A bioactive glass-based cranial defect repair composite material and a method of making the same

Abstract

The application discloses a bioactive glass-based skull defect repairing composite material and a preparation method thereof, and relates to the technical field of skull defect repairing materials.The bioactive glass-based skull defect repairing composite material comprises the following raw materials in parts by weight: collagen 10-12 parts, bioactive glass 40-50 parts, natural polysaccharide 5-8 parts, hydroxyapatite 20-30 parts, modified reinforcing agent 6-8 parts, antibacterial agent 1-2 parts and deionized water 100-150 parts.The bioactive glass-based skull defect repairing composite material prepared by the application has good bending resistance and antibacterial performance.

Description

Technical Field

[0001] This invention relates to the field of skull defect repair materials, specifically to a bioactive glass-based skull defect repair composite material and its preparation method. Background Technology

[0002] Skull defects are a common clinical problem in neurosurgery, mainly caused by trauma, tumor resection, infection, congenital malformations, and decompression surgery. Defects not only severely affect a patient's appearance but also deprive brain tissue of its complete protection, increasing the risk of complications such as brain injury, infection, and cerebrospinal fluid leakage. Therefore, timely and effective cranial repair is crucial for restoring the integrity of the cranial cavity and protecting brain function. Currently, commonly used repair materials include autologous bone, allogeneic bone, titanium alloys, polymethyl methacrylate (PMMA), and polymeric materials. While autologous bone grafting has good biocompatibility and osteoinductive properties, it presents challenges such as donor site complications, limited bone volume, and secondary surgical trauma. Allogeneic bone, while avoiding donor site damage, faces risks such as immune rejection. Metallic materials like titanium alloys have high mechanical strength and stability, but they only mechanically integrate with bone tissue, lacking bioactivity and failing to promote osseointegration; they are also prone to artifacts during imaging examinations. PMMA is easy to mold, but the exothermic reaction during polymerization may damage surrounding tissues, and it lacks osteoinductive properties; long-term use may lead to loosening or infection. Bioactive glass, as a novel inorganic biomaterial, possesses excellent biocompatibility, osteoconductivity, and osteoinductive properties. It can rapidly form a hydroxyapatite layer in bodily fluids, establishing a strong chemical bond with bone tissue and stimulating osteoblast differentiation and new bone formation, demonstrating significant advantages in bone defect repair. However, traditional bioactive glass suffers from problems such as high brittleness, low mechanical strength, and insufficient toughness, making it difficult to withstand the complex mechanical loads of the skull on its own. Furthermore, its processing and shaping are challenging, limiting its widespread application in skull defect repair.

[0003] Chinese invention patent CN102294049A discloses a bioactive glass-chitosan composite bone repair material, its preparation method, and its uses. The method involves adding chitosan to a dilute hydrochloric acid solution and stirring until the chitosan is completely dissolved to obtain solution I; adding distilled water to sodium β-glycerophosphate, stirring, and filtering to remove bacteria to obtain solution II; mixing solution II and solution I and stirring for 1-2 hours to obtain solution III; adding bioactive glass to solution III and stirring for 36-48 hours to obtain solution IV; injecting solution IV into a mold and drying it until it becomes a gel, then freezing at -80℃ and drying to obtain the bioactive glass-chitosan composite scaffold material. This invention has a relatively simple preparation process, easily controllable process parameters, good dispersibility and thermal stability of the bioactive glass, and the prepared bioactive glass-chitosan composite bone repair material exhibits good bioactivity and biocompatibility, as well as good mechanical properties; however, its antibacterial properties are still insufficient.

[0004] Therefore, there is an urgent need to develop a composite repair material based on bioactive glass and incorporating the advantages of other materials, so as to simultaneously meet the requirements of biological and mechanical properties and achieve safe, effective and convenient repair of skull defects. Summary of the Invention

[0005] To address the shortcomings of existing technologies, the purpose of this invention is to provide a bioactive glass-based composite material for repairing skull defects and its preparation method.

[0006] To achieve the above objectives, the present invention provides the following technical solution: A bioactive glass-based composite material for repairing skull defects comprises the following raw materials in parts by weight: Collagen 10-12 parts, bioactive glass 40-50 parts, natural polysaccharide 5-8 parts, hydroxyapatite 20-30 parts, modifier and reinforcing agent 6-8 parts, antibacterial agent 1-2 parts, deionized water 100-150 parts; The antibacterial agent is prepared by the following method: S1: 4',5,7-Trihydroxyflavanone reacts with epichlorohydrin to form a tricyclic oxide compound. S2: 2-Oleoyl-1-palmitinyl-3-phosphocholine reacts with 7-amino-1-heptanthiol to generate intermediate 1. S3: Intermediate 1 reacts with a triepoxide to generate an antibacterial agent.

