A high-adhesion acrylamide / hyaluronic acid composite hydrogel and a preparation method thereof

Abstract

The present application relates to the technical field of biomedical polymer materials, and particularly relates to a high-adhesion acrylamide / hyaluronic acid composite hydrogel and a preparation method thereof, the hydrogel comprising the following raw material components: (DA-OHA) aqueous solution, acrylamide (AM) and crosslinking agent. The preparation method of the hydrogel comprises the following steps: (1) preparing a dopamine-modified aldehyde-based hyaluronic acid (DA-OHA) aqueous solution with a mass / volume ratio of 6%; (2) adding acrylamide (AM) and crosslinking agent MBAM to the aqueous solution obtained in step (1) and stirring until completely dissolved to obtain a precursor solution; (3) transferring the precursor solution obtained in step (2) to a mold and irradiating with an ultraviolet light crosslinking instrument to perform light crosslinking and solidification to obtain the composite hydrogel. The composite hydrogel prepared by the present application has excellent water absorption and water retention, structural stability, gentle degradation, strong tissue adhesion and excellent mechanical properties, and can be used as an ideal wound dressing material, and has wide clinical transformation prospects and application value.

Description

Technical Field

[0001] This invention belongs to the field of biomedical polymer materials technology, and particularly relates to a highly adhesive acrylamide / hyaluronic acid composite hydrogel and its preparation method. Background Technology

[0002] Hydrogels are a class of hydrophilic polymer materials with a three-dimensional network structure. Due to their excellent biocompatibility, high swelling capacity and flexible structure, they have broad application prospects in fields such as bioengineering, tissue engineering and medical dressings.

[0003] Traditional hydrogels are mostly prepared by single chemical cross-linking or physical cross-linking methods, which generally have defects such as weak mechanical properties, poor tissue adhesion, excessive swelling leading to structural collapse, and uncontrollable degradation rate. They are difficult to meet the requirements of medical dressings for a synergistic balance of material adhesion, mechanical strength, and biodegradability.

[0004] In existing technologies, acrylamide (PAM)-based hydrogels have been extensively studied due to their excellent hydrophilicity and moldability. However, these hydrogels suffer from poor adhesion and insufficient mechanical strength, making it difficult to adhere tightly to wound or tissue surfaces. Furthermore, they are prone to rupture under physiological conditions, limiting their long-term application in medical settings. Polysaccharide hydrogels (such as trehalose and hyaluronic acid) exhibit excellent biocompatibility and biodegradability, but they suffer from excessively high swelling rates and uncontrollable degradation rates. Excessive swelling can lead to hydrogel structural collapse, while excessively rapid degradation fails to provide long-term tissue support, and excessively slow degradation can hinder metabolic excretion after tissue repair. The core reason for these problems lies in the fact that the cross-linking network of single-component hydrogels lacks dynamic interaction sites, failing to form a stable structure that combines adhesion, mechanical properties, and degradation regulation. Additionally, the synergistic effects between different components are not effectively regulated, failing to achieve a balanced optimization of various properties.

[0005] Chinese patent CN111253592A discloses a photocrosslinked γ-polyglutamic acid hydrogel, its preparation method, and its applications. This method utilizes the carbon-carbon double bonds on 2-aminoethyl methacrylate hydrochloride to generate free radical polymerization under light and the coordination effect of Fe3+, crosslinking γ-polyglutamic acid to form a three-dimensional network structure hydrogel. Specifically, the hydrogel prepared by this invention is a single polymer double-crosslinked network (γ-PGA chains are simultaneously crosslinked by covalent and coordinate bonds), mainly addressing the technical problem of poor mechanical properties. However, this invention relies solely on the surface properties of the material and does not improve the technical problem of weak hydrogel adhesion.

[0006] Chinese patent CN119875154A discloses a method for preparing high-viscosity photocrosslinked sodium hyaluronate hydrogel, comprising the following steps: dissolving sodium hyaluronate in deionized water / N,N-dimethylformamide to obtain a sodium hyaluronate solution; mixing the sodium hyaluronate solution with a conjugated diene glycidyl ester / N,N-dimethylformamide solution to obtain a pre-formed sodium hyaluronate gel; adding composite antibacterial microspheres and a photoinitiator to the pre-formed sodium hyaluronate gel, and then performing a photocrosslinking reaction. This invention utilizes a grafting technique with conjugated diene glycidyl ester to introduce photocrosslinkable double bonds, forming a single crosslinked network of sodium hyaluronate itself. In other words, the viscosity of this invention is increased by the density of photocrosslinking between sodium hyaluronate chains. It is well known that hyaluronic acid itself has very weak adhesion, tending towards lubrication and not sticking to tissues. The photocrosslinking in this invention only forms an internal covalent network and does not enhance the adhesion to tissues.

[0007] In summary, no reports have yet documented a composite hydrogel that combines dopamine-modified aldehyde-based hyaluronic acid with acrylamide to construct a covalent-physical dual crosslinking network via photocrosslinking, achieving an optimal balance between adhesion, swelling, degradation, and mechanical properties. Therefore, developing a medical hydrogel with stable mechanical properties, strong tissue adhesion, and gradual and controllable degradation is of great significance for expanding the application of hydrogels in wound repair, medical dressings, and other technological fields. Summary of the Invention

[0008] To address the shortcomings of existing technologies, the technical problem to be solved by this invention is to provide a highly adhesive acrylamide / hyaluronic acid composite hydrogel with synergistic optimization of its adhesion, swelling, degradation and mechanical properties, and its preparation method.

[0009] To solve the above-mentioned technical problems, the technical solution adopted by the present invention is: a highly adhesive acrylamide / hyaluronic acid composite hydrogel, comprising the following raw material components: an aqueous solution of dopamine-modified aldehyde-based hyaluronic acid (DA-OHA), acrylamide (AM), and a crosslinking agent N,N-methylenebisacrylamide (MBAM); wherein, the dopamine-modified aldehyde-based hyaluronic acid (DA-OHA) accounts for 0%-35% of the total mass of DA-OHA and acrylamide; the amount of crosslinking agent N,N'-methylenebisacrylamide added is 0.1%-0.5% of the mass of acrylamide; and the dopamine grafting rate of the dopamine-modified aldehyde-based hyaluronic acid is 10%-30%.

