An injectable porous composite bone repair hydrogel material based on a thermally induced sacrificial template method and its preparation method

Abstract

The present invention discloses an injectable porous composite bone repair hydrogel material based on a thermally induced sacrificial template method and a preparation method thereof. The method comprises: 1) preparing gelatin microspheres; 2) preparing drug-loaded mesoporous manganese dioxide; 3) pre-mixing the drug-loaded mesoporous manganese dioxide, angiogenic drugs, and bone marrow mesenchymal stem cells in a biodegradable and UV-curable polymer solution under light-proof conditions, then cooling to 4°C and mixing the gelatin microspheres; when used, the resulting mixed solution is directly injected into the bone defect site for in-situ UV curing, and the gelatin microspheres are dissolved and sacrificed under the action of body temperature, forming a porous structure within the gel matrix. This composite hydrogel material provides cells with a pore structure for material exchange and cell migration based on the thermally induced sacrificial template method, while having anti-inflammatory, angiogenic, and osteogenic effects. In addition, in-situ injection and UV curing can match the shape of irregular bone defects, and can achieve efficient bone defect repair locally.

Description

Technical Field

[0001] The present invention relates to the field of biomedical material preparation, and in particular to an injectable porous composite bone repair hydrogel material based on a thermally induced sacrificial template method and a preparation method thereof. Background Art

[0002] With the development of society, the incidence of bone defects caused by various reasons has increased year by year. Common sites of bone defects are the skull and long bones of the limbs. Bone defects above a critical size are difficult to heal on their own, causing great pain and life burden to patients. Currently, the common methods for repairing bone defects in clinical practice are autologous bone transplantation and allogeneic bone transplantation. A common method of autologous bone transplantation is iliac crest bone transplantation. Although there is no risk of rejection, it will bring additional trauma and the risk of donor site infection; allogeneic bone is expensive, and the potential immune rejection problem is difficult to solve. For this reason, it is urgent to design a biomaterial that can efficiently promote defect repair in situ.

[0003] With the vigorous development of tissue engineering, various hydrogel materials that promote bone defect repair have emerged. However, common hydrogel materials are basically solid structures, lacking pore structures that support cell ingrowth and migration, as well as oxygen / nutrient exchange, which is not conducive to cell survival, proliferation, diffusion and other behaviors; at the same time, hydrogels do not have good biological activity and cannot achieve directed induction of stem cell differentiation. Even if some drug-loaded hydrogels can meet the relevant drug administration requirements, there are still common problems such as burst release of drugs, short drug action cycle, single biological activity, and mismatch between the biological activity function and the natural bone repair process. These defects greatly limit its bone-promoting effect. Accordingly, the present invention designs an injectable porous composite bone repair hydrogel material based on a thermally induced sacrificial template method, which solves the above problems through a local porous structure and a multiple drug sustained-release system. Summary of the Invention

[0004] The present invention addresses the shortcomings of existing technologies and combines the advantages of various materials, methods, and processes to provide an injectable porous composite bone repair hydrogel material based on a thermally induced sacrificial template method and its preparation method. This material can be injected in situ and can be used in various irregular bone defect sites. After application, it forms a porous structure within the gel matrix, providing channels for cell exchange and migration. It also exhibits anti-inflammatory, angiogenic, and osteogenic effects, enabling efficient local bone defect repair.

[0005] The present invention is implemented by the following technical solution, which specifically includes the following steps:

[0006] A method for preparing an injectable porous composite bone repair hydrogel material based on a thermally induced sacrificial template method, comprising:

[0007] 1) Preparation of Gelatin Microspheres: Prepare a gelatin solution of a certain concentration as the dispersed phase under heating conditions; liquid paraffin containing Span-80 as the continuous phase. Slowly add the dispersed phase dropwise to the continuous phase preheated at 50°C. Emulsify under mechanical stirring for at least 30 minutes, then cool the system to 4°C and maintain for at least 30 minutes. Wash at 4°C to obtain gelatin microspheres and store frozen.

