Novel photo-response enhanced sterilization-anti-sticking functional hydrogel as well as preparation method and application of novel photo-response enhanced sterilization-anti-sticking functional hydrogel

Abstract

The invention relates to a novel photo-response enhanced sterilization-anti-sticking functional hydrogel and a preparation method and application thereof, the hydrogel raw materials comprise a photo-response degradation cationic functional monomer, an amino type tree-like branched molecule and an inorganic photo-response biological material, and the concentration of the photo-response degradation cationic functional monomer is 0.2-25 wt%; the concentration of the amino type dendritic branched molecules is 0.2 to 35 weight percent; and the concentration of the inorganic photoresponse biological material is 0.1-20 wt%. The hydrogel has the advantages that the cationic groups of the hydrogel can effectively kill part of pathogenic microorganisms under the condition of no light, and under the irradiation of light, the hydrogel not only has the effects of photoresponse sterilization and bacterial adhesion resistance, but also can excite the loaded photoresponse nano-substances to release ROS (reactive oxygen species) to deeply kill the pathogenic microorganisms; therefore, the material can be safely used in the material fields of medical catheters, wound dressings, hemodialysis and the like.

Description

Technical Field

[0001] The invention belongs to the technical field of biomedical polymer materials, and specifically relates to a novel light-responsive enhanced bactericidal-anti-adhesive functional hydrogel and a preparation method and use thereof. Background Art

[0002] Hydrogel is a polymer gel that can retain a large amount of water and biological fluids. It is a soft material with a three-dimensional network structure formed by hydrophilic polymers through chemical or physical crosslinking. Hydrogel has excellent toughness, elasticity and softness, good biocompatibility, and is widely used in biomedicine, shape memory materials and other fields. In recent years, microbial contamination has become a global challenge facing mankind, seriously threatening human health and environmental safety. In order to solve the problem of microbial infection, the research on antibacterial hydrogel in the field of biomedicine has been at the forefront of continuous development and innovation, and has made many significant progress. Hydrogel with multiple functions can not only be antibacterial, but also promote wound healing, control inflammatory response, slow release of drugs, etc. This multifunctional hydrogel can meet complex medical needs and improve the therapeutic effect (CN115926372 A, CN 116731345 A, CN 113980185 A, CN 116178752A). However, with the wide application of antibacterial hydrogel in medicine, bioengineering and other fields, it also faces some challenges and difficulties. For example, some antibacterial hydrogels may only have antibacterial activity against specific types of bacteria or fungi, but the effect is not as expected when facing a broad spectrum of pathogens (CN 116478331 A). The antibacterial effect of some hydrogels may gradually weaken over time, especially when used in vivo, because due to the complexity of the biological environment, maintaining long-lasting antibacterial activity is a challenging problem (CN116077618 A). In order to increase the antibacterial properties, some hydrogels often arbitrarily add some antibacterial agents such as silver and antibiotics. Although the combination of hydrogel and antibiotics can realize the on-demand release of drugs, avoid excessive use of antibiotics, and reduce toxic side effects, the use of antibiotics still has the risk of bacterial resistance (CN 115645603 A, CN 116212123 A, CN 115998904 A).

[0003] In order to solve the above problems, the current popular method is to prepare multifunctional hydrogels by light response (CN 116808210 A,). For example, the photothermal photodynamic antibacterial hydrogel with p-hour / glucose dual responsive drug release disclosed in CN 116474161 A, the p-hour / illumination dual responsive antibacterial hydrogel microspheres designed in CN 113045775 A, and the He Hui team of Guangxi University prepared an in-situ hydrogel wound dressing based on white light and NIR dual light responsive cellulose nanofibers. Although the above hydrogels have good antioxidant properties and photothermal photodynamic antibacterial properties, the preparation process is cumbersome and requires a large amount of solvent, so there is a lack of potential for industrial production. CN 116549716 A uses carboxymethyl chitosan and oxidized sodium alginate as raw materials, and loads fluorescent substrate 4-methylumbelliferone-β-D-glucuronide and antibacterial agent UCNPs@TiO2 nanoparticles, and forms a hydrogel dressing with both bacterial in-situ detection and light responsive antibacterial through Schiff base reaction. However, although the hydrogel prepared by this method has light response, the antibacterial effect does not reach 99%. CN 116617450 A, by grafting serotonin onto the gelatin molecular chain for modification, the modified gelatin is then compounded with a PA@Fe complex, and a responsive hemostatic antibacterial hydrogel based on the physiological coagulation mechanism is prepared by utilizing the biological rapid response hemostatic effect of serotonin and the photothermal antibacterial ability of the PA@Fe complex. However, the antibacterial rate of the obtained hydrogel against E. coli and S. aureus is only 98% at most. The BP / Bi2O3 / ε-PL@APBA-g-OCS / PVA hydrogel prepared by invention patent CN 116440317 A, the iron-chelated semi-interpenetrating network photothermal antibacterial hydrogel designed by CN 116751375 A, the photothermal and silver ion synergistic antibacterial hydrogel dressing disclosed in CN 116077719A, and the zwitterionic polymer based on trimethylamine nitride (TMAO) developed by Jiang Shaoyi's team at the University of Washington. Although the above hydrogels all have photothermal antibacterial effects, the single light response only produces an antibacterial effect after the temperature is maintained for a period of time, but it also has adverse effects on surrounding tissues over time. Summary of the invention

[0004] In view of the above-mentioned problems existing in the prior art, the purpose of the present invention is to design and provide a new type of photoresponsive enhanced bactericidal-anti-adhesive functional hydrogel and its preparation method and use technical solutions. The advantage of this hydrogel is that the cationic groups it carries can effectively kill some pathogenic microorganisms in the absence of light. Under the irradiation of light, in addition to having photoresponsive bactericidal-anti-bacterial adhesion effects, it can also stimulate the loaded photoresponsive nanomaterials to release reactive oxygen species (ROS) for the purpose of deep-level killing of pathogenic microorganisms, which enables it to be safely used in medical catheters, wound dressings, hemodialysis and other material fields.