[0007] The modified reinforcing agent is prepared by the following method: A1: 4-Vinyl-1-cyclohexene-1,2-epoxy reacts with 2,4,6,8-tetramethylcyclotetrasiloxane to generate epoxy-modified siloxane. A2: Epoxy-modified siloxane reacts with 3,6,9,12,15,18-hexaoxane-nonadecanoic acid to generate a modified reinforcing agent.

[0008] In step S1, the molar ratio of 4',5,7-trihydroxyflavanone to epichlorohydrin is 1:(3.05-3.1).

[0009] In step S2, the molar ratio of 2-oleoyl-1-palmitin glycerol-3-phosphate choline to 7-amino-1-heptanethiol is 1:(1.05-1.1).

[0010] In step S3, the molar ratio of intermediate 1 to tricyclic oxide is (3.05-3.1):1.

[0011] In step A1, the molar ratio of 4-vinyl-1-cyclohexene-1,2-epoxy to 2,4,6,8-tetramethylcyclotetrasiloxane is 4.03:1.

[0012] In step A2, the molar ratio of the epoxy-modified siloxane to 3,6,9,12,15,18-hexaoxane-nonadecanoic acid is 1:4.05.

[0013] The collagen is recombinant human collagen.

[0014] The natural polysaccharide is chitosan.

[0015] A method for preparing a bioactive glass-based composite material for repairing skull defects includes the following steps: (1) Weigh out the following by weight: 10-12 parts of collagen, 40-50 parts of bioactive glass, 5-8 parts of natural polysaccharide, 20-30 parts of hydroxyapatite, 6-8 parts of modifier and enhancer, 1-2 parts of antibacterial agent, and 100-150 parts of deionized water. (2) Mix deionized water and collagen, add bioactive glass, natural polysaccharides, hydroxyapatite, modifier and enhancer, and antibacterial agent, and then homogenize under high pressure, freeze dry and sterilize by irradiation to obtain the product.

[0016] Due to the adoption of the above technical solutions, the beneficial effects of the present invention include: The bioactive glass-based skull defect repair composite material prepared by this invention has bending resistance and antibacterial properties. Attached Figure Description

[0017] Figure 1 The 1H NMR spectrum of the triepoxide compound prepared in step S1 of Example 1; Figure 2 This is a high-resolution mass spectrum of the tricyclic oxide compound prepared in step S1 of Example 1; Figure 3 The 1H NMR spectrum of intermediate 1 prepared in step S2 of Example 1; Figure 4 The high-resolution mass spectrum of intermediate 1 prepared in step S2 of Example 1; Figure 5 The 1H NMR spectrum of the antibacterial agent prepared in step S3 of Example 1; Figure 6 This is a high-resolution mass spectrum of the antibacterial agent prepared in step S3 of Example 1; Figure 7 The 1H NMR spectrum of the epoxy-modified siloxane prepared in step A1 of Example 4; Figure 8 This is a high-resolution mass spectrum of the epoxy-modified siloxane prepared in step A1 of Example 4; Figure 9 The 1H NMR spectrum of the modified reinforcing agent prepared in step A2 of Example 4; Figure 10This is a high-resolution mass spectrum of the modified reinforcing agent prepared in step A2 of Example 4. Detailed Implementation

[0018] The following description, in conjunction with specific embodiments, provides further details, but the present invention is not limited to these embodiments.

[0019] Example 1: Preparation of antibacterial agent: S1: Add 250 ml of DMF (N,N-dimethylformamide), 0.1 mol of 4',5,7-trihydroxyflavanone, 0.305 mol of epichlorohydrin, and 0.005 mol of tetrabutylammonium bromide to the reaction flask, stir and mix well, heat to 60℃, react for 5 h, cool to 0℃, and slowly add 165 ml of DMF. A 2M sodium hydroxide solution was added dropwise over 1 hour. After the addition was complete, the temperature was raised to 40°C and the reaction was carried out for 2 hours. The mixture was then cooled to room temperature and slowly added to 600 ml of ice water. The mixture was then extracted three times with ethyl acetate (250 ml each time). The organic phases were combined, washed twice with deionized water (150 ml each time), and then washed once with 150 ml of saturated sodium chloride solution. The mixture was dried over 50 g of anhydrous sodium sulfate, filtered, and rotary evaporated at 70°C to constant weight. The solution was slowly poured into 300 ml of petroleum ether, stirred, and a solid precipitated. The solid was filtered, washed twice with cold petroleum ether (50 ml each time), and dried under vacuum at 50°C for 10 hours to obtain a triepoxide compound. The reaction equation is shown below.

[0020] Its proton nuclear magnetic resonance spectrum is as follows: Figure 1 As shown, its 1H NMR spectrum data are as follows: 1 H NMR (400 MHz, DMSO- d 6 δ 7.31 – 7.22 (m, 2H), 6.96 – 6.85 (m, 2H), 6.34 (d, J = 2.3 Hz, 1H), 6.23 (d, J = 2.3 Hz, 1H), 5.60 (tt, J = 5.9, 2.7 Hz, 1H), 4.35 – 3.91 (m, 6H), 3.59 – 3.44 (m, 3H), 3.29 (dd, J = 7.6, 2.9 Hz, 3H), 3.13 – 3.01 (m, 4H), 2.84 (dd, J = 16.8, 5.9 Hz, 1H); its high-resolution mass spectrum is shown below. Figure 2 As shown, HRMS (m / z): 441.1475 [M+H] + .