[0010] In the above-mentioned highly adhesive acrylamide / hyaluronic acid composite hydrogel, the mass-volume ratio of the dopamine-modified aldehyde-based hyaluronic acid aqueous solution is 6%, wherein the molecular weight of the dopamine-modified aldehyde-based hyaluronic acid ranges from 100,000 to 200,000 Daltons.

[0011] The aforementioned high-adhesion acrylamide / hyaluronic acid composite hydrogel further includes the photoinitiator Irgacure-2959; the amount of photoinitiator Irgacure-2959 added is 0.5%-2% of the total mass of the system, and the forming thickness of the hydrogel is controlled to be 0.5-2.5 mm.

[0012] The aforementioned highly adhesive acrylamide / hyaluronic acid composite hydrogel has a covalent-physical dual crosslinked network structure; wherein the covalent crosslinking is formed by photopolymerization of acrylamide and a crosslinking agent, and the physical crosslinking is formed by multiple hydrogen bonding interactions.

[0013] In the aforementioned highly adhesive acrylamide / hyaluronic acid composite hydrogel, when the dopamine-modified aldehyde-based hyaluronic acid (DA-OHA) accounts for 25% of the total mass of DA-OHA and acrylamide, the hydrogel achieves an optimal balance in terms of adhesion, swelling, and degradation.

[0014] A method for preparing a highly adhesive acrylamide / hyaluronic acid composite hydrogel includes the following steps:

[0015] (1) Prepare an aqueous solution of dopamine-modified aldehyde-based hyaluronic acid (DA-OHA) with a mass-volume ratio of 6%;

[0016] (2) Add acrylamide (AM) and crosslinking agent MBAM to the aqueous solution obtained in step (1) above, and stir until completely dissolved to obtain a uniformly mixed precursor solution;

[0017] (3) Transfer the precursor liquid obtained in step (2) to a preset mold and perform cross-linking and curing to obtain a composite hydrogel.

[0018] The preparation method of the above-mentioned high-adhesion acrylamide / hyaluronic acid composite hydrogel, in step (2), also includes the photoinitiator Irgacure-2959.

[0019] In the above-mentioned method for preparing highly adhesive acrylamide / hyaluronic acid composite hydrogel, in step (3), an ultraviolet crosslinker is used for irradiation, with a light intensity of 0.5-3 W / cm² and an irradiation time of 3-10 min, and the hydrogel is controlled to have a molding thickness of 0.5-2.5 mm for photocrosslinking and curing.

[0020] In the above-mentioned method for preparing highly adhesive acrylamide / hyaluronic acid composite hydrogel, in step (2), dopamine-modified aldehyde hyaluronic acid (DA-OHA) accounts for 25% of the total mass of dopamine-modified aldehyde hyaluronic acid (DA-OHA) and acrylamide.

[0021] In the above-mentioned method for preparing highly adhesive acrylamide / hyaluronic acid composite hydrogel, in step (2), the dopamine grafting rate of dopamine-modified aldehyde-modified hyaluronic acid is controlled at 10%-30%.

[0022] The advantages of the high-adhesion acrylamide / hyaluronic acid composite hydrogel and its preparation method of the present invention are as follows: The present invention constructs a dual polymer composite system composed of a polyacrylamide covalent network and a dopamine-modified hyaluronic acid physical network. In this dual polymer composite system, the PAM covalent network and the DA-OHA physical network interpenetrate with each other to form an interpenetrating / semi-interpenetrating composite network structure. This composite network structure achieves the technical effects of high swelling, strong tissue adhesion, stable degradation, and mechanical enhancement of the hydrogel through the synergistic effect of covalent cross-linking and multiple hydrogen bonds.

[0023] The composite hydrogel system constructed in this invention comprehensively solves the technical problems of existing PAM hydrogels, such as insufficient water absorption and retention, poor tissue adhesion, and weak mechanical properties, as well as conventional polysaccharide composite hydrogels, such as high swelling and easy instability, and uncontrollable degradation rate. It has excellent water absorption and retention, structural stability, slow degradation, strong tissue adhesion, and excellent mechanical properties, and can be used as an ideal wound dressing material with broad clinical translation prospects and application value. Attached Figure Description

[0024] Figure 1 The images show the adhesion effect of the hydrogel prepared in this invention under bending conditions of 180°, 120°, 90°, and 60°.

[0025] Figure 2 The image shows the morphological characteristics of the lyophilized composite hydrogel prepared in Example 4 of this invention using scanning electron microscopy (SEM).

[0026] Figure 3 The graphs show the swelling ratio test results of the hydrogels prepared in Examples 1-5.

[0027] Figure 4 The graphs show the degradation rate performance of the hydrogels prepared in Examples 1-5.

[0028] Figure 5 The graphs show the adhesive strength test results of the hydrogels prepared in Examples 1-5.

[0029] Figure 6 The graphs show the compressibility test results of the hydrogels prepared in Examples 1-5.

[0030] Figure 7 The graphs show the swelling ratio test results of the composite hydrogels prepared in Examples 4 and 6.

[0031] Figure 8 The graphs show the degradation rate performance of the composite hydrogels prepared in Examples 4 and 6.

[0032] Figure 9 These are test graphs showing the adhesive strength properties of the composite hydrogels prepared in Examples 4 and 6.

[0033] Figure 10 The figures show the compression performance test results of the composite hydrogels prepared in Examples 4 and 6. Detailed Implementation

[0034] The present invention will be further described in detail below with reference to the accompanying drawings and specific embodiments.

[0035] In this invention, unless otherwise stated, directional terms such as "upper" and "lower" generally refer to the upper and lower positions of the device in its actual use or operating state, specifically the drawing directions in the accompanying drawings; while "inner" and "outer" refer to the outline of the device. Furthermore, in the description of this application, the term "comprising" means "including but not limited to". The terms first, second, third, etc., are used merely as illustrative purposes and do not impose numerical requirements or establish an order. The term "multiple" means "two or more".

[0036] A highly adhesive acrylamide / hyaluronic acid composite hydrogel comprises the following raw material components: an aqueous solution of dopamine-modified aldehyde-based hyaluronic acid (DA-OHA), acrylamide (AM), and a crosslinking agent N,N-methylenebisacrylamide (MBAM); wherein, the dopamine-modified aldehyde-based hyaluronic acid (DA-OHA) accounts for 25% of the total mass of DA-OHA and acrylamide; the amount of crosslinking agent N,N'-methylenebisacrylamide added is 0.1%-0.5% of the mass of acrylamide; and the dopamine grafting rate of the dopamine-modified aldehyde-based hyaluronic acid is 10%-30%.

