Antibacterial hydrogel with dual temperature response function and preparation method and application thereof

Abstract

The present invention discloses an antibacterial hydrogel with dual temperature response function and its preparation and application. The antibacterial hydrogel is prepared by mixing a homogeneous solution, a water-soluble free radical initiator and a promoter, reacting in an inert atmosphere, and then mixing with a water-insoluble drug suspension, stirring and reacting in an inert atmosphere, injecting the obtained solution into a mold, and performing a free radical copolymerization reaction for 24 to 36 hours under oxygen isolation, and obtaining the product after washing and ultraviolet irradiation. The present invention prepares a dual temperature-sensitive hydrogel with both UCST and LCST, and at the same time gives the hydrogel drug controlled release and intelligent adhesion properties, while also ensuring that the hydrogel has excellent antibacterial properties and is non-cytotoxic.

Description

Technical Field

[0001] The invention relates to an antibacterial hydrogel, in particular to an antibacterial hydrogel with dual temperature response functions and preparation and application thereof, and belongs to the technical field of biomedical materials. Background Art

[0002] Medical dressings are medical materials used to protect wounds. During the wound healing process, they can protect the skin while promoting wound healing, avoiding wound infection, and providing an environment conducive to wound healing. Traditional medical dressings simply cover the wound. Although they have a certain protective effect, they are difficult to meet the treatment needs of complex and diverse wounds in terms of water-blocking and air-permeable, blocking bacteria, and promoting wound healing. In order to provide a better healing environment for the wound and reduce damage to the wound, and in order to have multiple functionalities to meet the needs of complex clinical treatment, new medical dressings have also been continuously developed in recent years, especially hydrogel dressings, which have gradually replaced traditional medical dressings and become a more ideal new type of medical dressing in clinical practice.

[0003] Chinese invention patent CN201610898993.8 discloses a method for preparing a nanosilver / zinc oxide composite hydrogel with antibacterial surface, in which nanosilver and zinc oxide are loaded on a prepared carboxymethyl cellulose hydrogel to prepare an antibacterial hydrogel dressing. The hydrogel has good antibacterial properties, but since nanosilver has strong cytotoxicity, it will damage normal cells during the sterilization process, and nanosilver is mostly loaded on the surface of the hydrogel, there is a problem of explosive release when it first contacts the wound, which is not conducive to wound healing. The Chinese invention patent CN202011176184.9 applied for by the inventor's research group loaded copper ions in the form of copper-based metal organic framework nanoparticles in a cross-linked hydrogel of a natural polymer - gN-isopropylacrylamide, and prepared a copper-based MOF hydrogel functionalized antibacterial film. Compared with silver ions, copper ions effectively reduced cytotoxicity. The results of the mouse wound healing test showed that this type of MOF material achieved a sustained-release effect of copper ions, but the pore size of the hydrogel prepared by this technology could not be changed, and the efficiency of MOF particles and copper ions diffusing from the hydrogel to the wound could not be changed. The controlled release of copper ions relying solely on copper MOF particles was not obvious, and the hydrogel matrix prepared with gelatin as the raw material had no obvious adhesion to the skin. It could not yet form a good adhesion with the skin and needed to be fixed with a secondary dressing, which increased the cost. Summary of the invention

[0004] The purpose of the present invention is to develop an antibacterial hydrogel with dual temperature response functions, drug controlled release performance and intelligent adhesion performance, and a preparation method thereof.

[0005] Another object of the present invention is to provide the use of the antibacterial hydrogel with dual temperature response function in the preparation of wound dressings.

[0006] An antibacterial hydrogel with dual temperature response function, which is prepared by mixing a homogeneous solution, a water-soluble free radical initiator and a promoter, reacting them in an inert atmosphere, and then mixing them with a water-insoluble drug suspension, stirring and reacting them in an inert atmosphere, injecting the obtained solution into a mold, and performing a free radical copolymerization reaction for 24 to 36 hours in an oxygen-free environment, and obtaining the product after washing and ultraviolet irradiation;

[0007] The homogeneous solution is prepared by dissolving sulfobetaine methacrylate and N-isopropylacrylamide in deionized water, adding a crosslinking agent containing a disulfide bond whose reactive group is a carbon-carbon double bond, and then ultrasonically treating the solution.

[0008] The water-insoluble drug suspension is prepared by dissolving an antibacterial drug loaded with copper ions and having a metal-organic framework structure in deionized water and then subjecting the drug to ultrasonic treatment.

[0009] To further achieve the purpose of the present invention, preferably, the copper ion-loaded antibacterial drug with a metal-organic framework structure is prepared by dissolving an organic ligand 1,3,5-benzenetricarboxylic acid (H3BTC) in a mixed solution of ethanol and deionized water, adding the solution dropwise to an aqueous solution of a copper-containing compound, and stirring the solution at room temperature to react to form a suspension; the suspension is centrifuged to separate particles, washed, freeze-dried, and then fully ground; the aqueous solution of the copper-containing compound is prepared by dissolving copper acetate monohydrate in a mixed solution of ethanol and deionized water, and ultrasonically oscillating the solution until it is uniformly dispersed.

[0010] Preferably, the molar ratio of the copper acetate monohydrate to 1,3,5-benzenetricarboxylic acid is 1:0.5-2.0; the volume ratio of ethanol to deionized water in the mixed solution is 1:1.0-2.0; the stirring reaction time at room temperature is 30-60 minutes, and the stirring rate is 300-500rpm; the washing is successively washed with ethanol solution and deionized water, the number of ethanol solution washings is 2-3 times, and the number of deionized water washings is 1-2 times; the ultrasonic oscillation time is 1-5 minutes; the mass concentration range of 1,3,5-benzenetricarboxylic acid in the mixed solution is 2-10%, and the mass concentration range of copper acetate monohydrate in the mixed solution is 3-15%.

[0011] Preferably, the mass concentration of the copper ion-loaded antibacterial drug having a metal-organic framework structure dissolved in deionized water is 1 to 5%.

[0012] Preferably, the cross-linking agent containing a disulfide bond whose reactive group is a carbon-carbon double bond is N,N'-bis(acryloyl)cystamine or N,N'-bis(acryloyl)cystamine; the free radical initiator is ammonium persulfate, potassium persulfate or sodium persulfate; the accelerator is tetramethylethylenediamine, hexamethylphosphoric triamide or N,N-dimethylacrylurea; and the inert atmosphere is an atmosphere formed by nitrogen, argon or helium.

