A hydrogel and its preparation method and application

Abstract

The present invention provides a hydrogel and its preparation method and application, belonging to the field of biomedical materials technology. The raw materials of the hydrogel provided by the present invention include chitosan quaternary ammonium salt, polyvinyl alcohol, N-(2-acryloyloxyethyl)-N-(4-phenylboronic acid methyl) N,N-dimethylammonium bromide, 3-[[2-(methacryloyloxy)ethyl]dimethylammonium]propane-1-sulfonate, acrylic acid, acrylic acid-N-succinimidyl ester and initiator in a mass ratio of (0.025-0.075):(0.0015-0.0040):(0.3-1.2):(0.3-1.2):(0.3-1.2):(0.03-0.12):0.01. The present invention is based on the electrostatic interaction between the components, induced phase separation polymerization to prepare a hydrogel with strong viscosity on one side and essentially no viscosity on the other side.

Description

Technical Field

[0001] The present invention belongs to the technical field of biomedical materials, and in particular relates to a hydrogel and a preparation method and application thereof. Background Art

[0002] Hydrogel wound dressings have the properties of providing a moist microenvironment, isolating the wound site from bacteria, loading drugs to relieve wound inflammation, sterilizing and disinfecting, stopping bleeding and accelerating wound healing. They have attracted much attention as an ideal substitute or auxiliary for suturing organ defects.

[0003] In order to ensure that the hydrogel can quickly adhere to the wound and block the bleeding point, the hydrogel must have high adhesion properties. However, the prepared hydrogel adhesive has strong viscosity on both sides. During in vitro use, it is inevitable that it will come into contact with the outside world and adhere, affecting the normal use of the dressing. This requires that the hydrogel dressing not only has strong adhesion to the injured tissue, but also has anti-adhesion properties to other normal tissues, that is, one side has strong adhesion, while the other side has no adhesion or weak adhesion. At present, anti-postoperative adhesion hydrogel dressings pay too much attention to anti-postoperative adhesion properties, but ignore the adhesion properties of the adhesive, and have little application value.

[0004] Therefore, how to prepare a hydrogel that can not only tightly adhere to moist tissues but also prevent postoperative organ adhesion has become a technical problem that needs to be solved urgently in this field. Summary of the Invention

[0005] The present invention aims to provide a hydrogel, a preparation method thereof, and its application. The hydrogel provided by the present invention has strong adhesiveness on one side, which can tightly adhere to moist tissue, and is substantially non-adhesive on the other side, which can prevent postoperative organ adhesion.

[0006] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0007] The invention provides a hydrogel, the raw materials of which include chitosan quaternary ammonium salt, polyvinyl alcohol, N-(2-acryloyloxyethyl)-N-(4-phenylboronic acid methyl) N,N-dimethylammonium bromide, 3-[[2-(methacryloyloxy)ethyl]dimethylammonium]propane-1-sulfonate, acrylic acid, acrylic acid-N-succinimide ester, an initiator and water;

[0008] The mass ratio of the chitosan quaternary ammonium salt, polyvinyl alcohol, N-(2-acryloyloxyethyl)-N-(4-phenylboronic acid methyl) N,N-dimethylammonium bromide, 3-[[2-(methacryloyloxy)ethyl]dimethylammonium]propane-1-sulfonate, acrylic acid, acrylic acid-N-succinimide ester and initiator is (0.025-0.075):(0.0015-0.0040):(0.3-1.2):(0.3-1.2):(0.3-1.2):(0.03-0.12):0.01.

[0009] Preferably, the ammonium salt content of the chitosan quaternary ammonium salt is ≥90%.

[0010] Preferably, the mass ratio of the chitosan quaternary ammonium salt, polyvinyl alcohol, N-(2-acryloyloxyethyl)-N-(4-phenylboronic acid methyl) N,N-dimethylammonium bromide, 3-[[2-(methacryloyloxy)ethyl]dimethylammonium]propane-1-sulfonate, acrylic acid, acrylic acid-N-succinimide ester and initiator is (0.025-0.070):(0.0020-0.0035):(0.3-0.9):(0.3-0.9):(0.3-0.9):(0.05-0.10):0.01.

[0011] Preferably, the mass ratio of the chitosan quaternary ammonium salt, polyvinyl alcohol, N-(2-acryloyloxyethyl)-N-(4-phenylboronic acid methyl) N,N-dimethylammonium bromide, 3-[[2-(methacryloyloxy)ethyl]dimethylammonium]propane-1-sulfonate, acrylic acid, acrylic acid-N-succinimide ester and initiator is (0.025-0.050):(0.0025-0.0030):(0.5-0.6):(0.5-0.6):(0.5-0.6):(0.05-0.08):0.01.

[0012] The present invention also provides a method for preparing the hydrogel described in the above technical solution, comprising the following steps:

[0013] (1) mixing chitosan quaternary ammonium salt, polyvinyl alcohol, N-(2-acryloyloxyethyl)-N-(4-phenylboronic acid methyl) N,N-dimethylammonium bromide, 3-[[2-(methacryloyloxy)ethyl]dimethylammonium]propane-1-sulfonate, acrylic acid, acrylic acid-N-succinimidyl ester, an initiator, and water to obtain a mixed solution;

[0014] (2) subjecting the mixed solution obtained in step (1) to a polymerization reaction to obtain a hydrogel.

