Photocured biological tissue adhesive patch, method for preparing the same, and use thereof

Abstract

The application discloses a photocured biological tissue adhesive patch and a preparation method and application thereof, and relates to the technical field of biomedical materials. The photocured biological tissue adhesive patch comprises a composite polymer soluble microneedle, wherein the photocured biological tissue adhesive patch is prepared from a prepolymer solution comprising the following components: (1) methacrylated gelatin (GelMA); (2) oxidized dextran (ODex); (3) polyvinyl alcohol (PVA); and (4) a photoinitiator, wherein the photoinitiator comprises LAP; and the weight ratio of the methacrylated gelatin, the oxidized dextran, the polyvinyl alcohol and the photoinitiator is (5-10):(3-6):(3-8):(0.05-0.3). The photocured biological tissue adhesive patch has excellent tissue integration promotion effect, is particularly suitable for a conjunctival transplantation and other surgeries requiring high-quality tissue integration, has wide clinical application adaptability and good industrialization prospect.

Description

Technical Field

[0001] This invention relates to the field of biomedical materials technology, and in particular to a photocurable biological tissue adhesive patch, its preparation method, and its application. Background Technology

[0002] Tissue adhesives, as an important supplement or alternative to traditional sutures, play a crucial role in wound closure, tissue repair, and surgical procedures. An ideal tissue adhesive should possess excellent biocompatibility, sufficient adhesive strength, a controllable curing process, and flexibility that matches the mechanical properties of the tissue. Currently, commonly available tissue adhesives include cyanoacrylates, fibrin glues, and synthetic systems based on natural polymers such as gelatin, hyaluronic acid, and chitosan.

[0003] (1) Suture technique

[0004] Made of non-absorbable (such as nylon, polypropylene) or absorbable (such as catgut, polylactic acid) suture materials, these sutures are used in conjunction with surgical needles. The graft is mechanically aligned with the implant bed by puncturing the tissue, and the suture tension maintains its position until the tissue heals. While considered the gold standard for ophthalmic surgeries such as conjunctival transplantation, it has significant limitations. The sutures, being foreign bodies, may continuously irritate the ocular surface, and the procedure is complex and requires a high level of surgical skill.

[0005] (2) Traditional tissue adhesives

[0006] Fibrin glue is a two-component system containing fibrinogen and thrombin, typically applied using a specialized applicator. It simulates the final stage of the coagulation cascade, where fibrinogen, under the action of thrombin, forms a fibrin network, achieving tissue adhesion. While it exhibits good biocompatibility, its adhesive strength is insufficient, and it degrades rapidly in the moist environment of the ocular surface, failing to provide long-term stable fixation.

[0007] Cyanoacrylate adhesives are single-component liquid cyanoacrylate monomers that rapidly polymerize upon contact with tissue anions. They undergo anionic polymerization upon contact with surface moisture or amino acids, forming long polycyanoacrylate chains that create mechanical interlocking and covalent bonds. While exhibiting high adhesive strength, they lack flexibility, and their degradation products may be cytotoxic, making them unsuitable for sensitive ocular tissues.

[0008] (3) Photocurable hydrogel system

[0009] In recent years, visible light-cured bioadhesives have attracted widespread attention due to their excellent spatiotemporal controllability and ease of operation. These materials are typically composed of photosensitive polymers (such as methacrylamide gelatin, GelMA) and photoinitiators (such as LAP), which can rapidly form a cross-linked network under specific wavelengths of light to achieve tissue adhesion. Among them, GelMA has become one of the most commonly used basic materials in photocurable tissue adhesives due to its inherent cell compatibility, biodegradability, and ease of functionalization.

[0010] Based on photosensitive natural polymers such as methacrylamide gelatin (GelMA) and oxidized dextran (ODex), combined with visible light initiators (such as LAP), under visible light irradiation, the photoinitiator generates active free radicals, initiating the polymerization of methacrylamide groups to form a covalent cross-linked network. Simultaneously, the aldehyde groups of ODex react with the amino groups of GelMA through a Schiff base reaction, constructing a double cross-linked network, which can significantly improve the mechanical strength and adhesive stability of the material. However, direct application to the ocular surface faces problems such as interference from tissue surface moisture and poor adhesion to curved tissues.

[0011] (4) Soluble microneedle system

[0012] Typically, microneedles are made of water-soluble polymers (such as hyaluronic acid, gelatin, and polyvinyl alcohol) to form micron-sized needle arrays that carry drugs or active ingredients. After penetrating the outermost barrier of the skin or tissue, the microneedles dissolve, releasing the loaded components; temporary anchoring is provided by the mechanical interlocking of the needles. They are mainly used for transdermal drug delivery, with limited application in tissue fixation, and lack specific interface designs for moist tissue surfaces. For example, a similar existing technology is soluble microneedle patches based on natural polymer derivatives such as GelMA. Another example is the use of a combination of GelMA and ODex, molded using microneedles, utilizing their photocuring properties and Schiff base reactions to form a cross-linked network for drug delivery or tissue repair. However, such systems typically act directly on the tissue without pre-treating the bonding interface. In a moist environment, the water film that may exist at the interface can hinder the formation of efficient chemical bonds, limiting further improvements in adhesive strength.

[0013] (5) Focusing on enhancing adhesion through interfacial chemical modification. Some studies have attempted to pretreat tissue surfaces with compounds containing active groups (such as N-hydroxysuccinimide ester, NHS) before adhesion, hoping to react with the amino groups on the tissue surface and introduce more cross-linking sites at the interface. However, if used alone without a sophisticated synergistic design with the adhesive system, its effect is limited, and residual interfacial water molecules remain a challenge.

[0014] (6) A dual-network hydrogel system named "GelMA-ODex@RRHD". This system combines GelMA with oxidized dextran (ODex) and introduces an environmentally responsive crosslinking mechanism. However, this system is mainly designed and applied as an injectable hydrogel. Its morphology is a traditional monolithic structure and it is not combined with microneedle array technology. Therefore, it cannot further enhance the adhesive strength through physical interlocking effect, and it is also difficult to actively cope with the adverse effects of the interfacial water environment.

[0015] Despite significant progress in photocurable hydrogel adhesives, they still face some common challenges at the bonding interface: excessive moisture on the tissue surface dilutes the prepolymer, hindering effective contact and chemical bonding between the adhesive and the tissue interface; insufficient initial adhesion may cause material displacement before curing; and a flat bonding interface limits the mechanical interlocking between the adhesive and the tissue, affecting the final bond strength.

[0016] 2. Shortcomings and deficiencies of existing technologies

[0017] Based on the analysis of the above-mentioned existing technologies, their main drawbacks and shortcomings in ophthalmic surgeries such as conjunctival transplantation are as follows:

[0018] (1) It hinders direct "communication" between the transplanted plant and the planting bed.

