A core-shell structure degradable polyester-inorganic composite microsphere, a preparation method and application thereof

Abstract

The application discloses a kind of degradable polyester-inorganic composite microspheres of core-shell structure and preparation method and application, belong to the field of biomedical materials.The microsphere includes the inner core formed by hydrophobic degradable polyester material, the shell layer formed by amphiphilic degradable polyester material, and at least two inorganic materials and surface modifier;The inorganic material is enriched in the inner core with hydrophobic degradable polyester after being hydrophobically modified;Inorganic material is selected from at least two of magnesium hydroxide, hydroxyapatite, beta-tricalcium phosphate, zinc oxide and barium sulfate, and active ions are released in the degradation process to achieve the synergistic function of acid-base buffering and antibacterial and anti-inflammatory.The microsphere can be applied to medical and beauty injection filling, bone defect repair and visualization-therapy integrated implant materials, with uniform particle size, precise core-shell structure, inorganic material core enrichment, multi-functional synergy and other advantages.

Description

Technical Field

[0001] This invention relates to a core-shell structured biodegradable polyester-inorganic composite microsphere, its preparation method, and its application, belonging to the field of biomedical materials. Background Technology

[0002] Core-shell microspheres, composed of core and shell materials with different properties, can integrate the characteristics of both materials, possessing composite functions that cannot be achieved by a single material. They hold broad application prospects in drug delivery, tissue engineering, and cosmetic fillers. However, hydrophobic surfaces of biodegradable polyesters such as polylactic acid (PLA), polycaprolactone (PVC), and polylactide-glycolic acid copolymers can easily trigger uncontrollable inflammatory and foreign body reactions after implantation. Furthermore, their hydrolysis and degradation in vivo release low-molecular-weight acidic products, potentially leading to local tissue acidification, enhanced cytotoxicity, and exacerbated inflammation, especially in pH-sensitive applications such as bone repair and tumor treatment. To overcome these issues, researchers have used an emulsification-solvent evaporation method. This involves first dissolving and emulsifying PLA and a first PEG-PLA to form a primary emulsion, then adding the primary emulsion to an aqueous solution containing a second PEG-PLA compound with different molecular weights for curing to form core-shell PLA microspheres with a PEG-PLA shell and a PLA core. However, this method suffers from excessively wide particle size distribution, insufficient structural control precision, and lacks integration of inorganic functional materials. Other researchers have attempted to introduce single inorganic materials with acid-base buffering capabilities (such as magnesium hydroxide and hydroxyapatite) to neutralize acidic degradation products. However, their poor compatibility with polymers often leads to technical challenges in microsphere preparation, including uneven particle size distribution, inorganic material agglomeration, and uncontrollable release behavior. Furthermore, current technologies for verifying core-shell structures primarily rely on expensive equipment such as transmission electron microscopes, making them difficult to apply under conventional laboratory conditions. Although several studies have focused on developing core-shell structured microspheres and polyester-inorganic composite microspheres, these existing technologies still suffer from common problems such as low functional integration due to the limited variety of inorganic materials, poor dispersion and easy agglomeration of inorganic materials in polymer matrices, insufficient precision in microsphere structure control, and a lack of rapid and convenient detection methods for core-shell structures. Therefore, developing a core-shell structured biodegradable polyester-inorganic composite microsphere with precise positioning of functional components within the microsphere, precise controllable structural hierarchy, high functional integration, controllable degradation, and stable processing is of significant research value and industrial importance for promoting the development of biomedical materials. Summary of the Invention

[0003] To address the shortcomings of existing technologies, this invention provides a core-shell structured biodegradable polyester-inorganic composite microsphere. The microsphere has a distinct core-shell structure, comprising a core formed by a hydrophobic biodegradable polyester material, a shell formed by an amphiphilic biodegradable polyester material, at least two inorganic materials, and a surface modifier. After being hydrophobically modified by the surface modifier, the inorganic material is enriched together with the hydrophobic biodegradable polyester material in the core. The shell is formed by the self-assembly of the amphiphilic biodegradable polyester material and covers the surface of the core. The inorganic material is selected from at least two of magnesium hydroxide, hydroxyapatite, β-tricalcium phosphate, zinc oxide, and barium sulfate, and the at least two inorganic materials synergistically release their respective active ions during the degradation of the microspheres to achieve the synergistic function of acid-base buffering and antibacterial and anti-inflammatory effects. The microspheres have a particle size of 10~200μm, a particle size variation coefficient of less than 5%, a sphericity greater than 0.9, and a surface roughness Ra of 0.5~2.0μm; Preferably, the pH of the microspheres is maintained between 6.5 and 7.8 during the degradation process in phosphate buffer, and the degradation cycle is 12 weeks to 36 months.

[0004] Preferably, the hydrophobic biodegradable polyester material is selected from one or more of polylactic acid, polycaprolactone, poly(L-lactide-glycolic acid), and poly(L-lactide-caprolactone), and the weight-average molecular weight of the hydrophobic biodegradable polyester material is 20kDa~200kDa, the molecular weight distribution width is ≤2.5, and its mass accounts for 50%~90% of the total mass of the microspheres; The amphiphilic biodegradable polyester material is selected from one or more of methoxy polyethylene glycol-block-L-polylactic acid, methoxy polyethylene glycol-block-polycaprolactone, and methoxy polyethylene glycol-block-poly(L-lactide-glycolic acid). The weight-average molecular weight of the amphiphilic biodegradable polyester material is 10kDa~100kDa, the molecular weight distribution width is ≤2.5, and its mass accounts for 10%~50% of the total mass of the microspheres. The total mass of the inorganic material accounts for 1% to 10% of the total mass of the microspheres.

[0005] Preferably, the polylactic acid is selected from one or more of L-polylactic acid, racemic polylactic acid, and D-polylactic acid. The magnesium hydroxide has a particle size of 50-200 nm; the hydroxyapatite has a particle size of 0.1-15 μm and is selected from nanowires or nanoparticles with an aspect ratio of 1:1 to 10:1; the β-tricalcium phosphate has a particle size of 0.1-15 μm; the zinc oxide has a particle size of 20-500 nm; and the barium sulfate has a particle size of 100-500 nm.

[0006] Preferably, the surface modifier is one or more of stearic acid, silane coupling agent or oleic acid, and its amount is 10% to 50% of the total mass of the inorganic material; in the amphiphilic biodegradable polyester material, the weight-average molecular weight of the polyethylene glycol block is 1kDa to 10kDa, and the weight-average molecular weight of the biodegradable polyester block is 10kDa to 100kDa.

[0007] Preferably, the at least two inorganic materials include barium sulfate and magnesium hydroxide, or barium sulfate and zinc oxide, or barium sulfate, magnesium hydroxide and zinc oxide, and the microspheres have X-ray imaging, acid-base buffering and antibacterial functions.