[0013] Preferably, the mass ratio of the sulfonate betaine methacrylate to N-isopropyl acrylamide is 1:1-2.5; the sulfonate betaine methacrylate and N-isopropyl acrylamide constitute monomers, the monomer content accounts for 10-20% of the total mass of the solution, the cross-linking agent accounts for 0.2-1% of the total mass of the monomers; the initiator accounts for 0.5-1% of the total mass of the monomers; the molar ratio of the initiator to the accelerator is 1:1-2.

[0014] Preferably, the reaction time under the inert atmosphere is 5-10 minutes; the stirring reaction time is 1 to 5 minutes; the temperature of the free radical copolymerization reaction is 28 to 32° C.; and the mass percentage concentration of the water-insoluble drug in the solution during the stirring reaction under the inert atmosphere is 0.05 to 2%.

[0015] Preferably, the material of the mold is polytetrafluoroethylene, and the ultraviolet radiation intensity is 100-500 μW / cm 2 The irradiation time is 5 to 15 minutes; the washing is performed with deionized water at a low temperature, the washing temperature is 0 to 10° C., and the number of washing times is 1 to 2 times.

[0016] The preparation method of the antibacterial hydrogel with dual temperature response function comprises the following steps: dissolving sulfobetaine methacrylate and N-isopropylacrylamide in deionized water, adding a crosslinker containing a disulfide bond whose reactive group is a carbon-carbon double bond, preparing a homogeneous solution by ultrasonic treatment, adding a water-soluble free radical initiator and a promoter, adding a suspension of a water-insoluble drug after reacting in an inert atmosphere, stirring and reacting in an inert atmosphere, injecting the obtained solution into a mold, isolating oxygen for free radical copolymerization for 24 to 36 hours, washing the obtained product, and irradiating it with ultraviolet light to obtain an antibacterial hydrogel with dual temperature response function.

[0017] Application of the antibacterial hydrogel with dual temperature response function in the preparation of wound dressings.

[0018] The present invention combines the temperature-sensitive behavior of the hydrogel pore size change caused by the weakening of the zwitterionic hydrogel ion effect with the increase of temperature and the different abilities of the amide groups on poly (N-isopropylacrylamide) to form hydrogen bonds at different temperatures, and realizes the dual temperature response of the hydrogel dressing through physical and chemical effects, and realizes the controlled release of drugs and the controlled adhesion of the hydrogel dressing to the skin, while also ensuring excellent antibacterial properties and no cytotoxicity.

[0019] The present invention has the following advantages and effects compared with the prior art:

[0020] 1) In the present invention, two thermosensitive monomers are used to prepare hydrogels through a crosslinker containing a disulfide bond, which provides biodegradability for the hydrogels; the two thermosensitive monomers are copolymerized with each other instead of being grafted, which greatly retains the characteristics of the two monomers, ensures the biocompatibility and UCST response of SBMA and the LCST response of NIPAM and the adhesion of the polymer, so that the prepared hydrogel has dual temperature responses, both of which are close to the skin temperature, and can very conveniently trigger the two functions.

[0021] 2) Compared with the traditional single stimulus responsive hydrogel, the present invention has dual temperature sensitivity of LCST and UCST. In the early stage of wound healing, the UCST response is triggered by cold compress, the pore size of the hydrogel is reduced, and the fluidity of water molecules and antibacterial particles is weakened, so as to achieve sustained release of the drug and avoid rapid release of the drug. When the hydrogel dressing is replaced, the hydrogel dressing is slightly heated to trigger the LCST response, and the isopropyl hydrophobic effect on the NIPAM in the hydrogel is enhanced, so that the hydrogen bonding effect inside the hydrogel is enhanced and the hydrogen bonding effect with the skin is weakened, thereby weakening its adhesion to the skin and avoiding secondary damage to the wound. Through these two temperature responses, the two functions of controlled release and intelligent adhesion of the drug can be achieved simultaneously, which can better meet the needs of complex and diverse clinical wounds.

[0022] 3) Compared with the traditional non-temperature-sensitive drug-loaded antibacterial hydrogel, the antibacterial hydrogel with dual temperature response function of the present invention can respond to environmental stimuli and control the release amount of drugs, and has a better sustained release effect. At low temperatures, the pore size of the hydrogel is reduced, and the release rate of the drug is significantly reduced. In the early stage of wound formation, cold compress is more conducive to wound healing and tissue growth. The sustained release effect at low temperatures can avoid the explosive release of drugs in the early stage of wound healing, which is more conducive to wound healing. Compared with traditional hydrogel dressings, the present invention has better adhesion to the skin, and the size of the adhesion can be changed by changing the temperature, which is easy to peel and replace the dressing, reducing secondary damage to the wound.

[0023] 4) In the preparation process of the loaded drug (copper MOF particles), the present invention adopts the method of pre-ultrasonic dispersion and dropwise addition for synthesis, which reduces the agglomeration of copper acetate in the solution, makes the reaction more complete, the product more uniform, and improves the yield. The antibacterial drug loaded with copper ions having a metal-organic framework structure of the present invention is combined with the UCST response, and the two work together to enhance the sustained release effect of copper ions.

[0024] 5) The antibacterial hydrogel dressing of the present invention has excellent antibacterial properties, can effectively kill Staphylococcus aureus and Escherichia coli, and has good biocompatibility and no cytotoxicity.

[0025] 6) The antibacterial hydrogel dressing of the present invention has good swelling performance and can absorb a large amount of exudate to prevent wound surface fluid accumulation and bacterial growth. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 The graphs show the change in transmittance at different temperatures with temperature for Example 1 (PSN-MOF-1), Example 2 (PSN-MOF-2), Example 3 (PSN-MOF-3), Comparative Example 2 (Gel) and Comparative Example 3 (Gel-3).

[0027] Figure 2 These are electron microscope images of Example 2 (PSN-MOF-2) at different temperatures.

[0028] Figure 3 The release of copper ions from Example 2 (PSN-MOF-2) at different temperatures.

[0029] Figure 4 The copper ion release of Example 2 (PSN-MOF-2), Comparative Example 2 (Gel) and Comparative Example 3 (Gel-3) at 15°C.

[0030] Figure 5 : is the adhesion force-displacement curve of Example 2 (PSN-MOF-2) on the skin at 35°C and 45°C.

[0031] Figure 6 The adhesion force-displacement curves of Example 2 (PSN-MOF-2) and Comparative Example 3 (Gel-3) when adhered to the skin at 35°C.

[0032] Figure 7 The antibacterial effects of the hydrogels of Example 1 (PSN-MOF-1), Example 2 (PSN-MOF-2), Example 3 (PSN-MOF-3) and Comparative Example 1 (Gel-1).

