CN118126267A - Application of a modified bioactive glass in the preparation of multifunctional hydrogel - Google Patents

Abstract

The invention provides bioactive glass compound methacryloylated gelatin containing surface modification of a dipropenyl quaternary ammonium cationic silane coupling agent in a molecular structure, and the like, and the multifunctional hydrogel with uniform inter-phase material dispersion, high stability and high strength is obtained through free radical copolymerization reaction in an aqueous solution in the presence of a regulating monomer. The bioactive glass particles are bonded in the gaps of the three-dimensional network of the hydrogel, so that the mechanical property of the hydrogel is not reduced, the storage stability is reduced and the use is limited due to the fact that the hydrogel is doped with inorganic materials. In addition, the raw material proportion for preparing the hydrogel can be adjusted in a large range, and the obtained hydrogel variety is determined by the biomedical application field and the use requirement, so that the application range is wide.

Description

Application of a modified bioactive glass in the preparation of multifunctional hydrogel

Technical Field

The present invention relates to an application of modified bioactive glass in the preparation of multifunctional hydrogel, wherein the modified bioactive glass refers to bioactive glass whose surface is modified by a silane coupling agent containing diallyl quaternary ammonium cations in its molecular structure; the multifunctional hydrogel refers to a hydrogel having antibacterial and antimicrobial functions, soft tissue healing stimulation functions, bone defect repair functions, and excellent mechanical properties, and belongs to the field of biological/medical functional composite materials.

Background Art

Hydrogel is a composite material that contains a large number of water molecules in a hydrophilic polymer with a three-dimensional network structure. According to the actual application needs, functional groups can be grafted onto the hydrophilic polymer chain structure in the hydrogel to form a functional hydrogel; water-soluble functional small molecules or functional macromolecules can also be incorporated into the water molecules contained in the hydrogel to obtain a functional hydrogel with high storage stability and homogeneity. If non-water-soluble functional substances are incorporated into the water molecules contained in the hydrogel, the stability of the obtained heterogeneous functional hydrogel is relatively poor, and even affects the applicability of the hydrogel. For example, the composite hydrogel of bioactive glass mixed with hydrophilic polymers has been one of the hottest areas of preparation and application research in the past decade.

The bioactive glass is an inorganic powder material composed mainly of the quaternary chemical composition of SiO2-CaO-P2O5-Na2O. The reason why the bioactive glass has biological activity is mainly because the alkali metal ions or alkaline earth metals connected by non-bridging oxygen in the three-dimensional network of the bioglass are easily soluble in water and released in the aqueous medium, and can exchange ions with the body tissue, so it is called bioactive glass. A large number of studies over the past few decades have confirmed that bioactive glass has good osteogenic properties and biocompatibility, as well as self-degradation properties. When bioactive glass is used as a material for repairing bone defects, it can quickly regenerate bone tissue, and the regenerated bone structure and mechanical properties match the bone defect site well; at the same time, studies have shown that bioactive glass can promote the regeneration of soft tissues such as skin, and has the function of significantly promoting the healing of skin wounds. Some scholars have cultured bioactive glass with intestinal epithelial cells and found that bioactive glass can promote the proliferation of intestinal epithelial cells. The above research results all show the important use of bioactive glass in the field of biomedicine. However, the dispersibility of bioactive glass particles in human tissues or hydrogels is very poor, and they are easy to agglomerate. In addition, the combination of bioactive glass and organic polymers is relatively loose, which causes a significant decrease in the stability and mechanical properties of bioactive glass mixed with hydrogels, and affects its performance. In order to solve the inherent defects of bioactive glass, there have been related studies at home and abroad, such as CN201210358478.2, CN201611163396.7, CN201811478997.6, and CN201911356221.1, which publicly reported the use of silane coupling agents to modify the surface of bioactive glass, improve the interfacial compatibility of bioactive glass and organic polymers by bonding, improve its binding ability and dispersibility with organic polymers, and enhance the mechanical properties of composite materials. In view of this, combined with the previous research results of our research group ZL201910993648.6, ZL2021107850204, ZL201910994314.0, ZL201811189217, CN2023100519084, CN202310116727.5, CN 202310116725.6, the inventors re-functionalized the commercially available 3-aminopropyl silane coupling agent and created a multifunctional silane coupling agent with a novel molecular structure for surface modification of bioactive glass. The multifunctional silane coupling agent has a structure shown in general formula (A):

Wherein R in the general formula (A) is selected from C ₁ to C ₁₈ hydrocarbon groups, preferably CH ₃ or C ₂ H ₅ , R ₁ is selected from H or methyl, n is selected from a natural number between 1 and 2000, Y is selected from C ₁ to C ₁₈ hydrocarbon groups or ^X- is selected from one of ^Cl- , ^Br- , ^{I- or} _{p - CH3C6H4SO3-} ; wherein _R2 is selected from _{a C1} - _C18 hydrocarbon group, and m is selected from a natural number between 0 and 200.

It is obvious that the hydrolyzable group in the molecular structure of the multifunctional silane coupling agent is still the traditional trialkoxy group; while the amino group in the 3-aminopropyl silane coupling agent first undergoes an aza-Michael addition reaction with diallylamino polyether acrylate, and then undergoes a quaternary ammonium salt reaction with an alkylating agent, so that the molecular structure of the multifunctional silane coupling agent has multiple quaternary ammonium cations. The application of the multifunctional silane coupling agent of general formula (A) to the surface modification of bioactive glass can not only obtain the enhanced effects of antibacterial and antibacterial properties, biocompatibility, and hydrophilicity of the modified bioactive glass surface; at the same time, the diallyl ammonium retained on the surface of the modified bioactive glass also has the characteristics of copolymerization with other olefin monomers or unsaturated organic polymer materials.

