing, and drying process involves separating the polymerized dopamine nanoparticles by centrifugation after the polymerization reaction is complete, and then washing them with water or a suitable solvent to remove unreacted dopamine and byproducts. The nanoparticles are then 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 polydopamine nanoparticles were characterized by dynamic light scattering (DLS), transmission electron microscopy (TEM), and Fourier transform infrared spectroscopy (FTIR) to confirm that they meet the expected requirements.

[0058] Step S4: Integrate the gallium-containing biomimetic mineralized particles with the polymeric dopamine nanoparticles to obtain composite microspheres of gallium-containing biomimetic mineralized particles and polymeric dopamine nanoparticles.

[0059] Furthermore, the mass ratio of the gallium-containing biomimetic mineralized particles to the polymerized dopamine nanoparticles ranges from 1:10 to 10:1. A mass ratio less than 1:10 is detrimental to the integration of the composite microspheres, and the osteogenic efficacy is significantly weakened after compositing, hindering osteogenic differentiation. A mass ratio greater than 10:1 is also detrimental to the integration of the composite microspheres, and excessive gallium content reduces the biocompatibility of the composite microspheres.

[0060] Furthermore, the biomimetic mineralized particles of gallium are mixed with the polymeric dopamine nanoparticles and the pH is adjusted to the range of 7-7.8. If the pH value is too low, the biomimetic mineralized particles will decompose, and their structure and composition will change. If the pH value is too high, the polymeric dopamine nanoparticles will become unstable, and the integration of the composite microspheres will be more difficult.

[0061] The composite microspheres are prepared by mixing and stirring a gallium-containing biomimetic mineralized microsphere solution with a polymeric dopamine nanoparticle solution. Utilizing the adhesive and reducing properties of dopamine, a polymeric dopamine nanoparticle layer is formed on the surface and within the pores of the biomimetic mineralized microspheres. This not only enhances the stability of the composite microspheres but also further strengthens their antibacterial osteointegration properties.

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

[0063] Through the above steps, a composite microsphere can be constructed that contains both gallium-containing biomimetic mineralized microspheres that are antibacterial and promote osteointegration, and polymeric dopa nanoparticles that enhance adhesion and functionalize. This composite microsphere can effectively inhibit bacterial infection while improving osteogenic differentiation.

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

[0065] Example 1

[0066] A method for preparing anti-infection composite microspheres of gallium-containing biomimetic mineralized particles and polydopamine nanoparticles includes 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. Simultaneously, slowly add 100 mg of ammonium persulfate (APS) to the solution as an initiator, and continue stirring to ensure that the APS is completely dissolved.

[0069] 3. Maintain stirring for 24 hours to promote the oxidative polymerization of dopamine, forming polydopamine nanoparticles. The resulting polydopamine nanoparticles are as follows: Figure 1 As shown.

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

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

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

[0073] 6. Add the mSBF solution to a glass bottle, loosen the cap, and react in a high-pressure steam sterilizer at 120℃ for 6 hours. Remove the bottle, allow it to cool naturally, filter through filter paper, and dry to obtain gallium-containing biomimetic mineralized particles for later use. The TEM structure of the obtained gallium-containing biomimetic mineralized particles is shown below. Figure 2 As shown.

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

[0075] 8. Measure 50 mL of the polydopamine nanoparticle solution (5 mg / mL) prepared in step 4. Ensure the solution is thoroughly stirred before mixing to guarantee uniform dispersion of the polydopamine nanoparticles.

[0076] 9. Under continuous stirring, slowly pour 50 mL of polydopamine nanoparticle solution into 50 mL of the biomimetic mineralized microsphere (2 mg / mL) solution prepared in step 6. The pouring rate should be controlled at 2 drops per second to avoid aggregation caused by excessively high local concentrations.

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

[0078] 11. Solvents were removed by rotary evaporation or freeze-drying to obtain anti-infection composite microspheres of gallium-containing biomimetic mineralized particles and polymerized dopamine nanoparticles.

[0079] Comparative Example 1

[0080] The comparative example is a biomimetic mineralized particle containing gallium, prepared using the same steps as in Example 1.

[0081] Comparative Example 2

[0082] The comparative example is polydopamine nanoparticles, prepared using the same steps as in Example 1.

