A biomedical tissue adhesive and its preparation method

Abstract

This invention relates to the field of medical materials technology, specifically to a biomedical tissue adhesive and its preparation method. This application provides a biomedical tissue adhesive whose raw materials include a prepolymer and a polyphenolic compound. The prepolymer includes one or more combinations of polyvinyl alcohol, acrylic acid, and N-hydroxysuccinimide acrylate. The biomedical tissue adhesive provided by this invention can quickly and persistently adhere to moist tissue surfaces, exhibits good biocompatibility, and allows for simple and controllable clinical application conditions.

Description

Technical Field

[0001] This invention belongs to the field of medical materials technology, specifically relating to a biomedical tissue adhesive and its preparation method. Background Technology

[0002] Wound healing is a critical issue in surgery. After tissue damage, the formation of new tissue and the remodeling of tissue function can take months to a year, becoming a crucial factor in assessing surgical success. Currently, surgery primarily employs physical closure techniques such as sutures and staples. However, these techniques can cause secondary trauma during surgery and postoperative inflammatory responses, and are difficult to apply to complex tissues. In contrast, tissue adhesives offer advantages such as ease of use, shorter operation time, and rapid wound healing, demonstrating broad application prospects. Despite the potential advantages of tissue adhesives compared to traditional suturing techniques, existing tissue adhesives still have some limitations: slow adhesion kinetics, low mechanical strength, and poor interfacial bonding with moist biological tissues. For example, α-cyanoacrylate cures rapidly, but has low mechanical strength and is prone to producing toxic degradation products under physiological conditions. Fibrinogen adhesives exhibit good biocompatibility and degradability, but their curing speed is slow, their adhesive strength is low, and they pose a potential risk of viral infection. Hydrogels, on the other hand, are materials with high water content and a three-dimensional structure, similar to biological tissues, exhibiting good biocompatibility and diverse forms suitable for complex tissues. Currently, various hydrogels have been developed for wound repair, but long-term practice has shown that hydrogel adhesives still have problems such as low adhesion performance, slow adhesion speed, and easy water absorption, which leads to a decline in mechanical properties and makes them unable to match tissues.

[0003] Furthermore, when dealing with moist wounds involving internal tissues, water molecules on the tissue surface hinder the diffusion of adhesive molecules, preventing them from bonding with the tissue's functional groups. Both commercially available tissue adhesives and hydrogel adhesives exhibit poor or no adhesion to tissues, meaning they cannot effectively stop bleeding or close wounds. An ideal medical tissue adhesive should meet the following criteria: safe and non-toxic, non-carcinogenic, possessing good and durable adhesion in a moist environment, good biocompatibility, and gradually degradable and absorbed within the tissue. Summary of the Invention

[0004] To overcome the problems existing in the prior art, the present invention aims to provide a biomedical tissue adhesive and its preparation method. The present invention utilizes the synergistic effect of acrylic acid, polyvinyl alcohol, N-hydroxysuccinimide acrylate and polyphenolic compounds to prepare a biomedical tissue adhesive that can quickly and persistently adhere to moist tissue surfaces, has good biocompatibility, and is simple and controllable for clinical implementation, and can be used to solve the problems in the prior art.

[0005] To achieve the above and other related objectives, the first aspect of the present invention provides a biomedical tissue adhesive, wherein the raw materials of the biomedical tissue adhesive include a prepolymer and a polyphenolic compound, wherein the prepolymer includes one or more of polyvinyl alcohol, acrylic acid and N-hydroxysuccinimide acrylate.

[0006] In any embodiment of this application, the concentration of polyvinyl alcohol in the solution of the prepolymer is 3% to 15% (w / w), and the degree of alcoholysis of the polyvinyl alcohol is above 75%.

[0007] In any embodiment of this application, the concentration of acrylic acid in the solution of the prepolymer is 15% to 30% (w / w).

[0008] In any embodiment of this application, the concentration of N-hydroxysuccinimide acrylate in the prepolymer solution is 0.1% to 2% (w / w).

[0009] In any embodiment of this application, the polyphenolic compound is selected from one or more combinations of tannic acid, catechol, catechol derivatives, pyrogallol, dopamine, dopamine derivatives, caffeic acid, caffeic acid derivatives, gallic acid, gallic acid derivatives, catechins, and catechin derivatives.

[0010] In any embodiment of this application, the solution concentration of the polyphenolic compound is 0.5% to 8% (w / w).

[0011] In any embodiment of this application, the prepolymer further includes a crosslinking agent and / or a photoinitiator.

[0012] In any embodiment of this application, the crosslinking agent includes one or more combinations of methyl acrylic anhydride gelatin and polyethylene glycol diacrylate N,N'-methylenebisacrylamide.