[0021] S2: Under nitrogen protection, add 450 ml of tetrahydrofuran, 0.105 mol of 7-amino-1-heptanthiol, 0.1 mol of 2-oleoyl-1-palmitotin glycerol-3-phosphate choline, and 0.5 g of photoinitiator 184 to the reaction flask, stir and mix well, and at room temperature, at an intensity of 8.4 mW / cm². 2 After irradiation under a 365nm UV LED lamp for 2 hours, the mixture was rotary evaporated at 45℃ to constant weight. 200ml of dichloromethane was added to dissolve the precipitate, and the solution was washed with 150ml of saturated sodium chloride solution. The organic phase was dried over 20g of anhydrous sodium sulfate, filtered, and rotary evaporated at 45℃ to constant weight. 300ml of n-hexane was added, and the mixture was stirred at room temperature for 30 minutes to precipitate. The precipitate was filtered, washed with cold n-hexane (3×50ml), and dried under vacuum at 45℃ for 12 hours to obtain intermediate 1. The reaction equation is shown below:

[0022] Its proton nuclear magnetic resonance spectrum is as follows Figure 3 As shown, its hydrogen NMR spectrum data is as follows: 1 H NMR (400 MHz, Chloroform- d δ 5.02 (p, J = 5.2 Hz, 1H), 4.45 (dd, J = 12.2, 5.1 Hz, 1H), 4.25 – 4.15 (m, 4H), 3.96 (dd, J = 11.6, 5.2 Hz, 1H), 3.63 (t, J = 3.1 Hz, 2H), 3.17 (s, 9H), 2.80 (p, J = 5.8 Hz, 1H), 2.71 – 2.24 (m, 8H), 1.69 – 1.21 (m, 66H), 0.94 – 0.84 (m, 6H); its high-resolution mass spectrum is shown below. Figure 4 As shown, HRMS (m / z): 907.6862 [M+H] + .

[0023] S3: Under nitrogen protection, 800 ml of anhydrous tetrahydrofuran, 0.305 mol of intermediate 1, 0.1 mol of triepoxide, and 0.03 mol of triethylamine were stirred and mixed thoroughly. The mixture was heated to reflux for 7 hours, cooled to room temperature, and rotary evaporated at 50°C to constant weight. The final weight was determined by diluting the mixture with 500 ml of a mixed solution of tetrahydrofuran and n-hexane (V... 四氢呋喃 :V 正己烷 Recrystallize the mixture (1:3 ratio), filter, and vacuum dry at 50°C for 12 hours to obtain the antibacterial agent. The reaction equation is shown below:

[0024]

[0025] Its proton nuclear magnetic resonance spectrum is as follows Figure 5 As shown, its 1H NMR spectrum data are as follows: 1 H NMR (400 MHz, Chloroform- d ) δ 7.30 – 7.26 (m, 2H), 6.93 – 6.84 (m, 2H), 6.31 (d, J = 2.3Hz, 1H), 6.17 (d, J = 2.3 Hz, 1H), 5.57 (tt, J = 5.9, 2.7 Hz, 1H), 5.02 (p, J = 5.1 Hz, 3H), 4.77 (tt, J = 6.5, 4.8 Hz, 3H), 4.45 (dd, J = 12.2, 5.1 Hz, 3H), 4.24 – 4.06 (m, 15H), 3.99 – 3.81 (m, 12H), 3.63 (t, J = 3.1 Hz, 6H),3.17 (s, 27H), 3.12 – 2.23 (m, 35H), 1.68 – 1.20 (m, 192H), 0.94 – 0.83 (m, 18H); its high-resolution mass spectrum is shown below. Figure 6 As shown, HRMS (m / z): 3162.2088 [M+H] + .

