Biocompatible hydrogel containing hyaluronic acid, polyethylene glycol, and silicone components.

Abstract

The present invention relates to a biocompatible hydrogel comprising hyaluronic acid, polyethylene glycol, and a silicone-containing component, more particularly to a biocompatible hydrogel produced by inducing inter- and / or intra-molecular crosslinking of hyaluronic acid, polyethylene glycol, and a silicone-containing component only by irradiation without the addition of reactive groups, chemical crosslinkers, etc., a method for producing the same, and use of the same.

Description

Technical Field

[0001] This application claims priority based on Korean Patent Application No. 2021-0006872, filed on January 18, 2021, and the entire specification of that application is incorporated herein by reference.

[0002] The present invention relates to a biocompatible hydrogel containing hyaluronic acid, polyethylene glycol, and a silicone-containing component. More specifically, the present invention relates to a biocompatible hydrogel produced by inducing intermolecular and / or intramolecular crosslinking of hyaluronic acid, polyethylene glycol, and a silicone-containing component only by radiation irradiation without adding a reactive group, a chemical crosslinking agent, etc., a method for producing the same, and use thereof.

Background Art

[0003] In recent years, hydrogels have attracted much attention in the medical field, and wide applications are expected, such as medical fillers, release systems for bioactive substances, organs using three-dimensional structures, tissue regeneration, etc.

[0004] Such hydrogels have generally been produced by a method of adding a chemical substance such as a crosslinking agent and / or a curing agent to a polymer material and crosslinking it. However, since the crosslinking agent and / or curing agent used in the crosslinking reaction is harmful to the living body, when a hydrogel produced using such a crosslinking agent and / or curing agent is used in the living body, there is a problem of causing harmful effects. In particular, such hydrogels are not suitable for use as medical and pharmaceutical materials, for example, wound dressings, drug delivery carriers, contact lenses, cartilage, intestinal adhesion preventives, etc. Further, when a crosslinking agent and / or a curing agent is used, the residual crosslinking agent and / or curing agent in the hydrogel after production must be removed, so that not only the production process is complicated, but also the production cost is increased.

[0005] Therefore, efforts are being made to produce hydrogels derived from polymers without using crosslinking agents and / or curing agents, and as a result of these efforts, there have been reports of the production of hydrogels by irradiating synthetic polymers with radiation.

[0006] However, hydrogels derived from synthetic polymers are unsuitable for pharmaceutical applications due to their biocompatibility and biodegradability. Therefore, there is a need to develop hydrogels that are formed solely by intramolecular or intermolecular crosslinking of biocompatible molecules, without the use of crosslinking agents, curing agents, or organic solvents.

[0007] On the other hand, hyaluronic acid is a biomolecular substance that is a type of polysaccharide in which repeating units composed of N-acetylglucosamine and D-glucuronic acid are linearly linked. Since its first isolation from the fluid filling the eyeballs of animals, it has been known to be abundant in animal placentas, synovial fluid, pleural fluid, skin, and rooster combs, and is also produced by microorganisms of the genus Streptococcus, such as Streptococcus equii and Streptococcus zoepidemicus.

[0008] Hyaluronic acid has excellent biocompatibility and high viscoelasticity in solution, and is widely used not only in cosmetic applications such as cosmetic additives, but also in various pharmaceutical applications such as ophthalmic surgical aids, joint function improvers, drug delivery substances, and eye drops. However, hyaluronic acid alone is easily decomposed in the body or under acidic or alkaline conditions, severely limiting its use. Therefore, chemical crosslinking agents are generally added to the production of hyaluronic acid-based hydrogels (Patent Document 1).

[0009] In particular, it is well known in the industry that biocompatible polymers such as carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, and carboxymethyl starch can form gels by irradiation (Non-Patent Documents 1-3). However, in the case of hyaluronic acid, irradiation easily causes decomposition reactions such as a decrease in molecular weight and a decrease in viscosity (Patent Document 2). Therefore, hyaluronic acid-based hydrogels produced by irradiation, i.e., hyaluronic acid-based hydrogels produced solely by irradiation without the addition of chemical crosslinking agents, organic chemicals, etc., have not yet been reported.

[0010] Patent Document 3 presents a method for producing Merck gel for filler treatment, which includes a step of producing a bulk hydrogel by crosslinking hyaluronic acid by irradiating a 10-20 w / v% hyaluronic acid aqueous solution with an electron beam for 30 seconds to 5 minutes at a dose of 0.5-5 kGy. However, due to the properties of hyaluronic acid, which can absorb water up to several times its own weight, it is practically very difficult to produce a 10-20 w / v% hyaluronic acid aqueous solution in a normal manufacturing facility, and there is a limitation that it is impossible to produce hydrogels with various physical properties.

[0011] On the other hand, silicone is a biocompatible polymer material that is not only heat-stable and has excellent oxygen permeability, but is also transparent, non-toxic. Due to these characteristics, silicone-containing compounds are used as biomaterials in catheters, drains, pacemakers, membrane oxygenators, and ear and nose prostheses. They are also used in the medical supplies field for dressings to promote wound healing and improve scarring, and are used in a wide range of applications, from contact lenses to medical devices such as prostheses and elastic polymers. In particular, in cosmetics, silicone-containing ingredients are often used not only to improve the spreadability of cosmetics, but also to act as a skin lubricant, adding shine without stickiness. They can also form a thin layer after application to the skin, preventing moisture evaporation.

[0012] Thus, if hydrogels containing both hyaluronic acid and silicone-containing components, which exhibit high biocompatibility and various advantages, can be manufactured without the use of chemical crosslinking agents or organic solvents, they are expected to be useful in the development of pharmaceuticals, medical devices, quasi-drugs, cosmetics, and skin beauty products. [Prior art documents] [Patent Documents]

[0013] [Patent Document 1] International Publication No. 2013 / 055832 [Patent Document 2] Korean Published Patent Publication No. 2008-0086016 [Patent Document 3] Korean Registered Patent No. 2070878 [Non-patent literature]

[0014] [Non-Patent Document 1] Nuclear Instruments and Methods in Physics Research B 208 (2003) 320-324 [Non-Patent Document 2] Carbohydrate Polymers 112 (2014) 412-415 [Non-Patent Document 3] Nuclear Instruments and Methods in Physics Research B 211 (2003) 533-544 [Overview of the project] [Problems that the invention aims to solve]

[0015] As a result of repeated research to provide a hyaluronic acid and silicone-based biocompatible hydrogel produced only by radiation irradiation without using chemical crosslinking agents, organic chemicals, etc., the inventors of the present invention discovered that by using polyethylene glycol, another biocompatible polymer, in combination, it is possible to produce hydrogels containing hyaluronic acid, polyethylene glycol, and silicone-containing components that exhibit various physical properties under specific production conditions, and thus completed the present invention.

