Anti-swelling hydrogel biological adhesive as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of high polymer materials, and discloses an anti-swelling hydrogel biological adhesive as well as a preparation method and application thereof. The preparation method comprises the following steps: dissolving a monomer, a cross-linking agent and a photoinitiator in water, and carrying out ultraviolet polymerization to form a first layer of hydrogel network; soaking the network in a precursor solution of a second-layer network containing acrylic acid, acrylic acid-N-succinimide ester, a cross-linking agent and a photoinitiator, and carrying out ultraviolet light-induced polymerization to construct a dual-network structure; and carrying out freeze drying treatment to obtain the hydrogel biological adhesive. The double-network structure in the prepared double-network hydrogel adhesive endows the material with excellent anti-swelling performance, the structural stability can be kept in a water environment, and long-term stable wet adhesion performance and mechanical performance are shown. The hydrogel biological adhesive has good biocompatibility and conductivity, not only can promote hemostasis and sealing of tissue wounds such as skin and internal organs, but also can be used as a flexible sensor for monitoring electrocardiosignals and electromyographic signals.

Description

Technical Field

[0001] This invention belongs to the field of polymer materials technology, specifically relating to an anti-swelling hydrogel bioadhesive, its preparation method, and its application. Background Technology

[0002] In clinical surgery, emergency trauma care, and accidental injury management, rapid and effective hemostasis is crucial for highly vascularized tissues such as the liver, kidneys, and heart. Traditional hemostasis methods (such as suturing, electrocoagulation, and surgical gauze compression) have significant limitations. Sutures can cause secondary damage, electrocoagulation can lead to thermal necrosis of tissues, and gauze is difficult to provide a reliable seal under high bleeding pressure. Furthermore, the application of these methods is greatly limited in minimally invasive surgery or complex tissue repair.

[0003] In recent years, hydrogel bioadhesives have been regarded as next-generation hemostatic materials due to their excellent biocompatibility and tunable mechanical properties. Natural bioadhesion systems (such as mussel byssal silk, barnacles, and spider silk) achieve wet adhesion through mechanisms such as interfacial dehydration, metal ion chelation, or covalent cross-linking, providing important inspiration for the design of biomimetic hydrogel adhesives. Based on this, researchers have developed a variety of synthetic hydrogel adhesives.

[0004] However, existing hydrogel bioadhesives still have the following key performance defects in the application of hemostasis in highly vascularized tissues. (1) High swelling leads to deterioration of mechanical properties: Existing polyacrylic acid hydrogels can swell up to 900% in physiological or aqueous environments, resulting in a loose polymer network structure and a significant reduction in elastic modulus, making it difficult to withstand the burst pressure of highly vascularized tissues; excessive swelling may also cause the adhesive to break, resulting in the risk of secondary bleeding, which seriously limits its application in high-pressure tissue environments such as the heart and blood vessels. (2) Anti-swelling strategies often sacrifice adhesion performance: Although hydrophobic modification can inhibit swelling, hydrophobic groups will weaken the interfacial hydrogen bonds and electrostatic interactions, resulting in a decrease in wet adhesion strength; although the introduction of inorganic fillers helps to enhance mechanical properties, they may occupy adhesion active sites, causing a significant decrease in adhesion strength, making it difficult to meet the adhesion requirements of wet tissues. (3) Insufficient long-term mechanical stability: Single-network hydrogels are prone to fatigue fracture in dynamic physiological environments (such as heartbeat and respiratory movements), and although existing double-network hydrogels improve strength, they lack effective tissue adhesion groups and cannot meet the requirements of long-term adhesion in wet conditions. (4) Difficult to balance high pressure tolerance and rapid hemostasis performance: Clinically, hemostatic materials are required to withstand burst pressure of >400 mmHg (such as in cardiac surgery), but most hydrogel adhesives have a sudden drop in burst pressure after swelling. Summary of the Invention

[0005] The purpose of this invention is to provide an anti-swelling hydrogel bioadhesive, its preparation method and application, which solves various problems existing in the clinical hemostasis of existing hydrogel bioadhesives.

