In-situ photocuring viscous gel film material, film preparation method and application

Abstract

The invention discloses an in-situ photocuring viscous gel film material, a film preparation method and application, and belongs to the field of new materials and medical health. The method mainly comprises the following steps: (1) preparing a polymer solution with a certain mass fraction, and stirring until the polymer solution is completely dissolved for later use; (2) preparing a photocrosslinkable monomer solution with a certain mass fraction, and stirring until the photocrosslinkable monomer solution is completely dissolved for later use; (3) uniformly mixing the solutions in the steps (1) and (2) according to a certain proportion, and regulating to a certain viscosity for later use; (4) adding a certain mass of photoinitiator and cross-linking agent into the solution in the step (3), and stirring until the photoinitiator and cross-linking agent are completely dissolved to obtain a photocurable hydrogel precursor solution; and (5) coating a wound with the precursor solution of the hydrogel film in the step (4), and polymerizing under a certain illumination time to obtain the high-adhesion hydrogel adhesive film with topology entanglement, which is used for sealing irregular wounds after operation.

Description

Technical field:

[0001] The invention relates to a preparation method and application of an in-situ photocurable hydrogel film capable of achieving wet environment adhesion on irregular wounds for wound sealing, and belongs to the field of medical health. Background technology:

[0002] In recent years, major diseases such as cancer have been increasing, and surgery is the key to treating these diseases. Among them, closing the wound after surgery is a necessary means to ensure wound healing. Currently, surgical suture is the main means for doctors to close the wound. However, this process requires blocking the artery first and the suture time is long. For hemorrhagic injuries or minimally invasive surgery, the risk factor of the operation is greatly increased. In addition, the suturing technology needs to penetrate the tissue and cause damage to the tissue, which can lead to poor healing problems. Tissue adhesives use the physical and chemical effects between them and the tissue to directly close the wound, avoiding the problem of tissue damage, shortening the operation time, and improving the safety of the operation, becoming a new technology to replace traditional sutures.

[0003] Studies have shown that wounds heal faster in a wet environment than in a dry scab. In a moderately wet environment, the migration speed of epithelial cells in the wound increases significantly, and the recovery speed is twice that of when it is completely dry. Due to its water-swelling properties, the hydrogel adhesive film can provide the required wet environment for epithelial cells and promote wound healing. However, the swelling of the hydrogel adhesive film in a wet state causes its adhesion to the wound tissue to be significantly weakened, making it difficult to inhibit blood outflow. In response to this problem, the researchers proposed the use of a hydrophobic cross-linker to improve the anti-swelling properties of the hydrogel adhesive film, thereby achieving adhesion in a wet environment (Wen YQ, Advanced Materials, 2024, 36, 2310164.). However, the molded hydrogel adhesive film can only seal flat wounds, and the irregular wounds cut during actual surgery are difficult to fit tightly, which limits its application.

[0004] The present invention designs a hydrogel adhesive film material that can form a strong topological entanglement effect between a fluid hydrogel monomer that can be photopolymerized in situ and a tissue, which can be used for various wound closures to achieve rapid wound healing in a wet state. The hydrogel precursor solution penetrates into the tissue, and after light exposure, it quickly polymerizes and cross-links to form a hydrogel film, and the polymer chain segments form a strong topological entanglement with the tissue, achieving seamless adhesion in a wet state. Due to the good fluidity of the hydrogel precursor solution, it can penetrate into wounds of different structures, form a topological entanglement with the tissue at the molecular level, and tightly adhere to the wound surface to inhibit wound bleeding. In addition, due to the stretchability and water absorption and swelling characteristics of the hydrogel film, the adhesive film can remove the blood exuded from the wound and will not fall off during living body movement. Therefore, the hydrogel adhesive film prepared by in situ photopolymerization of hydrogel monomers can achieve rapid, high-strength and seamless adhesion to wet wounds, which has important research significance and application value. Summary of the invention:

[0005] The purpose of the present invention is to prepare an in-situ photocured hydrogel adhesive film, by applying a hydrogel precursor solution to the wound, using its fluidity to penetrate into the wound tissue, and after light-induced in-situ polymerization, the polymer chain segments and tissues form a topological entangled structure at the molecular level, adhere to the wound surface, and achieve rapid and seamless closure of wounds of different structures and sizes in a wet state. The hydrogel adhesive film prepared by this method exhibits strong hemostasis and wound healing promotion capabilities on irregular wounds, which can significantly save surgical time and reduce surgical risks.