[0013] In any embodiment of this application, the photoinitiator includes α-ketoglutaric acid and / or Irgacure 2959.

[0014] In any embodiment of this application, the concentration of the crosslinking agent in the solution of the prepolymer is 0.01% to 0.1% (w / w).

[0015] In any embodiment of this application, the concentration of the photoinitiator in the solution of the prepolymer is 0.05% to 0.5% (w / w).

[0016] The second aspect of this application provides a method for preparing the aforementioned biomedical tissue adhesive, comprising the following steps:

[0017] 1) The polyvinyl alcohol, acrylic acid, N-hydroxysuccinimide acrylate, crosslinking agent and photoinitiator are mixed in the proportions of the first aspect mentioned above, and stirred to obtain a prepolymer solution;

[0018] 2) The prepolymer solution obtained in step 1) is photocrosslinked to obtain a hydrogel;

[0019] 3) The hydrogel described in step 2) is immersed in a polyphenol compound solution to obtain an adhesive precursor;

[0020] 4) Dry the adhesive precursor described in step 3) to obtain a biomedical tissue adhesive.

[0021] In any embodiment of this application, in step 1), the stirring time is 4 to 12 hours.

[0022] In any embodiment of this application, in step 2), the reaction time for photocrosslinking is 5 to 20 minutes.

[0023] In any embodiment of this application, in step 3), the soaking treatment is carried out in the dark, and the soaking time is 12 to 48 hours.

[0024] In any embodiment of this application, the drying is freeze drying and / or vacuum drying.

[0025] The third aspect of this application provides the use of the described biomedical tissue adhesive or the described preparation method in the preparation of medical adhesive materials.

[0026] The beneficial effects of this invention are as follows:

[0027] 1. The medical tissue adhesive provided by this invention can quickly absorb moisture and retain water for a long time on moist tissue surfaces, and achieve rapid and long-lasting adhesion to tissue surfaces, thus achieving the purpose of sutureless wound closure. The clinical implementation conditions are simple and controllable.

[0028] This invention uses acrylic acid and polyvinyl alcohol as the molecular backbone to construct a three-dimensional porous gel topological network structure, enabling the material to rapidly absorb liquids from the tissue surface. Initial weak connections are formed between the hydroxyl groups on the material surface and those on the tissue surface through hydrogen bonds. By grafting N-hydroxysuccinimide onto the hydroxyl groups of acrylic acid and polyvinyl alcohol, a first strong adhesion site that covalently reacts with the amino groups on the tissue surface is constructed. Introducing polyphenolic groups into the network structure creates multiple hydrogen bonds, stabilizing the tissue adhesion gel topological network structure and improving the material's biomechanical strength. Simultaneously, the introduced polyphenolic groups can react with the amino and thiol groups on the tissue surface through Schiff base reactions and Michael addition reactions, forming a second strong adhesion site, thereby further enhancing the tissue adhesion strength.

[0029] 2. The medical tissue provided by this invention is post-treated with low concentration tannic acid, which significantly reduces the swelling rate of the tissue adhesive.

[0030] Natural polyphenols, such as tannic acid, have low cytotoxicity, antioxidant and antibacterial activities. They can form non-covalent bonds with polymer skeletons through hydrogen bonding, thereby enhancing overall mechanical strength and significantly reducing the swelling rate of tissue adhesives. At the same time, they can enhance adhesion to various surfaces through hydrogen bonding, ionic bonding and π-π stacking.

[0031] 3. The medical tissue adhesive provided by this invention is completely biodegradable and has good biocompatibility. Attached Figure Description

[0032] Figure 1 The scanning electron microscope (SEM) results of Example 1 and Comparative Example 1 are shown. Figure 1 A is a cross-sectional scanning electron microscope image of Example 1. Figure 1 B is a scanning electron microscope image of the cross section of Comparative Example 1.

[0033] Figure 2 The Fourier transform infrared spectra of Example 1 and Comparative Example 1 are shown. Detailed Implementation

[0034] Before further describing specific embodiments of the present invention, it should be understood that the scope of protection of the present invention is not limited to the specific embodiments described below; it should also be understood that the terminology used in the embodiments of the present invention is for describing specific embodiments and not for limiting the scope of protection of the present invention; in the specification and claims of the present invention, unless otherwise expressly stated in the text, the singular forms "a", "an", and "this" include the plural forms.

