Preparation method of drug-loaded fibroin hard tissue repair implant

Abstract

The invention provides a preparation method of a drug-loaded fibroin hard tissue repair implant, which comprises the following steps: S1, degumming silk to obtain fibroin fibers; s2, dissolving fibroin fibers in a solvent to obtain a silk fibroin salt solution; s3, adding the silk fibroin solution into an ethanol solution, and carrying out bidirectional dialysis to obtain fibroin gel; s4, soaking and rinsing the fibroin gel to obtain pure fibroin gel; and S5, immersing the fibroin gel in the drug-loaded composition solution for drug-loaded treatment, and finally drying to obtain the drug-loaded fibroin hard tissue repair implant. The problem that infection is caused after an existing fibroin material is implanted is solved, and the drug loading capacity of the fibroin material is improved.

Description

Technical Field

[0001] The invention relates to the field of bone repair materials, and in particular to a method for preparing a drug-loaded silk fibroin hard tissue repair implant. Background Art

[0002] Bone is a very important organ in the human body, with the functions of hematopoiesis, regulation and storage of key minerals, and maintenance of life. The ideal fracture internal fixation material needs to meet the strength requirements of fracture internal fixation and be safely degraded by the human body. It needs to provide a certain strength and stability in the early stage of fracture healing to achieve the fixation effect. As the bone tissue gradually heals, the material is gradually degraded and absorbed by the human body, and the stress is transferred to the healing bone tissue, which promotes the repair of fractures and effectively avoids the occurrence of osteoporosis symptoms. Since the 1960s, scientists have begun to study bioabsorbable fracture internal fixation devices. To date, the research and development and use of absorbable fracture internal fixation device materials have made certain progress, and have been used to a certain extent in oral and maxillofacial bone surgery, allowing millions of fracture patients to recover. Absorbable fracture internal fixation materials can be roughly divided into absorbable metals and absorbable polymers. Various applications of natural polymers such as collagen, chitosan, cellulose and silk in modern medicine have been widely studied. In recent years, the above-mentioned natural polymers have gradually attracted the attention of researchers in the field of fracture internal fixation. In addition to having good mechanical properties and bioabsorbability, an ideal fracture internal fixation device should also have osteogenic activity, antibacterial properties and other functions. However, silk itself lacks certain biological activity, does not have the biochemical conditions to trigger cell recruitment and proliferation, and is difficult to promote bone growth. At the same time, implant-related infection is one of the important reasons for secondary surgery of orthopedic internal fixation devices, and studies have shown that silk will promote the growth of Staphylococcus aureus to a certain extent. After implantation, it is easy to form bacterial biofilms on the surface of the material, increasing the risk of related infections. In patent CN201811336242.2, anhydrous silk fibroin is dissolved in a volatile solvent, and then a drug-containing suspension is added to the solution, and finally dried to obtain a solid drug-loaded silk fibroin wire. This method has complicated steps, and other impurities may be introduced during the drug addition process, and there is a risk of residual organic solvents. Summary of the invention

[0003] Technical problem to be solved: The purpose of the present invention is to provide a method for preparing a drug-loaded silk fibroin hard tissue repair implant, to solve the current problem of infection caused by silk fibroin implantation, and to increase the drug loading capacity of silk fibroin materials.