The gelling substance used to prepare hydrogels is called a hydrophilic polymer, also known as a gel matrix. It is divided into three categories according to the source of the hydrophilic polymer: (1) natural organic polymers and their chemically modified derivatives, such as collagen, gelatin, methacrylated gelatin, sodium alginate, aldehyde-modified sodium alginate, hyaluronic acid, methacrylated hyaluronic acid, hydroxypropylated chitosan, methacryloyl chitosan, modified starch, modified cellulose, etc.; (2) synthetic organic polymers, such as polylactic acid, polyvinyl alcohol, methacrylated polyvinyl alcohol, polyacrylamide, polyacrylic acid, polyhydroxyethyl acrylate, polybetaine, polyquaternary ammonium salt, cationic polyurethane, zwitterionic polyurethane, etc.; (3) decellularized matrix (decellularized matrix), etc. Gelatin or chitosan are natural water-soluble polymers, cheap, non-biotoxic, low-priced, and have excellent tissue compatibility, biodegradability, and bioavailability. Gelatin or chitosan are preferred materials for preparing hydrogels. Gelatin or chitosan hydrogels can be used as controlled release carriers of growth factors or drugs, as well as growth scaffolds for cells and tissues. However, hydrogels such as gelatin or chitosan have poor mechanical strength, are too hydrophilic, and have too fast a degradation rate, which is difficult to match the rate of bone tissue regeneration, limiting their wide application. There are a large number of amino groups and hydroxyl groups in the side chains of gelatin or chitosan macromolecules, so some chemical monomers or polymers can be used to modify them. For example, methacrylic anhydride is used to methacrylate the amino groups on the side chains of macromolecules such as gelatin, and methacrylated gelatin undergoes a free radical-induced polymerization reaction in an aqueous solution to obtain a polymethacrylated gelatin hydrogel. The degradation performance, stability, and mechanical strength of the polymethacrylated gelatin hydrogel are improved, and it has been applied to the research of cell culture and bone tissue engineering. However, methacrylated gelatin hydrogels cannot be applied to weight-bearing parts, have general osteogenic properties, and have poor repair functions for soft tissue or bone defects.

In summary, in order to overcome the inherent defects of existing bioactive glass and the insufficient functionality of hydrogels such as methacrylylated gelatin, the present invention uses bioactive glass whose surface is modified by a dipropylene quaternary ammonium cationic silane coupling agent in its molecular structure and compounded with methacrylylated gelatin, etc. In the presence of a tuning monomer, a free radical copolymerization reaction in an aqueous solution is performed to obtain a multifunctional composite hydrogel with uniform dispersion of interphase substances, high storage stability, controllable bioactivity and high mechanical strength.

Summary of the invention

The invention relates to an application of modified bioactive glass in preparing a multifunctional hydrogel, which is achieved by the following steps: according to the mass percentage of 2-20% of modified bioactive glass, 2-20% of unsaturated hydrophilic polymer, 2-20% of tunable monomer, 0.1-1.5% of free radical initiator and 40-90% of deionized water, deionized water, unsaturated hydrophilic polymer, tunable monomer, modified bioactive glass and free radical initiator are weighed in sequence, mixed together to form an aqueous solution, and a "one-pot" free radical copolymerization reaction is carried out for 0.4-40 hours at a temperature controlled at 15-90° C. under _N2 protection, and then the temperature of the copolymer solution is reduced to a gelling temperature to obtain the multifunctional hydrogel;

The specific implementation of the application of the modified bioactive glass in the preparation of the multifunctional hydrogel of the present invention can also be carried out by the following steps: according to the mass ratio, respectively preparing an aqueous solution ① composed of a tunable monomer, an unsaturated hydrophilic polymer and a free radical initiator; and an aqueous solution ② composed of an unsaturated hydrophilic polymer, a modified bioactive glass, a tunable monomer and a free radical initiator; the aqueous solution ① is subjected to a free radical copolymerization reaction for 0.4 to 40 hours at a temperature of 15 to 90° C. under the protection of _N2 to obtain a first-stage copolymer solution; the aqueous solution ② is added to the first-stage copolymer solution, mixed evenly, and then subjected to a free radical copolymerization reaction for 0.4 to 40 hours at a temperature of 15 to 90° C. under the protection of _N2 to obtain a second-stage copolymer solution, and the temperature of the second-stage copolymer solution is slowly reduced to the gelation temperature to obtain the multifunctional hydrogel;

The specific feature of the application of the modified bioactive glass in the preparation of multifunctional hydrogel described in the present invention is that the modified bioactive glass refers to bioactive glass whose surface is modified by using a diallyl quaternary ammonium cationic silane coupling agent containing a molecular structure.