[0035] The "range" disclosed in this application is defined by a lower limit and an upper limit. A given range is defined by selecting a lower limit and an upper limit, which define the boundaries of a particular range. Ranges defined in this way can include or exclude endpoints and can be arbitrarily combined; that is, any lower limit can be combined with any upper limit to form a range. For example, if ranges of 60–120 and 80–110 are listed for a specific parameter, it is understood that ranges of 60–110 and 80–120 are also expected. Furthermore, if minimum range values ​​of 1 and 2 are listed, and if maximum range values ​​of 3, 4, and 5 are listed, then the following ranges are all expected: 1–3, 1–4, 1–5, 2–3, 2–4, and 2–5. In this application, unless otherwise stated, the numerical range "a–b" represents a shortened representation of any combination of real numbers between a and b, where a and b are real numbers. For example, the numerical range "0~5" indicates that all real numbers between "0~5" have been listed in this article; "0~5" is simply a shortened representation of these numerical combinations. Furthermore, when a parameter is stated as an integer ≥2, it is equivalent to disclosing that the parameter is, for example, an integer such as 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, etc.

[0036] Unless otherwise specified, all steps of this application may be performed sequentially or randomly, preferably sequentially. For example, the method includes steps 1) and 2), indicating that the method may include steps 1) and 2) performed sequentially, or it may include steps 2) and 1) performed sequentially.

[0037] When numerical ranges are given in the embodiments, it should be understood that, unless otherwise stated in the present invention, both endpoints of each numerical range and any value between the two endpoints may be selected. Unless otherwise defined, all technical and scientific terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art. In addition to the specific methods, apparatus, and materials used in the embodiments, based on the knowledge of the prior art possessed by one of ordinary skill in the art and the description of this invention, any prior art methods, apparatus, and materials similar to or equivalent to those described, apparatus, and materials in the embodiments of this invention may be used to implement the present invention.

[0038] Unless otherwise stated, the experimental methods, detection methods, and preparation methods disclosed in this invention all employ conventional techniques from the fields of pharmaceutics, pharmaceutical analysis, medicinal chemistry, analytical chemistry, molecular biology, biochemistry, and related areas. These techniques have been well described in existing literature.

[0039] The first aspect of this application provides a biomedical tissue adhesive. The raw materials of the biomedical tissue adhesive include prepolymers and polyphenolic compounds. The prepolymers include one or more combinations of polyvinyl alcohol, acrylic acid, and N-hydroxysuccinimide acrylate. The above raw materials can be dissolved in deionized water, aqueous solutions, or organic solvents to form a polyphenolic compound solution or a prepolymer solution. Aqueous solutions include physiological solutions and buffer solutions. Physiological solutions include physiological saline, Ringer's solution, Löwenstein's solution, and Tyrode's solution, etc. Buffer solutions include phosphate buffer, citrate buffer, carbonate buffer, acetate buffer, Tris buffer, etc. Organic solvents include one or more combinations of methanol, toluene, ethanol, diethyl ether, and cyclohexane. Those skilled in the art should understand that solvents capable of dissolving the raw materials described in this invention are all within the scope of protection.

[0040] In the biomedical tissue adhesive provided in this application, the concentration of polyvinyl alcohol in the prepolymer solution is 3% to 15% (w / w); preferably, it is 3% to 5% (w / w), 5% to 6% (w / w), 6% to 10% (w / w), or 10% to 15% (w / w).

[0041] The biomedical tissue adhesive provided in this application has a degree of hydrolysis of polyvinyl alcohol of 75% or higher; preferably, it is 75-80% (w / w), 80-85% (w / w), 85-95% (w / w), or greater than 95%. The degree of hydrolysis refers to the percentage of hydroxyl groups in the product obtained after hydrolysis compared to the original functional groups.

[0042] In the biomedical tissue adhesive provided in this application, the concentration of acrylic acid in the prepolymer solution is 15%–30% (w / w); preferably, it is 15%–18% (w / w), 18%–25% (w / w), or 25%–30% (w / w). Using acrylic acid monomers, compared to high-molecular-weight polyacrylic acid, results in more stable reaction quality and easier grafting of succinimide. Since acrylic acid has a certain degree of toxicity, unreacted monomers need to be eluted during subsequent processing. Acrylic acid has good solubility and is easy to elute, reducing the overall toxicity risk of the product.

[0043] In the biomedical tissue adhesive provided in this application, the concentration of N-hydroxysuccinimide acrylate in the prepolymer solution is 0.1% to 1% (w / w); preferably, it is 0.1% to 0.2% (w / w), 0.2% to 0.5% (w / w), 0.5% to 1% (w / w), or 1% to 2% (w / w), etc.

[0044] Using acrylic acid and polyvinyl alcohol as the molecular backbone, a three-dimensional porous gel topological network structure is constructed, enabling the material to rapidly absorb liquids from the tissue surface. Initial weak connections are formed between the hydroxyl groups on the material surface and those on the tissue surface through hydrogen bonds. N-hydroxysuccinimide acrylate can be used to graft N-hydroxysuccinimide onto the hydroxyl groups of acrylic acid and polyvinyl alcohol, constructing the first strong adhesive sites that covalently react with the amino groups on the tissue surface, resulting in a tissue adhesive with strong adhesive strength.