[0026] Example 2: Preparation of antibacterial agent: S1: Add 250 ml DMF, 0.1 mol 4',5,7-trihydroxyflavanone, 0.308 mol epichlorohydrin, and 0.005 mol tetrabutylammonium bromide to a reaction flask, stir and mix well, heat to 65 °C, react for 4.5 h, cool to 0 °C, slowly add 165 ml 2M sodium hydroxide solution dropwise over 1 h, after which heat to 40 °C and react for 2 h; cool to room temperature, slowly add 600 ml ice water, then extract three times with ethyl acetate (250 ml each time), combine the organic phases, wash twice with deionized water (150 ml each time), wash once with 150 ml saturated sodium chloride solution, dry with 50 g anhydrous sodium sulfate, filter, rotary evaporate at 70 °C to constant weight, slowly pour into 300 ml petroleum ether, stir, precipitate solid, filter, wash twice with cold petroleum ether (50 ml each time), and vacuum dry at 50 °C for 10 h to obtain triepoxide compound; S2: Under nitrogen protection, add 450 ml of tetrahydrofuran, 0.108 mol of 7-amino-1-heptanthiol, 0.1 mol of 2-oleoyl-1-palmitotin glycerol-3-phosphate choline, and 0.5 g of photoinitiator 184 to the reaction flask, stir and mix well, and at room temperature, at an intensity of 8.4 mW / cm².2 After irradiation under a 365nm UV LED lamp for 1.5h, the mixture was rotary evaporated at 45℃ to constant weight. 200ml of dichloromethane was added to dissolve the precipitate, and the solution was washed with 150ml of saturated sodium chloride solution. The organic phase was dried over 20g of anhydrous sodium sulfate, filtered, and rotary evaporated at 45℃ to constant weight. 300ml of n-hexane was added, and the mixture was stirred at room temperature for 30min to precipitate the precipitate. The precipitate was filtered, washed with cold n-hexane (3×50ml), and dried under vacuum at 45℃ for 12h to obtain intermediate 1. S3: Under nitrogen protection, 800 ml of anhydrous tetrahydrofuran, 0.308 mol of intermediate 1, 0.1 mol of triepoxide, and 0.03 mol of triethylamine were stirred and mixed thoroughly. The mixture was heated to reflux for 6 hours, cooled to room temperature, and rotary evaporated at 50°C to constant weight. The final weight was determined by diluting the mixture with 500 ml of a mixed solution of tetrahydrofuran and n-hexane (V... 四氢呋喃 :V 正己烷 =1:3), filtered, vacuum dried at 50℃ for 12h to obtain the antibacterial agent.

[0027] Example 3: Preparation of antibacterial agent: S1: Add 250 ml DMF, 0.1 mol 4',5,7-trihydroxyflavanone, 0.31 mol epichlorohydrin, and 0.005 mol tetrabutylammonium bromide to a reaction flask, stir and mix well, heat to 70 °C, react for 4 h, cool to 0 °C, slowly add 165 ml 2M sodium hydroxide solution dropwise over 1 h, after which heat to 40 °C and react for 2 h; cool to room temperature, slowly add 600 ml ice water, then extract three times with ethyl acetate (250 ml each time), combine the organic phases, wash twice with deionized water (150 ml each time), wash once with 150 ml saturated sodium chloride solution, dry with 50 g anhydrous sodium sulfate, filter, rotary evaporate at 70 °C to constant weight, slowly pour into 300 ml petroleum ether, stir, precipitate solid, filter, wash twice with cold petroleum ether (50 ml each time), and dry under vacuum at 50 °C for 10 h to obtain triepoxide compound; S2: Under nitrogen protection, add 450 ml of tetrahydrofuran, 0.11 mol of 7-amino-1-heptanthiol, 0.1 mol of 2-oleoyl-1-palmitotin glycerol-3-phosphate choline, and 0.5 g of photoinitiator 184 to the reaction flask, stir and mix well, and at room temperature, at an intensity of 8.4 mW / cm². 2 After irradiation under a 365nm UV LED lamp for 1 hour, the mixture was rotary evaporated at 45℃ to constant weight. 200ml of dichloromethane was added to dissolve the precipitate, and the solution was washed with 150ml of saturated sodium chloride solution. The organic phase was dried with 20g of anhydrous sodium sulfate, filtered, and rotary evaporated at 45℃ to constant weight. 300ml of n-hexane was added, and the mixture was stirred at room temperature for 30 minutes to precipitate. The precipitate was filtered, washed with cold n-hexane (3×50ml), and dried under vacuum at 45℃ for 12 hours to obtain intermediate 1. S3: Under nitrogen protection, 800 ml of anhydrous tetrahydrofuran, 0.31 mol of intermediate 1, 0.1 mol of triepoxide, and 0.03 mol of triethylamine were stirred and mixed thoroughly. The mixture was heated to reflux and reacted for 5 hours. After cooling to room temperature, the mixture was rotary evaporated at 50°C to constant weight. The final weight was determined by diluting the mixture with 500 ml of a mixed solution of tetrahydrofuran and n-hexane (V... 四氢呋喃 :V 正己烷 =1:3), filtered, vacuum dried at 50℃ for 12h to obtain the antibacterial agent.