[0008] Preferably, when the at least two inorganic materials include magnesium hydroxide and zinc oxide, the microspheres simultaneously release Mg during the degradation process. 2+ and Zn 2+ Mg 2+ With Zn 2+ The molar release ratio is 2:1 to 6:1.

[0009] Preferably, the microspheres further comprise an active ingredient selected from one or more small molecule drugs, peptides, proteins, nucleic acids, or growth factors, and the active ingredient is loaded in the core.

[0010] Second, the present invention also provides a method for preparing the above-mentioned core-shell structured biodegradable polyester-inorganic composite microspheres, comprising the following steps: (1) Hydrophobic modification of inorganic materials: At least two inorganic materials and a surface modifier are dispersed in anhydrous ethanol and stirred at 60-80°C for 2-6 hours. After centrifugation, washing and drying, hydrophobic modified inorganic materials are obtained. The surface modifier is one or more of stearic acid, silane coupling agent or oleic acid, and its amount is 10%-50% of the total mass of the inorganic materials. (2) The hydrophobic modified inorganic material, hydrophobic biodegradable polyester material and amphiphilic biodegradable polyester material obtained in step (1) are dissolved together in an organic solvent to form an oil phase; the organic solvent is selected from one or more of dichloromethane, chloroform, acetone and ethyl acetate, and the total mass concentration of the hydrophobic biodegradable polyester material and the amphiphilic biodegradable polyester material in the oil phase is 5%~15%; (3) The oil phase obtained in step (2) is injected into a microfluidic device as the dispersed phase, and a monodisperse water-in-oil emulsion droplet is prepared using a polyvinyl alcohol aqueous solution as the continuous phase; the microfluidic device is a flow focusing type or a T-channel chip with a channel size of 50~200μm; the concentration of the polyvinyl alcohol aqueous solution is 1wt%~5wt%, and the flow rate ratio of the water phase to the oil phase is 2:1~10:1; (4) Drop the collected emulsion at 30~45℃ and stir at 150~600rpm for 6~24 hours to evaporate the organic solvent and solidify the microspheres; (5) After centrifugation, washing with deionized water and freeze drying, core-shell structured biodegradable polyester-inorganic composite microspheres were obtained.

[0011] Preferably, the hydrophobic modification reaction conditions in step (1) are: 70°C, 300 rpm stirring reaction for 4 hours; the oil phase in step (2) also contains active ingredients, which are selected from one or more of small molecule drugs, peptides, proteins, nucleic acids or growth factors.

[0012] Preferably, the polyvinyl alcohol in step (3) is polyvinyl alcohol with a degree of hydrolysis of 87%~89%; the flow rate ratio of the aqueous phase to the oil phase in step (3) is 5:1; the stirring and evaporation temperature in step (4) is 35°C, the stirring speed is 200 rpm, and the evaporation time is 8 hours.

[0013] Third, this invention also provides a rapid detection method for the core-shell structure of the above-mentioned core-shell biodegradable polyester-inorganic composite microspheres, comprising the following steps: (1) Preparation of Oil Red O staining solution: Weigh Oil Red O powder, dissolve it in an organic solvent, and prepare Oil Red O staining solution; (2) Take the dried microsphere sample, add the Oil Red O staining solution obtained in step (1), and stain by shaking on a shaker at room temperature; (3) After staining, centrifuge and discard the supernatant, add organic solvent and gently blow and rinse to remove unbound residual dye, then centrifuge again and discard the supernatant. (4) Wash with distilled water, centrifuge and discard the supernatant. Finally, resuspend the microspheres in distilled water and observe them under an optical microscope. If the core of the microsphere is red and the shell is colorless, it indicates that it has a core-shell structure.

[0014] Preferably, in the detection method, the organic solvents in steps (1) and (3) are independently selected from one or more of isopropanol, ethanol, and methanol; and the mass concentration of the Oil Red O staining solution is 0.1% to 1%.

[0015] Preferably, in the detection method, the shaking speed of the shaker in step (2) is 50~100 rpm, and the staining time is 5~15 minutes.

[0016] Fourth, the present invention also provides the application of the above-mentioned core-shell structured biodegradable polyester-inorganic composite microspheres in the preparation of facial injection filler materials, bone defect repair materials, drug controlled release carriers or imaging-therapeutic integrated implant materials.

[0017] Preferably, the facial injectable filler is an injectable filler compounded with hyaluronic acid or collagen for soft tissue regeneration and contouring.

[0018] Preferably, the bone defect repair material is a bone repair material used to fill nonunion, bone cysts, or alveolar bone defects to promote osteogenesis and vascularization.

[0019] Preferably, the imaging-therapeutic integrated implant material is an implant material used for intraoperative positioning and postoperative efficacy tracking, and for local delivery of antibiotics, antitumor drugs, anti-inflammatory factors, or growth factors.

[0020] The beneficial effects of this invention are: Compared with the prior art, the present invention has the following beneficial effects: (1) The present invention blends at least two hydrophobically modified inorganic materials with hydrophobic biodegradable polyester materials and amphiphilic biodegradable polyester materials in a specific ratio in a volatile organic solvent. The self-assembly behavior of the amphiphilic biodegradable polyester materials at the oil-water interface drives the formation of the core-shell structure. At the same time, the strong affinity between the hydrophobically modified inorganic materials and the hydrophobic biodegradable polyester materials is used to achieve the precise enrichment of inorganic materials in the core, which significantly improves the dispersion and compatibility of inorganic materials in the polyester core and avoids the aggregation and leakage of inorganic materials; (2) The present invention achieves the integration of multiple functions by selecting at least two inorganic materials and realizing their synergistic release: for example, magnesium hydroxide provides acid-base buffering capacity to neutralize acidic products of polyester degradation, zinc oxide provides broad-spectrum antibacterial and anti-inflammatory functions, barium sulfate provides X-ray imaging function, and hydroxyapatite or β-tricalcium phosphate provides calcium ion promotion Osteogenesis, multiple ion synergistic release can achieve antibacterial-osteogenic-contrast-anti-inflammatory multifunctional synergy, and the synergistic effect is significantly better than the use of each inorganic material alone; (3) The present invention is prepared by microfluidic method, the microsphere particle size distribution is extremely narrow (variance coefficient <5%), the sphericity is high (>0.9), and the degradation rate and ion release cycle can be flexibly controlled by adjusting the polyester type, molecular weight and inorganic material content. The degradation cycle can be adjusted between 12 weeks and 36 months; (4) The present invention also provides a method for rapid detection of core-shell structure by Oil Red O. By using Oil Red O to specifically stain the hydrophobic core, the core-shell structure can be quickly and intuitively determined without expensive equipment, which is suitable for routine laboratory and industrial quality control applications; (5) The preparation method of the present invention is simple to operate, has low organic solvent residue, is suitable for medical grade continuous large-scale production, and is widely applicable to various clinical needs such as facial tissue filling and regeneration, bone repair, tumor adjuvant therapy, and infection control. Attached Figure Description

[0021] Figure 1 Electron micrograph of the phase separation behavior of emulsion droplets in Example 1; Figure 2 These are the freeze-dried core-shell structured microspheres from Example 1; Figure 3 The results of water contact angle measurement are shown. The first row, from left to right, consists of the control group, Example 1, and Example 2. The second row, from left to right, consists of Example 3, Comparative Example 4, and Comparative Example 6. Figure 4 The results of Oil Red O staining of the microspheres in Example 1 are shown. Detailed Implementation

[0022] The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without creative effort are within the scope of protection of the present invention.