[0033] Figure 8The OD values ​​of the antibacterial hydrogel extract with dual temperature response function in Example 1 (PSN-MOF-1), Example 2 (PSN-MOF-2), Example 3 (PSN-MOF-3) and Comparative Example 1 (Gel-1) after co-culture with L929 cells for 1, 4 and 7 days were determined by the CCK-8 method.

[0034] Fig. 9 The survival status of L929 cells cultured in the cytotoxicity experiments with the hydrogels in Example 1 (PSN-MOF-1), Example 2 (PSN-MOF-2), Example 3 (PSN-MOF-3) and Comparative Example 1 (Gel-1) on the 1st and 4th days. DETAILED DESCRIPTION

[0035] The following description is only the preferred embodiment of the present invention, and is not intended to limit the present invention. For those skilled in the art, the present invention may have various changes and variations. Any modification, equivalent replacement and improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention. The implementation conditions adopted in the examples can be further adjusted according to actual conditions, and the undescribed implementation conditions are usually conventional experimental conditions.

[0036] Example 1

[0037] 1) 0.42 g of 1,3,5-benzenetricarboxylic acid was dissolved in 10 ml of a mixed solution of water and ethanol in a volume ratio of 1:1 to obtain solution A, 0.60 g of cupric acetate monohydrate was dissolved in 10 ml of a mixed solution of water and ethanol in a volume ratio of 1:1 to obtain solution B, solution B was ultrasonically treated for 10 min and then stirred, solution A was added dropwise to solution B at a rate of 5 ml / min, and mixed with solution B in a volume ratio of 1:1 to obtain solution C.

[0038] 2) Solution C was stirred at room temperature at 300 rpm for 30 min to form a gel-like dark turquoise suspension, and the suspension was placed in a centrifuge and centrifuged at 10,000 r / min to obtain a precipitate, which was then washed twice with an ethanol solution (60% by volume) and once with deionized water. The washed precipitate was frozen for 12 h and then vacuum dried for 2 days to obtain drug particles (MOF).

[0039] 3) 12 mg of the prepared drug was added to 2 ml of deionized water and ultrasonically treated for 5 min to obtain a drug suspension.

[0040] 4) Take 1.11 g of sulfobetaine methacrylate (SBMA) and 0.72 g of N-isopropylacrylamide (NIPAM) and dissolve them in 10 ml of deionized water, then add 7.2 mg of crosslinker N,N'-bis(acryloyl)cystamine (BAC) to the solution, sonicate the solution for 5 min until the monomer and the crosslinker are completely dissolved, pass nitrogen into the solution to isolate the air, then add 12 mg of initiator potassium persulfate and 15 μl of accelerator tetramethylethylenediamine to the system for reaction, and react for 10 min under nitrogen.

[0041] 5) 2 ml of the prepared drug suspension was added dropwise to the reaction system of step 4), and the reaction was continued for 5 min at a stirring rate of 100 rpm until the drug particles were evenly distributed in the system, to obtain solution D.

[0042] 6) Solution D was injected into a 20 mm × 20 mm, 2 mm thick polytetrafluoroethylene mold, isolated from oxygen, reacted at 30 °C for 24 h, then washed twice with 10 °C deionized water, and then heated with 100 μW / cm 2 After ultraviolet irradiation treatment for 15 minutes, the antibacterial hydrogel PSN-MOF-1 with dual temperature response function was obtained.

[0043] Example 2

[0044] 1) 0.42 g of 1,3,5-benzenetricarboxylic acid was dissolved in 10 ml of a mixed solution of water and ethanol in a volume ratio of 1:1 to obtain solution A, 0.60 g of cupric acetate monohydrate was dissolved in 10 ml of a mixed solution of water and ethanol in a volume ratio of 1:1 to obtain solution B, solution B was ultrasonically treated for 10 min and then stirred, solution A was added dropwise to solution B at a rate of 5 ml / min, and mixed with solution B in a volume ratio of 1:1 to obtain solution C.

[0045] 2) Solution C was stirred at room temperature at 300 rpm for 30 min to form a gel-like dark turquoise suspension, and the suspension was placed in a centrifuge and centrifuged at 10,000 r / min to obtain a precipitate, which was then washed twice with an ethanol solution (60% by volume) and once with deionized water. The washed precipitate was frozen for 12 h and then vacuum dried for 2 days to obtain drug particles (MOF).

[0046] 3) 24 mg of the prepared drug was added to 2 ml of deionized water and ultrasonically treated for 5 min to obtain a drug suspension.

[0047] 4) Take 1.11 g of sulfobetaine methacrylate (SBMA) and 0.72 g of N-isopropylacrylamide (NIPAM) and dissolve them in 10 ml of deionized water, then add 7.2 mg of crosslinker N,N'-bis(acryloyl)cystamine (BAC) to the solution, sonicate the solution for 5 min until the monomer and the crosslinker are completely dissolved, pass nitrogen into the solution to isolate the air, then add 12 mg of initiator potassium persulfate and 15 μl of accelerator tetramethylethylenediamine to the system for reaction, and react for 10 min under nitrogen.

[0048] 5) 2 ml of the prepared drug suspension was added dropwise to the reaction system of step 4), and the reaction was continued for 5 min at a stirring rate of 100 rpm until the drug particles were evenly distributed in the system, to obtain solution D.

[0049] 6) Solution D was injected into a 20 mm × 20 mm, 2 mm thick polytetrafluoroethylene mold, isolated from oxygen, reacted at 30 °C for 24 h, then washed twice with 10 °C deionized water, and then heated with 100 μW / cm 2 After ultraviolet irradiation treatment for 15 minutes, the antibacterial hydrogel PSN-MOF-2 with dual temperature response function was obtained.

[0050] Example 3

[0051] 1) 0.42 g of 1,3,5-benzenetricarboxylic acid was dissolved in 10 ml of a mixed solution of water and ethanol in a volume ratio of 1:1 to obtain solution A, 0.60 g of cupric acetate monohydrate was dissolved in 10 ml of a mixed solution of water and ethanol in a volume ratio of 1:1 to obtain solution B, solution B was ultrasonically treated for 10 min and then stirred, solution A was added dropwise to solution B at a rate of 5 ml / min, and mixed with solution B in a volume ratio of 1:1 to obtain solution C.