The preparation method of the modified bioactive glass is as follows: according to the mass ratio of dipropylene quaternary ammonium cationic silane coupling agent/methanol or ethanol/water of 5-50:5-50:5-50, weigh the dipropylene quaternary ammonium cationic silane coupling agent, methanol or ethanol and water in turn, mix them together, prepare a dipropylene quaternary ammonium cationic silane coupling agent solution at room temperature, then add the bioactive glass under stirring, heat to 50-90°C and react for 2-20 hours; end the reaction process, reduce the temperature of the reaction system to room temperature, filter, wash the filter cake with ethanol 1-3 times, send the washed filter cake into a vacuum dryer, control the temperature at 25-65°C and vacuum dry to constant weight to obtain the modified bioactive glass. The amount of dipropylene quaternary ammonium cationic silane coupling agent in the molecular structure is 5-500% of the mass of the bioactive glass.

The molecular structure contains a dipropylene quaternary ammonium cationic silane coupling agent having a structure shown in the general formula (A):

Wherein R in the general formula (A) is selected from C ₁ to C ₁₈ hydrocarbon groups, R ₁ is selected from H or methyl, n is selected from a natural number between 1 and 200, and Y is selected from C ₁ to C ₁₈ hydrocarbon groups or ^X- is selected from one of ^Cl- , _{Br-, I- or p-CH3C6H4SO3-} ^{; wherein} _{R2 is selected from} a _C1 - _C18 hydrocarbon group, and m is selected from a natural number between 0 and 200.

The preparation method of the diallyl quaternary ammonium cationic silane coupling agent of general formula (A) is to dissolve diallylamino polyether acrylate in a solvent, control the temperature at 5 to 35°C, ₂ , start stirring and slowly add 3-aminopropyl silane coupling agent, the amount of diallylamino polyether acrylate is 2.0 to 2.2 times the molar amount of 3-aminopropyl silane coupling agent; after the addition of 3-aminopropyl silane coupling agent is completed, slowly increase the temperature of the reaction system to 35 to 90° C. and react for 2 to 20 hours to end the aza-Michael addition reaction process; add an alkylating agent to the reaction system, the amount of the alkylating agent is 1.0 to 3.5 times the molar amount of 3-aminopropyl silane coupling agent, keep the temperature and continue to react for 2 to 20 hours to end the quaternary ammonium salt reaction process; then remove part of the solvent by rotary evaporation, cool to room temperature, precipitate a crude product, and purify the crude product to obtain a diallyl quaternary ammonium cationic silane coupling agent having a structure shown in general formula (A);

The diallylamino polyether acrylate has a structure shown in general formula (B):

Wherein _R1 in the general formula (B) is selected from H or methyl, and n is selected from a natural number between 1 and 200.

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 amount of the solvent used is 1 to 10 times the mass of the 3-aminopropylsilane coupling agent.

The 3-aminopropyl silane coupling agent has a structure shown in general formula (C):

Wherein R in the general formula (C) is selected from C ₁ to C ₁₈ hydrocarbon groups, preferably methyl or ethyl.

The alkylating agent has a structure shown in general formula (D):

Y-X

General formula (D)

Wherein Y in the general formula (D) is selected from C ₁ to C ₁₈ hydrocarbon groups or X is selected from one of Cl, Br, I or p-CH ₃ C ₆ H ₄ SO ₃ , wherein R ₂ is selected from a C ₁ to C ₁₈ hydrocarbon group, and m is selected from a natural number between 0 and 200.

The bioactive glass refers to a silicon- _{based glass powder material composed of SiO2-CaO-P2O5-Na2O as chemical components} , or a silicon-based glass powder material after the silicon-based glass powder material is doped with K ⁺ , Mg2 ⁺ , Sr2 ⁺ , Zn2 ⁺ , Cu2 ⁺ , B3 ⁺ , Al3 ⁺ , Ti4 ⁺ or Zr4 ⁺ ions; based on the mass of its chemical components, the mass percentage of _SiO2 is 40-80%, the mass percentage of CaO is 10-60%, the mass percentage of _P2O5 is 3-20%, and the mass percentage of _Na2O is 10-60%, and the doping mass percentage of K ⁺ , Mg2 ⁺ , Sr2 ⁺ , Zn2 ⁺ , Cu2 ⁺ , _B3 ⁺ , Al3 ⁺ , Ti4 ⁺ or Zr4 ⁺ ions is 0.25-25% of the mass of the silicon-based glass powder material or is selected as needed.

The unsaturated hydrophilic polymer refers to one or more of methacrylated gelatin, methacrylated chitosan, methacrylated sodium alginate, methacrylated hyaluronic acid or methacrylic silk fibroin.

The toning monomer refers to one or more of N-vinyl pyrrolidone, methacrylic acid, 2-hydroxyethyl methacrylate, N-methylacrylamido glycinamide, glyceryl methacrylate, glyceryl dimethacrylate, polyethylene glycol dimethacrylate or an unsaturated quaternary ammonium salt having a structure represented by the general formula (E);

The unsaturated quaternary ammonium salt has a structure shown in the general formula (E):

wherein _R1 in the general formula (E) is selected from H or methyl, _R3 is selected from _C1 - _C18 hydrocarbon group, Y is selected from _C1 - _C18 hydrocarbon group or X- is selected from one of ^Cl- , ^Br- , ^{I- or} _{p - CH3C6H4SO3-} ; wherein _R2 is selected from _{a C1} - _C18 hydrocarbon group, and m is selected from a natural number between 0 and 200.

The free radical initiator is selected from one or more of ammonium persulfate, sodium persulfate, potassium persulfate, azobisisobutylamidine hydrochloride, azobisisobutylimidazoline hydrochloride, phenyl (2,4,6-trimethylbenzoyl) phosphate lithium salt, 4-isobutylphenyl-4'-methylphenyliodine hexafluorophosphate, 2-hydroxy-2-methyl-1-[4-(2-hydroxyethoxy)phenyl]-1-propanone or 2-hydroxy-2-methyl-1-phenyl-1-propanone.