[0037] The composite hydrogel also includes the photoinitiator Irgacure-2959; the amount of photoinitiator Irgacure-2959 added is 0.5%-2% of the total mass of the system, and the forming thickness of the hydrogel is controlled to be 0.5-2.5 mm; the mass-volume ratio of dopamine-modified aldehyde-based hyaluronic acid aqueous solution is 6%, and the molecular weight of dopamine-modified aldehyde-based hyaluronic acid ranges from 100,000 to 200,000 Daltons; the composite hydrogel has a covalent-physical double crosslinking network structure; wherein, the covalent crosslinking is formed by photopolymerization of acrylamide and crosslinking agent, and the physical crosslinking is formed by multiple hydrogen bonding; when the dopamine grafting rate is 10%, the hydrogel degradation rate is slow; when the grafting rate is 30%, the hydrogel degradation rate is fast; when dopamine-modified aldehyde-based hyaluronic acid (DA-OHA) accounts for 25% of the total mass of DA-OHA and acrylamide, the hydrogel achieves the optimal balance in terms of adhesion, swelling, and degradation.

[0038] A method for preparing a highly adhesive acrylamide / hyaluronic acid composite hydrogel includes the following steps:

[0039] (1) Prepare an aqueous solution of dopamine-modified aldehyde-based hyaluronic acid (DA-OHA) with a mass-volume ratio of 6%;

[0040] (2) Add acrylamide (AM) and crosslinking agent MBAM to the aqueous solution obtained in step (1) above, and stir until completely dissolved to obtain a uniformly mixed precursor solution;

[0041] (3) Transfer the precursor liquid obtained in step (2) to a preset mold and perform cross-linking and curing to obtain a composite hydrogel.

[0042] In step (2), the photoinitiator Irgacure-2959 is also included. In step (3), ultraviolet light crosslinking instrument is used for irradiation, with a light intensity of 0.5-3 W / cm² and an irradiation time of 3-10 min, to perform photocrosslinking curing. In step (2), the dopamine-modified aldehyde-based hyaluronic acid (DA-OHA) accounts for 25% of the total mass of dopamine-modified aldehyde-based hyaluronic acid (DA-OHA) and acrylamide. The dopamine grafting rate of the dopamine-modified aldehyde-based hyaluronic acid is controlled at 10%-30%.

[0043] The PAM covalent backbone and DA-OHA multiple hydrogen bond synergistic system of this invention, due to the introduction of a dopamine-catechol structure, can form multiple strong interactions with biological tissues, resulting in significantly higher adhesion strength. This allows the hydrogel to adhere to, wet, and firmly grasp the tissue surface. The PAM covalent network provides strength, while the DA-OHA hydrogen bonds provide toughening and reversible deformation, thus enhancing mechanical properties. The high hydrophilicity and hydrogen bonding of DA-OHA (polysaccharide) greatly improve the swelling properties of the hydrogel. Furthermore, the degradation performance of the composite hydrogel of this invention can be flexibly controlled by adjusting the DA-OHA addition ratio and dopamine grafting rate to adapt to different wound healing needs.

[0044] like Figure 1 As shown, the adhesion stability of the hydrogel was visually verified through dynamic bending real-world photography. The results showed that the hydrogel adhered to the substrate remained tightly bonded to the substrate during continuous large-angle bending from 180° to 60°, without any lifting, slippage, or detachment. This clearly demonstrates that the hydrogel has excellent adhesion stability and can well match the dynamic deformation requirements of wounds in active areas of the human body, maintaining a stable adhesion effect even during daily activities of the wound.

[0045] like Figure 2As shown, the hydrogel forms a continuous, interconnected three-dimensional porous network structure without significant defects such as pore collapse, structural damage, or large-area dense blockage; the main pore size is concentrated around 30 μm. The pore size diagram of this composite hydrogel reveals a structure of large pores nested within small pores. This large-pore structure enables rapid absorption of wound exudate, while the secondary micropores and pore wall folds increase the specific surface area of ​​the hydrogel, providing sufficient interface for the full exposure of dopamine catechol active sites and the loading and sustained release of functional drugs. Simultaneously, the continuous and intact pore walls provide stable structural support for the hydrogel, which, combined with its excellent mechanical properties, wet adhesion properties, and other macroscopic properties, fully meets the application requirements of medical wound dressings.

[0046] The present application will be specifically described below through specific embodiments. The following embodiments are only some embodiments of the present application and are not intended to limit the present application.

[0047] Example 1

[0048] This embodiment provides a highly adhesive acrylamide / hyaluronic acid composite hydrogel as a blank control, used to compare its performance with that of the composite hydrogel of the present invention. Its preparation method includes the following steps:

[0049] (1) Raw material preparation: Acrylamide (AM) 360mg, crosslinking agent N,N-methylenebisacrylamide (MBAM) 3mg, photoinitiator Irgacure-2959 6mg, deionized water 3mL;

[0050] (2) Preparation of precursor solution: Add the above raw materials into a container in sequence and stir at room temperature for 2 hours until the system is uniform and transparent to obtain the precursor solution;

[0051] (3) Photocrosslinking curing: The above precursor liquid is transferred to a preset mold and cured by irradiation with an ultraviolet crosslinking instrument. The ultraviolet wavelength is 365nm, the light intensity is 0.9W / cm², the light irradiation time is 3min, and the forming thickness of the hydrogel is controlled to be 2.5mm. After curing, pure PAM hydrogel is obtained.

[0052] The pure PAM hydrogel prepared in this embodiment was subjected to performance tests, and the results are as follows: the porcine skin adhesion strength was 7 kPa, the equilibrium swelling rate was 130%, the degradation rate in PBS buffer (simulating physiological environment) was 100% after 14 days, and the compressive strength was 30 kPa. This blank control hydrogel, which forms a rigid network with all-carbon covalent bonds through free radical copolymerization of MBAM and acrylamide, possesses certain mechanical stability, but its adhesion, swelling, and degradation controllability are poor, failing to meet the requirements for use in biomedical dressings.