[0028] Example 4: Preparation of the modified reinforcing agent: A1: Under nitrogen protection, 400 ml of anhydrous toluene, 20 mg of platinum catalyst, and 0.403 mol of 4-vinyl-1-cyclohexene-1,2-epoxy were added to a reaction flask. The mixture was stirred and stirred until homogeneous. The temperature was raised to 70 °C, and then 100 ml of a toluene solution containing 0.1 mol of 2,4,6,8-tetramethylcyclotetrasiloxane was slowly added dropwise over 30 min. After the addition was complete, the reaction was allowed to proceed for 8 h. The mixture was then rotary evaporated at 70 °C to constant weight and dried under vacuum at 70 °C for 10 h to obtain the epoxy-modified siloxane. The reaction equation is shown below:

[0029] Its proton nuclear magnetic resonance spectrum is as follows Figure 7 As shown, its 1H NMR spectrum data are as follows: 1 H NMR (400 MHz, Chloroform- d δ 3.19 (dt, J = 3.8, 3.4 Hz, 4H), 3.06 (td, J = 4.3, 3.8 Hz, 4H), 2.02 – 1.58 (m, 28H), 1.46 – 1.33 (m, 8H), 0.88 – 0.63 (m, 8H), 0.02 (s, 12H); its high-resolution mass spectrum is shown below. Figure 8 As shown, HRMS (m / z): 737.3682 [M+H] + .

[0030] A2: Under nitrogen protection, 1000 ml of xylene and 0.1 mol of epoxy-modified siloxane were added to a reaction flask, stirred and mixed, and heated to 100 °C. Then, 0.02 mol of triphenylphosphine and 0.405 mol of 3,6,9,12,15,18-hexaoxane-nonadecanoic acid were added, stirred and mixed, and reacted for 8 h. After cooling to room temperature, the mixture was rotary evaporated at 60 °C to constant weight. 500 ml of dichloromethane was added to dissolve the precipitate, and the solution was washed successively with 200 ml of deionized water and 150 ml of saturated sodium chloride solution. The precipitate was dried over 80 g of anhydrous sodium sulfate, filtered, and slowly added dropwise to 300 ml of cold diethyl ether to precipitate the precipitate. The precipitate was filtered, washed with cold diethyl ether (3 × 50 ml), and dried under vacuum at 60 °C for 12 h to obtain the modified reinforcing agent. The reaction equation is shown below:

[0031] Its proton nuclear magnetic resonance spectrum is as follows Figure 9 As shown, its 1H NMR spectrum data are as follows: 1 H NMR (400 MHz, Chloroform- d δ 4.78 (dt, J = 6.0, 5.3 Hz, 4H), 4.19 – 4.08 (m, 8H), 3.94 (tdd, J = 6.7, 6.0, 5.5 Hz, 4H), 3.72 – 3.56 (m, 80H), 3.38 (s, 12H), 2.88 (d, J = 5.5 Hz, 4H), 2.00 – 1.33 (m, 36H), 0.89 – 0.63 (m, 8H), 0.02 (s, 12H); its high-resolution mass spectrum is shown below. Figure 10 As shown, HRMS (m / z): 1978.0193 [M+H] + .

[0032] Example 5: Preparation of bioactive glass-based composite material for repairing skull defects: (1) Weigh out: 100g of collagen (recombinant human collagen), 400g of bioactive glass, 50g of natural polysaccharide (chitosan), 200g of hydroxyapatite, 60g of modifier (prepared in Example 4), 10g of antibacterial agent (prepared in Example 1), and 1000g of deionized water; (2) Mix deionized water with collagen and stir at 500 rpm for 2 hours. Add bioactive glass, natural polysaccharide, hydroxyapatite, modifier, and antibacterial agent. Place the mixture in a high-pressure homogenizer and homogenize it 5 times under a pressure of 20 MPa. Then place it in a polytetrafluoroethylene mold (100 mm × 50 mm × 10 mm) and freeze dry at -50 °C for 24 hours. Sterilize it by irradiation with γ-rays (irradiation dose 25 kGy) for 2 hours to obtain a bioactive glass-based skull defect repair composite material.

[0033] Example 6: Preparation of bioactive glass-based composite material for repairing skull defects: (1) Weigh out: 110g of collagen (recombinant human collagen), 450g of bioactive glass, 60g of natural polysaccharide (chitosan), 250g of hydroxyapatite, 70g of modifier (prepared in Example 4), 15g of antibacterial agent (prepared in Example 2), and 1200g of deionized water; (2) Mix deionized water with collagen and stir at 500 rpm for 2 hours. Add bioactive glass, natural polysaccharide, hydroxyapatite, modifier, and antibacterial agent. Place the mixture in a high-pressure homogenizer and homogenize it 5 times under a pressure of 20 MPa. Then place it in a polytetrafluoroethylene mold (100 mm × 50 mm × 10 mm) and freeze dry at -50 °C for 24 hours. Sterilize it by irradiation with γ-rays (irradiation dose 25 kGy) for 2 hours to obtain a bioactive glass-based skull defect repair composite material.

