Application of a Functional Silane Coupling Agent in the Surface Modification of Bioactive Glass

Abstract

The present invention uses a commercially available 3-aminopropylsilane coupling agent, 2-hydroxyethyl methacrylate or 2-hydroxyethyl acrylate, and one of an alkylating agent, a polyether sulfonate, γ-propanesultone or γ-butyrolactone as raw materials, and prepares a functionalized silane coupling agent containing a dihydroxy quaternary ammonium cation, or a dihydroxy sulfobetaine, or a dihydroxy carboxybetaine in its molecular structure through a Michael addition reaction and a quaternization reaction, which is used for the surface modification of bioactive glass, and obtains enhanced biocompatibility, antibacterial and antifungal properties, and hydrophilicity after the surface modification of bioactive glass.

Description

Technical Field

[0001] The present invention relates to the application of a functionalized silane coupling agent in the surface modification of bioactive glass, and particularly to the use of a silane coupling agent containing a dihydroxy quaternary ammonium cation, or a dihydroxy sulfobetaine, or a dihydroxy carboxy betaine in its molecular structure for the surface modification of bioactive glass, belonging to the field of functional composite materials. Technical Background

[0002] Bioactive glass is an inorganic material mainly composed of a quaternary chemical composition of SiO 2 -CaO-P 2 O 5 -Na 2 O. The reason why bioactive glass has bioactivity is mainly that the alkali metal and alkaline earth metal ions connected by non-bridging oxygen in the three-dimensional network of bioactive glass are soluble in water and released in an aqueous medium. Na + or Ca 2+ is easily soluble in water and released to form a hydrated silicic acid gel layer, so it is called bioactive glass. For decades, a large number of studies have confirmed that bioactive glass particles have good osteogenic properties, good biocompatibility and self-degradation properties. When bioactive glass is used as a material for repairing bone defects, it can quickly regenerate bone tissue, and the structure and mechanical properties of the regenerated bone match well with the bone defect site. There are also studies showing that bioactive glass can promote the regeneration of soft tissues such as skin and has a significant function of promoting the healing of skin wounds. Some scholars cultured bioactive glass with intestinal epithelial cells and found that bioactive glass can promote the proliferation of intestinal epithelial cells. However, the dispersibility of bioactive glass powder in the human body or organic polymers is very poor, and the combination of bioactive glass and the organic phase is relatively loose, which affects the mechanical properties and use functions of the composite material. To solve these problems, relevant studies at home and abroad, such as CN201210358478.2, CN201611163396.7, CN201811478997.6, CN201911356221.1, etc., have been publicly reported to use silane coupling agents to modify the surface of bioactive glass, and improve the interfacial compatibility between bioactive glass and organic polymers through chemical bonding, and improve its binding ability and dispersibility with organic polymers.

[0003] A silane coupling agent is an organosilicon compound containing a hydrolyzable group and a functional group in its molecular structure, and its structure is usually represented as Y n SiX (4-n), where X in the molecular structure of the silane coupling agent represents a hydrolyzable group, including alkoxy groups, acyl groups, chlorine atoms, etc.; Y represents a functional group, including alkenyl groups, epoxy groups, amino groups, mercapto groups, hydroxyl groups, isocyanate groups, haloalkyl groups, etc.; n is an integer selected from 1 to 3. When the X group hydrolyzes, Si-X is converted to Si-OH. The hydroxyl groups in Si-OH can not only dehydrate and condense with each other to form Si-O-Si bonds, but also combine with Si-OH on the surface of glass, silica, ceramics, some metal materials or other molecules to form Si-O-Si bonds. In this way, functional groups such as alkenyl groups, epoxy groups, amino groups, mercapto groups, hydroxyl groups, isocyanate groups, and halogen atoms that can undergo chemical reactions can be introduced onto the surface of glass, silica, ceramics, or some metal materials. Therefore, silane coupling agents are mainly used for surface modification of silica materials or ceramics, etc., or to improve the interfacial compatibility of their composites. According to the functional group characteristics of existing silane coupling agents, the surface characteristics of the materials to be treated, the modification requirements, and the application needs in some new fields, the re-functionalization of existing silane coupling agents has attracted people's attention. The re-functionalization of the silane coupling agent is mainly achieved by bonding structural units with more powerful functions to its functional groups, thereby endowing the materials to be modified with new functions and new uses. For example, CN201010503258.5, CN201610807720.8, CN202010940152.5, CN202110914812.7, CN201610766177.1, CN202010446615.2, CN201910559445.6, CN201811365280.0, CN201310134973.X, etc. have disclosed silane coupling agents carrying quaternary ammonium cations, zwitterions, or containing polyether chains, as well as copolymers containing zwitterionic olefin monomers and olefin silane coupling agents. As surface modifiers for inorganic materials such as the glass or silica gel, positive effects have been achieved.