[0016] Therefore, an object of the present invention is to provide a hydrogel formed only by intermolecular crosslinking, intramolecular crosslinking, or intermolecular and intramolecular crosslinking of hyaluronic acid, polyethylene glycol (PEG), and a silicone-containing component.

[0017] Another object of the present invention is to provide a method for producing a hydrogel formed only by intermolecular crosslinking, intramolecular crosslinking, or intermolecular and intramolecular crosslinking of hyaluronic acid, polyethylene glycol (PEG), and a silicone-containing component, which includes the following steps: (a) A step of adding hyaluronic acid, polyethylene glycol, and a silicone-containing component to water to prepare a solution; (b) A step of irradiating the solution produced in the step (a) with radiation to induce crosslinking of the materials.

[0018] Another object of the present invention is to provide a cell delivery agent, drug delivery, anti-adhesion agent, cell support, dental filling material, orthopedic filling material, wound dressing, or skin filling material containing the hydrogel.

[0019] Another object of the present invention is to provide a composition for skin application to a wound site containing the hydrogel as an active ingredient.

[0020] Also, it provides a composition for skin application to a wound site consisting of the hydrogel.

[0021] Also, it provides a composition for skin application to a wound site consisting essentially of the hydrogel.

[0022] Another object of the present invention is to provide the use of the hydrogel for manufacturing a skin application formulation for wound sites.

[0023] Another object of the present invention is to provide a method for treating a wound site by applying an effective amount of a composition containing a hydrogel as an active ingredient to the skin of an individual in need. [Means for solving the problem]

[0024] To achieve the above-mentioned objectives of the present invention, the present invention provides a hydrogel formed by intermolecular crosslinking, intramolecular crosslinking, or solely by intermolecular and intramolecular crosslinking of hyaluronic acid, polyethylene glycol (PEG), and a silicone-containing component.

[0025] To achieve another objective of the present invention, the present invention provides a method for producing a hydrogel formed by intermolecular crosslinking of hyaluronic acid, polyethylene glycol (PEG), and a silicone-containing component, or solely by intermolecular and intramolecular crosslinking, comprising the following steps: (a) A step of preparing a solution by adding hyaluronic acid, polyethylene glycol, and a silicone-containing component to water; (b) A step of irradiating the solution produced in step (a) with radiation to induce crosslinking of the material.

[0026] To achieve another objective of the present invention, the present invention provides cell signaling molecules, drug delivery agents, anti-adhesion agents, cell supports, dental fillers, orthopedic fillers, wound dressings, or skin fillers comprising the hydrogel.

[0027] To achieve another objective of the present invention, the present invention provides a composition for skin application to wound sites, comprising the hydrogel as an active ingredient.

[0028] Furthermore, the present invention provides a composition for skin application to wound sites, comprising the hydrogel described above.

[0029] Furthermore, the present invention provides a composition for skin application to wound sites, which is essentially made of the hydrogel.

[0030] To achieve another objective of the present invention, the present invention provides the use of the hydrogel for producing a skin application formulation for wound sites.

[0031] To achieve another objective of the present invention, the present invention provides a method for treating a wound site by applying an effective amount of a composition containing a hydrogel as an active ingredient to the skin of an individual in need.

[0032] The present invention will be described in detail below.

[0033] The present invention provides a hydrogel formed by inter-molecular cross-linking, intra-molecular cross-linking, or solely by inter-molecular and molecular cross-linking of hyaluronic acid, polyethylene glycol (PEG), and a silicone-containing component.

[0034] Methods for producing hydrogels using polymers typically involve the use of crosslinking agents to induce crosslinking of the polymers. In methods that induce crosslinking of polymers using crosslinking agents, the crosslinking agent mediates bonding between or within polymers, meaning the crosslinking agent may be incorporated into the hydrogel. If the concentration of the crosslinking agent is high, it may remain in the reactant in an active state, or unreacted material may remain after the reaction, leading to the problem that a purification process is essential during the hydrogel production process. Furthermore, crosslinking agents remaining in the hydrogel may cause several side effects after administration to the body. However, the inventors have confirmed that by irradiating a mixed aqueous solution of hyaluronic acid, polyethylene glycol, and a silicone-containing component with an electron beam under specific conditions, intermolecular or intramolecular crosslinking of hyaluronic acid, polyethylene glycol, and / or the silicone-containing component is induced, and a hydrogel is formed. A hydrogel formed solely by the bonding of hyaluronic acid, polyethylene glycol, and / or silicone-containing components themselves, without containing external substances such as internal crosslinking agents or metal cations added for physical crosslinking, has not been previously reported and is being disclosed for the first time by the present inventors through this invention.

[0035] On the other hand, biocompatibility is essential for all medical materials, not just polymer materials, and this biocompatibility can be defined in two ways. In a broad sense, biocompatibility means possessing both the desired function and safety for the living body, while in a narrow sense, biocompatibility means biological safety for the living body, i.e., non-toxicity and sterilization function.

[0036] Furthermore, since the biocompatible hydrogel of the present invention is formed solely by intermolecular or intramolecular crosslinking of hyaluronic acid, polyethylene glycol, and / or silicone-containing components, it has the advantage of being extremely biocompatible, as it does not have the aforementioned problems associated with hyaluronic acid-based hydrogels manufactured by conventional methods. Moreover, since the hydrogel of the present invention can be manufactured by irradiating an aqueous solution with radiation without using organic solvents, it does not require contamination or complex processes that may occur during the manufacturing process, making it highly applicable industrially.

[0037] In other words, the hydrogel provided in the present invention is characterized in that no additional functional groups are bonded to the hyaluronic acid, polyethylene glycol, and silicone-containing components, and no crosslinking agents other than hyaluronic acid and polyethylene glycol are directly involved in or mediating the crosslinking.

[0038] In this invention, hyaluronic acid, which is the raw material for biocompatible hydrogels, has extremely high utility as a carrier for drugs and the like due to the multifunctional functional groups present in its chemical structure. Furthermore, its physicochemical properties such as biocompatibility and biodegradability give it superior potential for use compared to synthetic polymers in the pharmaceutical field.

