Hydrogel composition, hydrogels and methods and uses thereof

Abstract

The present application provides a kind of hydrogel composition, hydrogel and its preparation method and purposes.The hydrogel composition includes: buffer system, the buffer system includes polyacid and biological buffer agent;And, gel component, the gel component includes plant polyphenol and sulfur-containing fatty acid compound;Wherein, the mass ratio of plant polyphenol and sulfur-containing fatty acid compound is 1:2-10, preferably 1:2.5~5.The hydrogel composition of the present application can be used to prepare hydrogel, the hydrogel has antibacterial, antioxidant, anti-radical and the like performance.And, the hydrogel also has good self-repairing performance, tissue adhesion and biocompatibility, is suitable for bacterial infection type wound, local hemorrhage and open wound healing.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of biomaterials, and particularly relates to a hydrogel composition, a hydrogel and a preparation method and use thereof, and particularly relates to a medical hydrogel composition, a medical hydrogel, a preparation method and use thereof, and a kit for preparing a medical hydrogel. BACKGROUND

[0002] Wounds caused by accidental trauma or bacterial infection are inevitable in daily life, often accompanied by bleeding and pus. The commonly used clinical methods include sutures, anastomosis devices and metal wires for repairing large skin defects, which will bring an unpleasant treatment experience to patients and increase the risk of secondary infection without the help of disinfectants or antibiotics. At present, researchers have found that hydrogel is the best choice for wound healing.

[0003] Hydrogel is a kind of tissue sealing material used for sealing and plugging when the tissue is injured, bleeding, and fluid (tissue fluid, gas) leakage. Due to the retention of a large amount of water in the hydrophilic network, the hydrogel can provide a moist environment for the wound bed, extract wound exudates and promote wound healing. Secondly, unlike rubber, plastic resin or biological macromolecules, hydrogel usually has many unique properties, such as pressure-induced shape adjustment, controllable mechanical strength, ideal biomimetic properties and accessibility of drug / nanomaterial loading. Thirdly, the cross-linked network of hydrogel is strong enough to avoid excessive swelling or dissolution in water conditions during the actual wound healing process.

[0004] So far, various researches have reported multifunctional polyethylene glycol-based, acrylic acid-based, carbohydrate-based, polypeptide-based and polyvinyl alcohol-based adhesive gels for wound dressings. However, most of the above hydrogels require complex preparation processes, monomers, precise chemical design of toxic cross-linking agents or heavy metals, and tedious post-synthesis treatment. Although many biological macromolecules are considered as potential green raw materials instead of synthetic polymers for adhesive hydrogels, they usually face difficulties in formulating standards for corresponding products due to different production sites, variable molecular weights and different extraction methods

[0005] The current mainstream hydrogels can be divided into four categories: biostable, biodegradable, synthetic stable and synthetic degradable. In addition, the hydrogel based on antibacterial peptide is limited in its wide application due to its expensive cost and low stability caused by protein hydrolysis degradation and cytotoxicity.

[0006] Biostable tissue medical glue is a material cross-linked by biological base materials and chemical reagents, such as BioGlue of Cryolife which is a tissue sealing material mainly composed of biological albumin and glutaraldehyde; biodegradable tissue medical glue is a material made of biological base materials and biodegradable absorbable materials, such as Tisseel of Baxter which is a biodegradable tissue glue of fibrin origin; synthetic stable tissue medical glue is a material mainly composed of α-cyanoacrylate, which forms tissue adhesion through anionic polymerization at the tissue interface, but the polymer does not have biodegradability; synthetic degradable tissue medical glue is mainly composed of chemically modified polyethylene glycol, and with the breakage of cross-linking bonds, polyethylene glycol penetrates through the cell membrane, endocytosis and is metabolized out of the body.

[0007] Therefore, it is a technical problem to be solved to study a hydrogel composition and a hydrogel with simple production method and sustainable resources. SUMMARY

[0008] Problems to be solved by the invention

[0009] In view of the technical problems in the prior art, the present application first provides a hydrogel composition, which can be used to prepare a hydrogel having antibacterial, antioxidant, and anti-free radical properties. Moreover, the hydrogel also has good self-repairing performance, tissue adhesion and biocompatibility, and is suitable for bacterial infection type wounds, local bleeding and open wound healing.

[0010] Further, the present application also provides a preparation method of the hydrogel, which is simple and easy to operate, green and pollution-free, does not add metal ions and harmful compounds, and has low cost.

[0011] Solution for solving the problem

[0012] The present application first provides a hydrogel composition, which comprises:

[0013] a buffer system comprising a polyacid and a biological buffer; and,

[0014] a gel-forming component comprising a plant polyphenol and a sulfur-containing fatty acid compound; wherein,

[0015] The mass ratio of the plant polyphenol and the sulfur-containing fatty acid compound is 1:2-10, preferably 1:2.5-5.

[0016] According to the hydrogel composition of the present application, the mass ratio of the polyacid and the biological buffer is 1:4-10, and the mass ratio of the polyacid and the sulfur-containing fatty acid compound is 1:5-60.