[0045] The biomedical tissue adhesive provided in this application uses a polyphenolic compound selected from one or more combinations of tannic acid, catechol, catechol derivatives, pyrogallol, pyrogallol derivatives, dopamine, dopamine derivatives, caffeic acid, caffeic acid derivatives, gallic acid, gallic acid derivatives, catechins, and catechin derivatives. The concentration of the polyphenolic compound solution is 0.5%–8% (w / w); preferably, it is 0.5%–1% (w / w), 1%–1.5% (w / w), or 1.5%–5% (w / w), 5%–8% (w / w), etc. Polyphenolic compounds are widely used in the biological field due to their antioxidant, vascular protective, and tumor-preventing physiological functions. Catechols, such as dopamine and dopamine derivatives, are important components of the adhesive proteins secreted by marine mussels. These components can form long-term effective adhesion to various surfaces through hydrogen bonding, ionic bonding, π-π stacking, and other interactions. Furthermore, the poor adhesion performance and excessive swelling behavior of traditional tissue adhesives in a moist in vivo environment have become major obstacles to many applications and functionalization studies.

[0046] In one specific embodiment of this application, the polyphenolic compound is tannic acid. Tannic acid is a naturally occurring antioxidant polyphenol with low cytotoxicity, antioxidant, and antibacterial activities. Under alkaline conditions, tannic acid can be oxidized to ortho-quinones, which can form non-covalent bonds with the polymer backbone through hydrogen bonding, thereby enhancing the overall mechanical strength.

[0047] By introducing polyphenolic groups into a network structure built with acrylic acid and polyvinyl alcohol as the molecular backbone, a multi-hydrogen bond-stabilized tissue adhesion gel topological network structure is formed, improving the biomechanical strength of the material itself. Simultaneously, the introduced polyphenolic groups can react with amino and thiol groups on the tissue surface to undergo Schiff base reactions and Michael addition reactions, forming a second strong adhesive site, thereby further enhancing tissue adhesion strength. The Schiff base reaction refers to the reaction of the carbonyl group in the polyphenolic group with an amino group to generate an organic compound containing imine or methylimine characteristic groups. The Michael addition reaction refers to the conjugate addition reaction of carbanions to α, β-unsaturated aldehydes, ketones, carboxylic acids, esters, nitriles, nitro compounds, etc., i.e., the reaction of polyphenolic groups with thiol groups.

[0048] The prepolymer in the biomedical tissue adhesive provided in this application further includes a crosslinking agent and / or a photoinitiator.

[0049] The biomedical tissue adhesive provided in this application uses a crosslinking agent comprising one or more combinations of methyl acrylate gelatin (GelMA), polyethylene glycol diacrylate (PEGDA), and N,N'-methylenebisacrylamide (MBAA). In the prepolymer solution, the concentration of the crosslinking agent is 0.01% to 0.1% (w / w); preferably, it is 0.01% to 0.05% (w / w), 0.05% to 0.08% (w / w), or 0.08% to 0.1% (w / w), etc.

[0050] The biomedical tissue adhesive provided in this application uses α-ketoglutaric acid and / or Irgacure 2959 as a photoinitiator. In the prepolymer solution, the concentration of the photoinitiator is 0.05%–0.5% (w / w); preferably, it is 0.05%–0.1% (w / w), 0.1%–0.2% (w / w), or 0.2%–0.5% (w / w), etc. A photoinitiator, also known as a photosensitizer or photocuring agent, is a compound that can absorb energy of a certain wavelength in the ultraviolet (250-420 nm) or visible (400-800 nm) light region, generating free radicals, cations, etc., thereby initiating monomer polymerization, cross-linking, and curing.

[0051] The biomedical tissue adhesive provided in this application contains prepolymer raw materials including polyvinyl alcohol, acrylic acid, N-hydroxysuccinimide acrylate, crosslinking agent and photoinitiator. The prepolymer is a substance produced by the reaction of the aforementioned five raw materials. The prepolymer needs to undergo photocrosslinking to form a hydrogel. The hydrogel is then immersed in a polyphenol compound solution and reacted again to generate the biomedical tissue adhesive.

[0052] The mechanism of action of the biomedical tissue adhesive provided by this invention is as follows: The biomedical tissue adhesive of this invention is in a dry state and requires no special treatment before use. It can be directly adhered to moist tissue surfaces. The dual network structure composed of acrylic acid and polyvinyl alcohol in the adhesive can act as a medium for water absorption and retention. The hydroxyl groups in the tissue adhesive and the N-succinimide acrylate grafted with acrylic acid can form covalent and non-covalent bonds with the tissue surface, exhibiting high adhesion strength. Introducing polyphenolic groups into the network structure further enhances the tissue adhesion strength through the formation of multiple hydrogen bonds.