[0004] In view of this, combining the previous research results of the research group such as ZL201910993648.6, ZL2021107850204, ZL201910994314.0, ZL201811189217, CN2023100519084, CN202310116727.5, CN 202310116725.6, etc., the inventor carried out a re-functionalization design on the commercially available 3-aminopropylsilane coupling agent, and created a dihydroxy-functionalized silane coupling agent containing quaternary ammonium cations, or sulfobetaine, or carboxybetaine in its molecular structure. The functionalized silane coupling agent is prepared from the commercially available 3-aminopropylsilane coupling agent, hydroxyethyl acrylate, and one of alkylating agents, or γ-propanesultone or γ-butyrolactone as raw materials through aza-Michael addition reaction and quaternization reaction. The hydrolyzable group in the molecular structure of the functionalized silane coupling agent of the present invention is still the traditional trialkoxy group; and the primary amino group in the 3-aminopropylsilane coupling agent first undergoes an almost quantitative aza-Michael addition reaction with hydroxyethyl acrylate, and then a quaternization reaction with an alkylating agent, or γ-propanesultone, or γ-butyrolactone, to obtain the dihydroxy-functionalized silane coupling agent containing quaternary ammonium cations, or sulfobetaine, or carboxybetaine of the present invention. Thus, when the functionalized silane coupling agent of the present invention is used for the surface modification of bioactive glass, the enhanced effects of biocompatibility, antibacterial and antifungal properties, and hydrophilicity of the surface-modified bioactive glass can be obtained. Summary of the Invention

[0005] The present invention provides an application of a functionalized silane coupling agent in the surface modification of bioactive glass, which is realized through the following process: Weigh methanol or ethanol, the functionalized silane coupling agent, and water in sequence according to the mass ratio of methanol or ethanol / functionalized silane coupling agent / water being 5-50:5-50:5-50, prepare a functionalized silane coupling agent solution at room temperature, then add bioactive glass particles under stirring, raise the temperature to 50-90 °C and react for 2-20 hours to end the reaction process; then cool the temperature of the reaction product to room temperature, filter, wash the filter cake with methanol or ethanol, send the washed filter cake into a vacuum drying phase, and vacuum dry it at a controlled temperature of 25-65 °C to constant weight to obtain the surface-modified bioactive glass.

[0006] Wherein the dosage of the functionalized silane coupling agent is 5-500% of the mass of the bioactive glass particles.

[0007] The functionalized silane coupling agent has the structure shown in the general formula (A):

[0008]

[0009] Wherein R in the general formula (A) is selected from C1 ~C 18 Hydrocarbyl, R 1 Selected from H or methyl, when Y is selected from C 1 ~C 18 hydrocarbyl or when, X - Selected from Cl - 、Br - 、I - or p-CH 3 C 6 H 4 SO 3 - one of; when Y is selected from -CH 2 CH 2 CH 2 SO 3 - 、or -CH 2 CH 2 CH 2 CO 2 - when, X - does not select any counter anion.

