Natural light crosslinked hydrogel comprising mxene and method for preparing same

Abstract

The present invention relates to a natural light crosslinked hydrogel comprising MXene and a method for preparing same. The present invention provides a natural polymeric hydrogel formed through natural light crosslinking in a non-harmful visible light spectrum. As the hydrogel comprises a drug and MXene, the hydrogel exhibits excellent biocompatibility with no cytotoxicity. It has been confirmed that the hydrogel can maximize a wound healing effect by modulating photothermal reactions and controlling drug release. Accordingly, the hydrogel may be effectively used for wound treatment as a pharmaceutical composition, a quasi-drug composition, and a cosmetic composition.

Description

Natural light crosslinked hydrogel containing MXENE and method for producing the same

[0001] The present invention relates to a natural light crosslinking hydrogel comprising MXene and a method for producing the same.

[0002] Hydrogel dressings based on biopolymers have shown significant effectiveness in wound healing, covering wounds, protecting the skin from external infections, and inducing skin cell regeneration. Recently, composite hydrogels have been developed that combine drugs, cells, and biomaterials to induce active and rapid tissue regeneration.

[0003] When manufacturing hydrogels, one of the most important factors to consider is the crosslinking method. Hydrogels typically require external light stimulation, such as a crosslinking agent or UV radiation, for gelation. The most desirable crosslinking method for forming a complex hydrogel is one that prevents damage or loss of materials such as drugs and cells during the process. The hydrogel formation process using a crosslinking agent requires the use of an appropriate amount of crosslinking agent to maintain bioactivity, and separate equipment or processes are required to form the hydrogel.

[0004] UV photocrosslinking is a widely used technique in materials science and biomedicine, using light to form covalent bonds between two or more molecules. It can be used to create 3D structures with high spatial resolution, patterned surfaces, biomaterials, and drug delivery systems. However, it also has the potential to cause photodamage and phototoxicity.

[0005] Therefore, research on natural photocrosslinking, which minimizes photodamage and leverages the benefits of UV photocrosslinking, is highly beneficial for the manufacture of composite dressings that maximize wound healing. Visible photocrosslinking technology involves ruthenium. Visible photocrosslinking using a ruthenium photoinitiator (PI) offers several advantages. First, it allows for spatiotemporal control over the crosslinking process, enabling precise and rapid manipulation of hydrogel materials. Furthermore, it can be used in the presence of biological molecules such as proteins and nucleic acids without causing significant damage or interfering with their function. Furthermore, its low toxicity and biocompatibility make it suitable for in vivo applications.

[0006] Ruthenium can cross-link tyrosine in certain biopolymers, such as collagen type I, gelatin, silk fibroin, methacrylated hyaluronic acid, methacrylated gelatin, methacrylated collagen type I, and PEGDA. Biopolymer-based hydrogels, which have been actively researched and developed in the medical field, have the ability to be produced rapidly and environmentally friendly. Furthermore, they are highly suitable for the development of composite hydrogels to maximize therapeutic efficacy, as they do not cause damage or loss of constituents when combined with drugs or biological agents that promote bioactivity. These characteristics have made ruthenium cross-linking an emerging tool for biomedical engineering, such as the development of 3D bioprinting inks, bioscaffolds, and drug delivery systems.

[0007] Against this backdrop, the inventors of the present invention have conducted extensive research to develop a hydrogel formulation that is effective for wound healing and biocompatible while minimizing damage to the combined materials using a ruthenium photocrosslinking method. As a result, the inventors have developed a composite hydrogel containing a bioactive agent for wound healing including MXene and PDRN, which exhibits excellent cell proliferation and cell migration required for wound healing, and have confirmed that it inhibits bacterial growth through a photothermal reaction and rapid wound healing, thereby completing the present invention.

[0008] [Prior Art Literature]

[0009] [Non-patent literature]

[0010] (Non-patent literature 1) Whittaker, JL et al., 2014, J. Mater. Chem. B, 2(37), 6259-6270 (2014.06.19)

[0011] An object of the present invention is to provide a hydrogel for wound healing comprising two or more natural polymers, a photoinitiator, and MXene.

[0012] Another object of the present invention is to provide a method for producing a hydrogel, comprising the steps of: i) preparing a first mixture by mixing two or more natural polymer solutions with a photoinitiator; ii) preparing a second mixture by adding MXene to the first mixture; and iii) preparing a hydrogel by irradiating the second mixture with visible light.

[0013] Another object of the present invention is to provide a pharmaceutical composition for wound treatment comprising the hydrogel.

[0014] Another object of the present invention is to provide a wound treatment quasi-drug composition comprising the hydrogel.

[0015] Another object of the present invention is to provide a cosmetic composition comprising the hydrogel.

[0016] The advantages and features of the present invention, and the methods for achieving them, will become clearer with reference to the embodiments described in detail below together with the accompanying drawings. However, the present invention is not limited to the embodiments disclosed below and may be implemented in various different forms. These embodiments are provided solely to ensure that the disclosure of the present invention is complete and to fully inform those skilled in the art of the scope of the present invention, and the present invention is defined solely by the scope of the claims.

[0017] The terminology used herein is for the purpose of describing embodiments only and is not intended to limit the present invention. In this specification, the singular also includes the plural unless specifically stated otherwise. As used herein, the terms "comprises" and / or "comprising" do not exclude the presence or addition of one or more other components in addition to the mentioned components. Like reference numerals refer to like components throughout the specification, and "and / or" includes each and any combination of one or more of the mentioned components. Although "first", "second", etc. are used to describe various components, these components are not limited by these terms. These terms are only used to distinguish one component from another. Therefore, it should be understood that a first component mentioned below may also be a second component within the technical spirit of the present invention.

[0018] Unless otherwise defined, all terms (including technical and scientific terms) used herein may be used in their common sense to those skilled in the art to which the present invention pertains. Furthermore, terms defined in commonly used dictionaries are not to be interpreted ideally or excessively unless explicitly and specifically defined otherwise.

[0019] The present invention provides a hydrogel for wound treatment comprising two or more natural polymers, a photoinitiator, and MXene.

[0020] The gel of the present invention refers to a substantially diluted cross-linked system that does not exhibit flow in a normal state.

[0021] The hydrogel of the present invention refers to a gel comprising a network of hydrophilic polymer chains. The hydrogel has a highly absorbent natural or synthetic polymer network.

[0022] The natural polymer of the present invention refers to a natural macromolecule comprising a plurality of repeated subunits.