[0005] The main contents and technical solutions of the present invention are as follows:

[0006] A novel photoresponsive enhanced bactericidal-anti-adhesive functional hydrogel, wherein the hydrogel raw materials include photoresponsive degradable cationic functional monomers, amino-type dendritic branched molecules and inorganic photoresponsive biomaterials, wherein the concentration of the photoresponsive degradable cationic functional monomers is 0.2-25wt%; the concentration of the amino-type dendritic branched molecules is 0.2-35wt%; and the concentration of the inorganic photoresponsive biomaterial is 0.1-20wt%.

[0007] The novel photoresponsive enhanced bactericidal-anti-adhesive functional hydrogel is characterized in that the photoresponsive degradable cationic functional monomer is prepared by modification of benzyl alcohol, wherein the structural formula of benzyl alcohol is as follows:

[0008]

[0009] Wherein, R1-R3, each occurrence is the same or different: is H, halogen (Cl, Br or I), CH, O, NO2, etc., a straight-chain alkyl, straight-chain alkoxy or thioalkoxy group having 1 to 20 C atoms; or a branched or cyclic alkyl, alkoxy or thioalkoxy group having 3 to 20 C atoms; or an aromatic or heteroaromatic ring system having 5 to 30 aromatic atoms, which may be substituted by one or more non-aromatic groups, and two or more adjacent non-aromatic groups may also form a monocyclic or polycyclic aliphatic ring system with each other;

[0010] Preferably, the structure of benzyl alcohol is selected from at least one of the following structures;

[0011]

[0012] The novel light-responsive enhanced bactericidal-anti-adhesive functional hydrogel is characterized in that the amino-type dendritic branched molecules are selected from at least one of poly(propylene-imine), dendritic poly(amide-amine), hyperbranched poly(amide-amine), dendritic polylysine and their derivatives, and the terminal amine modification ratio of the amino-type dendritic branched molecules is 5%-95%, preferably 10%-80%.

[0013] The novel photoresponsive enhanced bactericidal-anti-adhesive functional hydrogel is characterized in that the inorganic photoresponsive biomaterial is selected from at least one of carbon-based nanomaterials, metal nanomaterials, graphite carbon nitride, transition metal oxides, transition metal disulfides and their derivatives;

[0014] Preferably, the carbon-based nanomaterial is selected from at least one of graphene, carbon nanotubes, graphene oxide, nanodiamonds and carbon quantum dots;

[0015] Preferably, the metal nanomaterial is gold nanoparticles;

[0016] Preferably, the transition metal oxide is TiO2 nanoparticles;

[0017] Preferably, the transition metal disulfide is selected from at least one of MoS2 and WS2.

[0018] A novel photoresponsive enhanced bactericidal-anti-adhesive functional hydrogel, characterized in that: the concentration of photoresponsive degradable cationic functional monomers is 5-20wt%; the concentration of amino-type dendritic branched molecules is 2-15wt%; and the concentration of inorganic photoresponsive biomaterials is 5-10wt%.

[0019] A method for preparing a novel photoresponsive enhanced bactericidal-anti-adhesive functional hydrogel, characterized by comprising the following steps:

[0020] S1. Synthesis of a photoresponsive degradable cationic functional monomer: adding an anhydrous dimethylformamide solution of bromoacetyl chloride to a mixed solution of anhydrous dimethylformamide of benzyl alcohol and triethylamine at 0-4°C, stirring the mixture at 0-4°C for 1-3 hours, and then stirring at room temperature for 6-12 hours; after purification, stirring with 2-(dimethylamino)ethyl methacrylate at 50-80°C for 24-48 hours under a nitrogen atmosphere, and obtaining a photoresponsive degradable cationic functional monomer after precipitation and washing;

[0021] S2. Functionalization modification of amine-based dendritic branched molecules: The amine-based dendritic branched molecules are prepared into a solution with a concentration of 0.2-25wt%, 0-1.6mL of triethylamine is added, purged with nitrogen for 30-60 minutes, 2-bromoisobutyryl bromide (BIBB) is added dropwise to the solution, and then reacted in a nitrogen atmosphere for 24-48 hours; then, the solution is polymerized with the S1 photodegradable cationic functional monomer, and a dendritic branched cationic functional polymer is obtained after purification;

[0022] S3. The dendritic branched cationic functional polymer obtained in S2 is compounded with 0.1-20wt% of an inorganic photoresponsive biomaterial, and then the inorganic photoresponsive biomaterial without a load is thoroughly washed with deionized water to obtain a dendritic branched cationic functional polymer compounded with an inorganic photoresponsive biomaterial;

[0023] S4. Cross-link the dendritic branched cationic functional polymer composite of the inorganic photoresponsive biomaterial obtained in S3 with a cross-linking agent, remove the unreacted cross-linking agent, and obtain a photoresponsive enhanced bactericidal-anti-adhesive functional hydrogel.

[0024] The method for preparing the novel light-responsive enhanced bactericidal-anti-adhesive functional hydrogel is characterized in that in S2: the solvent is at least one of methanol, ethanol, n-propanol, and isopropanol.