[0017] According to the hydrogel composition of the present application, wherein the polyacid comprises one or more than two combinations of ethylenediaminetetraacetic acid, citric acid, tartaric acid, phytic acid; the biological buffer comprises one or more than two combinations of tris-hydroxymethyl aminomethane, phosphate, chloride salt;

[0018] The plant polyphenol comprises one or more than two combinations of flavonoids, tannins, anthocyanins, phenolic acids; preferably comprises one or more than two combinations of theaflavins, tannic acid, proanthocyanidins; the sulfur-containing fatty acid compound comprises alpha-lipoic acid.

[0019] The present application also provides a hydrogel formed by the reaction of the plant polyphenol and the sulfur-containing fatty acid compound of the gel-forming component of the present application in the presence of a buffer system.

[0020] According to the hydrogel of the present application, wherein the tissue adhesion strength of the hydrogel is 2-12KPa; the maximum swelling rate of the hydrogel is 200-250%; the elongation at break of the hydrogel is 350-550%, and the maximum tensile strength is 3.5-5.5KPa.

[0021] The present application also provides a preparation method of the hydrogel according to the present application, which comprises the step of mixing the components of the hydrogel composition in a solvent;

[0022] Preferably, the preparation method comprises the following steps:

[0023] Step 1) dissolving the polyacid and the biological buffer in a solvent to obtain a buffer system;

[0024] Step 2) dissolving the plant polyphenol in the buffer system to obtain a premix;

[0025] Step 3) dissolving the sulfur-containing fatty acid compound in the premix, then injecting into a mold and cooling to obtain the hydrogel.

[0026] According to the preparation method of the present application, wherein in step 1), the mass ratio of the polyacid, the biological buffer and the solvent is 1:4-10:25-50; the temperature for dissolving the polyacid and the biological buffer is 10-60℃;

[0027] In step 2), the mass ratio of the plant polyphenol and the solvent is 1:5-10; the temperature for dissolving the plant polyphenol is 40-60℃, and the dissolving time is 3-5min;

[0028] In the step 3), the mass ratio of the sulfur-containing fatty acid compound to the solvent is 1:2-3; the temperature for dissolving the sulfur-containing fatty acid compound is 40-60 DEG C; the cooling temperature is 0-25 DEG C, and the cooling time is 6-12 h.

[0029] The present application also provides a hydrogel patch comprising the hydrogel according to the present application or the hydrogel prepared by the method for preparing the hydrogel according to the present application.

[0030] The present application also provides a hydrogel powder comprising the hydrogel according to the present application or the hydrogel prepared by the method for preparing the hydrogel according to the present application.

[0031] The present application also provides the use of the hydrogel according to the present application or the hydrogel prepared by the method for preparing the hydrogel according to the present application in the preparation of a wound healing product, an internal organ or soft tissue wound closure product, a tissue fluid sealing product, a hemostasis aid and a soft tissue repair patch.

[0032] Effects of the present application

[0033] The hydrogel composition of the present application can be used to prepare a hydrogel having antibacterial, antioxidant, anti-free radical and other properties. Moreover, the hydrogel also has good self-repairing performance, tissue adhesion and biocompatibility, and is suitable for bacterial infection type wounds, local bleeding and open wound healing.

[0034] Further, the preparation method of the hydrogel of the present application is simple and easy to operate, green and pollution-free, does not add metal ions and harmful compounds, has low cost, and is suitable for mass production. BRIEF DESCRIPTION OF DRAWINGS

[0035] Figure 1 The appearance of the hydrogel of the present application is shown.

[0036] Figure 2 The infrared spectrum of the hydrogel of the present application is shown.

[0037] Figure 3 The swelling rate of the hydrogel in Example 1 of the present application is shown.

[0038] Figure 4 The adhesion force curve (a) and the adhesion strength (b) of the hydrogel to different materials in Example 1 of the present application are shown.

[0039] Figure 5 The ultraviolet-visible spectrophotometer spectrum of the hydrogel against 1,1-diphenyl-2-trinitrophenylhydrazine (DPPH) free radical in Example 1 of the present application is shown.

[0040] Figure 6(a) shows a schematic diagram of the use of the hydrogel in Example 1 of the present application for wound healing in BALC / c mice infected with Staphylococcus aureus, and (b) shows a HE staining section of the wound tissue.

[0041] Figure 7 (a) shows a photograph of the use of the hydrogel in Example 1 of the present application for hemostasis in rat liver, and (b) shows a statistical diagram of the amount of bleeding. DETAILED DESCRIPTION

[0042] Various exemplary embodiments, features, and aspects of the present application will be described in detail below. The word "exemplary" is used herein to mean "serving as an example, instance, or illustration." Any implementation described herein as "exemplary" is not necessarily to be construed as preferred or advantageous over other implementations.

[0043] In addition, in order to better illustrate the present application, numerous specific details are set forth in the following detailed description. One skilled in the art will understand, however, that the application can be practiced without certain of the specific details herein. In other instances, well-known methods, structures, apparatuses, and steps have not been described in detail in order to avoid obscuring the subject matter of the present application.