[0039] In this invention, hyaluronic acid means all hyaluronic acid, hyaluronic acid salts, or mixtures of hyaluronic acid and hyaluronic acid salts. Hyaluronic acid salts may be one or more selected from the group consisting of sodium hyaluronate, potassium hyaluronate, calcium hyaluronate, magnesium hyaluronate, zinc hyaluronate, cobalt hyaluronate, and tetrabutylammonium hyaluronate, but are not limited thereto.

[0040] In this invention, polyethylene glycol offers numerous advantages in the fields of drug delivery and tissue engineering. Typically, it has high solubility in organic solvents, is non-toxic, does not cause rejection reactions in the immune system, exhibits excellent biocompatibility, can easily encapsulate and release drugs as a drug delivery body, and is used in the pharmaceutical industry as a material approved for use in the human body by the U.S. Food and Drug Administration. Furthermore, polyethylene glycol improves the biocompatibility of polymers used in blood contact and exhibits the greatest effect in inhibiting protein adsorption, making it widely used as a biomaterial among hydrophilic polymers.

[0041] In the present invention, the silicone-containing component is a component containing at least one [-Si-O-] unit, selected from monomers, macromers, or prepolymers. Preferably, total Si and bonded O are present in the silicone-containing component in an amount exceeding 20% ​​by weight of the total molecular weight of the silicone-containing component, preferably exceeding 30% by weight. The silicone-containing component may also contain polymerizable active groups such as acrylate, methacrylate, acrylamide, methacrylamide, vinyl, N-vinyl lactam, N-vinylamide, and styryl functional groups, but for the purposes of the present invention, it is preferable that the silicone-containing component excludes the above functional groups.

[0042] Examples of silicone-containing components useful for the present invention can be found in U.S. Patents 3,808,178, 4,120,570, 4,136,250, 4,153,641, 4,740,533, 5,034,461, and 5,070,215, as well as in European Patent Application Publication No. 080539, which describe many examples of silicone-containing components.

[0043] Non-limiting examples of the silicone-containing component in the present invention include polydimethylsiloxane, caprylylmethyltrisiloxane, octamethylcyclotetrasiloxane, decamethylcyclopentasiloxane, dimethicone, and cyclosiloxane, preferably polydimethylsiloxane, and most preferably trimethylsilyl-terminated poly(dimethylsiloxane) having the structure of the following formula 1. [ka]

[0044] The hydrogel provided by the present invention may be characterized in that it is manufactured by a method comprising the following steps: (a) A step of preparing a solution by adding hyaluronic acid, polyethylene glycol, and a silicone-containing component to water; (b) A step of irradiating the solution produced in step (a) with radiation to induce crosslinking of the material.

[0045] Through various examples, the inventors have established conditions for producing hydrogels consisting solely of intermolecular and / or intramolecular crosslinking of hyaluronic acid, polyethylene glycol, and silicone-containing components by irradiation.

[0046] According to one embodiment of the present invention, it was confirmed that no hydrogel was formed when an aqueous solution containing hyaluronic acid and a silicone-containing component was irradiated with an electron beam. However, it was confirmed that when polyethylene glycol was added to hyaluronic acid and the silicone-containing component and irradiated with an electron beam under certain conditions, hydrogels exhibiting various physical properties were formed.

[0047] According to another embodiment of the present invention, it was confirmed that when an aqueous solution containing only polyethylene glycol and a silicone-containing component is irradiated with an electron beam, sufficient crosslinking is not induced, and an incomplete hydrogel is formed.

[0048] According to various embodiments of the present invention, it has been confirmed that various combinations of conditions are crucial for inducing intermolecular and / or intramolecular crosslinking of hyaluronic acid, polyethylene glycol, and silicone-containing components using radiation irradiation to produce hydrogels. Specifically, it has been confirmed that hydrogels will not form if the molecular weight / concentration of hyaluronic acid, the molecular weight / concentration of polyethylene glycol, the molecular weight / concentration of the silicone-containing compound, and the energy irradiation amount do not meet specific conditions. Furthermore, it has been confirmed that it is possible to produce hydrogels exhibiting various physical properties by appropriately controlling these conditions.

[0049] In step (a) of the present invention, polyethylene glycol with a molecular weight of 15 to 50 kDa can be used, preferably polyethylene glycol with a molecular weight of 15 to 40 kDa, and most preferably polyethylene glycol with a molecular weight of 20 to 35 kDa.

[0050] Using polyethylene glycol with a molecular weight of less than 15 kDa may result in the hydrogel not forming upon electron beam irradiation. Using polyethylene glycol with a molecular weight of more than 40 kDa may result in problems where, when the hydrogel forms at low radiation doses, it is not perfectly formed, with excessive air bubbles or cracking within the hydrogel. Furthermore, if the molecular weight is too high (above 40 kDa), when PEG is injected into the body, its biodegradability decreases, making it difficult to excrete from the body and potentially causing problems due to its prolonged presence in the body.

[0051] Furthermore, in step (a) of the present invention, polyethylene glycol can be added to water at a concentration of 0.1 to 3% (w / v), preferably at a concentration of 0.1 to 2% (w / v), and more preferably at a concentration of 0.5 to 1.5% (w / v). Most preferably, it can be added to water at a concentration of 0.5 to 1.0% (w / v).

[0052] If the polyethylene glycol concentration is too low, the crosslinking reaction is not properly induced, and a hydrogel is not formed. If it is too high, only the crosslinking reaction between polyethylene glycol chains becomes dominant, and the hydrogel and residual solution coexist. In other words, a gel in which all three components are uniformly crosslinked is not formed, and there is a limit to how far the crosslinking reaction can proceed, with only some of the components crosslinking.

[0053] In step (a) above, hyaluronic acid with a molecular weight of 50 to 3000 kDa can be used. Preferably, hyaluronic acid with a molecular weight of 70 to 2700 kDa can be used, and most preferably, hyaluronic acid with a molecular weight of 100 to 2500 kDa can be used.

[0054] If the molecular weight of hyaluronic acid is outside the range and too small, a uniform gel cannot be formed, and if the molecular weight is excessively large, a gel may not be formed at all.

[0055] Furthermore, in step (a) of the present invention, hyaluronic acid can be added to water at a concentration of 0.05 to 3% (w / v), preferably at a concentration of 0.1 to 2% (w / v), and more preferably at a concentration of 0.5 to 1.5% (w / v). Most preferably, it can be added to water at a concentration of 0.5 to 1.0% (w / v).