[0006] An in-situ photocurable viscous gel film material, characterized in that a photocurable hydrogel precursor solution is formed by mixing a raw material polymer, a photocrosslinkable monomer, a photoinitiator and a crosslinking agent, and the hydrogel precursor solution is photocured in-situ at a location where in-situ curing is required to form a thin film;

[0007] The preparation of hydrogel precursor solution includes the following steps:

[0008] (1) preparing a polymer solution of a certain mass fraction, stirring it until it is completely dissolved and then setting it aside;

[0009] (2) preparing a certain mass fraction of a photo-crosslinkable monomer solution, stirring it until it is completely dissolved and setting it aside for use;

[0010] (3) mixing the solutions in step (1) and (2) in a certain proportion to obtain a solution of a certain viscosity for standby use;

[0011] (4) adding a certain amount of photoinitiator and crosslinker to the solution in step (3), stirring until they are completely dissolved, to obtain a photocurable hydrogel precursor solution;

[0012] There are many polymers that can be used in step (1), such as polyacrylic acid (PAA), polyacrylamide, polyvinyl alcohol, chitosan, alginate, gelatin, silk fibroin, collagen, fibrin, ε-poly-L-lysine, etc., with a mass fraction of 5% to 15%;

[0013] In step (2), the monomer is an organic small molecule with a double bond, such as acrylic acid (AA), acrylamide (AM), 2-(methacryloyloxy)ethyl]dimethyl-(3-sulfonatepropyl)ammonium hydroxide (DMAPS), methacrylic acid, low molecular weight polyethylene glycol methacrylate, etc., with a mass fraction of 10% to 80%;

[0014] The mass ratio of the polymer solution to the photo-crosslinkable monomer solution in step (3) is 1:8 to 2:1;

[0015] In step (4), the initiator is a photoinitiator, such as phenyl (2,4,6-trimethylbenzoyl) lithium phosphate (LAP) and ammonium persulfate (APS), and the mass fraction in the precursor solution is 0.1% to 3%, and the cross-linking agent is N,N-methylenebis (acrylamide) (MBA) and the like, and the mass fraction in the precursor solution is 0.1% to 1%;

[0016] The precursor solution of the hydrogel film in step (4) is applied to the wound, and in situ polymerization is performed by ultraviolet light at a certain light intensity and illumination time to obtain a hydrogel adhesive film with topological entanglement and strong adhesion. The light source intensity is 50 to 800 mW·cm -2 The irradiation time is 10 to 600 seconds.

[0017] The in-situ photocured hydrogel adhesive film prepared by the present invention is applied to irregular wound closure and exhibits good adhesion and stability. The in-situ photocured hydrogel adhesive film is evaluated using a variety of substrates and irregular postoperative wounds.

[0018] Technical principle of the present invention:

[0019] The present invention applies a fluid hydrogel precursor solution on the wound, and the solution can penetrate into the wound tissue, and photopolymerization is used to form a hydrogel adhesive film with a topological entangled structure of polymer segments and tissues in situ. The monomers in the precursor form a cross-linked network structure under the action of a photoinitiator and a cross-linking agent, and form an interpenetrating network with a linear polymer, so as to absorb the exuded blood and inhibit the excessive swelling of the hydrogel adhesive film, thereby ensuring its strong adhesion ability in a wet state. By utilizing the fluidity of the hydrogel film precursor solution, the different micro-nano structures of the entire wound can be completely covered to achieve seamless closure. Description of the drawings:

[0020] Figure 1 The rheology of the hydrogel adhesive film during in-situ photocuring;

[0021] Figure 2 In-situ film formation and adhesion of in-situ photocured hydrogel adhesive films on various substrates (Example 1);

[0022] Figure 3 Fluorescence confocal imaging of in situ film formation and adhesion of hydrogel adhesive film on pig skin (Example 2). Specific implementation method:

[0023] The present invention is described in detail below in conjunction with specific embodiments, but the present invention is not limited to the following embodiments.