[0015] Preferably, in step (1), the mixing of chitosan quaternary ammonium salt, polyvinyl alcohol, N-(2-acryloyloxyethyl)-N-(4-phenylboronic acid methyl) N,N-dimethylammonium bromide, 3-[[2-(methacryloyloxy)ethyl]dimethylammonium]propane-1-sulfonate, acrylic acid, acrylic acid-N-succinimide ester, initiator and water comprises the following steps:

[0016] 1) mixing chitosan quaternary ammonium salt and part of water to obtain chitosan quaternary ammonium salt solution;

[0017] 2) mixing polyvinyl alcohol and remaining water to obtain a polyvinyl alcohol solution;

[0018] 3) mixing the chitosan quaternary ammonium salt solution obtained in step 1), the polyvinyl alcohol solution obtained in step 2), N-(2-acryloyloxyethyl)-N-(4-phenylboronic acid methyl) N,N-dimethylammonium bromide, 3-[[2-(methacryloyloxy)ethyl]dimethylammonium]propane-1-sulfonate, acrylic acid, acrylic acid-N-succinimidyl ester, and an initiator;

[0019] There is no order for steps 1) and 2).

[0020] Preferably, the concentration of the polyvinyl alcohol solution in step 2) is 0.5-1.5 wt%.

[0021] Preferably, the polymerization reaction in step (2) is carried out under ultraviolet light irradiation.

[0022] Preferably, the wavelength of the ultraviolet light is 385 nm, the power of the ultraviolet light is 18 to 54 W, and the ultraviolet light irradiation time is 3 to 10 minutes.

[0023] The present invention also provides the use of the hydrogel described in the above technical solution or the hydrogel prepared by the preparation method described in the above technical solution in medical dressings.

[0024] The invention provides a hydrogel, the raw materials of which include chitosan quaternary ammonium salt, polyvinyl alcohol, N-(2-acryloyloxyethyl)-N-(4-phenylboronic acid methyl) N,N-dimethylammonium bromide, 3-[[2-(methacryloyloxy)ethyl]dimethylammonium]propane-1-sulfonate, acrylic acid, acrylic acid-N-succinimide ester, initiator and water; the chitosan quaternary ammonium salt, polyvinyl alcohol, N-(2-acryloyloxyethyl)-N-(4-phenylboronic acid methyl) N,N-dimethylammonium bromide, 3-[[2-(methacryloyloxy)ethyl]dimethylammonium]propane-1-sulfonate, acrylic acid, acrylic acid-N-succinimide ester, initiator and water; The mass ratio of phenylboronic acid (methyl) N,N-dimethylammonium bromide, 3-[[2-(methacryloyloxy)ethyl]dimethylammonium]propane-1-sulfonate, acrylic acid, acrylic acid-N-succinimidyl ester and initiator is (0.025-0.075):(0.0015-0.0040):(0.3-1.2):(0.3-1.2):(0.3-1.2):(0.03-0.12):0.01. The present invention uses electrostatic interaction between the components to induce phase separation polymerization to prepare a hydrogel with strong viscosity on one side (capable of tightly adhering to moist tissues) and substantially no viscosity on the other side (capable of preventing postoperative organ adhesion). The chitosan quaternary ammonium salt contains abundant ammonium cations, and 3-[[2-(methacryloyloxy)ethyl]dimethylammonio]propane-1-sulfonate and acrylic acid contain sulfonic acid and carboxyl anions, respectively. Through the electrostatic interaction of the anions and cations, a large amount of 3-[[2-(methacryloyloxy)ethyl]dimethylammonio]propane-1-sulfonate and acrylic acid molecules are adsorbed on the chitosan quaternary ammonium salt chain to generate macromolecular polymerized monomers. During the polymerization process, the molecular weight of the macromolecular polymerized monomers increases sharply, and their solubility in the system decreases, thereby rapidly precipitating to form the lower layer of the hydrogel. The remaining monomers that are not adsorbed on the chitosan quaternary ammonium salt (acrylic acid-N-succinimidyl ester and N-(2-acryloyloxyethyl)-N-(4-phenylboronic acid methyl) N,N-dimethylammonium bromide) are polymerized to form the upper layer of the hydrogel; N-(2-acryloyloxyethyl)-N-(4-phenylboronic acid methyl) N,N-dimethylammonium bromide has good solubility and barnacle-like adhesion, giving the upper surface of the hydrogel strong wet tissue adhesion properties; chitosan quaternary ammonium salt can make the hydrogel have high biocompatibility, strong antibacterial properties and hemostatic properties; polyvinyl alcohol helps the swelling behavior of the hydrogel, allowing it to expand rapidly after absorbing water, forming a moist environment, which is conducive to cell growth and tissue repair; acrylic acid-N-succinimidyl ester can undergo amine ester exchange reaction with the adhesive tissue, quickly achieving adhesion between the hydrogel and the tissue. Experimental results show that the upper surface bonding strength of the hydrogel provided by the present invention is 87.762~149.582J / m 2 , the lower surface bonding strength is 0~24.43J / m 2The contact angle of the upper surface is 87-102°; the contact angle of the lower surface is 61-77°; the antibacterial rate against Escherichia coli is more than 80%; the antibacterial rate against Staphylococcus aureus is more than 70%; the hemostatic volume of mouse liver is 16.93-64.44g, and the hemostatic time is 128.67-192.33s. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 This is the NMR spectrum of N-(2-acryloyloxyethyl)-N-(4-phenylboronic acid methyl) N,N-dimethylammonium bromide in Example 1;