[0008] 2) Preparation of drug-loaded mesoporous manganese dioxide: The mesoporous manganese dioxide material was prepared using a precipitation method using potassium permanganate and hydrogen peroxide. After washing and dialysis, the prepared mesoporous manganese dioxide was loaded with the osteopromoting drug within the pores of the mesoporous manganese dioxide using an ultrasonic loading method.

[0009] 3) Preparation of the porous hydrogel material: Under sterile, light-protected, and heated conditions, a biodegradable, UV-curable polymer was dissolved in a PBS solution containing a photoinitiator. An angiogenic drug and drug-loaded mesoporous manganese dioxide were added sequentially at 37°C and vortexed to mix thoroughly. BMSCs were then added and pipetted evenly. After cooling the solution to 4°C, a predetermined amount of gelatin microspheres was added and mixed thoroughly to obtain an injectable premix.

[0010] When in use, the above premixed liquid is injected into the defect area and then UV-cured. Under the action of body temperature, the gelatin microspheres dissolve and sacrifice to form a porous structure, thereby achieving full-cycle repair of the bone defect.

[0011] In the above technical solution, further, in step 1), the concentration of the gelatin solution is 8-12 wt%, the dissolution temperature is 40-50° C.; the concentration of Span-80 in the continuous phase is 1-2 wt%; and the volume ratio of the dispersed phase to the continuous phase is 1:15-1:25;

[0012] Furthermore, the mechanical stirring speed in step 1) is 1500-2500 rpm / min; the cleaning is: first, use a large amount of acetone to clean the microspheres until there is essentially no oil phase component, then use ethanol to remove the acetone solvent, and finally use ultrapure water to wash away the ethanol, and the above solvents are all pre-cooled to 4°C.

[0013] Furthermore, the particle size of the gelatin microspheres prepared in step 1) is preferably 10 to 30 μm.

[0014] Further, in step 2), the preparation process of mesoporous manganese dioxide is as follows: prepare a 0.05-0.2 mol / L KMnO4 aqueous solution, then slowly add a mass concentration of 20-30% hydrogen peroxide, and add 1 mol / L KOH during this process to maintain the pH of the solution at a weak alkaline level (about 8-10); after no obvious bubbles are generated, stop adding hydrogen peroxide, continue stirring at room temperature for 30-60 minutes, and let it stand for 2-4 hours; filter the product, wash the filter cake 3-5 times with deionized water, and then redisperse it in deionized water, stir and wash it for at least 24 hours, stop stirring, and wait for it to settle naturally. The above filtration-washing-dispersion-washing-sedimentation steps need to be repeated for 1-2 weeks;

[0015] Furthermore, in step 2), the drug-loaded mesoporous manganese dioxide is prepared as follows: the mesoporous manganese dioxide is placed in a PBS solution containing an osteogenic drug, ultrasonically loaded to allow the drug to enter the pores of the mesoporous manganese dioxide, and then freeze-dried. This process is repeated 3-5 times. The mesoporous manganese dioxide is added at a concentration of 0.1-0.5 wt%. The osteogenic drug can be one or more of BMP-2, BMP-7, SGF, IGF, etc., at a concentration of 5-10 mg / ml. The ultrasonic loading power is 80-100 W, the loading time is 30-60 minutes, and the loading temperature is 0-4°C.

[0016] Furthermore, in step 3), the biodegradable and UV-curable polymer may be one of HAMA and Alg-MA, and the added concentration of the polymer is 10-25 wt%; the photoinitiator may be one or more of LAP, Irgacure, and I2959, and the concentration is 0.1-0.25 wt%; the angiogenic drug may be one or more of VEGF, PGF, a-FGF, b-FGF, TGF, PD-ECGF, TNF, etc., and the concentration is 1-2 mg / ml; the added amount of drug-loaded mesoporous manganese dioxide is 0.1-0.5 wt%; the added amount of BMSCs is 1-2*10 5 / ml; the addition amount of gelatin microspheres is 2-5wt%; the UV wavelength is 405nm, the power is 30-50W, and the time is 30-60s.