[0053] The biomedical tissue adhesive provided in this application has a uniform array of micropores on its surface. The depth of each micropore in the micropore array is 50% to 100% of the thickness of the adhesive film layer. In a specific embodiment of this application, when the thickness of the adhesive film layer is 200 μm, the depth of each micropore is 100 μm to 200 μm; preferably, it is 100 to 120 μm, 120 to 150 μm, or 150 to 200 μm, etc. The depth of each micropore can be consistent with the thickness of the tissue adhesive, in which case each micropore can penetrate the tissue adhesive. The spacing between the micropores in the adhesive film layer between the micropore arrays is 10 to 100 μm; preferably, it is 10 to 50 μm, 50 to 80 μm, or 80 to 100 μm. The micropore spacing allows a uniform array of micropores to be regularly formed on the surface of the adhesive film layer. Due to the presence of the micropore array, the surface roughness and specific surface area of ​​the tissue adhesive are improved, making it easier to adhere to tissues and positively influencing cell adhesion, migration, and differentiation. The pore size of each micropore in the micropore array is 10–1000 μm; preferably, it is 10–100 μm, 100–500 μm, or 500–1000 μm. The cross-sectional shape of each micropore in the tissue adhesive micropore array is diverse, such as triangular, rectangular, or elliptical. This diverse micropore structure can adapt to complex tissue surfaces. Although high surface tension at small dimensions can easily cause micropores to collapse and shrink, the tissue adhesive utilizes its dissipative matrix to maintain the stability of this structure. The micropore structure is beneficial for enhancing tissue adhesion performance. When the tissue adhesive of this application adheres to tissue, water and air in the micropores can be expelled by pressing or other methods, creating a pressure difference between the inside and outside of the micropores, thereby generating additional suction, reducing the relative sliding between the tissue adhesive and the tissue surface in the initial stage of adhesion, and improving the adhesion performance of the tissue adhesive.

[0054] A second aspect of this application provides a method for preparing a biomedical tissue adhesive, comprising the following steps:

[0055] 1) The polyvinyl alcohol, acrylic acid, N-hydroxysuccinimide acrylate, crosslinking agent and photoinitiator in the aforementioned biomedical tissue adhesive are mixed in the proportions of the first aspect and stirred to obtain a prepolymer solution.

[0056] 2) The prepolymer solution from step 1) is photocrosslinked to obtain a hydrogel;

[0057] 3) The hydrogel from step 2) is immersed in the polyphenol compound solution in the aforementioned biomedical tissue adhesive to obtain the adhesive precursor;

[0058] 4) Dry the adhesive precursor from step 3) to obtain a biomedical tissue adhesive.

[0059] In the preparation method provided in this application, step 1) involves mixing the polyvinyl alcohol, acrylic acid, N-hydroxysuccinimide acrylate, crosslinking agent, and photoinitiator in the aforementioned biomedical tissue adhesive according to the proportions specified in the first aspect, stirring and mixing to obtain a prepolymer solution. The prepolymer solution, by mass percentage, comprises the following components: 15–30% (w / w) acrylic acid, 3%–15% (w / w) polyvinyl alcohol, 0.1%–2% (w / w) N-succinimide acrylate, 0.1%–1% (w / w) crosslinking agent, 0.05%–0.5% (w / w) photoinitiator, with the remainder being a solution of polyphenolic compounds or a prepolymer solution in water, an aqueous solution, or an organic solvent. The aqueous solution includes physiological solutions and buffer solutions. Physiological solutions include physiological saline, Ringer's solution, Löwenstein's solution, and Tyrode's solution, etc., while buffer solutions include phosphate buffer, citrate buffer, carbonate buffer, acetate buffer, Tris buffer, etc. Organic solvents include one or more combinations of methanol, toluene, ethanol, diethyl ether, and cyclohexane. Those skilled in the art should understand that solvents capable of dissolving the raw materials described in this invention are all within the scope of protection. The stirring time is 4–12 hours; preferably, it is 4–8 hours, 8–10 hours, or 10–12 hours. In a specific embodiment of this application, deionized water can be used as the solution during stirring. During this process, acrylic acid and polyvinyl alcohol react to form a three-dimensional porous gel topological network structure as the molecular backbone. N-hydroxysuccinimide acrylate performs N-hydroxysuccinimide surface grafting modification on the hydroxyl groups of acrylic acid and polyvinyl alcohol, constructing a first strong adhesion site that covalently reacts with the amino groups on the tissue surface. A crosslinking agent can crosslink the aforementioned compounds. A photoinitiator can initiate the curing of the aforementioned compounds under conditions such as ultraviolet light.