[0052] 2) Solution C was stirred at room temperature at 300 rpm for 30 min to form a gel-like dark turquoise suspension, and the suspension was placed in a centrifuge and centrifuged at 10,000 r / min to obtain a precipitate, which was then washed twice with an ethanol solution (60% by volume) and once with deionized water. The washed precipitate was frozen for 12 h and then vacuum dried for 2 days to obtain drug particles (MOF).

[0053] 3) 48 mg of the prepared drug was added to 2 ml of deionized water and ultrasonically treated for 5 min to obtain a drug suspension.

[0054] 4) Take 1.11 g of sulfobetaine methacrylate (SBMA) and 0.72 g of N-isopropylacrylamide (NIPAM) and dissolve them in 10 ml of deionized water, then add 7.2 mg of crosslinker N,N'-bis(acryloyl)cystamine (BAC) to the solution, sonicate the solution for 5 min until the monomer and the crosslinker are completely dissolved, pass nitrogen into the solution to isolate the air, then add 12 mg of initiator potassium persulfate and 15 μl of accelerator tetramethylethylenediamine to the system for reaction, and react for 10 min under nitrogen.

[0055] 5) 2 ml of the prepared drug suspension was added dropwise to the reaction system of step 4), and the reaction was continued for 5 min at a stirring rate of 100 rpm until the drug particles were evenly distributed in the system, to obtain solution D.

[0056] 6) Solution D was injected into a 20 mm × 20 mm, 2 mm thick polytetrafluoroethylene mold, isolated from oxygen, reacted at 30 °C for 24 h, then washed twice with 10 °C deionized water, and then heated with 100 μW / cm 2 After ultraviolet irradiation treatment for 15 minutes, the antibacterial hydrogel PSN-MOF-3 with dual temperature response function was obtained.

[0057] Example 4

[0058] 1) 0.42 g of 1,3,5-benzenetricarboxylic acid was dissolved in 10 ml of a mixed solution of water and ethanol in a volume ratio of 1:1 to obtain solution A, 0.60 g of cupric acetate monohydrate was dissolved in 10 ml of a mixed solution of water and ethanol in a volume ratio of 1:1 to obtain solution B, solution B was ultrasonically treated for 10 min and then stirred, solution A was added dropwise to solution B at a rate of 5 ml / min, and mixed with solution B in a volume ratio of 1:2 to obtain solution C.

[0059] 2) Solution C was stirred at room temperature at 300 rpm for 30 min to form a gel-like dark turquoise suspension, and the suspension was placed in a centrifuge and centrifuged at 10,000 r / min to obtain a precipitate, which was then washed twice with an ethanol solution (60% by volume) and once with deionized water. The washed precipitate was frozen for 12 h and then vacuum dried for 2 days to obtain drug particles (MOF).

[0060] 3) 48 mg of the prepared drug was added to 2 ml of deionized water and ultrasonically treated for 5 min to obtain a drug suspension.

[0061] 4) 1.11 g of sulfobetaine methacrylate (SBMA) and 0.72 g of N-isopropylacrylamide (NIPAM) were dissolved in 10 ml of deionized water, and 14.4 mg of crosslinker N,N'-bis(acryloyl)cystamine (BAC) was added to the solution. The solution was ultrasonicated for 5 min until the monomer and the crosslinker were completely dissolved, nitrogen was introduced into the solution to isolate the air, and then 12 mg of initiator potassium persulfate and 15 μl of promoter tetramethylethylenediamine were added to the system for reaction, and the reaction was carried out for 10 min under nitrogen.

[0062] 5) 2 ml of the prepared drug suspension was added dropwise to the reaction system of step 4), and the reaction was continued for 5 min at a stirring rate of 100 rpm until the drug particles were evenly distributed in the system, to obtain solution D.

[0063] 6) Solution D was injected into a 20 mm × 20 mm, 2 mm thick polytetrafluoroethylene mold, isolated from oxygen, reacted at 30 °C for 24 h, then washed twice with 10 °C deionized water, and then heated with 100 μW / cm 2 After ultraviolet irradiation treatment for 15 minutes, the antibacterial hydrogel PSN-MOF-4 with dual temperature response function was obtained.

[0064] Example 5

[0065] 1) 0.42 g of 1,3,5-benzenetricarboxylic acid was dissolved in 10 ml of a mixed solution of water and ethanol in a volume ratio of 1:1 to obtain solution A, 0.60 g of cupric acetate monohydrate was dissolved in 10 ml of a mixed solution of water and ethanol in a volume ratio of 1:1 to obtain solution B, solution B was ultrasonically treated for 10 min and then stirred, solution A was added dropwise to solution B at a rate of 5 ml / min, and mixed with solution B in a volume ratio of 1:1 to obtain solution C.

[0066] 2) Solution C was stirred at room temperature at 300 rpm for 30 min to form a gel-like dark turquoise suspension, and the suspension was placed in a centrifuge and centrifuged at 10,000 r / min to obtain a precipitate, which was then washed twice with an ethanol solution (60% by volume) and once with deionized water. The washed precipitate was frozen for 12 h and then vacuum dried for 2 days to obtain drug particles (MOF).

[0067] 3) 48 mg of the prepared drug was added to 2 ml of deionized water and ultrasonically treated for 5 min to obtain a drug suspension.

[0068] 4) Take 1.11 g of sulfobetaine methacrylate (SBMA) and 0.72 g of N-isopropylacrylamide (NIPAM) and dissolve them in 10 ml of deionized water, then add 7.2 mg of crosslinker N,N'-bis(acryloyl)cystamine to the solution, sonicate the solution for 5 min until the monomer and crosslinker are completely dissolved, pass nitrogen into the solution to isolate the air, then add 12 mg of initiator ammonium persulfate and 15 μl of accelerator hexamethylphosphoric acid triamide to the system for reaction, and react for 10 min under nitrogen.

[0069] 5) 2 ml of the prepared drug suspension was added dropwise to the reaction system of step 4), and the reaction was continued for 5 min at a stirring rate of 100 rpm until the drug particles were evenly distributed in the system, to obtain solution D.

[0070] 6) Solution D was injected into a 20 mm × 20 mm, 2 mm thick polytetrafluoroethylene mold, isolated from oxygen, reacted at 30 °C for 24 h, then washed twice with 10 °C deionized water, and then heated with 100 μW / cm 2 After ultraviolet irradiation treatment for 15 minutes, the antibacterial hydrogel PSN-MOF-5 with dual temperature response function was obtained.