[0023] The natural polymer of the present invention may be two or more selected from the group consisting of alginate, heparin, silk fibroin, silk sericin, methylcellulose, gellan gum, chitosan, fibrinogen, collagen, gelatin, and hyaluronan, but is not limited thereto.

[0024] In a specific embodiment of the present invention, the natural polymer is a natural polymer containing tyrosine, and the natural polymer containing tyrosine may include gelatin and silk fibroin.

[0025] The gelatin of the present invention refers to a mixture of peptides and proteins produced by partial hydrolysis of collagen. Collagen is the main structural protein of the extracellular space in the skin, bones, and connective tissues of animals such as cattle, chickens, pigs, horses, and fish.

[0026] The silk fibroin of the present invention is a component obtained from silkworm cocoons, which can prevent hydrophobicity and cell death and improve cell anchoring ability.

[0027] Based on 100 parts by weight of the entire hydrogel of the present invention, the gelatin is contained in an amount of 1 to 30 parts by weight, and the silk fibroin is contained in an amount of 1 to 50 parts by weight.

[0028] The above gelatin and silk fibroin are controlled within the above content range to ensure that the physicochemical properties of the hydrogel, such as crosslinking density, swelling, and rigidity, are suitable for skin application and wound healing.

[0029] The MXene of the present invention is a type of photothermodynamic material that can be used as an external stimulant for wound healing. The heat generated by MXene can stimulate growth factor production, promoting cell proliferation and tissue regeneration. Furthermore, the high surface area of ​​MXene allows for the adsorption and release of bioactive substances, such as growth factors and antibiotics, that enhance tissue regeneration and prevent infection.

[0030] The MXene of the present invention may be any one selected from the group consisting of Ti3C2, Ti2C, Nb2C and V2C, and more specifically, may be Ti3C2.

[0031] The photoinitiator of the present invention means one compound or a combination of two or more compounds that generates free radicals when exposed to light.

[0032] The photoinitiator of the present invention may include a ruthenium compound, and the photoinitiator may further include sodium persulfate, ammonium persulfate, or potassium persulfate.

[0033] The hydrogel of the present invention is crosslinked in the visible light range, wherein the visible light range has a wavelength of 400 to 450 nm, and the crosslinking can be rapidly achieved within 1 to 2 minutes.

[0034] The hydrogel of the present invention can carry a drug and continuously control the release of the drug. Any drug of the present invention can be carried if it is hydrophilic. The hydrophilic drug may be at least one selected from the group consisting of alendronate, doxorubicin hydrochloride, varenicline, neomycin, and therapeutic peptides, nucleic acids, or proteins, but is not limited thereto. The drug may include, but is not limited to, PDRN.

[0035] The PDRN of the present invention is a DNA fragment extracted from sperm cells of salmon or trout. It exhibits various therapeutic effects, including improved angiogenesis, promotion of osteoblast activity, increased collagen synthesis, and anti-inflammatory effects. PDRN is known to have minimal side effects because it is degraded by non-specific DNA nucleases and excreted in urine or feces. Therefore, combining MXene and PDRN with a hydrogel-based dressing can accelerate wound healing through a synergistic effect.

[0036] In addition, the present invention provides a method for producing the hydrogel, comprising the steps of: i) preparing a first mixture by mixing two or more natural polymer solutions with a photoinitiator; ii) preparing a second mixture by adding MXene to the first mixture; and iii) preparing a hydrogel by irradiating the second mixture with visible light.

[0037] The MXene of the present invention may be any one selected from the group consisting of Ti3C2, Ti2C, Nb2C and V2C, and more specifically, may be Ti3C2.

[0038] Based on 100 parts by weight of the entire hydrogel of the present invention, the gelatin may be included in an amount of 1 to 30 parts by weight, and the silk fibroin may be included in an amount of 1 to 50 parts by weight.

[0039] In a specific embodiment of the present invention, i) 5 parts by weight of silk fibroin and 10 parts by weight of gelatin were dissolved by stirring at 40 to 60° C., and 2 mM of a ruthenium (II) compound and 20 mM of sodium persulfate were added to prepare a first mixture, ii) 500 μg / mL of Ti3C2MXene was added to the first mixture to prepare a second mixture, and iii) cross-linking was performed by reacting in a visible light range of 400 to 450 nm for 1 to 2 minutes to produce a hydrogel (Fig. 1).

[0040] In addition, the present invention provides a wound dressing comprising the hydrogel.

[0041] The wound dressing of the present invention may include other ingredients. For example, water loss control agents may be added to reduce the permeability of the wound dressing material. Water loss control agents may include glycolipids, ceramides, fatty acids, cholesterol, triglycerides, stearyl esters, and silicone oil.

[0042] A plasticizer may be added to the above wound dressing, preferred plasticizers are glycerol and water, but propylene glycol and butanol may be used.

[0043] A hydration control agent may be added to the above wound dressing material, the preferred hydration control agent being isopropyl alcohol, but ethanol, glycerol, butanol and propylene glycol may also be used.

[0044] The above wound dressing may further include a backing sheet extending over the active layer on the opposite side of the active layer facing the wound. The backing sheet is larger than the active layer, so that a free area extends around the active layer to form a so-called island dressing.

[0045] In addition, the present invention provides a pharmaceutical composition for wound treatment comprising the hydrogel.

[0046] The term pharmaceutical composition of the present invention may be used interchangeably with pharmaceutical composition.

[0047] The pharmaceutical composition of the present invention may contain 10 to 95 wt% of the hydrogel as an active ingredient based on the total weight of the composition. In addition, the pharmaceutical composition of the present invention may additionally contain one or more active ingredients exhibiting the same or similar function in addition to the above-mentioned active ingredient.

[0048] The pharmaceutical composition of the present invention may additionally contain a pharmaceutically acceptable additive.

[0049] The above additives may further include suitable carriers, excipients and diluents commonly used in the manufacture of pharmaceutical compositions.

[0050] The pharmaceutical composition of the present invention may include a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier is one commonly used in the preparation of pharmaceutical formulations, and may include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil.

[0051] The pharmaceutical composition of the present invention can be formulated and used in the form of oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, dressings, etc., or in the form of external preparations or sterile injection solutions, according to conventional methods. Specifically, when formulating, it can be prepared using diluents or excipients such as fillers, bulking agents, binders, wetting agents, disintegrants, and surfactants that are commonly used.