[0044] Unless otherwise defined, all terms used in the present specification, including technical or scientific terms, have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. It will be further understood that the terms of the present application should be interpreted as having a meaning that is consistent with their meaning in the context of the relevant art and the technical specifications of the present application.

[0045] In the present specification, unless otherwise specified, "%" means mass %.

[0046] In the present specification, the use of "may" includes both the meaning of performing an action and the meaning of not performing an action.

[0047] In the present specification, references to "some specific / preferred embodiments", "other specific / preferred embodiments", "embodiments", and the like, mean that the particular element(s) (e.g., feature, structure, property, and / or characteristic) being described is included in at least one embodiment described herein, and can or can not be present in other embodiments. In addition, it should be understood that the described elements can be combined in any suitable manner in various embodiments.

[0048] In the present specification, the use of "a numerical range of value A to value B" means a range including the end point values A and B.

[0049] In addition, in the present specification, the "water" includes deionized water, distilled water, ion-exchange water, double-distilled water, high-purity water, purified water, and the like, any feasible water that can be used.

[0050] In the present specification, when "room temperature" is used, the temperature can be 10-40℃.

[0051] <First aspect>

[0052] The present application first provides a hydrogel composition, in particular a medical hydrogel composition, comprising:

[0053] a buffer system comprising a polyacid and a biological buffer; and,

[0054] a gelling component comprising a plant polyphenol and a sulfur-containing fatty acid compound; wherein,

[0055] The mass ratio of the plant polyphenol and the sulfur-containing fatty acid compound is 1:2-10, preferably 1:2.5-5.

[0056] The gelling component and the buffer system can be separate, and the gelling component and the buffer system components are mixed a few hours (e.g., 6-12 hours) before use. Preferably, the polyacid and the biological buffer in the buffer system can be separate, and the polyacid and the biological buffer are mixed a few hours (e.g., 6-12 hours) before use. The plant polyphenol and the sulfur-containing fatty acid compound in the gelling component can also be separate, and the plant polyphenol and the sulfur-containing fatty acid compound are mixed a few hours (e.g., 6-12 hours) before use. In general, the buffer system can be mixed with the plant polyphenol, and then mixed with the sulfur-containing fatty acid compound to gel. After preparation is complete, the product can be used after being placed at room temperature for 6-12 hours. The product can be plastic-sealed as an adhesive bandage.

[0057] In actual application, the gelling component and the buffer system can be stored separately, and then mixed before use. For example, the polyacid and the biological buffer of the buffer system can be dissolved in a solvent, and then mixed with the plant polyphenol and the sulfur-containing fatty acid compound to gel. The present application does not limit the storage method of each component in the tissue medical adhesive composition, and a person skilled in the art can select a specific storage method according to needs, which is within the scope of the present application.

[0058] In the present application, the sulfur-containing fatty acid compound is used as a polymerization monomer, and the plant polyphenol is used as a chemical crosslinking agent. The plant polyphenol can undergo a Michael addition reaction with the sulfur-containing fatty acid compound, thereby forming a gel network. The polyacid in the buffer system can act as a supramolecular crosslinking agent, which can form hydrogen bonds with the carboxyl group of the sulfur-containing fatty acid compound, thereby improving the mechanical properties of the hydrogel. In addition, by using the above plant polyphenol, the prepared hydrogel can have certain antibacterial properties while ensuring safety.

[0059] The hydrogel prepared from the hydrogel composition of the present application has functional groups such as polyphenol groups and carboxyl groups in the chemical structure of the hydrogel, and has good adhesion to protein-rich tissues such as skin.

[0060] In the present application, the mass ratio of the plant polyphenol and the sulfur-containing fatty acid compound is 1:2-10, preferably 1:2.5-5, for example, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, etc. The present inventors have found that when the mass ratio of the plant polyphenol and the sulfur-containing fatty acid compound is 1:2-10, the elongation at break of the hydrogel prepared therefrom can be 350-550%, and the maximum tensile strength can be 3.5-5.5 KPa, and the mechanical properties are excellent. Further, in order to facilitate the formation of a gel, the mass ratio of the plant polyphenol and the sulfur-containing fatty acid compound is preferably 1:2.5-5.

[0061] In some specific embodiments, the mass ratio of the polyacid and the biological buffer is 1:4-10, for example, 1:5, 1:6, 1:7, 1:8, 1:9, etc. When the mass ratio of the polyacid and the biological buffer is 1:4-10, the obtained hydrogel is transparent, and the adhesion is not significantly reduced by the loss of moisture.

[0062] Further, in the present application, the mass ratio of the polyacid and the sulfur-containing fatty acid compound can be 1:5-60, preferably 1:10-50, for example, 1:10, 1:20, 1:25, 1:30, 1:35, 1:40, 1:45, 1:50, 1:55, etc. When the mass ratio of the polyacid and the sulfur-containing fatty acid compound is 1:5-60, the mechanical properties of the obtained hydrogel are excellent.

