Hydrogels with both wet adhesion and antioxidant functions, their preparation methods and applications

Abstract

This invention belongs to the field of hydrogel technology and discloses a hydrogel with both wet adhesion and antioxidant functions, its preparation method, and its applications. This hydrogel aims to solve the problems of weak adhesion and inability to continuously regulate the oxidative stress microenvironment in moist environments found in existing dressings. It comprises a dual-network structure and an antioxidant: the first network is formed by dynamic borate ester bond crosslinking of a polymer containing catechol groups and a crosslinking agent containing boric acid groups, endowing the material with wet adhesion and self-healing capabilities; the second network is a photocrosslinked static network, providing structural support. The synergistic effect of the dual networks enables the hydrogel to have strong and durable adhesion to moist tissue surfaces. The contained phenolic hydroxyl antioxidant achieves loading and sustained release through interaction with borate ester bonds, thereby continuously scavenging free radicals and promoting wound healing. This hydrogel has excellent biocompatibility and is suitable for wound care in moist environments such as exudative wounds and periodontal pockets.

Description

Technical Field

[0001] This invention belongs to the field of hydrogel technology, specifically relating to a hydrogel, its preparation method, and its application. Background Technology

[0002] Existing dressings for moist wounds (such as exudative wounds and periodontal pockets) face two main challenges: weak or short-lasting adhesion in moist environments, and a lack of ability to actively and continuously regulate the wound's oxidative stress microenvironment. For example, while ordinary PVA hydrogels or chitosan gels have some biocompatibility, they lack a strong and long-lasting adhesion mechanism for moist tissues. Dressings that simply load drugs often release the drug too quickly and fail to adhere tightly to the wound, resulting in short-lived local effective concentrations and limited efficacy. Therefore, achieving on-demand drug release in moist wound environments is a major challenge. Summary of the Invention

[0003] In view of this, the present invention provides a hydrogel with a dual-network structure to achieve strong wet adhesion and controlled sustained release of antioxidants.

[0004] The technical solution is as follows: A hydrogel with both wet adhesion and antioxidant functions comprises a composite network formed by the interpenetration of a first polymer network and a second polymer network, and an antioxidant dispersed in the composite network. The first polymer network is formed by dynamic borate ester bonds formed between a first long-chain polymer containing catechol groups and a quaternary ammonium crosslinking agent containing boric acid groups. The second polymer network is a static covalent network formed by photo-initiated crosslinking of a second long-chain polymer containing carbon-carbon double bonds. The antioxidant contains phenolic hydroxyl groups, which can form reversible borate ester bonds with the boric acid groups in the first polymer network, thereby achieving the loading and controlled release regulation of the antioxidant in the composite network.

[0005] In some possible embodiments, the raw materials forming the first polymer network include a first long-chain polymer and a quaternary ammonium crosslinking agent. Further, in some embodiments, the raw materials for the first polymer network include a first long-chain polymer containing catechol groups and a quaternary ammonium crosslinking agent containing boric acid groups. The catechol groups in the first long-chain polymer react with the boric acid groups of the quaternary ammonium crosslinking agent to generate the first polymer network. The first long-chain polymer contains catechol groups, which not only endow the hydrogel with the ability to adhere to moist tissue surfaces, but also its abundant hydroxyl groups provide sites for subsequent reactions with the boric acid groups of the quaternary ammonium crosslinking agent. The boric acid groups contained in the quaternary ammonium crosslinking agent can form reversible borate ester bonds with the catechol / diol groups of the first long-chain polymer.

[0006] In some possible embodiments, the first long-chain polymer is cationic guar gum, and the quaternary ammonium crosslinking agent containing boric acid groups is N1-(4-bromobenzyl)-N3-(4-bromophenyl)-N1,N1,N3,N3-tetramethylpropane-1,3-diamine.

[0007] In some possible embodiments, the raw materials for forming the second polymer network include a second long-chain polymer containing carbon-carbon double bonds, and the carbon-carbon double bonds between the second long-chain polymers are cross-linked by a photo-initiated reaction to generate the second polymer network.

[0008] In some possible embodiments, the second long-chain polymer comprises polyvinyl alcohol with styrylpyridinium salt groups modified on its side chains. Under ultraviolet light irradiation, its SBQ groups undergo an addition reaction to form a permanent, stable second polymer network, providing structural integrity to the composite network.

