Surface controllable microspheres with controllable cracking and mineralization, and preparation method and application thereof

Abstract

This invention discloses a microsphere with controllable surface cracking and mineralization, its preparation method, and its applications. This invention forms a uniform and robust mineralized layer by precisely controlling the crack structure on the microsphere surface and utilizing this crack structure to provide physically confined nucleation sites. The surface-controlled cracking and mineralization microspheres of this invention exhibit a degradation rate matching bone regeneration. Furthermore, this invention has advantages such as simple process, easy scale-up, no need for expensive equipment, and suitability for mass production.

Description

Technical Field

[0001] This invention belongs to the field of biomedical polymer materials technology, and in particular relates to a microsphere with controllable surface cracking and mineralization, its preparation method and application. Background Technology

[0002] Poly(p-dioxanone) (PPDO) possesses excellent biodegradability, flexibility, and biocompatibility, and has been used in surgical sutures, tissue engineering scaffolds, and other applications. To enhance its bone repair capabilities, surface modification is often employed, such as plasma treatment, collagen or gelatin coating, and bioactive glass composites.

[0003] In recent years, bone filling materials in the form of microspheres (such as artificial bone powder and alveolar bone filling materials) have attracted attention due to their good fluidity, injectability, and ability to fill irregular defects.

[0004] PPDO has a hydrophobic surface and lacks osteoinductive activity, so direct application cannot promote mineralization. Existing surface modification methods struggle to form uniform and controllable micro / nano structures on microsphere surfaces, particularly lacking precise control over these structures. Mineralization often relies on surface functional groups or rough structures, but the inertness of PPDO surfaces makes it difficult to form uniform mineralization layers with poor adhesion.

[0005] Therefore, there is an urgent need for a new method to form a controllable micro / nano structure and a uniform mineralized layer with strong bonding on the surface of PPDO microspheres. Summary of the Invention

[0006] To address at least some of the technical problems in the prior art, this invention provides microspheres with controllable surface cracking and mineralization, a method for their preparation, and their applications. Specifically, this invention includes the following:

[0007] In a first aspect, the present invention provides a microsphere with controllable surface cracking and mineralization, comprising a polydioxanone sphere and a mineralization layer, wherein the surface of the polydioxanone sphere has a controllable cracking structure to provide physically confined nucleation sites, and the mineralization layer is formed at the nucleation sites provided by the cracking structure.

[0008] In some embodiments, the microspheres with controllable surface cracking and mineralization according to the present invention, wherein the depth of the crack structure is 0.1-15 μm.

[0009] In some embodiments, the microspheres with controllable surface cracking and mineralization according to the present invention have a particle size of 50-500 μm.

[0010] In some embodiments, the microspheres with controllable surface cracking and mineralization according to the present invention, wherein the mineralization layer comprises at least one of hydroxyapatite, calcium silicate, tricalcium phosphate, tetracalcium phosphate, calcium pyrophosphate, calcium dihydrogen phosphate, calcium hydrogen phosphate, octacalcium phosphate, calcium carbonate, calcium peroxide, calcium citrate, and calcium sulfate.

[0011] A second aspect of the invention provides a composition for bone repair or bone filling, comprising microspheres with controllable surface cracking and mineralization as described in this invention.

[0012] A third aspect of the present invention provides a method for preparing microspheres with controllable surface cracking and mineralization according to the present invention, comprising the following steps: (1) Using an alkaline solution to etch polydioxanone microspheres, polydioxanone microspheres with a controllable cracking structure on the surface are obtained. (2) The polydioxanone microspheres with a controllable cracking structure on the surface are mineralized in a mineralizing solution to obtain microspheres with controllable cracking and mineralization on the surface.

[0013] In some embodiments, according to the method for preparing microspheres with controllable surface cracking and mineralization according to the present invention, the alkaline solution includes NaOH solution and / or KOH solution.

[0014] In some embodiments, according to the method for preparing microspheres with controllable surface cracking and mineralization according to the present invention, the concentration of the alkaline solution is 0.1-4 mol / L.

[0015] In some embodiments, the method for preparing microspheres with controllable surface cracking and mineralization according to the present invention involves etching at 25-60°C for 0.50-30 h.