[0004] Technical solution: A method for preparing a drug-loaded silk fibroin hard tissue repair implant, comprising the following steps: S1. degumming the silk to obtain silk fibroin fibers; S2. dissolving the silk fibroin fibers in a solvent to obtain a silk fibroin salt solution; S3. adding the silk fibroin solution to an ethanol solution for bidirectional dialysis to obtain a silk fibroin gel; S4. soaking and rinsing the silk fibroin gel to obtain pure silk fibroin gel; S5. Immerse the silk gel in the drug-loaded composition solution for drug loading treatment, and finally dry and process to obtain a drug-loaded silk hard tissue repair implant. Preferably, the solvent in step S2 is any one of a 9.3M lithium bromide solution or a calcium chloride-ethanol-water ternary solution with a molar ratio of 1:2:8. Preferably, the concentration of the ethanol solution in step S3 is 40-90 wt %, and the time of the bidirectional dialysis is 10-40 h. Preferably, the drug-loaded composition in step S4 is selected from at least one of antibacterial drugs, osteogenic drugs, angiogenic drugs, and immunomodulatory drugs. Preferably, the antibacterial drug is selected from at least one of β-lactams, macrolides, quinolones, lincomycins, polypeptides, aminoglycosides, tetracyclines, chloramphenicol, rifamycins, fosfomycins, and peptide lactones; the osteogenic drug is selected from at least one of bone morphogenetic protein-2, icariin, and bisphosphonates; the angiogenic drug is selected from at least one of vascular endothelial growth factor drugs, antiplatelet drugs, vasodilators, and metabolic activators; and the immunomodulatory drug is selected from at least one of immunopotentiators, immunosuppressants, bidirectional immunomodulators, and traditional Chinese medicine immunomodulators. Preferably, in step S4, the concentration of the antibacterial drug is 0.01-100 mg / ml, and the concentration of the osteogenic drug is 0.01-100 mg / ml. Preferably, the silk fibroin solution in step S2 further contains an osteoconductive material. Preferably, the osteoconductive material is selected from at least one of hydroxyapatite, calcium phosphate ceramics, calcium phosphate bone cement and calcium silicon material. Beneficial effects: The preparation method of the drug-loaded silk fibroin hard tissue repair implant of the present invention has the following advantages: 1. In the present invention, antibacterial drugs, osteogenic drugs, angiogenic drugs, and immunomodulatory drugs are added into silk-based screws by physical adsorption to prepare antibacterial absorbable screws, thereby providing long-lasting antibacterial activity and reducing the risk of a second operation caused by infection and other complications; 2. In the present invention, when the implant is in a gel state, physical adsorption is used to make the implant adsorb drugs. Compared with the implant adsorbing drugs in a dry state, this method has a higher adsorption rate and a long-term release effect; 3. The screw prepared by the present invention has excellent mechanical properties and biocompatibility, and is convenient for adding various functional molecules into the material to give the material new functions. 4. The preparation method of the present invention has a simple process, avoids the use of toxic reagents, circumvents the problem of large-scale loss and bacterial denaturation of SF in conventional dialysis, and improves the production efficiency of silk fibroin screws. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 The drug loading methods in Example 5 and Comparative Example 2 are explored, including: (a) vancomycin standard curve; (b) drug utilization rate of different drug loading methods; (c) drug loading rate of different drug loading methods; (d) sustained release rate of different drug loading methods for 14 days; Figure 2 The drug loading rate, drug utilization rate and sustained release rate in Examples 5-8, wherein: (a) drug utilization rate and sustained release rate at different VAN concentrations; (b) sustained release rate at different VAN concentrations. DETAILED DESCRIPTION The present invention is further described below in conjunction with embodiments and drawings. The following embodiments are explanations of the present invention and the present invention is not limited to the following embodiments: The antibacterial drug selected in the examples and comparative examples is vancomycin hydrochloride (VAN). Example 1 A method for preparing a drug-loaded silk fibroin hard tissue repair implant comprises the following steps: S1. Add the mulberry silk to deionized water at 100°C, with a bath ratio of 1:50 and a sodium carbonate concentration of 0.05wt% for degumming. After 30 minutes, take out the silk and continue to rub it with deionized water to remove the surface sericin. After repeating this step three times, put the silk fiber with the sericin removed into an oven at 60°C to dry it to obtain silk fiber; S2. Add silk fibroin to lithium bromide solution, the mass volume ratio of silk fibroin to lithium bromide solution is 1 g:4 mL, seal and place in a 60°C oven to dissolve for 4 hours, and obtain a silk fibroin salt solution after full dissolution; S3. The silk fibroin salt solution was placed in a dialysis bag and allowed to stand for 2 hours to eliminate bubbles generated by the injection of the solution. The dialysis bags were then immersed in a 40 wt% ethanol solution for 72 hours, and the ethanol solution was replaced every 12 hours. The silk fibroin salt solution was transformed into a gel state through solvent exchange to obtain a silk fibroin gel; S4. Transfer the silk fibroin gel to deionized water for soaking and rinsing to remove ethanol and other residues to obtain pure silk fibroin gel; S5. Immerse the pure silk fibroin gel in 0.8 mg / mL vancomycin