[0024] Embodiment 1:

[0025] (1) Prepare a 10% PAA solution and stir for 48 hours until it is completely dissolved;

[0026] (2) preparing a photo-crosslinkable monomer solution of 40% by weight of AA and 30% by weight of DMAPS, stirring until completely dissolved and setting aside for use;

[0027] (3) mixing the solutions in step (1) and (2) in a ratio of 1:1, adjusting the viscosity to a certain value, and setting aside;

[0028] (4) adding 1% initiator APS and 0.3% crosslinker MBA to the solution in (3), stirring for 2 h until completely dissolved, to obtain an in-situ photocurable hydrogel adhesive film precursor solution;

[0029] (5) The hydrogel adhesion film precursor solution in (4) was coated on glass, polyacrylamide (PAM) hydrogel film, pig skin, copper, alumina and nylon, respectively. -2 The UV light was irradiated for 100s to form an in-situ photocured hydrogel adhesive film, which was then adhered to a variety of substrates (attachment Figure 2 ).

[0030] Embodiment 2:

[0031] (1) Prepare a 10% PAA solution and stir for 48 hours until it is completely dissolved;

[0032] (2) preparing a photo-crosslinkable monomer solution of 40% by weight of AA and 30% by weight of DMAPS, stirring until completely dissolved and setting aside for use;

[0033] (3) mixing the solutions in step (1) and (2) in a ratio of 1:1, adjusting the viscosity to a certain value, and setting aside;

[0034] (4) adding 1% initiator APS and 0.3% crosslinker MBA to the solution in (3), stirring for 2 h until completely dissolved, to obtain an in-situ photocurable hydrogel adhesive film precursor solution;

[0035] (5) The hydrogel adhesive film precursor solution in (4) was coated on pig skin and kept in dark for 30 min. -2 The film was irradiated with ultraviolet light for 100 s to form an in-situ photocured hydrogel adhesive film, which was then adhered to the pig skin.

[0036] (6) Wash the sample prepared in (4) three times with PBS, embed the sample with an embedding agent, and freeze it on dry ice;

[0037] (7) Cut longitudinal sections with a freezing microtome, with a thickness of 30 μ;

[0038] (8) The confocal fluorescence microscope was used to image the skin, with the excitation wavelength set to 490 nm and bright field images collected. The following results were obtained: the gel film penetrated more than 400 μm below the surface of the pig skin (see Appendix Figure 3 ).

[0039] Embodiment 3:

[0040] (1) Prepare a 10% PAA solution and stir for 48 hours until it is completely dissolved;

[0041] (2) preparing a photo-crosslinkable monomer solution of 30% by weight of AA and 40% by weight of DMAPS, stirring until completely dissolved and setting aside for use;

[0042] (3) mixing the solutions in step (1) and (2) in a ratio of 1.5:1, adjusting the viscosity to a certain value, and setting aside;

[0043] (4) adding 1% initiator APS and 0.3% crosslinker MBA to the solution in (3), stirring for 2 h until completely dissolved, to obtain an in-situ photocurable hydrogel adhesive film precursor solution;

[0044] (5) The hydrogel adhesive film precursor solution in (4) was coated on pig skin at 200 mW·cm -2 The film was irradiated with ultraviolet light for 200 s to form an in situ photocured hydrogel adhesion film, which was then adhered to the pig skin.

[0045] Embodiment 4:

[0046] (1) Prepare a 10% PAM solution and stir for 48 hours until it is completely dissolved;

[0047] (2) preparing a photo-crosslinkable monomer solution of 20% by mass of AM and 40% by mass of DMAPS, stirring until completely dissolved and setting aside for use;

[0048] (3) mixing the solutions in step (1) and (2) in a ratio of 1:1, adjusting the viscosity to a certain value, and setting aside;

[0049] (4) Add 0.3% of initiator LAP and 0.1% of crosslinker MBA to the solution in (3), and stir for 2 hours until completely dissolved to obtain an in-situ photocurable hydrogel adhesive film precursor solution.

[0050] (5) The hydrogel adhesive film precursor solution in (4) was coated on pig skin at 200 mW·cm -2 The film was irradiated with ultraviolet light for 300 s to form an in situ photocured hydrogel adhesion film, which was then adhered to the pig skin.