[0010] Wherein R 2 Selected from C 1 ~C 18 hydrocarbyl, m is selected from natural numbers between 0 and 2000.

[0011] Existing relevant research results and application tests have taught us that: the structural units in the functionalized silane coupling agent described in the present invention can be optimized and selected purposefully for Y, R + on N 1 and R 2 according to actual needs of functions, effects and properties. For example, if hydrophilic function is emphasized too much, Y of the silane diol is preferably CH 3 , R 2 is preferably H or CH 3 ; if hydrophilic, antibacterial, sterilization functions are emphasized, Y of the silane diol is preferably C 12 H 25 or C 7 H 8 , R 1 and R 2 are preferably CH 3 ; if the main purposes are modification such as hydrophilicity, antibacterial, antifouling, biocompatibility, anti - coagulation, etc., Y is preferably R 2 is selected as CH 3 , m is preferably 8 - 25.

[0012] The preparation method of the functionalized silane coupling agent described in the present invention is to dissolve the 3-aminopropylsilane coupling agent with the structure shown in general formula (B) in a solvent, control the temperature at 5-35°C, start stirring, and slowly add hydroxyethyl methacrylate or hydroxyethyl acrylate. The dosage of hydroxyethyl methacrylate or hydroxyethyl acrylate is 2.0-2.2 times the molar amount of the 3-aminopropylsilane coupling agent; after the addition of hydroxyethyl methacrylate or hydroxyethyl acrylate is completed, slowly raise the temperature of the reaction system to 35-90°C and react for 2-20 hours to end the aza-Michael addition reaction process; keep the reaction temperature, add an alkylating agent, or propanesultone, or γ-butyrolactone to the reaction system. The dosage of the alkylating agent, or propanesultone or γ-butyrolactone is 1.0-1.5 times the molar amount of the 3-aminopropylsilane coupling agent, and continue to react for 2-20 hours to end the quaternization reaction process; then rotary evaporate to remove part of the solvent, and then lower the temperature of the reaction system to room temperature to separate out the crude product. The crude product is then purified to obtain the functionalized silane coupling agent with the structure shown in general formula (A).

[0013] Among them, the 3-aminopropylsilane coupling agent has the structure shown in general formula (B):

[0014]

[0015] Among them, R in general formula (B) is selected from C1-C18 hydrocarbon groups.

[0016] The solvent refers to one or more of methanol, ethanol, propanol, tetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, dimethyl sulfoxide, N-methylpyrrolidone, N,N-dimethylformamide, N,N-diethylformamide or hexamethylphosphoramide; the dosage of the solvent is 1-10 times the mass of general formula (B).

[0017] The alkylating agent has the structure shown in general formula (C):

[0018] Y-X

[0019] General formula (C)

[0020] Among them, Y in general formula (C) is selected from C 1 -C 18 hydrocarbon group or When, X is selected from Cl, Br, I or p-CH 3 C 6 H 4 SO 3 One of them, where m is a natural number between 0 and 2000, and R 2 is selected from C 1 -C 18 hydrocarbon group.

[0021] The beneficial effects of the application of the functionalized silane coupling agent in the surface modification of bioactive glass provided by the present invention are as follows:

[0022] ① The structure of the functionalized silane coupling agent described in the present invention is novel, the preparation method is simple, the raw materials for preparation are mostly commercially available products, the product yields in each step of the preparation process are high, and the purification technology of the dihydroxy-functionalized silane coupling agent is simple and the process is easy to implement.

[0023] ② The functionalized silane coupling agent described in the present invention is easily soluble in water and can be dissolved in a large amount of alcohol solvents. The use method of the functionalized silane coupling agent is simple and almost no volatile toxic organic substances are generated.

[0024] ③ Using the functionalized silane coupling agent described in the present invention to modify the surface of bioactive glass, the process is simple and the modification effect is remarkable. Specific embodiments

[0025] In order to further understand the present invention, specific descriptions are made through embodiments, and the purpose is to better understand the content of the present invention. Therefore, the use of the functionalized silane coupling agent not listed in the embodiments for the surface modification of bioactive glass should not be regarded as a limitation to the protection scope of the present invention.