[0071] Example 6

[0072] 1) 0.42 g of 1,3,5-benzenetricarboxylic acid was dissolved in 10 ml of a mixed solution of water and ethanol in a volume ratio of 1:1 to obtain solution A, 0.60 g of cupric acetate monohydrate was dissolved in 10 ml of a mixed solution of water and ethanol in a volume ratio of 1:1 to obtain solution B, solution B was ultrasonically treated for 10 min and then stirred, solution A was added dropwise to solution B at a rate of 5 ml / min, and mixed with solution B in a volume ratio of 1:0.5 to obtain solution C.

[0073] 2) Solution C was stirred at room temperature at 300 rpm for 30 min to form a gel-like dark turquoise suspension, and the suspension was placed in a centrifuge and centrifuged at 10,000 r / min to obtain a precipitate, which was then washed twice with an ethanol solution (60% by volume) and once with deionized water. The washed precipitate was frozen for 12 h and then vacuum dried for 2 days to obtain drug particles (MOF).

[0074] 3) 48 mg of the prepared drug was added to 2 ml of deionized water and ultrasonically treated for 5 min to obtain a drug suspension.

[0075] 4) 1.11 g of sulfobetaine methacrylate (SBMA) and 0.72 g of N-isopropylacrylamide (NIPAM) were dissolved in 10 ml of deionized water, and 7.2 mg of crosslinker N,N'-bis(acryloyl)cystamine was added to the solution. The solution was sonicated for 5 min until the monomer and the crosslinker were completely dissolved. Nitrogen was introduced into the solution to isolate the air. Then, 12 mg of initiator ammonium persulfate and 15 μl of accelerator hexamethylphosphoric acid triamide were added to the system for reaction, and the reaction was carried out for 10 min under nitrogen.

[0076] 5) 2 ml of the prepared drug suspension was added dropwise to the reaction system of step 4), and the reaction was continued for 5 min at a stirring rate of 100 rpm until the drug particles were evenly distributed in the system, to obtain solution D.

[0077] 6) Solution D was injected into a 20 mm × 20 mm, 2 mm thick polytetrafluoroethylene mold, isolated from oxygen, reacted at 30 °C for 24 h, then washed twice with 10 °C deionized water, and then heated with 100 μW / cm 2 After ultraviolet irradiation treatment for 15 minutes, the antibacterial hydrogel PSN-MOF-6 with dual temperature response function was obtained.

[0078] Example 7

[0079] 1) 0.42 g of 1,3,5-benzenetricarboxylic acid was dissolved in 10 ml of a mixed solution of water and ethanol in a volume ratio of 1:1 to obtain solution A, 0.60 g of cupric acetate monohydrate was dissolved in 10 ml of a mixed solution of water and ethanol in a volume ratio of 1:1 to obtain solution B, solution B was ultrasonically treated for 10 min and then stirred, solution A was added dropwise to solution B at a rate of 5 ml / min, and mixed with solution B in a volume ratio of 1:1 to obtain solution C.

[0080] 2) Solution C was stirred at room temperature at 300 rpm for 30 min to form a gel-like dark turquoise suspension, and the suspension was placed in a centrifuge and centrifuged at 10,000 r / min to obtain a precipitate, which was then washed twice with an ethanol solution (60% by volume) and once with deionized water. The washed precipitate was frozen for 12 h and then vacuum dried for 2 days to obtain drug particles (MOF).

[0081] 3) 24 mg of the prepared drug was added to 2 ml of deionized water and ultrasonically treated for 5 min to obtain a drug suspension.

[0082] 4) Take 1.11 g of sulfobetaine methacrylate (SBMA) and 0.72 g of N-isopropylacrylamide (NIPAM) and dissolve them in 10 ml of deionized water, then add 7.2 mg of crosslinker N,N'-bis(acryloyl)cystamine (BAC) to the solution, sonicate the solution for 5 min until the monomer and crosslinker are completely dissolved, pass nitrogen into the solution to isolate the air, then add 24 mg of initiator potassium persulfate and 30 μl of accelerator tetramethylethylenediamine to the system for reaction, and react for 10 min under nitrogen.

[0083] 5) 2 ml of the prepared drug suspension was added dropwise to the reaction system of step 4), and the reaction was continued for 5 min at a stirring rate of 100 rpm until the drug particles were evenly distributed in the system, to obtain solution D.

[0084] 6) Solution D was injected into a 20 mm × 20 mm, 2 mm thick polytetrafluoroethylene mold, isolated from oxygen, reacted at 30 °C for 24 h, then washed twice with 10 °C deionized water, and then heated with 100 μW / cm 2 After ultraviolet irradiation treatment for 15 minutes, the antibacterial hydrogel PSN-MOF-7 with dual temperature response function was obtained.

[0085] Comparative Example 1

[0086] 1) 1.11 g of sulfobetaine methacrylate (SBMA) and 0.72 g of N-isopropylacrylamide (NIPAM) were dissolved in 10 ml of deionized water, and 7.2 mg of crosslinker N,N'-bis(acryloyl)cystamine (BAC) was added to the solution. The solution was ultrasonicated for 5 min until the monomer and the crosslinker were completely dissolved. Nitrogen was introduced into the solution to isolate the air. Then, 12 mg of initiator KPS and 15 μl of promoter TEMED were added to the system for reaction. The reaction was carried out for 15 min under nitrogen flow to obtain solution A.

[0087] 2) Solution A was injected into a 20 mm × 20 mm, 2 mm thick polytetrafluoroethylene mold, isolated from oxygen, reacted at 30 °C for 24 h, then washed twice with 10 °C deionized water, and then heated with 100 μW / cm 2 The resulting mixture was irradiated with ultraviolet light for 15 min to obtain hydrogel Gel-1.

[0088] Comparative Example 2

[0089] 1) Dissolve 27.3 mg of copper sulfate pentahydrate in 2 ml of deionized water to obtain solution A.

[0090] 2) Take 1.11 g of sulfobetaine methacrylate (SBMA) and 0.72 g of N-isopropylacrylamide (NIPAM) and dissolve them in 10 ml of deionized water, then add 7.2 mg of crosslinker N,N'-bis(acryloyl)cystamine (BAC) to the solution, sonicate the solution for 5 min until the monomer and crosslinker are completely dissolved, pass nitrogen into the solution to isolate the air, then add 12 mg of initiator KPS and 15 μl of promoter TEMED to the system for reaction, and react for 10 min under nitrogen.

[0091] 3) Solution A was added dropwise to the reaction system of step 2), and the reaction was continued for 5 min at a stirring rate of 100 rpm to obtain solution B.

[0092] 4) Solution B was injected into a 20 mm × 20 mm, 2 mm thick polytetrafluoroethylene mold, isolated from oxygen, reacted at 30 °C for 24 h, then washed twice with 10 °C deionized water, and then heated with 100 μW / cm 2 The resulting mixture was irradiated with ultraviolet light for 15 min to obtain hydrogel Gel-2.