[0019] Existing adhesive techniques (such as fibrin glue, cyanoacrylate, and traditional photocurable hydrogels) typically apply the adhesive directly between the graft and the implant bed, forming a physical barrier. This may hinder cell migration and proliferation, timely nutrient penetration, and signaling molecule exchange, delaying the healing process and affecting tissue integration quality. Furthermore, it may alter the local microenvironment, which is detrimental to epithelialization. This is a fundamental deficiency of existing technologies in promoting tissue regeneration, directly impacting the long-term outcomes of the surgery.

[0020] (2) Insufficient adhesion reliability in humid environments

[0021] The ocular surface is constantly moist, making it difficult for existing adhesives to form a stable and strong bond at aqueous interfaces. Moisture dilutes the adhesive precursor, reducing the concentration of the active ingredient. Furthermore, water molecules compete for adhesive sites, weakening interfacial interactions. Especially for hydrogel systems, excessive swelling can lead to adhesive failure. This directly results in decreased adhesive strength, making graft displacement or detachment more likely in the dynamic ocular surface environment.

[0022] (3) It is difficult to balance mechanical fixation with biocompatibility.

[0023] Current technologies cannot simultaneously meet the dual requirements of secure fixation and good biocompatibility. Sutures provide reliable fixation but cause inflammation and discomfort, biocompatible materials (such as fibrin glue) have insufficient adhesive strength, and high-strength adhesives (such as cyanoacrylate) may be cytotoxic. Clinicians often have to compromise between fixation effectiveness and patient comfort.

[0024] (4) Poor surface fit and ease of operation.

[0025] The surface of the eyeball is a complex curved surface, making it difficult for existing two-dimensional adhesive materials to achieve a tight fit. Poor matching between planar patches and the spherical sclera can result in adhesion dead zones. Material shrinkage during curing can also cause edge lifting, affecting the stability and uniformity of fixation and potentially leading to localized stress concentrations.

[0026] (5) Specific limitations of microneedle technology

[0027] Existing soluble microneedle systems have significant shortcomings in tissue fixation applications. Primarily designed for drug delivery, they lack sufficient adhesive properties, typically do not consider interfacial chemical modification, rely solely on physical anchoring, have limited material formulations, and cannot form multi-layered cross-linked networks, thus restricting the effectiveness and scope of microneedle technology in tissue fixation.

[0028] In summary, while current closest existing technologies have explored microneedle physical anchoring, interfacial chemical modification, and dual-network hydrogels, they have not yet organically integrated these strategies into a single system. In particular, there is a significant technological gap in how to use microneedle patches, combined with interfacial pretreatment and multiple cross-linking chemistry, to synergistically address common challenges in tissue adhesion such as interfacial water interference, weak initial adhesion, and insufficient mechanical interlocking. Therefore, an innovative and systematic solution is urgently needed. Summary of the Invention

[0029] To address the technical problems existing in the prior art, embodiments of the present invention provide a photocurable biological tissue adhesive patch, its preparation method, and its application. The technical solution is as follows:

[0030] A photocurable bio-tissue adhesive patch, the photocurable bio-tissue adhesive patch comprising composite polymer soluble microneedles, wherein the photocurable bio-tissue adhesive patch is prepared from a prepolymer solution containing the following components:

[0031] (1) Methacrylated gelatin (GelMA);

[0032] (2) Oxidized dextran (ODex);

[0033] (3) Polyvinyl alcohol (PVA); and

[0034] (4) A photoinitiator, wherein the photoinitiator includes: LAP;

[0035] The weight ratio of the methacrylamide gelatin, the oxidized dextran, the polyvinyl alcohol and the photoinitiator is (5-10): (3-6): (3-8): (0.05-0.3).

[0036] Optionally, the height of the microneedle is 200μm-700μm;

[0037] And / or, the height of the microneedle is 300μm-500μm;

[0038] And / or, the spacing between the microneedles is 500μm-900μm;

[0039] And / or, the microneedle spacing is 600μm-800μm;

[0040] And / or, the bottom diameter of the microneedle is 200μm-400μm;

[0041] And / or, the bottom diameter of the microneedle is 250μm-350μm.

[0042] And / or, the microneedle is cone-shaped.

[0043] Optionally, the weight ratio of the oxidized dextran, the polyvinyl alcohol, and the photoinitiator is (7-10):(4-5):(4-6):(0.2-0.3).

[0044] And / or, in the prepolymer solution, the solvent of the prepolymer solution is phosphate buffer or ultrapure water;

[0045] And / or, the grafting rate of the methacrylamide gelatin is 20%-80%;

[0046] And / or, the grafting rate of the methacrylamide gelatin is 50%-70%;

[0047] And / or, the degree of oxidation of the oxidized dextran is 60%-90%;

[0048] And / or, the degree of oxidation of the oxidized dextran is 70%-80%;

[0049] And / or, the molecular weight of the polyvinyl alcohol is 85,000-124,000, and / or, the degree of alcoholysis is 87%-89%;

[0050] And / or, the molecular weight of the polyvinyl alcohol is 95,000-110,000;

[0051] And / or, in the prepolymer solution, the concentration of the methacrylamide gelatin is 5%-10% w / v;

[0052] And / or, in the prepolymer solution, the concentration of the oxidized dextran is 3%-6% w / v;

[0053] And / or, in the prepolymer solution, the concentration of the polyvinyl alcohol is 3%-8% by w / v;

[0054] And / or, in the prepolymer solution, the concentration of the photoinitiator is 0.05%-0.3% by w / v.

[0055] The method for preparing the photocurable biological tissue adhesive patch includes:

[0056] (1) The methacrylamide gelatin, oxidized dextran, polyvinyl alcohol and photoinitiator are dissolved in a solvent to prepare a prepolymer solution;

[0057] (2) The prepolymer liquid is poured into a microneedle mold and dried to form the photocurable biological tissue adhesive patch.

[0058] Optionally, the solvent is phosphate buffer or ultrapure water;

[0059] And / or, in the prepolymer solution, the concentration of the methacrylamide gelatin is 5%-10% w / v;

[0060] And / or, in the prepolymer solution, the concentration of the oxidized dextran is 3%-6% w / v;

[0061] And / or, in the prepolymer solution, the concentration of the polyvinyl alcohol is 3%-8% by w / v;

[0062] And / or, in the prepolymer solution, the concentration of the photoinitiator is 0.05%-0.3% (w / v);

[0063] And / or, the height of the microneedle is 200μm-700μm;

[0064] And / or, the height of the microneedle is 300μm-500μm;

[0065] And / or, the spacing between the microneedles is 500μm-900μm;

[0066] And / or, the microneedle spacing is 600μm-800μm;

[0067] And / or, the bottom diameter of the microneedle is 200μm-400μm;

[0068] And / or, the bottom diameter of the microneedle is 250μm-350μm.

[0069] And / or, the microneedle is cone-shaped;

[0070] And / or, the drying and molding temperature is 25-37°C.

[0071] The method of using the aforementioned photocurable biological tissue adhesive patch includes:

[0072] (1) Apply AA-NHS solution to the surface of the tissue to be bonded, moisten it, and then blot away the excess water;

[0073] (2) Apply the photocurable biological tissue adhesive patch to the adhesive position after step (1) treatment, so that it dissolves and forms a high-concentration prepolymer solution in situ;

[0074] (3) The high-concentration prepolymer liquid is cured by irradiation with visible light, thereby achieving the bonding.