[0006] This invention is achieved through the following technical solution: This invention discloses a method for preparing an anti-swelling hydrogel bioadhesive, comprising the following steps: (1) Mix the monomer, crosslinking agent and photoinitiator to prepare precursor A solution; Acrylic acid and N-succinimide acrylate, crosslinking agent and photoinitiator were mixed to prepare precursor B solution; (2) Then the precursor A solution was poured into a mold consisting of two parallel glass plates separated by a silicone pad and subjected to the first ultraviolet light irradiation to obtain the first layer of hydrogel network. (3) Immerse the first layer of hydrogel network in the precursor B solution until equilibrium is reached to obtain the hydrogel sample; (4) The hydrogel sample is sandwiched between two glass plates and subjected to a second ultraviolet light irradiation to form a uniform double network hydrogel; (5) The double-network hydrogel was soaked in a large amount of deionized water to rinse away the residue, and finally freeze-dried to obtain an anti-swelling hydrogel bioadhesive.

[0007] Furthermore, in step (1), the monomer is hydroxyethyl methacrylate, 2-acrylamide-2-methylpropanesulfonic acid, or acryloyloxyethyltrimethylammonium chloride.

[0008] Furthermore, in step (1), the crosslinking agent is N,N'-methylenebisacrylamide.

[0009] Furthermore, in step (1), the photoinitiator is 2-hydroxy-2-methylphenylacetone.

[0010] Furthermore, in step (1), when preparing the precursor A solution, the molar ratio of monomer, crosslinking agent and photoinitiator is 100:1~6:0.1.

[0011] Furthermore, in step (2), the ultraviolet light irradiation conditions are: light intensity 15 ~ 30 mW / cm². 2 Irradiation time: 4 h ~ 8 h.

[0012] Furthermore, in step (1), when preparing the precursor B solution, the mass ratio of acrylic acid and N-succinimide acrylate, crosslinking agent and photoinitiator is 20:2:0.1:0.2, calculated as 100 parts of precursor B solution, and the remainder is deionized water.

[0013] Furthermore, in step (5), the freeze-drying process specifically involves freezing the rinsed double-network hydrogel at -20 ℃ to -80 ℃ for 2 h to 24 h, and then cold-drying it in a freeze dryer for 2 d to 5 d.

[0014] The present invention also discloses an anti-swelling hydrogel bioadhesive prepared by the aforementioned preparation method.

[0015] Furthermore, the present invention also discloses the application of the described anti-swelling hydrogel bioadhesive in wound adhesion, hemostasis, and monitoring of electrocardiogram and electromyogram signals.

[0016] Compared with the prior art, the present invention has the following beneficial technical effects: This invention also discloses a method for preparing an anti-swelling hydrogel bioadhesive. Monomers, crosslinking agents, and photoinitiators are dissolved in water, and a first-layer hydrogel network is formed through a first UV-induced polymerization. This network is then immersed in an aqueous precursor solution containing monomers acrylic acid and N-succinimide acrylate, a crosslinking agent, and a photoinitiator, and undergoes a second UV-induced polymerization to construct a dual-network structure. Finally, the hydrogel bioadhesive is obtained through freeze-drying. In this invention, after obtaining the first-layer hydrogel network, it is directly immersed in a precursor B solution. After reaching equilibrium, a second polymerization is performed, causing the two network structures to interpenetrate, eliminating the layered structure and forming a uniform dual-network structure. In the initial stage of adhesion to the tissue surface, the carboxyl groups in the polyacrylic acid (PAA) and polyacrylic acid-N-succinimide acrylate (PAA-NHS) networks form hydrogen bonds (non-covalent bonds) with groups on the tissue surface. Simultaneously, the NHS active ester forms stable amide bonds (covalent bonds) with amines on the tissue surface. The physical interaction of hydrogen bonds provides temporary adhesion, while the addition of N-succinimide acrylate forms covalent bonds, and the NHS-mediated covalent bonds endow it with durable and stable adhesion properties.