hydrochloride solution at room temperature for 24 hours to load the silk-based material with vancomycin, then dry the material in a ventilated environment for 48 hours to obtain a silk fibroin hard tissue repair implant loaded with vancomycin hydrochloride. Example 2 A method for preparing a drug-loaded silk fibroin hard tissue repair implant comprises the following steps: S1. Add the mulberry silk to deionized water at 100°C, with a bath ratio of 1:50 and a sodium carbonate concentration of 0.05wt% for degumming. After 30 minutes, take out the silk and continue to rub it with deionized water to remove the surface sericin. After repeating this step three times, put the silk fiber with the sericin removed into an oven at 60°C to dry it to obtain silk fiber; S2. Add silk fibroin to lithium bromide solution, the mass volume ratio of silk fibroin to lithium bromide solution is 1 g:4 mL, seal and place in a 60°C oven to dissolve for 4 hours, and obtain a silk fibroin salt solution after full dissolution; S3. The silk fibroin salt solution was placed in a dialysis bag and allowed to stand for 2 hours to eliminate bubbles generated by the injection of the solution. The dialysis bags were then immersed in a 60 wt % ethanol solution for 72 hours, and the ethanol solution was replaced every 12 hours. The silk fibroin salt solution was transformed into a gel state through solvent exchange to obtain a silk fibroin gel; S4. Transfer the silk fibroin gel to deionized water for soaking and rinsing to remove ethanol and other residues to obtain pure silk fibroin gel; S5. Immerse the pure silk fibroin gel in 0.8 mg / mL vancomycin hydrochloride solution at room temperature for 24 hours to load the silk-based material with vancomycin, then dry the material in a ventilated environment for 48 hours to obtain a silk fibroin hard tissue repair implant loaded with vancomycin hydrochloride. Example 3 A method for preparing a drug-loaded silk fibroin hard tissue repair implant comprises the following steps: S1. Add the mulberry silk to deionized water at 100°C, with a bath ratio of 1:50 and a sodium carbonate concentration of 0.05wt% for degumming. After 30 minutes, take out the silk and continue to rub it with deionized water to remove the surface sericin. After repeating this step three times, put the silk fiber with the sericin removed into an oven at 60°C to dry it to obtain silk fiber; S2. Add silk fibroin to lithium bromide solution, the mass volume ratio of silk fibroin to lithium bromide solution is 1 g:4 mL, seal and place in a 60°C oven to dissolve for 4 hours, and obtain a silk fibroin salt solution after full dissolution; S3. The silk fibroin salt solution was placed in a dialysis bag and allowed to stand for 2 hours to eliminate bubbles generated by the injection of the solution. The dialysis bags were then immersed in a 70 wt % ethanol solution for 72 hours, and the ethanol solution was replaced every 12 hours. The silk fibroin salt solution was transformed into a gel state through solvent exchange to obtain a silk fibroin gel; S4. Transfer the silk fibroin gel to deionized water for soaking and rinsing to remove ethanol and other residues to obtain pure silk fibroin gel; S5. Immerse the pure silk fibroin gel in 0.8 mg / mL vancomycin hydrochloride solution at room temperature for 24 hours to load the silk-based material with vancomycin, then dry the material in a ventilated environment for 48 hours to obtain a silk fibroin hard tissue repair implant loaded with vancomycin hydrochloride. Example 4 A method for preparing a drug-loaded silk fibroin hard tissue repair implant comprises the following steps: S1. Add the mulberry silk to deionized water at 100°C, with a bath ratio of 1:50 and a sodium carbonate concentration of 0.05wt% for degumming. After 30 minutes, take out the silk and continue to rub it with deionized water to remove the surface sericin. After repeating this step three times, put the silk fiber with the sericin removed into an oven at 60°C to dry it to obtain silk fiber; S2. Add silk fibroin to lithium bromide solution, the mass volume ratio of silk fibroin to lithium bromide solution is 1 g:4 mL, seal and place in a 60°C oven to dissolve for 4 hours, and obtain a silk fibroin salt solution after full dissolution; S3. The silk fibroin salt solution was placed in a dialysis bag and allowed to stand for 2 hours to eliminate bubbles generated by the injection of the solution. The dialysis bags were then immersed in an 80 wt % ethanol solution for 72 hours, and the ethanol solution was replaced every 12 hours. The silk fibroin salt solution was transformed into a gel state through solvent exchange to obtain a silk fibroin gel; S4. Transfer the silk fibroin gel to deionized water for soaking and rinsing to remove ethanol and other residues to obtain pure silk fibroin gel; S5. Immerse the pure silk fibroin gel in 0.8 mg / mL vancomycin hydrochloride solution at room temperature for 24 hours to load the silk-based material with vancomycin, then dry the material in a ventilated environment for 48 hours to obtain a silk fibroin hard tissue repair implant loaded with vancomycin hydrochloride. Example 5 A method for preparing a drug-loaded silk fibroin hard tissue repair implant comprises the following steps: S1. Add the mulberry silk to deionized water at 100°C, with a bath ratio of 1:50 and a sodium carbonate concentration of 0.05wt% for degumming. After 30 minutes, take out the silk and continue to rub it with deionized water to remove the surface sericin. After repeating this step three times, put the silk fiber with the sericin removed into an oven at 60°C to dry it to obtain silk fiber; S2. Add silk fibroin to lithium bromide solution, the mass volume ratio of silk fibroin to lithium bromide solution is 1 g:4 mL, seal and place in a 60°C oven to