[0075] Optionally, the concentration of the AA-NHS solution is 1-3% w / v;

[0076] And / or, the wavelength of the visible light is 400-500 nm;

[0077] And / or, the irradiation power is 10-50 mW / cm². 2 ;

[0078] And / or, the irradiation time is 30-240 seconds;

[0079] And / or, the high-concentration prepolymer liquid forms a triple crosslinking network during the curing process: (1) Photo-initiated double bond crosslinking: the methacryloyl group of GelMA forms a covalent network through free radical polymerization; (2) Schiff base crosslinking: ODex forms dynamic covalent bonds with GelMA and the amino groups on the tissue surface; (3) Amide bond crosslinking: the acryloyl group of AA-NHS participates in photo-crosslinking, and its NHS ester group forms a stable amide bond with the amino groups of the tissue.

[0080] The application of the aforementioned photocurable biological tissue adhesive patch in the preparation of tissue adhesive kits.

[0081] A tissue adhesive kit, the kit comprising:

[0082] (1) The photocurable biological tissue adhesive patch;

[0083] (2) AA-NHS solution.

[0084] Optionally, the concentration of the AA-NHS solution is 1-3% w / v.

[0085] The beneficial effects of the technical solutions provided in the embodiments of the present invention include at least the following:

[0086] 1. Excellent organizational integration facilitates better results.

[0087] With its peripheral fixation method, the microneedle patch achieves secure fixation on the outside of the adhesive area, completely avoiding the physical barrier formed between the graft and the implant bed that traditional adhesives create. This creates ideal conditions for cell migration, nutrient exchange, and signal transduction. Direct contact between the graft and the implant bed significantly accelerates the epithelialization process, promotes vascularization and tissue regeneration, and is particularly suitable for surgeries requiring high-quality tissue integration, such as conjunctival transplantation.

[0088] 2. High bonding strength and stability

[0089] Triple crosslinking synergistic enhancement: photo-initiated double bond crosslinking provides a stable covalent network framework, Schiff base reaction constructs a dynamically reversible crosslinking network to enhance toughness, and amide bond crosslinking achieves a strong bond at the tissue interface.

[0090] Mechanical interlocking assistance: The microneedle array penetrates the tissue surface, providing additional physical anchoring, which effectively complements traditional chemical adhesives.

[0091] 3. Advantages of in-situ formation of high-concentration prepolymer solution

[0092] Achieving concentrations difficult with traditional methods: Through a microneedle patch drying-redissolving process, a prepolymer solution with a significantly higher concentration than that obtained using traditional solution methods is formed at the tissue interface. The hydrogel formed after curing the high-concentration prepolymer solution exhibits higher mechanical strength, lower swelling ratio, and better dimensional stability, making it suitable for precise surgical applications. It also overcomes the technical bottleneck of unevenly applying high-viscosity prepolymer solutions.

[0093] 4. Excellent adaptability to humid environments

[0094] The microneedle patch absorbs an appropriate amount of surface moisture to dissolve while eliminating excessive moisture interference, maintaining optimal adhesion conditions in a humid environment. AA-NHS pretreatment not only introduces additional cross-linking sites but also significantly enhances interfacial reaction efficiency by disrupting the Schiff base balance and exposing more aldehyde groups.

[0095] 5. Excellent operability and clinical applicability

[0096] The introduction of PVA gives the dry patch suitable flexibility, making it easy to cut to the required shape and size, smoothly fit the anatomical structure of curved tissues, and prevent it from cracking during operation.

[0097] A specific concentration ratio ensures that the prepolymer solution has a suitable viscosity, effectively eliminating air bubbles at the mold needle tip during vacuum degassing, thus ensuring the integrity of the microneedles and the reliability of puncture.

[0098] 6. Controllable curing process and biosafety

[0099] Irradiation with 400-500nm visible light, curing time of 30-240 seconds, 10-50mW / cm 2 The power range ensures sufficient cross-linking while avoiding photodamage to tissues. Based on natural polymer derivatives such as GelMA and ODex, all components have undergone biosafety verification, making them suitable for use on sensitive tissues such as the ocular surface.

[0100] 7. Wide range of clinical applications

[0101] Conjunctival transplantation offers significant advantages. Its fixation method, similar to a "biological contact lens," is suitable for various scenarios such as pterygium surgery and conjunctival defect repair. It can also be extended to other delicate surgeries and applied to other surgical fields requiring precise fixation and improved tissue integration.

[0102] 8. Reliability and scalability of the preparation process

[0103] The process parameters are clearly defined: the concentration range of each component, microneedle structural parameters, curing conditions, etc., have all been systematically optimized to ensure consistently stable product quality. It is easy to scale up production, and the preparation process is compatible with traditional microneedle manufacturing processes, demonstrating promising industrialization prospects. Attached Figure Description

[0104] To more clearly illustrate the technical solutions in the embodiments of the present invention, the accompanying drawings used in the description of the embodiments will be briefly introduced below. Obviously, the accompanying drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0105] Figure 1 This is a diagram illustrating the flexibility of the microneedle patch provided in Embodiment 1 of the present invention;

[0106] Figure 2 This is a diagram of the microneedle morphology of the microneedle patch provided in Embodiment 1 of the present invention;

[0107] Figure 3 This is a diagram showing the solubility of the microneedles provided in Embodiment 1 of the present invention;

[0108] Figure 4 This is a diagram showing that the microneedle patch provided in Embodiment 1 of the present invention can be re-cured by light after dissolution;

[0109] Figure 5 This is a diagram showing that the microneedle patch provided in Embodiment 1 of the present invention can dissolve and adhere to the tissue after being applied to it.

[0110] Figure 6This is a graph showing the adhesive strength of the microneedle patch provided in Embodiment 1 of the present invention;

[0111] Figure 7 The figure shows that the microneedle patch provided in Embodiment 1 of the present invention can achieve long-lasting adhesion and maintain a low swelling rate. Detailed Implementation

[0112] The technical solution of the present invention will now be described with reference to the accompanying drawings.

[0113] In embodiments of the present invention, words such as "exemplarily," "for example," etc., are used to indicate that something is an example, illustration, or description. Any embodiment or design described as "exemplary" in the present invention should not be construed as being more preferred or advantageous than other embodiments or designs. Specifically, the use of the word "exemplary" is intended to present the concept in a concrete manner. Furthermore, in embodiments of the present invention, the meaning expressed by "and / or" can be both, or either one.

[0114] In this invention, AA-NHS refers to N-hydroxysuccinimide acrylate.

[0115] In this invention, methacrylamide gelatin (GelMA) refers to a photosensitive biomaterial obtained by methacrylamide modification of gelatin.

[0116] In this invention, oxidized dextran refers to the conversion of hydroxyl groups in dextran into aldehyde groups through a chemical oxidation reaction.