[0052] Solid preparations for oral administration include, but are not limited to, tablets, pills, powders, granules, and capsules. These solid preparations may be prepared by mixing the active ingredient with at least one excipient, such as starch, calcium carbonate, sucrose, or lactose. Furthermore, in addition to simple excipients, lubricants such as magnesium stearate and talc may also be used. In addition to liquids and liquid paraffin for oral administration, various excipients, such as wetting agents, sweeteners, flavoring agents, and preservatives, may be added to prepare the preparation.

[0053] Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized preparations, and tablets. Non-aqueous solutions and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate.

[0054] The pharmaceutical composition of the present invention may further include, in addition to the above ingredients, a lubricant, a wetting agent, a sweetener, a flavoring agent, an emulsifier, a suspending agent, a preservative, etc.

[0055] The pharmaceutical composition of the present invention can be administered orally or parenterally, and in the case of parenteral administration, can be administered subcutaneously, intramuscularly, transdermally, etc.

[0056] The appropriate dosage of the pharmaceutical composition of the present invention varies depending on factors such as the formulation method, administration method, patient's age, weight, sex, pathological condition, food, administration time, administration route, excretion rate and reaction sensitivity, and the extent of the patient's wound, and can be appropriately selected by a person skilled in the art, and can be administered once a day or several times a day as needed.

[0057] The pharmaceutical composition of the present invention can be manufactured in a unit dosage form or can be manufactured by placing it in a multi-dose container by formulating it using a pharmaceutically acceptable carrier and / or excipient according to a method that can be easily performed by a person having ordinary skill in the art to which the present invention pertains, and the like. In this case, the formulation can be in the form of a solution, suspension or emulsion in an oil or aqueous medium, or in the form of an extract, powder, granule, tablet or capsule, and can additionally include a dispersant or stabilizer.

[0058] The subjects of administration of the present invention include, but are not particularly limited to, humans, monkeys, cows, horses, pigs, sheep, chickens, cats, dogs, mice, rabbits, etc.

[0059] In addition, the present invention provides a wound treatment quasi-drug composition comprising the hydrogel.

[0060] The pharmaceutical composition of the present invention is characterized in that wound healing activity is enhanced through the composition including the hydrogel manufactured by the manufacturing method of the present invention.

[0061] The pharmaceutical composition of the present invention may further include, in addition to the hydrogel, a pharmaceutically acceptable carrier, excipient, or diluent, as needed. The pharmaceutically acceptable carrier, excipient, or diluent is not limited as long as it can achieve the effects of the present invention, and may include, for example, fillers, bulking agents, binders, wetting agents, disintegrants, surfactants, lubricants, sweeteners, fragrances, preservatives, and the like.

[0062] When the composition of the present invention is used as a quasi-drug, one or more active ingredients having wound healing activity may be additionally included, in which case the wound healing activity of the composition of the present invention may be further increased. When adding the above-mentioned active ingredients, skin safety due to combined use, ease of formulation, and stability of the active ingredients may be taken into consideration. The above-mentioned additional active ingredients may be included in an amount of 0.0001 to 10 wt% (w / w) based on the total weight of the quasi-drug composition, and the above content range may be appropriately adjusted by those skilled in the art in consideration of skin safety, ease of formulation, etc.

[0063] The quasi-drug composition of the present invention may be, but is not particularly limited to, an external preparation, powder, sterilizing disinfectant, ointment, lotion, internal preparation, wet tissue, spray patch, band or patch, etc., and the formulation method, dosage, method of use, components, etc. of the quasi-drug may be appropriately selected by a person skilled in the art from conventional techniques known in the art.

[0064] In addition, the present invention provides a cosmetic composition comprising the hydrogel.

[0065] The cosmetic composition of the present invention can be prepared in a formulation selected from the group consisting of, but not limited to, a mask pack, a solution, an external ointment, a cream, a foam, a nourishing toner, an emollient toner, a perfume, an emollient, an emulsion, a makeup base, an essence, a soap, a liquid cleanser, a bath agent, a sunscreen cream, a sun oil, a suspension, an emulsion, a paste, a gel, a lotion, a powder, a surfactant-containing cleansing, an oil, a powder foundation, an emulsion foundation, a wax foundation, a patch, and a spray.

[0066] The above cosmetic composition may additionally include one or more cosmetically acceptable carriers that are incorporated into general skin cosmetics, and may appropriately incorporate conventional ingredients such as oil, water, surfactants, moisturizers, lower alcohols, thickeners, chelating agents, pigments, preservatives, fragrances, etc., but is not limited thereto.

[0067] The cosmetically acceptable carrier included in the cosmetic composition of the present invention varies depending on the formulation of the cosmetic composition.

[0068] When the formulation of the present invention is an ointment, paste, cream, or gel, animal oil, vegetable oil, wax, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycol, silicone, bentonite, silica, talc, zinc oxide, etc. may be used as carrier components, but are not limited thereto. These may be used alone or in combination of two or more.

[0069] When the formulation of the present invention is a powder or spray, lactose, talc, silica, aluminum hydroxide, calcium silicate, polyamide powder, etc. can be used as a carrier component, and especially in the case of a spray, a propellant such as chlorofluorohydrocarbon, propane / butane, or dimethyl ether can be additionally included, but is not limited thereto. These can be used alone or in combination of two or more.

[0070] The present invention provides a natural light crosslinking hydrogel comprising MXene and a method for producing the same, and by including a drug and MXene in a natural polymer hydrogel formed by natural light crosslinking in a harmless visible light range, the hydrogel is free of cytotoxicity, has excellent biocompatibility, regulates a photothermal reaction, and controls the release of a drug, thereby maximizing a wound healing effect, and thus can be usefully used as a pharmaceutical composition for wound treatment, a quasi-drug composition, and a cosmetic composition.

[0071] Figure 1 is a schematic diagram showing the manufacturing process of a SFG (Silk Fibroin / Gelatin) composite hydrogel dressing containing MXene and a drug according to the present invention.

[0072] Figure 2 is a diagram showing whether crosslinking occurs depending on the presence or absence of natural light (visible light in the range of 400 to 450 nm) during crosslinking of the hydrogel of the present invention.

[0073] Figure 3 is a diagram showing a comparison of the pore sizes of hydrogel cross-sections according to the type of polymer.

[0074] Figure 4 is a diagram showing the evaluation of the stability and deformation recovery ability of the hydrogel for skin attachment.