[0026] Figure 2 This is a SEM image of the upper surface of the hydrogel prepared in Example 1;

[0027] Figure 3 This is a SEM image of the lower surface of the hydrogel prepared in Example 1;

[0028] Figure 4 This is a SEM image of the upper surface of the hydrogel prepared in Example 2;

[0029] Figure 5 This is a SEM image of the lower surface of the hydrogel prepared in Example 2;

[0030] Figure 6 This is a SEM image of the upper surface of the hydrogel prepared in Example 3;

[0031] Figure 7 This is the SEM image of the lower surface of the hydrogel prepared in Example 3. DETAILED DESCRIPTION

[0032] The invention provides a hydrogel, the raw materials of which include chitosan quaternary ammonium salt, polyvinyl alcohol, N-(2-acryloyloxyethyl)-N-(4-phenylboronic acid methyl) N,N-dimethylammonium bromide, 3-[[2-(methacryloyloxy)ethyl]dimethylammonium]propane-1-sulfonate, acrylic acid, acrylic acid-N-succinimide ester, an initiator and water;

[0033] The mass ratio of the chitosan quaternary ammonium salt, polyvinyl alcohol, N-(2-acryloyloxyethyl)-N-(4-phenylboronic acid methyl) N,N-dimethylammonium bromide, 3-[[2-(methacryloyloxy)ethyl]dimethylammonium]propane-1-sulfonate, acrylic acid, acrylic acid-N-succinimide ester and initiator is (0.025-0.075):(0.0015-0.0040):(0.3-1.2):(0.3-1.2):(0.3-1.2):(0.03-0.12):0.01.

[0034] The present invention has no particular limitation on the sources of the raw materials, and commercially available products known to those skilled in the art may be used.

[0035] The raw materials for preparing the hydrogel of the present invention include chitosan quaternary ammonium salt; the ammonium salt content of the chitosan quaternary ammonium salt is preferably ≥90%. In the present invention, the chitosan quaternary ammonium salt contains abundant ammonium cations, which can react with 3-[[2-(methacryloyloxy)ethyl]dimethylammonio]propane-1-sulfonate and acrylic acid through the electrostatic interaction of anions and cations to generate macromolecular polymerized monomers. During the polymerization process, the molecular weight of these macromolecular polymerized monomers increases dramatically, and their solubility in the system decreases, causing them to quickly precipitate and form the lower layer of the hydrogel. The remaining monomers (acrylic acid-N-succinimidyl ester and N-(2-acryloyloxyethyl)-N-(4-phenylboronic acid methyl) N,N-dimethylammonium bromide) that are not adsorbed on the chitosan quaternary ammonium salt polymerize to form the upper layer of the hydrogel. In addition, the chitosan quaternary ammonium salt can impart high biocompatibility, strong antibacterial properties, and hemostatic properties to the hydrogel.

[0036] The raw materials used to prepare the hydrogel of the present invention also include polyvinyl alcohol; the polyvinyl alcohol preferably has a molecular weight of 50,000 to 100,000 g / mol. In the present invention, the polyvinyl alcohol contributes to the swelling behavior of the hydrogel, enabling it to expand rapidly after absorbing water, creating a moist environment that is conducive to cell growth and tissue repair.

[0037] The raw materials used to prepare the hydrogel of the present invention also include N-(2-acryloyloxyethyl)-N-(4-phenylboronic acid methyl) N,N-dimethylammonium bromide. In the present invention, the N-(2-acryloyloxyethyl)-N-(4-phenylboronic acid methyl) N,N-dimethylammonium bromide has barnacle-like wet adhesive properties. Based on the principle of macroscopic phase separation polymerization induced by electrostatic interaction, it is located in the upper layer of the hydrogel, resulting in the upper layer of the hydrogel having adhesive properties, while the lower surface does not have adhesive properties.

[0038] In the present invention, the structural formula of the N-(2-acryloyloxyethyl)-N-(4-phenylboronic acid methyl) N,N-dimethylammonium bromide is shown in Formula I:

[0039]

[0040] In the present invention, the preparation method of N-(2-acryloyloxyethyl)-N-(4-phenylboronic acid methyl) N,N-dimethylammonium bromide preferably comprises the following steps:

[0041] 4-(Bromomethyl)phenylboronic acid, 2-(dimethylamino)ethyl acrylate and an organic solvent are mixed and subjected to an ammonium salt reaction to obtain N-(2-acryloyloxyethyl)-N-(4-phenylboronic acid methyl)N,N-dimethylammonium bromide.

[0042] In the present invention, the mass ratio of the 4-(bromomethyl)phenylboronic acid to 2-(dimethylamino)ethyl acrylate is preferably (2-3):(1-2). As an embodiment, the mass ratio of the 4-(bromomethyl)phenylboronic acid to 2-(dimethylamino)ethyl acrylate can be 2.5:1.57.

[0043] In the present invention, the organic solvent is preferably tetrahydrofuran. The present invention has no particular limitation on the amount of the organic solvent, as long as the raw materials are completely dissolved.

[0044] The present invention has no particular limitation on the operation of mixing the 4-(bromomethyl)phenylboric acid, 2-(dimethylamino)ethyl acrylate and the organic solvent, and the technical scheme for preparing the mixed material well known to those skilled in the art can be used.

[0045] In the present invention, the temperature of the ammonium salt reaction is preferably room temperature; the duration of the ammonium salt reaction is preferably 20 to 25 hours, more preferably 24 hours; and the ammonium salt reaction is preferably carried out under sealed conditions. Limiting the temperature and time of the ammonium salt reaction to the above ranges can further improve the degree of reaction.