[0017] The dual-network hydrogel adhesive prepared in this invention possesses excellent anti-swelling properties due to its dual-network structure, maintaining structural stability in an aqueous environment. It also exhibits long-term stable wet adhesion and mechanical properties. This hydrogel bio-adhesive combines good biocompatibility and conductivity, effectively promoting hemostasis and closure of wounds in skin and internal organs. Furthermore, it can be used as a flexible sensor for monitoring electrocardiogram (ECG) and electromyography (EMG) signals. This invention achieves performance optimization through a simple photopolymerization process, utilizes readily available and inexpensive raw materials, and is suitable for large-scale production, showing broad application prospects in medical dressings and wearable medical monitoring.

[0018] Furthermore, in preparing precursor A solution, the monomers are hydroxyethyl methacrylate, 2-acrylamide-2-methylpropanesulfonic acid, or acryloyloxyethyltrimethylammonium chloride. After polymerization, the resulting polyhydroxyethyl methacrylate is a neutral polymer, poly-2-acrylamide-2-methylpropanesulfonic acid is a polyanionic polymer, and polyacryloyloxyethyltrimethylammonium chloride is a polycationic polymer. Three representative polymers from hydrogel materials were selected, demonstrating broad applicability.

[0019] This invention discloses an anti-swelling hydrogel bioadhesive employing a dual-network structure design. The first network layer restricts water absorption and swelling of the bioadhesive and enhances its mechanical properties. The second network layer is a polyacrylate-N-succinimide hydrogel, which achieves strong adhesion to various wet tissues through synergistic interactions of non-covalent bonds (hydrogen bonds) and covalent bonds (amide bonds). Based on this dual-network structure design, this invention successfully achieves synergistic optimization of anti-swelling performance and wet adhesion performance. The prepared hydrogel bioadhesive exhibits excellent overall performance, specifically: significantly improved anti-swelling performance; high wet adhesion strength and excellent burst pressure resistance; stable mechanical properties over a long period; and even after prolonged immersion in aqueous solutions, its adhesion performance, modulus, and tensile strength do not show significant weakening.

[0020] The anti-swelling hydrogel bioadhesive prepared by this invention has rapid hemostatic properties. On the one hand, the porous structure formed by the freezing technology enables it to rapidly absorb a large amount of blood, achieving immediate hemostasis. On the other hand, its anti-swelling ability and long-term mechanical stability effectively prevent the adhesive from falling off, ensuring a long-term sealing effect. Finally, its good biocompatibility meets safety standards. Attached Figure Description

[0021] Figure 1 The swelling changes of the hydrogel bioadhesives prepared in Example 3 and Comparative Example 1 of this invention after soaking in water for 0 h and 120 h are shown in the graph. Among them, (a) is a photograph of Comparative Example 1 after soaking in water for 0 h; (b) is a photograph of Example 3 after soaking in water for 0 h; (c) is a photograph of Comparative Example 1 after soaking in water for 120 h; and (d) is a photograph of Example 3 after soaking in water for 120 h. Figure 2 The stress-strain curves of the hydrogel bioadhesive prepared in Example 3 of this invention after immersion in water for 24 h and 120 h are shown. Figure 3 Images of the hydrogel bio-adhesive prepared in Example 3 of this invention after being soaked in water for 0 h and 24 h after being bonded to pigskin on both sides; Figure 4 The burst pressure of the hydrogel bioadhesive prepared in Examples 1-4 and Comparative Example 1 of this invention; Figure 5 To compare the biocompatibility of the dual-network hydrogel bioadhesives of Examples 1-4 and the single-network hydrogel bioadhesive of Comparative Example 1 with culture dishes as a control condition. Figure 6 This describes the hemostasis model and hemostasis performance of Example 3 in this invention. Figure 7Figure 1 shows the electrocardiogram and electromyogram measured by Example 3 and commercial electrodes in this invention; (a) Figure 2 shows the electrocardiogram measured by Example 3 and commercial electrodes; (b) Figure 3 shows the electromyogram measured by Example 3 and commercial electrodes. Detailed Implementation

[0022] To make the objectives, technical solutions, and advantages of the present invention clearer, the following detailed description is provided in conjunction with the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention; that is, the described embodiments are only a part of the embodiments of the present invention, and not all of them.