[0053] Example 2

[0054] This embodiment provides a highly adhesive acrylamide / hyaluronic acid composite hydrogel, the preparation method of which includes the following steps:

[0055] (1) Preparation of DA-OHA aqueous solution: Prepare an aqueous solution of dopamine-modified aldehyde-based hyaluronic acid (DA-OHA) with a mass-volume ratio of 6%, stir for 4 hours until completely dissolved, and set aside for later use; wherein, the dopamine grafting rate of DA-OHA is controlled at 10%-30%;

[0056] (2) Take 0.315 mL of the dopamine-modified aldehyde-based hyaluronic acid (DA-OHA) aqueous solution prepared in step (1), add 360 mg of acrylamide (AM), 3 mg of crosslinking agent N,N-methylenebisacrylamide (MBAM), 6 mg of photoinitiator Irgacure-2959 and 2.685 mL of deionized water, stir at room temperature for 2 h until the system is uniform and transparent to obtain the precursor solution; wherein, the proportion of dopamine-modified aldehyde-based hyaluronic acid (DA-OHA) in the total mass of AM and DA-OHA is 5%;

[0057] (3) Transfer the precursor liquid obtained in step (2) into a preset mold and cure it by irradiation with an ultraviolet crosslinker. The ultraviolet wavelength is 365nm, the light intensity is 0.9W / cm², the light time is 3min, and the thickness of the hydrogel is controlled to be 0.5mm. After curing, a composite hydrogel is obtained.

[0058] The content of DA-OHA in the 0.315 mL aqueous solution of dopamine-modified aldehyde-based hyaluronic acid (DA-OHA) was 18.9 mg.

[0059] The composite hydrogel prepared in this embodiment was subjected to performance tests, and the results are as follows: the porcine skin adhesion strength was 8 kPa, the equilibrium swelling rate was 125%, the degradation rate in PBS buffer after 14 days was 100%, and the compressive strength was 80 kPa. Compared with the pure PAM hydrogel in Example 1, the adhesion strength and compressive strength of the hydrogel in this embodiment were improved to a certain extent, indicating that the introduction of DA-OHA can initially improve the mechanical and adhesive properties of the hydrogel. However, due to the low amount of DA-OHA added, the improvement effect was limited, and the degradation rate was too fast, which could not meet the needs of medium- and long-term wound healing.

[0060] The reagents used in the embodiments of this application all adopt the following specifications: acrylamide (AM, reagent grade, purity 99%, molecular weight 71.08 Da), N,N'-methylenebisacrylamide (MBAM, reagent grade, purity 97%, molecular weight 154.17 Da), photoinitiator Irgacure-2959 (purity 98%, molecular weight 225.25 Da), hyaluronic acid (HA, molecular weight 100,000-200,000 Da, hereinafter referred to as OHA), dopamine hydrochloride (purity 98%, molecular weight 189.64 Da, hereinafter referred to as DA), N-hydroxysuccinimide (NHS, 99% biotechnology grade, molecular weight 115.09 Da), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC, purity 98.5%, molecular weight 191.7 Da). The above reagents are of uniform specifications to ensure experimental repeatability and result stability.

[0061] The specific preparation method of DA-OHA in this invention is as follows:

[0062] Regarding the amide bond grafting method with a 10% grafting rate:

[0063] (1) Dissolve 1.0 g HA in 100 mL deionized water, stir at 25 °C for 3 h, then add 0.21 g sodium periodate, protect from light, react for 2 h, then add 0.5 mL ethylene glycol and react for 1 h to remove excess sodium periodate. After the reaction is complete, pack the reaction solution into a dialysis membrane (molecular weight cutoff of 1000 Da) and dialyze with ultrapure water for three days, then freeze-dry to obtain sponge-like OHA solid;

[0064] (2) Dissolve 1.0g of the OHA solid obtained by the above method in 100mL of PBS (pH=5) buffer solution, stir at 25℃ for 3h, then add 0.2g of EDC and 0.4g of NHS and stir for 1h, then add 0.4g of dopamine and react at 25℃ in the dark for 24h. After the reaction is completed, put the reaction solution into a dialysis membrane (molecular weight cutoff of 3500Da) and dialyze with ultrapure water for two days. Freeze dry to obtain sponge-like DA-OHA solid.

[0065] Regarding the Schiff base grafting method with a 30% grafting rate:

[0066] (1) Dissolve 1.0 g HA in 100 mL PBS (pH=5) buffer solution, stir at 25 °C for 6 h, then add 0.5 g sodium periodate, protect from light, react for 5 h, then add 1 mL ethylene glycol and react for 1 h to remove excess sodium periodate. After the reaction is complete, load the reaction solution into a dialysis membrane (molecular weight cutoff of 1000 Da) and dialyze with ultrapure water for three days, then freeze-dry to obtain sponge-like OHA solid;

[0067] (2) Take 1.0g of the OHA solid obtained by the above method and dissolve it in 100mL of PBS (pH=5) buffer solution. Stir at 25℃ for 1h, then add 0.5g of dopamine and react at 25℃ in the dark for 10h. After the reaction is completed, put the reaction solution into a dialysis membrane (molecular weight cutoff of 3500Da) and dialyze it with ultrapure water for two days. Freeze dry to obtain sponge-like DA-OHA solid.

[0068] Example 3

[0069] This embodiment provides a highly adhesive acrylamide / hyaluronic acid composite hydrogel, the preparation method of which includes the following steps:

[0070] (1) Preparation of DA-OHA aqueous solution: Same as in Example 2, prepare an aqueous solution of dopamine-modified aldehyde-based hyaluronic acid (DA-OHA) with a mass-volume ratio of 6%, stir for 4 hours until completely dissolved, and set aside; the dopamine grafting rate of DA-OHA is controlled at 10%-30%;

[0071] (2) Take 1 mL of the dopamine-modified aldehyde-based hyaluronic acid (DA-OHA) aqueous solution prepared in step (1), then add 360 mg of acrylamide (AM), 3 mg of crosslinking agent N,N-methylenebisacrylamide (MBAM), 6 mg of photoinitiator Irgacure-2959 and 2 mL of deionized water, stir at room temperature for 2 h until the system is uniform and transparent to obtain the precursor solution; wherein, the dopamine-modified aldehyde-based hyaluronic acid (DA-OHA) accounts for 15% of the total mass of AM and DA-OHA.