The design concept of the present invention is based on chemical principles:

⑴ Existing relevant research results and application test statements and demonstrations ^have taught that the structural units in the multifunctional silane coupling agent of the present invention can be optimized and selected according to the actual functions, effects and performances. If the hydrophilic function is overly emphasized as the main modification purpose of the multifunctional silane coupling agent, Y and R ₂ can be preferably selected as CH ₃ or C ₂ H ₅ , and n can be selected from 1 to 3; if the hydrophilic, antibacterial and sterilization functions are emphasized as the main modification purpose _of the multifunctional silane coupling agent, Y can be preferably dodecyl or benzyl, and n can be selected from 1 to 3; if the hydrophilic, antibacterial, antifouling and biocompatibility modification is the main purpose, Y can be preferably selected as R ₂ is preferably CH ₃ or C ₂ H ₅ , and m and n can be 8-25.

(2) The multifunctional silane coupling agent of the present invention is used to modify the bioactive glass to achieve three purposes: first, the modified bioactive glass has higher hydrophilicity, good dispersibility in aqueous solution, and no sedimentation; the easy agglomeration characteristics of the modified bioactive glass itself have been eliminated, which is conducive to the stability of the particle size of the modified bioactive glass. Secondly, the diallyl quaternary ammonium cations retained on the surface of the modified bioactive glass participate in the free radical copolymerization reaction of the unsaturated hydrophilic polymer, and the bioactive glass particles are bonded to the three-dimensional network of the hydrogel, which will not cause the hydrogel to have problems such as decreased static storage stability, decreased mechanical properties, and limited use due to the incorporation of inorganic materials. Third, there can be more than two diallyl quaternary ammonium cations on one modification point of the modified bioactive glass, and its free radical copolymerization reaction with the unsaturated hydrophilic polymer adds "crosslinking points" between the three-dimensional network of the hydrogel, which is of great significance for improving the mechanical properties of the hydrogel.

⑶ The application of the modified bioactive glass of the present invention in the preparation of multifunctional hydrogel, the selected raw materials: unsaturated hydrophilic polymer/modifying monomer/modified bioactive glass, the composite mass percentage of which can be prepared in a large range; the preparation process of the hydrogel can adopt a "one-pot" copolymerization process to obtain a functional composite hydrogel with a fully cross-linked structure, or a staged copolymerization process to obtain a functional composite hydrogel with interpenetrating network characteristics and a partially cross-linked structure, which is determined by the application field and use requirements of the hydrogel.

Compared with the prior art, the beneficial effects of the application of the modified bioactive glass in the preparation of multifunctional hydrogel are as follows:

① The raw materials for preparing the hydrogel of the present invention are mostly commercially available products, the product yield of each step of the preparation process is high, the preparation and purification technology of the multifunctional silane coupling agent and modified bio-corrugated glass is simple and reliable, and the process is simple and easy to implement.

② The surface-modified bioactive glass of the present invention is stable in storage and does not agglomerate; it has good dispersibility in water and does not settle.

③ The raw material ratio of the hydrogel prepared by the present invention can be adjusted in a wide range, and the type of hydrogel obtained is determined by its biomedical application field and use requirements, and has a wide range of applications.

DETAILED DESCRIPTION

In order to further understand the present invention, it is specifically described by way of examples, the purpose of which is to better understand the content of the present invention. Therefore, the use of the surface-modified bioactive glass not listed in the examples for the preparation of the multifunctional hydrogel should not be regarded as limiting the scope of protection of the present invention.

Example 1 Preparation of multifunctional hydrogel (A-1)

Step 1: Preparation of multifunctional silane coupling agent of formula (A-1)

78 g (about 0.202 mol) of diallylamino polyether methacrylate of formula (B-1) was dissolved in 320 g of methanol and added into a reactor. Stirring was started and the temperature was controlled at 10-15°C. Under _N2 protection, 22 g (about 0.1 mol) of aminosilane coupling agent of commercial brand KH-550 was slowly added. After the addition of KH-550 aminosilane coupling agent was completed, the reaction temperature was gradually increased to 35-45°C and the reaction was continued for 12 hours. Thereafter, 44 g of benzyl chloride (about 0.349 mol) was added into the reactor. After the reaction temperature was increased to 70-90°C and the reaction was carried out for 20 hours, part of the methanol was removed by rotary evaporation, and the temperature of the reaction product system was then lowered to room temperature to precipitate a light yellow solid substance. The substance was filtered, washed with dehydrated acetone, and vacuum dried to obtain a multifunctional silane coupling agent of formula (A-1).

KH-550 is the trade name of 3-aminopropyltriethoxysilane. The product of the aza-Michael addition reaction of the product with the diallylamino polyether methacrylate of formula (B-1) is sampled, separated and purified, and the yield of the intermediate tertiary amine is calculated to be about 97.3%, and the yield of the multifunctional silane coupling agent of formula (A-1) is about 89.7%. The IR spectrum of the multifunctional silane coupling agent also shows strong absorption peaks near 1726nm and 1108nm; the elemental analysis results (theoretical value %): C61.45 (62.00), H8.03 (8.47), N3.01 (3.10), indicating that it is consistent with the designed molecular formula of formula (A-1) C70H114Cl3N3O14Si. The product of the multifunctional silane coupling agent of formula (A-1) is further analyzed by nuclear magnetic resonance and mass spectrometry, confirming that the chemical structure of the product of the preparation process of the present invention is consistent with the theoretical design.