[0017] Compared with the prior art, the present invention has the following advantages:

[0018] 1. The present invention uses gelatin, mesoporous manganese dioxide, angiogenic drugs, osteogenic drugs, and biodegradable and UV-curable polymers to prepare an injectable porous composite bone repair hydrogel material based on a thermally induced sacrificial template method through a combination of processes including emulsification-gelation, precipitation, ultrasonic loading, photocuring, and sacrificial template methods. The selection of these raw materials and the combined processes are unique to the present invention.

[0019] 2. This invention is dedicated to a full-cycle repair strategy for bone defect repair. The cell-laden gel provides a local cell source for the defect, solving the problem of difficult cell recruitment with traditional materials. The angiogenic drug encapsulated in the gel matrix can initially promote the formation of angiogenesis and osteogenic microenvironment through direct diffusion, providing support for the subsequent osteogenesis process. The drug-loaded mesoporous manganese dioxide is also encapsulated within the hydrogel matrix. Due to the dual physical coating of the mesopores and the hydrogel matrix, it can achieve a longer-term release effect of osteogenic factors. It can also slowly release manganese ions to exert a local anti-inflammatory effect. At the same time, the good biodegradability of the hydrogel provides space for the growth of new bone tissue in the later stage. This full-cycle repair strategy is the first of its kind in this invention and is highly innovative.

[0020] 3. Considering the challenges of conventional hydrogels, which are solid and difficult for cells to grow into and migrate within, and have low nutrient and metabolic waste exchange efficiency, this invention innovatively selects HAMA and AlgMA as the hydrogel matrix components. These hydrogels are UV-curable and resist physical gelation even at low temperatures (approximately 4°C). Furthermore, by cleverly leveraging the physical phase transition of gelatin, which gels at low temperatures and dissolves at high temperatures, the method employs an emulsification-gelation method. By controlling the amount of emulsifier and the speed of mechanical stirring, the method produces gelatin microspheres of appropriate particle size and physical gelation. The gelatin microspheres are then added to the hydrogel material, where they spontaneously dissolve at body temperature (approximately 37°C) to form a porous structure, providing a 3D space for material exchange, cell proliferation, and migration, offering a new approach to bone repair material innovation. Furthermore, the size of the pore structure can be controlled by controlling the particle size of the gelatin microspheres, preferably 10-30 microns, similar to cell size. The number of pores can be adjusted by controlling the amount of gelatin microspheres added. Conventional methods for forming porous structures in hydrogels involve various chemical modifications, which inevitably reduce their biocompatibility and repair efficiency. The present invention innovatively adds gelatin microspheres and uses a thermal sacrificial template method to form a porous structure in the hydrogel structure by purely physical means, greatly promoting cell proliferation efficiency without affecting its biocompatibility. The above combined process is original to the present invention.

[0021] 4. To address the common initial local foreign body inflammatory response in conventional implants, the present invention innovatively uses mesoporous manganese dioxide as a hydrogel filler, enabling it to simultaneously exert the dual effects of anti-inflammatory and sustained release: the manganese ions produced by manganese dioxide have a strong local anti-inflammatory effect and a weak osteogenic effect; its microporous structure is conducive to drug loading and sustained release, and together with the hydrogel matrix, it forms a dual physical barrier, solving the problem of initial drug burst release in traditional drug-loaded hydrogels and greatly prolonging the drug action time; 5. To address the diverse morphologies of bone defects, the present invention injects a premixed solution locally into the defect and uses UV light curing, so that the cured hydrogel can fit the defect shape well, preventing the formation of cavities that hinder defect repair, while facilitating early drug loading, cell loading, and other operations, greatly simplifying the process;

[0022] 6. The present invention cleverly overcomes the difficulties of drug loading by combining various conventional processes: although the mesoporous manganese dioxide micropores are conducive to drug loading and sustained release, the high surface tension of the pore openings makes drug loading difficult. The present invention uses ultrasonic loading method combined with multiple cycle operations to achieve sufficient and uniform drug loading. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 SEM image of gelatin microspheres (corresponding to Example 1);

[0024] Figure 2 TEM image of mesoporous manganese dioxide microspheres (corresponding to Example 1);

[0025] Figure 3 SEM image of the injectable porous composite bone repair hydrogel material based on the thermally induced sacrificial template method (corresponding to Example 1);

[0026] Figure 4 Release curves of manganese ions, angiogenic drugs, and osteogenic drugs in the injectable porous composite bone repair hydrogel material based on the thermally induced sacrificial template method (corresponding to Example 2). DETAILED DESCRIPTION

[0027] The technical solution of the present invention is further described in detail below with reference to the accompanying drawings and specific embodiments.