[0009] In some possible embodiments, the antioxidant contains phenolic hydroxyl groups.

[0010] In some possible embodiments, the antioxidant is dihydromyricetin. Dihydromyricetin, as a natural extract, also offers sustainability advantages, giving the gel a significant cost advantage and the potential for large-scale production.

[0011] This invention also provides a method for preparing a hydrogel, comprising:

[0012] A first solution containing the first long-chain polymer (e.g., cationic guar gum) is mixed with a second solution containing the crosslinking agent (e.g., TSPBA) to carry out a first crosslinking reaction, forming a pre-gelled first polymer network, to obtain a first mixture.

[0013] The first mixture is mixed with a third solution containing a second long-chain polymer (e.g., PVA-SBQ) to obtain a second mixture;

[0014] The antioxidant is dispersed in the second mixture to obtain a third mixture;

[0015] The third mixture is placed under light irradiation to cause the second long-chain polymer to undergo a photocrosslinking reaction, forming the second polymer network, thereby obtaining the final dual-network hydrogel (denoted as PSCTD). The first, second, and third solutions can all be aqueous solutions.

[0016] In some possible embodiments, the above preparation method satisfies at least one of the following conditions:

[0017] A. The mass concentration of the first long-chain polymer in the first solution is 2.5% w / v to 3.5% w / v; for example, it can be 2.5% w / v, 2.6% w / v, 2.8% w / v, 3% w / v, 3.2% w / v, 3.4% w / v, or 3.5% w / v, etc.

[0018] B. The mass concentration of the quaternary ammonium crosslinking agent in the second solution is 2.5% w / v to 3.5% w / v; for example, it can be 2.5% w / v, 2.6% w / v, 2.8% w / v, 3% w / v, 3.2% w / v, 3.4% w / v, or 3.5% w / v, etc.

[0019] C. The first solution and the second solution are mixed at a volume ratio of 1:1-1.2; for example, the ratio can be 1:1, 1:1.05, 1:1.1, 1:1.15, or 1:1.2, etc.

[0020] D. The pH of the first mixture is 6.5-7.4; for example, it can be 6.5, 6.7, 6.9, 7, 7.2, 7.3 or 7.4, etc.

[0021] E. The volume fraction of the second long-chain polymer in the third solution is 13-17%; for example, it can be 13%, 14%, 15%, 16%, or 17%.

[0022] F. The third solution and the second mixture are mixed at a volume ratio of 1:1-1.2; for example, the ratio can be 1:1, 1:1.05, 1:1.1, 1:1.15, or 1:1.2.

[0023] G. The mass concentration of the antioxidant in the third mixture is 1-2 mg / ml; for example, it can be 1 mg / ml, 1.1 mg / ml, 1.3 mg / ml, 1.5 mg / ml, 1.7 mg / ml, 1.9 mg / ml or 2 mg / ml, etc.

[0024] The first crosslinking reaction for generating the first polymer network is carried out at room temperature; the second crosslinking reaction for generating the second polymer network is carried out by irradiation with ultraviolet light (365 nm, 10 mW / cm²) for 5-30 seconds.

[0025] This invention also provides the application of the above-described hydrogel or the hydrogel prepared by the above method in dressings to promote wound healing and / or reduce the risk of wound infection. Therefore, the above-described hydrogel can be used to prepare multi-functional wound gels that combine wet adhesion and antioxidant functions.

[0026] Compared with the prior art, the beneficial effects of the present invention are:

[0027] The first polymer network contains catechol groups, which can form various non-covalent bonds with proteins on the surface of moist tissues, achieving instant adhesion. At the same time, the first polymer network contains reversible borate ester bonds, making it a reversible dynamic network. The first polymer network endows the gel with self-healing and stress dissipation capabilities. The second long-chain polymer generates a second polymer network through an addition reaction. The second polymer network is a relatively stable static network. When the second polymer network and the first polymer network interweave to form a composite network, they work synergistically, enabling the gel to produce strong and durable adhesion to the surface of moist tissues.