[0023] The detailed description of the embodiments of the present invention provided in the following figures is not intended to limit the scope of the claimed invention, but merely to illustrate one selected embodiment of the invention. All other embodiments obtained by those skilled in the art based on the figures and embodiments of the present invention without inventive effort are within the scope of protection of the present invention.

[0024] It should be noted that the terms “comprising,” “including,” or any other variations are intended to cover non-exclusive inclusion, such that a process, element, method, article, or apparatus that comprises a list of elements includes not only those elements but also other elements not expressly listed, or elements inherent to the process, element, method, article, or apparatus.

[0025] This invention discloses a method for preparing an anti-swelling bio-adhesive, which uses a continuous two-step polymerization method and freeze-drying technology to prepare a poly(hydroxyethyl methacrylate) / poly(N-succinimide acrylate) hydrogel bio-adhesive (hereinafter referred to as PHEMA / PAA-NHS). Specifically, it includes the following steps: (1) First, monomer A, crosslinking agent and photoinitiator are mixed to prepare precursor A solution; Acrylic acid and N-succinimide acrylate, crosslinking agent and photoinitiator were mixed to prepare precursor B solution; (2) Then the precursor A solution was poured into a mold consisting of two parallel glass plates separated by a silicone pad, and subjected to the first ultraviolet light irradiation to obtain the first layer of hydrogel. (3) Immerse the first layer of hydrogel obtained in step (2) in the precursor B solution until equilibrium is reached to obtain a hydrogel sample; (4) The hydrogel sample is sandwiched between two glass plates and subjected to a second ultraviolet light irradiation to form a double network hydrogel.

[0026] (5) The double-network hydrogel was rinsed in a large amount of deionized water to remove unreacted small molecule residues and then freeze-dried to obtain an anti-swelling hydrogel bioadhesive.

[0027] The features and performance of the present invention will be further described in detail below with reference to embodiments.

[0028] Example 1 This invention discloses a method for preparing an anti-swelling bioadhesive, comprising the following steps: 1) Take 1 M hydroxyethyl methacrylate (HEMA) monomer. Calculate the amount of hydroxyethyl methacrylate added as 100%. Take 1 mol% N,N'-methylenebisacrylamide (MBAA) crosslinking agent and 0.1 mol% 2-hydroxy-2-methylphenylacetone (HMPP) initiator. Add HEMA, MBAA, and HMPP to deionized water and stir thoroughly to obtain the first precursor A solution.

[0029] The concentrations (mol%) of crosslinking agent and photoinitiator are related to the monomer concentration, and the following description is omitted.

[0030] 2) The precursor A solution was injected into a glass mold. The glass mold consisted of two parallel glass plates (10 cm long × 10 cm wide × 0.5 mm thick) separated by 500 μm silicon pads. After being irradiated with ultraviolet light (365 nm) in air for 4 hours, the first layer of PHEMA hydrogel network was formed.

[0031] 3) Calculate 100 parts of precursor B solution, add 20 wt% acrylic acid (AA), 2 wt% acrylate-N-succinimide (AA-NHS), 0.1 wt% MBAA crosslinking agent and 0.2 wt% HMPP photoinitiator to deionized water, and stir thoroughly to obtain precursor B solution.

[0032] 4) Immerse the first layer of PHEMA hydrogel network in precursor B solution until swelling equilibrium is reached. Sandwich the immersed PHEMA hydrogel between two glass plates and expose it to a second UV light (365 nm) in air for 1 hour to form a PHEMA / PAA-NHS double network hydrogel.

[0033] 5) After rinsing the PHEMA / PAA-NHS dual-network hydrogel with water, freeze it at -75 ℃ for 24 h, and then freeze-dry it for 5 days to obtain the hydrogel bio-adhesive. Store the PHEMA / PAA-NHS hydrogel bio-adhesive at 4 ℃.