dissolve for 4 hours, and obtain a silk fibroin salt solution after full dissolution; S3. The silk fibroin salt solution was placed in a dialysis bag and allowed to stand for 2 hours to eliminate bubbles generated by the injection of the solution. The dialysis bags were then immersed in a 90 wt% ethanol solution for 72 hours, and the ethanol solution was replaced every 12 hours. The silk fibroin salt solution was transformed into a gel state through solvent exchange to obtain a silk fibroin gel; S4. Transfer the silk fibroin gel to deionized water for soaking and rinsing to remove ethanol and other residues to obtain pure silk fibroin gel; S5. Immerse the pure silk fibroin gel in 0.8 mg / mL vancomycin hydrochloride solution at room temperature for 48 hours to load the silk-based material with vancomycin, then dry the material in a ventilated environment for 48 hours to obtain a silk fibroin hard tissue repair implant loaded with vancomycin hydrochloride. Example 6 The difference between Example 6 and Example 5 is that the concentration of vancomycin hydrochloride in step S5 is 0.4 mg / mL. Example 7 The difference between Example 7 and Example 5 is that the concentration of vancomycin hydrochloride in step S5 is 1.2 mg / mL. Example 8 The difference between Example 8 and Example 5 is that the concentration of vancomycin hydrochloride in step S5 is 1.6 mg / mL. Comparative Example 1 A method for preparing a drug-loaded silk fibroin hard tissue repair implant comprises the following steps: S1. Add the mulberry silk to deionized water at 100°C, with a bath ratio of 1:50 and a sodium carbonate concentration of 0.05wt% for degumming. After 30 minutes, take out the silk and continue to rub it with deionized water to remove the surface sericin. After repeating this step three times, put the silk fiber with the sericin removed into an oven at 60°C to dry it to obtain silk fiber; S2. Add silk fibroin to lithium bromide solution, the mass volume ratio of silk fibroin to lithium bromide solution is 1 g:4 mL, seal and place in a 60°C oven to dissolve for 4 hours, and obtain a silk fibroin salt solution after full dissolution; S3. The silk fibroin salt solution was placed in a dialysis bag and allowed to stand for 2 hours to eliminate bubbles generated by the injection of the solution. The dialysis bags were then immersed in a 20 wt% ethanol solution for 72 hours, and the ethanol solution was replaced every 12 hours. The silk fibroin salt solution was transformed into a gel state through solvent exchange to obtain a silk fibroin gel; S4. Transfer the silk fibroin gel to deionized water for soaking and rinsing to remove ethanol and other residues to obtain pure silk fibroin gel; S5. Immerse the pure silk fibroin gel in 0.8 mg / mL vancomycin hydrochloride solution at room temperature for 24 hours to load the silk-based material with vancomycin, then dry the material in a ventilated environment for 48 hours to obtain a silk fibroin hard tissue repair implant loaded with vancomycin hydrochloride. Comparative Example 2 A method for preparing a drug-loaded silk fibroin hard tissue repair implant comprises the following steps: S1. Add the mulberry silk to deionized water at 100°C, with a bath ratio of 1:50 and a sodium carbonate concentration of 0.05wt% for degumming. After 30 minutes, take out the silk and continue to rub it with deionized water to remove the surface sericin. After repeating this step three times, put the silk fiber with the sericin removed into an oven at 60°C to dry it to obtain silk fiber; S2. Add silk fibroin to lithium bromide solution, the mass volume ratio of silk fibroin to lithium bromide solution is 1 g:4 mL, seal and place in a 60°C oven to dissolve for 4 hours, and obtain a silk fibroin salt solution after full dissolution; S3. The silk fibroin salt solution was placed in a dialysis bag and allowed to stand for 2 hours to eliminate bubbles generated by the injection of the solution. The dialysis bags were then immersed in an 80 wt % ethanol solution for 72 hours, and the ethanol solution was replaced every 12 hours. The silk fibroin salt solution was transformed into a gel state through solvent exchange to obtain a silk fibroin gel; S4. Transfer the silk fibroin gel to deionized water for soaking and rinsing to remove ethanol and other residues to obtain pure silk fibroin gel; S5. Dry the pure silk fibroin gel and process it, immerse the silk-based solid material in 0.8 mg / mL vancomycin hydrochloride solution at room temperature for 48 hours to load the silk-based material with vancomycin, and then dry the material in a fume hood for 48 hours to obtain the silk-based material loaded with vancomycin hydrochloride. The physical and mechanical properties of the silk fibroin gels prepared in Examples 1-5 and Comparative Example 1 were tested, and the test results are shown in Table 1 below: Table 1 Statistics of the physical and mechanical properties of silk fibroin gels prepared in Examples 1-5 As can be seen from Table 1, when the ethanol concentration is 40-90wt%, the initial compression modulus of the gel gradually increases with the increase of ethanol concentration. When the ethanol concentration is 90wt%, the initial compression modulus of the gel shows a downward trend. The gel prepared at 80wt% ethanol concentration has the highest compression modulus and strength, which are 3.25±0.20MPa and 0.59±0.05MPa, respectively. The gel prepared at this concentration has the strongest mechanical properties. From the test results of the moisture content of silk fibroin gel, it can be seen that the silk fibroin gel prepared by this method has a high moisture content. The moisture content of all gels is above 80%. The moisture content shows a trend of first increasing and then decreasing with the increase of ethanol concentration. The gel