[0025] The method for preparing a novel photoresponsive enhanced bactericidal-anti-adhesive functional hydrogel is characterized in that in S3: the concentration of the inorganic photoresponsive biomaterial is 0.1-20wt%, preferably 2-15wt%, and more preferably 5-10wt%; the particle size of the inorganic photoresponsive biomaterial is 1-500nm, and the preferred particle size is 50-100nm.

[0026] The method for preparing the novel light-responsive enhanced bactericidal-anti-adhesive functional hydrogel is characterized in that in S4: the cross-linking agent is one of epichlorohydrin, glutaraldehyde, o-phthalaldehyde, isophthalaldehyde, terephthalaldehyde, phthalic acid, isophthalic acid, terephthalic acid, trimesic acid, dopamine, tannic acid, gallic acid, and catechol.

[0027] The novel light-responsive enhanced bactericidal-anti-adhesive functional hydrogel prepared by the method is used as a bactericidal product, an anti-adhesive product or an anti-biofilm product.

[0028] The application of the novel light-responsive enhanced bactericidal-anti-adhesive functional hydrogel in the preparation of antibacterial, anti-adhesive and anti-biofilm materials.

[0029] The beneficial effects of the present invention are as follows:

[0030] 1) Using photoresponsive degradable cations as functional monomers has simple design, convenient synthesis, low cost, and is conducive to industrial production. In addition, photoresponsive degradable cation functional monomers can give materials photoresponsive properties, which can effectively improve the multifunctional properties of materials.

[0031] 2) The dendritic branched molecules have abundant terminal active functional groups, and the terminal reaction sites are controllable, so the terminal functional groups can be functionally designed. With the dendritic branched molecules as the core, photoresponsive degradable cationic functional monomers are introduced to their ends through atomic free radical polymerization to obtain three-dimensional dendritic branched cationic functional polymers with photoresponsiveness. Because of the large number of cavity structures inside, they can encapsulate specific functional nanoparticles, thereby enhancing the deep-level killing of pathogenic microorganisms.

[0032] 3) The inorganic photoresponsive biomaterial is compounded with the photoresponsive dendritic branched cationic functional polymer, which can stimulate the inorganic photoresponsive biomaterial to release ROS under light conditions to enhance the bactericidal ability of the hydrogel. At the same time, under light conditions, the cationic functional groups are degraded and the cations are converted into zwitterions, achieving the effect of resisting the release of killed bacteria, thereby giving the hydrogel a photoresponsive enhanced bactericidal-anti-adhesive function, so that it can be safely used in medical catheters, wound dressings, hemodialysis and other material fields, reducing the harm of bacterial inflammation and infection to human life and health. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figure 1 It is a schematic diagram of the process of the preparation method of the present invention. DETAILED DESCRIPTION

[0034] The beneficial effects of the present invention are further demonstrated by corresponding experimental data below.

[0035] The experimental test method used in the present invention is as follows:

[0036] (1) Sterilization rate performance test

[0037] Staphylococcus aureus (ATCC 25923) and Escherichia coli (ATCC 25922) were used to evaluate the antibacterial properties of the hydrogel. The two bacteria were first incubated on Luria-Bertani (LB) agar medium at 37°C overnight, and then the bacterial colonies on the plate were inoculated into 25 mL of LB medium and shaken at 37°C for 10 hours. Then, the bacterial solution was diluted with phosphate buffered saline (PBS) solution to a final concentration of 10 5 CFU mL -1 The hydrogel was made into a disc with a diameter of 1 cm (thickness of 5 mm). After sterilization, 0.1 mL of a 10 5 The diluted bacterial suspension of CFU / ml was used as the inoculated bacterial solution and dropped onto the surface of each sample, and then treated under light conditions for 10 minutes. Three parallel experiments were performed for each sample. After the end, 1 mL of PBS was added to each sample, and the sample was repeatedly washed. After sufficient shaking, the washing solution was diluted with phosphate saline buffer, and 1 mL was inoculated into nutrient agar medium. After culturing at (35±1)℃ for 20-24 hours, the live bacteria were counted. The antibacterial rate was calculated as follows:

[0038] Sterilization rate = (N B -N A ) / N B ×100%, where N B is the colony count (CFU) of the negative control after 24 hours of culture, N A It is the colony count (CFU) of the hydrogel sample after 24 hours of culture.

[0039] (2) Anti-bacterial adhesion test:

[0040] For antibacterial assays, the substrate was sterilized with 75% ethanol solution and rinsed with PBS, then placed in a 12-well sterile plate. Subsequently, 3 mL of bacterial suspension was added to the wells and cultured at 37 ° C for a predetermined time (24 hours for Escherichia coli and 12 hours for Staphylococcus aureus) at 100 rpm. After the incubation, all samples were washed 3 times with sterile PBS and placed in the dark for 15 minutes using a LIVE / DEAD BackLight Viability Kit (Thermo Fisher Scientific Inc.), rinsed with sterile PBS, and then observed using an Axio Observer A1 inverted fluorescence microscope.

[0041] The technical scheme of the present invention will be clearly and completely described below in conjunction with the drawings and embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, rather than all the embodiments. The embodiments described below are exemplary and are intended to be used to explain the present invention, and cannot be understood as limiting the present invention.