[0075] Figure 5 is a diagram showing the drug release amount depending on the presence or absence of MXene in a drug-loaded hydrogel and the presence or absence of NIR irradiation according to temperature.

[0076] Figure 6 is a diagram showing the evaluation of cytotoxicity and proliferation rate according to the presence or absence of MXene and the presence or absence of NIR irradiation.

[0077] Figure 7 is a diagram showing the evaluation of cell recovery ability according to the presence or absence of MXene and the presence or absence of drug inclusion.

[0078] Figure 8 is a graph showing the results of evaluating cell recovery ability.

[0079] Hereinafter, the present invention will be described in more detail through the following examples and experimental examples. However, the scope of the present invention is not limited to the following examples and experimental examples, but includes modifications of technical concepts equivalent thereto.

[0080] Example 1. Characterization

[0081] Field emission scanning electron microscopy (FE-SEM, Zeiss, DEU) is a method for measuring the structure. The sample preparation process is as follows. To confirm the structure of Ti3C2MXene, a small amount of powder was distributed into the carbon type. Intercalated MXene was prepared by reacting with tetramethylammonium hydroxide (TMAOH, TCI, JPN) at room temperature for 3 days. To confirm the shape of the spheroid and the cells cultured on a titanium plate, the sample was reacted with 5% glutaraldehyde (Sigma Aldrich, USA) for 30 minutes, washed with phosphate buffer saline (PBS, Corning, USA), dried, and then coated with platinum.

[0082] To confirm the structure of the hydrogel, the middle of the hydrogel was cut in liquid nitrogen after freeze-drying and then coated with platinum. X-ray diffraction (XRD, Rigaku, JPN) was performed to confirm the composition and crystallinity of the MXene and silk fibroin / gelatin hydrogel. The basic components of MXene (Ti3C2) were analyzed using Fourier transform infrared spectroscopy (FT-IR, 640-IR, Agilent, GBR).

[0083] Example 2. NIR effect of MXene

[0084] 1 W / Cm 2The thermal response of Ti3C2MXenes was investigated by irradiating them with NIR (PSU-III-LED, Cnilaser, CHN) at 808 nm at an intensity of . MXenes were prepared by diluting 1000 μg / mL in DW. The thermal changes were measured for 5 cycles by turning the NIR on and off at 5-min intervals using a thermal imaging camera (FLIR, USA). The thermal changes were measured with a thermal imaging camera. In addition, various intensities from 0.25 to 1 W / cm 2 The thermal change of Ti3C2 was measured.

[0085] Example 3. Preparation of silk fibroin

[0086] Five grams of silkworm cocoons (Uljinsilk, KOR) were degummed by boiling in 0.02 M sodium carbonate (Na2CO3, Kanto, JPN) for 1 h and then rinsed three times with distilled water for 20 min each. After drying, the degummed silk was dissolved in 9.3 M lithium bromide (LiBr, Sigma Aldrich, USA) at 60 °C for 4 h. To remove salts, the dissolved solution was dialyzed against deionized water for 48 h using a dialysis membrane with a molecular weight cutoff of 3000 (Spectrum Laboratories, USA). A silk fibroin solution with a concentration of approximately 5 wt% was obtained.

[0087] Example 4. Preparation of SFG (Silk Fibroin-Gelatin) Hydrogel

[0088] SFG hydrogels were prepared by adding gelatin powder (Porcine, Type A, Sigma Aldrich, USA) in amounts (0 to 15%) to 5 wt% SF, and were prepared so that they were uniformly dissolved with SF at 60°C.

[0089] The experimental groups were named as follows: 5% SF (SF5), 10% Gelatin (G10), 5% SF + 2.5% Gelatin (SFG2.5), 5% SF + 5% Gelatin (SFG5), 5% SF + 10% Gelatin (SFG10), 5% SF + 15% Gelatin (SFG15).

[0090] 2 mM Tris(2,2'-bipyridyl)ruthenium(II) chloride hexahydrate (Ruthenium, Advanced biomatrix, USA) and 20 mM sodium persulfate (SPS, Advanced biomatrix, USA) were added, and cross-linking was performed for 1 minute and 30 seconds under visible light of 400 to 450 nm to prepare a hydrogel.

[0091] SFG-MXene hydrogels were prepared by adding MXene under the same conditions. Subsequently, experiments were conducted using SFG10, and SFG10 and MXene dissolved at 500 μg / mL were designated Ru and RuMX, respectively.

[0092] Example 5. Characteristics of SFG hydrogel

[0093] Hydrogels with a diameter of 5 mm were prepared and dried via freeze-drying. The internal structure of the hydrogels was confirmed using FE-SEM. Structural differences between the prepared hydrogels were confirmed using XRD.

[0094] To confirm the difference in mechanical strength, a rheometer (DHR-1, TA instruments, USA) and compression test (Instron, USA) were performed. The rheometer was set to 1% strain at 25°C and 0.5 to 10 Hz for a sample with a diameter of 25 mm and a height of 2 mm, and the oscillation frequency was measured. To measure the difference in physical properties according to the crosslinking process of the SFG solution, 1 mL of the prepared solution was dispensed onto a 25 mm substrate, and the oscillation frequency was measured while crosslinking with visible light.

[0095] To conduct a compression test according to the composition of the hydrogel, cylindrical samples with a height of 12 mm and a height of 10 mm were prepared, and a compression test was performed by applying a load of 10 N.

[0096] Example 6. Swelling and degradation of SFG hydrogel

[0097] To predict the wetting and degradation behavior of hydrogels in vivo, hydrogels were prepared, immersed in PBS, and incubated at 37°C. The hydrogel weight was measured every hour to analyze the degree of swelling and degradation.

[0098] Example 7. Hydrogel drug release

[0099] To determine the drug release conditions according to near-infrared (NIR) light in hydrogels, Ru and RuMX were prepared, and 100 μg / mL polydeoxyribonucleotide (PDRN, Genoss, KOR) was added to both materials.

[0100] Two hydrogels were cross-linked by reacting with visible light (400 to 450 nm) for 1 minute and 30 seconds, and each was placed in 1 mL of PBS, and the PBS was changed over time. NIR was measured at 1 W / cm for 3 hours. 2 It was investigated for 5 minutes at the intensity of .

[0101] To confirm the detection of PDRN, drug release was monitored using Pico Green (Invitrogen, USA). After the reaction, 100 μL of PBS and Pico Green containing the released PDRN were added, and the amount of PDRN was determined using a fluorescence-capable microplate. Hydrogels loaded with PDRN in Ru and RuMX were designated RuP and RuMXP, respectively.