prepared at 80wt% ethanol concentration has the lowest moisture content. Therefore, ethanol has a regulating effect on the mechanical properties and moisture content of the gel. The silk fibroin gel obtained by ethanol replacement has a high drug loading capacity. In order to compare the two drug delivery methods, the silk-based materials of different forms in Example 5 and Comparative Example 2 were immersed in the same concentration of vancomycin solution (0.8 mg / ml). By comparing the drug loading rate, drug utilization rate and drug sustained release effect of the two drug delivery methods, a better drug delivery method was found. Figure 1 (a) is the standard curve of vancomycin hydrochloride tested by UV spectrophotometer; Figure 1 (b) shows the drug utilization rate of the two drug loading methods after immersion for 12h, 24h, 36h, and 48h. It can be seen from the figure that the drug utilization rate of the gel-based drug loading at 12h and 24h is significantly higher than that of the dry SF-based drug loading, proving that the gel-based drug loading is more efficient. Figure 1 (c) is the drug loading rate of the two drug loading methods at different time points. Similarly, at 12h and 24h, the drug loading rate of the gel state (Example 5) is significantly higher than that of the dry silk-based material (Comparative Example 2). However, there is no significant difference between the two drug loading methods at 36h and 48h, which proves that the gel-state silk-based material is more conducive to the entry of drugs. This should be because the internal structure of the gel-state silk-based material is fluffy and the intermolecular gap is large, which is more conducive to the uniform penetration of drugs and can absorb and accommodate more drugs. This drug loading method is more conducive to achieving efficient drug loading. The 24h time point was selected to explore the sustained-release effect of the two drug loading methods. Figure 1 (d) is the cumulative release rate of vancomycin hydrochloride. At 336h, the cumulative release rate of the gel state reached 49.59±3.93%, while the cumulative release rate of the dry drug loading method reached 72.70±9.28%. It can also be seen from the figure that the overall release rate of the gel drug is slow, while the dry drug loading method has a faster release rate in the first 96h. This may be due to the dense structure of the dry silk-based material, which makes it difficult for the drug to penetrate into the interior, resulting in uneven distribution of the drug in the silk-based material. The drug adsorbed on the surface of the material is first released quickly, resulting in a fast release rate in the early stage of the drug. Based on the above data, the gel drug loading can achieve more efficient drug loading and long-term release. In order to explore the loading effect of different concentrations of vancomycin hydrochloride in pure silk gel, the pure silk gel material was immersed in vancomycin solutions of different concentrations (0.4 mg / ml, 0.8 mg / ml, 1.2 mg / ml, 1.6 mg / ml), and the drug loading rate, drug utilization rate and sustained release rate were tested by UV spectrophotometer. Figure 2(a) is the test result of drug loading rate and drug utilization rate. It can be seen from the figure that with the increase of vancomycin hydrochloride concentration, the drug loading rate shows a gradual upward trend, and the drug utilization rate shows a gradual downward trend. When the concentration of vancomycin hydrochloride is 0.4 mg / ml, the drug loading rate is only 5.49±0.10%, but the drug utilization rate is the highest, which is 68.59±1.24%, proving that increasing the drug concentration can load more drugs. This may be because the higher the concentration of vancomycin hydrochloride, the greater the concentration difference between the material and the vancomycin hydrochloride solution, the faster the speed of vancomycin hydrochloride flowing into the material, and the more drugs the material can load in a limited time. Figure 2 (b) is the sustained release rate test result of different concentrations of vancomycin hydrochloride. It can be seen from the figure that the higher the concentration of vancomycin hydrochloride, the slower the sustained release rate of the drug. At 168h, the sustained release rates of materials with different concentrations of vancomycin hydrochloride were 49.49±1.83%, 42.49±1.79%, 33.69±1.03%, and 31.09±2.37%, respectively, indicating that increasing the drug concentration can increase the sustained release time of the drug. This may be due to the fact that within a limited time (24h), the higher the concentration of vancomycin hydrochloride, the more drugs enter the material, and the greater the proportion of the internal drug amount to the total drug amount. When the drug is released, a small amount of drugs in the outside are first released by dissolution and diffusion, and more drugs in the inside can be released slowly, resulting in the phenomenon that the higher the concentration of vancomycin hydrochloride, the slower the release rate of the material. Therefore, according to the different parts of the site of use, the pure silk gel can be immersed in different drug-carrying compositions to obtain hard tissue repair implants with different drug loading rates and sustained release effects. Obviously, the above embodiments are merely examples for the purpose of clear explanation, and are not intended to limit the implementation methods. For those skilled in the art, other different forms of changes or modifications can be made based on the above description. It is not necessary and impossible to list all the implementation methods here. The obvious changes or modifications derived therefrom are still within the scope of protection of the invention.