[0023] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to this invention. The preferred embodiments and materials described herein are for illustrative purposes only and do not limit the scope of this application.

[0024] Unless otherwise specified, the experimental methods used in the following examples are conventional methods, and the experimental materials used in the following examples are all purchased from commercial channels.

[0025] Example 1: Core-shell structured biodegradable polyester-inorganic composite microspheres (mPEG-PCL / PCL / Mg(OH)2 / ZnO) Components: Hydrophobic biodegradable polyester material: Polycaprolactone (PCL, model Capa6500, weight-average molecular weight approximately 50 kDa, molecular weight distribution width 1.8) 5g; Amphiphilic biodegradable polyester material: Methoxy polyethylene glycol-block-polycaprolactone (mPEG-PCL, mPEG block weight-average molecular weight approximately 5 kDa, PCL block weight-average molecular weight approximately 50 kDa, total weight-average molecular weight approximately 55 kDa, molecular weight distribution width 1.9) 5g, total polyester weight 10g. Inorganic materials: Magnesium hydroxide nanosheets (average particle size 100 nm, purity ≥99.5%) 0.8g, accounting for 8wt% of the total polyester mass; Zinc oxide (average particle size 40 nm, purity ≥99%) 0.2g, accounting for 2wt% of the total polyester mass; Total inorganic materials 1.0g, accounting for 9.09% of the total mass of microspheres (10g + 1.0g = 11.0g). Hydrophobic modifier: stearic acid (pharmaceutical grade, purity ≥98%) 0.3g, accounting for 30wt% of the total inorganic material mass. Active ingredient: resveratrol (purity ≥98%) 0.3g, accounting for 3wt% of the total polyester mass.

[0026] Preparation method: Weigh 0.8g of magnesium hydroxide nanosheets, 0.2g of zinc oxide, and 0.3g of stearic acid, disperse them in 50mL of anhydrous ethanol, and stir with a magnetic stirrer at 300rpm for 4 hours at 70℃. After the reaction, collect the precipitate by centrifugation at 4000rpm, wash it three times with anhydrous ethanol, and dry it under vacuum at 60℃ for 12 hours to obtain the hydrophobically modified inorganic material. Dissolve 5g of polycaprolactone, 5g of methoxy polyethylene glycol-block-polycaprolactone, 0.3g of resveratrol, and the hydrophobically modified inorganic material obtained in the previous step in 100mL of dichloromethane, and stir magnetically (400rpm) until completely dissolved (about 2 hours) to form an oil phase with a polyester material mass concentration of about 10% (10g polyester / 100mL dichloromethane). The oil phase was injected into a flow-focusing microfluidic chip (channel size 100 μm) as the dispersed phase, and the continuous phase was a 2 wt% aqueous solution of polyvinyl alcohol 1788 (degree of hydrolysis 87%~89%). The flow rate ratio of the continuous phase to the dispersed phase was controlled at 5:1, and the emulsion droplets were collected. The collected emulsion droplets were transferred to a 500 mL Erlenmeyer flask and placed in a 35℃ constant temperature water bath shaker. The solvent was evaporated by stirring at 200 rpm for 8 hours to solidify the microspheres. The solidified microspheres were centrifuged at 4000 rpm for 10 minutes, the supernatant was discarded, and the precipitate was washed three times with deionized water (50 mL deionized water each time, vortexed resuspended and centrifuged). Finally, the washed microspheres were placed in a freeze dryer and freeze-dried at a cold trap temperature of -55℃ and a vacuum degree of <100 Pa for 48 hours to obtain core-shell structured biodegradable polyester-inorganic composite microspheres, which can be used for facial anti-aging filling.

[0027] Example 2: Core-shell structured biodegradable polyester-inorganic composite microspheres (mPEG-PLLA / PLLA / HA / Mg(OH)2 / ZnO) Composition: Hydrophobic biodegradable polyester material: polylactic acid (PLLA, weight average molecular weight approximately 60 kDa, molecular weight distribution width 1.7) 8g; Amphiphilic biodegradable polyester material: methoxy polyethylene glycol-block-polylactic acid (mPEG-PLLA, mPEG block weight average molecular weight approximately 5 kDa, PLLA block weight average molecular weight approximately 50 kDa, total weight average molecular weight approximately 55 kDa, molecular weight distribution width 1.9) 2g, total polyester weight 10g. Inorganic materials: Nano-hydroxyapatite (nHA, average particle size 200nm, aspect ratio approximately 3:1, purity ≥99%) 0.5g, accounting for 5wt% of the total polyester mass; magnesium hydroxide nanosheets (average particle size 100nm, purity ≥99.5%) 0.4g, accounting for 4wt% of the total polyester mass; zinc oxide (average particle size 40nm, purity ≥99%) 0.1g, accounting for 1wt% of the total polyester mass; total inorganic materials 1.0g, accounting for 9.09% of the total mass of microspheres (10g + 1.0g = 11.0g). Hydrophobic modifier: Stearic acid (pharmaceutical grade, purity ≥98%) 0.3g, accounting for 30wt% of the total inorganic materials mass.

[0028] Preparation method: Weigh 0.5g of nano-hydroxyapatite, 0.4g of magnesium hydroxide nanosheets, 0.1g of zinc oxide, and 0.3g of stearic acid, disperse them in 50mL of anhydrous ethanol, and stir with a magnetic stirrer at 300rpm for 4 hours at 70℃. After the reaction, collect the precipitate by centrifugation at 4000rpm, wash it three times with anhydrous ethanol, and vacuum dry it at 60℃ for 12 hours to obtain the hydrophobically modified inorganic material. Dissolve 8g of L-polylactic acid, 2g of methoxy polyethylene glycol-block-L-polylactic acid, and the hydrophobically modified inorganic material obtained in the previous step in 100mL of dichloromethane, and stir magnetically (400rpm) until completely dissolved (about 2 hours) to form an oil phase with a polyester material mass concentration of about 10% (10g polyester / 100mL dichloromethane). The oil phase was injected into a flow-focusing microfluidic chip (channel size 100 μm) as the dispersed phase, and the continuous phase was a 2 wt% aqueous solution of polyvinyl alcohol 1788 (degree of alcoholysis 87%~89%). The flow rate ratio of the continuous phase to the dispersed phase was controlled at 5:1, and the emulsion droplets were collected. The collected emulsion droplets were transferred to a 500 mL Erlenmeyer flask and placed in a 35℃ constant temperature water bath shaker. The solvent was evaporated by stirring at 200 rpm for 8 hours to solidify the microspheres. The solidified microspheres were centrifuged at 4000 rpm for 10 minutes, the supernatant was discarded, and the precipitate was washed three times with deionized water (50 mL deionized water each time, vortexed resuspended and centrifuged). Finally, the washed microspheres were placed in a freeze dryer and freeze-dried at a cold trap temperature of -55℃ and a vacuum degree of <100 Pa for 48 hours to obtain core-shell structured biodegradable polyester-inorganic composite microspheres, which can be used for bone repair.