[0034] Reaction Mechanism: Under ultraviolet light irradiation at a specific wavelength (preferably 365 nm), the photoinitiator absorbs photons to generate an excited state, activating the co-initiator component through intramolecular energy transfer, and synergistically generating active free radicals with specific spatial characteristics. These active free radicals undergo addition reactions with monomers containing double bonds. Finally, the active groups in the crosslinking agent participate in the reaction, constructing an interpenetrating network structure, ultimately forming a three-dimensional polymer network with crosslinking density.

[0035] Example 2 The difference between Example 1 and Example 2 is that: When preparing precursor A solution, take 1 M HEMA, and calculate based on the amount of hydroxyethyl methacrylate added as 100%. Take 2 mol% MBAA and 0.1 mol% HMPP. Add HEMA, MBAA and HMPP to deionized water and stir thoroughly to obtain precursor A solution.

[0036] Example 3 The difference between Example 1 and Example 2 is that: When preparing precursor A solution, take 1 M HEMA, and calculate based on the amount of hydroxyethyl methacrylate added as 100%. Take 4 mol% MBAA and 0.1 mol% HMPP, add HEMA, MBAA and HMPP to deionized water, and stir thoroughly to obtain precursor A solution.

[0037] Example 4 The difference between Example 1 and Example 2 is that: When preparing precursor A solution, take 1 M HEMA, and calculate based on the amount of hydroxyethyl methacrylate added as 100%. Take 6 mol% MBAA and 0.1 mol% HMPP, add HEMA, MBAA and HMPP to deionized water, and stir thoroughly to obtain precursor A solution.

[0038] Example 5 The difference between Example 1 and Example 2 is that: After preparing the PHEMA / PAA-NHS dual-network hydrogel, it was washed with water, frozen at -80 ℃ for 24 h, and then freeze-dried in a freeze dryer for 5 days to obtain the hydrogel bioadhesive. The PHEMA / PAA-NHS hydrogel bioadhesive was stored at room temperature (25 ℃).

[0039] Example 6 The difference between Example 1 and Example 2 is that: After preparing the PHEMA / PAA-NHS dual-network hydrogel, it was washed with water, frozen at -20 ℃ for 24 h, and then freeze-dried for 5 days to obtain the hydrogel bioadhesive. The PHEMA / PAA-NHS hydrogel bioadhesive was stored at 4 ℃.

[0040] Example 7 The difference between Example 1 and Example 2 is that: After preparing the PHEMA / PAA-NHS dual-network hydrogel, it was washed with water, frozen at -75 ℃ for 24 h, and then freeze-dried for 2 days to obtain the hydrogel bioadhesive. The PHEMA / PAA-NHS hydrogel bioadhesive was stored at 4 ℃.

[0041] Example 8 The difference between Example 1 and Example 2 is that: To prepare precursor A solution, 1 M of 2-acrylamide-2-methylpropanesulfonic acid (AMPS) was taken. Assuming the amount of AMPS added was 100%, 4 mol% MBAA and 0.1 mol% HMPP were added to deionized water and stirred thoroughly to obtain precursor A solution. This formed the first layer of a poly(2-acrylamide-2-methylpropanesulfonic acid) PAMPS hydrogel network.

[0042] Example 9 The difference between Example 1 and Example 2 is that: To prepare precursor A solution, 1 M acryloyloxyethyltrimethylammonium chloride (DMAEA-Q) was taken. Assuming the amount of DMAEA-Q added was 100%, 4 mol% MBAA and 0.1 mol% HMPP were added to deionized water and stirred thoroughly to obtain precursor A solution. This formed the first layer of polyacryloyloxyethyltrimethylammonium chloride PDMAEA-Q hydrogel network.

[0043] The following is a summary of the data from the examples, as shown in Table 1: Table 1

[0044] Comparative Example 1 1) Calculate 100 parts of precursor solution, add 20 wt% AA, 2 wt% AA-NHS, 0.1 wt% MBAA and 0.2 wt% HMPP to deionized water, stir thoroughly to obtain precursor solution.