[0016] In some embodiments, according to the method for preparing microspheres with controllable surface cracking and mineralization according to the present invention, the mineralization liquid includes simulated body fluid.

[0017] A fourth aspect of the invention provides the application of microspheres with controllable surface cracking and mineralization according to the invention in the preparation of bone repair or bone filling medical products.

[0018] This invention forms a uniform and robust mineralized layer by precisely controlling the crack structure on the surface of microspheres and utilizing this crack structure to provide physically confined nucleation sites. The surface-controlled cracking and mineralized microspheres of this invention exhibit a degradation rate that matches bone regeneration. Furthermore, this invention has advantages such as simple process, easy scale-up, no need for expensive equipment, and suitability for mass production. Attached Figure Description

[0019] Figure 1 The EDS analysis results of the microspheres in Example 1 are shown.

[0020] Figure 2 A transmission electron microscope (TEM) image of the microspheres from Example 2 is shown.

[0021] Figure 3 The EDS analysis results of the microspheres in Example 2 are shown.

[0022] Figure 4 The SEM results of the mineralized microspheres in Example 2 are shown.

[0023] Figure 5 The SEM results of the microspheres before mineralization in Example 3 are shown.

[0024] Figure 6 The SEM results of the microspheres before mineralization in Example 4 are shown.

[0025] Figure 7 The SEM results of the microspheres in Comparative Example 1 are shown.

[0026] Figure 8 The EDS analysis results of the microspheres in Comparative Example 1 are shown.

[0027] Figure 9 The SEM results of the microspheres in Comparative Example 2 are shown.

[0028] Figure 10 The SEM results for the three microspheres in Comparative Example 3 are shown. Detailed Implementation

[0029] Various exemplary embodiments of the present invention will now be described in detail. This detailed description should not be considered as a limitation of the present invention, but rather as a more detailed description of certain aspects, features, and embodiments of the present invention.

[0030] It should be understood that the terminology used in this invention is merely for describing particular embodiments and is not intended to limit the invention. Furthermore, with respect to numerical ranges in this invention, it should be understood that the upper and lower limits of the range and each intermediate value between them are specifically disclosed. Any stated value or intermediate value within a stated range, as well as each smaller range between any other stated value or intermediate value within said range, are also included in this invention. The upper and lower limits of these smaller ranges may be independently included or excluded from the range.

[0031] Unless otherwise stated, 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. While only preferred methods and materials have been described herein, any methods and materials similar or equivalent to those described herein may be used in the implementation or testing of this invention.

[0032] Microspheres In one aspect, the present invention provides a microsphere with controllable surface cracking and mineralization, comprising a polydioxanone sphere and a mineralization layer, wherein the surface of the polydioxanone sphere has a controllable cracking structure (preferably a uniform network cracking structure or a groove structure) to provide physically confined nucleation sites, and the mineralization layer is formed at the nucleation sites provided by the cracking structure.

[0033] To improve bone repair or bone filling effects, the particle size of microspheres and the size of surface crack structures can be controlled within a suitable range. In this invention, the depth of the cracked structure is 0.1-15 μm, preferably 0.3-14 μm, even more preferably 0.5-13 μm, further preferably 0.7-12 μm, more preferably 0.9-11 μm, and even more preferably 1-10 μm, for example 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10 μm; the length of the cracked structure is 0.2-10 μm, preferably 0.3-8 μm, even more preferably 0.4-6 μm, and even more preferably 0.5-5 μm, for example 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5 μm; and the particle size of the microspheres is 50-500 μm, preferably 60-450 μm, and even more preferably 70-400 μm. μm, further preferably 80-350 μm, more preferably 90-300 μm, and even more preferably 100-250 μm, for example 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250 μm.

[0034] In this invention, the composition of the mineralization layer is not particularly limited, as long as it can form a mineralization layer through mineralization and has active ingredients that promote bone repair. The composition of the mineralization layer includes, but is not limited to, hydroxyapatite, calcium silicate, tricalcium phosphate, tetracalcium phosphate, calcium pyrophosphate, calcium dihydrogen phosphate, calcium hydrogen phosphate, octacalcium phosphate, calcium carbonate, calcium peroxide, calcium citrate, and calcium sulfate. In a preferred embodiment, the mineralization layer is hydroxyapatite.