[0029] Example 3: Core-shell structured biodegradable polyester-inorganic composite microspheres (mPEG-PLGA / PLGA / BaSO4 / Mg(OH)2 / ZnO) Components: Hydrophobic biodegradable polyester material: Poly(L-lactide-glycol) (PLGA, LA:GA=50:50, weight average molecular weight approximately 35kDa, molecular weight distribution width 1.8) 7g; Amphiphilic biodegradable polyester material: Methoxy polyethylene glycol-block-poly(L-lactide-glycol) (mPEG-PLGA, mPEG block weight average molecular weight approximately 5kDa, PLGA block weight average molecular weight approximately 50kDa, total weight average molecular weight approximately 55kDa, molecular weight distribution width 1.9) 3g, total polyester weight 10g. Inorganic materials: Barium sulfate (average particle size 200nm, purity ≥99%) 0.5g, accounting for 5wt% of the total polyester mass; magnesium hydroxide nanosheets (average particle size 100nm, purity ≥99.5%) 0.4g, accounting for 4wt% of the total polyester mass; zinc oxide (average particle size 40nm, purity ≥99%) 0.1g, accounting for 1wt% of the total polyester mass; total inorganic materials 1.0g, accounting for 9.09% of the total mass of microspheres (10g + 1.0g = 11.0g). Hydrophobic modifier: Stearic acid (pharmaceutical grade, purity ≥98%) 0.3g, accounting for 30wt% of the total inorganic materials mass. Active ingredient: Doxorubicin (DOX, doxorubicin hydrochloride, purity ≥98%) 0.3g, accounting for 3wt% of the total polyester mass.

[0030] Preparation method: Weigh 0.5g barium sulfate, 0.4g magnesium hydroxide nanosheets, 0.1g zinc oxide, and 0.3g stearic acid, disperse them in 50mL anhydrous ethanol, and stir with a magnetic stirrer at 300rpm for 4 hours at 70℃. After the reaction, collect the precipitate by centrifugation at 4000rpm, wash three times with anhydrous ethanol, and vacuum dry at 60℃ for 12 hours to obtain the hydrophobically modified inorganic material. Dissolve 7g poly(L-lactide-glycolic acid), 3g methoxy polyethylene glycol-block-poly(L-lactide-glycolic acid), 0.3g doxorubicin, and the hydrophobically modified inorganic material obtained in the previous step in 100mL dichloromethane, and stir magnetically (400rpm) until completely dissolved (about 2 hours) to form an oil phase with a polyester material mass concentration of about 10% (10g polyester / 100mL dichloromethane). The oil phase was injected into a flow-focusing microfluidic chip (channel size 100 μm) as the dispersed phase, and the continuous phase was a 2 wt% aqueous solution of polyvinyl alcohol 1788 (degree of alcoholysis 87%~89%). The flow rate ratio of the continuous phase to the dispersed phase was controlled at 5:1, and the emulsion droplets were collected. The collected emulsion droplets were transferred to a 500 mL Erlenmeyer flask and placed in a 35℃ constant temperature water bath shaker. The solvent was evaporated by stirring at 200 rpm for 8 hours to solidify the microspheres. The solidified microspheres were centrifuged at 4000 rpm for 10 minutes, the supernatant was discarded, and the precipitate was washed three times with deionized water (50 mL deionized water each time, vortex resuspended and centrifuged). Finally, the washed microspheres were placed in a freeze dryer and freeze-dried at a cold trap temperature of -55℃ and a vacuum degree of <100 Pa for 48 hours to obtain core-shell structured biodegradable polyester-inorganic composite microspheres that can be used for tumor treatment and imaging.

[0031] Comparative Example 1: Single Inorganic Material Control (Contains only Mg(OH)2, excluding ZnO, and the total inorganic content is the same as in Example 1) Composition: Basically the same as in Example 1, except that the total of 1.0g of 0.8g Mg(OH)2 and 0.2g ZnO in Example 1 is replaced with 1.0g of Mg(OH)2 alone, while the other components remain unchanged (5g hydrophobic polyester PCL, 5g amphiphilic polyester mPEG-PCL, 0.3g resveratrol, 0.3g stearic acid).

[0032] Preparation method: Weigh 1.0 g of magnesium hydroxide nanosheets and 0.3 g of stearic acid, disperse them in 50 mL of anhydrous ethanol, and stir with a magnetic stirrer at 300 rpm for 4 hours at 70 °C. After the reaction, collect the precipitate by centrifugation at 4000 rpm, wash three times with anhydrous ethanol, and vacuum dry at 60 °C for 12 hours to obtain hydrophobically modified magnesium hydroxide. Dissolve 5 g of PCL, 5 g of mPEG-PCL, 0.3 g of resveratrol and the hydrophobically modified magnesium hydroxide obtained in the previous step in 100 mL of dichloromethane, and stir magnetically until completely dissolved to form an oil phase. Prepare emulsion droplets using the same microfluidic parameters as in Example 1 (flow focusing chip, channel size 100 μm, 2% PVA aqueous solution as continuous phase, water-oil flow rate ratio 5:1), evaporate the solvent at 35 °C and 200 rpm for 8 hours to solidify, centrifuge, wash with water, and freeze dry.

[0033] Comparative Example 2: Single Inorganic Material Control (Contains only ZnO, excluding Mg(OH)2, with the same total inorganic content as Example 1) Composition: Basically the same as in Example 1, except that the total of 1.0g of 0.8g Mg(OH)2 and 0.2g ZnO in Example 1 is replaced with 1.0g of ZnO alone, while the other components remain unchanged.

[0034] Preparation method: Weigh 1.0 g of zinc oxide and 0.3 g of stearic acid, disperse them in 50 mL of anhydrous ethanol, and stir the mixture at 70 °C with a magnetic stirrer at 300 rpm for 4 hours. After the reaction is complete, centrifuge at 4000 rpm to collect the precipitate, wash it three times with anhydrous ethanol, and dry it under vacuum at 60 °C for 12 hours to obtain hydrophobically modified zinc oxide. The remaining steps are exactly the same as those in Comparative Example 1.