[0117] In this invention, the Chinese name of LAP is lithium phenyl (2,4,6-trimethylbenzoyl)phosphate; the English name is lithium phenyl-2,4,6-trimethylbenzoylphosphinate; the CAS number is 85073-19-4; and the molecular weight is 294.21.

[0118] The technical problem to be solved by this invention is as follows:

[0119] (1) Solving the problem of physical barriers between grafts and the transplant bed hindering tissue integration

[0120] Existing adhesives are applied directly between the graft and the implantation bed, forming an isolation layer that hinders cell communication and tissue regeneration. The primary objective of this invention is to provide a peripheral fixation strategy that achieves secure fixation outside the adhesive area using microneedle patches, while ensuring direct contact between the graft and the implantation bed, creating ideal conditions for cell migration, nutrient exchange, and tissue integration.

[0121] (2) Overcoming the problem of insufficient adhesion reliability on moist tissue surfaces

[0122] Moisture in moist tissue environments such as the ocular surface can dilute traditional adhesives and compete for binding sites, leading to decreased adhesive strength. This invention aims to develop an adhesive system that actively responds to moist environments by using microneedle patches to absorb water and dissolve, forming a high-concentration prepolymer solution that establishes a stable and robust chemical bond at the tissue interface.

[0123] (3) Achieving in-situ formation of high-concentration prepolymer solution at the tissue interface

[0124] Traditional solution-based methods for preparing high-concentration prepolymer solutions have excessively high viscosity, making uniform application difficult, and they are still diluted by tissue fluid in practical applications. One of the key objectives of this invention is to utilize the drying-redissolving properties of microneedle patches to form high-concentration prepolymer solutions in situ on tissue surfaces, which are difficult to achieve using traditional methods, thereby obtaining a hydrogel adhesive layer with higher mechanical strength and lower swelling rate.

[0125] (4) Improve the fit and ease of operation of curved surfaces

[0126] The complex morphology of curved tissues such as the eyeball poses a challenge to the adhesion of adhesive materials. This invention aims to provide a patch material with moderate flexibility that can well conform to biological curved surfaces, and to ensure the integrity of the needle body through an improved microneedle forming process, while maintaining the ease of clinical operation.

[0127] (5) Advantages of synergistic integration of physical anchoring and chemical bonding

[0128] Existing technologies often focus on a single mechanism and fail to fully leverage synergistic effects. This invention also aims to organically combine the mechanical interlocking of microneedles with multiple chemical cross-linkings, achieving a synergistic enhancement of physical and chemical adhesion mechanisms through interface pretreatment, material formulation optimization, and innovative application methods.

[0129] (6) Optimize material properties to meet clinical operation requirements

[0130] To address the problems of high brittleness and difficult molding in existing microneedle systems, this invention aims to optimize the composition and concentration of materials to ensure that the material has sufficient flexibility for easy handling and cutting, while also guaranteeing the quality of microneedle molding, and controlling the viscosity to effectively eliminate air bubbles during mold filling.

[0131] I. Core Components and Proportions

[0132] This invention provides a photocurable biological tissue adhesive patch based on composite polymer soluble microneedles, the core components of which include:

[0133] Methacrylamide gelatin (GelMA): with a concentration range of 5%-10% w / v, it serves as a major building block of photocrosslinking networks, providing cell adhesion sites and biodegradability. The amino groups on its molecular chain participate in Schiff base reactions and amidation reactions.

[0134] Oxidized dextran (ODex): with a concentration range of 3%-6% w / v, it provides aldehyde groups, reacts with the amino groups of GelMA to form Schiff bases to build a second cross-linking network, and at the same time reacts with the amino groups on the tissue surface to enhance interfacial adhesion.

[0135] Polyvinyl alcohol (PVA): Concentration range of 3%-8% w / v. ① Enhances the flexibility of dried microneedle patches, prevents brittleness, and facilitates handling and cutting; ② Adjusts the viscosity of the prepolymer solution and optimizes air bubble removal during the microneedle molding process; ③ Participates in the construction of hydrogel networks, improving mechanical properties.

[0136] Photoinitiator LAP: with a concentration range of 0.05%-0.3% w / v, it generates free radicals under irradiation with 400-500nm visible light, which initiates the photopolymerization reaction of the methacryloyl groups of GelMA.

[0137] II. Microneedle Structure

[0138] The microneedle patch of the present invention has the following structural parameters:

[0139] Needle height: 200-700μm, preferably 300-500μm; needle height below 200μm results in insufficient puncture depth and poor mechanical anchoring effect; needle height above 700μm is prone to breakage and causes strong discomfort during application.

[0140] Needle spacing: 500-900μm, preferably 600-800μm; a needle spacing of less than 500μm results in poor patch flexibility; a needle spacing of more than 900μm results in insufficient anchor points per unit area.

[0141] Needle-shaped: Conical structure;

[0142] Bottom diameter: 200-400μm, preferably 250-350μm; a bottom diameter below 200μm results in insufficient needle tip strength; a bottom diameter above 400μm results in excessive puncture resistance.

[0143] Structural advantages:

[0144] The conical design facilitates tissue puncture and reduces insertion resistance;

[0145] A specific aspect ratio ensures sufficient mechanical strength and tissue anchoring effect;

[0146] A reasonable pin spacing ensures the flexibility of the patch and facilitates its application to curved tissues.

[0147] III. Preparation Method

[0148] 1. Preparation of prepolymer solution

[0149] Dissolve GelMA, ODex, PVA, and LAP in phosphate buffer solution according to the concentration ranges mentioned above, and mix thoroughly. The concentration of each component must be strictly controlled within this range. Too high a concentration will result in excessive viscosity, making it difficult to effectively remove air bubbles during vacuuming of the microneedle mold, thus affecting the quality of needle tip formation; too low a concentration will result in insufficient needle strength.

[0150] 2. Microneedle molding

[0151] The prepolymer solution is poured into a microneedle mold, and vacuum degassing is performed to ensure that no air bubbles remain at the needle tip. It is then slowly dried and shaped under specific temperature conditions (25-37℃). During this process, the synergistic effect of the components ensures that the microneedles possess suitable mechanical strength and solubility.

[0152] IV. Application Methods and Working Principles

[0153] 1. Tissue surface pretreatment

[0154] AA-NHS interface pretreatment: Apply a 1-3% AA-NHS solution to the tissue surface to be bonded, moisten, and then blot away excess moisture. The NHS ester groups in AA-NHS react with the amino groups on the tissue surface, introducing additional acryloyl groups at the tissue interface. This process simultaneously disrupts the potential Schiff base balance between tissue surface proteins and ODex, exposing more aldehyde groups and creating conditions for subsequent multiple cross-linking. Without the AA-NHS pretreatment step, the Schiff base balance on the tissue surface cannot be disrupted, more aldehyde groups cannot be exposed, and additional acryloyl groups cannot be introduced to participate in photocrosslinking to form amide bonds and enhance interfacial bonding.