[0083] Example 2

[0084] The preparation method of the composite microspheres containing gallium-containing biomimetic mineralization particles and polydopamine nanoparticles in this embodiment is the same as in Example 1, except that the reaction conditions of the simulated body fluid under high temperature and high pressure are changed to "reaction in a high-pressure steam sterilizer at 100°C for 8 hours and then removal", and the ratio of gallium-containing biomimetic mineralization particles to polydopamine nanoparticles is changed to 1:2 wt%. The specific operation steps are as follows:

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

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

[0087] 2. Add the mSBF solution to a glass bottle, loosen the cap, react in a high-pressure steam sterilizer at 120℃ for 6 hours, remove the bottle, allow it to cool naturally, filter it with filter paper, and dry it to obtain gallium-containing biomimetic mineralized particles for later use.

[0088] 3. Collect gallium-containing biomimetic mineral particles by centrifugation, wash them several times with deionized water, 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 pH of the solution to 8.5.

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

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

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

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

[0094] Experiment Example 1, Application Experiment

[0095] Comparative experiments were conducted to evaluate the anti-infection effects of the anti-infection composite microspheres (Example 1) compared to polydopamine nanoparticles alone (Comparative Example 1) and gallium-containing biomimetic mineralized particles alone (Comparative Example 2).

[0096] a. The anti-infection composite microspheres prepared in Example 1 were dispersed in physiological saline to simulate a body fluid environment. The gallium release curve is shown below. Figure 3 As shown.

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

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

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

[0100] e. The anti-infective effects of the anti-infective composite microspheres (Example 1) compared to those of polydopamine nanoparticles alone (Comparative Example 1) and gallium-containing biomimetic mineralized particles alone (Comparative Example 2) are as follows: Figure 5 , Figure 6 As shown, the antibacterial effect of the composite microspheres is significantly stronger than that of the individual polydopamine nanoparticles and the individual gallium-containing biomimetic mineralized particles for Staphylococcus aureus and Escherichia coli.

[0101] f. SD rats were selected to construct a skull defect model. Equal amounts of polydopamine nanoparticles, gallium-containing biomimetic mineralization particles, and composite microspheres were added to the skull defect site. The osteogenic effect on the skull was observed after one month of rat culture. Figure 7 As shown in the image, Micro-CT scans of the skull defects in the composite microsphere group revealed that newly formed bone almost completely filled the skull defects. In contrast, the rats in the polydopamine nanoparticle and gallium-containing biomimetic mineralization particle groups still exhibited significant skull defects and poor osteogenic effects. This indicates that the composite microspheres are significantly more effective in promoting osteogenic differentiation than either the gallium-containing mineralization particles or the polydopamine nanoparticles alone.

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

[0103] Although preferred embodiments of the invention have been described, those skilled in the art, upon learning the basic inventive concept, can make other changes and modifications to these embodiments. Therefore, the appended claims are intended to be interpreted as including both the preferred embodiments and all changes and modifications falling within the scope of the invention.

[0104] Obviously, those skilled in the art can make various modifications and variations to this invention without departing from its spirit and scope. Therefore, if these modifications and variations fall within the scope of the claims of this invention and their equivalents, this invention also intends to include these modifications and variations.

Claims

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

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

3. A method for preparing composite microspheres of gallium-containing biomimetic mineralized particles and polydopamine nanoparticles according to any one of claims 1-2, characterized in that, The method includes: A modified simulated body fluid was obtained by adding a gallium-containing solution to the simulated body fluid. The modified simulated body fluid was reacted under high temperature and high pressure, and then naturally cooled, filtered, and dried to obtain gallium-containing biomimetic mineralized particles. Dopamine hydrochloride was dissolved in water, then an initiator was added, the pH was adjusted, and the mixture was heated and stirred to react. After centrifugation, washing, and drying, polydopamine nanoparticles were obtained. By integrating the gallium-containing biomimetic mineralized particles with the polydopamine nanoparticles, composite microspheres containing gallium-containing biomimetic mineralized particles and polydopamine nanoparticles are obtained.

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

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

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

4.

7. The preparation method according to claim 3, characterized in that, The mass ratio of the gallium-containing biomimetic mineralized particles to the polymeric dopamine nanoparticles ranges from 1:10 to 10:

1.

8. The use of the composite microspheres of gallium-containing biomimetic mineralized particles and polydopamine nanoparticles as described in any one of claims 1-2 in the preparation of anti-infective drugs.

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