Step 2: Preparation of surface modified bioactive glass (A-1)

Weigh 86 grams of ethanol, 14 grams of multifunctional silane coupling agent of formula (A-1), and 100 grams of water, add them into a reaction flask at room temperature, stir evenly to prepare a multifunctional silane coupling agent solution. Then put 30 grams of calcium phosphosilicon bioactive glass with a particle size of ≤10μm (purchased from Wuhan Kemik Biomedical Technology Co., Ltd.) into it, ultrasonically treat for 0.5 hours, heat to 70-80℃ and stir for 6 hours, end the reaction process, cool and filter, wash the filter cake three times with ethanol, control the temperature at 50-55℃ and vacuum dry to constant weight, and obtain 40.8 grams of surface modified bioactive glass (A-1).

Using the same method and procedure, 29.2 grams of blank bioactive glass sample was prepared. It can be calculated that the net weight gain of the surface-modified bioactive glass (A-1) was 11.6 grams. It can be deduced that the reaction efficiency of the multifunctional silane coupling agent of formula (A-1) on the surface of the bioactive glass is 91.7%.

In the IR spectrum of the surface-modified bioactive glass (A-1) relative to the blank bioactive glass sample, medium-strong and strong absorption peaks are added at 2932nm, 2873nm, 1724nm and 1108nm, which should belong to the vibration absorption of methyl, methylene, ester carbonyl and C-O-C, respectively, indicating that the surface-modified bioactive glass (A-1) has the structural characteristics of carboxylic acid ester and ether bond.

Step 3: Preparation of multifunctional hydrogel (A-1)

80 g of deionized water, 3.5 g of methacryloyl gelatin with a degree of substitution of 0.3, 10.5 g of glyceryl methacrylate, 0.5 g of glyceryl dimethacrylate, 0.5 g of ammonium persulfate, and 5.0 g of modified bioactive glass (A-1) were weighed in sequence to prepare an aqueous solution. Under _N2 protection, the temperature was controlled at 60°C to carry out a "one-pot" free radical copolymerization reaction for 12 hours. After cooling, the multifunctional hydrogel (A-1) was obtained.

Comparative Example 1

According to the operating method of step 1 of Example 1, 50 g of deionized water, 2.5 g of methacryloyl gelatin with a substitution degree of 0.3, 5.5 g of methacrylate, 0.25 g of dimethacrylate, 0.25 g of ammonium persulfate, and 5.0 g of modified bioactive glass (A-1) were weighed in sequence and mixed to prepare an aqueous solution ①; then 30 g of deionized water, 1.0 g of methacryloyl gelatin with a substitution degree of 0.3, 5.0 g of methacrylate, 0.25 g of dimethacrylate, and 0.25 g of ammonium persulfate were weighed and mixed to prepare an aqueous solution ②; the aqueous solution ① was subjected to a free radical copolymerization reaction for 6 hours at a temperature of 60° C. under N ₂ protection to obtain a first-stage copolymer solution; the aqueous solution ② was added to the first-stage copolymer solution, mixed evenly, and then subjected to a free radical copolymerization reaction for 6 hours at a temperature of 60° C. under N ₂ protection to obtain a second-stage copolymer solution, and the multifunctional hydrogel (A-1′) was obtained after cooling.

Comparative Example 2

According to the operating method of step 1 of Example 1, 85 g of deionized water, 3.5 g of methacryloyl gelatin with a degree of substitution of 0.3, 10.5 g of glyceryl methacrylate, 0.5 g of glyceryl dimethacrylate, and 0.5 g of ammonium persulfate were weighed in sequence to prepare an aqueous solution. Under _N2 protection, the temperature was controlled at 60°C to carry out a "one-pot" free radical copolymerization reaction for 6 hours. After cooling, the hydrogel (A-1") was obtained.

Example 2 Preparation of multifunctional hydrogel (A-2)

According to the operation method of step 1 of Example 1, the diallylamino polyether methacrylate of formula (B-1) was replaced with 2-(N,N-diallylamino)ethyl methacrylate, and the benzyl chloride was replaced with ω-methoxypolyethylene glycol-400 p-toluenesulfonate to obtain the multifunctional silane coupling agent of formula (A-2) with a yield of 91.4%. The IR spectrum, ¹ H-NMR, mass spectrometry analysis and elemental analysis results (theoretical value %) of the multifunctional silane coupling agent of formula (A-2) are: C53.09 (55.50), H7.93 (8.80), N1.64 (1.72), indicating that it is basically consistent with the molecular formula of formula (A-2) C ₁₁₄ H ₂₁₃ N ₃ O ₄₄ S ₂ Si, thereby judging that the chemical structure of the multifunctional silane coupling agent product of formula (A-2) is consistent with the theoretical design.