[0056] If the hyaluronic acid concentration is too high, it may become difficult to form a hydrogel by electron beam irradiation, and a hydrogel may not form at all. Furthermore, as the concentration increases, the solubility of hyaluronic acid decreases, making sample preparation difficult and potentially causing problems in the manufacturing process. If the hyaluronic acid concentration is too low, there is a limitation in that the hydrogel's properties may not be fully exhibited during subsequent use.

[0057] According to one embodiment of the present invention, it was confirmed that when the concentration of hyaluronic acid in the aqueous solution used for hydrogel production is higher than the concentration of polyethylene glycol, the viscosity of the resulting hydrogel decreases and the adhesive strength improves. Conversely, it was confirmed that when the concentration of hyaluronic acid in the aqueous solution used for hydrogel production is lower than the concentration of polyethylene glycol, the viscosity of the resulting hydrogel increases and the adhesive strength decreases.

[0058] Therefore, by adjusting the concentrations of hyaluronic acid and polyethylene glycol in the aqueous solution in step (a) above, it is possible to produce a hydrogel exhibiting the desired viscosity and adhesive strength.

[0059] In step (a) above, the silicone-containing component can be a silicone-containing component with a molecular weight of 100 to 10000 Da. Preferably, a silicone-containing component with a molecular weight of 200 to 10000 Da can be used. Most preferably, a silicone-containing component with a molecular weight of 200 to 9000 Da can be used.

[0060] If the molecular weight of the silicone-containing component is less than 100 Da, a problem may occur where a hydrogel is not formed by electron beam irradiation. If the molecular weight exceeds 10,000 Da, a problem may occur where the transparency of the generated hydrogel decreases.

[0061] If the molecular weight of the silicone exceeds the above range when preparing the aqueous solution before electron beam irradiation, it may not mix well with hyaluronic acid and polyethylene glycol, and even after electron beam irradiation, a hydrogel may not form as a single unit, resulting in separation of the components.

[0062] Furthermore, in step (a) of the present invention, the silicone-containing component can be added to water at a concentration of 0.1 to 3% (w / v), preferably at a concentration of 0.1 to 2% (w / v), and more preferably at a concentration of 0.5 to 1.5% (w / v). Most preferably, it can be added to water at a concentration of 0.5 to 1.0% (w / v).

[0063] If the silicone concentration exceeds the above range when preparing the aqueous solution before electron beam irradiation, it may not mix well with hyaluronic acid and polyethylene glycol, and even after electron beam irradiation, a hydrogel may not form as a single unit, resulting in separation of the components.

[0064] The molecular weight / concentration conditions of the hyaluronic acid, polyethylene glycol, and silicone-containing components used in step (a) of the present invention can be controlled by those skilled in the art to exhibit desirable physical properties depending on the purpose for which the hydrogel is used.

[0065] For example, when using a hydrogel as a wound dressing, it is preferable that the hydrogel is transparent, has high viscoelasticity, and exhibits excellent adhesive properties. For this reason, it may be desirable to use an aqueous solution containing hyaluronic acid at a concentration of 0.01-0.5% (w / v) with a density of 2000-3000 kDa, polyethylene glycol at a concentration of 0.5-1% (w / v) with a density of 25-40 kDa, and a silicone-containing component at a concentration of 0.1-0.5% (w / v) with a density of 100-1000 Daa in the above-mentioned step (a).

[0066] On the other hand, step (b) of the present invention is a step of irradiating the solution produced in step (a) with radiation to induce cross-linking of the material.

[0067] The hydrogel formed by the above-described radiation irradiation has the advantage of not having the residual toxicity problems present in hydrogels produced by chemical methods, and can achieve a sterilization effect simultaneously with crosslinking. The radiation used in this process may be one or more selected from the group consisting of gamma rays, ultraviolet rays, X-rays, and electron beams. Electron beams are preferred.

[0068] According to one embodiment of the present invention, it has been confirmed that the radiation dose and / or energy intensity irradiated in step (b) above to form the hydrogel can vary depending on the molecular weight / concentration of the hyaluronic acid, polyethylene glycol, and silicone-containing components used in step (a) above. Furthermore, even under conditions where a hydrogel is formed, the physical properties of the hydrogel can change depending on the radiation dose and / or energy intensity irradiated.

[0069] The radiation dose irradiated in step (b) of the present invention is not particularly limited in range, but is preferably 0.5 to 300 kGy, more preferably 2 to 300 kGy, and most preferably 5 to 150 kGy. If the radiation dose is less than 0.5 kGy, sufficient crosslinking may not occur, resulting in incomplete hydrogel formation, and if it exceeds 300 kGy, problems may arise such as the formation of air bubbles inside the hydrogel.

[0070] Furthermore, the energy intensity of the radiation irradiated in step (b) above may be 0.5 to 20 MeV. Preferably, it may be 1 to 10 MeV, and more preferably, 1 to 5 MeV. Most preferably, it may be 1 to 2.5 MeV.

[0071] If the radiation energy intensity is too low, a hydrogel may not form. Conversely, if the radiation energy intensity is too high, the shape of the formed hydrogel may be damaged, potentially leading to the formation of bubbles or cracking within the hydrogel.

[0072] Practical examples of specific manufacturing conditions for producing the hydrogels provided in the present invention are specifically presented in the embodiments of the present invention. The present invention also provides a method for producing a hydrogel formed by intermolecular crosslinking, intramolecular crosslinking, or solely by intermolecular and intramolecular crosslinking of hyaluronic acid, polyethylene glycol (PEG), and a silicone-containing component, comprising the following steps: (a) A step of preparing a solution by adding hyaluronic acid, polyethylene glycol, and silicone to water; (b) A step of irradiating the solution produced in step (a) with radiation to induce crosslinking of the material.

[0073] The specific details of each step in the above manufacturing method can be applied similarly as previously described.

[0074] The present invention also provides cell signaling molecules, drug delivery agents, adhesion inhibitors, cell supports, dental fillers, orthopedic fillers, wound dressings (sheet type, gel type, spray type, cream type, etc.), or skin fillers containing the hydrogel.