[0045] 2) The precursor solution was injected into a glass mold. The glass mold consisted of two parallel glass plates (10 cm long × 10 cm wide × 0.5 mm thick) separated by a 500 μm silicon pad. After being irradiated with ultraviolet light (365 nm) in air for 1 hour, PAA-NHS hydrogel was formed.

[0046] 3) After washing the PAA-NHS hydrogel with water, freeze it in a refrigerator and then freeze-dry it to obtain a single-network hydrogel bioadhesive.

[0047] To verify the performance of the dual-network hydrogel bioadhesive prepared by the present invention, verification examples are also provided.

[0048] The swelling properties of the dual-network hydrogel bioadhesive prepared in the embodiments of the present invention and the single-network hydrogel bioadhesive prepared in the comparative example were tested. The specific test method was as follows: the dual-network hydrogel bioadhesive and the single-network hydrogel bioadhesive were immersed in water at room temperature for 5 days. The mass of the bioadhesive before and after swelling was measured at each pre-specified time interval. The ratio of the swollen mass minus the initial mass to the initial mass was the swelling rate. Please refer to Table 2 and... Figure 1 .

[0049] Table 2 shows the swelling rate of the dual-network hydrogel bioadhesives of Examples 1-9 and the single-network hydrogel bioadhesive of Comparative Example 1 in water over time. Figure 1 This is a diagram showing the swelling changes of the dual-network hydrogel bioadhesive in water, using Example 3 as an example. Figure 1 Figure (a) in the figure is a photograph of Comparative Example 1 after soaking in water for 0 h; Figure 1 Figure (b) is a photograph of Example 3 after soaking in water for 0 h; Figure 1 Figure (c) in the figure is a photograph of Comparative Example 1 after soaking in water for 120 h; Figure 1 Figure (d) in the table is a photograph of Example 3 after soaking in water for 120 h. Table 2 and Figure 1 The results clearly and intuitively demonstrate that the dual-network hydrogel bioadhesives of Examples 1-9 have good anti-swelling ability.

[0050] Table 2

[0051] The mechanical properties of the dual-network hydrogel bioadhesives of Examples 1-9 were tested using a commercial testing machine at room temperature. The samples were cut into dumbbell shapes with a gauge length of 12 mm and a width of 2 mm, and stretched at a constant speed of 100 mm / min. The stress value corresponding to the peak point of the stress-strain curve was the fracture stress. The samples were immersed in water for 24 h and 120 h to evaluate the mechanical stability of the dual-network hydrogel bioadhesives. Tables 3 and 4 show the fracture stress and elastic modulus of Examples 1-9 after immersion in water for 24 h and 120 h, respectively. It is worth noting that Comparative Example 1 was too brittle after immersion in water to be tested for its mechanical properties, therefore its fracture stress and elastic modulus cannot be given. The results in Tables 2 and 3 show that after immersion in water for up to 120 h, the fracture stress and elastic modulus of the hydrogel bioadhesives obtained from Examples 1-9 with their dual-network structure design did not weaken, indicating that they possess long-term stable mechanical properties.

[0052] Table 3

[0053] Table 4

[0054] Please see Figure 2 , Figure 2 The mechanical stability was tested using Example 3 as an example. After immersion treatments for 24 h and 120 h, the hydrogel bio-adhesive retained its initial mechanical properties. The tensile strength (168 kPa) and Young's modulus (73 kPa) of the immersed sample were almost identical to the original tensile strength (174 kPa) and Young's modulus (76 kPa). This demonstrates that the dual-network hydrogel bio-adhesive possesses long-term mechanical stability. The adhesion ability of the dual-network hydrogel bio-adhesive of Example 3 and the single-network hydrogel bio-adhesive of Comparative Example 1 to porcine skin tissue in a humid environment was tested. Specifically, the hydrogel bio-adhesive was adhered to both sides of the porcine skin and immersed in water for 24 h. Please refer to [link to relevant documentation]. Figure 3 , Figure 3 The adhesion properties of the hydrogel bioadhesives of Example 3 and Comparative Example 1 after immersion in water for 0 h and 24 h are measured. Figure 3 As can be seen, the dual-network hydrogel bio-adhesive of Example 3 did not detach, swell, or break down after adhering to porcine skin tissue for 24 hours, while the single-network hydrogel bio-adhesive of Comparative Example 1 swelled and detached and broke down in some areas.