[0042] Example 1

[0043] 1) Synthesis of photodegradable cationic functional monomers: Bromoacetyl chloride (37.5 mmol, 3.2 mL) was dissolved in anhydrous N,N-dimethylformamide (40 mL), and added dropwise to a mixed solution of 4,5-dimethoxy-2-nitrobenzyl alcohol (30 mmol, 6.4 g) and triethylamine (37.5 mmol, 5.3 mL) in anhydrous N,N-dimethylformamide (40 mL) at 0°C. The mixture was stirred at 0°C for 1 hour and then at room temperature for 12 hours. The product was purified. Then the purified compound (10 mmol, 3.55 g), 2-(dimethylamino)ethyl methacrylate (10 mmol, 1.68 mL) and acetonitrile (100 mL) were added to a 250 mL round-bottom flask, and the mixture was stirred at 60 ° C for 24 hours under a nitrogen atmosphere. After the reaction, the solvent was removed by a rotary evaporator, and the product (compound 2) was precipitated with anhydrous ether and washed with anhydrous ether to obtain a light yellow powder, which was stored at 4 ° C in the dark;

[0044] 2) Synthesis of dendritic branched cationic functional polymers: First, a dendritic polyamidoamine with an amino group at the end and a molecular weight of 28954 was added to dimethyl amide to prepare a solution with a concentration of 10wt%, 1.6mL of triethylamine was added, and after purging with N2 for 30 minutes, the flask was placed in an ice bath, and then 1.44mL of 2-bromoisobutyryl bromide (BIBB) was added dropwise to the solution with a syringe under electromagnetic stirring. The reaction was carried out in an N2 atmosphere for 24 hours, and the sample was precipitated and washed. The precipitated and washed sample was placed in a three-necked flask containing 100mL of 50% methanol solution, and then the final product (2.0g, 7.15mmol) and 2,2-bipyridine (0.31g, 2mmol) obtained in step (2) were added under magnetic stirring. After purging the system with N2 for 1 hour, CuCl (0.10g, 1mmol) was added to the solution, and the reaction was carried out at room temperature under nitrogen flow for 12 hours. The polymer was precipitated and washed, and freeze-dried for use;

[0045] 3) dissolving the dendritic branched cationic functional polymer obtained in step 2 in methanol, adding 1 wt % SiO2 for loading, and then thoroughly washing the unloaded SiO2 with deionized water;

[0046] 4) Add appropriate amount of glutaraldehyde to the SiO2 loaded dendritic branched cationic functional polymer solution obtained in the third step for cross-linking to obtain a hydrogel, and thoroughly wash the hydrogel with PBS solution to remove unreacted glutaraldehyde to obtain a functional hydrogel.

[0047] Example 2-12: The structural formula of benzyl alcohol was adjusted, and the rest was the same as Example 1.

[0048] Comparative Example 1: A proper amount of glutaraldehyde was added to a dendritic polyamidoamine with an amino molecular weight of 28954 for cross-linking to obtain a hydrogel, and the hydrogel was thoroughly washed with a PBS solution to remove unreacted glutaraldehyde to obtain a functional hydrogel.

[0049] Comparative Example 2: According to step 1) of Example 1, a photodegradable cationic functional monomer is obtained, and then a photodegradable cationic polymer is synthesized by free radical polymerization to further prepare a hydrogel sample.

[0050] Comparative Example 3: The photodegradable cationic polymer was prepared according to the steps of Comparative Example 2, and then compounded with a dendritic polyamidoamine having an amino molecular weight of 28954 according to step 4) to obtain a hydrogel sample.

[0051] Comparative Example 4: A photodegradable cationic polymer was prepared according to the steps of Comparative Example 2, and then compounded with a dendritic polyamidoamine having an amino molecular weight of 28954, and a hydrogel sample was prepared according to steps 3) and 4).

[0052] Comparative Example 5: A hydrogel sample was prepared according to steps 1), 2) and 4) of Example 1.

[0053] Comparative Example 6: A hydrogel sample was prepared according to steps 2), 3) and 4) of Example 1.

[0054] Comparative Example 7: A hydrogel sample was prepared according to the steps of Example 1, and the sample was treated under non-light conditions.

[0055] The bactericidal-anti-adhesive effect of the photoresponsive enhanced bactericidal-anti-adhesive functional hydrogels prepared in Examples 1-12 and Comparative Examples 1-6 was evaluated, and the results are shown in Table 1 below.

[0056] Table 1 Evaluation table of sterilization-anti-sticking effect of Examples 1-12 and Comparative Examples 1-6

[0057]

[0058]

[0059]

[0060] The results of Examples 1-12 and Comparative Examples 1-7 show that, compared with the hydrogel without grafted photodegradable cationic functional monomers, or the hydrogel without SiO2 loading, or the hydrogel only grafted with photodegradable cationic functional monomers, or the hydrogel only loaded with SiO2, the photoresponsive enhanced bactericidal-anti-adhesive functional hydrogel has excellent photoresponsive bactericidal performance and anti-adhesive performance. It is worth noting that the structural formula of benzyl alcohol has little effect on the antibacterial performance.