[0026] Example 1 Preparation of surface-modified bioactive glass (A-1)

[0027] Step 1: Preparation of the functionalized silane coupling agent of formula (A-1):

[0028]

[0029] Dissolve 30 g (about 0.215 mol) of 2-hydroxyethyl methacrylate in 320 g of methanol and put it into a reaction kettle. Start stirring. Under the protection of N2, slowly add 22 g (about 0.1 mol) of the commercially available brand KH-550 amino silane coupling agent at a controlled temperature of 10-15 °C. After the addition of the KH-550 amino silane coupling agent is completed, gradually raise the reaction temperature to 35-45 °C and continue the reaction for 12 hours. Then add 15 g (about 0.119 mol) of benzyl chloride into the reaction kettle, raise the reaction temperature to 70-90 °C and react for 20 hours. Then rotary evaporate to remove part of the methanol, and then lower the temperature of the reaction product system to room temperature to precipitate a beige waxy solid substance. Wash it three times with dehydrated acetone and then vacuum dry at a controlled temperature of 35-45 °C to obtain the functionalized silane coupling agent of formula (A-1).

[0030] KH-550 is the commercial brand name of 3-aminopropyltriethoxysilane. For the aza-Michael addition reaction product of it and 2-hydroxyethyl methacrylate, after sampling, separation and purification, the yield of the intermediate tertiary amine is calculated to be about 99.5%, and the yield of the multifunctional silane coupling agent of formula (A-1) is about 91.4%. The IR spectrum of the functionalized silane coupling agent of formula (A-1) also shows strong absorption peaks near 3458 nm, 2934 nm, 2876 nm, 1726 nm and 1108 nm; the results of elemental analysis (theoretical value %): C 56.45 (56.78), H 8.33 (8.51), N 2.27 (2.37), indicating that the structure of the product of the functionalized silane coupling agent of formula (A-1) is in line with the theoretical designed molecular formula C 28 H 50 ClNO 8 Si. The product of the functionalized silane coupling agent of formula (A-1) is also analyzed by nuclear magnetic resonance and mass spectrometry, and it is confirmed that the chemical structure of the product in the preparation process of the present invention is in line with the theoretical design.

[0031] Step 2: Preparation of surface-modified bioactive glass (A-1): Weigh 76 g of ethanol, 21.3 g of the functionalized silane coupling agent of formula (A-1), and 100 g of water, and add them to the reaction flask in sequence at room temperature, and stir evenly to prepare the functionalized silane coupling agent solution of formula (A-1). Then add 30 g of calcium phosphate-silica-based bioactive glass with a particle size ≤ 10 μm (purchased from Wuhan Kemic Biomedical Technology Co., Ltd.) into it. After ultrasonic treatment for 0.5 h, raise the temperature to 70-80 °C and stir and react for 6 h. End the reaction process, cool down and filter, wash the filter cake three times with ethanol, and vacuum dry at a controlled temperature of 50-55 °C to constant weight to obtain 47.8 g of surface-modified bioactive glass (A-1).

[0032] Using the same method and procedure as above, 29.2 g of a blank sample of bioactive glass is prepared. It can be calculated that the net weight increase of the surface-modified bioactive glass (A-1) is 8.6 g. From this, the reaction efficiency of the functionalized silane coupling agent of formula (A-1) on the surface of bioactive glass is 92.3%.

[0033] In the IR spectrum of the surface-modified bioactive glass (A-1) relative to the blank sample of bioactive glass, medium-strong to strong absorption peaks are increased at 3454 nm, 2930 nm, 2878 nm, 1724 nm and 1106 nm, etc., which should respectively belong to the vibration absorptions of hydroxyl, methyl, methylene, ester carbonyl and C-O-C, indicating that the surface-modified bioactive glass (A-1) has the structural characteristics of hydroxyl, carboxylic ester and ether bond.