[0051] Embodiment 5:

[0052] (1) Prepare a 15% PAM solution and stir for 48 hours until it is completely dissolved;

[0053] (2) preparing a photo-crosslinkable monomer solution of 25% by mass of AM and 40% by mass of DMAPS, stirring until completely dissolved and setting aside for use;

[0054] (3) mixing the solutions in step (1) and (2) in a ratio of 1:1, adjusting the viscosity to a certain value, and setting aside;

[0055] (4) adding 0.3% of initiator LAP and 0.1% of crosslinker MBA to the solution in (3), stirring for 2 h until completely dissolved, to obtain an in-situ photocurable hydrogel adhesive film precursor solution;

[0056] (5) The hydrogel adhesive film precursor solution in (4) was coated on pig skin at 300 mW·cm -2 The film was irradiated with ultraviolet light for 150 s to form an in situ photocured hydrogel adhesion film, which was then adhered to the pig skin.

[0057] Embodiment 6:

[0058] (1) Prepare a 20% PAA solution and stir for 48 hours until it is completely dissolved;

[0059] (2) preparing a photo-crosslinkable monomer solution of 20% by mass of AM and 30% by mass of polyethylene glycol methacrylate, stirring until completely dissolved and setting aside for use;

[0060] (3) mixing the solutions in step (1) and (2) in a ratio of 1:1, adjusting the viscosity to a certain value, and setting aside;

[0061] (4) adding 0.5% initiator APS and 0.2% crosslinker MBA to the solution in (3), stirring for 2 h until completely dissolved, to obtain an in-situ photocurable hydrogel adhesive film precursor solution;

[0062] (5) The hydrogel adhesive film precursor solution in (4) was coated on pig skin at 200 mW·cm -2 The film was irradiated with ultraviolet light for 250 s to form an in situ photocured hydrogel adhesion film, which was then adhered to the pig skin.

[0063] Embodiment 7:

[0064] (1) Prepare a 20% PAA solution and stir for 48 hours until it is completely dissolved;

[0065] (2) preparing a photo-crosslinkable monomer solution of 30% by weight AM and 20% by weight polyethylene glycol methacrylate, stirring until completely dissolved and setting aside for use;

[0066] (3) mixing the solutions in step (1) and (2) in a ratio of 1:1.5, adjusting the viscosity to a certain value, and setting aside;

[0067] (4) adding 0.5% initiator APS and 0.2% crosslinker MBA to the solution in (3), stirring for 2 h until completely dissolved, to obtain an in-situ photocurable hydrogel adhesive film precursor solution;

[0068] (5) The hydrogel adhesive film precursor solution in (4) was coated on pig skin at 250 mW·cm -2 The film was irradiated with ultraviolet light for 180 s to form an in situ photocured hydrogel adhesion film, which was then adhered to the pig skin.

[0069] Embodiment 8:

[0070] (1) Prepare a 20% PAM solution and stir for 48 hours until it is completely dissolved;

[0071] (2) preparing a photo-crosslinkable monomer solution of 20% by mass of AA and 30% by mass of polyethylene glycol methacrylate, stirring until completely dissolved and setting aside for use;

[0072] (3) mixing the solutions in step (1) and (2) in a ratio of 1:1, adjusting the viscosity to a certain value, and setting aside;

[0073] (4) adding 0.8% of initiator LAP and 0.3% of crosslinker MBA to the solution in (3), stirring for 2 h until completely dissolved, to obtain an in-situ photocurable hydrogel adhesive film precursor solution;

[0074] (5) The hydrogel adhesive film precursor solution in (4) was coated on pig skin at 200 mW·cm -2 The film was irradiated with ultraviolet light for 250 s to form an in situ photocured hydrogel adhesion film, which was then adhered to the pig skin.

[0075] Embodiment 9:

[0076] (1) Prepare a 20% PAM solution and stir for 48 hours until it is completely dissolved;

[0077] (2) preparing a photo-crosslinkable monomer solution of 30% by weight of AA and 20% by weight of polyethylene glycol methacrylate, stirring the solution until the solution is completely dissolved and setting aside for use;

[0078] (3) mixing the solutions in step (1) and (2) in a ratio of 1:1.5, adjusting the viscosity to a certain value, and setting aside;

[0079] (4) adding 0.8% of initiator LAP and 0.3% of crosslinker MBA to the solution in (3), stirring for 2 h until completely dissolved, to obtain an in-situ photocurable hydrogel adhesive film precursor solution;

[0080] (5) The hydrogel adhesive film precursor solution in (4) was coated on pig skin at 250 mW·cm -2 The film was irradiated with ultraviolet light for 220 s to form an in situ photocured hydrogel adhesion film, which was then adhered to the pig skin.