[0060] In the preparation method provided in this application, step 2) involves photocrosslinking the prepolymer solution from step 1) to obtain a hydrogel. The photocrosslinking reaction time is 5–20 min; preferably, it is 5–10 min, 10–15 min, or 15–20 min. Photocrosslinking refers to the reaction in which a compound undergoes photolysis upon exposure to light, or when a portion of a bond opens, generating free radicals and other activated molecules that bond together, leading to the formation of a network structure in the polymer chains. Photoinitiators can absorb energy of a certain wavelength under ultraviolet light (250-420 nm), generating free radicals, cations, etc., thereby initiating the crosslinking and curing of polyvinyl alcohol, acrylic acid, and N-hydroxysuccinimide acrylate. In a specific embodiment of this application, the photocrosslinking is performed under an ultraviolet lamp.

[0061] In the preparation method provided in this application, step 3) involves immersing the hydrogel from step 2) in the aforementioned polyphenol compound solution of the biomedical tissue adhesive to obtain the adhesive precursor. Immersion refers to the complete submersion of the hydrogel in the polyphenol compound solution. The concentration of the polyphenol compound solution is 0.5%–8% (w / w); preferably, it is 0.5%–1% (w / w), 1%–1.5% (w / w), or 1.5%–5% (w / w), 5%–8% (w / w), etc. The solvent for the polyphenol compound solution is selected from water, aqueous solutions, or organic solvents to form polyphenol compound solutions or prepolymer solutions. Aqueous solutions include physiological solutions and buffer solutions. Physiological solutions include physiological saline, Ringer's solution, Löwenstein's solution, and Tyrode's solution, etc. Buffer solutions include phosphate buffer, citrate buffer, carbonate buffer, acetate buffer, Tris buffer, etc. Organic solvents include one or more combinations of methanol, toluene, ethanol, diethyl ether, and cyclohexane. The immersion treatment is carried out under light-protected conditions for a reaction time of 12–48 h; preferably, it is 12–24 h, 24–36 h, or 36–48 h. The addition of the polyphenol compound in this step is to introduce polyphenol groups into the cross-linked network structure after step 2), forming multiple hydrogen bonds, stabilizing the tissue adhesion gel topology and improving the biomechanical strength of the material itself, while simultaneously forming a second strong adhesive site, thereby further enhancing the tissue adhesion strength.

[0062] In the preparation method provided in this application, step 4) involves drying the adhesive precursor from step 3) to obtain a biomedical tissue adhesive. The drying process can be freeze-drying and / or vacuum drying.

[0063] The third aspect of this application provides the use of the aforementioned biomedical tissue adhesive or the aforementioned preparation method in the preparation of medical adhesive materials.

[0064] The present application is further illustrated below by way of examples, but these examples do not limit the scope of the application. All reagents are commercially available analytical grade products.

[0065] Example 1

[0066] A prepolymer solution was prepared, comprising 15% (w / w) polyvinyl alcohol with a degree of hydrolysis of 75%, 20% (w / w) acrylic acid, 0.1% (w / w) N,N'-methylenebisacrylamide, 0.05% (w / w) α-ketoglutaric acid, and 0.5% (w / w) N-hydroxysuccinimide acrylate in deionized water. The solution was stirred thoroughly to obtain the prepolymer solution.

[0067] The prepolymer solution was poured into a mold with a thickness of 500 μm and crosslinked under UV light for 20 min to form a hydrogel. The hydrogel was then immersed in a 1.0% (w / w) tannic acid solution under light-protected conditions for 24 h, yielding a tissue adhesive precursor. This precursor was then freeze-dried in situ to obtain the tissue adhesive.

[0068] Comparative Example 1

[0069] A prepolymer solution was prepared, comprising 15% (w / w) of polyvinyl alcohol with a degree of hydrolysis of 75%, 20% (w / w) of acrylic acid, 0.1% (w / w) of N,N'-methylenebisacrylamide, 0.05% (w / w) of α-ketoglutaric acid, and 0.5% (w / w) of N-hydroxysuccinimide acrylate in a deionized aqueous solution. The solution was stirred thoroughly to obtain the prepolymer solution.

[0070] The prepolymer solution was poured into a mold with a thickness of 500 μm and crosslinked under UV light for 20 min to form a hydrogel. The hydrogel was then freeze-dried in situ to obtain the tissue adhesive.

[0071] Example 2

[0072] A prepolymer solution was prepared, comprising 8% (w / w) polyvinyl alcohol with a degree of hydrolysis of 85%, 30% (w / w) acrylic acid, 0.1% (w / w) N,N'-methylenebisacrylamide, 0.05% (w / w) α-ketoglutaric acid, and 1% (w / w) N-hydroxysuccinimide acrylate in deionized water. The solution was stirred thoroughly to obtain the prepolymer solution.