[0046] After the ammonium salt reaction is completed, the product obtained by the ammonium salt reaction is preferably filtered, washed and dried in sequence to obtain N-(2-acryloyloxyethyl)-N-(4-phenylboronic acid methyl) N,N-dimethylammonium bromide.

[0047] In the present invention, the filtration is preferably suction filtration. The present invention has no particular limitation on the operation of the suction filtration, and any operation well known to those skilled in the art can be used.

[0048] The present invention has no particular limitation on the washing operation, and any operation well known to those skilled in the art may be used.

[0049] The present invention has no particular limitation on the drying operation, and the product may be dried to a constant weight.

[0050] The raw materials used to prepare the hydrogel of the present invention also include 3-[[2-(methacryloyloxy)ethyl]dimethylammonio]propane-1-sulfonate. In the present invention, the 3-[[2-(methacryloyloxy)ethyl]dimethylammonio]propane-1-sulfonate contains sulfonic acid anions, which adsorb onto the chitosan quaternary ammonium salt chains through the electrostatic interaction of anions and cations, generating macromolecular monomers. During the polymerization process, the molecular weight of these macromolecular monomers increases dramatically, while their solubility in the system decreases, causing them to quickly precipitate and form the lower layer of the hydrogel.

[0051] The raw materials used to prepare the hydrogel of the present invention also include acrylic acid. In this invention, the acrylic acid contains carboxylic acid anions, which, through the electrostatic interaction of anions and cations, adsorb onto the chitosan quaternary ammonium salt chains to form macromolecular monomers. During the polymerization process, the molecular weight of these macromolecular monomers increases dramatically, and their solubility in the system decreases, causing them to quickly precipitate and form the lower layer of the hydrogel.

[0052] The raw materials used to prepare the hydrogel of the present invention also include acrylate-N-succinimidyl ester. In the present invention, acrylate-N-succinimidyl ester is not adsorbed on the chitosan quaternary ammonium salt, thereby polymerizing to form the upper layer of the hydrogel. Furthermore, acrylate-N-succinimidyl ester acts as an adhesive, capable of undergoing an amine transesterification reaction with the adhesive tissue, rapidly achieving adhesion between the hydrogel and the tissue. Compared to other adhesives, it can further improve the adhesion of the hydrogel's upper layer.

[0053] The raw materials for preparing the hydrogel of the present invention also include an initiator; the initiator is preferably at least one of 2-hydroxy-4'-(2-hydroxyethoxy)-2-methylpropiophenone, lithium phenyl-2,4,6-trimethylbenzoylphosphinate, and KIPEM photoinitiator. In the present invention, the initiator is used to initiate the polymerization reaction.

[0054] The raw materials for preparing the hydrogel of the present invention also include water. In the present invention, the water is a solvent for dissolving the raw materials.

[0055] The present invention has no particular limitation on the amount of water used, as long as the raw materials are completely dissolved.

[0056] In the present invention, the mass ratio of chitosan quaternary ammonium salt, polyvinyl alcohol, N-(2-acryloyloxyethyl)-N-(4-phenylboronic acid methyl) N,N-dimethylammonium bromide, 3-[[2-(methacryloyloxy)ethyl]dimethylammonium]propane-1-sulfonate, acrylic acid, acrylic acid-N-succinimidyl ester, and initiator is (0.025-0.075):(0.0015-0.0040):(0.3-1.2):(0.3-1.2):(0.3-1.2):(0.03-0.12):0.01. By limiting the mass ratio of each raw material to the above range, the present invention can produce a hydrogel with strong adhesion on one side (capable of tightly adhering to moist tissue) and substantially no adhesion on the other side (capable of preventing postoperative organ adhesion).

[0057] As an embodiment, the mass ratio of the chitosan quaternary ammonium salt, polyvinyl alcohol, N-(2-acryloyloxyethyl)-N-(4-phenylboronic acid methyl) N,N-dimethylammonium bromide, 3-[[2-(methacryloyloxy)ethyl]dimethylammonium]propane-1-sulfonate, acrylic acid, acrylic acid-N-succinimide ester and initiator can be (0.025-0.070): (0.002 0~0.0035):(0.3~0.9):(0.3~0.9):(0.3~0.9):(0.05~0.10):0.01, and can also be (0.025~0.050):(0.0025~0.0030):(0.5~0.6):(0.5~0.6):(0.5~0.6):(0.05~0.08):0.01.

[0058] The present invention uses electrostatic interaction between the components to induce phase separation polymerization to prepare a hydrogel with strong viscosity on one side (capable of tightly adhering to moist tissues) and substantially no viscosity on the other side (capable of preventing postoperative organ adhesion). The chitosan quaternary ammonium salt contains abundant ammonium cations, and 3-[[2-(methacryloyloxy)ethyl]dimethylammonio]propane-1-sulfonate and acrylic acid contain sulfonic acid and carboxyl anions, respectively. Through the electrostatic interaction of the anions and cations, a large amount of 3-[[2-(methacryloyloxy)ethyl]dimethylammonio]propane-1-sulfonate and acrylic acid molecules are adsorbed on the chitosan quaternary ammonium salt chain to generate macromolecular polymerized monomers. During the polymerization process, the molecular weight of the macromolecular polymerized monomers increases sharply, and their solubility in the system decreases. , thereby quickly precipitating to form the lower layer of the hydrogel; the remaining monomers that were not adsorbed on the chitosan quaternary ammonium salt (acrylic acid-N-succinimidyl ester and N-(2-acryloyloxyethyl)-N-(4-phenylboronic acid methyl) N,N-dimethylammonium bromide) polymerized to form the upper layer of the hydrogel; N-(2-acryloyloxyethyl)-N-(4-phenylboronic acid methyl) N,N-dimethylammonium bromide has good solubility and barnacle-like adhesion, giving the upper surface of the hydrogel strong wet tissue adhesion properties; chitosan quaternary ammonium salt can make the hydrogel have high biocompatibility, strong antibacterial properties and hemostatic properties; polyvinyl alcohol contributes to the swelling behavior of the hydrogel, enabling it to expand rapidly after absorbing water, forming a moist environment that is conducive to cell growth and tissue repair.