[0102] Example 8. Cell viability of Ru, RuMX hydrogel

[0103] To confirm the proliferation and differentiation of cells in the hydrogel, hMSCs and NIH3T3 (Sigma Aldrich, USA) cells were used. 200 μL of Ru and RuMX hydrogels were prepared in a confocal dish (SPL, KOR), and hMSCs (1 x 10 4 ), NIH3T3 (1 x 10 5 ) cells / mL and performed cell attachment experiments.

[0104] After attaching the cells, near-infrared light was applied at 1 W / cm 2 The hydrogels were irradiated with near-infrared light for 5 minutes. The hydrogels irradiated with near-infrared light were named Ru(NIR) and RuMX(NIR). After washing with PBS on the 1st, 3rd, and 5th days, 500 μL of EDTA was sprayed to reduce cell adhesion, and 500 μL of cell culture medium was added to Trypan blue (Corning, USA) to stain the total volume of 1 mL, and the number of cells was measured.

[0105] Additionally, NIH3T3 cells were attached and stained with phalloidin. After washing with PBS, they were fixed with 4% PFA for 15 minutes, reacted with Triton X-100 for 10 minutes, and then reacted with phalloidin reagent for 1 hour. After the reaction was completed, the cells were washed once with PBS, stained with DAPI for 10 minutes, washed with PBS, and cell attachment was confirmed by CLSM.

[0106] Example 9. Cell migration in Ru, RuMX hydrogels

[0107] To examine the wound healing effect of cells, cell migration was performed. NIH3T3 cells were cultured in six wells, grown to 100% proliferation, and cells were scraped from the center of the plate using a blue tip. They were washed with PBS and cultured in DMEM culture medium for more than 2 hours, ensuring the cells remained stable. For the experimental group, hydrogels were made with TCP, Ru, RuP, RuMX, and RuMXP, placed in inserted cells (SPL, KOR), and 7 mL of culture medium was added to immerse the hydrogels.

[0108] Also, 1 W / cm 2 Cell movement according to drug release was investigated by irradiating the NIR (near infrared) of the intensity, and photographs were taken at 0, 12, 24, and 36 hours, and changes in area and length according to cell proliferation were measured.

[0109] Example 10. Antibacterial activity of Ru, RuMX hydrogel

[0110] To evaluate the antibacterial activity of the hydrogel, Escherichia coli (ATCC-11775) and Staphylococcus epidermidis (ATCC-14990) were cultured. UV spectrophotometer (Nabi, Microdigital, KOR) at 600 nm, OD=1 was 2.5 x 10 for E. coli. 8 , 2.0 x 10 for S. epidermidis8 It was confirmed that the value was colony-forming units (CFU) / mL.

[0111] For the bacterial growth test, 10 mL of nutrient medium (BD difco, USA) was added to a sterile tube, and 0.1 mL of bacteria (1 x 10 7 CFU / mL) was added and cultured at 37°C with shaking at 150 rpm. Ru, RuP, RuMX, and RuMXP hydrogels were placed in the tube and 1 W / Cm 2 The samples were exposed to NIR for 5 minutes every hour at an intensity of . The absorbance of the samples over time was measured at 600 nm.

[0112] To measure the colony forming units (CFU) of the strains, 15 mL of nutrient agar medium (BD difco, USA) was spread onto petri plates to create agar plates. The agar plates were dispensed, spread, and incubated in a 37°C incubator. After 24 hours, colonies in all samples were counted.

[0113] Example 11. In vivo experiment for wound healing using Ru hydrogel

[0114] Animal care and experimental protocols were approved by the Institutional Animal Care and Use Committee of Dankook University, Cheonan Campus, Republic of Korea (DKU 21-062). The animals were housed in a 12-hour light-dark cycle, maintained under constant temperature and humidity (RH 55±5%, 25±5°C). Food and water were provided ad libitum, and all experimental procedures followed the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health (NIH Publication No. 85-23, revised 2011).

[0115] To examine the wound healing effect of hydrogels, SKH-1 nude mice (hairless mice, Orient bio, KOR) were used. First, the mice were anesthetized by intraperitoneal injection of 2% avertin (Sigma Aldrich, USA), and the dorsal skin was sterilized with ethanol and povidone. The skin was excised symmetrically on both sides of the mouse's back, creating circles with a diameter of less than 8 mm. Hydrogel (Ru, RuP, RuMX, RuMXP) solutions were applied to the excised areas, and crosslinking was performed by irradiating them with visible light (400–450 nm) for 1 minute and 30 seconds. The areas were then sealed with Tegaderm (0.4 W / Cm). 2 NIR of the intensity was irradiated to the wound twice a day for 30 minutes.

[0116] Example 12. Histological analysis of wound healing

[0117] Mice in the wound healing model were sacrificed on days 7 and 14, respectively. Wounds were incised to a size of 1 cm × 1 cm and fixed with 4% PFA solution. The fixed tissues were made into paraffin blocks and sliced ​​at 5 μm thickness using a Leica rotary microtome (Leica, DEU). The sectioned samples were stained with hematoxylin and eosin (H&E) and observed using a CKX53 microscope (Olympus, JPN).

[0118] Example 13. Evaluation of the wound healing process

[0119] The wound healing process was observed through a camera for 14 days. The area of ​​the wound healing compared to the initial wound was measured using image J (n=4), and the healing rate was calculated using the following formula.

[0120] Wound healing rate = (A0-At) / A0 x 100

[0121] A0 and At represent the initial wound area and the wound area measured on that day, respectively. The thickness of the recovered epidermis and the density of the dermal layer were measured in the dermal cell area within the dermal layer using H&E staining.

[0122] Example 14. Statistical Analysis

[0123] All quantitative results were collected at least three times in each group. Statistical analysis was performed using the t-test, and comparisons between groups were analyzed using the one-way ANOVA test. Differences with a P value < 0.05 were considered statistically significant (* p < 0.05, ** p < 0.01, *** p < 0.001).

[0124] Experimental Example 1. Analysis of the physicochemical properties of SFG composite hydrogels.

[0125] The preparation of the SFG (Silk Fibroin-Gelatin) composite hydrogel according to the present invention is as shown in Fig. 1. The effect of ruthenium ions on the crosslinking of the SF and G composite hydrogel under visible light was observed as shown in Fig. 2. Crosslinking of the hydrogel could be observed in the surface layer 10 seconds after light exposure, and the hydrogel was completely crosslinked within 30 seconds.