[0034] Example 2 Preparation of surface-modified bioactive glass (A-2)

[0035] According to the operation method of Step 1 in Example 1, benzyl chloride was replaced with ω-methoxypolyethylene glycol-400 p-toluenesulfonate to prepare the functionalized silane coupling agent of formula (A-2) with a yield of 91.4%. The IR spectrum of the multifunctional silane coupling agent of formula (A-2), 1 1H-NMR, mass spectrometry analysis and elemental analysis results (theoretical values %): C 53.09 (53.86), H 8.62 (8.83), N 1.04 (1.10), indicating that it basically coincides with the molecular formula C 57 H 111 NO 25 SSi, thus determining that the chemical structure of the product of the functionalized silane coupling agent of formula (A-2) coincides with the theoretical design.

[0036]

[0037] Using the method and procedure of Step 2 in Example 1, the functionalized silane coupling agent of formula (A-2) was used to perform surface modification on the calcium phosphate-silicate-based bioactive glass powder with a particle size ≤ 10 μm produced by Wuhan Kemike Biopharmaceutical Technology Co., Ltd. to obtain surface-modified bioactive glass (A-2). By means of IR spectral analysis, it was determined that the surface-modified bioactive glass (A-2) has the structural characteristics of hydroxyl groups, carboxylic acid esters and ether bonds.

[0038] Preparation of Surface-Modified Bioactive Glass (A-3) in Example 3

[0039] According to the method and operation steps of Example 1, the calcium phosphate-silicate-based bioactive glass powder with a particle size ≤ 10 μm produced by Wuhan Kemike Biopharmaceutical Technology Co., Ltd. in Step 2 of Example 1 was replaced with bioactive glass produced by Hebei Yougu Biotech Co., Ltd. with a SiO 2 content of 45%, CaO 2 content of 24.5%, Na 2 O content of 24.5%, P 2 O 5 content of 6.0%, brand name Yougulin, powder with a particle size ≤ 45 μm, to obtain surface-modified bioactive glass (A-3). By means of infrared spectral analysis, it was determined that the surface-modified bioactive glass (A-3) has the structural characteristics of hydroxyl groups, carboxylic acid esters and ether bonds.

[0040] Preparation of Surface-Modified Bioactive Glass (A-4) in Example 4

[0041] According to the method and operation steps of Example 1, the KH-550 amino silane coupling agent in Step 1 was replaced with KH-540 amino silane coupling agent, and benzyl chloride was replaced with dodecyl bromide to prepare the functionalized silane coupling agent of formula (A-4) with a yield of 78.1%. The IR spectrum of the functionalized silane coupling agent of formula (A-4),1 H-NMR, mass spectrometry and elemental analysis results (theoretical value %): C55.18 (55.39), H9.78 (9.94), Br11.61 (12.71), indicating that the product structure of formula (A-4) conforms to the designed molecular formula C 29 H 62 BrNO 6 Si, thus confirming that the chemical structure of formula (A-4) is consistent with the theoretical design.

[0042]

[0043] According to the method and operation steps of Example 1, the calcium phosphosilicon bioactive glass powder with a particle size of ≤10 μm produced by Wuhan Kemik Biomedical Technology Co., Ltd. in step 2 is replaced with nano bioactive glass (the nano bioactive glass is homemade according to the disclosed technology of ZL02110586.3). The nano bioactive glass is surface-modified using a functionalized silane coupling agent of formula (A-4) to obtain surface-modified nano bioactive glass (A-4). Using infrared spectroscopy analysis, it is proved that the surface-modified nano bioactive glass (A-4) has the structural characteristics of hydroxyl, carboxylate and ether bonds.

[0044] Example 5 Properties of the bioactive glass before and after surface modification in Examples 1 to 4

[0045] 1.5 g of the surface-modified bioactive glass in Examples 1 to 4 were taken respectively, and tablets were prepared using a tablet press. The pure water contact angle of each tablet under static conditions was measured using a contact angle meter. The results are shown in Table 1.