[0035] Composition In one aspect, the present invention provides a composition for bone repair or bone filling, comprising microspheres with surface-controlled cracking and mineralization as described herein.

[0036] In a preferred embodiment, the composition further comprises pharmaceutically acceptable excipients, each of which must be “acceptable” meaning that it is compatible with other components of the formulation (e.g., the polydioxanone of the present invention) and does not harm the patient. Examples of the excipients include, but are not limited to, binders, pore-forming agents, curing regulators, shaping agents, dispersants, developers, buffers, and preservatives. Examples of binders include, but are not limited to, sodium alginate, chitosan, gelatin, collagen, and hyaluronic acid. Examples of pore-forming agents include, but are not limited to, sodium chloride, sucrose, polyethylene glycol, ammonium bicarbonate, and ice crystal particles. Examples of curing regulators include, but are not limited to, citric acid, sodium citrate, disodium hydrogen phosphate, sodium dihydrogen phosphate, and calcium sulfate. Examples of shaping agents include, but are not limited to, glycerol, sorbitol, mannitol, and povidone. Examples of dispersants include, but are not limited to, polysorbate 80, poloxamer 188, and lecithin. Examples of developers include, but are not limited to, barium sulfate, zirconium oxide, and iodides. Examples of buffers include, but are not limited to, phosphate buffer, tris(hydroxymethyl)aminomethane buffer, and HEPES buffer. Examples of preservatives include, but are not limited to, benzyl alcohol and phenoxyethanol.

[0037] Preparation method In one aspect, the present invention provides a method for preparing microspheres with controllable surface cracking and mineralization, comprising the steps (1)-(2), which are described in detail below.

[0038] Step (1) of the present invention is the step of obtaining PPDO microspheres with a cracked surface structure. In a preferred embodiment, a concentration of 0.1-4 mol / L is used (preferably 0.2-3.8 mol / L, more preferably 0.3-3.6 mol / L, further preferably 0.4-3.4 mol / L, more preferably 0.5-3.2 mol / L, even more preferably 0.5-3 mol / L, for example 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3). The PPDO microspheres are etched with an alkaline solution (e.g., but not limited to NaOH solution, KOH solution, etc.) at 25-60°C (preferably 26-58°C, more preferably 27-56°C, further preferably 28-54°C, more preferably 29-52°C, and even more preferably 30-50°C, e.g., 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50°C) for 0.5-30 h (preferably 0.6-29 h, more preferably 0.7-28 h, further preferably 0.8-27 h, more preferably 0.9-26 h) for 0.5-30 h (preferably 0.6-29 h, more preferably 0.7-28 h, further preferably 0.8-27 h, and more preferably 0.9-26 h) for 0.5-30 h (preferably 0.9-26 h). h, more preferably 1-25h, for example 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5, 18, 18.5, 19, 19.5, 20, 20.5, 21, 21.5, 22, 22.5, 23, 23.5, 24, 24.5, 25 h), to obtain PPDO microspheres exhibiting a cracked structure, wherein the solid-liquid ratio of the microspheres to the alkaline solution is 1 g:(10-30) mL, preferably 1 g:(11-29) mL, and even more preferably 1 g:(10-30) mL. g: (12-28) mL, more preferably 1 g: (13-27) mL, more preferably 1 g: (14-26) mL, even more preferably 1 g: (15-25) mL, for example 1 g: 15 mL, 1 g: 16 mL, 1 g: 17 mL, 1 g: 18 mL, 1 g: 19 mL, 1 g: 20 mL, 1 g: 21 mL, 1 g: 22 mL, 1 g: 23 mL, 1 g: 24 mL, 1 g: 25 mL.Understandably, to obtain excellent etching results, etching can be carried out under stirring conditions. The stirring speed is preferably 100-200 rpm, more preferably 110-190 rpm, and even more preferably 120-180 rpm, such as 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, and 180 rpm.

[0039] Optionally, after etching, the water can be washed with an aqueous solvent (such as, but not limited to, deionized water, distilled water, reverse osmosis water, high-purity water, etc.) until neutral, and then dried. The drying method is not particularly limited and can be carried out using drying methods known in the art, such as, but not limited to, freeze drying, vacuum drying, etc.