[0155] 2. Patch Placement and Dissolution

[0156] A specific peripheral fixation application mode: A microneedle patch is placed over the pre-treated adhesion site, and gentle pressure causes the microneedles to penetrate the tissue. Microneedle penetration provides mechanical interlocking, increases the contact area, and enhances initial fixation. The dried microneedle patch absorbs moisture from the tissue surface and dissolves, forming a high-concentration prepolymer solution in situ. If a traditional internal adhesion mode is used, a physical barrier will form between the graft and the implantation bed, hindering tissue integration.

[0157] The drying-redissolving process forms a high-concentration prepolymer solution. Without the drying-redissolving process of the microneedle patch, it is impossible to achieve a high-concentration prepolymer solution at the tissue interface, which is difficult to achieve with traditional methods, and it is also impossible to solve the problem of difficult application of high-viscosity liquids.

[0158] Key technical effects: The concentration of the prepolymer liquid formed in this process is much higher than that achievable by traditional solution methods, and the viscosity is suitable, which can be evenly distributed at the tissue interface. After curing, it forms a hydrogel with higher mechanical strength and lower swelling rate.

[0159] If a traditional built-in adhesive method is used, a physical barrier will be formed between the graft and the implantation bed, hindering tissue integration.

[0160] 3. Light curing

[0161] Irradiate with visible light with a wavelength of 400-500nm and a power of 10-50mW / cm. 2 The time is 30-240 seconds. The triple cross-linking network formed is: photo-initiated double bond cross-linking (the methacryloyl group of GelMA forms a covalent network through free radical polymerization), Schiff base cross-linking (the aldehyde group of ODex forms a dynamic covalent bond with GelMA and the amino group on the tissue surface), and amide bond cross-linking (the acryloyl group introduced by AA-NHS participates in photo-cross-linking, and its NHS ester group forms a stable amide bond with the amino group of the tissue).

[0162] 4. Technological Advantages and Innovations

[0163] (1) Peripheral fixed mode

[0164] Microneedle patches achieve fixation on the outside of the adhesive area, fixing the graft like a "biocontact lens" to ensure direct contact between the graft and the implantation bed, without the adhesive barrier hindering cell communication and tissue integration.

[0165] (2) In-situ formation of high-concentration prepolymer solution

[0166] By using the drying-redissolving process of microneedle patches, a high-concentration prepolymer solution that is difficult to prepare using traditional methods can be achieved at the tissue interface, solving the problem of difficult application of high-viscosity liquids while avoiding tissue fluid dilution.

[0167] (3) Multiple synergistic enhancement mechanisms

[0168] Mechanical reinforcement: Microneedle arrays provide physical anchoring;

[0169] Chemical enhancement: Synergistic effect of triple chemical cross-linking networks;

[0170] Interface enhancement: AA-NHS pretreatment optimizes the interface chemical environment.

[0171] (4) User-friendliness

[0172] The dry patch has good flexibility, making it easy to cut and handle;

[0173] The viscosity of the prepolymer solution was optimized to ensure the quality of microneedle formation;

[0174] The curing parameters have been validated, balancing ease of operation with curing effect.

[0175] To make the technical problems, technical solutions and advantages of the present invention clearer, a detailed description will be given below in conjunction with the accompanying drawings and specific embodiments.

[0176] Unless otherwise specified, the experimental methods described in the following embodiments are conventional experimental methods well known to those skilled in the art, and are performed according to the techniques or conditions described in the literature in this field or according to the product instructions. Where specific conditions are not specified in the experimental methods, they are generally operated under conventional conditions.

[0177] Unless otherwise specified, all materials and reagents described in the following examples are commercially available.

[0178] Example 1

[0179] A photocurable biological tissue adhesive patch comprises: methacrylamide gelatin, oxidized dextran, polyvinyl alcohol, and photoinitiator LAP. The weight ratio of the methacrylamide gelatin, the oxidized dextran, the polyvinyl alcohol, and the photoinitiator is 10:5:5:0.25.

[0180] The methacrylamide gelatin had a grafting rate of 60% and was purchased from Suzhou Yongqinquan Intelligent Equipment Co., Ltd. (EFL-GM-60).

[0181] The oxidized dextran was 90% oxidized and was purchased from Suzhou Yongqinquan Intelligent Equipment Co., Ltd. (EFL-ODex-001).

[0182] The polyvinyl alcohol has a molecular weight of 110,000 and a degree of hydrolysis of 88%, and can be purchased from Shanghai Maclean Biochemical Technology Co., Ltd., Aladdin Biochemical Technology Co., Ltd., or Sigma-Aldrich Trading Co., Ltd. (PVA1788).

[0183] The method for preparing the photocurable biological tissue adhesive patch includes:

[0184] (1) Methacrylamide gelatin, oxidized dextran, polyvinyl alcohol and photoinitiator LAP are dissolved in a solvent to prepare a prepolymer solution.

[0185] In the prepolymer solution, the concentration of GelMA is 10% w / v (g / ml), the concentration of ODex is 5% w / v, the concentration of PVA is 5% w / v, the concentration of LAP is 0.25% w / v, and the solvent is phosphate buffer.

[0186] (2) The prepolymer liquid is poured into a microneedle mold and dried to form the photocurable biological tissue adhesive patch. The microneedles in the mold have a needle height of 500 μm, a needle spacing of 700 μm, and a needle bottom diameter of 270 μm. The needle shape of the microneedles is conical. The drying temperature is 30℃.

[0187] The method of using the aforementioned photocurable biological tissue adhesive patch includes:

[0188] (1) Apply AA-NHS solution to the surface of the tissue to be bonded, moisten it, and then blot away the excess water;

[0189] (2) Apply the photocurable biological tissue adhesive patch to the adhesive position after step (1) so that it absorbs the moisture on the tissue surface and dissolves, forming a high-concentration prepolymer solution in situ.

[0190] (3) The high-concentration prepolymer liquid is cured by irradiation with visible light, thereby achieving the bonding. The wavelength of the visible light is 405 nm, the irradiation time is 240 seconds, and the irradiation power is 30 mW / cm². 2 .

[0191] The concentration of the AA-NHS solution is 2% (w / v %).

[0192] The high-concentration prepolymer liquid forms a triple crosslinking network during the curing process: (1) Photo-initiated double bond crosslinking: the methacryloyl group of GelMA forms a covalent network through free radical polymerization; (2) Schiff base crosslinking: ODex forms dynamic covalent bonds with GelMA and the amino groups on the tissue surface; (3) Amide bond crosslinking: the acryloyl group of AA-NHS participates in photo-crosslinking, and its NHS ester group forms a stable amide bond with the amino groups on the tissue.

[0193] Example 2

[0194] A photocurable biological tissue adhesive patch comprises: methacrylamide gelatin, oxidized dextran, polyvinyl alcohol, and photoinitiator LAP. The weight ratio of the methacrylamide gelatin, the oxidized dextran, the polyvinyl alcohol, and the photoinitiator is 5:3:3:0.05.

[0195] The grafting rate of the methacrylamide gelatin is 20%.