Weigh 70 grams of ethanol, 30 grams of multifunctional silane coupling agent of formula (A-2), and 100 grams of water, add them into the reaction flask in turn at room temperature, and stir them evenly to prepare a multifunctional silane coupling agent solution. Then, 30 grams of calcium phosphosilicon bioactive glass with a particle size of ≤10μm (purchased from Wuhan Kemik Biomedical Technology Co., Ltd.) is added thereto, and after ultrasonic treatment for 0.5 hours, the temperature is raised to 70-80°C and stirred for reaction for 6 hours, the reaction process is terminated, the temperature is lowered and filtered, the filter cake is washed three times with ethanol, and the temperature is controlled at 50-55°C and vacuum dried to constant weight to obtain modified bioactive glass (A-2). Using IR spectral analysis, it is determined that the modified bioactive glass (A-2) has the structural characteristics of carboxylic acid esters and ether bonds.

80 g of deionized water, 3.5 g of methacryloyl gelatin with a degree of substitution of 0.3, 10.5 g of glyceryl methacrylate, 0.5 g of glyceryl dimethacrylate, 5.0 g of modified bioactive glass (A-2), and 0.5 g of ammonium persulfate were weighed in sequence, mixed together to form an aqueous solution, and the temperature was controlled at 60° C. under N ₂ protection to carry out a "one-pot" free radical copolymerization reaction for 12 hours. After cooling, the multifunctional hydrogel (A-2) was obtained.

Example 3 Preparation of multifunctional hydrogel (A-3)

According to the operating method of step 1 of Example 1, 75 g of deionized water, 3.5 g of methacryloyl gelatin with a degree of substitution of 0.3, 10.5 g of glyceryl methacrylate, 0.5 g of glyceryl dimethacrylate, 10.0 g of modified bioactive glass (A-2), and 0.5 g of ammonium persulfate were weighed in sequence, mixed together to form an aqueous solution, and the temperature was controlled at 60° C. under _N2 protection to carry out a "one-pot" free radical copolymerization reaction for 12 hours. After cooling, the multifunctional hydrogel (A-2′) was obtained.

Example 4 Preparation of multifunctional hydrogel (A-4)

According to the method and operation steps of Example 1, the calcium phospho-silicon bioactive glass powder with a particle size of ≤10 μm produced by Wuhan Kemik Biomedical Technology Co., Ltd. in step 2 of Example 1 was replaced with a bioactive glass with a SiO2 content of 45%, a _CaO2 content of 24.5%, a _Na2O content of 24.5%, and a _P2O5 content of 6.0 _% produced by Hebei _Yougu Biotechnology Co., Ltd., with a brand name of Yougulin and a particle size of ≤45 μm powder, to obtain a surface-modified bioactive glass (A-3). By infrared spectroscopy analysis, it was determined that the surface-modified bioactive glass (A-3) had the structural characteristics of carboxylate and ether bonds.

80 g of deionized water, 3.5 g of methacryloyl gelatin with a degree of substitution of 0.3, 10.5 g of glyceryl methacrylate, 0.5 g of glyceryl dimethacrylate, 0.5 g of ammonium persulfate, and 5.0 g of surface-modified bioactive glass (A-3) were weighed in sequence to prepare an aqueous solution. Under _N2 protection, the temperature was controlled at 60°C to carry out a "one-pot" free radical copolymerization reaction for 20 hours. After cooling, the multifunctional hydrogel (A-4) was obtained.

Example 5 Preparation of multifunctional hydrogel (A-5)

According to the method and operation steps of Example 1, 14 grams of the multifunctional silane coupling agent of formula (A-1) in step 2 was replaced with 30 grams of the multifunctional silane coupling agent of formula (A-1) to obtain surface-modified bioactive glass (A-4); 0.5 grams of ammonium persulfate in step 3 was replaced with 1.0 grams of potassium persulfate, and the remaining operations were the same as in Example 1 to obtain the multifunctional hydrogel (A-5).

Example 6 Preparation of multifunctional hydrogel (A-6)

According to the method and operating steps of Example 1, 79 g of deionized water, 5.0 g of methacryloyl gelatin with a degree of substitution of 0.3, 10.5 g of glyceryl methacrylate, 0.5 g of glyceryl dimethacrylate, 1.5 g of phenyl (2,4,6-trimethylbenzoyl) lithium phosphate, and 5.0 g of surface-modified bioactive glass (A-1) were weighed in sequence to prepare an aqueous solution. Under _N2 protection, ultraviolet light with a wavelength of 365 nm was used at room temperature to perform a "one-pot" free radical copolymerization reaction for 30 minutes to obtain the multifunctional hydrogel (A-6).

Example 7 Preparation of multifunctional hydrogel (A-7)

According to the method and operating steps of Example 1, 70 g of deionized water, 3.5 g of sodium methacrylate with a degree of substitution of 0.3, 10.5 g of glyceryl methacrylate, 0.5 g of glyceryl dimethacrylate, 5.0 g of modified bioactive glass (A-1), and 0.5 g of phenyl (2,4,6-trimethylbenzoyl) lithium phosphate were weighed in sequence to prepare an aqueous solution, and irradiated with ultraviolet light of a wavelength of 365 nm at room temperature under _N2 protection to carry out a "one-pot" free radical copolymerization reaction for 40 minutes to obtain the multifunctional hydrogel (A-7).

Example 8 Preparation of multifunctional hydrogel (A-8)

According to the method and operating steps of Example 1, 80 g of deionized water, 3.5 g of sodium methacrylate with a degree of substitution of 0.3, 6.5 g of glyceryl methacrylate, 5.0 g of N-vinyl pyrrolidone, 0.5 g of glyceryl dimethacrylate, 5.0 g of modified bioactive glass (A-4), and 1.5 g of phenyl (2,4,6-trimethylbenzoyl) lithium phosphate were weighed in sequence to prepare an aqueous solution, and irradiated with ultraviolet light of a wavelength of 365 nm at room temperature under _N2 protection for a "one-pot" free radical copolymerization reaction for 40 minutes to obtain the multifunctional hydrogel (A-8).