[0075] According to one embodiment of the present invention, a wound dressing made with the hydrogel according to the present invention not only exhibits significantly superior adhesion to the wound site compared to commercial wound dressings, but also significantly reduces scar formation during the wound healing process. This means that the excellent water content of the hyaluronic acid contained in the hydrogel allows for the absorption and maintenance of various endogenous wound repair factors secreted from the wound, thereby exhibiting a self-healing effect, while the excellent oxygen permeability of the silicone-containing component ensures a smooth supply of oxygen necessary for the wound healing process.

[0076] In this invention, the term "wound" refers to a condition in which the continuity of tissue is destroyed by external pressure. Wounds include abrasions, bruises, burns, and cuts caused by blades.

[0077] In this invention, by changing the manufacturing conditions within the range described above according to the desired application, a hydrogel that satisfies various physical properties such as viscoelasticity and adhesion can be provided. Furthermore, since no chemical crosslinking agents or organic chemical substances are used in the manufacturing process, it has excellent biocompatibility and can be used in a variety of applications.

[0078] Biocompatible hydrogels are widely used in applications such as cell signaling molecules, drug delivery systems, adhesion inhibitors, cell supports, dental fillers, orthopedic fillers, wound dressings (sheet type, gel type, spray type, cream type, etc.), and skin fillers. Research on these applications is also actively progressing in the industry, so it is obvious to any ordinary engineer that the hydrogel provided in this invention can also be used for the above applications.

[0079] The cell signaling molecules, drug delivery agents, adhesion inhibitors, cell supports, dental fillers, orthopedic fillers, wound dressings (sheet type, gel type, spray type, cream type, etc.), or skin fillers provided in the present invention may further contain various conventional additives in addition to the hydrogel. The types of these additives are not particularly limited, but may include, for example, dyes, coloring pigments, vegetable oils, thickeners, pH adjusters, osmotic pressure regulators, vitamins, antioxidants, inorganic salts, preservatives, solvents, isotonic agents, suspending agents, emulsifiers, stabilizers, anesthetics, disinfectants, wound treatment agents, and the like.

[0080] The present invention also provides a composition for skin application to wound sites, comprising a hydrogel as an active ingredient.

[0081] The above-mentioned composition for application to the skin of a wound site may further contain known drugs, disinfectants, etc. that can help heal wounds, and can be used as a wound dressing in the form of a sheet, gel, spray, or cream.

[0082] The present invention provides the use of the above-mentioned hydrogel for manufacturing a formulation for application to the skin of a wound site.

[0083] The present invention provides a method for treating a wound site by applying an effective amount of a composition containing the above-mentioned hydrogel as an active ingredient to the skin of an individual requiring it.

[0084] The "effective amount" in this invention refers to an amount that, when administered to an individual, shows an effect of improving, treating, detecting, diagnosing, or inhibiting or reducing the progression of a wound. The "individual" may be an animal, preferably a mammal, and may include humans, or it may be a cell, tissue, organ, etc., derived from an animal. The individual may also be a patient who requires the effect.

[0085] The “treatment” of this invention comprehensively refers to improving the wound site or symptoms caused by the wound, which may include healing, substantially preventing, or improving the condition of the wound. This includes, but is not limited to, reducing, healing, or preventing one or most symptoms.

[0086] In this specification, the term "contains" is used interchangeably with "contains" or "characterizes" and does not exclude additional components or steps of a method not specifically mentioned in the compositions or methods according to the present invention. Furthermore, the term "consists of" means excluding additional elements, steps, or components not separately described. The term "essentially consists of" means that, within the scope of a composition or method, it may include materials or steps that do not substantially affect its basic properties in addition to the described materials or steps. [Effects of the Invention]

[0087] The hydrogel of the present invention is manufactured by inducing intermolecular and / or intramolecular crosslinking of hyaluronic acid, polyethylene glycol, and silicone-containing components using an electron beam. Therefore, there is absolutely no risk of toxicity problems occurring in the human body due to contamination with organic solvents or crosslinking agents. Furthermore, no separate purification process is required in the manufacturing process, and mass production is possible with only a short period of electron beam irradiation, making it extremely efficient in terms of productivity. In addition, because the hydrogel of the present invention has excellent biocompatibility, it can be very usefully utilized in the development of cell signaling molecules, drug delivery molecules, adhesion inhibitors, cell supports, dental fillers, orthopedic fillers, wound dressings, or skin fillers. [Brief explanation of the drawing]

[0088] [Figure 1] Figure 1 shows the results of visually observing whether or not hydrogel formation occurred after irradiating 1% 100kDa hyaluronic acid, 1% PEG of various molecular weights, and 1% silicone aqueous solutions of various molecular weights with an electron beam. [Figure 2] Figure 2 shows the results of visually observing whether or not hydrogels were formed after irradiating 1% 1200kDa hyaluronic acid, 1% PEG of various molecular weights, and 1% silicone aqueous solutions of various molecular weights with an electron beam. [Figure 3] Figure 3 shows the results of visually observing whether hydrogel formation occurred after irradiating 1% 100kDa hyaluronic acid, 1% 35kDa PEG, and 1% silicone aqueous solutions of various molecular weights with an electron beam. [Figure 4] Figure 4 shows the results of visually observing whether or not hydrogel formation occurred after irradiating 1% 2500kDa hyaluronic acid, 1% PEG of various molecular weights, and 1% silicone aqueous solutions of various molecular weights with an electron beam. [Figure 5] Figure 5 shows the results of visually observing whether hydrogel formation occurred after irradiating 1% 100kDa hyaluronic acid, 1% 35kDa PEG, and 1% 9000Da silicone aqueous solution with electron beams of various doses. [Figure 6] Figure 6 shows the results of visually observing whether or not hydrogel formation occurred after irradiating 1% 2500kDa hyaluronic acid, 1% or 0.5% 35kDa PEG, and 1% or 0.5% 237Da or 9000Da silicone aqueous solutions with an electron beam. [Figure 7] Figure 7 shows the results of visual observation of the process from irradiation with an electron beam (EB) to freeze-drying of 0.5% hyaluronic acid at 2500 kDa, 1% EG at 35 kDa, and a 0.5% 237 Da silicone aqueous solution. [Figure 8] Figure 8 shows the experimental process in a wound animal model. [Figure 9]Figure 9 shows the results of visually observing the wound site over time in wound models of an animal wound model, after treatment with the untreated (control), positive control group (Mediform), and the hydrogel (HA-PEG-Si gel) according to the present invention. [Figure 10] Figure 10 shows the results of visually observing whether or not hydrogel formation occurred after placing 1% 2500kDa hyaluronic acid, 1% 35kDa PEG, and 0.5% 237Da silicone aqueous solution into large containers and irradiating them with an electron beam. [Figure 11] Figure 11 shows the results of evaluating the water content of freeze-dried hydrogels according to the embodiments of the present invention. [Figure 12] Figure 12 shows comparative photographs of freeze-dried hydrogels before and after hydration according to an example of the present invention. [Figure 13] Figure 13 shows the results of spectroscopic structural analysis of a hydrogel according to an embodiment of the present invention using UV-Vis spectroscopy (EB: electron beam irradiation). [Figure 14] Figure 14 shows the structural analysis results of a hydrogel according to an embodiment of the present invention by FT-IR spectroscopy (Before EB: before electron beam irradiation, After EB: after electron beam irradiation). [Figure 15] Figure 15 shows the results of visual observation of a hydrogel using an electron microscope (SEM) according to an embodiment of the present invention. [Modes for carrying out the invention]