[0093] Comparative Example 3

[0094] 1) 0.42 g (2 mmol) of 1,3,5-benzenetricarboxylic acid and 0.60 g (3 mmol) of copper acetate monohydrate were dissolved in 10 mL of ethanol and deionized water, respectively, and then the two solutions were mixed and stirred at 300 rpm for about 25 min at room temperature to form a gel-like dark turquoise suspension; the particles were separated by centrifugation of the suspension, and washed three times with a 50% ethanol solution, and the obtained solid was freeze-dried, fully ground into powder, and sealed for storage.

[0095] 2) 3 g of pig skin gelatin was dissolved in 30 ml of 0.25 M carbonate buffer solution (pH = 9) at 50°C; 0.36 ml of methacrylic anhydride was added dropwise to the gelatin carbonate buffer solution at a rate of 0.1 ml / min under stirring; the system was reacted in a 60°C constant temperature water bath for 3 h, 5 volumes of phosphate buffer solution (pH = 7.2-7.4) were added to terminate the reaction, and the product was transferred to a dialysis bag with a molecular weight cutoff of 8000-14000, and dialyzed with deionized water for 5 days to remove impurities and unreacted monomers; the methacrylated gelatin (Gel-MA) solution was then freeze-dried.

[0096] 3) 100 mg of Gel-MA and 120 mg of N-isopropylacrylamide synthesized in step (1) were dissolved in 5 mL of deionized water, and 4.4 mg of Irgacure 2959 photoinitiator was added to prepare a homogeneous solution; then 3 mg of the copper-based MOF nanoparticles prepared in step (2) were added, stirred and mixed to form a suspension, and the suspension was poured into a mold, nitrogen was passed for 5 min to drive out oxygen, and UV light was irradiated at an irradiation intensity of 10 mW / cm 2 , the irradiation time was 3 min; finally, the crude antibacterial film product was washed 5 times with deionized water and freeze-dried to obtain a copper-based MOF hydrogel Gel-3.

[0097] The hydrogel dressings prepared in the above examples and comparative examples were subjected to the following tests:

[0098] 1. Temperature response performance test

[0099] The hydrogels prepared in Example 1 (PSN-MOF-1), Example 2 (PSN-MOF-2), Example 3 (PSN-MOF-3), Comparative Example 2 (Gel-2) and Comparative Example 3 (Gel-3) were placed in glass cuvettes, and the transmittance of the hydrogels at a wavelength of 500 nm at different temperatures was measured using an ultraviolet spectrophotometer, and then a curve of the transmittance of the hydrogels and the temperature was plotted. Figure 1 The curves of the transmittance of Example 1 (PSN-MOF-1), Example 2 (PSN-MOF-2), Example 3 (PSN-MOF-3), Comparative Example 2 (Gel) and Comparative Example 3 (Gel-3) at different temperatures are shown. Figure 1 It can be seen that Example 1 (PSN-MOF-1), Example 2 (PSN-MOF-2), and Example 3 (PSN-MOF-3) have obvious UCST (near 32°C) and LCST (near 38°C), while Comparative Example 2 (Gel-2) has overlapping UCST and LCST, and has no dual temperature sensitivity. Comparative Example 3 (Gel-3) only has LCST (near 32°C) and is lower than the human skin temperature.

[0100] The test results show that the prepared antibacterial hydrogel has a dual temperature response function. The antibacterial drugs loaded with copper ions with a metal-organic framework structure limit the release of copper ions and will not affect the polymerization of the hydrogel and the expression of dual temperature response. Compared with the hydrogel formed by NIPAM alone, the hydrogel formed by the copolymerization of SBMA and NIPAM has an additional UCST transition that can be used to achieve drug release function, and the LCST of the hydrogel containing NIPAM can be increased to above the human skin temperature to prevent the hydrogel from falling off the skin.

[0101] 2. Scanning electron microscope test

[0102] Three groups of samples of Preparation Example 2 (PSN-MOF-2) were placed in a water bath at 15°C, 35°C and 45°C for 5 min, respectively, and then quickly taken out, quenched with liquid nitrogen, and then freeze-dried in a freeze dryer for 24 h. The obtained dry gel samples were cut into slices of appropriate size and glued to a stage with conductive glue. Then, the samples were evacuated and gold-sprayed. The microstructure of the sample surface was observed with a scanning electron microscope, as shown in FIG. Figure 2 As shown, the microstructure of Example 2 (PSN-MOF-2) at different temperatures was obtained. Figure 2 It can be seen that the pore size of Example 2 (PSN-MOF-2) is the largest at human skin temperature (around 35°C), with a diameter of about 10 μm. The pore size decreases to about 5 μm at 45°C. When the temperature drops to 15°C, the hydrogel pore size decreases to about 2 μm. Compared with 35°C, the pore size is reduced by 80%.

[0103] The test results show that Example 2 (PSN-MOF-2) has a reduced pore size at low and high temperatures, and has dual temperature-sensitive responses of LCST and UCST. In addition, the reduced pore size of the hydrogel will lead to the obstruction of the diffusion of water molecules and antibacterial particles, so the sustained release of drugs can be achieved at low temperatures.

[0104] 3. Copper ion release test

[0105] Weigh two groups of prepared Example 2 (PSN-MOF-2), Comparative Example 2 (Gel-2) and Comparative Example 3 (Gel-3), each 2 g, and place them in 100 ml of deionized water in a 35°C water bath and 100 ml of deionized water in a 15°C water bath, respectively. Determine the concentration of copper ions in the solution at intervals of 1, 2, 4, 8, 12, 24, 48 and 72 h, and draw the cumulative release curve of copper ions at different temperatures. Figure 3 and Figure 4 As shown, the release curve of copper ions of Example 2 (PSN-MOF-2) at different temperatures was obtained, and Figure 3 The copper ion release curves of Example 2 (PSN-MOF-2), Comparative Example 2 (Gel-2) and Comparative Example 3 (Gel-3) at 15°C. Figure 3 It can be seen that the copper ion release rate of Example 2 (PSN-MOF-2) at low temperature is significantly lower than that at skin temperature (35°C); Figure 4 It can be seen that the copper ions of Comparative Example 2 (Gel-2) are completely released within 48 hours, the copper ion release amount of Comparative Example 3 (Gel-3) is 89% at 72 hours, and the copper ion release amount of Example 2 (PSN-MOF-2) is 76% at 72 hours.