[0028] Comparative Example 1

[0029] 1) Preparation of drug-loaded mesoporous manganese dioxide: Prepare 0.1 mol / L KMnO4 aqueous solution, then slowly add 30% hydrogen peroxide, and add 1 mol / L KOH was used to maintain the pH of the solution at a weak alkaline level (about 8-10); after no obvious bubbles were generated, the addition of hydrogen peroxide was stopped, stirring was continued at room temperature for 60 minutes, and the mixture was allowed to stand for 2 hours; the product was filtered, washed with deionized water 4 times, and then redispersed in deionized water, stirred and washed for 24 hours, and then stirred and allowed to settle naturally; the above-mentioned filtration-washing-dispersion-washing-sedimentation steps were repeated for 1 week; the prepared mesoporous manganese dioxide was washed and dialyzed, and then prepared into a PBS solution containing 0.5 wt% mesoporous manganese dioxide, to which 10 mg / ml BMP-2 was added, and the solution was loaded at 4°C for 60 minutes using 80W ultrasound; 2) Preparation of hydrogel material: Under sterile, light-proof and 37°C heating conditions, (10 wt%) HAMA was dissolved in a PBS solution containing (0.25 wt%) LAP, 1 mg / ml VEGF and 0.1 wt% drug-loaded mesoporous manganese dioxide were added in sequence, and vortexed to mix evenly, and then 2*10 5 BMSCs at a concentration of 1000 cells / ml are pipetted and evenly mixed to obtain an injectable premix. When used, the premix is ​​injected into the defect area and then UV-cured for 60 seconds to repair the bone defect.

[0030] The injectable hydrogel material had an in vitro degradation rate of 59% after 30 days, and live-dead cell fluorescence staining proved that the living cells accounted for 75%; after it was injected into a mouse skull defect model and solidified, micro-CT showed that the skull defect repair ability was general, and HE staining showed that the local inflammatory reaction was more obvious.

[0031] Example 1

[0032] 1) Preparation of gelatin microspheres: Prepare a 10 wt% gelatin solution under heating conditions as the dispersed phase; liquid paraffin containing 1 wt% Span-80 as the continuous phase; slowly add the dispersed phase dropwise to the continuous phase preheated at 50°C, stir at 2000 rpm / min, emulsify for 30 minutes, and then cool the system to 4°C and maintain for 30 minutes. Subsequently, wash with precooled acetone, ethanol, and ultrapure water at 4°C to obtain gelatin microspheres and store frozen. Figure 1 );

[0033] 2) Preparation of drug-loaded mesoporous manganese dioxide: Prepare 0.1 mol / L KMnO4 aqueous solution, then slowly add 30% hydrogen peroxide, and add 1 mol / L KOH was used to maintain the pH of the solution at a weak alkaline level (about 8-10); after no obvious bubbles were generated, the addition of hydrogen peroxide was stopped, stirring was continued at room temperature for 60 minutes, and the mixture was allowed to stand for 2 hours; the product was filtered, washed with deionized water 4 times, and then redispersed in deionized water, stirred and washed for 24 hours, and then stirred and allowed to settle naturally; the above-mentioned filtration-washing-dispersion-washing-sedimentation steps were repeated for 1 week; the prepared mesoporous manganese dioxide was washed and dialyzed, and then prepared into a PBS solution containing 0.5wt% mesoporous manganese dioxide, to which 10mg / ml BMP-2 was added, and the solution was loaded at 4°C for 60 minutes using 80W ultrasound; 3) Preparation of porous hydrogel material: Under sterile, light-proof and 37°C heating conditions, (10wt%) HAMA was dissolved in a PBS solution containing (0.25wt%) LAP, 1mg / ml VEGF and 0.1wt% drug-loaded mesoporous manganese dioxide were added in sequence, and vortexed to mix evenly, and then 2*10 5 After the solution is cooled to 4°C, 2 wt% gelatin microspheres are added and mixed to obtain an injectable premix, which is an injectable porous composite bone repair hydrogel material. When used, it is injected into the defect area and UV-cured for 60 seconds. Under the action of body temperature, the gelatin microspheres dissolve and form a porous structure, thus achieving full-cycle repair of bone defects.