[0089] The present invention will be described in detail below with reference to the following examples. However, the following examples are for illustrative purposes only and the present invention is not limited thereto.

[0090] Example 1: Production of hyaluronic acid (HA)-polyethylene glycol (PEG) silicone hydrogel by electron beam irradiation We conducted screening experiments to determine the conditions under which hydrogels could be formed by varying the molecular weights of HA, PEG, and silicone. HA has three molecular weights: 100kDa, 1200kDa, and 2500kDa. PEG comes in five molecular weights: 1 kDa, 3 kDa, 10 kDa, 20 kDa, and 35 kDa. Four different molecular weights of silicone (trimethylsiloxy terminated polydimethylsiloxane) were used: 237 kDa, 1250 kDa, 4000 kDa, and 9000 kDa.

[0091] The electron beam irradiation dose used at this time was fixed at 2.5 MeV and 10 kGy, and each of the aforementioned materials was prepared in a 1% (w / v) aqueous solution and irradiated with the electron beam.

[0092] First, summarizing the results under conditions where 100 kDa HA was used, we confirmed that when the molecular weight of PEG was less than 20 kDa, hydrogel was not formed regardless of the molecular weight of the silicone. Furthermore, we confirmed that the viscoelasticity actually decreased compared to before electron beam irradiation (Table 1).

[0093] [Table 1]

[0094] It was confirmed that most hydrogels are formed when the molecular weight of PEG is 20 kDa or higher, regardless of the molecular weight of the silicone. However, it was also observed that the hydrogels tend to become more opaque as the molecular weight of the silicone increases. Furthermore, it was confirmed that hydrogels with 35 kDa PEG added do not easily break down but instead bind together to form elastic clumps.

[0095] The hydrogels produced under all conditions exhibited the property of easily adhering to but easily detaching from the conical tube wall, and these characteristics were confirmed to be unaffected by the molecular weight of the silicone (Figure 1).

[0096] Next, summarizing the results under conditions where 1200 kDa HA was used, it was confirmed that, similar to the results obtained using 100 kDa HA, when the molecular weight of PEG was less than 20 kDa, no hydrogel was formed regardless of the molecular weight of the silicone, and the trend and properties were identical (Table 2).

[0097] [Table 2]

[0098] However, hydrogels containing 35 kDa PEG and 9000 Da silicone exhibited greater flowability compared to hydrogels made with silicones of other molecular weights. They also showed characteristics closer to liquid properties (Figures 2 and 3).

[0099] Next, summarizing the results under the conditions where 2500 kDa HA was used, it was confirmed that, similar to the results obtained using 100 kDa and 1200 kDa HA, when the molecular weight of PEG was less than 20 kDa, no hydrogel was formed regardless of the molecular weight of the silicone, and the presence or absence of hydrogel formation was identical (Table 3 and Figure 4).

[0100] [Table 3]

[0101] Through the experimental results described above, it was confirmed that the molecular weight range of PEG significantly affects hydrogel formation when producing hydrogels by irradiating aqueous solutions containing 1% (w / v) of HA, PEG, and silicone with an electron beam.

[0102] Next, using three components with high molecular weight, we similarly confirmed the feasibility of hydrogel formation at multiple electron beam irradiation doses. -Aqueous solution conditions: 1% HA (2500 kDa) + 1% PEG (35 kDa) + 1% silicone (9000 Da) - Electron beam irradiation conditions: 2.5 MeV, 10 kGy, 50 kGy, 100 kGy, 200 kGy

[0103] As a result, as shown in Figure 5, it was confirmed that a hydrogel was formed from an electron beam irradiation dose of 10 kGy. Furthermore, when compared with a silicone with a molecular weight of 237 Da, it was confirmed that the hydrogel containing silicone with a molecular weight of 9000 Da was even more opaque. On the other hand, under the 200 kGy condition, a significant increase in air bubbles was observed within the generated hydrogel.

[0104] Next, experiments were conducted by varying the concentrations of HA, PEG, and silicone to investigate the differences in hydrogel formation and properties depending on the concentration. The concentrations of the aqueous solutions of HA, PEG, and silicone were changed to 0.5% or 1%.

[0105] In this experiment, 2500 kDa HA and 35 kDa PEG were immobilized and used, and two molecular weight silicones, 237 Da and 9000 Da, were used. The experiment was carried out by irradiating with an electron beam of 2.5 MeV and 10 kGy.

[0106] The results for this are shown in Figure 6.

[0107] As can be seen in Figure 6, it was confirmed that hydrogels were formed under all manufacturing conditions. Specifically, it was confirmed that hydrogels formed when the HA concentration was higher than the PEG concentration had high adhesive strength but low viscoelasticity (or shape retention), while hydrogels formed when the HA concentration was lower than PEG had strong viscoelasticity (or shape retention) but low adhesive strength.

[0108] When the concentrations of HA and PEG were the same, it was confirmed that both adhesive strength and viscoelasticity (or morphological retention) were maintained to some extent, but it was confirmed that the disc shape could not be completely maintained.

[0109] It was confirmed that the higher the concentration of silicone, the greater the adhesive strength of the formed hydrogel, and that the higher the molecular weight of the silicone, the more cloudy the color of the formed hydrogel became.

[0110] Example 2: Efficacy evaluation of HA+PEG+silicone hydrogel wound dressing Experiments were conducted to evaluate the wound dressing efficacy of a hydrogel manufactured under the conditions of 0.5% 2500kDa HA + 1% 35kDa PEG + 0.5% 237Da silicone (2.5 MeV, 10kGy), which maintained the disk shape well, exhibited the hardest physical properties, and had high transparency, as described in Example 1 above.