[0126] There was no difference in gelation time between hydrogel groups with different SF:G ratios. Pore structure is one of the most important parameters of hydrogels for biomedical applications. To investigate the relationship between pore structure and SF:G ratio, the fractured surfaces of the hydrogels were observed using SEM, as shown in Figure 3. The average pore sizes of SF and G were 68.61 ± 11.97 μm and 108.46 ± 25.83 μm, respectively.

[0127] The difference in pore size is primarily due to a combination of the crosslinking density and hydrophilicity of the molecules. Crosslinking density is closely related to the amount of tyrosine. Hydrogels with higher crosslinking density have smaller pores. Gelatin contains tyrosine groups in its molecules, but the total tyrosine content of gelatin molecules (~0.05%) is much lower than that of silk fibroin molecules (~5%).

[0128] As shown in Figure 3, the SFG composite hydrogel exhibited smaller pore sizes than the pure form. Because the SFG composite group contained more polymer than the SF group, its crosslinking density increased, resulting in smaller pore sizes than the SF group. In contrast, the SFG10 group exhibited larger pore sizes than the other SFG composite groups.

[0129] Gelatin is a hydrophilic polymer, whereas silk fibroin is somewhat hydrophobic. Because the effect of gelatin is more pronounced in SFG10 than in other SFG groups, the hydrogel becomes more hydrophilic and absorbs more water, resulting in larger pore sizes. Since one of the primary roles of hydrogel wound dressings is to absorb exudate from the wound, the physicochemical properties of the hydrogel are very important.

[0130] Comparing the swelling ratios of each hydrogel group, all groups except SF showed positive swelling, which increased with increasing gelatin content. The hydrophobicity of the silk fibroin molecules resulted in a large initial shrinkage after hydrogel formation. The swelling results are also consistent with the pore structure data. The hydrophobic silk fibroin excreted some water from the hydrogel, resulting in a negative swelling ratio for SF, and the pore size of the SF group was smaller than that of the G group. For wound healing, it is important to ensure that the hydrogel adheres to the wound site for a long period of time without rapid degradation. The degradation behavior of the hydrogels was examined, and the SF group showed the most stable characteristics under degradation conditions, while the G group showed the lowest stability. The degradation rate of the SFG composite hydrogel group increased with increasing gelatin content. The degradation rate of the SFG group significantly decreased after 10 days, with 60-80% of the original mass remaining.

[0131] This suggests that the SF or SFG group would be suitable for wound dressing due to its physicochemical stability.

[0132] Experimental Example 2. Mechanical Properties of SFG Composite Hydrogels

[0133] Wound dressing materials are subjected to continuous mechanical loads during use. Therefore, rheological analysis of the composite hydrogel was performed to investigate its mechanical properties.

[0134] The storage modulus is SF5 (1800), SFG2.5 (1800), SFG5 (3900), SFG10 (4800), SFG15 (8000), and G10 (4000) dyne / Cm depending on the composition. 2 The difference was shown in the loss modulus. The loss modulus decreases as the viscosity increases, and the storage modulus indicates elasticity, with a higher value indicating greater elasticity.

[0135] The mechanical properties of the hydrogels were further investigated through compression tests. The results confirmed that all mechanical properties of the composite hydrogels increased with increasing gelatin content. Both dynamic and static tests revealed that the mechanical properties of the composite hydrogels were significantly affected by gelatin content.

[0136] The mechanical properties of the hydrogels were also influenced by the mechanical properties of the polymer itself and the crosslinking density. SF hydrogels exhibited significantly weaker properties than gelatin hydrogels. Therefore, the mechanical properties of the composite hydrogels improved after adding gelatin. The SFG15 group exhibited the highest strength value compared to the gelatin hydrogel.

[0137] These results may be due to the high cross-linking density of the matrix due to the large amount of polymer phase. However, the SFG15 group showed lower physicochemical stability compared to other composite hydrogel groups due to its high gelatin content.

[0138] Therefore, the SFG10 group showed the most reasonable performance results, and further tests were performed as a control material group for the MXene composite hydrogel group.

[0139] Experimental Example 3. Drug release from hydrogel containing MXene

[0140] The use of MXene as a composite material has great potential to produce highly stable and effective materials that can optimize hydrogel dressings. The unique lamellar structure of MXene is revealed by FE-SEM imaging of Ti3C2. The formation of the MXene lamellar structure occurs layer by layer as the aluminum layer is gradually etched from the MAX phase. The size of the MXene particles is observed to be approximately 10-20 μm in diameter. X-ray diffraction analysis was performed to analyze the crystal structure of Ti3C2. The analysis results showed major peaks at (002), (006), and (008), which is consistent with previous studies, indicating successful removal of the aluminum layer through etching.

[0141] The chemical composition and functional groups present on the surface of Ti3C2MXene were revealed by FT-IR spectra. The spectra revealed the presence of negative functional groups, such as OH, formed at the edges during MXene production due to the formation of oxygen functional groups. FT-IR elemental analysis of Ti3C2 confirmed the presence of major Ti peaks, including Ti-O-Ti and Ti-C, which calibrate the purity of MXene.

[0142] The photothermal effect is one of the most remarkable properties of Ti3C2MXene, as is widely known from various types of MXenes. When irradiated with near-infrared (NIR) light in the 808 nm range, Ti3C2MXene undergoes a vibrational response, resulting in an increase in temperature. 1 W / cm 2 Repeated application of an output NIR laser to a 1 mg / mL MXene suspension resulted in a maximum temperature increase of approximately 80°C, and upon irradiation, the temperature returned to the initial level within 5 min. The photothermal effect remained constant even with repeated irradiation.

[0143] This suggests that the photothermal effect of Ti3C2MXene can be utilized to control the drug release rate and regulate the temperature of the treatment site, potentially improving the therapeutic efficacy.

[0144] The concentration of MXene and the output of the near-infrared (NIR) laser play an important role in the photothermal effect of MXene. Therefore, the temperature change was observed and analyzed. The temperature increase of MXene was highest at 1 mg / mL, and a stronger photothermal effect was observed as the intensity increased. Therefore, 1 W / cm 2 The highest temperature rise was observed in .

[0145] This demonstrates that MXene exhibits sufficient photothermal effects and that the optimal temperature can be controlled for each application by adjusting the concentration and NIR intensity.