[0028] Antioxidants containing phenolic hydroxyl groups are dispersed and interspersed in the composite network. The phenolic hydroxyl groups of the antioxidants react with the boric acid groups of some crosslinking agents to form borate ester bonds. In conjunction with the above-mentioned composite network, the release behavior of antioxidants is regulated, so that the hydrogel can be continuously released to scavenge free radicals when used as a dressing, thereby achieving long-term sustained release of the drug. Attached Figure Description

[0029] Figure 1 Figure 1: Results of the hydrogel bottle inversion experiment in the example.

[0030] Figure 2 The rheological properties of the hydrogel in the examples.

[0031] Figure 3 : Adhesion strength of the hydrogel in the embodiment.

[0032] Figure 4 Antioxidant activity of the gel.

[0033] Figure 5 Biocompatibility of the gel.

[0034] Figure 6 : The cell-protective effect of gels. Detailed Implementation

[0035] The embodiments of the present invention will now be described with reference to the accompanying drawings. The terminology used in the embodiments section is for illustrative purposes only and is not intended to limit the scope of the invention.

[0036] The processing order described in the following embodiments is merely an example and is not limited to the processing order set forth herein. Rather, the processing order may be changed based on the implementation methods disclosed in this application, except for processes that must occur in a specific order. All other embodiments obtained through these changes are within the scope of protection of this application.

[0037] In this embodiment, cationic guar gum (CGG) is used as the first long-chain polymer, N1-(4-bromobenzyl)-N3-(4-bromophenyl)-N1,N1,N3,N3-tetramethylpropane-1,3-diamine (TSPBA) is used as the crosslinking agent, polyvinyl alcohol with styrylpyridinium salt side chain modification is used as the second long-chain polymer, and dihydromyricetin is used as the antioxidant. The hydrogel is prepared based on the following method:

[0038] S100. A first solution containing a first long-chain polymer is mixed with a second solution containing a crosslinking agent at a volume ratio of 1:1, and a crosslinking reaction is carried out at room temperature to form a pregel (first polymer network) crosslinked by dynamic borate ester bonds, resulting in a first mixture with a pH of approximately 7.0.

[0039] S200. The third solution containing the second long-chain polymer is mixed with the first mixture at a volume ratio of 1:1 to obtain the second mixture; the third solution is an aqueous solution, wherein the mass fraction of the second long-chain polymer in the third solution is 15%.

[0040] S300. The antioxidant is fully dispersed in the second mixture by vortexing and short-term ultrasound to obtain the third mixture, in which the mass concentration of the antioxidant is 1.5 mg / ml.

[0041] S400. The third mixture is injected into the mold and irradiated for 10 seconds under an ultraviolet light source with a wavelength of 365 nm and an intensity of 10 mW / cm². PVA-SBQ undergoes photocrosslinking to form a second polymer network, thus obtaining the final double-network hydrogel (denoted as PSCTD).

[0042] Three experiments were conducted according to the above embodiments, and the parameters of each experiment are shown in the table below:

[0043] Table 1: Effect of different raw material ratios on hydrogel formation and properties (Examples)

[0044]

[0045] Compared with the prior art, the present invention has the following beneficial effects:

[0046] 1. Experiments show that the hydrogel preparation method provided in this application is simple and mild, involving only solution mixing at room temperature and final UV curing (e.g., Figure 1 As shown in the figure, no complex and expensive equipment is required. All raw materials used can be commercially available and cost-effective chemicals. It has advantages such as simple preparation process and ease of promotion.