[0035] Comparative Example 3: Two inorganic materials with doubled total content (Mg(OH)2 and ZnO, 1.0g each, with a total inorganic content twice that of Example 1) Composition: Hydrophobic PCL 5g, amphiphilic mPEG-PCL 5g, Mg(OH)2 1.0g, ZnO 1.0g (total 2.0g, accounting for 20wt% of total polyester mass), stearic acid 0.6g, resveratrol 0.3g. The remaining components remain unchanged.

[0036] Preparation method: Weigh 1.0g magnesium hydroxide, 1.0g zinc oxide and 0.6g stearic acid, and treat them according to the same hydrophobic modification method as in Comparative Example 1. Dissolve 5g PCL, 5g mPEG-PCL, 0.3g resveratrol and all hydrophobic modified inorganic materials in 100mL dichloromethane. The remaining preparation steps are exactly the same as in Example 1.

[0037] Comparative Example 4: Solid microspheres without amphiphilic polyester (without core-shell structure) Composition: 10g hydrophobic PCL (containing no amphiphilic polyesters), 0.8g Mg(OH)2, 0.2g ZnO, 0.3g stearic acid, 0.3g resveratrol. The types and contents of inorganic materials are exactly the same as in Example 1.

[0038] Preparation method: Weigh 0.8g magnesium hydroxide, 0.2g zinc oxide and 0.3g stearic acid, and treat them according to the same hydrophobic modification method as in Comparative Example 1. Dissolve 10g PCL, 0.3g resveratrol and all the hydrophobic modified inorganic materials in 100mL dichloromethane. The remaining preparation steps are exactly the same as in Example 1 (also using microfluidic method).

[0039] Comparative Example 5: Control group without hydrophobic modification of inorganic materials Composition: exactly the same as in Example 1 (Mg(OH)2 0.8g, ZnO 0.2g, PCL 5g, mPEG-PCL 5g, resveratrol 0.3g), but without the use of stearic acid to hydrophobically modify the inorganic materials.

[0040] Preparation method: 0.8g of unmodified magnesium hydroxide, 0.2g of unmodified zinc oxide, 5g of PCL, 5g of mPEG-PCL, and 0.3g of resveratrol were directly dissolved in 100mL of dichloromethane and magnetically stirred until completely dissolved. The remaining preparation steps (microfluidic parameters, curing, washing, and lyophilization) were exactly the same as in Example 1.

[0041] Comparative Example 6: Prior Art Comparison (Refer to the method in CN121445950A, but with the same combination of inorganic materials as in Example 1) For a fair comparison, this comparative example adopts the core-shell structure preparation strategy (two-step emulsification method) of the existing technology CN121445950A, but adds the same combination of inorganic materials as in Example 1 (Mg(OH)2 0.8g, ZnO 0.2g) to compare the structural control precision and functional integration effect.

[0042] Components: Core material: PCL (molecular weight 50kDa) 5g, Mg(OH)2 0.8g, ZnO 0.2g, stearic acid 0.3g; Shell material: mPEG-PCL (mPEG 5kDa-PCL 50kDa) 5g; Emulsion stabilizer: PVA 1788 type.

[0043] Preparation method: The inorganic material was hydrophobically modified using the same method as in Example 1. 5g of PCL and all the hydrophobically modified inorganic material were dissolved in 50mL of dichloromethane to form an inner oil phase. The inner oil phase was added to 200mL of a 2% PVA aqueous solution and emulsified at 800rpm for 15 minutes using a mechanical stirrer to form a primary emulsion. The primary emulsion was slowly added to 500mL of a 2% PVA aqueous solution containing 5g of mPEG-PCL, and the solvent was evaporated by stirring at 35°C and 200rpm for 8 hours to solidify. Subsequent centrifugation, washing, and lyophilization were performed in the same manner as in Example 1.

[0044] The following methods were used to test all the above embodiments and comparative examples: Data detection methods (including additions and refinements) (I) Methods for determining microsphere particle size and coefficient of variation (CV value) Approximately 100 mg of dried microspheres were dispersed in 2 mL of deionized water, with 2 drops of 0.1% Tween-80 added as a dispersant. The mixture was sonicated for 2 minutes to ensure thorough dispersion. Microsphere images were captured using an optical microscope. In ImageJ software, the following steps were performed sequentially: scale calibration, grayscale conversion, threshold separation, binarization, particle separation, and automatic analysis. The particle size of at least 500 microspheres was statistically analyzed, and the average particle size and coefficient of variation (CV) were calculated as follows: CV = (standard deviation / average particle size) × 100%.

[0045] (II) Method for determining the sphericity of microspheres The dried microsphere samples were uniformly dispersed on conductive tape and sputter-coated with gold (sputter-coating current 10mA, sputter-coating time 90 seconds). The morphology of the microspheres was observed and images were acquired using a scanning electron microscope at different magnifications. At least 5 fields of view were randomly collected for each sample, and at least 50 microspheres were randomly selected from each field of view. The major axis length (a) and minor axis length (b) of each microsphere were measured using ImageJ image analysis software. The sphericity was calculated using the formula sphericity = b / a. The average value of all measurements was taken as the sphericity of the sample.

[0046] (III) Method for measuring the surface roughness (Ra) of microspheres The surface morphology of the microspheres was scanned using atomic force microscopy. Microsphere samples were dispersed on a mica sheet surface and scanned in air using a tapping mode. The scanning range was 5 μm × 5 μm, and the scanning rate was 1.0 Hz. NanoScope Analysis software was used to perform plane fitting and roughness analysis on the scanned images. The arithmetic mean surface roughness Ra value was recorded. At least five different regions of the surface of each microsphere were measured for each sample, and the average value was taken.

[0047] (iv) Method for determining the mechanical strength (compressive strength) of microspheres A microsphere strength tester was used. Approximately 50 mg of dried microsphere sample was evenly spread on the sample stage to form a monolayer of microspheres. The probe was pressed downwards at a speed of 0.1 mm / s, with a compression distance of 80% of the microsphere layer thickness. The maximum force during compression was recorded. The compressive strength was calculated using the formula σ = Fmax / A, where Fmax is the maximum compressive force (in N) and A is the probe contact area (in mm²). 2 Each sample was measured at 10 different locations, and the average value was taken.

[0048] (v) Method for determining pH value during microsphere degradation Take 100 mg of microsphere sample and place it in a centrifuge tube containing 10 mL of phosphate-buffered saline (PBS, pH 7.4, containing 0.02% sodium azide to inhibit bacterial growth). Shake at 100 rpm in a 37°C constant temperature shaking incubator. Replace all buffer with fresh PBS every 7 days. Measure the pH of the removed buffer using a precision pH meter. Perform three replicates for each sample and take the average value.