[0111] The manufactured hydrogel underwent a further lyophilization process for use as a wound dressing. After lyophilization, the disc shape was maintained, and the lyophilized hydrogel easily detached from the electron beam irradiation reactor (Figure 7).

[0112] An animal model was created using BALB / c mice to evaluate the efficacy of wound dressings.

[0113] Under gas anesthesia, the hair on the backs of BALB / c mice was thoroughly removed. Then, a 10 mm diameter biopsy punch was used to create one wound on each side. Freeze-dried hydrogel was placed in both wounds, and the area was dressed with medical paper tape.

[0114] To prevent mice from chewing on the tape, a 50 mL tube was cut into a 2 cm lengthwise strip, which was then used to further cover the dressed area. The freeze-dried hydrogel was replaced every three days to monitor the size of the wound (Figure 8).

[0115] At this time, a group was added in which participants received Medifoam, a commercially available wound dressing, in the same size as the hydrogel manufactured according to the present invention, and changed it every three days. A control group was also added as a control group, in which no treatment was applied to the wound. A total of three groups were monitored for 27 days, and the efficacy of the wound dressing was compared and evaluated.

[0116] The results for this are shown in Figure 9.

[0117] As shown in Figure 9, no significant differences were observed among the three groups in terms of wound healing or skin regeneration rate. However, in the control group, it was observed that straw and foreign objects easily adhered to the wound site. This not only failed to protect the wound site but also presented a potential risk of infection.

[0118] In the case of the Medifoam group, while it was able to protect the wound site compared to the control group, it was confirmed that, due to the characteristics of the Medifoam product, it did not easily adhere to the wound site, and the wound site came into contact with the product, resulting in deeper scarring.

[0119] In the case of the freeze-dried hydrogel (HA-PEG-Silicone) group manufactured according to the present invention, thanks to its ability to protect the wound site and its properties of easily adhering to the wound site, the side effects that occur in the Medifoam group due to contact between the wound sites were significantly reduced, and after 27 days of monitoring, it was confirmed that the remaining scar was the smallest.

[0120] Example 3: Preparation of large-volume hydrogels for mass production In order to confirm whether the hydrogel produced in small quantities in Example 1 could also be produced under large-scale production conditions, additional experiments were conducted by increasing the sample volume and area of ​​the electron beam irradiation reactor.

[0121] When the sample volume was doubled in an electron beam irradiation reactor (2.5 MeV, 10 kGy) that had been used for conventional electron beam irradiation experiments, it was confirmed that a hydrogel with physical properties very similar to that of conventional hydrogels was produced, despite the sample volume doubling (Figure 10).

[0122] Furthermore, experiments were conducted using a reactor with a larger surface area (3.5 cm in diameter) than the reactor previously used as an existing electron beam irradiation reactor (2.5 cm in diameter). It was confirmed that when electron beam irradiation was performed, a hydrogel exhibiting the same physical properties could be produced even with a larger surface area.

[0123] Example 4: Evaluation of the water content of HA+PEG+silicone hydrogel Similar to Example 1 described above, HA+PEG+silicone hydrogels of various compositions shown in Table 4 below were prepared, and their water content was evaluated.

[0124] [Table 4]

[0125] The moisture content was calculated using the following formula. Moisture content (Swelling Index,%)=(Ws-Wd) / Wd*100 Ws: Weight of hydrogel containing water, Wd: Weight of dry hydrogel

[0126] Figure 11 shows the water content of each hydrogel produced with the composition shown in Table 4 above, and Figure 12 shows comparative photographs of the freeze-dried hydrogels before and after water incorporation.

[0127] As shown in Figure 11, - Under the same molecular weight conditions for PEG / silicone, the water content due to HA molecular weight is higher when HA is 100kDa than when HA is 2500kDa or HA is 1200kDa. - Under the same molecular weight conditions for HA / silicone, the water content due to PEG molecular weight is higher for PEG 20kDa than for PEG 35kDa. - In the case of hydrogels formed solely from PEG 20kDa and PEG 35kDa compositions, there is no significant difference in water content. However, when mixed with HA, the water content is significantly higher when the PEG molecular weight is 20kDa compared to when it is 35kDa. - Under conditions where the HA / PEG molecular weight is the same, the water content due to the silicone molecular weight shows that silicone 237Da has the highest water content. - Silicone 1250Da and 4000Da showed a decrease in water content as molecular weight increased, but it was confirmed that the water content increased again in silicone 9000Da.

[0128] Example 5: Structural analysis of HA+PEG+silicone hydrogel In the same manner as in Example 1 above, hydrogels of various compositions shown in Table 5 below were prepared, and their structures were analyzed using UV-Vis, FT-IR, and SEM.

[0129] [Table 5]

[0130] Spectroscopic structural analysis using UV-Vis spectroscopy revealed, as shown in Figure 13, that, with the exception of the hydrogel composed solely of PEG, samples #6, 7, 8, and 9 containing hyaluronic acid showed an increase in absorbance from the UV-B to UV-A region, while no absorption was observed in the visible light region beyond 400 nm. In the case of the hydrogel composed solely of PEG, the difference in absorbance before and after electron beam irradiation was confirmed to be minute.

[0131] As a result of structural analysis by FT-IR spectroscopy, as shown in Figure 14, all samples after hydrogel formation by electron beam irradiation showed a temperature of 560 cm⁻¹. -1 An increase in the peak was observed. This was determined to be a result of increased bending of CO bonds due to PEG self-crosslinking.

[0132] On the other hand, after irradiation with an electron beam, 843 cm⁻¹ -1 The magnitude of the nearby peaks decreased. We concluded that the skeletal vibration of the CC coupling associated with self-bridged connection had decreased.

[0133] In the case of PEG, electron beam irradiation improves the function of the hydrogel after hydrogel formation, resulting in a 3369 cm⁻¹ temperature. -1A new OH stretching vibration peak was observed. Due to a self-crosslinking reaction, at 1345 cm², -1 CH bending vibrations (bending) and 842, 947 cm -1 The CC skeletal vibration band decreased. In PEG before electron beam irradiation, it was 1093 cm⁻¹. -1 A typical triplet splitting pattern peak was observed at CO, resulting from stretching vibrational stretching.