[0081] Embodiment 10:

[0082] (1) Prepare a 30% PAA solution and stir for 48 hours until it is completely dissolved;

[0083] (2) preparing a photo-crosslinkable monomer solution of AA with a mass fraction of 30%, stirring until completely dissolved and setting aside for use;

[0084] (3) mixing the solutions in step (1) and (2) in a ratio of 1:1, adjusting the viscosity to a certain value, and setting aside;

[0085] (4) adding 0.3% of initiator LAP and 0.1% of crosslinker MBA to the solution in (3), stirring for 2 h until completely dissolved, to obtain an in-situ photocurable hydrogel adhesive film precursor solution;

[0086] (5) The hydrogel adhesive film precursor solution in (4) was coated on pig skin at 300 mW·cm -2 The film was irradiated with ultraviolet light for 240 s to form an in situ photocured hydrogel adhesion film, which was then adhered to the pig skin.

[0087] Figure 1 This illustrates the rapid formation of in situ photocured hydrogel films;

[0088] Figure 2 It is explained that the hydrogel adhesive film forms adhesion on various substrates by in-situ photocuring;

[0089] Figure 3 This indicates that the molecules in the hydrogel adhesive film can penetrate into the tissue and form topological entanglement with the pig skin.

Claims

1. An in-situ light-cured viscous gel film material, characterized in that: A photocurable hydrogel precursor solution is formed by mixing a raw material polymer, a photocrosslinkable monomer, a photoinitiator and a crosslinking agent, and the hydrogel precursor solution is photocured in situ at a location where in-situ curing is required to form a film; The preparation of hydrogel precursor solution includes the following steps: (1) preparing a polymer solution of a certain mass fraction, stirring it until it is completely dissolved and then setting it aside; (2) preparing a certain mass fraction of a photo-crosslinkable monomer solution, stirring it until it is completely dissolved and setting it aside for use; (3) mixing the solutions in step (1) and (2) in a certain proportion to obtain a solution of a certain viscosity for standby use; (4) Add a certain amount of photoinitiator and crosslinker to the solution in step (3), and stir until they are completely dissolved to obtain a photocurable hydrogel precursor solution.

2. An in-situ light-cured adhesive gel film material according to claim 1, characterized in that: There are many polymers that can be used in step (1), such as polyacrylic acid (PAA), polyacrylamide, polyvinyl alcohol, chitosan, alginate, gelatin, silk fibroin, collagen, fibrin, ε-poly-L-lysine, etc., with a mass fraction of 5% to 15%.

3. An in-situ light-cured adhesive gel film material according to claim 1, characterized in that: In step (2), the monomer is an organic small molecule with a double bond, such as acrylic acid (AA), acrylamide (AM), 2-(methacryloyloxy)ethyl]dimethyl-(3-sulfonatepropyl)ammonium hydroxide (DMAPS), methacrylic acid, low molecular weight polyethylene glycol methacrylate, etc., with a mass fraction of 10% to 80%.

4. The in-situ photocurable adhesive gel film material according to claim 1, characterized in that: The mass ratio of the polymer solution to the photo-crosslinkable monomer solution in step (3) is 1:8 to 2:

1.

5. The in-situ photocurable adhesive gel film material according to claim 1, characterized in that: In step (4), the initiator is a photoinitiator, such as phenyl (2,4,6-trimethylbenzoyl) lithium phosphate (LAP) or ammonium persulfate (APS), and its mass fraction in the precursor solution is 0.1% to 3%.

6. The in-situ photocurable adhesive gel film material according to claim 1, characterized in that: The cross-linking agent is N,N-methylenebis(acrylamide) (MBA) or the like, and its mass fraction in the precursor solution is 0.1-1%.

7. An application of an in-situ light-cured viscous gel film material, characterized in that: As a drug that is directly applied on the wound and solidified in situ to form a thin film, by in situ polymerization under ultraviolet light at a certain light intensity and illumination time, a hydrogel adhesive film with strong adhesion and topological entanglement can be obtained, which can be used for wet adhesion of irregular wounds to seal the wound.

8. The use according to claim 7, wherein the light source intensity is 50 to 800 mW·cm -2 The irradiation time is 10 to 600 seconds.

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