[0059] The upper surface of the hydrogel provided by the present invention can firmly adhere to the tissue defect, and the maximum bonding strength can reach 149.582 J / m 2 The other opposite surface has no obvious stickiness to wet tissue, which can effectively solve the problem of postoperative adhesion and can be used as a wound sealant to prevent postoperative adhesion.

[0060] The present invention also provides a method for preparing the hydrogel described in the above technical solution, comprising the following steps:

[0061] (1) mixing chitosan quaternary ammonium salt, polyvinyl alcohol, N-(2-acryloyloxyethyl)-N-(4-phenylboronic acid methyl) N,N-dimethylammonium bromide, 3-[[2-(methacryloyloxy)ethyl]dimethylammonium]propane-1-sulfonate, acrylic acid, acrylic acid-N-succinimidyl ester, an initiator, and water to obtain a mixed solution;

[0062] (2) subjecting the mixed solution obtained in step (1) to a polymerization reaction to obtain a hydrogel.

[0063] The invention mixes chitosan quaternary ammonium salt, polyvinyl alcohol, N-(2-acryloyloxyethyl)-N-(4-phenylboronic acid methyl) N,N-dimethylammonium bromide, 3-[[2-(methacryloyloxy)ethyl]dimethylammonium]propane-1-sulfonate, acrylic acid, acrylic acid-N-succinimide ester, an initiator and water to obtain a mixed solution.

[0064] In the present invention, the mixing of chitosan quaternary ammonium salt, polyvinyl alcohol, N-(2-acryloyloxyethyl)-N-(4-phenylboronic acid methyl) N,N-dimethylammonium bromide, 3-[[2-(methacryloyloxy)ethyl]dimethylammonium]propane-1-sulfonate, acrylic acid, acrylic acid-N-succinimidyl ester, initiator and water preferably comprises the following steps:

[0065] 1) mixing chitosan quaternary ammonium salt and part of water to obtain chitosan quaternary ammonium salt solution;

[0066] 2) mixing polyvinyl alcohol and remaining water to obtain a polyvinyl alcohol solution;

[0067] 3) mixing the chitosan quaternary ammonium salt solution obtained in step 1), the polyvinyl alcohol solution obtained in step 2), N-(2-acryloyloxyethyl)-N-(4-phenylboronic acid methyl) N,N-dimethylammonium bromide, 3-[[2-(methacryloyloxy)ethyl]dimethylammonium]propane-1-sulfonate, acrylic acid, acrylic acid-N-succinimidyl ester, and an initiator;

[0068] There is no order for steps 1) and 2).

[0069] In the present invention, the chitosan quaternary ammonium salt is preferably mixed with a portion of water to obtain a chitosan quaternary ammonium salt solution.

[0070] In the present invention, the volume ratio of the mass of the chitosan quaternary ammonium salt to a portion of water is preferably (0.025-0.075) g: (1.5-3.5) mL, more preferably 0.025 g: 2.5 mL.

[0071] The present invention has no special limitation on the operation of mixing the chitosan quaternary ammonium salt and a portion of water, and the technical scheme for preparing the mixed material well known to those skilled in the art can be adopted.

[0072] In the present invention, polyvinyl alcohol and remaining water are preferably mixed to obtain a polyvinyl alcohol solution.

[0073] The present invention has no special limitation on the operation of mixing the polyvinyl alcohol and the remaining water, and the technical scheme for preparing the mixed material well known to those skilled in the art can be adopted.

[0074] In the present invention, the concentration of the polyvinyl alcohol solution is preferably 0.5 to 1.5 wt%, more preferably 1 wt%.

[0075] After obtaining the chitosan quaternary ammonium salt solution and the polyvinyl alcohol solution, the present invention preferably mixes the chitosan quaternary ammonium salt solution, the polyvinyl alcohol solution, N-(2-acryloyloxyethyl)-N-(4-phenylboronic acid methyl) N,N-dimethylammonium bromide, 3-[[2-(methacryloyloxy)ethyl]dimethylammonium]propane-1-sulfonate, acrylic acid, acrylic acid-N-succinimidyl ester and an initiator.

[0076] The present invention has no special limitation on the operation of mixing the chitosan quaternary ammonium salt solution, the polyvinyl alcohol solution, the N-(2-acryloyloxyethyl)-N-(4-phenylboronic acid methyl) N,N-dimethylammonium bromide, the 3-[[2-(methacryloyloxy)ethyl]dimethylammonium]propane-1-sulfonate, the acrylic acid, the acrylic acid-N-succinimidyl ester and the initiator, and a technical scheme for preparing the mixed material well known to those skilled in the art can be adopted.