[0061] Example 13

[0062] 1) Synthesis of photodegradable cationic functional monomers: Bromoacetyl chloride (37.5 mmol, 3.2 mL) was dissolved in anhydrous N,N-dimethylformamide (40 mL), and added dropwise to a mixed solution of 4,5-dimethoxy-2-nitrobenzyl alcohol (30 mmol, 6.4 g) and triethylamine (37.5 mmol, 5.3 mL) in anhydrous N,N-dimethylformamide (40 mL) at 0°C. The mixture was stirred at 0°C for 1 hour and then at room temperature for 12 hours. The product was purified. Then the purified compound (10 mmol, 3.55 g), 2-(dimethylamino)ethyl methacrylate (10 mmol, 1.68 mL) and acetonitrile (100 mL) were added to a 250 mL round-bottom flask, and the mixture was stirred at 60 ° C for 24 hours under a nitrogen atmosphere. After the reaction, the solvent was removed by a rotary evaporator, and the product (compound 2) was precipitated with anhydrous ether and washed with anhydrous ether to obtain a light yellow powder, which was stored at 4 ° C in the dark;

[0063] 2) Synthesis of dendritic branched cationic functional polymers: First, a dendritic polyamidoamine with an amino group at the end and a molecular weight of 517 was added to dimethyl amide to prepare a solution with a concentration of 10wt%, 1.6mL of triethylamine was added, and after purging with N2 for 30 minutes, the flask was placed in an ice bath, and then 1.44mL of 2-bromoisobutyryl bromide (BIBB) was added dropwise to the solution with a syringe under electromagnetic stirring. The reaction was carried out in an N2 atmosphere for 24 hours, and the sample was precipitated and washed. The precipitated and washed sample was placed in a three-necked flask containing 100mL of 50% methanol solution, and then the final product (2.0g, 7.15mmol) and 2,2-bipyridine (0.31g, 2mmol) obtained in step (2) were added under magnetic stirring. After purging the system with N2 for 1 hour, CuCl (0.10g, 1mmol) was added to the solution, and the reaction was carried out at room temperature under nitrogen flow for 12 hours. The polymer was precipitated and washed, and freeze-dried for use;

[0064] 3) dissolving the dendritic branched cationic functional polymer obtained in step 2 in methanol, adding 1 wt % SiO2 for loading, and then thoroughly washing the unloaded SiO2 with deionized water;

[0065] 4) Add appropriate amount of glutaraldehyde to the SiO2 loaded dendritic branched cationic functional polymer solution obtained in the third step for cross-linking to obtain a hydrogel, and thoroughly wash the hydrogel with PBS solution to remove unreacted glutaraldehyde to obtain a functional hydrogel.

[0066] Examples 14-17: The molecular weight of the dendrimer (polyamidoamine) was adjusted, and the rest was the same as Example 13.

[0067] Comparative Example 8: A proper amount of glutaraldehyde was added to a dendritic polyamidoamine with an amino molecular weight of 517 for cross-linking to obtain a hydrogel, and the hydrogel was thoroughly washed with a PBS solution to remove unreacted glutaraldehyde to obtain a functional hydrogel.

[0068] Comparative Example 9: According to step 1) of Example 13, a photodegradable cationic functional monomer is obtained, and then a photodegradable cationic polymer is synthesized by free radical polymerization to further prepare a hydrogel sample.

[0069] Comparative Example 10: The photodegradable cationic polymer was prepared according to the steps of Comparative Example 9, and then compounded with a dendritic polyamidoamine having an amino molecular weight of 28954 according to step 4) to obtain a hydrogel sample.

[0070] Comparative Example 11: A photodegradable cationic polymer was prepared according to the steps of Comparative Example 9, and then compounded with a dendritic polyamidoamine having an amino molecular weight of 28954, and a hydrogel sample was prepared according to steps 3) and 4).

[0071] Comparative Example 12: A hydrogel sample was prepared according to steps 1), 2) and 4) of Example 13.

[0072] Comparative Example 13: A hydrogel sample was prepared according to steps 2), 3) and 4) of Example 13.

[0073] Comparative Example 14: A hydrogel sample was prepared according to the steps of Example 13, and the sample was treated under non-light conditions.

[0074] The bactericidal-anti-adhesive effect of the light-responsive enhanced bactericidal-anti-adhesive functional hydrogels prepared by Examples 13-17 and Comparative Examples 8-14 was evaluated, and the results are shown in Table 2 below.

[0075] Table 2 Evaluation table of sterilization-anti-sticking effect of Examples 13-17 and Comparative Examples 8-14

[0076]

[0077] The results of Examples 13-17 and Comparative Examples 8-14 show that, compared with the hydrogels not grafted with photodegradable cationic functional monomers, or the hydrogels not loaded with SiO2, or the hydrogels only grafted with photodegradable cationic functional monomers, or the hydrogels only loaded with SiO2, the photoresponsive enhanced bactericidal-anti-adhesive functional hydrogels have excellent photoresponsive bactericidal performance and anti-adhesive performance. It is worth noting that as the molecular weight of the dendritic (polyamide-amine) increases, its antibacterial properties also increase. Similarly, in the present invention, when the dendritic branched molecules with amino groups at the ends are poly(propylene-imine), hyperbranched poly(amide-amine), dendritic polylysine and other derivatives, the functional hydrogels obtained therefrom also have the bactericidal-anti-adhesive effects described in the present invention.

[0078] Embodiment 18

[0079] 1) Synthesis of photodegradable cationic functional monomers: Bromoacetyl chloride (37.5 mmol, 3.2 mL) was dissolved in anhydrous N,N-dimethylformamide (40 mL), and added dropwise to a mixed solution of 4,5-dimethoxy-2-nitrobenzyl alcohol (30 mmol, 6.4 g) and triethylamine (37.5 mmol, 5.3 mL) in anhydrous N,N-dimethylformamide (40 mL) at 0°C. The mixture was stirred at 0°C for 1 hour and then at room temperature for 12 hours. The product was purified. Then the purified compound (10 mmol, 3.55 g), 2-(dimethylamino)ethyl methacrylate (10 mmol, 1.68 mL) and acetonitrile (100 mL) were added to a 250 mL round-bottom flask, and the mixture was stirred at 60 ° C for 24 hours under a nitrogen atmosphere. After the reaction, the solvent was removed by a rotary evaporator, and the product (compound 2) was precipitated with anhydrous ether and washed with anhydrous ether to obtain a light yellow powder, which was stored at 4 ° C in the dark;