[0055] The adhesion strength of the dual-network hydrogel bio-adhesives of all embodiments and the single-network hydrogel bio-adhesive of Comparative Example 1 was tested. The specific test method was as follows: cleaned pigskin was cut into thin slices with a length of 50 mm and a width of 10 mm and immersed in deionized water. Examples 1-9 and Comparative Example 1 were sandwiched between two pieces of pigskin tissue, and a gentle pressure of 5 kPa was applied at a stretching speed of 50 mm / min. Shear strength was defined as the maximum force during shearing divided by the adhesion area. Please refer to Table 5, which shows the adhesion strength of the dual-network hydrogel bio-adhesives of Examples 1-9 and the single-network bio-adhesive of Comparative Example 1 after immersion in water for 0 h and 24 h.

[0056] Table 5 shows that the dual-network hydrogel bioadhesives of Examples 1-9 have good adhesion strength. Even after soaking for 24 hours, the adhesion strength did not weaken, indicating stable wet adhesion properties. In contrast, Comparative Example 1 showed lower adhesion strength than Examples 1-9, and its adhesion strength decreased significantly after soaking for 24 hours.

[0057] Table 5

[0058] Burst pressure tests were conducted on the dual-network hydrogel bio-adhesives of Examples 1-9 and the single-network hydrogel bio-adhesive of Comparative Example 1. The specific test method was as follows: Pigskin was cut into rectangles, and a 1 mm diameter hole was drilled in the center. The pigskin was then fixed in a cubic box, with a 4 mm diameter hole drilled in the contact surface, ensuring the hole in the pigskin and the hole in the cubic box were centered. Subsequently, all the hydrogel bio-adhesives were adhered to the center of the hole in the pigskin. A digital pressure gauge and a syringe (50 mm) were connected to the cubic box. Before testing, the cubic box and syringe were filled with deionized water. During the test, the syringe was pushed to gently inject deionized water into the device, and the burst pressure was recorded. See [link to relevant documentation]. Figure 4 , Figure 4 The burst pressure of the hydrogel bioadhesive in Examples 1-4 and Comparative Example 1. Figure 4 It can be seen that, compared with Comparative Example 1, the dual-network hydrogel bioadhesives of Examples 1-4 have higher burst pressures, with the burst pressure of Example 3 reaching as high as 450 mmHg.

[0059] Biocompatibility was tested for the dual-network hydrogel bioadhesives of all embodiments and the single-network bioadhesive of Comparative Example 1. Please refer to [link to relevant documentation]. Figure 5 .Depend on Figure 5Viable / dead cell staining further confirmed that the hydrogel bioadhesives of Examples 1-4 and Comparative Example 1 maintained their typical spindle-shaped morphology and exhibited uniform green fluorescence under a microscope, while also showing a small amount of red fluorescence (i.e., dead cells), with no significant difference compared to the negative control (cell culture plate, TCP). The experimental results demonstrate the good biocompatibility of the hydrogel bioadhesives, verify their safety, and lay the foundation for their further biomedical applications.

[0060] Taking the dual-network hydrogel bioadhesive of Example 3 as an example, its rapid hemostatic ability was verified, with the blank group, gelatin sponge group, and the single-network bioadhesive of Comparative Example 1 serving as control groups. The experiment used rats weighing 200-250 g, and a liver section hemorrhage model was employed to evaluate the hemostatic potential. Please refer to... Figure 6 In a rat tissue section hemorrhage model, Example 3 achieved immediate hemostasis (20 ± 10 s). In contrast, the hemostasis time was significantly longer in the gelatin sponge group and the blank group, at 293 ± 64 s and 780 ± 90 s, respectively. Simultaneously, quantitative analysis showed that the control group 3 had the least bleeding (19 ± 10 mg), significantly lower than the gelatin sponge group (346 ± 63 mg) and the blank group (512 ± 50 mg). Comparative Example 1 also exhibited a longer hemostasis time and a greater bleeding volume. Therefore, the dual-network hydrogel bioadhesive of Example 3 possesses rapid hemostatic capabilities.