[0073] The prepolymer solution was poured into a mold with a thickness of 500 μm and crosslinked under UV light for 20 min to form a hydrogel. The gel was then immersed in a 1% (w / w) tannic acid solution under light-protected conditions for 24 h to obtain the tissue adhesive precursor. The tissue adhesive precursor was then freeze-dried in situ to obtain the tissue adhesive.

[0074] Example 3

[0075] A prepolymer solution was prepared, comprising 8% (w / w) polyvinyl alcohol with a degree of hydrolysis of 85%, 30% (w / w) acrylic acid, 0.1% (w / w) N,N'-methylenebisacrylamide, 0.05% (w / w) α-ketoglutaric acid, and 1% (w / w) N-hydroxysuccinimide acrylate in deionized water. The solution was stirred thoroughly to obtain the prepolymer solution.

[0076] The prepolymer solution was poured into a mold with a thickness of 500 μm to prepare micropores with a spacing of 80 μm, a depth of 150 μm, and a pore size of 200 μm. The micropores were then crosslinked under UV light for 20 min to form a hydrogel. The hydrogel was then immersed in a 1.5% (w / w) catechol solution under light-protected conditions for 24 h to obtain the tissue adhesive precursor. The tissue adhesive precursor was then freeze-dried in situ to obtain the tissue adhesive.

[0077] Example 4

[0078] Prepare a prepolymer solution containing 10% (w / w) of polyvinyl alcohol with a degree of hydrolysis of 75%, 25% (w / w) of acrylic acid, 0.1% (w / w) of polyethylene glycol diacrylate, 0.05% (w / w) of α-ketoglutaric acid, and 1% (w / w) of N-hydroxysuccinimide acrylate in a deionized aqueous solution. Stir the solution thoroughly to obtain the prepolymer solution.

[0079] The prepolymer solution was poured into a mold with a thickness of 500 μm and crosslinked under UV light for 20 min to form a hydrogel. The gel was then immersed in a 0.5% (w / w) tannic acid solution under light-protected conditions for 48 h to obtain the tissue adhesive precursor. The tissue adhesive precursor was then freeze-dried in situ to obtain the tissue adhesive.

[0080] Comparative Example 2

[0081] Prepare a prepolymer solution containing 1% (w / w) of polyvinyl alcohol with a degree of hydrolysis of 75%, 25% (w / w) of acrylic acid, 0.1% (w / w) of polyethylene glycol diacrylate, 0.05% (w / w) of α-ketoglutaric acid, and 1% (w / w) of N-hydroxysuccinimide acrylate in a deionized aqueous solution. Stir the solution thoroughly to obtain the prepolymer solution.

[0082] The prepolymer solution was poured into a mold with a thickness of 500 μm and crosslinked under UV light for 20 min to form a hydrogel. The gel was then immersed in a 0.5% (w / w) tannic acid solution under light-protected conditions for 48 h to obtain the tissue adhesive precursor. The tissue adhesive precursor was then freeze-dried in situ to obtain the tissue adhesive.

[0083] Comparative Example 3

[0084] Prepare a prepolymer solution containing 10% (w / w) of polyvinyl alcohol with a degree of hydrolysis of 75%, 10% (w / w) of acrylic acid, 0.1% (w / w) of polyethylene glycol diacrylate, 0.05% (w / w) of α-ketoglutaric acid, and 1% (w / w) of N-hydroxysuccinimide acrylate in a deionized aqueous solution. Stir the solution thoroughly to obtain the prepolymer solution.

[0085] The prepolymer solution was poured into a mold with a thickness of 500 μm and crosslinked under UV light for 20 min to form a hydrogel. The gel was then immersed in a 0.5% (w / w) tannic acid solution under light-protected conditions for 48 h to obtain the tissue adhesive precursor. The tissue adhesive precursor was then freeze-dried in situ to obtain the tissue adhesive.

[0086] The components of the above embodiments and comparative examples are shown in Table 1:

[0087] Table 1 Components of Biomedical Tissue Adhesives

[0088]

[0089]

[0090] The properties of the tissue adhesives prepared in the embodiments of the present invention were measured respectively:

[0091] (1) Scanning electron microscopy test

[0092] Test results as follows Figure 1 As shown, tannic acid treatment can help the adhesive form a loose structure, which facilitates water absorption and bonding.

[0093] (2) Fourier transform infrared spectrum

[0094] Test results as follows Figure 2 As shown, the adhesive prepared in Example 1 was measured at 1608 cm⁻¹. –1 And 1535cm –1 The presence of a distinct C=C characteristic peak indicates the successful introduction of the polyphenolic group, suggesting the formation of a second strong binding site.