[0080] 2) Synthesis of dendritic branched cationic functional polymers: First, a dendritic polyamidoamine with an amino group at the end and a molecular weight of 14215 was added to dimethyl amide to prepare a solution with a concentration of 5wt%, 1.6mL of triethylamine was added, and after purging with N2 for 30 minutes, the flask was placed in an ice bath, and then 1.44mL of 2-bromoisobutyryl bromide (BIBB) was added dropwise to the solution with a syringe under electromagnetic stirring. The reaction was carried out in an N2 atmosphere for 24 hours, and the sample was precipitated and washed. The precipitated and washed sample was placed in a three-necked flask containing 100mL of 50% methanol solution, and then the final product (2.0g, 7.15mmol) and 2,2-bipyridine (0.31g, 2mmol) obtained in step (2) were added under magnetic stirring. After purging the system with N2 for 1 hour, CuCl (0.10g, 1mmol) was added to the solution, and the reaction was carried out at room temperature under nitrogen flow for 12 hours. The polymer was precipitated and washed, and freeze-dried for use;

[0081] 3) dissolving the dendritic branched cationic functional polymer obtained in step 2 in methanol, adding 1 wt % SiO2 for loading, and then thoroughly washing the unloaded SiO2 with deionized water;

[0082] 4) Add appropriate amount of glutaraldehyde to the SiO2 loaded dendritic branched cationic functional polymer solution obtained in the third step for cross-linking to obtain a hydrogel, and thoroughly wash the hydrogel with PBS solution to remove unreacted glutaraldehyde to obtain a functional hydrogel.

[0083] Examples 19-21: The concentration of the dendrimer (polyamidoamine) was adjusted, and the rest was the same as Example 18.

[0084] Comparative Example 15: A proper amount of glutaraldehyde was added to a dendritic polyamidoamine with an amino molecular weight of 14215 for cross-linking to obtain a hydrogel. The hydrogel was thoroughly washed with a PBS solution to remove unreacted glutaraldehyde to obtain a functional hydrogel.

[0085] Comparative Example 16: According to step 1) of Example 18, a photodegradable cationic functional monomer was obtained, and then a photodegradable cationic polymer was synthesized by free radical polymerization to further prepare a hydrogel sample.

[0086] Comparative Example 17: The photodegradable cationic polymer was prepared according to the steps of Comparative Example 16, and then compounded with a dendritic polyamidoamine having an amino molecular weight of 28954 according to step 4) to obtain a hydrogel sample.

[0087] Comparative Example 18: A photodegradable cationic polymer was prepared according to the steps of Comparative Example 16, and then compounded with a dendritic polyamidoamine having an amino molecular weight of 28954, and a hydrogel sample was prepared according to steps 3) and 4).

[0088] Comparative Example 19: A hydrogel sample was prepared according to steps 1), 2) and 4) of Example 18.

[0089] Comparative Example 20: A hydrogel sample was prepared according to steps 2), 3) and 4) of Example 18.

[0090] Comparative Example 21: A hydrogel sample was prepared according to the steps of Example 18, and the sample was treated under non-light conditions.

[0091] The bactericidal-anti-adhesive effect of the photoresponsive enhanced bactericidal-anti-adhesive functional hydrogels prepared in Examples 18-23 and Comparative Examples 15-21 was evaluated, and the results are shown in Table 3 below.

[0092] Table 3 Evaluation table of sterilization-anti-sticking effect of Examples 18-21 and Comparative Examples 15-21

[0093]

[0094] The results of Examples 18-21 and Comparative Examples 15-21 show that, compared with the hydrogels without grafted photodegradable cationic functional monomers, or the hydrogels without SiO2 loading, or the hydrogels only grafted with photodegradable cationic functional monomers, or the hydrogels only loaded with SiO2, the photoresponsive enhanced bactericidal-anti-adhesive functional hydrogels have excellent photoresponsive bactericidal performance and anti-adhesive performance. It is worth noting that as the concentration of the dendrimer (polyamide-amine) increases, its antibacterial performance also increases.

[0095] Embodiment 22

[0096] 1) Synthesis of photodegradable cationic functional monomers: Bromoacetyl chloride (37.5 mmol, 3.2 mL) was dissolved in anhydrous N,N-dimethylformamide (40 mL), and added dropwise to a mixed solution of 4,5-dimethoxy-2-nitrobenzyl alcohol (30 mmol, 6.4 g) and triethylamine (37.5 mmol, 5.3 mL) in anhydrous N,N-dimethylformamide (40 mL) at 0°C. The mixture was stirred at 0°C for 1 hour and then at room temperature for 12 hours. The product was purified. Then the purified compound (10 mmol, 3.55 g), 2-(dimethylamino)ethyl methacrylate (10 mmol, 1.68 mL) and acetonitrile (100 mL) were added to a 250 mL round-bottom flask, and the mixture was stirred at 60 ° C for 24 hours under a nitrogen atmosphere. After the reaction, the solvent was removed by a rotary evaporator, and the product (compound 2) was precipitated with anhydrous ether and washed with anhydrous ether to obtain a light yellow powder, which was stored at 4 ° C in the dark;