[0034] Compared with Comparative Example 1, gelatin microspheres were added to form a porous structure. The porosity of the injectable porous hydrogel material was 78%, and the pore size was about 8-25 μm ( Figure 3 ), the in vitro degradation rate was 76% after 30 days, live-dead cell fluorescence staining proved that the living cells accounted for 92%, and confocal microscopy imaging showed that the cells grew into the micropores with obvious morphological extension; after being injected into the mouse skull defect model for solidification, compared with comparative example 1, micro-CT showed that the skull defect repair ability was stronger, and HE staining showed that the local inflammatory reaction was mild.

[0035] Example 2

[0036] 1) Preparation of Gelatin Microspheres: A 10 wt% gelatin solution was prepared under heating as the dispersed phase; liquid paraffin containing 1 wt% Span-80 was used as the continuous phase. The dispersed phase was slowly added dropwise to the continuous phase preheated at 50°C. After emulsification at 2000 rpm / min for 30 minutes, the system was cooled to 4°C and maintained for 30 minutes. The resulting gelatin microspheres were then washed with precooled acetone, ethanol, and ultrapure water at 4°C and stored frozen.

[0037] 2) Preparation of drug-loaded mesoporous manganese dioxide: Prepare 0.1 mol / L KMnO4 aqueous solution, then slowly add 30% hydrogen peroxide, and add 1 mol / L KOH was used to maintain the pH of the solution at a weak alkaline level (about 8-10); after no obvious bubbles were generated, the addition of hydrogen peroxide was stopped, stirring was continued at room temperature for 60 minutes, and the mixture was allowed to stand for 2 hours; the product was filtered, washed with deionized water 4 times, and then redispersed in deionized water, stirred and washed for 24 hours, and then stirred and allowed to settle naturally; the above-mentioned filtration-washing-dispersion-washing-sedimentation steps were repeated for 1 week; the prepared mesoporous manganese dioxide was washed and dialyzed, and then prepared into a PBS solution containing 0.5wt% mesoporous manganese dioxide, to which 10mg / ml BMP-2 was added, and the solution was loaded at 4°C for 60 minutes using 80W ultrasound; 3) Preparation of porous hydrogel material: Under sterile, light-proof and 37°C heating conditions, (10wt%) HAMA was dissolved in a PBS solution containing (0.25wt%) LAP, 1mg / ml VEGF and 0.1wt% drug-loaded mesoporous manganese dioxide were added in sequence, and vortexed to mix evenly, and then 20*10 4 After the solution is cooled to 4°C, 5 wt% gelatin microspheres are added and mixed to obtain an injectable premix. This is the injectable porous composite bone repair hydrogel material. When used, it is injected into the defect area and UV-cured for 60 seconds. Under the action of body temperature, the gelatin microspheres dissolve and form a porous structure, which can achieve full-cycle repair of bone defects.

[0038] Compared with Example 1, the dosage of gelatin microspheres was increased. The injectable porous hydrogel material had a porosity of 86%, a pore size of approximately 8-23 μm, a 30-day in vitro degradation rate of 84%, live-dead cell fluorescence staining demonstrated that 94% of the cells were live, and confocal microscopy imaging showed that the cells grew into the micropores and had more obvious morphological extension than in Example 1. After being injected into a mouse skull defect model and solidified, micro-CT showed that the skull defect had a strong repair ability, and HE staining showed that the local inflammatory reaction was mild.

[0039] Example 3

[0040] 1) Preparation of Gelatin Microspheres: A 10 wt% gelatin solution was prepared under heating as the dispersed phase; liquid paraffin containing 1 wt% Span-80 was used as the continuous phase. The dispersed phase was slowly added dropwise to the continuous phase preheated at 50°C. After emulsification at 2000 rpm / min for 30 minutes, the system was cooled to 4°C and maintained for 30 minutes. The resulting gelatin microspheres were then washed with precooled acetone, ethanol, and ultrapure water at 4°C and stored frozen.