[0196] The degree of oxidation of the oxidized dextran is 60%.

[0197] The polyvinyl alcohol has a molecular weight of 85,000 and a degree of alcoholysis of 87%.

[0198] The method for preparing the photocurable biological tissue adhesive patch includes:

[0199] (1) Methacrylamide gelatin, oxidized dextran, polyvinyl alcohol and photoinitiator LAP are dissolved in a solvent to prepare a prepolymer solution.

[0200] In the prepolymer solution, the concentration of GelMA is 5% w / v (g / ml), the concentration of ODex is 3% w / v, the concentration of PVA is 3% w / v, the concentration of LAP is 0.05% w / v, and the solvent is phosphate buffer.

[0201] (2) The prepolymer liquid is poured into a microneedle mold and dried to form the photocurable biological tissue adhesive patch. The microneedles in the mold have a needle height of 200 μm, a needle spacing of 500 μm, and a needle bottom diameter of 200 μm. The needle shape of the microneedles is conical. The drying temperature is 25℃.

[0202] The method of using the aforementioned photocurable biological tissue adhesive patch includes:

[0203] (1) Apply AA-NHS solution to the surface of the tissue to be bonded, moisten it, and then blot away the excess water;

[0204] (2) Apply the photocurable biological tissue adhesive patch to the adhesive position after step (1) so that it absorbs the moisture on the tissue surface and dissolves, forming a high-concentration prepolymer solution in situ.

[0205] (3) The high-concentration prepolymer liquid is cured by irradiation with visible light, thereby achieving the bonding. The wavelength of the visible light is 400 nm, the irradiation time is 240 seconds, and the irradiation power is 10 mW / cm². 2 .

[0206] The concentration of the AA-NHS solution is 1% (w / v %).

[0207] The high-concentration prepolymer liquid forms a triple crosslinking network during the curing process: (1) Photo-initiated double bond crosslinking: the methacryloyl group of GelMA forms a covalent network through free radical polymerization; (2) Schiff base crosslinking: ODex forms dynamic covalent bonds with GelMA and the amino groups on the tissue surface; (3) Amide bond crosslinking: the acryloyl group of AA-NHS participates in photo-crosslinking, and its NHS ester group forms a stable amide bond with the amino groups on the tissue.

[0208] Example 3

[0209] A photocurable biological tissue adhesive patch comprises: methacrylamide gelatin, oxidized dextran, polyvinyl alcohol, and photoinitiator LAP. The weight ratio of the methacrylamide gelatin, the oxidized dextran, the polyvinyl alcohol, and the photoinitiator is 10:6:8:0.3.

[0210] The grafting rate of the methacrylamide gelatin is 80%.

[0211] The degree of oxidation of the oxidized dextran is 75%.

[0212] The polyvinyl alcohol has a molecular weight of 105,000 and a degree of alcoholysis of 89%.

[0213] The method for preparing the photocurable biological tissue adhesive patch includes:

[0214] (1) Methacrylamide gelatin, oxidized dextran, polyvinyl alcohol and photoinitiator LAP are dissolved in a solvent to prepare a prepolymer solution.

[0215] In the prepolymer solution, the concentration of GelMA is 10% w / v (g / ml), the concentration of ODex is 6% w / v, the concentration of PVA is 8% w / v, the concentration of LAP is 0.3% w / v, and the solvent is phosphate buffer.

[0216] (2) The prepolymer liquid is poured into a microneedle mold and dried to form the photocurable biological tissue adhesive patch. The microneedles in the mold have a height of 700 μm, a spacing of 900 μm, and a bottom diameter of 400 μm. The microneedles are cone-shaped. The drying temperature is 37°C.

[0217] The method of using the aforementioned photocurable biological tissue adhesive patch includes:

[0218] (1) Apply AA-NHS solution to the surface of the tissue to be bonded, moisten it, and then blot away the excess water;

[0219] (2) Apply the photocurable biological tissue adhesive patch to the adhesive position after step (1) so that it absorbs the moisture on the tissue surface and dissolves, forming a high-concentration prepolymer solution in situ.

[0220] (3) The high-concentration prepolymer liquid is cured by irradiation with visible light, thereby achieving the bonding. The wavelength of the visible light is 500 nm, the irradiation time is 100 seconds, and the irradiation power is 50 mW / cm². 2 .

[0221] The concentration of the AA-NHS solution is 3% (w / v %).

[0222] The high-concentration prepolymer liquid forms a triple crosslinking network during the curing process: (1) Photo-initiated double bond crosslinking: the methacryloyl group of GelMA forms a covalent network through free radical polymerization; (2) Schiff base crosslinking: ODex forms dynamic covalent bonds with GelMA and the amino groups on the tissue surface; (3) Amide bond crosslinking: the acryloyl group of AA-NHS participates in photo-crosslinking, and its NHS ester group forms a stable amide bond with the amino groups on the tissue.

[0223] Example 4

[0224] A photocurable biological tissue adhesive patch comprises: methacrylamide gelatin, oxidized dextran, polyvinyl alcohol, and photoinitiator LAP. The weight ratio of the methacrylamide gelatin, the oxidized dextran, the polyvinyl alcohol, and the photoinitiator is 7.5:4.5:4.5:0.25.

[0225] The grafting rate of the methacrylamide gelatin is 70%.

[0226] The degree of oxidation of the oxidized dextran is 75%.

[0227] The polyvinyl alcohol has a molecular weight of 95,000 and a degree of alcoholysis of 89%.

[0228] The method for preparing the photocurable biological tissue adhesive patch includes:

[0229] (1) Methacrylamide gelatin, oxidized dextran, polyvinyl alcohol and photoinitiator LAP are dissolved in a solvent to prepare a prepolymer solution.

[0230] In the prepolymer solution, the concentration of GelMA is 7.5% w / v (g / ml), the concentration of ODex is 4.5% w / v, the concentration of PVA is 4.5% w / v, the concentration of LAP is 0.25% w / v, and the solvent is ultrapure water.

[0231] (2) The prepolymer liquid is poured into a microneedle mold and dried to form the photocurable biological tissue adhesive patch. The microneedles in the mold have a needle height of 300 μm, a needle spacing of 600 μm, and a needle bottom diameter of 250 μm. The needle shape of the microneedles is conical. The drying temperature is 25℃.

[0232] The method of using the aforementioned photocurable biological tissue adhesive patch includes:

[0233] (1) Apply AA-NHS solution to the surface of the tissue to be bonded, moisten it, and then blot away the excess water;

[0234] (2) Apply the photocurable biological tissue adhesive patch to the adhesive position after step (1) so that it absorbs the moisture on the tissue surface and dissolves, forming a high-concentration prepolymer solution in situ.

[0235] (3) The high-concentration prepolymer liquid is cured by irradiation with visible light, thereby achieving the bonding. The wavelength of the visible light is 400 nm, the irradiation time is 80 seconds, and the irradiation power is 50 mW / cm². 2 .

[0236] The concentration of the AA-NHS solution is 3% (w / v %).