[0097] 2) Synthesis of dendritic branched cationic functional polymers: First, a dendritic polyamidoamine with an amino group at the end and a molecular weight of 14215 was added to dimethyl amide to prepare a solution with a concentration of 5wt%, 1.6mL of triethylamine was added, and after purging with N2 for 30 minutes, the flask was placed in an ice bath, and then 1.44mL of 2-bromoisobutyryl bromide (BIBB) was added dropwise to the solution with a syringe under electromagnetic stirring. The reaction was carried out in an N2 atmosphere for 24 hours, and the sample was precipitated and washed. The precipitated and washed sample was placed in a three-necked flask containing 100mL of 50% methanol solution, and then the final product (2.0g, 7.15mmol) and 2,2-bipyridine (0.31g, 2mmol) obtained in step (2) were added under magnetic stirring. After purging the system with N2 for 1 hour, CuCl (0.10g, 1mmol) was added to the solution, and the reaction was carried out at room temperature under nitrogen flow for 12 hours. The polymer was precipitated and washed, and freeze-dried for use;

[0098] 3) dissolving the dendritic branched cationic functional polymer obtained in step 2 in methanol, adding 2 wt % SiO2 for loading, and then thoroughly washing the unloaded SiO2 with deionized water;

[0099] 4) Add appropriate amount of glutaraldehyde to the SiO2 loaded dendritic branched cationic functional polymer solution obtained in the third step for cross-linking to obtain a hydrogel, and thoroughly wash the hydrogel with PBS solution to remove unreacted glutaraldehyde to obtain a functional hydrogel.

[0100] Examples 23-26: The concentration of SiO2 was adjusted, and the rest was the same as Example 22.

[0101] Comparative Example 22: According to step 1) of Example 22, a photodegradable cationic functional monomer is obtained, and then a photodegradable cationic polymer is synthesized by free radical polymerization to further prepare a hydrogel sample.

[0102] Comparative Example 23: The photodegradable cationic polymer was prepared according to the steps of Comparative Example 22, and then compounded with a dendritic polyamidoamine having an amino molecular weight of 28954 according to step 4) to obtain a hydrogel sample.

[0103] Comparative Example 24: A photodegradable cationic polymer was prepared according to the steps of Comparative Example 22, and then compounded with a dendritic polyamidoamine having an amino molecular weight of 28954, and a hydrogel sample was prepared according to steps 3) and 4).

[0104] Comparative Example 25: A hydrogel sample was prepared according to steps 1), 2) and 4) of Example 22.

[0105] Comparative Example 26: A hydrogel sample was prepared according to steps 2), 3) and 4) of Example 22.

[0106] Comparative Example 27: A hydrogel sample was prepared according to the steps of Example 22, and the sample was treated under non-light conditions.

[0107] The bactericidal-anti-adhesive effect of the light-responsive enhanced bactericidal-anti-adhesive functional hydrogels prepared by Examples 22-25 and Comparative Examples 22-27 was evaluated, and the results are shown in Table 4 below.

[0108] Table 4 Evaluation table of sterilization-anti-sticking effect of Examples 22-25 and Comparative Examples 22-27

[0109]

[0110] The results of Examples 22-25 and Comparative Examples 22-27 show that compared with hydrogels not grafted with photodegradable cationic functional monomers, or hydrogels not loaded with SiO2, or hydrogels only grafted with photodegradable cationic functional monomers, or hydrogels only loaded with SiO2, the photoresponsive enhanced bactericidal-anti-adhesive functional hydrogels have excellent photoresponsive bactericidal performance and anti-adhesive performance. It is worth noting that as the concentration of SiO2 increases, SiO2 is stimulated to release ROS under ultraviolet light to enhance the bactericidal ability of the hydrogel. At the same time, under ultraviolet light, the cationic functional groups are degraded and the cations are converted to zwitterions, achieving the effect of resisting the release of killed bacteria, thereby enhancing the bactericidal-anti-adhesive function of the hydrogel.

[0111] From Tables 1-4, it can be seen that: with the dendritic branched molecule as the core, the photoresponsive degradable cationic functional monomer is introduced to its end through atomic free radical polymerization to obtain a three-dimensional dendritic branched cationic functional polymer with photoresponse. Because it has a large number of cavity structures inside, it can encapsulate specific functional nanoparticles, which serves the purpose of enhancing the deep killing of pathogenic microorganisms. The inorganic photoresponsive biomaterial is compounded with the photoresponsive dendritic branched cationic functional polymer, which can stimulate the inorganic photoresponsive biomaterial to release ROS under light conditions to enhance the bactericidal ability of the hydrogel. At the same time, under light conditions, the cationic functional group is degraded, and the cation is converted into a zwitterion, achieving the effect of resisting the release of killed bacteria, thereby giving the hydrogel a photoresponsive enhanced bactericidal-anti-adhesive function, so that it can be safely used in medical catheters, wound dressings, hemodialysis and other material fields, reducing the harm of bacterial inflammation and infection to human life and health.

[0112] The above are only preferred specific embodiments of the present invention, but the protection scope of the present invention is not limited thereto. Any technician familiar with the technical field can make equivalent replacements or changes according to the technical solutions and inventive concepts of the present invention within the technical scope disclosed by the present invention, which should be covered by the protection scope of the present invention.

Claims

1. A novel photoresponsive enhanced bactericidal-anti-adhesive functional hydrogel, the hydrogel raw materials comprising photoresponsive degradable cationic functional monomers, amino-type dendritic branched molecules and inorganic photoresponsive biomaterials, wherein the concentration of the photoresponsive degradable cationic functional monomers is 0.2-25wt%; the concentration of the amino-type dendritic branched molecules is 0.2-35wt%; the concentration of the inorganic photoresponsive biomaterial is 0.1-20wt%.