[0063] Specifically, in the present application, the polyacid includes one or a combination of two or more of ethylenediaminetetraacetic acid, citric acid, tartaric acid, and phytic acid; the plant polyphenol includes one or a combination of two or more of flavonoids, tannins, anthocyanins, and phenolic acids; preferably, one or a combination of two or more of theaflavins, tannic acid, and procyanidins; and the sulfur-containing fatty acid compound includes alpha-lipoic acid. For the polyacid, the present application preferably uses one or a combination of two or more of ethylenediaminetetraacetic acid, citric acid, and tartaric acid.

[0064] In addition, for the biological buffer, the present application is not particularly limited, and can be some biological buffers commonly used in the art. Specifically, the biological buffer can include one or a combination of two or more of tris-hydroxymethyl aminomethane, phosphate, and chloride salt; the phosphate can be potassium dihydrogen phosphate, disodium hydrogen phosphate, etc., and the chloride salt can be sodium chloride, potassium chloride, etc. By using a biological buffer, a buffer system with a pH value of 8-9 can be obtained, which is beneficial to gel formation.

[0065] Ethylenediaminetetraacetic acid (EDTA) is an organic compound with the chemical formula C60. 10 H 16 N₂O₈, structural formula: [Insert structural formula here], is a white powder at room temperature and pressure. It is a [structure here] that can react with Mg. 2+ Ca 2+ Mn 2+ Fe 2+ Chelating agents that bind to divalent metal ions. Because most nucleases and some proteases require Mg for their function. 2+ Therefore, it is often used as an inhibitor of nucleases and proteases; it can also be used to remove the inhibitory effect of heavy metal ions on enzymes.

[0066] Citric acid, also known as citric acid, with the molecular formula C6H8O7, is an important organic acid. It is a colorless crystal, odorless, with a strong sour taste, and readily soluble in water. It is a natural preservative and food additive. Tartaric acid, or 2,3-dihydroxybutyric acid, is a carboxylic acid with the chemical formula C4H6O6. It is found in many plants, such as grapes and tamarind. It is also one of the main organic acids in wine.

[0067] The inventors have discovered that ethylenediaminetetraacetic acid, citric acid, and tartaric acid are all polybasic acids with stronger acidity, and can be used as supramolecular crosslinking agents. This allows them to undergo hydrogen bonding with the carboxyl groups of sulfur-containing fatty acid compounds, thereby improving the mechanical properties of hydrogels.

[0068] In some specific embodiments, the present invention preferably uses flavonoid plant polyphenols, such as theabrownins. Theabrownins are a general term for various phenolic compounds in tea, and are the main components of fresh tea leaves, with catechins as the main component, accounting for 60% to 80% of the total polyphenolic substances. They are closely related to the color, taste, and aroma of tea. Furthermore, the inventors have found that tannin products are prone to oxidative denaturation with prolonged storage, while theabrownins are very stable in air. In addition, theabrownins have more chemical reaction sites and more benzene rings than tannins, which can effectively improve the strength of the hydrogel network and accelerate gelation.

[0069] Furthermore, α-lipoic acid can be used as the best-performing polymer monomer. α-Lipoic acid undergoes ring-opening polymerization upon heating, generating sulfur free radicals. The polyphenolic groups of plant polyphenols then undergo Michael addition reactions with these sulfur free radicals, forming a cross-linked gel network.

[0070] <Second aspect>

[0071] A second aspect of the present invention provides a hydrogel, which is formed by reacting plant polyphenols and sulfur-containing fatty acid compounds of the gelling component described in the first aspect of the present invention, in the presence of a buffer system.

[0072] Furthermore, the hydrogel also possesses antibacterial, antioxidant, and free radical scavenging properties, and exhibits excellent self-healing properties, tissue adhesion, and biocompatibility, making it suitable for healing bacterial-infected wounds, localized bleeding, and open wounds.

[0073] The hydrogel of this invention has polyphenol groups, carboxyl groups, and other groups, and exhibits good adhesion to tissues. Specifically, in this invention, the tissue adhesion strength of the hydrogel is 2-12 kPa, for example: 3 kPa, 4 kPa, 5 kPa, 6 kPa, 7 kPa, 8 kPa, 9 kPa, 10 kPa, 11 kPa, etc.

[0074] Hydrogels have a three-dimensional network structure, are insoluble in water, but swell in water, absorbing large amounts of water and increasing their volume. However, in some confined areas of the human body, highly swellable hydrogels may compress surrounding nerves, potentially interfering with normal bodily functions, and in severe cases, causing pressure necrosis of surrounding tissues. The hydrogel of this invention has a low maximum swelling rate, only 200-250%, for example, 210%, 220%, 230%, 240%, etc., which does not compress surrounding nerves and therefore does not significantly interfere with normal bodily functions. Because the hydrogel of this application has a low swelling rate and self-healing properties, it can adapt to complex and changing wearing environments, thus making it suitable for long-term wear as a gel patch.

[0075] <Third aspect>

[0076] A third aspect of the present invention provides a method for preparing a hydrogel according to the third aspect of the present invention, comprising the step of mixing the components of the hydrogel composition in a solvent, preferably, the solvent being water.