[0041] 2) Preparation of drug-loaded mesoporous manganese dioxide: Prepare 0.1 mol / L KMnO4 aqueous solution, then slowly add 30% hydrogen peroxide, and add 1 mol / L KOH was used to maintain the pH of the solution at a weak alkaline level (about 8-10); after no obvious bubbles were generated, the addition of hydrogen peroxide was stopped, stirring was continued at room temperature for 60 minutes, and the mixture was allowed to stand for 2 hours; the product was filtered, washed with deionized water 4 times, and then redispersed in deionized water, stirred and washed for 24 hours, and then stirred and allowed to settle naturally; the above-mentioned filtration-washing-dispersion-washing-sedimentation steps were repeated for 1 week; the prepared mesoporous manganese dioxide was washed and dialyzed, and then prepared into a PBS solution containing 0.5 wt% mesoporous manganese dioxide, to which 10 mg / ml BMP-2 was added, and the solution was loaded at 4°C for 60 minutes using 80W ultrasound; 3) Preparation of porous hydrogel material: Under sterile, light-proof and 37°C heating conditions, (10 wt%) HAMA was dissolved in a PBS solution containing (0.25 wt%) LAP, 1 mg / ml VEGF and 1 wt% drug-loaded mesoporous manganese dioxide were added in sequence, and vortexed to mix evenly, and then 20*10 4 After the solution is cooled to 4°C, 2 wt% gelatin microspheres are added and mixed to obtain an injectable premix, which is an injectable porous composite bone repair hydrogel material. When used, it is injected into the defect area and UV-cured for 60 seconds. Under the action of body temperature, the gelatin microspheres dissolve and form a porous structure, which can achieve full-cycle repair of bone defects.

[0042] Compared with Example 1, the dosage of mesoporous manganese dioxide was increased. The injectable porous hydrogel material had a porosity of 79%, a pore size of approximately 7-25 μm, a 30-day in vitro degradation rate of 80%, live-dead cell fluorescence staining demonstrated that living cells accounted for 82%, and confocal microscopy imaging showed that cells grew into the micropores with obvious morphological extension. After injection into a mouse skull defect model and solidification, micro-CT showed that the skull defect repair ability was slightly weaker than in Example 1, and HE staining showed that there was almost no local inflammatory response.

[0043] The foregoing description is merely a partial list of preferred embodiments of the present invention, intended only to facilitate understanding of the present invention and not to limit the present invention. It should be noted that variations and improvements are possible without departing from the spirit of the present invention, and all such variations and improvements fall within the scope of protection of the present invention.

Claims

1. A method for preparing an injectable porous composite bone repair hydrogel material based on a thermally induced sacrificial template method, characterized in that: The preparation steps include the following: 1) Preparation of gelatin microspheres: Prepare a gelatin solution as the dispersed phase under heated conditions; liquid paraffin containing Span-80 as the continuous phase. Slowly add the dispersed phase dropwise to the continuous phase preheated to 50°C. Emulsify under mechanical stirring for at least 30 minutes, then cool the system to 4°C and maintain for at least 30 minutes. Wash at 4°C to obtain gelatin microspheres, which are then frozen for storage. 2) Preparation of drug-loaded mesoporous manganese dioxide: The mesoporous manganese dioxide material was prepared using a precipitation method using potassium permanganate and hydrogen peroxide. After washing and dialysis, the prepared mesoporous manganese dioxide was loaded with an osteopromoting drug within its pores using a cyclic ultrasonic loading method to obtain the drug-loaded mesoporous manganese dioxide. 3) Preparation of porous hydrogel material: Under sterile, light-proof and heating conditions, a biodegradable and UV-curable polymer was dissolved in a PBS solution containing a photoinitiator. Angiogenic drugs and drug-loaded mesoporous manganese dioxide were added in sequence at 37°C and vortexed to mix evenly. Bone marrow mesenchymal stem cells (BMSCs) were then added and pipetted evenly. After the solution was cooled to 4°C, gelatin microspheres were added and mixed evenly to obtain an injectable premix. The premix was injected to obtain an injectable porous composite bone repair hydrogel material. The biodegradable and UV-curable polymer was methacrylated. The polymer is added to the PBS solution at a concentration of 10-25wt%; the photoinitiator is one or more of LAP and I2959 at a concentration of 0.1-0.25wt%; the angiogenic drug is one or more of VEGF, PGF, a-FGF, b-FGF, TGF, PD-ECGF, and TNF at a concentration of 1-2mg / ml; the amount of drug-loaded mesoporous manganese dioxide added is 0.1-0.5wt%; the amount of BMSCs added is 1-2×10 5 / ml; the addition amount of gelatin microspheres is 2-5wt%; the UV wavelength is 405nm, the power is 30-50w, and the time is 30-60s.