[0077] After obtaining the mixed solution, the present invention performs a polymerization reaction on the mixed solution to obtain a hydrogel.

[0078] In the present invention, the polymerization reaction is preferably carried out under ultraviolet light irradiation; the wavelength of the ultraviolet light is preferably 385 nm; the power of the ultraviolet light is preferably 18 to 54 W, more preferably 36 W; and the ultraviolet light irradiation time is preferably 3 to 10 minutes, more preferably 3 to 5 minutes. By limiting the process parameters of the polymerization reaction to the above ranges, the degree of polymerization reaction can be further improved.

[0079] The present invention is based on the electrostatic interaction between the components to induce phase separation polymerization, thereby preparing a hydrogel with asymmetric viscosity, and the process is simple.

[0080] The present invention also provides the use of the hydrogel described in the above technical solution or the hydrogel prepared by the preparation method described in the above technical solution in medical dressings.

[0081] The present invention has no special limitation on the operation of applying the hydrogel in medical dressings, and operations well known to those skilled in the art can be used.

[0082] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions of the present invention. Obviously, the embodiments described are only some of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts are within the scope of protection of the present invention.

[0083] Example 1

[0084] The raw materials of the hydrogel are chitosan quaternary ammonium salt, polyvinyl alcohol, N-(2-acryloyloxyethyl)-N-(4-phenylboronic acid methyl) N,N-dimethylammonium bromide, 3-[[2-(methacryloyloxy)ethyl]dimethylammonium]propane-1-sulfonate, acrylic acid, acrylic acid-N-succinimidyl ester, initiator and water;

[0085] The molecular weight of the polyvinyl alcohol is 50,000 to 100,000 g / mol;

[0086] The initiator is 2-hydroxy-4'-(2-hydroxyethoxy)-2-methylpropiophenone;

[0087] The chitosan quaternary ammonium salt has an ammonium salt content of 90% and is provided by Wuhan Lanabai Pharmaceutical Chemical Co., Ltd.

[0088] The structural formula of the N-(2-acryloyloxyethyl)-N-(4-phenylboronic acid methyl) N,N-dimethylammonium bromide is:

[0089]

[0090] The preparation method of N-(2-acryloyloxyethyl)-N-(4-phenylboronic acid methyl) N,N-dimethylammonium bromide is as follows: 2.5 g of 4-(bromomethyl)phenylboric acid is dissolved in 100 mL of tetrahydrofuran, 1.57 g of 2-(dimethylamino)ethyl acrylate is added, and the mixture is sealed and stirred at room temperature for 24 hours to perform an ammonium salt reaction, followed by filtration. The precipitate is then washed three times with tetrahydrofuran, and then dried under vacuum at 50° C. for 24 hours to obtain white powder N-(2-acryloyloxyethyl)-N-(4-phenylboronic acid methyl) N,N-dimethylammonium bromide;

[0091] The mass ratio of the chitosan quaternary ammonium salt, polyvinyl alcohol, N-(2-acryloyloxyethyl)-N-(4-phenylboronic acid methyl) N,N-dimethylammonium bromide, 3-[[2-(methacryloyloxy)ethyl]dimethylammonium]propane-1-sulfonate, acrylic acid, acrylic acid-N-succinimidyl ester and initiator is 0.025:0.0025:0.3:0.6:0.6:0.05:0.01;

[0092] The preparation method of the hydrogel comprises the following steps:

[0093] (1) stirring chitosan quaternary ammonium salt and a portion of water at room temperature for 5 hours to obtain a chitosan quaternary ammonium salt solution; wherein the mass ratio of chitosan quaternary ammonium salt to the volume ratio of the portion of water is 0.025 g:2.5 mL;

[0094] (2) mixing polyvinyl alcohol and remaining water to obtain a polyvinyl alcohol solution; wherein the concentration of the polyvinyl alcohol solution is 1 wt%;

[0095] (3) stirring the chitosan quaternary ammonium salt solution obtained in step (1), the polyvinyl alcohol solution obtained in step (2), N-(2-acryloyloxyethyl)-N-(4-phenylboronic acid methyl) N,N-dimethylammonium bromide, 3-[[2-(methacryloyloxy)ethyl]dimethylammonium]propane-1-sulfonate, acrylic acid, acrylic acid-N-succinimide ester and an initiator for 1 hour to obtain a transparent mixed solution;

[0096] (4) The mixed solution obtained in step (3) was irradiated with ultraviolet light at a wavelength of 385 nm and a power of 36 W for 3 minutes to perform a polymerization reaction to obtain a hydrogel.

[0097] The formula for preparing N-(2-acryloyloxyethyl)-N-(4-phenylboronic acid methyl) N,N-dimethylammonium bromide in Example 1 is:

[0098]

[0099] The NMR of N-(2-acryloyloxyethyl)-N-(4-phenylboronic acid methyl) N,N-dimethylammonium bromide in Example 1 is as follows: Figure 1 shown.

[0100] from Figure 1 It can be seen that N-(2-acryloyloxyethyl)-N-(4-phenylboronic acid methyl) N,N-dimethylammonium bromide was prepared in Example 1 of the present invention.

[0101] Example 2

[0102] On the basis of Example 1, the mass ratio of chitosan quaternary ammonium salt, polyvinyl alcohol, N-(2-acryloyloxyethyl)-N-(4-phenylboronic acid methyl) N,N-dimethylammonium bromide, 3-[[2-(methacryloyloxy)ethyl]dimethylammonium]propane-1-sulfonate, acrylic acid, acrylic acid-N-succinimide ester and initiator was modified to 0.025:0.0025:0.6:0.6:0.6:0.05:0.01, and other conditions remained unchanged.