[0072] (3) Transfer the precursor liquid obtained in step (2) to a preset mold and cure it by irradiation with an ultraviolet crosslinker. The ultraviolet wavelength is 365nm, the light intensity is 3W / cm², the light time is 5min, and the thickness of the hydrogel is controlled to be 1mm. After curing, a composite hydrogel is obtained.

[0073] The content of DA-OHA in 1 mL of dopamine-modified aldehyde-based hyaluronic acid (DA-OHA) aqueous solution is 60 mg.

[0074] The composite hydrogel prepared in this embodiment was subjected to performance tests, and the results are as follows: the porcine skin adhesion strength was 10 kPa, the equilibrium swelling rate was 130%, the degradation rate in PBS buffer after 14 days was 90%, and the compressive strength was 140 kPa. Compared with Example 2, the adhesion strength and compressive strength of the hydrogel in this embodiment were further improved, and the degradation rate was slowed down, indicating that with the increase of DA-OHA addition, the overall performance of the hydrogel was gradually optimized, but it still did not meet the optimal requirements for use as a biomedical dressing.

[0075] Example 4

[0076] This embodiment provides a highly adhesive acrylamide / hyaluronic acid composite hydrogel, the preparation method of which includes the following steps:

[0077] (1) Preparation of DA-OHA aqueous solution: Prepare an aqueous solution of dopamine-modified aldehyde-based hyaluronic acid (DA-OHA) with a mass-volume ratio of 6%, and stir at room temperature for 4 hours until completely dissolved, and set aside for later use; wherein, the dopamine grafting rate of DA-OHA is controlled at 10%;

[0078] (2) Take 2 mL of the dopamine-modified aldehyde-based hyaluronic acid (DA-OHA) prepared in step (1) and dissolve it in water. Then add 360 mg of acrylamide (AM), 3 mg of crosslinking agent (MBAM), 6 mg of photoinitiator Irgacure-2959, and 1 mL of deionized water in sequence. Stir at room temperature for 2 h until the system is uniform and transparent to obtain the precursor solution. The proportion of dopamine-modified aldehyde-based hyaluronic acid (DA-OHA) in the total mass of AM and DA-OHA is 25%.

[0079] (3) Transfer the precursor liquid obtained in step (2) to a preset mold and cure it by irradiation with an ultraviolet crosslinker. The ultraviolet wavelength is 365nm, the light intensity is 3W / cm², the light time is 5min, and the thickness of the hydrogel is controlled to be 1mm. After curing, a composite hydrogel is obtained.

[0080] The 2 mL of dopamine-modified aldehyde-based hyaluronic acid (DA-OHA) aqueous solution contained 120 mg of DA-OHA.

[0081] This embodiment provides a highly adhesive acrylamide / hyaluronic acid composite hydrogel with a DA-OHA content of 25% and a dopamine grafting rate of 10%, which is the optimal formulation with the best overall performance obtained by screening in this invention.

[0082] The composite hydrogel prepared in this embodiment underwent comprehensive performance testing, and the results are as follows: the porcine skin adhesion strength reached 27 kPa, which is nearly 4 times higher than that of the pure PAM hydrogel in Example 1; the equilibrium swelling rate reached 150%, which is the highest in the group, demonstrating excellent water absorption and retention capabilities, effectively absorbing wound exudate, while avoiding the structural instability defects of polysaccharide hydrogels under high swelling conditions; the degradation rate in PBS buffer was 20% after 14 days, and the mass retention rate remained stable at around 80%, indicating a gradual degradation behavior suitable for medium- to long-term wound healing cycles; the compressive strength reached 220 kPa, demonstrating excellent mechanical properties, and the ability to withstand the mechanical disturbances of daily wound activities while maintaining structural integrity.

[0083] The reason why the hydrogel has the best performance in this embodiment is that when the proportion of DA-OHA is 25%, the hydrogel achieves the optimal balance in terms of adhesion, swelling and degradation. The 10% dopamine grafting rate makes the DA-OHA structure stable and can form a uniform interpenetrating structure with the PAM network. Through the "PAM-MBAM rigid covalent crosslinked backbone + DA-OHA reversible multiple hydrogen bond synergistic reinforcement network", the synergistic optimization of various properties is achieved.

[0084] Example 5

[0085] This embodiment provides a highly adhesive acrylamide / hyaluronic acid composite hydrogel to investigate the effect of excessive DA-OHA addition on hydrogel properties. The preparation method includes the following steps:

[0086] (1) Preparation of DA-OHA aqueous solution: Same as in Example 2, prepare an aqueous solution of dopamine-modified aldehyde-based hyaluronic acid (DA-OHA) with a mass-volume ratio of 6%, stir at room temperature for 4 hours until completely dissolved, and set aside; wherein, the dopamine grafting rate of DA-OHA is controlled at 10%-30%;

[0087] (2) Take 3 mL of the dopamine-modified aldehyde-based hyaluronic acid (DA-OHA) aqueous solution prepared in step (1), and then add 360 mg of acrylamide (AM), 3 mg of crosslinking agent (MBAM), and 6 mg of photoinitiator Irgacure-2959 in sequence. Stir at room temperature for 2 h until the system is uniform and transparent to obtain the precursor solution; wherein, the dopamine-modified aldehyde-based hyaluronic acid (DA-OHA) accounts for 35% of the total mass of AM and DA-OHA, and no additional deionized water is required;

[0088] (3) Transfer the precursor liquid obtained in step (2) to a preset mold and cure it by irradiation with an ultraviolet crosslinker. The ultraviolet wavelength is 365nm, the light intensity is 3W / cm², the light time is 5min, and the thickness of the hydrogel is controlled to be 2.5mm. After curing, a composite hydrogel is obtained.

[0089] The 3 mL of dopamine-modified aldehyde-based hyaluronic acid (DA-OHA) aqueous solution contained 180 mg of DA-OHA.

[0090] The composite hydrogel prepared in this embodiment was subjected to performance tests, and the results are as follows: the adhesion strength to pigskin was 20 kPa, which was significantly lower than that in Example 4; the equilibrium swelling rate was 130%, which was also lower than that in Example 4; the degradation rate in PBS buffer after 14 days was 70%; and the compressive strength was 140 kPa, which was significantly lower than that in Example 4. The reason for this is that the excessive addition of DA-OHA (35%) resulted in an excessively high density of catechol groups, leading to covalent coupling between them and a reduction in the amount of effective groups used for adhesion. Simultaneously, the excessive enrichment of crosslinking sites within the system restricted the mobility of molecular chain segments, increasing network brittleness and causing a decline in all properties.