[0077] The preparation method of the hydrogel of the present invention is simple and easy to implement, green and pollution-free, does not add metal ions and harmful compounds, has low cost, and is suitable for mass production.

[0078] In some specific implementations, the preparation method includes the following steps:

[0079] Step 1) Dissolve the polybasic acid and the biological buffer in a solvent to obtain a buffer system;

[0080] Step 2) Dissolve the plant polyphenols in the buffer system to obtain a premix;

[0081] Step 3) After dissolving the sulfur-containing fatty acid compound in the premix, the mixture is injected into a mold and cooled to obtain a hydrogel.

[0082] The sulfur-containing fatty acid compounds of this invention, when dissolved in a premix, undergo a Michael addition reaction with plant polyphenols, rapidly forming a gel. Simultaneously, the polybasic acids form hydrogen bonds with the carboxyl groups of the sulfur-containing fatty acid compounds, enhancing the mechanical properties of the hydrogel. This hydrogel possesses antibacterial, antioxidant, and free radical scavenging properties, along with excellent self-healing capabilities, tissue adhesion, and biocompatibility, making it suitable for healing bacterial infections, localized bleeding, and open wounds.

[0083] In some specific implementations, in step 1), the mass ratio of the polybasic acid, the biological buffer, and the solvent is 1:4-10:25-50, for example: 1:5-9:30-45, 1:6-8:35-40, 1:7:38, etc.; the temperature for dissolving the polybasic acid and the biological buffer is 10-60℃, for example: 20℃, 30℃, 40℃, 50℃, etc. Preferably, the pH value of the buffer system can be 8-9.

[0084] When the mass ratio of the polybasic acid, the biological buffer, and the solvent is 1:4-10:25-50, the prepared hydrogel has an elongation at break of 350-550% and a maximum tensile strength of 3.5-5.5 kPa. Furthermore, the hydrogel is transparent and does not easily lose viscosity due to water loss. When the temperature for dissolving the polybasic acid and the biological buffer is 10-60°C, dissolution is accelerated without causing deterioration of the polybasic acid and the biological buffer, and the subsequent Michael addition reaction is not affected.

[0085] Furthermore, in this invention, in step 2), the mass ratio of the plant polyphenol to the solvent is 1:5-10, for example: 1:6, 1:7, 1:8, 1:9, etc. When the mass ratio of the plant polyphenol to the solvent is 1:5-10, the gelation speed can be effectively controlled, effectively avoiding the problem of the gelation speed being too fast to be injected into the mold. The temperature for dissolving the plant polyphenol is 40-60℃, for example: 45℃, 50℃, 55℃, 60℃, etc.; the dissolution time is 3-5 min, for example: 3.5 min, 4 min, 4.5 min, etc. When the temperature for dissolving the plant polyphenol is 40-60℃, the plant polyphenol will not lose its activity while accelerating dissolution, and it will not affect the subsequent Michael addition reaction.

[0086] Furthermore, in this invention, in step 3), the mass ratio of the sulfur-containing fatty acid compound to the solvent is 1:2-3, for example: 1:2.2, 1:2.4, 1:2.6, 1:2.8, etc. When the mass ratio of the sulfur-containing fatty acid compound to the solvent is 1:2-3, the solution viscosity is effectively increased, which is beneficial for the formation of gel after cross-linking of plant polyphenols. The temperature for dissolving the sulfur-containing fatty acid compound is 40-60℃, for example: 45℃, 50℃, 55℃, 60℃, etc. When the temperature for dissolving the plant polyphenols is 40-60℃, the sulfur-containing fatty acid compound will not lose its activity while accelerating dissolution, and it will not affect the subsequent Michael addition reaction.

[0087] In addition, to obtain a shaped hydrogel, it can be placed in a mold for cooling. Specifically, the cooling temperature is 0–25°C, for example: 5°C, 10°C, 15°C, 20°C, etc.; the cooling time is 6–12 hours, for example: 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, etc. When the cooling temperature is 0–25°C and the cooling time is 6–12 hours, a solidified hydrogel can be obtained, and the mechanical properties of the hydrogel are suitable.

[0088] <Fourth Aspect>

[0089] A fourth aspect of this invention provides several commonly used hydrogel products or kits and uses of hydrogels. The hydrogel products of this invention adhere to tissues, providing an antibacterial, biocompatible microenvironment thereby achieving tissue repair.

[0090] Specifically, the hydrogel prepared according to the second or third aspect of the present invention can be made into a hydrogel patch, for example, by slicing. The hydrogel patch of the present invention has a low swelling rate and self-healing properties, and can adapt to complex and changing wearing environments, thus enabling it to be used as a long-term wearable gel patch.

[0091] Furthermore, the hydrogel prepared by the second aspect or the third aspect of the present invention can also be pulverized (e.g., ground) to prepare a hydrogel powder, which can be directly sprayed onto the wound during use, making it simple and convenient to use.