[0049] (vi) Degradation cycle determination method The degradation cycle was defined as the time required for the microspheres to degrade in PBS to a mass loss rate of 95%. 100 mg of microspheres were placed in 10 mL of PBS and incubated at 37°C with shaking at 100 rpm. All microspheres were harvested every 4 weeks, lyophilized, weighed, and the mass loss rate was calculated. The time point when the mass loss rate was ≥95% was recorded as the degradation cycle. Three replicates were performed for each sample, and the average value was taken.

[0050] (vii) Method for determining the concentration of multiple ions released 100 mg of microsphere sample was placed in a centrifuge tube containing 10 mL of PBS (pH 7.4, containing 0.02% sodium azide) and incubated at 37°C with shaking at 100 rpm. Every 7 days, the entire buffer solution was replaced with fresh PBS. The removed buffer solution was filtered through a 0.22 μm filter, and the ion concentrations were determined using inductively coupled plasma atomic emission spectrometry (ICP-AES). Magnesium ions were measured at 285.213 nm, zinc ions at 213.857 nm, calcium ions at 317.933 nm, and barium ions at 455.403 nm. A standard curve was plotted using a series of concentration standard solutions, and the correlation coefficient R0 was calculated. 2 ≥0.999. Three parallel samples were prepared for each sample, and the average value was taken. Cumulative release over 28 days = Sum of release amounts at each time point.

[0051] (viii) Methods for determining antibacterial properties Strains were prepared: Staphylococcus aureus and Escherichia coli were inoculated separately onto tryptic soy agar plates and incubated at 37°C for 18–24 hours. Single colonies were picked and inoculated into liquid culture medium and incubated at 37°C with shaking (150 rpm) for 6–8 hours until the logarithmic growth phase. The bacterial concentration was then diluted to 1 × 10⁻⁶ with sterile physiological saline. 6 CFU / mL available for use.

[0052] Minimum inhibitory concentration (MIC) determination: The microbroth dilution method was used. 100 μL of culture medium was added to each well of a 96-well plate. 100 μL of microsphere sample suspension (prepared with sterile water, initial concentration 20 mg / mL) was added to well 1. This was serially diluted to well 10, resulting in final microsphere concentrations of 10.000, 5.000, 2.500, 1.250, 0.625, 0.313, 0.156, 0.078, 0.039, and 0.020 mg / mL for each well. 10 μL of bacterial suspension was added to each well, and the plates were incubated at 37°C for 18–24 hours. The lowest microsphere concentration that completely inhibited bacterial growth (clear liquid) was used as the MIC value.

[0053] Minimum bactericidal concentration (MBC) determination: Take 10 μL of culture medium from each well in which no bacterial growth was observed in the MIC determination, spread it on an agar plate, and incubate at 37°C for 24 hours. The lowest microsphere concentration that kills more than 99.9% of bacteria is taken as the MBC value.

[0054] Antibacterial rate determination: Take 100 mg of microsphere sample and place it in a 50 mL centrifuge tube, add 10 mL of bacterial suspension (approximately 1 × 10⁻⁶). 6 (CFU / mL), incubate at 37℃ with shaking for 24 hours (150 rpm). Take 100 μL of the culture medium and perform a 10-fold serial dilution. Take 100 μL of the appropriate dilution and spread it on a plate. Incubate at 37℃ for 24 hours and count the colonies. Inhibition rate (%) = (control viable count - sample viable count) / control viable count × 100%.

[0055] (ix) Methods for determining X-ray imaging performance Microsphere samples were dispersed in 1% agarose gel at a concentration of 10 mg / mL and injected into cylindrical molds with a diameter of 10 mm. Curing was performed at 4°C for 30 minutes. Imaging was performed using a clinical medical X-ray machine with the following parameters: tube voltage 60 kV, tube current 100 mA, exposure time 2.5 mAs, and focal length 100 cm. Pure polyester microspheres without added barium sulfate served as a negative control, and commercially available barium sulfate contrast agent (50 mg / mL) served as a positive control. Three radiologists independently scored the imaging clarity (0 points for no imaging, 1 point for slight imaging, 2 points for clear imaging, and 3 points for high-contrast clear imaging), and the average score was taken. Simultaneously, the grayscale value of the imaging area was measured using ImageJ, and the grayscale value of the positive control was normalized to 100%.

[0056] (x) Method for measuring water contact angle The microsphere material was evenly coated onto the surface of double-sided adhesive tape adhered to a glass slide using a soft brush, and any unadheded powder was blown away with a bulb syringe. 10 μL of deionized water was added using a contact angle meter, and the water contact angle was measured. Three parallel samples were prepared for each sample, and the average value was taken. The water contact angle of blank double-sided adhesive tape without any microsphere material was used as a control.

[0057] (xi) Rapid detection method for core-shell structure using Oil Red O Prepare a 0.5% (w / v) Oil Red O isopropanol solution. Place approximately 100 mg of dried microspheres into a 2 mL centrifuge tube, add 2 mL of Oil Red O staining solution, and stain by shaking at 100 rpm at room temperature for 15 min. Centrifuge at 4000 rpm for 1 min and discard the supernatant. Add 2 mL of isopropanol and wash for 1 min, centrifuge and discard the supernatant, add 2 mL of distilled water and wash, centrifuge and discard the supernatant, and finally resuspend in an appropriate amount of distilled water and observe under an optical microscope.