[0034] Example 7: Preparation of bioactive glass-based composite material for repairing skull defects: (1) Weigh out: 120g of collagen (recombinant human collagen), 500g of bioactive glass, 80g of natural polysaccharide (chitosan), 300g of hydroxyapatite, 80g of modifier (prepared in Example 4), 20g of antibacterial agent (prepared in Example 3), and 1500g of deionized water; (2) Mix deionized water with collagen and stir at 500 rpm for 2 hours. Add bioactive glass, natural polysaccharide, hydroxyapatite, modifier, and antibacterial agent. Place the mixture in a high-pressure homogenizer and homogenize it 5 times under a pressure of 20 MPa. Then place it in a polytetrafluoroethylene mold (100 mm × 50 mm × 10 mm) and freeze dry at -50 °C for 24 hours. Sterilize it by irradiation with γ-rays (irradiation dose 25 kGy) for 2 hours to obtain a bioactive glass-based skull defect repair composite material.

[0035] Comparative Example 1 The raw material composition and preparation method of the bioactive glass-based cranial defect repair composite material are basically the same as those in Example 6, except that the antibacterial agent is replaced with an equal weight of an antibacterial agent prepared by the following method: The preparation method of the antibacterial agent is basically the same as that in Example 2, except that the amount of intermediate 1 in step S3 is 0.208 mol.

[0036] Comparative Example 2 The raw material composition and preparation method of the bioactive glass-based cranial defect repair composite material are basically the same as those in Example 6, except that the antibacterial agent is replaced with an equal weight of an antibacterial agent prepared by the following method: The preparation method of the antibacterial agent is basically the same as that in Example 2, except that 2-oleoyl-1-palmitoyltin glycerol-3-phosphate choline in step S2 is replaced with an equimolar amount of 1-O-1'-(Z)-octadecenyl-2-hydroxy-sn-glycerol-3-phosphate choline.

[0037] Comparative Example 3 The raw material composition and preparation method of the bioactive glass-based cranial defect repair composite material are basically the same as those in Example 6, except that the antibacterial agent is replaced with an equal weight of an antibacterial agent prepared by the following method: The preparation method of the antibacterial agent is basically the same as that in Example 2, except that 7-amino-1-heptanethiol in step S2 is replaced with an equimolar amount of 4-aminobutane-1-thiol.

[0038] Comparative Example 4 The raw material composition and preparation method of the bioactive glass-based cranial defect repair composite material are basically the same as those in Example 6, except that the modifying reinforcing agent is replaced with an equal weight of the modifying reinforcing agent prepared by the following method: The preparation method of the modified reinforcing agent is basically the same as that in Example 4, except that the 4-vinyl-1-cyclohexene-1,2-epoxy in step A1 is replaced with an equimolar amount of 1,2-epoxy-5-hexene.

[0039] Comparative Example 5 The raw material composition and preparation method of the bioactive glass-based cranial defect repair composite material are basically the same as those in Example 6, except that the modifying reinforcing agent is replaced with an equal weight of the modifying reinforcing agent prepared by the following method: The preparation method of the modified reinforcing agent is basically the same as that in Example 4, except that 2,4,6,8-tetramethylcyclotetrasiloxane in step A1 is replaced with an equimolar amount of methyltris(dimethylsiloxane)silane; the amount of 4-vinyl-1-cyclohexene-1,2-epoxy is 0.303 mol; and the amount of 3,6,9,12,15,18-hexaoxane-nonadecanoic acid in step A2 is 0.305 mol.

[0040] Comparative Example 6 The raw material composition and preparation method of the bioactive glass-based cranial defect repair composite material are basically the same as those in Example 6, except that the modifying reinforcing agent is replaced with an equal weight of the modifying reinforcing agent prepared by the following method: The preparation method of the modified reinforcing agent is basically the same as that in Example 4, except that 3,6,9,12,15,18-hexaoxane-nonadecanoic acid in step A2 is replaced with an equimolar amount of lauric acid.

[0041] Comparative Example 7 The raw material composition and preparation method of the bioactive glass-based cranial defect repair composite material are basically the same as those in Example 6, except that the modifying reinforcing agent is replaced with an equal weight of the modifying reinforcing agent prepared by the following method: The preparation method of the modified reinforcing agent is basically the same as that in Example 4, except that 3,6,9,12,15,18-hexaoxane-nonadecanoic acid in step A2 is replaced with an equimolar amount of diethylene glycol monomethyl ether propionic acid.

[0042] The bioactive glass used in the embodiments and comparative examples of this application is model HQ-BG45s-D1, produced by Kunshan Huaqiao Science and Technology New Materials Co., Ltd.; the hydroxyapatite is model HAP03-20, produced by Nanjing Junzhuo Biotechnology Co., Ltd.; the recombinant human collagen is recombinant type III humanized collagen, produced by Zhuhai Jibaikang Biotechnology Co., Ltd.; and the chitosan has a number average molecular weight of 800 kDa and a degree of deacetylation of 80%.

[0043] The platinum catalyst used in Example 4 of this application was prepared by the following method: Weigh 0.205 g of chloroplatinic acid and add it to 9.88 g of isopropanol. Stir at room temperature for 2 h to fully dissolve the chloroplatinic acid in the isopropanol. The solution turns orange-yellow, and the platinum catalyst is obtained.