[0103] Example 3

[0104] On the basis of Example 1, the mass ratio of chitosan quaternary ammonium salt, polyvinyl alcohol, N-(2-acryloyloxyethyl)-N-(4-phenylboronic acid methyl) N,N-dimethylammonium bromide, 3-[[2-(methacryloyloxy)ethyl]dimethylammonium]propane-1-sulfonate, acrylic acid, acrylic acid-N-succinimide ester and initiator was modified to 0.025:0.0025:0.9:0.6:0.6:0.05:0.01, and other conditions remained unchanged.

[0105] The performance of the hydrogels prepared in Examples 1 to 3 was tested using the following method:

[0106] 1. Contact angle test: A drop of deionized water was dropped on the upper and lower surfaces of the hydrogel, and the contact angle between the droplet and the hydrogel surface was measured using a contact angle meter (OCA200, Data Physics, Germany). The results are shown in Table 1.

[0107] 2. Adhesive performance test: The adhesion strength of the hydrogels was tested using a 180° peel test method on a universal tester (XLW (PC), Samsung, China). The coupling agent (12 mg / mL, 50 L, EDC:NHS = 1:1 (w / w)) was applied to the bottom of the hydrogel (length = 40 mm, width = 10 mm, thickness = 1.5 mm). Then, the hydrogel coated with the coupling agent was pressed onto the substrate tissue (length = 60 mm, width = 15 mm) by a weight of 500 g. Polyethylene terephthalate (PET) film (the same size as the substrate tissue) was used as the hydrogel backing. The universal tester applied uniaxial tension while recording the changes in force (F) and displacement. The loading rate was constant at 50 mm / min. The interfacial toughness was calculated as the ratio between 2F and the hydrogel width. The data are reported as the mean ± 1 standard deviation (n = 5). The results are shown in Table 1.

[0108] 3. Antibacterial performance test: 2 mg of hydrogel was added to a glass bottle and the logarithmic growth phase of Escherichia coli (ATCC25922) was diluted to 10 using a turbidity tube. 6CFU, then, 10 mL of E. coli solution was added and co-cultured with the hydrogel for 1, 3, 5, 7, and 9 h in a constant temperature incubator at 37 ° C. After co-culture, 100 μL of the solution was added to LB solid medium and cultured in a constant temperature incubator at 37 ° C for 24 h. The single colonies were counted and compared with the control group. Staphylococcus aureus was also used under the same scheme, and the antibacterial rate I was calculated according to formula II:

[0109]

[0110] In formula II, C0 is the inhibition rate of the blank group, and C1 is the inhibition rate of the experimental group. The antibacterial properties are shown in Tables 2 and 3.

[0111] 4. Hemostatic Performance Test: Rats were anesthetized with an intraperitoneal injection of 4% chloral hydrate (100 g / mL) and fixed on a surgical board. The rat liver was exposed through an abdominal incision, and the tissue fluid surrounding the liver was carefully removed with medical gauze. Medical gauze was placed under the liver. A 1.5 cm long and 0.25 cm deep incision was made in the middle lobe of the liver with a scalpel. Then, gauze and hydrogel were applied to the wound. After complete hemostasis, the weight of blood absorbed by the filter paper was weighed and compared with that of the control group. Each group was tested three times. All animal experiments were conducted in accordance with the current guidelines for laboratory animal care. The hemostatic performance data are shown in Table 4.

[0112] Table 1 Adhesiveness and hydrophilicity of the upper and lower surfaces of the hydrogels prepared in Examples 1 to 3

[0113]

[0114]

[0115] Table 2 Antibacterial properties of the hydrogels prepared in Examples 1 to 3 against Escherichia coli

[0116]

[0117] Table 3 Antibacterial properties of the hydrogels prepared in Examples 1 to 3 against Staphylococcus aureus

[0118]

[0119] Table 4 Hemostatic properties of the hydrogels prepared in Examples 1 to 3

[0120] Serial number Mouse liver hemostasis volume (g) Mouse liver hemostasis time (s) gauze 249.37 198.33 Example 1 16.93 128.67 Example 2 26.93 154.67 Example 3 64.44 192.33

[0121] As can be seen from Tables 1 to 4, the hydrogel provided by the present invention has strong viscosity on one side and substantially no viscosity on the other side; and has excellent antibacterial, hemostatic and hydrophilic properties.

[0122] The SEM image of the upper surface of the hydrogel prepared in Example 1 is as follows: Figure 2 The SEM image of the lower surface of the hydrogel prepared in Example 1 is shown as follows: Figure 3 The SEM image of the upper surface of the hydrogel prepared in Example 2 is shown as follows: Figure 4 The SEM image of the lower surface of the hydrogel prepared in Example 2 is shown as follows: Figure 5 The SEM image of the upper surface of the hydrogel prepared in Example 3 is shown as follows: Figure 6 The SEM image of the lower surface of the hydrogel prepared in Example 3 is shown as follows: Figure 7 shown.