[0040] Understandably, to obtain a uniform network of cracked structures and thus improve bone repair, the concentration of the alkaline solution, etching time, and etching temperature can be adjusted within a suitable range. For example, when the concentration of the alkaline solution is high, the etching time can be reduced or the etching temperature can be lowered; when the concentration of the alkaline solution is low, the etching time can be increased or the etching temperature can be raised. In some implementations, when the alkaline concentration is 0.1-0.5 mol / L and the treatment time is 0.5-2 h, a shallow microcracked structure is formed; when the alkaline concentration is 1-2 mol / L and the treatment time is 4-12 h, a uniform network of cracked structures with a depth of 1-10 μm is formed; and when the alkaline concentration is ≥3 mol / L and the treatment time is ≥24 h, a network of cracked structures with a depth of 10-15 μm is formed.

[0041] In this invention, the method of obtaining PPDO microspheres is not particularly limited. They can be obtained by purchase or synthesized by chemical methods (such as, but not limited to, emulsification-solvent evaporation method, spray drying method, etc.).

[0042] Step (2) of the present invention is the step of obtaining microspheres with controllable surface cracking and mineralization. In a preferred embodiment, step (2) of the present invention includes subjecting the PPDO microspheres with the cracked surface structure to 1.5×SBF to 5×SBF (e.g., 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5×SBF) at 30-45°C (preferably 31-44°C, more preferably 32-43°C, even more preferably 33-42°C, e.g., 33, 34, 35, 36, 37, 38, 39, 40, 41, 42°C) at pH=7-8 (e.g., 7, 7). Mineralization is carried out under the conditions of 1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, and 8) for 1-14 days, preferably 2-14 days, even more preferably 3-14 days, further preferably 4-14 days, more preferably 5-14 days, and even more preferably 7-14 days, for example, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, and 14 days, wherein the solid-liquid ratio of PPDO microspheres to SBF is 1. 1 g: (20-40) mL, preferably 1 g: (21-39) mL, even more preferably 1 g: (22-38) mL, further preferably 1 g: (23-37) mL, more preferably 1 g: (24-36) mL, even more preferably 1 g: (25-35) mL, for example 1 g: 25 mL, 1 g: 26 mL, 1 g: 27 mL, 1 g: 28 mL, 1 g: 29 mL, 1 g: 30 mL, 1 g: 31 mL, 1 g: 32 mL, 1 g: 33 mL, 1 g: 34 mL, 1 g: 35 mL, fresh SBF is replaced every 1.5-2.5 days (e.g. 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5 days) to obtain the microspheres with controllable surface cracking and mineralization. Preferably, the mineralization layer preferentially nucleates within the cracks and grooves and gradually extends to the entire surface, forming a continuous or clustered mineralization layer. In a preferred embodiment, the thickness of the mineralization layer is 0.2-5 μm, preferably 0.3-4.5 μm, even more preferably 0.4-4 μm, and more preferably 0.5-3.5 μm, for example 0.5, 1, 1.5, 2, 2.5, 3, 3.5 μm.

[0043] Optionally, after mineralization, the microspheres can be washed with an aqueous solvent (e.g., but not limited to deionized water, distilled water, reverse osmosis water, high-purity water, etc.) and then dried. The drying method is not particularly limited and can be carried out using drying methods known in the art, such as, but not limited to, freeze drying, vacuum drying, room temperature drying, etc.

[0044] This invention enables continuous control over the formation, development, and eventual disintegration of cracked structures by adjusting the concentration of the alkaline solution, etching time, and etching temperature within a suitable range. Furthermore, by forming a controllable cracked structure and mineralization layer on the surface of PPDO microspheres, this invention significantly improves the bone repair effect of PPDO microspheres.

[0045] application One aspect of the present invention provides the application of microspheres with controllable surface cracking and mineralization according to the present invention in the preparation of bone repair or bone filling medical products. Examples of such medical products include, but are not limited to, microsphere scaffolds, injectable bone filler materials, composite bone filler particles, tissue engineering scaffolds, bone repair materials, artificial bone powder, etc.

[0046] In this invention, microspheres with controllable surface cracking and mineralization provide physical support in the early stages. As bone repair progresses, the PPDO in the microspheres slowly degrades, thereby providing space for osteoblasts and fibroblasts, and thus accelerating the repair of bone damage.