[0047] 2. Excellent adhesion in wet environments: The catechol groups in the dual-network gel can form various non-covalent interactions (such as hydrogen bonds, π-π stacking, and cation-π interactions) with proteins on the surface of moist tissues, achieving immediate and strong wet adhesion. Dynamic borate ester bonds endow the network with self-repair and stress dissipation capabilities, synergizing with the second static network to make the adhesion durable and strong, able to withstand the shear forces from tissue activities (such as joint flexion and extension, chewing) and possessing self-healing properties (such as...). Figure 2 As shown, the left figure shows the curves of the storage modulus (G') and loss modulus (G'') of the gel as strain increases. When the strain is <900%, G' is always higher than G'', indicating that the material has a stable solid-like gel structure. As the strain increases, above 900%, the modulus decreases rapidly, showing typical "strain softening" behavior; the right figure shows that the gel structure can recover after being damaged when the strain alternates between 1% and 1000%, proving that the gel has good self-healing properties. Figure 3 As shown, the left figure is a schematic diagram of the hydrogel's instantaneous underwater adhesion to suspend a 500g weight in the embodiment. The right figure is a bar chart showing the overlap shear adhesion strength of the un-drug-loaded hydrogel and the drug-loaded hydrogel on moist pigskin in the embodiment. The PSCDT gel exhibits significantly higher adhesion strength, indicating that the introduction of its components effectively enhances the material's adhesion to biological tissues. The tests in the above embodiments show that the hydrogel generated using the scheme of this application can firmly adhere to moist pigskin, tooth enamel, and even mucosal surfaces. This hydrogel can achieve strong adhesion between pigskin and glass underwater, suspending a 500g weight, and the overlap shear strength of moist pigskin reaches 60-80 kPa, demonstrating excellent adhesion performance in wet environments.

[0048] 3. Intelligent drug sustained release and long-lasting antioxidant function: The loaded phenolic hydroxyl-containing antioxidant (such as dihydromyricetin) can not only directly scavenge free radicals, but its phenolic hydroxyl groups can also form reversible borate ester bonds with borate groups in the network. This dynamic bonding effect enables the antioxidant to be "anchored" and "responsively released" in the complex network (such as the weakening of bonding in slightly acidic or high ROS environments caused by oxidative stress), thereby avoiding drug burst release and achieving long-lasting and controllable antioxidant therapeutic effects (such as...). Figure 4 As shown in the left figure: DPPH free radical scavenging rate of gel extracts at different concentrations. The scavenging rate increases with increasing extract concentration, demonstrating that the active ingredients in the gel have a significant dose-dependent antioxidant capacity. The right figure shows the quantitative analysis of the left figure.

[0049] 4. Good biocompatibility and safety: The raw materials used (such as cationic guar gum, polyvinyl alcohol derivatives, and dihydromyricetin) all exhibit good biocompatibility. Cell experiments have confirmed that the hydrogel and its extract are non-cytotoxic and effectively protect cells from oxidative damage. Figure 5As shown, cell viability (CCK-8 assay) of L929 fibroblasts and RAW264.7 macrophages co-cultured with different gels (PSCT, PSCTD). Compared with the control group, cell viability in both gel treatments did not decrease significantly, indicating good biocompatibility of the materials (ns indicates no statistical difference). Figure 6 As shown, the gel protects against H2O2-induced oxidative damage in RAW264.7 cells. The cell viability of the H2O2-treated group decreased significantly, while pre- or simultaneous treatment with PSCT or PSCTD gels significantly maintained cell viability, indicating that the gel extract has a protective effect against cell damage caused by oxidative stress.

[0050] Comparative Experiment 1:

[0051] The following comparative examples adjusted the mass fraction of the first long-chain polymer in the first solution and the mass fraction of the crosslinking agent in the second solution, while the remaining experimental conditions were exactly the same as in Experiment 1 of the above examples. The specific details of the mass fraction of the first long-chain polymer and the mass fraction of the crosslinking agent in each comparative example are shown in the table below:

[0052] Table 1: Effect of improper first network ratio on hydrogel properties (Comparative Experiment 1)

[0053] The experiments in the above embodiments and comparative examples show that when the mass concentration of the first long-chain polymer in the first solution is 2.5%-3.5% w / v and the mass concentration of the crosslinking agent in the second solution is 2.5%-3.5% w / v, a stable dynamic pregel network can be formed without affecting the subsequent photocrosslinking and curing of the second long-chain polymer, ultimately achieving the strongest wet adhesion performance. Figure 1 As shown, in the bottle inversion experiment, the gel remained fluid before UV curing and rapidly gelled after UV irradiation. Glass overlap shear tests indicated that the dynamic pregel structure formed in the second mixture of Example 2 was suitable, providing an ideal environment for the uniform dispersion and sufficient photocrosslinking of the second long-chain polymer, and exhibiting the strongest adhesion in the shear test. Other combinations (such as CGG 3% / TSPBA 6% / 12%) affected the photocuring uniformity of the second long-chain polymer due to the excessive viscosity of the pregel; CGG 2% / TSPBA 3% resulted in decreased final gel performance due to insufficient dynamic network strength in the second mixture. The dual networks (CGG-TSPBA dynamic network, PVA-SBQ static network) in the hydrogel generated in Example 2 produce a synergistic effect, enabling the gel to achieve strong and durable adhesion to wet surfaces and achieve long-term sustained drug release.