Example 9 Preparation of multifunctional hydrogel (A-9)

According to the method and operating steps of Example 1, 83 g of deionized water, 3.5 g of sodium methacrylate with a degree of substitution of 0.3, 5.5 g of glyceryl methacrylate, 5.0 g of N-vinyl pyrrolidone, 2.5 g of unsaturated quaternary ammonium salt of formula (E-1), 0.5 g of potassium persulfate, and 5.0 g of modified bioactive glass (A-4) were weighed in sequence to prepare an aqueous solution. Under _N2 protection, the temperature was controlled at 60°C, and a "one-pot" free radical copolymerization reaction was carried out for 12 hours. After cooling, the multifunctional hydrogel (A-9) was obtained.

Example 10 Preparation of multifunctional hydrogel (A-10)

According to the method and operating steps of Example 1, 81 g of deionized water, 3.5 g of sodium methacryloyl alginate with a degree of substitution of 0.3, 10.5 g of hydroxyethyl methacrylate, 5.0 g of modified bioactive glass (A-4), 5.5 g of unsaturated quaternary ammonium salt of formula (E-1), and 0.5 g of phenyl (2,4,6-trimethylbenzoyl) lithium phosphate were weighed in sequence to prepare an aqueous solution, and irradiated with ultraviolet light of a wavelength of 365 nm at room temperature under _N2 protection for a "one-pot" free radical copolymerization reaction for 40 minutes to obtain the multifunctional hydrogel (A-10).

Example 11 Preparation of multifunctional hydrogel (A-11)

According to the method and operating steps of Example 1, 75 g of deionized water, 3.5 g of sodium methacrylate with a degree of substitution of 0.3, 8.5 g of hydroxyethyl methacrylate, 5.0 g of modified bioactive glass (A-4), 7.5 g of unsaturated quaternary ammonium salt of formula (E-1), and 0.5 g of phenyl (2,4,6-trimethylbenzoyl) lithium phosphate were weighed in sequence to prepare an aqueous solution, and irradiated with ultraviolet light of a wavelength of 365 nm at room temperature under _N2 protection to carry out a "one-pot" free radical copolymerization reaction for 40 minutes to obtain the multifunctional hydrogel (A-11).

Example 12 Properties of Multifunctional Hydrogels (A-1 to A-11)

The multifunctional hydrogels of Examples A-1 to A-11 were respectively made into 50*10*2 mm strips and cylinders with a diameter of 10 mm and a height of 5 mm. The tensile strength and compressive strength of each were measured using an electronic universal testing machine at room temperature. The specific results are shown in Table 1.

Table 1 Properties of multifunctional hydrogels of Examples A-1 to A-11

Claims (10)

1. The application of the modified bioactive glass in preparing the multifunctional hydrogel is realized through the following steps: according to the mass percentage of 2-20% of modified bioactive glass, 2-20% of unsaturated hydrophilic polymer, 2-20% of adjustable monomer, 0.1-1.5% of free radical initiator and 40-90% of deionized water, sequentially weighing deionized water, unsaturated hydrophilic polymer, adjustable monomer, modified bioactive glass and free radical initiator, mixing to prepare an aqueous solution, under the protection of N ₂, controlling the temperature to 15-90 ℃, carrying out free radical copolymerization reaction of a one-pot formula for 0.4-40 hours, and obtaining the multifunctional hydrogel, wherein the modified bioactive glass is the bioactive glass subjected to surface modification by adopting a silane coupling agent containing a dipropenyl quaternary ammonium cation in a molecular structure;

Wherein the silane coupling agent containing the dipropenyl quaternary ammonium cation in the molecular structure has a structure shown in a general formula (A):

Wherein R in the general formula (A) is selected from C ₁～C₁₈ alkyl, R ₁ is selected from H or methyl, n is selected from natural numbers between 1 and 200, and Y is selected from C ₁～C₁₈ alkyl or X ^- is selected from Cl ^-、Br^-、I^- or one of p-CH ₃C₆H₄SO₃ ^-; wherein R ₂ is selected from C ₁～C₁₈ alkyl, m is selected from natural numbers between 0 and 200;

The bioactive glass is a silicon-based glass powder material formed by taking SiO ₂-CaO-P₂O₅-Na₂ O as a chemical component, or a silicon-based glass powder material doped with K ⁺、Mg²⁺、Sr²⁺、Zn²⁺、Cu²⁺、B³⁺、Al³⁺、Ti⁴⁺ or Zr ⁴⁺ ions; according to the mass of each chemical component, the mass percent of SiO ₂ is 40-80%, the mass percent of CaO is 10-60%, the mass percent of P ₂O₅ is 3-20%, the mass percent of Na ₂ O is 10-60%, and the doping mass percent of K⁺、Mg²⁺、Sr^{2 +}、Zn²⁺、Cu²⁺、B³⁺、Al³⁺、Ti⁴⁺ or Zr ⁴⁺ ions is selected according to the requirement.

2. The use of a modified bioactive glass for the preparation of a multifunctional hydrogel according to claim 1, characterized in that said unsaturated hydrophilic polymer is one or more of methacryloylated gelatin, methacryloylated chitosan, methacryloylated sodium alginate, methacryloylated hyaluronic acid or silk fibroin.