2. A novel photoresponsive enhanced bactericidal-anti-adhesive functional hydrogel as claimed in claim 1, characterized in that The photoresponsive degradable cationic functional monomer is prepared by modifying benzyl alcohol, wherein the structural formula of benzyl alcohol is as follows: Wherein, R1-R3, each occurrence being the same or different: is H, halogen (Cl, Br or I), CH3O or NO2, a straight-chain alkyl, straight-chain alkoxy or thioalkoxy group having 1 to 20 C atoms; or a branched or cyclic alkyl, alkoxy or thioalkoxy group having 3 to 20 C atoms; or an aromatic or heteroaromatic ring system having 5 to 30 aromatic atoms, which may be substituted by one or more non-aromatic groups, and two or more adjacent non-aromatic groups may also form a monocyclic or polycyclic aliphatic ring system with each other; Preferably, the structure of benzyl alcohol is selected from at least one of the following structures; 3. A novel photoresponsive enhanced bactericidal-anti-adhesive functional hydrogel as claimed in claim 1, characterized in that The amino-type dendritic branched molecules are selected from at least one of poly(propylene-imine), dendritic poly(amide-amine), hyperbranched poly(amide-amine), dendritic polylysine and their derivatives, and the terminal amine modification ratio of the amino-type dendritic branched molecules is 5%-95%, preferably 20%-80%.

4. A novel photoresponsive enhanced bactericidal-anti-adhesive functional hydrogel as claimed in claim 1, characterized in that The inorganic light-responsive biomaterial is selected from at least one of carbon-based nanomaterials, metal nanomaterials, graphite carbon nitride, transition metal oxides, transition metal disulfides and derivatives thereof; Preferably, the carbon-based nanomaterial is selected from at least one of graphene, carbon nanotubes, graphene oxide, nanodiamonds and carbon quantum dots; Preferably, the metal nanomaterial is gold nanoparticles; Preferably, the transition metal oxide is TiO2 nanoparticles; Preferably, the transition metal disulfide is selected from at least one of MoS2 and WS2.

5. A novel photoresponsive enhanced bactericidal-anti-adhesive functional hydrogel as claimed in claim 1, characterized in that: The concentration of the photoresponsive degradable cationic functional monomer is 5-20wt%; the concentration of the amino-type dendritic branched molecules is 2-15wt%; and the concentration of the inorganic photoresponsive biomaterial is 5-10wt%.

6. The method for preparing a novel photoresponsive enhanced bactericidal-anti-adhesive functional hydrogel according to claim 1, characterized in that The following steps are involved: S1. Synthesis of a photoresponsive degradable cationic functional monomer: adding an anhydrous dimethylformamide solution of bromoacetyl chloride to a mixed solution of anhydrous dimethylformamide of benzyl alcohol and triethylamine at 0-4°C, stirring the mixture at 0-4°C for 1-3 hours, and then stirring at room temperature for 6-12 hours; after purification, stirring with 2-(dimethylamino)ethyl methacrylate at 50-80°C for 24-48 hours under a nitrogen atmosphere, and obtaining a photoresponsive degradable cationic functional monomer after precipitation and washing; S2. Functionalization modification of amine-based dendritic branched molecules: The amine-based dendritic branched molecules are prepared into a 0.2-25wt% solution, 0-1.6mL of triethylamine is added, purged with nitrogen for 30-60 minutes, 2-bromoisobutyryl bromide (BIBB) is added dropwise to the solution, and then reacted in a nitrogen atmosphere for 24-48 hours; then, the solution is polymerized with the S1 photodegradable cationic functional monomer, and a dendritic branched cationic functional polymer is obtained after purification; S3. The dendritic branched cationic functional polymer obtained in S2 is compounded with 0.1-20wt% of an inorganic photoresponsive biomaterial, and then the inorganic photoresponsive biomaterial without a load is thoroughly washed with deionized water to obtain a dendritic branched cationic functional polymer compounded with an inorganic photoresponsive biomaterial; S4. Cross-link the dendritic branched cationic functional polymer composite of the inorganic photoresponsive biomaterial obtained in S3 with a cross-linking agent, remove the unreacted cross-linking agent, and obtain a photoresponsive enhanced bactericidal-anti-adhesive functional hydrogel.

7. A method for preparing a novel photoresponsive enhanced bactericidal-anti-adhesive functional hydrogel as claimed in claim 6, characterized in that In S2: the solvent is at least one of methanol, ethanol, n-propanol, and isopropanol; In S3: the concentration of the inorganic photoresponsive biomaterial is 0.1-20wt%, preferably 3-15wt%, more preferably 5-10wt%; the particle size of the inorganic photoresponsive biomaterial is 1-500nm, preferably 50-100nm.

8. The method for preparing a novel photoresponsive enhanced bactericidal-anti-adhesive functional hydrogel according to claim 6, characterized in that In S4: the cross-linking agent is one of epichlorohydrin, glutaraldehyde, o-phthalaldehyde, isophthalaldehyde, terephthalaldehyde, phthalic acid, isophthalic acid, terephthalic acid, trimesic acid, dopamine, tannic acid, gallic acid, and catechol.

9. Use of the novel light-responsive enhanced bactericidal-anti-adhesive functional hydrogel according to any one of claims 1 to 8 in the preparation of bactericidal products, anti-adhesive products, and anti-biofilm products.

10. Use of the novel light-responsive enhanced bactericidal-anti-adhesive functional hydrogel according to any one of claims 1 to 8 in the preparation of antibacterial, anti-adhesive and anti-biofilm materials.

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