[0046] Table 1 Water contact angle measurement results of each sample in Examples 1 to 4

[0047] Example 1 2 3 4 Blank Water contact angle (°) 0 0 0 0 10.5

[0048] The results in Table 1 confirm that the hydrophilicity of the bioactive glass is significantly improved after surface treatment.

Claims

1. Application of a functionalized silane coupling agent in the surface modification of bioactive glass, characterized in that, The application is realized through the following steps: Weigh methanol or ethanol, functional silane coupling agent, and water in a mass ratio of 5-50:5-50:5-50 in sequence, and prepare a functional silane coupling agent solution at room temperature. Then, add bioactive glass particles under stirring. The mass ratio of the dosage of the functional silane coupling agent to the mass of the bioactive glass particles is 5-500:

100. Heat up to 50-90 °C and react for 2-20 hours to end the reaction process. Then, cool the temperature of the reaction product to room temperature, filter, wash the filter cake with methanol or ethanol, send the washed filter cake into a vacuum drying phase, and vacuum dry it at a controlled temperature of 25-65 °C until constant weight to obtain surface-modified bioactive glass. The functional silane coupling agent has the structure shown in the general formula (A): wherein R in the general formula (A) is selected from C 1 ~C 18 hydrocarbyl, R 1 is selected from H or methyl, and Y is selected from , X - is selected from p -CH 3 C 6 H 4 SO 3 - ; wherein R 2 select C 1 ~C 18 hydrocarbyl, and m is a natural number selected from 0 to 2000.

2. According to the application of a functionalized silane coupling agent in the surface modification of bioactive glass described in claim 1, characterized in that The preparation method of the functionalized silane coupling agent is to dissolve 3-aminopropylsilane coupling agent in a solvent, control the temperature at 5-35 °C, start stirring and slowly add 2-hydroxyethyl methacrylate or 2-hydroxyethyl acrylate. The dosage of 2-hydroxyethyl methacrylate or 2-hydroxyethyl acrylate is 2.0-2.2 times the molar amount of the 3-aminopropylsilane coupling agent; after the feeding of 2-hydroxyethyl methacrylate or 2-hydroxyethyl acrylate is completed, slowly raise the temperature of the reaction system to 35-90 °C and react for 2-20 hours to end the Michael addition reaction process; keep the reaction temperature, add an alkylating agent to the reaction system. The dosage of the alkylating agent is 1.0-1.5 times the molar amount of the 3-aminopropylsilane coupling agent, and continue to react for 2-20 hours to end the quaternization reaction process; then rotary evaporate to remove part of the solvent, and then lower the temperature of the reaction system to room temperature to separate out the crude product. The crude product is further purified to obtain a functionalized silane coupling agent with the structure shown in general formula (A); wherein the dosage of the solvent is 1-10 times the mass of the 3-aminopropylsilane coupling agent.

3. According to the application of a functionalized silane coupling agent in the surface modification of bioactive glass described in claim 2, characterized in that The 3-aminopropylsilane coupling agent has the structure shown in general formula (B): ； Among them, R in the general formula (B) is selected from C 1 ~C 18 hydrocarbyl groups.

4. According to the application of a functionalized silane coupling agent in the surface modification of bioactive glass described in claim 2, characterized in that The solvent refers to one or more of methanol, ethanol, propanol, tetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, dimethyl sulfoxide, N-methylpyrrolidone, N,N-dimethylformamide, N,N-diethylformamide or hexamethylphosphoramide.

5. According to the application of a functionalized silane coupling agent in the surface modification of bioactive glass described in claim 2, characterized in that The alkylating agent has the structure shown in general formula (C): ； Among them, Y in the general formula (C) is selected as , X is selected as p -CH 3 C 6 H 4 SO 3 , where m is selected from natural numbers between 0 and 2000, R 2 is selected as C 1 ~C 18 hydrocarbyl group.

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