[0106] The test results show that the copper ion-loaded antibacterial drug with a metal-organic framework structure has a sustained release effect on the release of copper ions. The UCST thermosensitivity of Example 2 (PSN-MOF-2) makes the pore size of the hydrogel smaller at low temperatures, inhibits the diffusion of water molecules and drug particles, and further improves the sustained release effect of copper ions.

[0107] 4. Adhesion performance test

[0108] Take two pieces of Example 2 (PSN-MOF-2) and Comparative Example 3 (Gel-3) with a size of 20 mm × 20 mm and a thickness of 2 mm, respectively, and attach them to fresh pig skin for 10 minutes, then place them at 35°C and 45°C for 30 minutes, respectively, and then use a universal tensile machine to measure the adhesion between the hydrogel and the pig skin to obtain the adhesion-displacement curve between the hydrogel and the skin tissue. Figure 5 and Figure 6 As shown, the adhesion force-displacement curves of Example 2 (PSN-MOF-2) adhering to the skin at 35°C and 45°C, and the adhesion force-displacement curves of Example 2 (PSN-MOF-2) and Comparative Example 3 (Gel-3) adhering to the skin at 35°C were obtained. Figure 5 It can be seen that Example 2 (PSN-MOF-2) can adhere well to the skin at 35°C, and when it rises to 45°C, the adhesion effect is significantly weakened, making it easier to de-adhere; Figure 6 It can be seen that the adhesion effect of Comparative Example 3 (Gel-3) to skin tissue at skin temperature (around 35° C.) is much lower than that of Example 2 (PSN-MOF-2).

[0109] The test results show that the copolymerization of SBMA and NIPAM raises the LCST of the hydrogel to above the temperature of human skin, giving the hydrogel the effect of smart adhesion. Example 2 (PSN-MOF-2) does not rely on secondary dressings. After the temperature rises to 40°C, the adhesion drops significantly. When it is removed and replaced, it will not tear the skin or wound, avoiding secondary damage to the wound; Comparative Example 3 (Gel-3) needs to be used in conjunction with an antibacterial film material to attach to human skin, which is more expensive and troublesome to replace.

[0110] 5. Antibacterial performance test

[0111] Example 1 (PSN-MOF-1), Example 2 (PSN-MOF-2), Example 3 (PSN-MOF-3) and Comparative Example 1 (Gel-1) were cut into 20 mm diameter and 2 mm thick pieces and placed in a culture dish. 1 ml of saline and 1 ml of bacteria (1×10 6CFU / ml), then transfer the culture dish to a 37℃ constant temperature incubator and culture for 24h, then take the bacterial suspension in the culture dish and spread it on the agar medium, then transfer the agar medium to a 37℃ constant temperature incubator and culture for 24h before taking pictures. Figure 7 As shown, the antibacterial effect diagrams of the hydrogels of Example 1 (PSN-MOF-1), Example 2 (PSN-MOF-2), Example 3 (PSN-MOF-3) and Comparative Example 1 (Gel-1) were obtained. Figure 7 It can be seen that Example 1 (PSN-MOF-1), Example 2 (PSN-MOF-2), and Example 3 (PSN-MOF-3) all have different degrees of inhibitory effects on Escherichia coli and Staphylococcus aureus. The antibacterial rate of Example 1 (PSN-MOF-1) reaches 70%, the antibacterial rate of Example 2 (PSN-MOF-2) reaches 88%, and the antibacterial rate of Example 3 (PSN-MOF-3) reaches 96%. Comparative Example 1 (Gel-1) has no obvious inhibitory effect on Escherichia coli and Staphylococcus aureus, and the antibacterial rate is less than 20%.

[0112] The test results show that the antibacterial hydrogel with dual temperature response function loaded with copper ion antibacterial agent has good antibacterial properties.

[0113] 6. Cytotoxicity Test

[0114] The OD values ​​of the hydrogel extracts of Example 1 (PSN-MOF-1), Example 2 (PSN-MOF-2), Example 3 (PSN-MOF-3) and Comparative Example 1 (Gel-1) co-cultured with L929 cells for 1, 4 and 7 days were measured by CCK-8 method, and the cell morphology and live / dead cell staining of each group of cells under the microscope were observed at this time. Figure 8 and Fig. 9 As shown, the OD values ​​of the extracts of Example 1 (PSN-MOF-1), Example 2 (PSN-MOF-2), Example 3 (PSN-MOF-3) and Comparative Example 1 (Gel-1) hydrogels co-cultured with L929 cells for 1, 4 and 7 days, and the survival of L929 cells cultured with Example 1 (PSN-MOF-1), Example 2 (PSN-MOF-2), Example 3 (PSN-MOF-3) and Comparative Example 1 (Gel-1) hydrogels on the 1st and 4th days in the cytotoxicity experiment were obtained. Figure 8 and Fig. 9 It can be seen that the hydrogels of Example 1 (PSN-MOF-1), Example 2 (PSN-MOF-2), and Example 3 (PSN-MOF-3) promote the proliferation behavior of L929 cells; while Comparative Example 1 (Gel-1) has no promoting effect on the proliferation behavior of L929 cells.

[0115] The test results show that the antibacterial hydrogel with dual temperature response function loaded with copper ion antibacterial agent has good biocompatibility, no cytotoxicity, and can promote cell growth.

[0116] The present invention loads a water-insoluble antibacterial drug into a poly (sulfobetaine methacrylate-ss-N-isopropylacrylamide) dual temperature response hydrogel formed by free radical polymerization of two temperature-sensitive monomers, and prepares an antibacterial hydrogel with dual temperature response and two properties of drug controlled release and intelligent adhesion. The cross-linking agent BAC containing a disulfide bond is used to make the dressing have good biodegradability, SBMA provides the hydrogel with good biocompatibility, good self-healing performance and UCST response, and NIPAM compensates for the defect of poor skin adhesion effect of zwitterionic hydrogel while providing LCST response. Moreover, the two monomers are co-monomers with each other, so that the prepared polymer hydrogel is more suitable for temperature response on human skin than the hydrogel temperature-sensitive transition point prepared by the two monomers separately. Moreover, compared with responses such as light, magnetism, and pH, the temperature stimulus response has the least harm to the human body and is the most convenient to operate.

[0117] In the early stage of wound healing, the present invention triggers the UCST response by cold compress, reduces the pore size of the hydrogel, reduces the release of MOF particles, and synergizes with the sustained release effect of the MOF particles themselves to slow down the drug release and prolong the release cycle. When the dressing needs to be replaced or removed, it is slightly heated to trigger the LCST response so that the dressing no longer adheres to the skin, ensuring that the hydrogel can adhere closely to the skin in the working state while avoiding secondary damage to the wound when changing the dressing.