[0146] One of the major challenges in composite materials is dispersion stability. Accurate results can only be achieved when the material or solution is evenly dispersed. Images of gels with and without MXene demonstrate that the MXene particles in the hydrogels produced in this invention are well dispersed without aggregation or sedimentation. This suggests that the hydrogels have high viscosity in a liquid state and that rapid crosslinking maintains the MXene dispersion stability.

[0147] Furthermore, since MXene is an excellent elastic material, it was expected to influence the mechanical properties. Therefore, rheological and compression tests were performed to analyze the mechanical properties using well-dispersed hydrogels.

[0148] The mechanical properties of SFG10 and SFG10MX hydrogels were determined through rheological measurements. The addition of MXene increased the storage modulus from 460 Pa to 700 Pa. SFG10MX exhibited higher average values ​​for both modulus and strength compared to SFG10, a trend similar to that observed in compression tests. However, a decrease in strain values ​​was observed. These results indicate that the addition of high-performance materials can alter the fundamental properties of hydrogels.

[0149] The mechanical properties of SFG10 were improved simply by adding MXene, as evidenced by a decrease in strain values ​​due to the material's reinforcing effect. The mechanical analysis suggests that the addition of MXene alone can improve the mechanical properties of SFG10 hydrogels.

[0150] Adhesion to skin is a critical factor in evaluating the effectiveness of a material in skin regeneration experiments. To investigate whether hydrogels maintain their morphological and adhesive properties on tissue surfaces without damage, porcine skin, similar to human skin, was used to test the hydrogel's resistance to stretching, torsion, bending, and hydraulic pressure after crosslinking (Figure 4).

[0151] The hydrogel-coated skin maintained its original shape and adhesion without significant degradation of physical properties even under strong stress. This demonstrates that the ruthenium-mediated visible light-crosslinked silk fibroin / gelatin composite hydrogel used in the present invention possesses excellent skin adhesion and mechanical stability.

[0152] PDRN, extracted from salmon DNA, is similar to human DNA and has virtually no side effects or toxicity, making it a natural medicine that can be taken in high doses. It can also be combined synergistically with other drugs and substances to enhance their effects, and is currently used in cosmetics and therapeutics.

[0153] As a result of observing the release behavior of PDRN together with the MXene photothermal reaction in Fig. 5, a large difference in the amount of PDRN released was observed depending on whether NIR irradiation was applied in the hydrogel group containing MXene, and it was confirmed that the release of PDRN was faster at 37 ℃, which is similar to the human body temperature.

[0154] In addition, the photothermal effect was exhibited even when the drug was simply mixed without loading the drug using the drug charge and functional group, which can be explained by the MXene lamellar structure, indicating that the drug can penetrate into the gap between the large surface areas, and thus PDRN release is possible through MXene vibration even if the electric polarity is different.

[0155] This suggests that although no significant inflection point was observed due to burst-like PDRN release induced by near-infrared light, ultimately more drug was released across the overall slope.

[0156] Experimental Example 4. Evaluation of Cell Viability in Hydrogels

[0157] PDRN is known to be non-toxic, and in the present invention, no toxicity was observed at a high concentration of 200 μg / ml (Figure 6). To assess the potential synergistic effect of increased cellular activity through infrared-induced drug release, it is important to evaluate the effects of hydrogels and infrared radiation on cells. To investigate whether the hydrogel surface and infrared radiation affect cytotoxicity and proliferation rate, cells were directly attached to the hydrogel surface and cell numbers were compared.

[0158] NIH3T3 fibroblast cells were used in the experiment, and the control group was divided into groups according to the presence or absence of infrared radiation from RuMX hydrogel. The results showed no cytotoxicity, and cell proliferation rates were very similar.

[0159] These results suggest that the hydrogel and cells are highly compatible, allowing cells to proliferate without toxicity.

[0160] Despite containing a large amount of MXene, the MXene contained in the hydrogel was evenly distributed and did not directly affect the cell adhesion surface. Phalloidin and DAPI staining of the hydrogel surface revealed that all groups maintained very stable cell morphology for cell attachment and proliferation on the first day.

[0161] Cell proliferation on the hydrogel surface was stable and successful for three days. Because SF and G are natural cell-friendly polymers, they can inhibit cell adhesion caused by ruthenium and MXene, enabling proliferation without toxicity.

[0162] Experimental Example 5. Wound Healing Evaluation Using Hydrogel

[0163] The wound healing test, also known as the scratch test, is a two-dimensional technique established in vitro through cell migration. Cell migration experiments were performed to determine the wound healing effects of ruthenium, MXene, and PDRN. All experiments were performed in a medium containing 5% fetal bovine serum (FBS) to minimize nutrient loss and assess the efficacy of the drugs.

[0164] NIR is 1 W / cm 2 The intensity of the PDRN-free Ru and RuMX groups showed no significant difference in wound healing compared to the TCP group.

[0165] The group containing PDRN was set at a concentration of 50 μg / mL, and the wound healing area was quantified and analyzed. The RuMXP group showed a significant wound healing effect compared to the TCP, Ru, and RuMX groups, with the scratched area completely healed within 36 hours. Furthermore, the RuMXP group showed a faster wound healing rate than the RuP group (Fig. 7).

[0166] This suggests that the photothermal effect of MXene induced by near-infrared irradiation induces faster drug release, thereby increasing the rate of wound healing. Furthermore, PDRN can maximize therapeutic efficacy by promoting cell proliferation while controlling drug release.

[0167] The antibacterial properties of 2D nanomaterials have attracted considerable interest in various fields such as environmental engineering, biotechnology, and medicine. A newly developed 2D nanomaterial, Ti3C2Tx MXene, is known to exhibit excellent antibacterial activity against both Gram-negative and Gram-positive bacteria. In this study, the antibacterial properties of a MXene-containing hydrogel dressing were evaluated through qualitative and quantitative antibacterial tests using the Gram-negative bacteria Escherichia coli (E. coli) and the Gram-positive bacteria Staphylococcus epidermidis (S. epidermidis) on wound skin.

[0168] Evaluation of bacterial inhibition using MXene and NIR irradiation confirmed that the MXene-containing hydrogel dressing has the ability to inhibit bacterial growth.

[0169] Qualitative and quantitative analyses showed that bacterial growth was slower in the MXene-containing hydrogel group, and the MXene hydrogel group exposed to NIR showed the lowest bacterial colony forming unit (CFU) value.

[0170] This suggests that the vibration and heat generation of MXene due to NIR exposure inhibits bacterial growth around the hydrogel, suggesting that MXene has antibacterial properties.