[0044] The flexural strength and antibacterial properties of the bioactive glass-based skull defect repair composite materials prepared in the examples and comparative examples were tested, and the test results are shown in Table 1.

[0045] Bending strength test: The bioactive glass composite materials prepared in Examples 5-7 and Comparative Examples 1-7 were cut into specimens with dimensions of 45mm × 4mm × 3mm. The bending strength of the specimens was tested using an electronic universal testing machine with a loading speed of 0.5mm / min and a span of 20mm. The maximum load at which the specimen fractured was recorded, and the bending strength was calculated according to the following formula:

[0046] In the formula, is the bending strength, MPa; F is the maximum load at which the specimen breaks, N; L is the span, mm; b is the width of the specimen, mm; h is the height of the specimen, mm.

[0047] Antibacterial performance test: The bioactive glass-based cranial defect repair composite materials prepared in the examples and comparative examples were cut into uniform circular shapes (9 mm in diameter and 2 mm in thickness), placed in capped glass bottles containing PBS buffer (0.1 M, pH=7.4), and autoclaved at 121°C for 15 min. After aeration and cooling, they were further sterilized by UV irradiation in a clean bench for 1 h. The tested bacterial species was Staphylococcus aureus. Individual colonies were picked from the test strain and diluted with physiological saline to a bacterial concentration of 10. 8 CFU / ml. Drop 100 μl of bacterial suspension onto LB solid medium, spread the suspension evenly with a spreader, attach the cut-out test sample, seal, and place the culture dish in a 37℃ biochemical incubator for constant temperature incubation. After 24 h, remove the dish to observe the bacterial growth on the medium and record the size of the inhibition zone.

[0048] Table 1 Performance Indicators of Bioactive Glass-Based Skull Defect Repair Composite Materials

[0049] As can be seen from Table 1, the bioactive glass-based skull defect repair composite materials prepared in Examples 5-7 of this application have excellent bending resistance and antibacterial properties.

[0050] The antibacterial agent prepared in this application is centered on a flavanone and linked with multifunctional functional groups such as hydrophobic alkyl chains, quaternary ammonium salt cations, phosphate groups, and thioether bonds. The quaternary ammonium salt cation, as a strongly positively charged center, can rapidly bind to negatively charged teichoic acid or lipopolysaccharides on the bacterial cell wall through electrostatic attraction, disrupting the membrane potential and promoting the accumulation of the antibacterial agent on the bacterial surface. The negatively charged phosphate group forms an inner salt with the quaternary ammonium salt cation center, regulating the amphiphilicity of the molecule and enhancing its stable adsorption on the material surface, thereby improving the fixation and durability of the antibacterial agent in the composite material. Simultaneously, the phosphate group has good hydrophilicity and hydrogen bonding ability, which can improve the dispersibility and interfacial wettability of the molecule, enhancing its compatibility with bioactive glass substrates. Furthermore, by regulating the local ionic environment and synergistically acting with cations and hydrophobic segments, the phosphate group can further inhibit bacterial adhesion and biofilm formation. Hydrophobic alkyl chains insert into the bacterial phospholipid bilayer, increasing membrane permeability and causing leakage of contents; flavanones inhibit key enzymes (such as DNA gyrase) through their benzopyranone structure, interfering with bacterial metabolism; simultaneously, hydroxyl groups enhance hydrophilicity, contributing to uniform dispersion and sustained contact sterilization on the material surface. The synergistic effect of multiple functional groups enables the antibacterial agent to possess both contact sterilization and mild inhibitory effects, exhibiting high biocompatibility with bioactive glass. In cranioplasty, this effectively reduces the risk of postoperative infection while maintaining low cytotoxicity and long-lasting antibacterial properties.

[0051] In Comparative Example 3, replacing 7-amino-1-heptanethiol with 4-aminobutane-1-thiol shortened the carbon chain length, reduced the hydrophobicity of the molecules, weakened the ability of the long chains to embed and disrupt the bacterial lipid bilayer membrane, and decreased the interfacial orientation ability, reducing the synergistic effect of electrostatic adsorption and membrane perturbation, resulting in a decrease in antibacterial performance.

[0052] The modified reinforcing agent prepared in this application uses a cyclic polysiloxane as a rigid core and has a four-arm star-shaped hybrid structure, each arm incorporating a cyclohexyl group and a long polyether chain. The rigid cyclohexyl group provides a localized anti-deformation skeleton, enhancing the composite material's resistance to bending loads; the long polyether chain segments effectively buffer external impacts and dissipate fracture energy through molecular chain movement, preventing brittle cracking; simultaneously, the long polyether chains form physical entanglements during curing, increasing the overall crosslinking density and toughness. The ether bonds and hydroxyl groups can form a hydrogen bond network with the silanol groups on the surface of bioactive glass, preventing interfacial debonding and promoting stress transfer from the matrix to the reinforcing phase. The rigid polysiloxane skeleton provides support and stability, while the flexible polyether chains absorb stress and buffer external forces. When the modified reinforcing agent is added to the bioactive glass-based cranial defect repair composite material, it can significantly improve bending resistance and toughness.