[0061] Using the dual-network hydrogel bioadhesive from Example 3 as an example, its application in monitoring electrocardiogram (ECG) and electromyography (EMG) signals was verified. Please refer to [link / reference]. Figure 7 a. The electrocardiogram (ECG) signal recorded by the electrodes of Example 3 showed no significant difference compared to the ECG signal obtained using commercial electrodes. Please refer to [link / reference]. Figure 7 b. The electromyographic signals recorded by the electrodes of Example 3 showed no significant difference compared to the electromyographic signals obtained using commercial electrodes.

[0062] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and not to limit it. Although the present invention has been described in detail with reference to the above embodiments, those skilled in the art should understand that modifications or equivalent substitutions can still be made to the specific implementation of the present invention. Any modifications or equivalent substitutions that do not depart from the spirit and scope of the present invention should be covered within the protection scope of the present invention.

Claims

1. A method for preparing an anti-swelling hydrogel bioadhesive, characterized in that, Includes the following steps: (1) Mix the monomer, crosslinking agent and photoinitiator to prepare precursor A solution; Acrylic acid and N-succinimide acrylate, crosslinking agent and photoinitiator were mixed to prepare precursor B solution; (2) Then the precursor A solution was poured into a mold consisting of two parallel glass plates separated by a silicone pad and subjected to the first ultraviolet light irradiation to obtain the first layer of hydrogel network. (3) Immerse the first layer of hydrogel network in the precursor B solution until equilibrium is reached to obtain the hydrogel sample; (4) The hydrogel sample is sandwiched between two glass plates and subjected to a second ultraviolet light irradiation to form a uniform double network hydrogel; (5) The double-network hydrogel was soaked in a large amount of deionized water to rinse away the residue, and finally freeze-dried to obtain an anti-swelling hydrogel bio-adhesive.

2. The method for preparing an anti-swelling hydrogel bioadhesive according to claim 1, characterized in that, In step (1), the monomer is hydroxyethyl methacrylate, 2-acrylamide-2-methylpropanesulfonic acid or acryloyloxyethyltrimethylammonium chloride.

3. The method for preparing an anti-swelling hydrogel bioadhesive according to claim 1, characterized in that, In step (1), the crosslinking agent is N,N'-methylenebisacrylamide.

4. The method for preparing an anti-swelling hydrogel bioadhesive according to claim 1, characterized in that, In step (1), the photoinitiator is 2-hydroxy-2-methylphenylpropanone.

5. The method for preparing an anti-swelling hydrogel bioadhesive according to claim 1, characterized in that, In step (1), when preparing precursor A solution, the molar ratio of monomer, crosslinking agent and photoinitiator is 100:1~6:0.

1.

6. A method for preparing an anti-swelling hydrogel bioadhesive according to claim 1, characterized in that, In step (2), the ultraviolet light irradiation conditions are: light intensity 15 ~ 30 mW / cm². 2 Irradiation time: 4 h ~ 8 h.

7. The method for preparing an anti-swelling hydrogel bioadhesive according to claim 1, characterized in that, In step (1), when preparing precursor B solution, the mass ratio of acrylic acid and N-succinimide acrylate, crosslinking agent and photoinitiator is 20:2:0.1:0.2, and the remainder is deionized water, calculated as 100 parts of precursor B solution.

8. A method for preparing an anti-swelling hydrogel bioadhesive according to claim 1, characterized in that, In step (5), the freeze-drying process is as follows: the rinsed double network hydrogel is first frozen at -20 ℃ to -80 ℃ for 2 h to 24 h, and then cold-dried in a freeze dryer for 2 d to 5 d.

9. An anti-swelling hydrogel bioadhesive prepared by the preparation method according to any one of claims 1-8.

10. The application of the anti-swelling hydrogel bioadhesive of claim 9 in wound adhesion, hemostasis, and monitoring of electrocardiogram and electromyogram signals.

Images