Claims

1. A method for preparing a drug-loaded silk fibroin hard tissue repair implant, characterized in that: The following steps are involved: S1. degumming the silk to obtain silk fibroin fibers; S2. dissolving the silk fibroin fibers in a solvent to obtain a silk fibroin salt solution; S3. adding the silk fibroin solution to an ethanol solution for bidirectional dialysis to obtain a silk fibroin gel; S4. soaking and rinsing the silk fibroin gel to obtain pure silk fibroin gel; S5. Immerse the silk gel in the drug-loaded composition solution for drug loading treatment, and finally dry and process to obtain a drug-loaded silk hard tissue repair implant.

2. The method for preparing the drug-loaded silk fibroin hard tissue repair implant according to claim 1, characterized in that: The solvent in step S2 is any one of a 9.3M lithium bromide solution or a ternary solution of calcium chloride-ethanol-water with a molar ratio of 1:2:

8.

3. The method for preparing the drug-loaded silk fibroin hard tissue repair implant according to claim 1, characterized in that: The concentration of the ethanol solution in step S3 is 40-90 wt %, and the time of the bidirectional dialysis is 10-40 h.

4. The method for preparing the drug-loaded silk fibroin hard tissue repair implant according to claim 1, characterized in that: The drug-carrying composition in step S4 is selected from at least one of antibacterial drugs, osteogenic drugs, angiogenic drugs, and immunomodulatory drugs.

5. The method for preparing the drug-loaded silk fibroin hard tissue repair implant according to claim 4, characterized in that: The antibacterial drug is selected from at least one of β-lactams, macrolides, quinolones, lincomycins, polypeptides, aminoglycosides, tetracyclines, chloramphenicol, rifamycins, fosfomycins, and peptide lactones; the osteogenic drug is selected from at least one of bone morphogenetic protein-2, icariin, and bisphosphonates; the angiogenic drug is selected from at least one of vascular endothelial growth factor drugs, antiplatelet drugs, vasodilators, and metabolic activators; and the immunomodulatory drug is selected from at least one of immunopotentiators, immunosuppressants, bidirectional immunomodulators, and traditional Chinese medicine immunomodulators.

6. The method for preparing the drug-loaded silk fibroin hard tissue repair implant according to claim 1, characterized in that: In step S4, the concentration of the antibacterial drug is 0.01-100 mg / ml, and the concentration of the osteogenic drug is 0.01-100 mg / ml.

7. The method for preparing the drug-loaded silk fibroin hard tissue repair implant according to claim 1, characterized in that: The silk fibroin solution in step S2 also contains an osteoconductive material.

8. The method for preparing the drug-loaded silk fibroin hard tissue repair implant according to claim 7, characterized in that: The bone conduction material is selected from at least one of hydroxyapatite, calcium phosphate ceramics, calcium phosphate bone cement and calcium silicon material.

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