[0053] In the modified reinforcing agent prepared in Comparative Example 5, methyltris(dimethylsiloxane)silane has a three-arm star structure and its silane-hydrogen content is lower than that of four-membered cyclosiloxane. At the same time, the open-chain siloxane is too flexible and loses the rigid ring support effect of cyclotetrasiloxane, resulting in insufficient rigid crosslinking points and weakened resistance to bending deformation. The stress dissipation efficiency is reduced, which leads to a decrease in bending performance.

[0054] In Comparative Example 7, after replacing 3,6,9,12,15,18-hexaoxanecoic acid in step A2 with an equimolar amount of diethylene glycol monomethyl ether propionic acid, the shorter chain segments of diethylene glycol monomethyl ether propionic acid resulted in insufficient flexibility, weakened intermolecular entanglement, and difficulty in forming an effective energy dissipation structure, leading to increased stress concentration. In addition, the short chain structure reduced the interfacial compatibility with the matrix, causing a decrease in stress transfer efficiency, thereby resulting in a decrease in bending performance.

[0055] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. However, any modifications, alterations, and variations made by those skilled in the art without departing from the scope of the present invention based on the disclosed technical content are equivalent embodiments of the present invention. Furthermore, any modifications, alterations, and variations made to the above embodiments based on the essential technology of the present invention are still within the protection scope of the present invention.

Claims

1. A bioactive glass-based composite material for repairing skull defects, characterized in that, The ingredients include the following parts by weight: Collagen 10-12 parts, bioactive glass 40-50 parts, natural polysaccharide 5-8 parts, hydroxyapatite 20-30 parts, modifier and reinforcing agent 6-8 parts, antibacterial agent 1-2 parts, deionized water 100-150 parts; The antibacterial agent is prepared by the following method: S1: 4',5,7-Trihydroxyflavanone reacts with epichlorohydrin to form a tricyclic oxide compound. S2: 2-Oleoyl-1-palmitinyl-3-phosphocholine reacts with 7-amino-1-heptanthiol to generate intermediate 1. S3: Intermediate 1 reacts with a tricyclic oxide compound to generate an antibacterial agent; The modified reinforcing agent is prepared by the following method: A1: 4-Vinyl-1-cyclohexene-1,2-epoxy reacts with 2,4,6,8-tetramethylcyclotetrasiloxane to generate epoxy-modified siloxane. A2: Epoxy-modified siloxane reacts with 3,6,9,12,15,18-hexaoxane-nonadecanoic acid to generate a modified reinforcing agent.

2. The bioactive glass-based composite material for repairing skull defects according to claim 1, characterized in that, In step S1, the molar ratio of 4',5,7-trihydroxyflavanone to epichlorohydrin is 1:(3.05-3.1).

3. The bioactive glass-based composite material for repairing skull defects according to claim 1, characterized in that, In step S2, the molar ratio of 2-oleoyl-1-palmitin glycerol-3-phosphate choline to 7-amino-1-heptanethiol is 1:(1.05-1.1).

4. The bioactive glass-based composite material for repairing skull defects according to claim 1, characterized in that, In step S3, the molar ratio of intermediate 1 to tricyclic oxide is (3.05-3.1):

1.

5. The bioactive glass-based composite material for repairing skull defects according to claim 1, characterized in that, In step A1, the molar ratio of 4-vinyl-1-cyclohexene-1,2-epoxy to 2,4,6,8-tetramethylcyclotetrasiloxane is 4.03:

1.

6. The bioactive glass-based composite material for repairing skull defects according to claim 1, characterized in that, In step A2, the molar ratio of the epoxy-modified siloxane to 3,6,9,12,15,18-hexaoxane-nonadecanoic acid is 1:4.

05.

7. The bioactive glass-based composite material for repairing skull defects according to claim 1, characterized in that, The collagen is recombinant human collagen.

8. The bioactive glass-based composite material for repairing skull defects according to claim 1, characterized in that, The natural polysaccharide is chitosan.

9. A method for preparing a bioactive glass-based skull defect repair composite material according to any one of claims 1-8, characterized in that, Includes the following steps: (1) Weigh out the following by weight: 10-12 parts of collagen, 40-50 parts of bioactive glass, 5-8 parts of natural polysaccharide, 20-30 parts of hydroxyapatite, 6-8 parts of modifier and enhancer, 1-2 parts of antibacterial agent, and 100-150 parts of deionized water. (2) Mix deionized water and collagen, add bioactive glass, natural polysaccharides, hydroxyapatite, modifier and enhancer, and antibacterial agent, and then homogenize under high pressure, freeze dry and sterilize by irradiation to obtain the product.

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