[0058] As shown in Table 1, Examples 1 to 3, which employed the microfluidic method, all exhibited extremely narrow particle size distributions (CV < 5%), classifying them as monodisperse microspheres. In contrast, Comparative Example 6, using a two-step emulsification method, showed an extremely high coefficient of variation in particle size, demonstrating the significant advantage of the microfluidic method in precise particle size control. Comparative Example 5, lacking hydrophobic modification of the inorganic material, exhibited inferior sphericity and surface roughness compared to Examples 1 to 3, indicating that hydrophobic modification is a crucial prerequisite for achieving uniform dispersion of inorganic materials in the polyester matrix and maintaining the integrity of the microsphere structure. Table 2 shows the degradation pH stability. The pH values ​​of Examples 1, Comparative Example 1, and Comparative Example 2 after 28 days of degradation demonstrate that Mg(OH)2 possesses excellent acid-base buffering capacity, while ZnO lacks this function. However, the combined use of both can simultaneously achieve both buffering and antibacterial functions. Example 2 maintained a physiologically suitable weakly alkaline range, further proving that the buffering strength can be flexibly controlled by adjusting the Mg(OH)2 content. From Tables 3 and 4, the MIC, antibacterial rate, and degradation pH of Comparative Examples 1 and 2 show that Comparative Examples 1 and 2 completely lack pH buffering capacity. However, Example 1 has only 1 / 5 the Zn content of Comparative Example 2. Combined with the MIC and antibacterial rate, it can be seen that even with a significantly reduced Zn content, it still maintains strong antibacterial activity close to that of Comparative Example 2, while also possessing excellent pH buffering capacity. This fully demonstrates that Mg... 2+ and Zn 2+ The synergistic effect between them allows Mg(OH)2 to maintain a neutral local microenvironment pH, preventing Zn from being affected.2+ The intense burst release and potential cytotoxicity under acidic conditions allow low doses of ZnO to exert highly efficient antibacterial function. In Examples 2 and 3, the Zn content was 1 / 10 of Comparative Example 2. Combined with MIC and inhibition rate, it can be seen that although the parameters were lower than in Example 1, a highly efficient antibacterial rate of over 90% was maintained even with a 90% reduction in Zn dosage. It also possesses pH buffering function, further verifying the core value of the synergistic Mg / Zn ratio in the integrated antibacterial-buffering design. In Comparative Example 3, doubling the total amount of Mg and Zn and changing the Mg / Zn molar ratio to 1:1 further improved the antibacterial performance, but the excessively alkaline pH was detrimental to the physiological environment, proving the scientific rationality of the preferred Mg / Zn molar ratio and the 1%~10% total inorganic content range of this invention. From the perspective of ion release, Comparative Example 5 Mg... 2+ The release rate was 3.9 times that of Example 1. Due to the lack of hydrophobic modification, inorganic materials agglomerated on the surface of the microspheres, resulting in a severe burst release, demonstrating that hydrophobic modification is a necessary prerequisite for controlled sustained release. Comparative Example 4, lacking a core-shell structure, exhibited a significantly higher ion release rate than Example 1, proving that a core-shell structure can effectively delay the release rate of core ions. Although Comparative Example 6 possessed a core-shell structure, the use of a two-step emulsification method resulted in an extremely wide particle size distribution (CV = 30.10%) and unstable ion release ratio, demonstrating the significant advantages of the microfluidic method of this invention in precise structural control and batch consistency. Furthermore, as shown in Table 4, the MIC values ​​exhibited a stepwise distribution because the serial dilution method could only measure specific concentration points. Moreover, the strong antibacterial properties of Comparative Examples 5 and 4 were due to burst release rather than controlled sustained release, further demonstrating the technical advantage of the stable release of this invention. As shown in Table 5, Example 3, containing 0.5g of barium sulfate, achieved an X-ray imaging clarity score of 2.3 and a relative grayscale value of 42%, indicating a positive correlation between the imaging effect and the BaSO4 content. The remaining samples without barium sulfate failed to develop, verifying the effectiveness of barium sulfate as a developing agent. The water contact angle results showed that Example 1, with its amphiphilic polyester shell, was significantly lower than that of Comparative Example 4, which lacked a shell, demonstrating that the amphiphilic polyester shell effectively improves the hydrophilicity of the microsphere surface, thus reducing protein adsorption and inflammatory responses.

[0059] The core-shell structure of this invention is based on the thermodynamically driven self-assembly behavior of amphiphilic biodegradable polyester at the oil-water interface. When an oil phase containing hydrophobic polyester, hydrophobically modified inorganic material, and amphiphilic polyester is sheared by the aqueous phase in a microfluidic channel to form micron-sized droplets, the hydrophobic segments PCL of the amphiphilic polyester, such as mPEG-PCL, become entangled with the hydrophobic polyester segments in the oil phase due to hydrophobic interactions, while its hydrophilic segments mPEG tend to extend into the aqueous phase to reduce the interfacial energy. This entropy-driven process causes the amphiphilic polyester to arrange itself in an orderly manner at the oil-water interface, forming a stable interfacial film. The hydrophobic polyester and the hydrophobically modified inorganic material with strong affinity for it are "squeezed" into the interior of the droplets. As the organic solvent slowly evaporates, the droplets gradually concentrate and solidify, eventually forming a core-shell structured microsphere with a hydrophobic polyester / inorganic material core and an amphiphilic polyester shell. Hydrophobic modification plays a crucial dual role in this process: on the one hand, after treatment with modifiers such as stearic acid, hydrophobic alkyl chains are grafted onto the surface of the inorganic materials, significantly improving their compatibility with hydrophobic polyesters, thus ensuring their stable locking within the core and preventing migration to the interface or aqueous phase; on the other hand, hydrophobic modification effectively reduces the tendency for aggregation between inorganic materials, allowing them to be uniformly dispersed at the nanoscale in the oil phase, guaranteeing the uniform distribution of inorganic materials within the core after subsequent solvent evaporation and curing. Unmodified inorganic materials, such as in Comparative Example 5, have surfaces rich in polar groups such as -OH, exhibiting poor compatibility with hydrophobic polyesters. They exhibit severe aggregation in the oil phase and tend to migrate to the oil-water interface or even enter the aqueous phase during emulsification, leading to increased microsphere surface roughness, decreased sphericity, and disordered distribution of inorganic materials within the microspheres, ultimately triggering a severe ion burst release, with a release amount 3.9 times that of Example 1. The synergistic release mechanism of the inorganic materials lies in the fact that during microsphere degradation, water molecules penetrate into the core, first reacting with the exposed Mg(OH)2 to release Mg. 2+ and OH - This neutralizes acidic products such as lactic acid generated during polyester degradation, maintaining the local microenvironment pH between 6.5 and 7.8. As degradation progresses, ZnO is gradually exposed and releases Zn. 2+ It provides antibacterial properties. Mg 2+ and Zn 2+ The simultaneous release of Zn produces a synergistic effect, and the buffering effect of Mg(OH)2 prevents Zn from being released. 2+ The cytotoxicity caused by burst release under acidic conditions, and Zn 2+The antibacterial effect of the core-shell structure compensates for the insufficient antibacterial activity of Mg(OH)2. Both are spatially enriched in the core and released synchronously during degradation. This precise matching is key to achieving synergistic function. The core-shell structure acts as a physical barrier, slowing down the rate of water molecule penetration into the core, thereby effectively controlling the degradation and ion release rate of the inorganic material and avoiding burst release. For example, the release amount is significantly increased in the comparative example without the shell, achieving a continuous and stable release for 20-36 weeks. This invention, through the organic combination of microfluidic technology, hydrophobic modification, and core-shell structure design, successfully achieves the precise enrichment and controllable release of inorganic materials in the core of microspheres, providing a universal platform for the development of multifunctional biomedical materials.

[0060] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims and their equivalents.

[0061] The present invention and its embodiments have been described above. This description is not restrictive, and the accompanying drawings are only one embodiment of the present invention. The actual application is not limited to this. In conclusion, if those skilled in the art are inspired by this description and design similar methods and embodiments without departing from the spirit of the present invention, they should all fall within the protection scope of the present invention.