[0047] Example 1 The following illustrates the preparation method and characterization of microspheres with controllable surface cracking and mineralization.

[0048] 1. Preparation (1) 200 μm PPDO microspheres were prepared by emulsification-solvent evaporation method or spray drying method, wherein the solvent was dichloromethane and the drying conditions were: vacuum drying at room temperature for 24 h; (2) The PPDO microspheres were placed in a 0.2 M KOH solution at a solid-liquid ratio of 1 g: 20 mL, etched at 25 °C for 1 h under stirring at 100-200 rpm, washed with deionized water 3-5 times until neutral, and freeze-dried or vacuum-dried at 35 °C. (3) PPDO microspheres with cracked structure were placed in 1.5× simulated body fluid (1.5×SBF) for mineralization treatment for 7 days (37℃, 100-1500 r / min stirring) at a solid-liquid ratio of 1 g: 30 mL. Fresh SBF was replaced every 2 days to induce hydroxyapatite deposition in the cracked grooves and on the surface. The microspheres were removed, gently washed with deionized water, dried at room temperature, and sealed and dried for storage.

[0049] The simulated body fluid was dissolved in deionized water in the order and amount of each component listed in Table 1.

[0050] Table 1 Chemical composition of SBF solution 2. Characterization The morphology of the microspheres was tested using scanning electron microscopy (SEM) to observe the changes in morphology before and after alkali treatment, as well as the correlation between the degree of cracking and the treatment time and temperature.

[0051] The microspheres were analyzed using energy-dispersive X-ray spectroscopy (EDS), and the results are as follows: Figure 1 As shown, the microspheres are mainly composed of C (red), O (yellow), P (purple), and Ca (green), with a Ca / P ratio of 1.32.

[0052] Example 2 The following illustrates the preparation method and characterization of microspheres with controllable surface cracking and mineralization.

[0053] 1. Preparation (1) 200 μm PPDO microspheres were prepared by emulsification-solvent evaporation method or spray drying method, wherein the solvent was chloroform and the drying conditions were: vacuum drying at room temperature for 24 h. (2) The PPDO microspheres were placed in a 1.5 M KOH solution at a solid-liquid ratio of 1 g: 20 mL and etched at 40 °C for 8 h under stirring at 100-200 rpm. The microspheres were washed with deionized water 3-5 times until neutral and then freeze-dried or vacuum-dried at 35 °C to obtain PPDO microspheres with a cracked surface. (3) PPDO microspheres with cracked structures were placed in 2× simulated body fluid (SBF) for mineralization treatment for 10 days. Fresh SBF was replaced every 2 days to induce hydroxyapatite deposition in the cracked grooves and on the surface. The microspheres were then removed, gently washed with deionized water, dried at room temperature, and sealed and dried for storage.

[0054] 2. Characterization The results were observed using transmission electron microscopy. Figure 2 As shown, a hydroxyapatite (HAP) crystal layer is formed on the surface.

[0055] The microspheres were analyzed using energy-dispersive X-ray spectroscopy (EDS), and the results are as follows: Figure 3 As shown in Table 2, the microspheres are uniformly cracked (approximately 5 μm deep), fully covered with flower-like apatite, and have a Ca / P value of 1.68.

[0056] The mineralized PPDO microspheres with a cracked surface obtained in step (2) were observed using scanning electron microscopy, and the results are as follows: Figure 4 As shown, the cracks and their surface are covered with apatite crystals.

[0057] Table 2 EDS Analysis Results Example 3 PPDO microspheres of 200 μm were prepared by emulsification-solvent evaporation or spray drying; the PPDO microspheres were then etched in 1 M KOH solution at 40 °C for 0.2 h.

[0058] The results were observed using SEM. Figure 5 As shown, the surface of the microspheres has a uniform network of cracks with a groove depth of about 1-3 μm.

[0059] Example 4 200 μm PPDO microspheres were prepared by emulsification-solvent evaporation or spray drying; the PPDO microspheres were then etched in 1 M KOH solution at 40 °C for 2 h.