[0134] As confirmed by scanning electron microscopy (SEM), a lamellar layered structure was observed overall, as shown in Figure 15. In samples #6 and #7, which contained silicone, a very thin plate-like structure was observed, while in samples #8 and #9, which consisted only of HA and PEG, the interlayer spacing was wider than in the silicone-containing samples. In sample #10, which consisted only of PEG, a porous material closer to a honeycomb structure than a lamellar structure was observed.

[0135] Comparative Example 1: Production of HA+ Silicone Hydrogel by Electron Beam Irradiation When a 1% aqueous solution of 2500 kDa hyaluronic acid was mixed with either 237 Da silicone or 9000 Da silicone at a concentration of 1%, and then irradiated with a 2.5 MeV, 10 kGy electron beam, hydrogels were not synthesized in either composition. This confirmed that polyethylene glycol is essential for synthesizing hydrogels using hyaluronic acid and silicone.

[0136] Comparative Example 2: Production of PEG+ Silicone Hydrogel by Electron Beam Irradiation When a 1% aqueous solution of 35 kDa polyethylene glycol was mixed with either 237 Da silicone or 9000 Da silicone at a concentration of 1%, and then irradiated with a 2.5 MeV, 10 kGy electron beam, a partially formed hydrogel was synthesized with both compositions. Unlike hydrogels with added hyaluronic acid, the hydrogel did not form across the entire surface of the container; instead, a small, contracted circular gel formed only in the center, with the surrounding area remaining as solution. This confirmed that 100% hydrogel could not be produced using only polyethylene glycol and silicone, and that hyaluronic acid is essential for producing a hydrogel with a uniform composition.

[0137] Comparative Example 3: Production of HA+PEG+Collagen Hydrogel by Electron Beam Irradiation Hydrogel production was attempted by adding 1% collagen to an aqueous solution of 1% 2500kDa hyaluronic acid and 1% 35kDa PEG, and then irradiating it with an electron beam. When collagen was added to the hyaluronic acid solution, a white precipitate was observed, and even after irradiation with an electron beam, no hydrogel was synthesized, and the white precipitate did not disappear. In another recipe, when 35kDa polyethylene glycol was initially added to the 2500kDa hyaluronic acid solution before adding collagen, a white precipitate was also observed when collagen was added, and similarly, no hydrogel was produced even after irradiation with an electron beam. [Industrial applicability]

[0138] The hydrogel of the present invention is manufactured by inducing intermolecular and / or intramolecular crosslinking of hyaluronic acid, polyethylene glycol, and silicone-containing components using an electron beam. Therefore, there is absolutely no risk of toxicity problems in the human body due to contamination with organic solvents or crosslinking agents. Furthermore, it does not require separate purification processes in its manufacturing process, and mass production is possible with only a short period of electron beam irradiation, making it extremely efficient in terms of productivity. In addition, because the hydrogel of the present invention has excellent biocompatibility, it can be very useful in the development of cell signaling molecules, drug delivery agents, adhesion inhibitors, cell supports, dental fillers, orthopedic fillers, wound dressings, or skin fillers, and has very high industrial applicability.

Claims

1. Formed by intermolecular crosslinking, intramolecular crosslinking, or solely intermolecular and intramolecular crosslinking of hyaluronic acid (HA), polyethylene glycol (PEG), and silicone-containing components, the following process: (a) A step of preparing a solution by adding hyaluronic acid, polyethylene glycol, and a silicone-containing component to water; and (b) Manufactured by a method including the step of irradiating the solution produced in step (a) with radiation to induce crosslinking of the material, The polyethylene glycol has a molecular weight of 15 to 50 kDa and is added to water at a concentration of 0.1 to 3% (w / v). The hyaluronic acid has a molecular weight of 50 to 3000 kDa and is characterized by being added to water at a concentration of 0.05 to 3% (w / v), forming a hydrogel.

2. The hydrogel according to claim 1, characterized in that the intermolecular and intramolecular crosslinks are formed by radiation irradiation.

3. The hydrogel according to claim 2, characterized in that the radiation is one or more selected from the group consisting of gamma rays, ultraviolet rays, X-rays, and electron beams.

4. The hydrogel according to claim 1, characterized in that the silicone-containing component is selected from the group consisting of polydimethylsiloxane, caprylylmethyltrisiloxane, octamethylcyclotetrasiloxane, decamethylcyclopentasiloxane, dimethicone, and cyclosiloxane.

5. The hydrogel according to claim 1, characterized in that the silicone-containing component has a molecular weight of 100 to 10000 Da and is added to water at a concentration of 0.1 to 3% (w / v).

6. The hydrogel according to claim 1, characterized in that the radiation dose is 0.5 to 300 kGy.

7. The hydrogel according to claim 1, characterized in that the energy intensity of the radiation is 0.5 to 20 MeV.

8. The following steps: (a) A step of preparing a solution by adding hyaluronic acid, polyethylene glycol, and a silicone-containing component to water; and (b) A step of irradiating the solution produced in step (a) with radiation to induce crosslinking of the material, The polyethylene glycol has a molecular weight of 15 to 50 kDa and is added to water at a concentration of 0.1 to 3% (w / v). The hyaluronic acid has a molecular weight of 50 to 3000 kDa and is characterized by being added to water at a concentration of 0.05 to 3% (w / v). A method for producing a hydrogel formed by intermolecular crosslinking, intramolecular crosslinking, or solely intramolecular and intramolecular crosslinking of hyaluronic acid, polyethylene glycol (PEG), and a silicone-containing component.

9. The manufacturing method according to claim 8, characterized in that the viscosity of the hydrogel is adjusted by adjusting the concentration ratio of hyaluronic acid and polyethylene glycol in step (a) above.

10. A cell signaling body, a drug delivery body, an anti-adhesion agent, a cell support, a dental filler, an orthopedic filler, a skin filler, or a wound dressing, comprising the hydrogel described in any one of claims 1 to 7.

11. A sheet-type, cream-type, gel-type, or spray-type wound dressing comprising the hydrogel described in any one of claims 1 to 7.

12. A composition for topical application to wound sites, comprising the hydrogel described in any one of claims 1 to 7 as an active ingredient.

13. Use of the hydrogel according to any one of claims 1 to 7 for manufacturing a formulation for topical application to the skin of a wound site.

14. A method for treating a wound by applying an effective amount of a composition containing the hydrogel described in any one of claims 1 to 7 as an active ingredient to the skin of an individual (excluding humans) that requires it.

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