Claims

1. A core-shell structured biodegradable polyester-inorganic composite microsphere, characterized in that, The microspheres have a distinct core-shell structure, comprising a core formed of hydrophobic biodegradable polyester material, a shell formed of amphiphilic biodegradable polyester material, at least two inorganic materials, and a surface modifier. After being hydrophobically modified by the surface modifier, the inorganic material is enriched together with the hydrophobic biodegradable polyester material in the core. The shell is formed by the self-assembly of the amphiphilic biodegradable polyester material and covers the surface of the core. The inorganic material is selected from at least two of magnesium hydroxide, hydroxyapatite, β-tricalcium phosphate, zinc oxide, and barium sulfate, and the at least two inorganic materials synergistically release their respective active ions during the degradation of the microspheres to achieve the synergistic function of acid-base buffering and antibacterial and anti-inflammatory effects. The microspheres have a particle size of 10~200μm, a particle size variation coefficient of less than 5%, a sphericity greater than 0.9, and a surface roughness Ra of 0.5~2.0μm.

2. The core-shell structured biodegradable polyester-inorganic composite microspheres according to claim 1, characterized in that, The hydrophobic biodegradable polyester material is selected from one or more of polylactic acid, polycaprolactone, poly(L-lactide-glycolic acid), and poly(L-lactide-caprolactone), and the weight-average molecular weight of the hydrophobic biodegradable polyester material is 20kDa~200kDa, the molecular weight distribution width is ≤2.5, and its mass accounts for 50%~90% of the total mass of the microspheres; The amphiphilic biodegradable polyester material is selected from one or more of methoxy polyethylene glycol-block-L-polylactic acid, methoxy polyethylene glycol-block-polycaprolactone, and methoxy polyethylene glycol-block-poly(L-lactide-glycolic acid). The weight-average molecular weight of the amphiphilic biodegradable polyester material is 10kDa~100kDa, the molecular weight distribution width is ≤2.5, and its mass accounts for 10%~50% of the total mass of the microspheres. The total mass of the inorganic material accounts for 1% to 10% of the total mass of the microspheres.

3. The core-shell structured biodegradable polyester-inorganic composite microspheres according to claim 1, characterized in that, The surface modifier is one or more of stearic acid, silane coupling agent or oleic acid, and its amount is 10% to 50% of the total mass of the inorganic material; in the amphiphilic biodegradable polyester material, the weight average molecular weight of the polyethylene glycol block is 1kDa to 10kDa, and the weight average molecular weight of the biodegradable polyester block is 10kDa to 100kDa.

4. The core-shell structured biodegradable polyester-inorganic composite microspheres according to claim 1, characterized in that, The at least two inorganic materials include barium sulfate and magnesium hydroxide, or barium sulfate and zinc oxide, or barium sulfate, magnesium hydroxide and zinc oxide, and the microspheres have X-ray imaging, acid-base buffering and antibacterial functions.

5. The core-shell structured biodegradable polyester-inorganic composite microspheres according to claim 1, characterized in that, The microspheres also contain an active ingredient selected from one or more small molecule drugs, peptides, proteins, nucleic acids, or growth factors, which is loaded into the core.

6. A method for preparing core-shell structured biodegradable polyester-inorganic composite microspheres according to any one of claims 1 to 5, characterized in that, Includes the following steps: (1) Hydrophobic modification of inorganic materials: Disperse at least two inorganic materials and surface modifiers in anhydrous ethanol, stir and react at 60~80℃ for 2~6 hours, centrifuge, wash and dry to obtain hydrophobic modified inorganic materials; The surface modifier is one or more of stearic acid, silane coupling agent or oleic acid, and its amount is 10% to 50% of the total mass of the inorganic material; (2) The hydrophobic modified inorganic material, hydrophobic biodegradable polyester material and amphiphilic biodegradable polyester material obtained in step (1) are dissolved together in an organic solvent to form an oil phase; the organic solvent is selected from one or more of dichloromethane, chloroform, acetone and ethyl acetate, and the total mass concentration of the hydrophobic biodegradable polyester material and the amphiphilic biodegradable polyester material in the oil phase is 5%~15%; (3) The oil phase obtained in step (2) is injected into a microfluidic device as the dispersed phase, and a monodisperse water-in-oil emulsion droplet is prepared using a polyvinyl alcohol aqueous solution as the continuous phase; the microfluidic device is a flow focusing type or a T-channel chip with a channel size of 50~200μm; the concentration of the polyvinyl alcohol aqueous solution is 1wt%~5wt%, and the flow rate ratio of the water phase to the oil phase is 2:1~10:1; (4) Drop the collected emulsion at 30~45℃ and stir at 150~600rpm for 6~24 hours to evaporate the organic solvent and solidify the microspheres; (5) After centrifugation, washing with deionized water and freeze drying, core-shell structured biodegradable polyester-inorganic composite microspheres were obtained.

7. The preparation method according to claim 6, characterized in that, The hydrophobic modification reaction conditions in step (1) are: 70℃, 300rpm stirring reaction for 4 hours; the oil phase in step (2) also contains active ingredients, which are selected from one or more of small molecule drugs, peptides, proteins, nucleic acids or growth factors.

8. The preparation method according to claim 6, characterized in that, The polyvinyl alcohol mentioned in step (3) is polyvinyl alcohol with a degree of alcoholysis of 87%~89%; the flow rate ratio of the water phase to the oil phase in step (3) is 5:1; the stirring and evaporation temperature in step (4) is 35℃, the stirring speed is 200rpm, and the evaporation time is 8 hours.

9. A rapid detection method for the core-shell structure of biodegradable polyester-inorganic composite microspheres according to any one of claims 1 to 5, characterized in that, Includes the following steps: (1) Preparation of Oil Red O staining solution: Weigh Oil Red O powder, dissolve it in an organic solvent, and prepare Oil Red O staining solution; (2) Take the dried microsphere sample, add the Oil Red O staining solution obtained in step (1), and stain by shaking on a shaker at room temperature; (3) After staining, centrifuge and discard the supernatant, add organic solvent and gently blow and rinse to remove unbound residual dye, then centrifuge again and discard the supernatant. (4) Wash with distilled water, centrifuge and discard the supernatant. Finally, resuspend the microspheres in distilled water and observe them under an optical microscope. If the core of the microsphere is red and the shell is colorless, it indicates that it has a core-shell structure.

10. The application of the core-shell structured biodegradable polyester-inorganic composite microspheres according to any one of claims 1 to 5, or the core-shell structured biodegradable polyester-inorganic composite microspheres prepared by the preparation method according to any one of claims 6 to 8, in the preparation of facial injection filler materials, bone defect repair materials, drug controlled release carriers, or imaging-therapeutic integrated implant materials.

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