3. Use of a modified bioactive glass in the preparation of a multifunctional hydrogel according to claim 1, characterized in that the modifying monomers refer to: one or more of N-vinyl pyrrolidone, methacrylic acid, 2-hydroxyethyl methacrylate, N-methacrylamidoglycinamide, glycerol methacrylate, glycerol dimethacrylate, polyethylene glycol dimethacrylate or unsaturated quaternary ammonium salt with a structure shown in a general formula (E);

Wherein the unsaturated quaternary ammonium salt has a structure represented by the general formula (E):

Wherein R ₁ in formula (E) is selected from H or methyl, R ₃ is selected from C ₁～C₁₈ hydrocarbyl, Y is selected from C ₁～C₁₈ hydrocarbyl or X ^- is selected from one of Cl ^-、Br^-, I-or p-CH ₃C₆H₄SO₃ ^-; wherein R ₂ is selected from C ₁～C₁₈ alkyl, and m is selected from natural numbers between 0 and 200.

4. Use of a modified bioactive glass in the preparation of a multifunctional hydrogel according to claim 1, characterized in that the free radical initiator is selected from one or more of ammonium persulfate, sodium persulfate, potassium persulfate, azobisisobutylamidine hydrochloride, phenyl (2, 4, 6-trimethylbenzoyl) phosphate lithium, 4-isobutylphenyl-4' -methylphenyl iodohexafluorophosphate, 2-hydroxy-2-methyl-1- [4- (2-hydroxyethoxy) phenyl ] -1-propanone or 2-hydroxy-2-methyl-1-phenyl-1-propanone.

5. The use of a modified bioactive glass in the preparation of a multifunctional hydrogel according to claim 1, characterized in that the preparation method of the modified bioactive glass is as follows: sequentially weighing the silane coupling agent containing the dipropenyl quaternary ammonium cation, and mixing the methanol or the ethanol with the water according to the mass ratio of the silane coupling agent containing the dipropenyl quaternary ammonium cation to the methanol or the ethanol/the water of 5-50:5-50, preparing a silane coupling agent solution containing the dipropenyl quaternary ammonium cation at room temperature, stirring, adding bioactive glass, and heating to 50-90 ℃ for reacting for 2-20 hours; ending the reaction process, cooling the reaction system to room temperature, filtering, washing the filter cake for 1-3 times by using methanol or ethanol, sending the washed filter cake into a vacuum dryer, and vacuum drying to constant weight at the temperature of 25-65 ℃ to obtain the modified bioactive glass;

Wherein the molecular structure contains the dipropenyl quaternary ammonium cationic silane coupling agent in an amount which is 5-500% of the mass of the bioactive glass.

6. The application of the modified bioactive glass in preparing the multifunctional hydrogel according to claim 1, which is characterized in that the preparation method of the silane coupling agent containing the dipropenyl quaternary ammonium cations in the molecular structure is that diallylamine polyether acrylate is dissolved in a solvent, the temperature is controlled to be 5-35 ℃, under the protection of N ₂, 3-aminopropyl silane coupling agent is slowly added by starting stirring, and the dosage of the diallylamine polyether acrylate is 2.0-2.2 times of the molar quantity of the 3-aminopropyl silane coupling agent; after the 3-aminopropyl silane coupling agent is fed, slowly raising the temperature of the reaction system to 35-90 ℃ for reaction for 2-20 hours, and ending the aza-Michael addition reaction process; adding an alkylating reagent into a reaction system, wherein the dosage of the alkylating reagent is 1.0-3.5 times of the molar quantity of the 3-aminopropyl silane coupling agent, keeping the temperature for continuous reaction for 2-20 hours, and ending the quaternization reaction process; and then removing part of the solvent by rotary evaporation, cooling to room temperature, separating out a crude product, and purifying the crude product to obtain the silane coupling agent containing the dipropenyl quaternary ammonium cation in the molecular structure shown in the general formula (A).

7. The use of a modified bioactive glass for the preparation of a multifunctional hydrogel according to claim 6, wherein said diallylamine polyether acrylate has the structure of formula (C):

wherein R ₁ in the general formula (C) is selected from H or methyl, and n is selected from natural numbers between 1 and 200.

8. The use of a modified bioactive glass for the preparation of a multifunctional hydrogel according to claim 6, wherein said solvent is one or more of methanol, ethanol, propanol, tetrahydrofuran, 1, 4-dioxane, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, dimethyl sulfoxide, N-methylpyrrolidone, N-dimethylformamide, N-diethylformamide, or hexamethylphosphoramide; the dosage of the solvent is 1 to 10 times of the mass of the 3-aminopropyl silane coupling agent.

9. The use of a modified bioactive glass for the preparation of a multifunctional hydrogel according to claim 6, wherein said 3-aminopropyl silane coupling agent has a structure of formula (B):

wherein R in formula (B) is selected from C ₁～C₁₈ hydrocarbyl groups.

10. Use of a modified bioactive glass in the preparation of a multifunctional hydrogel according to claim 6, characterized in that said alkylating agent has the structure of general formula (D):

Wherein Y in formula (D) is selected from C ₁～C₁₈ hydrocarbon groups or X is selected from Cl, br, I or one of p-CH ₃C₆H₄SO₃, wherein R ₂ is selected from C ₁～C₁₈ alkyl, and m is selected from natural numbers between 0 and 200.