[0091] Regarding the swelling rate of Examples 1-5 of the present invention, as follows: Figure 3 As shown, the DA-OHA molecule contains a large number of strongly hydrophilic groups, and the total number of hydrophilic groups in the system increases significantly with increasing addition amount. This may be the reason for the significant increase in the swelling rate of the hydrogel. The swelling rate of Examples 4 to 5 decreased, which may be due to the significant increase in catechol groups leading to covalent coupling between them, making the cross-linked network more compact. The swelling rate of Example 4 reached the highest in the group, about 150%, and did not exhibit the structural instability problem that occurs in polysaccharide hydrogels under high swelling conditions, which also enabled it to better absorb wound exudate.

[0092] Regarding the degradation rates of Examples 1-5 of the present invention, as follows: Figure 4 As shown, the pure PAM hydrogel in Example 1 forms a rigid network with all-carbon covalent bonds through free radical copolymerization of MBAM and acrylamide. The high carbon-carbon single bond energy makes it extremely difficult to hydrolyze and break in physiological environments, resulting in almost no significant degradation during the 14-day test period, exhibiting only water absorption and swelling behavior. However, with the introduction and gradual increase in the proportion of DA-OHA, the hydrogel network gains some degradable backbone, ultimately showing a gradient increase in the degradation rate and a gradient decrease in mass retention rate with increasing DA-OHA addition.

[0093] Regarding the adhesive strength of embodiments 1-5 of the present invention, as follows: Figure 5As shown in the results of this porcine skin overlap shear experiment, the wet tissue adhesion strength of the hydrogel exhibits a non-linear variation pattern of first significantly increasing and then decreasing with the addition of DA-OHA. The 25% DA-OHA modified composite hydrogel (Example 4) reached the peak adhesion strength (approximately 27 kPa), nearly four times higher than the pure PAM blank hydrogel (Example 1). With increasing DA-OHA addition, the number of catechol groups on the hydrogel surface gradually increases, leading to strong hydrogen bonding with porcine skin tissue proteins. However, an excessive addition of 35% DA-OHA results in an excessively high density of catechol groups, causing covalent coupling between them and reducing the number of groups acting on adhesion, ultimately leading to a significant decrease in adhesion strength compared to the peak value.

[0094] Regarding the compression performance of embodiments 1-5 of the present invention, such as Figure 6 As shown, the composite hydrogel modified with 25% DA-OHA (Example 4) exhibited the best mechanical properties, with a compressive strength of approximately 230 kPa and a Young's modulus of approximately 33 kPa, significantly improved compared to the pure PAM blank hydrogel (Example 1, with a compressive strength of approximately 32 kPa and a Young's modulus of approximately 8 kPa). This significant improvement in performance stems from the introduction of DA-OHA, which constructs a "synergistic enhancement network of PAM-MBAM rigid covalent cross-linked framework + reversible multiple hydrogen bonds brought by DA-OHA." This efficiently dissipates energy through the fracture-reconstruction process of numerous reversible cross-linking sites under external force, thereby enhancing the hydrogel's resistance to compressive damage and deformation. When the DA-OHA content increased to 35%, the excessive enrichment of cross-linking sites in the system led to an excessively high cross-linking density, restricting the mobility of molecular chain segments and significantly increasing network brittleness, ultimately causing a significant drop in both compressive strength and Young's modulus compared to their peak values.

[0095] Example 6

[0096] This embodiment provides a highly adhesive acrylamide / hyaluronic acid composite hydrogel with a DA-OHA content of 25% and a dopamine grafting rate of 30%, used to investigate the effect of dopamine grafting rate on hydrogel properties. The preparation method includes the following steps:

[0097] (1) Preparation of DA-OHA aqueous solution: Same as in Example 2, prepare an aqueous solution of dopamine-modified aldehyde-based hyaluronic acid (DA-OHA) with a mass-volume ratio of 6%, stir for 4 hours until completely dissolved, and set aside; wherein, the dopamine grafting rate of DA-OHA is controlled at 30%;

[0098] (2) Take 2 mL of the dopamine-modified aldehyde-based hyaluronic acid (DA-OHA) prepared in step (1) and dissolve it in water. Then add 360 mg of acrylamide (AM), 3 mg of crosslinking agent (MBAM), 6 mg of photoinitiator Irgacure-2959, and 1 mL of deionized water in sequence. Stir at room temperature for 2 h until the system is uniform and transparent to obtain the precursor solution. Among them, DA-OHA accounts for 25% of the total mass of DA-OHA and AM.

[0099] (3) Transfer the precursor liquid obtained in step (2) to a preset mold and cure it by irradiation with an ultraviolet crosslinker. The ultraviolet wavelength is 365nm, the light intensity is 0.5W / cm², the light time is 3min, and the thickness of the hydrogel is controlled to be 0.5mm. After curing, a composite hydrogel is obtained.

[0100] The content of DA-OHA in 1 mL of dopamine-modified aldehyde-based hyaluronic acid (DA-OHA) aqueous solution is 120 mg.

[0101] like Figure 7 , 8 As shown in Figures 9 and 1, this test investigated the swelling performance of Example 6, which had a DA grafting rate of 30%, using Example 4 (10% DA grafting rate) as a control. The results showed that the equilibrium swelling rate of this example reached approximately 162%, significantly higher than Example 4. Other performance tests were conducted on the composite hydrogel prepared in this example, and the results are as follows: the porcine skin adhesion strength was 20 kPa, significantly lower than Example 4; the degradation rate in PBS buffer was 50% after 1 day, much faster than Example 4; and the compressive strength was 200 kPa, slightly lower than Example 4. The reason for this is that the high grafting rate of 30% increased the number of hydrophilic catechol sites in the system, improving the swelling performance. However, the excessively high density of catechol groups led to a large number of self-oxidative coupling and cross-linking reactions, consuming effective adhesion sites. This reduced the number of free effective catechol sites exposed at the gel-tissue interface for wet adhesion, directly weakening the interfacial adhesion ability and ultimately leading to poor adhesion performance and a faster degradation rate.