[0092] Furthermore, the present invention may also provide a hydrogel kit comprising the hydrogel composition described in the first aspect of the present invention and optionally a solvent; preferably, the buffer system and the gelling component of the hydrogel composition are stored separately, and the buffer system and the gelling component are mixed before use.

[0093] Furthermore, the polybasic acid and biological buffer in the buffer system are stored separately. Before use, the polybasic acid and biological buffer are dissolved in a solvent to obtain the buffer system. The plant polyphenols and sulfur-containing fatty acid compounds in the gelling component are stored separately. Before use, the plant polyphenols and sulfur-containing fatty acid compounds are dissolved in the buffer system sequentially to carry out a chemical reaction, ultimately obtaining a hydrogel.

[0094] The hydrogel described in this invention can be used to prepare wound healing products (especially bacterial infection wounds), closure products for visceral or soft tissue wounds (especially open wound healing), tissue fluid sealing products, hemostatic aids, and soft tissue repair patches, etc. Preferably, the hydrogel of this invention can seal bleeding wounds through tissue adhesion and can be used as a hemostatic aid, such as a bleeding sealant, suitable for rapid hemostasis of local bleeding, such as capillaries, veins, and muscular arteries.

[0095] Example

[0096] The embodiments of the present invention will be described in detail below with reference to examples. However, those skilled in the art will understand that the following examples are for illustrative purposes only and should not be considered as limiting the scope of the invention. Unless otherwise specified in the examples, conventional conditions or conditions recommended by the manufacturer are followed. Reagents or instruments whose manufacturers are not specified are all commercially available conventional products.

[0097] Example 1

[0098] One part of ethylenediaminetetraacetic acid (EDTA) and five parts of tris(hydroxymethyl)aminomethane (TMM) were dissolved in 25 parts of deionized water and stirred at 25°C until dissolved. Then, three parts of theaflavins were added and stirred at 60°C for 3 minutes until dissolved. First, five parts of α-lipoic acid were added and stirred at 60°C until dissolved. Then, another five parts of α-lipoic acid were added and stirred at 60°C until dissolved. Finally, the resulting liquid was poured into a mold and cooled at 25°C for 12 hours to obtain a hydrogel.

[0099] Example 2

[0100] One part citric acid and 7.5 parts tris(hydroxymethyl)aminomethane were dissolved in 25 parts deionized water and stirred at 60°C until dissolved. Then, 5 parts theaflavins were added and stirred at 60°C for 3 minutes until dissolved. First, 6.25 parts α-lipoic acid were added and stirred at 60°C until dissolved. Then, another 6.25 parts α-lipoic acid were added and stirred at 60°C until dissolved. Finally, the resulting liquid was poured into a mold and cooled at 0°C for 6 hours to obtain a hydrogel.

[0101] Example 3

[0102] One part tartaric acid and ten parts tris(hydroxymethyl)aminomethane were dissolved in 50 parts deionized water and stirred at 40°C until dissolved. Then, ten parts theaflavins were added and stirred at 60°C for 5 minutes until dissolved. First, ten parts α-lipoic acid were added and stirred at 40°C until dissolved. Then, another ten parts α-lipoic acid were added and stirred at 40°C until dissolved. Finally, the resulting liquid was poured into a mold and cooled at 25°C for 12 hours to obtain a hydrogel.

[0103] Example 4

[0104] One part of ethylenediaminetetraacetic acid (EDTA) and five parts of tris(hydroxymethyl)aminomethane (TMM) were dissolved in 30 parts of deionized water and stirred at 60°C until dissolved. Then, five parts of theaflavins were added and stirred at 60°C for 4 minutes until dissolved. Next, 25 parts of α-lipoic acid were added and stirred at 60°C until dissolved. Then, another 25 parts of α-lipoic acid were added and stirred at 60°C until dissolved. Finally, the resulting liquid was poured into a mold and cooled at 4°C for 6 hours to obtain a hydrogel.

[0105] Example 5

[0106] One part citric acid and eight parts tris(hydroxymethyl)aminomethane were dissolved in 45 parts deionized water and stirred at 25°C until dissolved. Then, 4.5 parts theaflavins were added and stirred at 50°C for 3 minutes until dissolved. First, 7.5 parts α-lipoic acid were added and stirred at 60°C until dissolved. Then, another 7.5 parts α-lipoic acid were added and stirred at 60°C until dissolved. Finally, the resulting liquid was poured into a mold and cooled at 25°C for 8 hours to obtain a hydrogel.

[0107] Example 6

[0108] One part of ethylenediaminetetraacetic acid (EDTA) and four parts of tris(hydroxymethyl)aminomethane (TMM) were dissolved in 30 parts of deionized water and stirred at 40°C until dissolved. Then, three parts of theaflavins were added and stirred at 40°C for 3 minutes until dissolved. First, five parts of α-lipoic acid were added and stirred at 50°C until dissolved. Then, another five parts of α-lipoic acid were added and stirred at 50°C until dissolved. Finally, the resulting liquid was poured into a mold and cooled at 10°C for 9 hours to obtain a hydrogel.