[0054] Comparative Experiment 2:

[0055] The types of antioxidants used in the following comparative examples have been adjusted, while the other experimental conditions remain exactly the same as in Experiment 1 of the above examples. The specific antioxidants used in each comparative example are shown in the table below:

[0056] Table 3: Effects of different antioxidants on drug sustained release and antioxidant effects (Comparative Experiment 2)

[0057]

[0058] The dynamic interaction between TSPBA, dihydromyricetin, and CGG, combined with the gel's network structure, enables slow and sustained drug release. In vitro antioxidant experiments (such as DPPH free radical scavenging experiments) demonstrate that the hydrogel provided in this application can achieve ROS-responsive release over a long period and maintain highly efficient free radical scavenging capabilities. The long-lasting antioxidant and sustained drug release effects of dihydromyricetin are significantly superior to other antioxidants (dihydroquercetin, macranthin, oleanolic acid).

[0059] Finally, it should be noted that the above description is merely a preferred embodiment of the present invention. Those skilled in the art, under the guidance of the present invention, can make various similar representations without departing from the spirit and claims of the present invention, and such modifications all fall within the protection scope of the present invention.

Claims

1. A hydrogel possessing both wet adhesion and antioxidant functions, characterized in that, The invention includes a composite network and an antioxidant dispersed in the composite network. The composite network comprises an interpenetrating first polymer network and a second polymer network, wherein the first polymer network contains borate ester bonds formed by the reaction of catechol groups and boric acid groups.

2. The hydrogel according to claim 1, characterized in that, The raw materials for forming the first polymer network include a first long-chain polymer containing catechol groups and a crosslinking agent containing boric acid groups. The catechol groups in the first long-chain polymer react with the boric acid groups in the crosslinking agent to generate the first polymer network.

3. The hydrogel according to claim 2, characterized in that, The first long-chain polymer is cationic guar gum, and the crosslinking agent containing boric acid groups is TSPBA.

4. The hydrogel according to claim 1, characterized in that, The second polymer network is formed by photo-initiated crosslinking of a second long-chain polymer, the side chains of which contain carbon-carbon double bonds that can be crosslinked by ultraviolet light.

5. The hydrogel according to claim 4, characterized in that, The second long-chain polymer is polyvinyl alcohol with styrylpyridinium salt groups modified on the side chain.

6. The hydrogel according to claim 1, characterized in that, The antioxidant contains phenolic hydroxyl groups.

7. The hydrogel according to claim 6, characterized in that, The antioxidant is dihydromyricetin.

8. A method for preparing a hydrogel as described in any one of claims 4-7, characterized in that, include: A first solution containing the first long-chain polymer is mixed with a second solution containing the crosslinking agent to obtain a first mixture; The first mixture is mixed with a third solution containing a second long-chain polymer to obtain a second mixture; The antioxidant is dispersed in the second mixture to obtain a third mixture; The second long-chain polymer in the third mixture undergoes a cross-linking reaction under light irradiation to generate the hydrogel.

9. The preparation method according to claim 8, characterized in that, At least one of the following conditions must be met: A. The mass concentration of the first long-chain polymer in the first solution is 2.5% w / v - 3.5% w / v; B. The mass concentration of the crosslinking agent in the second solution is 2.5% w / v - 3.5% w / v; C. The first solution and the second solution are mixed at a volume ratio of 1:1-1.2; D. The pH of the first mixture is 6.5-7.4; E. The volume fraction of the second long-chain polymer in the third solution is 13-17%; F. The third solution and the second mixture are mixed at a volume ratio of 1:1-1.2; G. The mass concentration of the antioxidant in the third mixture is 1-2 mg / ml.

10. The use of a hydrogel as described in any one of claims 1-7 or a hydrogel prepared by the method described in any one of claims 8-9 in a dressing.

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