[0237] The high-concentration prepolymer liquid forms a triple crosslinking network during the curing process: (1) Photo-initiated double bond crosslinking: the methacryloyl group of GelMA forms a covalent network through free radical polymerization; (2) Schiff base crosslinking: ODex forms dynamic covalent bonds with GelMA and the amino groups on the tissue surface; (3) Amide bond crosslinking: the acryloyl group of AA-NHS participates in photo-crosslinking, and its NHS ester group forms a stable amide bond with the amino groups on the tissue.

[0238] Performance testing:

[0239] The following uses Example 1 as an example to measure various properties of the microneedle patch. The results of other examples are similar to those of Example 1, and will not be repeated here.

[0240] 1. Determine the flexibility of the microneedle patch of Example 1. The determination method is as follows: After drying and molding, the microneedle patch is removed from the mold with tweezers, both sides are pressed and the overall bending of the patch is observed and whether there are any breaks or cracks.

[0241] Experimental results are as follows Figure 1 As shown.

[0242] Figure 1 This is a diagram illustrating the flexibility of the microneedle patch provided in Embodiment 1 of the present invention. As can be seen from the diagram, the microneedle patch exhibits good flexibility and will not break during normal transfer and operation.

[0243] Compared with the flexibility achievable by existing microneedle patches, the present invention has good flexibility, which facilitates the operation of adhesive microneedle patches in applications and has good practicality.

[0244] 2. The microneedle morphology of the microneedle patch in Example 1 was determined. The determination method is as follows: the substrate layer and needles of the microneedle patch were photographed and observed using an optical microscope and a scanning electron microscope.

[0245] Experimental results are as follows Figure 2 As shown.

[0246] Figure 2 This is a diagram showing the microneedle morphology of the microneedle patch provided in Embodiment 1 of the present invention. As can be seen from the diagram, the microneedles are spaced evenly, have uniform height, and are conical in shape. Figure 2 The scales in the text are 200μm for small icons and 500μm for large icons.

[0247] Compared with the microneedle morphology achievable by existing microneedle patches, the microneedle morphology of the present invention is uniform and stable, and the microneedle patch prepared by the template method has strong repeatability.

[0248] 3. Determination of the solubility of the microneedle patch from Example 1. The determination method is as follows: The microneedle patch was inserted into a 1.5% (w / v) agarose gel for testing, which is commonly used as a skin model. The microneedle patch was pressed onto the gel and left in the gel for different times (30 seconds, 60 seconds, and 120 seconds) before removal. The morphological changes of the microneedles before and after insertion were observed using a stereomicroscope, and the length of the microneedles was recorded.

[0249] Experimental results are as follows Figure 3 As shown.

[0250] Figure 3 This is a diagram showing the solubility of the microneedles provided in Embodiment 1 of the present invention. Figure 3 The left and right images, from top to bottom, show the morphology after dissolution at 0 seconds, 30 seconds, 60 seconds, and 120 seconds, respectively. The right image is a line graph showing the needle height after dissolution. The images demonstrate that the microneedles gradually dissolve after penetrating the simulated tissue, exhibiting good solubility.

[0251] Compared to the solubility achievable by existing microneedle patches, the present invention exhibits superior solubility, dissolving and diffusing after insertion into the tissue to form a high-concentration prepolymer solution. This increases the contact between the adhesive material and the tissue, providing better bonding strength for subsequent applications.

[0252] 4. Measurement of the microneedle patch of Example 1 after dissolution and subsequent photocuring. The measurement method is as follows: the microneedle patch was immersed in water for about 60 seconds and then photocured. The morphology of the hydrogel after photocuring was observed.

[0253] Experimental results are as follows Figure 4 As shown.

[0254] Figure 4 This is a diagram showing that the microneedle patch provided in Embodiment 1 of the present invention can be photocured again after dissolution. As can be seen from the diagram, the microneedle patch can form a water-insoluble hydrogel by photocuring after dissolution.

[0255] Compared with the existing microneedle patches that can be dissolved and then photocured again, the microneedle patches of the present invention can be photocured again after dissolution, indicating that the drying process of microneedle preparation does not affect the photocuring properties of the material itself.

[0256] 5. Determine the dissolution and adhesion of the microneedle patch of Example 1 to the tissue after application. The determination method is as follows: The microneedle patch was applied to the surface of pig muscle tissue according to the method, and the dissolution and tissue adhesion of the microneedle patch were observed immediately after the microneedle patch was inserted into the tissue (about 0 seconds), and after 30 seconds, 60 seconds and 120 seconds after insertion into the tissue and after light curing.

[0257] Experimental results are as follows Figure 5 As shown.

[0258] Figure 5 This is a diagram showing that the microneedle patch provided in Embodiment 1 of the present invention can dissolve and adhere to the tissue after being applied. As can be seen from the diagram, the microneedle patch can penetrate into the tissue and dissolve to form a high-concentration prepolymer solution. During this process, the prepolymer solution will make full contact with the tissue surface and gaps, increasing the bonding interface area and laying the foundation for strong adhesion.

[0259] Compared to existing microneedle patches that can dissolve and adhere to tissue after application, this invention can dissolve and achieve strong adhesion to tissue after application, which is not a characteristic of typical microneedle patches.

[0260] 6. The adhesive strength of the microneedle patch from Example 1 applied to the cornea, conjunctiva, and sclera was determined. The determination methods were as follows: interfacial adhesive strength was measured based on the standard 180° peel test (ASTM F2256). Shear tensile strength was measured based on the standard lap shear test (ASTM F2255). Adhesive tensile strength was measured based on the standard tensile test (ASTM F2258). Samples were applied to isolated porcine corneal, conjunctival, or scleral tissue and cured. The adhesive (cyanoacrylate) was used as a control. Tissues were covered with physiological saline to ensure moisture before application of the sample or cyanoacrylate. All tests were performed using a mechanical testing machine at a constant crosshead speed of 50 mm / min. Polymethyl methacrylate film was used as a rigid backing for the samples and tissues, and aluminum clamps were used to provide the holding points for the tensile tests.

[0261] Experimental results are as follows Figure 6 As shown.

[0262] Figure 6 This is a graph showing the adhesive strength of the microneedle patch provided in Example 1 of the present invention. As can be seen from the graph, the adhesive strength of Example 1 is comparable to that of the cyanoacrylate adhesive, exhibiting better tissue adhesion strength.

[0263] Compared to existing microneedle patches that can dissolve and adhere to tissue after application, this invention can dissolve and achieve strong adhesion to tissue after application, which is not a characteristic of typical microneedle patches.

[0264] 7. The long-term adhesion, swelling rate, and dimensional stability of the microneedle patch of Example 1 were determined. The determination methods are as follows: The microneedle patch applied to the tissue surface was immersed in water along with the tissue for 1, 2, 4, and 7 days. The in-situ condition of the patch was observed, and the mass change of the patch after photocuring was measured. The swelling rate was calculated as follows: Swelling rate = (mass at sampling - initial mass) / initial mass × 100%; the patch area growth rate was calculated as follows: Patch area growth rate = (patch base area at sampling - initial patch base area) / initial patch base area × 100%.