[0060] The results were observed using SEM. Figure 6 As shown, the surface of the microspheres has a uniform network of cracks with a groove depth of about 5-8 μm.

[0061] Example 5 A rabbit femoral condyle defect model was established, with a wound diameter of 5 mm and a depth of 8 mm. PPDO microspheres with controllable surface cracking and mineralization obtained in Example 2 were mixed with sodium alginate gel and injected.

[0062] Eight weeks later, Micro-CT scans showed that new bone formation in the defect area was good, with little residual material and no inflammation.

[0063] Comparative Example 1 200 μm PPDO microspheres were prepared using either the emulsification-solvent evaporation method or the spray drying method. The results were observed using SEM. Figure 7 As shown, the surface of PPDO microspheres that have not been treated with alkaline solution is smooth.

[0064] EDS analysis was performed, and the results are as follows: Figure 8 As shown, the unmineralized microspheres mainly consist of C, O, and Pt sprayed on for conductivity, with a Ca / P ratio of 0.

[0065] Comparative Example 2 200 μm PPDO microspheres were prepared using an emulsification-solvent evaporation method or a spray drying method. The PPDO microspheres were then etched in a 0.2 M NaOH solution at 25 °C for 0.2 h. SEM observation was performed, and the results are as follows: Figure 9 As shown, the surface has sparse, shallow cracks.

[0066] Comparative Example 3 200 μm PPDO microspheres were prepared by emulsification-solvent evaporation or spray drying; the PPDO microspheres were then etched in 4 M NaOH solution at 50 °C for 24 h.

[0067] The results are as follows Figure 10 As shown, excessive alkali treatment causes microspheres to rupture and fragment, rendering them unusable for bone repair.

[0068] Comparative Example 4 PPDO microspheres of 200 μm were prepared using an emulsification-solvent evaporation method or a spray drying method. The microspheres were then etched in a 4 M NaOH solution at 50 °C for 36 h. The microspheres partially dissolved and disintegrated, rendering them unsuitable for bone repair.

[0069] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some of the technical features. These modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A microsphere with controllable surface cracking and mineralization, characterized in that, It includes polydioxanone spheres and a mineralization layer, wherein the surface of the polydioxanone spheres has a controllable cracking structure to provide physically confined nucleation sites, and the mineralization layer is formed at the nucleation sites provided by the cracking structure.

2. The surface controllable cracking and mineralized microspheres of claim 1, wherein, The depth of the cracked structure is 0.1-15 μm.

3. The surface controllable cracking and mineralized microspheres of claim 1, wherein, The microspheres have a particle size of 50-500 μm.

4. The surface controllable cracking and mineralized microspheres of claim 1, wherein, The mineralized layer includes at least one of hydroxyapatite, calcium silicate, tricalcium phosphate, tetracalcium phosphate, calcium pyrophosphate, calcium dihydrogen phosphate, calcium hydrogen phosphate, octacalcium phosphate, calcium carbonate, calcium peroxide, calcium citrate, and calcium sulfate.

5. A composition for bone repair or bone filling, characterized by, It includes microspheres with controllable surface cracking and mineralization according to any one of claims 1-4.

6. The method for preparing microspheres with controllable surface cracking and mineralization according to any one of claims 1-4, characterized in that, It includes the following steps: (1) Using an alkaline solution to etch polydioxanone microspheres, polydioxanone microspheres with a controllable cracking structure on the surface are obtained. (2) The polydioxanone microspheres with a controllable cracking structure on the surface are mineralized in a mineralizing solution to obtain microspheres with controllable cracking and mineralization on the surface.

7. The method for preparing microspheres with controllable surface cracking and mineralization according to claim 6, characterized in that, The alkaline solution includes NaOH solution and / or KOH solution; Preferably, the concentration of the alkaline solution is 0.1-4 mol / L.

8. The method of claim 6, wherein the surface-controllable, cracking and mineralized microspheres are prepared by the steps of: Etch at 25-60℃ for 0.50-30 h.

9. The method of claim 6, wherein the surface controllable cracking and mineralized microspheres are prepared by the method comprising the steps of: The mineralization fluid includes simulated body fluids.

10. The application of the microspheres with controllable surface cracking and mineralization according to any one of claims 1-4 in the preparation of bone repair or bone filling medical products.

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