[0109] Comparative Example 1

[0110] The theabrownin in Example 1 was replaced with deionized water, and the other steps were performed in exactly the same manner as in Example 1 to prepare a hydrogel without theabrownin.

[0111] Performance test experiments

[0112] (1) Infrared testing

[0113] Dry KBr and lyophilized hydrogel powder were co-ground, placed in a metal mold, and pressure was applied to form KBr pellets, which were then measured using a Frontier infrared spectrometer. Figure 2 As shown, the hydrogel contains sulfur-benzene ring chemical bonds (S-Ar, 1057 cm⁻¹). -1 This demonstrates that theabrownins undergo a cross-linking chemical reaction with α-lipoic acid.

[0114] (2) Swelling rate of hydrogel

[0115] The hydrogel from Example 1 was freeze-dried and then immersed in water. The hydrogel was removed periodically, drained of surface moisture, and weighed. The swelling ratio of the hydrogel was calculated using the following formula:

[0116]

[0117] Where, m d Let m be the initial mass of the hydrogel. s This refers to the mass of the hydrogel after swelling. For example... Figure 3 As shown, the maximum swelling ratio of the hydrogel is 200-250%, which is a low swelling ratio hydrogel.

[0118] In addition, the maximum swelling ratio of the hydrogels in Examples 2-6 of this application is also 200-250%, which is a low swelling ratio hydrogel.

[0119] (3) Adhesion of hydrogels

[0120] The samples used for adhesion testing (aluminum sheet, wood chip, ceramic sheet, polytetrafluoroethylene, polyvinyl chloride, silicone rubber, and glass sheet) were 10 cm long and 2.5 cm wide. Two samples were bonded together using a hydrogel square patch (1 mm thick, 25 mm side length) prepared in Example 1, with a bonding area of ​​25 mm × 25 mm. The samples were then dried at room temperature for 24 h or at 60 °C for 8 h. The adhesive force was tested by axial tensile testing using a mechanical tensile tester. The adhesive force can be calculated using the following formula:

[0121]

[0122] Where F is the tensile strength (N) when the bonded sample separates, and A is the contact area (m²) between the two samples. 2 ).like Figure 4 As shown, the adhesion of the dried hydrogel to wood chips reached 250 kPa, while the adhesion to other materials was only 20-25 kPa. Compared to the hydrogel samples dried slowly at room temperature, the hydrogel dried at 60°C for 8 hours showed a significant increase in adhesion. These results indicate that the adhesion of the hydrogel can increase by 2-5 times as moisture is lost.

[0123] (4) Anti-free radical ability test

[0124] The solidified square hydrogel sheet (25 mm side length, 1 mm thickness) prepared in Example 1 was immersed in 0.15 mM DPPH ethanol solution for 10 min. The absorbance at 517 nm was observed using a UV-Vis spectrophotometer, and the free radical scavenging rate was calculated using the following formula:

[0125]

[0126] Where A c The absorbance of the control group DPPH ethanol solution at 517 nm is given, while A... s The absorbance of the sample solution (DPPH ethanol solution + hydrogel) at 517 nm is given. Figure 5 As shown, the hydrogel achieved a DPPH free radical scavenging rate of 90%. These results demonstrate that the hydrogel possesses excellent antioxidant and free radical scavenging capabilities against DPPH.

[0127] (5) Burn Healing Experiment

[0128] Male BALB / c mice (6 ± 20 weeks of age) were cultured at a constant temperature (21 ± 1 °C) and relative humidity (60 ± 5%) for at least 7 days. All mice underwent a 12-hour light-12-hour dark cycle and had free access to water and food. Mice were anesthetized prior to scalding treatment by intraperitoneal injection of 10% chloral hydrate at a dose of 30 mg / kg. Afterward, the hair on their backs was shaved. A brass cylinder (15 mm in diameter) was preheated in 90 °C hot water for 10 minutes and then pressed onto the skin on the mouse's back for 6 seconds to create a scald. Then, 10 μL of MRSA suspension (bacterial concentration 1 × 10⁻⁶) was applied. 8 CFU-mL -1 The hydrogel was evenly applied to the burn surface. After 10 minutes, the burn wound was covered with the hydrogel patch (24 mm in diameter) obtained in Example 1 (6 mice per group). The control group was treated with physiological saline for burn wound treatment. On days 1 and 3, mice were sacrificed, and wound tissue samples were collected for histological analysis. Skin tissue samples were homogenized in 1 mL of phosphate-buffered saline (PBS) and serially diluted. Bacterial concentration was assessed by electroplating the dilution on LB agar plates, and colony counts were performed after overnight incubation.

[0129] like Figure 6 As shown, compared with the hydrogel without theaflavins (Comparative Example 1) and the saline group, the hydrogel obtained in Example 1 has obvious antibacterial and healing-promoting effects. After the wound heals, the skin tissue is continuous and there is no obvious redness or swelling.