[0265] Experimental results are as follows Figure 7 As shown.

[0266] Figure 7 This figure illustrates that the microneedle patch provided in Embodiment 1 of the present invention achieves long-lasting adhesion and maintains a low swelling rate. As can be seen from the figure, after prolonged underwater immersion, the microneedle patch adheres firmly to the tissue surface, maintaining its initial properties without significant peeling or dissolution. It also maintains a low thickness, indicating that no significant swelling was observed. Quantitative swelling rate testing showed an equilibrium swelling rate of 14.84 ± 1.47%, and an equilibrium growth rate of 11.66 ± 2.12% for the patch area.

[0267] Compared with the long-term adhesion and swelling rate achievable by existing microneedle patches, the present invention has good long-term adhesion and swelling rate, and has the ability to maintain strong adhesion underwater. Moreover, it has a low swelling rate. This is due to the high concentration of prepolymer liquid formed when the microneedle patch dissolves on the tissue surface before curing, which makes the cross-linking in the cured hydrogel more compact, and thus further has a positive impact on its dimensional stability. Its low patch area growth rate reflects that it can maintain dimensional stability in water for a long time after adhesion and curing.

[0268] The above description is merely a specific embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any variations or substitutions that can be easily conceived by those skilled in the art within the technical scope disclosed in the present invention should be included within the scope of protection of the present invention. Therefore, the scope of protection of the present invention should be determined by the scope of the claims.

Claims

1. A photocurable biological tissue adhesive patch, characterized in that, The photocurable bio-tissue adhesive patch comprises composite polymer soluble microneedles, wherein the photocurable bio-tissue adhesive patch is prepared from a prepolymer solution containing the following components: (1) Methacrylated gelatin (GelMA); (2) Oxidized dextran (ODex); (3) Polyvinyl alcohol (PVA); and (4) A photoinitiator, wherein the photoinitiator includes: LAP; The weight ratio of the methacrylamide gelatin, the oxidized dextran, the polyvinyl alcohol and the photoinitiator is (5-10): (3-6): (3-8): (0.05-0.3).

2. The photocurable biological tissue adhesive patch according to claim 1, characterized in that, The height of the microneedles is 200μm-700μm; And / or, the height of the microneedle is 300μm-500μm; And / or, the spacing between the microneedles is 500μm-900μm; And / or, the microneedle spacing is 600μm-800μm; And / or, the bottom diameter of the microneedle is 200μm-400μm; And / or, the bottom diameter of the microneedle is 250μm-350μm; And / or, the microneedle is cone-shaped.

3. The photocurable biological tissue adhesive patch according to claim 1, characterized in that, The weight ratio of the oxidized dextran, the polyvinyl alcohol, and the photoinitiator is (7-10):(4-5):(4-6):(0.2-0.3). And / or, in the prepolymer solution, the solvent of the prepolymer solution is phosphate buffer or ultrapure water; And / or, the grafting rate of the methacrylamide gelatin is 20%-80%; And / or, the grafting rate of the methacrylamide gelatin is 50%-70%; And / or, the degree of oxidation of the oxidized dextran is 60%-90%; And / or, the degree of oxidation of the oxidized dextran is 70%-80%; And / or, the molecular weight of the polyvinyl alcohol is 85,000-124,000, and / or, the degree of alcoholysis is 87%-89%; And / or, the molecular weight of the polyvinyl alcohol is 95,000-110,000; And / or, in the prepolymer solution, the concentration of the methacrylamide gelatin is 5%-10% w / v; And / or, in the prepolymer solution, the concentration of the oxidized dextran is 3%-6% w / v; And / or, in the prepolymer solution, the concentration of the polyvinyl alcohol is 3%-8% by w / v; And / or, in the prepolymer solution, the concentration of the photoinitiator is 0.05%-0.3% by w / v.

4. The method for preparing a photocurable biological tissue adhesive patch according to any one of claims 1-3, characterized in that, The preparation method includes: (1) The methacrylamide gelatin, oxidized dextran, polyvinyl alcohol and photoinitiator are dissolved in a solvent to prepare a prepolymer solution; (2) The prepolymer liquid is poured into a microneedle mold and dried to form the photocurable biological tissue adhesive patch.

5. The preparation method according to claim 4, characterized in that, The solvent is phosphate buffer solution or ultrapure water; And / or, in the prepolymer solution, the concentration of the methacrylamide gelatin is 5%-10% w / v; And / or, in the prepolymer solution, the concentration of the oxidized dextran is 3%-6% w / v; And / or, in the prepolymer solution, the concentration of the polyvinyl alcohol is 3%-8% by w / v; And / or, in the prepolymer solution, the concentration of the photoinitiator is 0.05%-0.3% (w / v); And / or, the height of the microneedle is 200μm-700μm; And / or, the height of the microneedle is 300μm-500μm; And / or, the spacing between the microneedles is 500μm-900μm; And / or, the microneedle spacing is 600μm-800μm; And / or, the bottom diameter of the microneedle is 200μm-400μm; And / or, the bottom diameter of the microneedle is 250μm-350μm; And / or, the microneedle is cone-shaped; And / or, the drying and molding temperature is 25-37°C.

6. The method of using the photocurable biological tissue adhesive patch according to any one of claims 1-3, characterized in that, The method of use includes: (1) Apply AA-NHS solution to the surface of the tissue to be bonded, moisten it, and then blot away the excess water; (2) Apply the photocurable biological tissue adhesive patch according to any one of claims 1-3 to the adhesive site after the treatment in step (1), so that it dissolves and forms a high-concentration prepolymer solution in situ; (3) The high-concentration prepolymer liquid is cured by irradiation with visible light, thereby achieving the bonding.

7. The method of use according to claim 6, characterized in that, The concentration of the AA-NHS solution is 1-3% (w / v). And / or, the wavelength of the visible light is 400-500 nm; And / or, the irradiation power is 10-50 mW / cm². 2 ; And / or, the irradiation time is 30-240 seconds; And / or, the high-concentration prepolymer liquid forms a triple crosslinking network during the curing process: (1) Photo-initiated double bond crosslinking: the methacryloyl group of GelMA forms a covalent network through free radical polymerization; (2) Schiff base crosslinking: ODex forms dynamic covalent bonds with GelMA and the amino groups on the tissue surface; (3) Amide bond crosslinking: the acryloyl group of AA-NHS participates in photo-crosslinking, and its NHS ester group forms a stable amide bond with the amino groups of the tissue.

8. The use of the photocurable biological tissue adhesive patch according to any one of claims 1-3 in the preparation of a tissue adhesive kit.

9. A tissue adhesive kit, characterized in that, The kit includes: (1) The photocurable biological tissue adhesive patch according to any one of claims 1-3; (2) AA-NHS solution.

10. The tissue adhesive kit according to claim 9, characterized in that, The concentration of the AA-NHS solution is 1-3% (w / v).

Images