[0123] from Figures 2 to 7 It can be seen that the upper and lower surfaces of the hydrogel are both porous structures, with large pore size on the upper surface and small pore size on the lower surface; with the increase in the amount of N-(2-acryloyloxyethyl)-N-(4-phenylboronic acid methyl) N,N-dimethylammonium bromide, the difference in pore size between the upper and lower surfaces becomes smaller; although N-(2-acryloyloxyethyl)-N-(4-phenylboronic acid methyl) N,N-dimethylammonium bromide has a cation-π bond structure and large steric hindrance, a large amount of use will also cause it to have strong electrostatic interactions with 3-[[2-(methacryloyloxy)ethyl]dimethylammonium]propane-1-sulfonate and acrylic acid, making the molecular chains more densely arranged.

[0124] As can be seen from the above examples, the hydrogel provided by the present invention has strong adhesion on one side and can tightly adhere to moist tissues, while the other side is basically non-adhesive and can prevent postoperative organ adhesion.

[0125] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principles of the present invention. These improvements and modifications should also be regarded as within the scope of protection of the present invention.

Claims

1. A hydrogel, comprising chitosan quaternary ammonium salt, polyvinyl alcohol, N-(2-acryloyloxyethyl)-N-(4-phenylboronic acid methyl) N,N-dimethylammonium bromide, 3-[[2-(methacryloyloxy)ethyl]dimethylammonium]propane-1-sulfonate, acrylic acid, acrylic acid-N-succinimidyl ester, an initiator, and water; The mass ratio of the chitosan quaternary ammonium salt, polyvinyl alcohol, N-(2-acryloyloxyethyl)-N-(4-phenylboronic acid methyl) N,N-dimethylammonium bromide, 3-[[2-(methacryloyloxy)ethyl]dimethylammonium]propane-1-sulfonate, acrylic acid, acrylic acid-N-succinimide ester and initiator is (0.025-0.075):(0.0015-0.0040):(0.3-1.2):(0.3-1.2):(0.3-1.2):(0.03-0.12):0.

01.

2. The hydrogel according to claim 1, wherein The ammonium salt content of the chitosan quaternary ammonium salt is ≥90%.

3. The hydrogel according to claim 1, wherein The mass ratio of the chitosan quaternary ammonium salt, polyvinyl alcohol, N-(2-acryloyloxyethyl)-N-(4-phenylboronic acid methyl) N,N-dimethylammonium bromide, 3-[[2-(methacryloyloxy)ethyl]dimethylammonium]propane-1-sulfonate, acrylic acid, acrylic acid-N-succinimide ester and initiator is (0.025-0.070):(0.0020-0.0035):(0.3-0.9):(0.3-0.9):(0.3-0.9):(0.05-0.10):0.

01.

4. The hydrogel according to claim 1 or 3, characterized in that The mass ratio of the chitosan quaternary ammonium salt, polyvinyl alcohol, N-(2-acryloyloxyethyl)-N-(4-phenylboronic acid methyl) N,N-dimethylammonium bromide, 3-[[2-(methacryloyloxy)ethyl]dimethylammonium]propane-1-sulfonate, acrylic acid, acrylic acid-N-succinimide ester and initiator is (0.025-0.050):(0.0025-0.0030):(0.5-0.6):(0.5-0.6):(0.5-0.6):(0.05-0.08):0.

01.

5. The method for preparing the hydrogel according to any one of claims 1 to 4, comprising the following steps: (1) mixing chitosan quaternary ammonium salt, polyvinyl alcohol, N-(2-acryloyloxyethyl)-N-(4-phenylboronic acid methyl) N,N-dimethylammonium bromide, 3-[[2-(methacryloyloxy)ethyl]dimethylammonium]propane-1-sulfonate, acrylic acid, acrylic acid-N-succinimidyl ester, an initiator, and water to obtain a mixed solution; (2) subjecting the mixed solution obtained in step (1) to a polymerization reaction to obtain a hydrogel.

6. The preparation method according to claim 5, characterized in that In the step (1), the mixing of chitosan quaternary ammonium salt, polyvinyl alcohol, N-(2-acryloyloxyethyl)-N-(4-phenylboronic acid methyl) N,N-dimethylammonium bromide, 3-[[2-(methacryloyloxy)ethyl]dimethylammonium]propane-1-sulfonate, acrylic acid, acrylic acid-N-succinimide ester, initiator and water comprises the following steps: 1) mixing chitosan quaternary ammonium salt and part of water to obtain chitosan quaternary ammonium salt solution; 2) mixing polyvinyl alcohol and remaining water to obtain a polyvinyl alcohol solution; 3) mixing the chitosan quaternary ammonium salt solution obtained in step 1), the polyvinyl alcohol solution obtained in step 2), N-(2-acryloyloxyethyl)-N-(4-phenylboronic acid methyl) N,N-dimethylammonium bromide, 3-[[2-(methacryloyloxy)ethyl]dimethylammonium]propane-1-sulfonate, acrylic acid, acrylic acid-N-succinimidyl ester, and an initiator; There is no order for steps 1) and 2).

7. The preparation method according to claim 6, characterized in that The concentration of the polyvinyl alcohol solution in step 2) is 0.5-1.5 wt%.

8. The preparation method according to claim 5, characterized in that The polymerization reaction in step (2) is carried out under ultraviolet light irradiation.

9. The preparation method according to claim 8, characterized in that The wavelength of the ultraviolet light is 385 nm, the power of the ultraviolet light is 18 to 54 W, and the ultraviolet light irradiation time is 3 to 10 minutes.

10. Use of the hydrogel according to any one of claims 1 to 4 or the hydrogel prepared by the preparation method according to any one of claims 5 to 9 in medical dressings.

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