[0171] Mice were divided into four groups: Ru, RuP, RuMX, and RuMXP. A skin incision (1.2 cm x 1.2 cm) was made on the back of the mice, and the hydrogel was rapidly applied and cross-linked under visible light.

[0172] Wound healing was observed visually for up to two weeks after surgery. The Ru and RuMX experimental groups exhibited slow wound healing, with the dermis and epidermis slowly filling. Furthermore, despite the hydrogel's moisturizing properties, scab formation was observed.

[0173] This shows that while it is possible to maintain the moisture of the hydrogel without drugs, wound healing is slower without the therapeutic effect of drugs.

[0174] In contrast, RuP and RuMXP exhibited rapid wound healing, minimal scab formation, no signs of infection (inflammation), and excellent wound healing and skin regeneration effects. The wound healing rate of each group was quantified by measuring the wound area over time. The dressing containing both PDRN and MXene was the most effective in promoting wound healing (Fig. 8).

[0175] After 10 days of wound healing, the wound size was 49.2% for Ru, 56.8% for RuMX, and 65.1% for RuP, with a difference of less than 11% between the samples, but RuMXP showed the fastest recovery rate of 73.5%. There was a 24% difference between the slowest-recovering Ru group and the fastest-recovering RuMXP group, and only an 8% difference between the RuP group, which had the smallest difference. However, these results showed a much greater difference in recovery after 2 weeks. The recovery rate was more than 16% higher than the slowest-recovering Ru group and about 4.5% higher than the RuP group. The final wound healing size in the RuMXP group was reduced by 87.9%, and additional drug release was confirmed through NIR.

[0176] RuMXP showed a reduction in wound size compared to the other experimental groups, along with better quality of new skin tissue. H&E staining showed representative histological sections of wound healing in each group after two weeks. While new skin tissue was formed in all groups, Ru and RuMX showed incomplete epidermal formation and a slight decrease in dermal density, preventing complete wound healing.

[0177] The RuMXP group had a thicker epidermis than the RuP group. The measured epidermal thickness was 6.91 ± 1.38 μm in the RuMXP group, approximately twice as thick as the 3.50 ± 0.79 μm in the RuP group. In the other groups, dermal formation was not fully completed, except in the RuMXP group. In addition to observing empty spaces not occupied by tissue, eosinophilic inflammatory cells were more abundant around the wound site. Eosinophils increase rapidly during the inflammatory response of wound healing and gradually decrease after recovery.

[0178] The RuMXP group exhibited thicker epidermis and a wider distribution of neutrophils during the dermal and epidermal recovery phases. However, the Ru, RuP, and RuMX groups showed a relatively slower recovery rate compared to the RuMXP group, indicating that neutrophils were widely distributed throughout the dermal layer. These results were similar to those of the scratch test, suggesting that the RuMXP group exhibited the fastest wound healing rate.

[0179] The dermis, with its high density of blood vessels and nerves, plays a crucial role in temperature regulation and nerve transmission. Therefore, dense dermal regeneration restores skin function. The RuMXP group demonstrated a regenerated dermal density of 98.74±0.17% per 0.3 mm² area, approximately 20% higher than the RuP group.

[0180] This suggests that the RuMXP group exhibits the best drug release ability, which not only enhances therapeutic efficacy but also can be usefully used as a smart wound treatment composition that prevents external infection by MXene.

[0181] The silk fibroin-gelatin hydrogel system according to the present invention, containing PDRN, a DNA therapeutic agent, and ruthenium and MXene, non-toxic photoinitiators that react with natural light, exhibits excellent mechanical properties and maximizes wound healing efficacy through antimicrobial activity and precise drug release control. This innovative system can be usefully applied as a wound healing pharmaceutical composition, quasi-drug composition, and cosmetic composition, including a novel smart wound healing dressing.

[0182] While the embodiments of the present invention have been described above, the present invention is not limited to the above embodiments, but can be manufactured in various different forms. Those skilled in the art will understand that the present invention can be implemented in other specific forms without altering the technical spirit or essential characteristics of the present invention. Therefore, the embodiments described above should be understood to be illustrative in all respects and not restrictive.

Claims

A hydrogel for wound healing comprising a natural polymer having a molecular weight of 1.2 or higher, a photoinitiator and MXene.

2. In paragraph 1, A hydrogel characterized in that the above natural polymer is at least two selected from the group consisting of alginate, heparin, silk fibroin, silk sericin, methylcellulose, gellan gum, chitosan, fibrinogen, collagen, gelatin, and hyaluronan.

3. In paragraph 2, A hydrogel characterized in that the above natural polymer is a natural polymer containing tyrosine.

4. In paragraph 3, A hydrogel characterized in that the natural polymer containing the above tyrosine comprises gelatin and silk fibroin.

5. In paragraph 4, A hydrogel characterized in that the gelatin is contained in an amount of 1 to 30 parts by weight and the silk fibroin is contained in an amount of 1 to 50 parts by weight based on 100 parts by weight of the total hydrogel.

6. In paragraph 1, A hydrogel, characterized in that the photoinitiator comprises a ruthenium compound.

7. In paragraph 6, A hydrogel characterized in that the photoinitiator further comprises sodium persulfate, ammonium persulfate or potassium persulfate.

8. In paragraph 1, A hydrogel characterized in that the hydrogel is crosslinked in the visible light range.

9. In paragraph 8, A hydrogel characterized in that the visible light region has a wavelength of 400 to 450 nm.

10. In paragraph 8, A hydrogel characterized in that the cross-linking occurs within 1 to 2 minutes.

11. In paragraph 1, A hydrogel characterized in that the hydrogel carries a drug and controls the release of the drug.

12. In paragraph 11, A hydrogel, characterized in that the drug is hydrophilic.

13. In paragraph 11, A hydrogel characterized in that the drug comprises PDRN.

14. A method for producing a hydrogel according to claim 1, comprising the following steps: i) a step of preparing a first mixture by mixing two or more natural polymer solutions with a photoinitiator; ii) a step of preparing a second mixture by adding MXene to the first mixture; and iii) A step of producing a hydrogel by irradiating the second mixture with visible light.

15. A pharmaceutical composition for wound treatment comprising the hydrogel of any one of claims 1 to 13.

16. A wound treatment quasi-drug composition comprising the hydrogel of any one of claims 1 to 13.

17. A cosmetic composition comprising the hydrogel of any one of claims 1 to 13.

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