[0118] The antibacterial hydrogel with dual temperature response function of the present invention has an LCST of 32 to 40 degrees Celsius and a UCST of 26 to 32 degrees Celsius when the thickness is 1 to 2 mm. Both temperature-sensitive transition points are close to the skin temperature, and can better respond to external stimuli; the release rate of the drug is significantly reduced at low temperatures, and the explosive release of the drug can be effectively avoided during cold compresses in the early stage of wound formation; it can adhere well to the skin at room temperature, and the bonding strength is significantly reduced after heating, so that the dressing can be replaced without damaging the skin; it has an excellent swelling effect, can absorb a large amount of exudate generated by the wound surface, and has good antibacterial properties, biocompatibility, biodegradability, and no cytotoxicity.

[0119] The antibacterial hydrogel with dual temperature response function obtained by the present invention can be used for the healing of various complex wounds. It can be applied on the surface of injured skin to play the role of bacteria isolation, antibacterial and drug sustained release. It has good intelligent adhesion effect, ensures the effective fitting of the dressing to the skin, saves the use of secondary dressings, reduces secondary damage caused by repeated dressing changes, reduces wound infection, and improves the wound healing rate.

Claims

1. An antibacterial hydrogel with dual temperature response function, characterized in that: A homogeneous solution, a water-soluble free radical initiator and a promoter are mixed and reacted under an inert atmosphere, and then mixed with a water-insoluble drug suspension, stirred and reacted under an inert atmosphere, and the resulting solution is injected into a mold, and a free radical copolymerization reaction is carried out under oxygen isolation for 24 to 36 hours. The product is obtained after washing and ultraviolet irradiation; The homogeneous solution is composed of sulfobetaine methacrylate and N -isopropyl acrylamide is dissolved in deionized water, a cross-linking agent containing a disulfide bond whose reactive group is a carbon-carbon double bond is added, and then ultrasonic treatment is performed to obtain the obtained product; the sulfobetaine methacrylate is N -isopropyl acrylamide mass ratio is 1:1~2.5; sulfobetaine methacrylate and N -Isopropyl acrylamide constitutes the monomer, and the monomer content accounts for 10-20% of the total mass of the solution; The water-insoluble drug suspension is prepared by dissolving an antibacterial drug loaded with copper ions having a metal-organic framework structure in deionized water and then subjecting it to ultrasonic treatment; The copper ion-loaded antibacterial drug with a metal-organic framework structure is prepared by dissolving an organic ligand 1,3,5-benzenetricarboxylic acid in a mixed solution of ethanol and deionized water, dripping the solution into an aqueous solution of a copper compound, stirring and reacting at room temperature to form a suspension; centrifuging the suspension to separate particles, washing, freeze-drying, and then fully grinding; the aqueous solution of the copper compound is prepared by dissolving copper acetate monohydrate in a mixed solution of ethanol and deionized water, and ultrasonically oscillating until uniformly dispersed.

2. The antibacterial hydrogel with dual temperature response function according to claim 1, characterized in that: The molar ratio of the copper acetate monohydrate to 1,3,5-benzenetricarboxylic acid is 1:0.5-2.0; the volume ratio of ethanol to deionized water in the mixed solution is 1:1.0-2.0; the stirring reaction time at room temperature is 30-60 minutes, and the stirring rate is 300-500 rpm; the washing is performed by washing with ethanol solution and deionized water in sequence, the washing times of the ethanol solution are 2-3 times, and the washing times of the deionized water are 1-2 times; the ultrasonic oscillation time is 1-5 minutes; the mass concentration range of 1,3,5-benzenetricarboxylic acid in the mixed solution is 2-10%, and the mass concentration range of the copper acetate monohydrate in the mixed solution is 3-15%.

3. The antibacterial hydrogel with dual temperature response function according to claim 1, characterized in that: The copper ion-loaded antimicrobial drug having a metal-organic framework structure is dissolved in deionized water at a mass concentration of 1-5%.

4. The antibacterial hydrogel with dual temperature response function according to claim 1, characterized in that: The cross-linking agent containing a disulfide bond whose reactive group is a carbon-carbon double bond is N,N'-bis(acryloyl)cystamine; the free radical initiator is ammonium persulfate, potassium persulfate or sodium persulfate; the accelerator is tetramethylethylenediamine, hexamethylphosphoric triamide or N,N-dimethylacrylurea; and the inert atmosphere is an atmosphere formed by nitrogen, argon or helium.

5. The antibacterial hydrogel with dual temperature response function according to claim 1, characterized in that: The crosslinking agent accounts for 0.2-1% of the total mass of the monomers; the initiator accounts for 0.5-1% of the total mass of the monomers; and the molar ratio of the initiator to the accelerator is 1:1-2.

6. The antibacterial hydrogel with dual temperature response function according to claim 1, characterized in that: The reaction time under the inert atmosphere is 5-10 minutes; the stirring reaction time is 1-5 minutes; the temperature of the free radical copolymerization reaction is 28-32° C.; during the stirring reaction under the inert atmosphere, the mass percentage concentration of the water-insoluble drug in the solution is 0.05-2%.

7. The antibacterial hydrogel with dual temperature response function according to claim 1, characterized in that: The material of the mold is polytetrafluoroethylene, and the ultraviolet light irradiation intensity is 100~500μW / cm 2 The irradiation time is 5 to 15 minutes; the washing is performed with deionized water at a low temperature, the washing temperature is 0 to 10°C, and the number of washing times is 1 to 2 times.

8. The method for preparing the antibacterial hydrogel with dual temperature response function according to any one of claims 1 to 7, characterized in that: Sulfobetaine methacrylate and N -Isopropyl acrylamide is dissolved in deionized water, a cross-linking agent containing a disulfide bond whose reactive group is a carbon-carbon double bond is added, a homogeneous solution is prepared by ultrasonic treatment, a water-soluble free radical initiator and a promoter are added, and a suspension of a water-insoluble drug is added after reaction in an inert atmosphere. After stirring and reacting in an inert atmosphere, the obtained solution is injected into a mold, and oxygen is isolated to carry out a free radical copolymerization reaction for 24 to 36 hours. The obtained product is washed and irradiated with ultraviolet light to obtain an antibacterial hydrogel with dual temperature response function.

9. Use of the antibacterial hydrogel with dual temperature response function according to any one of claims 1 to 7 in the preparation of wound dressings.

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