[0102] Regarding the compression performance test results of Examples 4 and 6, as follows: Figure 10 As shown, the compressive strength of Example 6 is approximately 200 kPa and the Young's modulus is approximately 30 kPa, both slightly lower than those of Example 4. This performance difference stems from the different reinforcing effects of DA-OHA on the hydrogel network; the DA-OHA grafting density used in Example 6 is too high, making it prone to intramolecular self-crosslinking during gelation, preventing uniform interpenetrating structures with the PAM main link, and resulting in excessive enrichment of crosslinking sites within the system, leading to increased crosslinking density and restricted molecular chain mobility, ultimately manifesting as a slight decrease in compressive strength and Young's modulus.

[0103] By comparing the above Examples 1-6, it can be seen that the present invention can flexibly control the various properties of hydrogels by adjusting the amount of DA-OHA added, the dopamine grafting rate and the grafting method. Among them, the hydrogel of Example 4, with an DA-OHA addition of 25%, a dopamine grafting rate of 10% and stable grafting through amide bonds, has the best overall performance and can meet the actual application requirements of biomedical dressings.

[0104] In summary, this invention uses polyacrylamide (PAM) as a matrix and constructs a composite hydrogel system by introducing dopamine-grafted oxidized hyaluronic acid (DA-OHA) with different addition amounts and grafting methods. The hydrogel in Example 4, prepared with 25% DA-OHA, a 10% dopamine grafting rate, and stable grafting via amide bonds, represents the optimal formulation obtained through this research and screening. This hydrogel achieves a peak equilibrium swelling rate of approximately 150%, significantly improved compared to the pure PAM blank hydrogel. It possesses excellent water absorption and retention capabilities for efficient absorption of wound exudate while avoiding the structural instability inherent in polysaccharide hydrogels under high swelling conditions. Its degradation behavior is gradual, with a stable mass retention rate of approximately 80% over a 14-day testing period. The hydrogel exhibits excellent wet tissue adhesion properties, achieving an adhesion strength of approximately 27 kPa in porcine skin overlap shear tests, nearly four times higher than pure PAM hydrogel. It achieves stable adhesion to the tissue surface through catechol groups, effectively preventing dressing displacement and detachment. Simultaneously, the hydrogel possesses good mechanical properties, with a compressive strength of approximately 230 kPa and a Young's modulus of approximately 33 kPa, significantly improved compared to pure PAM hydrogel. Through a synergistic toughening system constructed by high-density reversible hydrogen bonds between the DA-OHA and PAM networks, it combines excellent compressive strength and deformation resistance, withstanding the mechanical disturbances of daily wound activities while maintaining structural integrity. In short, this composite hydrogel combines excellent water absorption and retention, structural stability, slow degradation, strong tissue adhesion, and superior mechanical properties, making it an ideal material for tissue engineering and wound dressings. Furthermore, its preparation process is simple and easy to operate, enabling mass production and demonstrating broad clinical translational prospects and application value.

[0105] The core of the PAM composite hydrogel of this invention lies in constructing a synergistic dual-network structure of "irreversible covalent main network + reversible hydrogen bond secondary network". The two are not simply physically blended, but form an interpenetrating, complementary, and synergistic composite system at the molecular scale, which together achieves the comprehensive technical effects of high swelling, strong tissue adhesion, stable degradation, and enhanced mechanical properties of the hydrogel, as detailed below:

[0106] First, the construction and implementation of the covalent cross-linking main network: Under ultraviolet light irradiation, the photoinitiator in the system is excited and decomposed to generate primary free radicals. These primary free radicals preferentially initiate the breaking and opening of the carbon-carbon double bonds of the acrylamide (AM) monomer, forming an AM active growth chain. During the chain growth process, the two carbon-carbon double bonds of the bifunctional cross-linking agent N,N'-methylenebisacrylamide (MBAM) are simultaneously initiated and opened, and respectively undergo copolymerization reactions with two independent AM active growth chains, thereby forming stable chemical cross-linking points at the molecular level. A large number of chemical cross-linking points are interconnected, and finally a three-dimensional irreversible covalent network of PAM-MBAM is constructed. This covalent network uses carbon-carbon covalent bonds as its core framework. Due to the extremely high bond energy of carbon-carbon covalent bonds, they are completely stable in the physiological water environment of the human body and will not undergo hydrolysis or breakage. This provides an indestructible basic structural support for the hydrogel, ensuring that the hydrogel maintains its overall structural integrity during subsequent water absorption, swelling, tissue adhesion, and degradation. Within the set 14-day degradation period, there is no obvious hydrolysis or breakage of the covalent backbone, laying a core foundation for the long-term structural stability of the hydrogel.

[0107] Secondly, the construction and function of the physical cross-linking secondary network: Simultaneously with the formation of the covalent main network, multiple reversible hydrogen bonds spontaneously form between the NH bonds in the amide groups (-CONH2) of the PAM main chain and the hydroxyl groups (-OH) on the DA catechol molecule, the hydroxyl groups on the OHA main chain, and the OH bonds in the carboxyl groups, through intermolecular forces. This constructs a physically cross-linking secondary network. These multiple hydrogen bonds are the primary binding mechanism between the PAM covalent network and the DA-OHA functional components, firmly binding the interpenetrating covalent main network and the DA-OHA functional components into a unified whole. This effectively prevents phase separation between the polysaccharide DA-OHA components and the PAM matrix, ensuring uniform distribution of the hydrogel components and guaranteeing the stability of the hydrogel's properties. Meanwhile, this type of hydrogen bond is reversible. Under external force, its low bond energy causes it to break preferentially over the carbon-carbon covalent bonds in the covalent backbone network. During the breaking process, a large amount of external force energy is dissipated, thereby avoiding stress concentration that could lead to the breakage of the covalent backbone and preventing plastic deformation or permanent damage to the hydrogel. When the external force is removed, the broken hydrogen bonds can quickly reform, allowing the hydrogel's network structure to recover rapidly. This, in turn, endows the hydrogel with excellent toughness and fatigue resistance, meeting the mechanical requirements of practical applications.