[0095] (3) Swelling rate test: The tissue adhesives of the above examples and comparative examples were used, and the thickness was measured and recorded as V0. They were soaked in PBS solution. On days 1, 2, 4, and 7, the swollen tissue adhesives were taken out, the surface water was wiped off with filter paper, and the thickness of the colloid was measured and recorded as Vs (s = 1, 2, 4, 7). The swelling rate Q = (Vs - V0) / V0, and the results are shown in Table 3.

[0096] Table 3 Swelling Rate Data

[0097] D1 D2 D4 D7 Example 1 21％ 25％ 25％ 25％ Comparative Example 1 185％ 205％ 205％ 205％ Example 2 12％ 18％ 18％ 20％ Example 3 26％ 31％ 31％ 31％ Example 4 18％ 20％ 20％ 20％ Comparative Example 2 1000％ 1200％ 1200％ 1250％ Comparative Example 3 85％％ 92％ 92％ 92％

[0098] (4) Adhesion strength evaluation

[0099] The above-described examples and comparative examples were used respectively, and their adhesion strength was tested according to YY / T 0729.1 Test Method for Adhesive Bonding Performance Part 1: Overlap-Shear Tensile Bearing Strength. Pigskin was washed and then soaked in PBS. The adhesive was applied to the moistened pigskin and pressed with a 200g weight for 10 minutes. A tensile testing machine was then used for shear testing. The test results are shown in Table 3.

[0100] Table 3 Adhesion strength data

[0101] Adhesion strength (kPa) Example 1 102.7 Comparative Example 1 56.4 Example 2 105.7 Example 3 117.3 Example 4 94.6 Comparative Example 2 46.3 Comparative Example 3 18.5

[0102] The above embodiments are merely illustrative of the principles and effects of the present invention and are not intended to limit the invention. Any person skilled in the art can modify or alter the above embodiments without departing from the spirit and scope of the present invention. Therefore, all equivalent modifications or alterations made by those skilled in the art without departing from the spirit and technical concept disclosed in the present invention should still be covered by the claims of the present invention.

Claims

1. A bio-medical tissue adhesive, characterized by, The raw materials of the biomedical tissue adhesive include a prepolymer and a polyphenol compound, the prepolymer includes a combination of polyvinyl alcohol, acrylic acid and acrylic acid N-hydroxysuccinimide ester, in a solution of the prepolymer, the concentration of the polyvinyl alcohol is 6-10% w / w or 10-15% w / w, the concentration of the acrylic acid is 18-25% w / w or 25-30% w / w, the polyphenol compound is tannic acid, and the prepolymer further includes a crosslinking agent and a photoinitiator; The preparation method of the biomedical tissue adhesive includes: 1) mixing the polyvinyl alcohol, the acrylic acid, the acrylic acid N-hydroxysuccinimide ester, the crosslinking agent and the photoinitiator by stirring to obtain a prepolymer solution; 2) performing photo-crosslinking on the prepolymer solution of step 1) to obtain a hydrogel; 3) soaking the hydrogel of step 2) in a solution of the polyphenol compound with a concentration of 0.5% to 8% w / w to obtain an adhesive precursor; 4) drying the adhesive precursor of step 3) to obtain the biomedical tissue adhesive.

2. The bio-medical tissue adhesive as claimed in claim 1, wherein, In the solution of the prepolymer, the alcoholysis degree of the polyvinyl alcohol is above 75%; And / or, in the solution of the prepolymer, the concentration of the acrylic acid N-hydroxysuccinimide ester is 0.1% to 2% w / w.

3. The bio-medical tissue adhesive as set forth in claim 1, wherein The solution concentration of the polyphenol compound is 0.5% to 8% w / w.

4. The bio-medical tissue adhesive as claimed in claim 1, wherein The crosslinking agent includes a combination of one or more of the following: type A acrylic anhydride gelatin, polyethylene glycol bisacrylate and N,N'-methylene bisacrylamide; And / or, the photoinitiator includes α-ketoglutaric acid and / or Irgacure 2959.

5. The bio-medical tissue adhesive as claimed in claim 4, wherein In the solution of the prepolymer, the concentration of the crosslinking agent is 0.01% to 0.1% w / w; and / or, in the solution of the prepolymer, the concentration of the photoinitiator is 0.05% to 0.5% w / w.

6. The bio-medical tissue adhesive as set forth in claim 1, wherein Further comprising one or more of the following features: a) in step 1), the stirring time is 4 to 12 hours; b) in step 2), the reaction time of the photo-crosslinking is 5 to 20 minutes; c) in step 3), the soaking treatment is carried out in the dark, and the soaking treatment time is 12 to 48 hours; d) in step 4), the drying is freeze-drying and / or vacuum drying.

7. Use of the biomedical tissue adhesive according to any one of claims 1 to 6 in the preparation of a medical adhesive material.

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