2. The method for preparing an injectable porous composite bone repair hydrogel material based on a thermally induced sacrificial template method according to claim 1, wherein: In step 1), the concentration of the gelatin solution is 8-12 wt %, and the dissolution temperature is 40-50° C.; the concentration of Span-80 in the continuous phase is 1-2 wt %; and the volume ratio of the dispersed phase to the continuous phase is 1:15-1:

25.

3. The method for preparing an injectable porous composite bone repair hydrogel material based on a thermally induced sacrificial template method according to claim 1, characterized in that: In step 1), the mechanical stirring speed is 1500-2500 rpm / min; the cleaning is specifically as follows: first, acetone is used to clean the microspheres until there is no oil phase component, then ethanol is used to remove the acetone solvent, and finally, ultrapure water is used to wash away the ethanol. All solvents must be pre-cooled to 4°C.

4. The method for preparing an injectable porous composite bone repair hydrogel material based on a thermally induced sacrificial template method according to claim 1, characterized in that: The particle size of the gelatin microspheres in step 1) is in the range of 10-30 μm.

5. The method for preparing an injectable porous composite bone repair hydrogel material based on a thermally induced sacrificial template method according to claim 1, characterized in that: In step 2), the mesoporous manganese dioxide is prepared as follows: a 0.05-0.2 mol / L KMnO4 aqueous solution is prepared, and hydrogen peroxide with a mass concentration of 20-30% is added dropwise, during which the solution pH is maintained at 8-10; after no obvious bubbles are generated, the hydrogen peroxide addition is stopped, and the mixture is stirred continuously at room temperature for 30-60 minutes, and allowed to stand for 2-4 hours; the product is filtered, the filter cake is washed with deionized water 3-5 times, and then redispersed in deionized water, stirred and washed for at least 24 hours, and then stirred and allowed to settle naturally; the above filtration-washing-dispersion-washing-settling steps are repeated for 1-2 weeks.

6. The method for preparing an injectable porous composite bone repair hydrogel material based on a thermally induced sacrificial template method according to claim 1, characterized in that: In step 2), the drug-loaded mesoporous manganese dioxide is prepared as follows: the mesoporous manganese dioxide is placed in a PBS solution containing an osteogenic drug, ultrasonically loaded to allow the drug to enter the pores of the mesoporous manganese dioxide, and then freeze-dried, and the above process is repeated 3-5 times; the concentration of the mesoporous manganese dioxide added to the solution is 0.1-0.5wt%; the osteogenic drug is one or more of BMP-2, BMP-7, SGF, and IGF, with a concentration of 5-10mg / ml; the ultrasonic loading power is 80-100W, the loading time is 30-60min, and the loading temperature is 0-4°C.

7. An injectable porous composite bone repair hydrogel material based on a thermally induced sacrificial template method, characterized in that: The material is prepared by the method according to any one of claims 1 to 6.

8. The injectable porous composite bone repair hydrogel material based on the thermally induced sacrificial template method according to claim 7, characterized in that: The material needs to be injected into the bone defect site and then subjected to in-situ UV curing. After curing, the gelatin microspheres are dissolved and sacrificed by body temperature, forming a porous structure within the gel matrix.

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