[0108] Finally, the synergistic effect and technical benefits of covalent and physical crosslinking: The synergistic effect of the covalently crosslinked main network and the physically crosslinked secondary network is the key to achieving high swelling, strong tissue adhesion, stable degradation, and enhanced mechanical properties in the hydrogel of this invention. Regarding high swelling performance, the covalently crosslinked main network provides a stable and uniform three-dimensional porous framework, ensuring that the hydrogel does not dissolve or collapse after absorbing water, and can accommodate a large number of water molecules entering the network interior. The hydrogen-bonded secondary network is moderately relaxed in the initial stage of water absorption, not hindering water molecule penetration. Simultaneously, the dynamic dissociation and recombination of hydrogen bonds adjusts the network pore size and hydrophilicity, enabling rapid and uniform diffusion of water molecules. The two work synergistically to achieve the dual effects of high swelling ratio and structural integrity after swelling. Regarding strong tissue adhesion, the covalent backbone provides sufficient bulk strength, preventing overall slippage or cohesive breakdown of the hydrogel when adhering to tissues. The numerous hydroxyl, carboxyl, and catechol groups on DA-OHA bind to the amino, hydroxyl, and carboxyl groups on the tissue surface through multiple interfacial interactions such as hydrogen bonding and π-π stacking. The hydrogen-bonded network ensures tight adhesion and micromorphological adaptation between the hydrogel and the tissue surface, synergistically achieving strong wet-surface tissue adhesion. In terms of stable degradation, the carbon-carbon covalent bonds of the covalent backbone are resistant to hydrolysis and extremely stable under physiological conditions, determining the hydrogel's degradation limit and skeletal stability, with no significant main chain breakage occurring within a 14-day degradation cycle. The hydrogen-bonded secondary network can gradually and gently dissociate with environmental factors such as pH and ionic strength, allowing the hydrogel to relax and degrade slowly layer by layer from the surface to the interior, avoiding sudden disintegration. Together, these factors achieve stable degradation and a controllable degradation cycle. In terms of mechanical reinforcement, the covalent main network plays the main role in load bearing, providing modulus and structural strength; the hydrogen bond network preferentially breaks and dissipates energy under external force, and quickly rebuilds after the external force is removed, providing toughness, energy dissipation performance and self-recovery ability. The two work together to endow the hydrogel with high elongation at break, high toughness and excellent fatigue resistance.

[0109] In summary, this invention, through the synergistic construction of a covalently cross-linked main network and a multiple hydrogen-bonded secondary network, enables the hydrogel to simultaneously possess the comprehensive technical effects of high swelling, strong tissue adhesion, stable degradation, and enhanced mechanical properties, and can be widely applied in biomedical and other related fields.

[0110] Of course, the above description is not intended to limit the present invention, and the present invention is not limited to the examples given above. Any changes, modifications, additions or substitutions made by those skilled in the art within the scope of the present invention should be protected by the present invention.

Claims

1. A highly adhesive acrylamide / hyaluronic acid composite hydrogel, characterized in that, The product comprises the following raw material components: an aqueous solution of dopamine-modified aldehyde-based hyaluronic acid (DA-OHA), acrylamide (AM), and a crosslinking agent N,N-methylenebisacrylamide (MBAM); wherein, the dopamine-modified aldehyde-based hyaluronic acid (DA-OHA) accounts for 0%-35% of the total mass of DA-OHA and acrylamide; the amount of crosslinking agent N,N'-methylenebisacrylamide added is 0.1%-0.5% of the mass of acrylamide; and the dopamine grafting rate of the dopamine-modified aldehyde-based hyaluronic acid is 10%-30%.

2. The highly adhesive acrylamide / hyaluronic acid composite hydrogel according to claim 1, characterized in that: The mass-volume ratio of the dopamine-modified aldehyde-based hyaluronic acid aqueous solution is 6%, wherein the molecular weight of the dopamine-modified aldehyde-based hyaluronic acid ranges from 100,000 to 200,000 Daltons.

3. The highly adhesive acrylamide / hyaluronic acid composite hydrogel according to claim 1, characterized in that: The composite hydrogel also includes the photoinitiator Irgacure-2959; the amount of photoinitiator Irgacure-2959 added is 0.5%-2% of the total mass of the system, and the molding thickness of the hydrogel is controlled to be 0.5-2.5 mm.

4. The highly adhesive acrylamide / hyaluronic acid composite hydrogel according to claim 1, characterized in that: The composite hydrogel has a covalent-physical dual crosslinked network structure; wherein the covalent crosslinking is formed by photopolymerization of acrylamide and crosslinking agent, and the physical crosslinking is formed by multiple hydrogen bonding.

5. The highly adhesive acrylamide / hyaluronic acid composite hydrogel according to claim 1, characterized in that: The dopamine-modified aldehyde-based hyaluronic acid (DA-OHA) accounts for 25% of the total mass of DA-OHA and acrylamide.

6. The method for preparing the highly adhesive acrylamide / hyaluronic acid composite hydrogel according to claims 1-5, characterized in that, Includes the following steps: (1) Prepare an aqueous solution of dopamine-modified aldehyde-based hyaluronic acid (DA-OHA) with a mass-volume ratio of 6%; (2) Add acrylamide (AM) and crosslinking agent MBAM to the aqueous solution obtained in step (1) above, and stir until completely dissolved to obtain a uniformly mixed precursor solution; (3) Transfer the precursor liquid obtained in step (2) to a preset mold and perform cross-linking and curing to obtain a composite hydrogel.

7. The method for preparing the highly adhesive acrylamide / hyaluronic acid composite hydrogel according to claim 6, characterized in that: Step (2) also includes the photoinitiator Irgacure-2959.

8. The method for preparing the highly adhesive acrylamide / hyaluronic acid composite hydrogel according to claim 7, characterized in that: In step (3), a UV crosslinker is used for irradiation with a light intensity of 0.5-3 W / cm² and an irradiation time of 3-10 min to perform photocrosslinking curing.

9. The method for preparing the highly adhesive acrylamide / hyaluronic acid composite hydrogel according to claim 6, characterized in that: In step (2), dopamine-modified aldehyde hyaluronic acid (DA-OHA) accounts for 25% of the total mass of dopamine-modified aldehyde hyaluronic acid (DA-OHA) and acrylamide.

10. The method for preparing the highly adhesive acrylamide / hyaluronic acid composite hydrogel according to claim 6, characterized in that: In step (2), the dopamine grafting rate of the dopamine-modified aldehyde-modified hyaluronic acid is controlled at 10%-30%.

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