[0130] (6) Hemostasis in rat liver

[0131] For the liver hemostasis model in SD rats, after one-quarter of the liver lobe was removed, the hydrogel patch (24 mm in diameter, 2 mm thick) obtained in Example 1 was adhered to the cut surface. A clean filter paper of known mass (M1) was then placed beneath the liver. Untreated bleeding sites served as negative controls, while gauze compression served as a positive control. After 3 minutes of blood flow, the filter paper was stained with blood and re-weighed (M2). The amount of blood loss was calculated as the difference in mass of the filter paper before and after blood staining: M2 - M1, (n = 4).

[0132] like Figure 7 As shown, the hydrogel patch can effectively adhere to the liver cut surface and inhibit bleeding, with a hemostatic efficiency of approximately 75% compared to the control group. These results indicate that the hydrogel patch obtained in this invention has the potential for use in surgical hemostasis.

[0133] (7) Mechanical property testing

[0134] Test methods for elongation at break and maximum tensile strength: The hydrogel samples from Examples 1-6 were cut into standard samples with a length of 10 cm, a thickness of 0.6 cm, and a width of 1 cm. These samples were then placed on a tensile testing apparatus for tensile testing. After the hydrogel fractured, the maximum tensile force and elongation at break were recorded. The maximum tensile force divided by the cross-sectional area is the maximum tensile strength. The results are shown in Table 1.

[0135] Method for testing tissue adhesion: The hydrogel samples (1 mm thick, 25 mm long and wide) of Examples 1-6 were adhered between two pieces of pigskin. The pigskin was then pulled apart using a mechanical tensile tester. The tissue adhesion was calculated as tensile force / gel contact area. The results are shown in Table 1 below.

[0136] Table 1

[0137]

[0138] As can be seen from Table 1, the hydrogel of the present invention has excellent mechanical properties and can be used as a hydrogel.

[0139] The above embodiments of the present invention are merely examples for clearly illustrating the present invention and are not intended to limit the implementation of the present invention. Those skilled in the art will recognize that other variations or modifications can be made based on the above description. It is neither necessary nor possible to exhaustively describe all possible implementations here. Any modifications, equivalent substitutions, and improvements made within the spirit and principles of the present invention should be included within the scope of protection of the claims of the present invention.

Claims

1. A hydrogel, characterized in that, In the presence of a buffer system, it is formed by the reaction of plant polyphenols and sulfur-containing fatty acid compounds in the gelling component. The buffer system comprises polybasic acids and biological buffers; and, The gelling components include plant polyphenols and sulfur-containing fatty acid compounds; wherein... The mass ratio of the plant polyphenols to the sulfur-containing fatty acid compounds is 1:2.5~5; The polyacids include one or more of ethylenediaminetetraacetic acid, citric acid, and tartaric acid; The plant polyphenol is theaflavin. The sulfur-containing fatty acid compound is α-lipoic acid. The biological buffer is tris(hydroxymethyl)aminomethane. The mass ratio of the polybasic acid to the biological buffer is 1:5-10, and the mass ratio of the polybasic acid to the sulfur-containing fatty acid compound is 1:10-20. The tissue adhesion strength of the hydrogel is 6.0-12 kPa.

2. The hydrogel according to claim 1, characterized in that, The hydrogel has a tissue adhesion strength of 8.5-12 kPa; a maximum swelling ratio of 200-250%; an elongation at break of 350-550%; and a maximum tensile strength of 3.5-5.5 kPa.

3. A method for preparing a hydrogel according to claim 1 or 2, characterized in that, This includes the step of mixing the components of the buffer system and the gelling component in a solvent.

4. The method according to claim 3, characterized in that, The preparation method includes the following steps: Step 1) Dissolve the polybasic acid and the biological buffer in a solvent to obtain a buffer system; Step 2) Dissolve the plant polyphenols in the buffer system to obtain a premix; Step 3) After dissolving the sulfur-containing fatty acid compound in the premix, the mixture is injected into a mold and cooled to obtain a hydrogel.

5. The preparation method according to claim 4, characterized in that, In step 1), the mass ratio of the polybasic acid, the biological buffer, and the solvent is 1:4-10:25-50; the temperature for dissolving the polybasic acid and the biological buffer is 10-60℃. In step 2), the mass ratio of the plant polyphenol to the solvent is 1:5-10; the temperature for dissolving the plant polyphenol is 40-60℃, and the dissolution time is 3-5 minutes. In step 3), the mass ratio of the sulfur-containing fatty acid compound to the solvent is 1:2-3; the temperature for dissolving the sulfur-containing fatty acid compound is 40-60℃; the cooling temperature is 0-25℃, and the cooling time is 6-12h.

6. A hydrogel patch, characterized in that, Hydrogels prepared by the method of preparing hydrogels according to claim 1 or 2 or according to any one of claims 3-5.

7. A hydrogel powder, characterized in that, This includes pulverizing the hydrogel prepared by the method according to claim 1 or 2 or the hydrogel prepared according to any one of claims 3-5.

8. The use of a hydrogel prepared by the method of preparing a hydrogel according to claim 1 or 2 or a hydrogel according to any one of claims 3-5 in the preparation of wound healing products, visceral or soft tissue wound closure products, tissue fluid sealing products, hemostatic aids and soft tissue repair patches.

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