A double-network skin repair hydrogel and its preparation method

Abstract

The present invention discloses a double-network skin repair hydrogel and its preparation method, which relates to the technical field of skin hydrogels. The technical solution is as follows: 2-aminoterephthalic acid and copper nitrate are dissolved in N,N-dimethylformamide, and after heating, centrifuged and separated, washed and dried to obtain MOFs powder. The MOFs powder is dispersed in deionized water, and silver nanoparticles are added to obtain functionalized MOFs. Azathioprine is dissolved in water and ultrasonically treated with the functionalized MOFs to form a drug carrier. The polymer and the cross-linking agent are heated in water to form the first network. The drug carrier is mixed with the first network and heated to form a fully cross-linked double-network gel. The double-network hydrogel of the present invention realizes the rapid initial release and late sustained release of drugs by precisely controlling the cross-linking density and conditions, significantly improving the treatment effect. Its structure integrates antibacterial and sustained release functions, loads drugs through functionalized MOFs, and at the same time ensures high mechanical strength and flexibility to adapt to the dynamic environment of the skin.

Description

Technical Field

[0001] The present invention relates to the technical field of skin hydrogels, and particularly to a double-network skin repair hydrogel and a preparation method thereof. Background Art

[0002] In recent years, with the development of biomedical materials and regenerative medicine, hydrogels, as materials with excellent biocompatibility, adjustable mechanical properties, and high water absorbency, have been widely used in fields such as skin repair, drug delivery, and tissue engineering. The application of hydrogels in skin repair is particularly important, as they can provide a protective barrier for damaged skin, maintain a moist environment, and promote tissue regeneration. However, traditional single-network hydrogels have certain limitations in drug release control, multifunctionality, and mechanical properties, making it difficult to meet the requirements for complex skin injury repair.

[0003] To improve the comprehensive performance of hydrogels, researchers have made many attempts in structural design and material modification. For example, by adjusting the crosslinking density and type of crosslinking agent of the hydrogel, its mechanical properties and drug release characteristics can be improved to a certain extent. In addition, adding nanoparticles or other functional materials to the hydrogel can endow it with various functions such as antibacterial and self-healing. However, these methods often only partially solve the problem, and there is still much room for improvement in comprehensive performance.

[0004] Despite various modification techniques and material design strategies, existing hydrogels still face many challenges in practical applications. First, precise control of drug release is a difficult point. Traditional hydrogels lack precise control means for regulating the drug release rate, resulting in too fast drug release in the initial stage or insufficient release in the later stage, and unable to achieve the ideal therapeutic effect. Most hydrogels cannot provide rapid symptom relief in the initial stage while also providing continuous drug release in the later stage to meet the long-term treatment needs.

[0005] In terms of mechanical properties, existing hydrogels also have deficiencies. Usually, in order to achieve a high drug release rate, the structural design of the hydrogel is often relatively loose, resulting in insufficient mechanical strength and elasticity. In this case, the hydrogel is prone to breakage or deformation during application, making it difficult to provide long-term stable physical protection. In addition, although some modification strategies can improve the mechanical strength of the hydrogel, they will reduce its flexibility and elasticity, affecting the comfort and adaptability of use.

[0006] The realization of multifunctionality is also a major problem in the existing technology. Although adding nanoparticles or functional materials can endow hydrogels with certain antibacterial, self-healing and other functions, how to effectively integrate multiple functions without affecting their basic properties and ensure the synergistic effect of these functions during application is still a technical difficulty. In practical applications, existing multifunctional hydrogels often fail to achieve the expected comprehensive effect due to functional conflicts or incompatibilities.

[0007] In addition, the existing technology also has obvious deficiencies in the repeatability and controllability of the preparation process. Since the hydrogel preparation process involves multiple complex steps, the parameter settings of each step have a significant impact on the performance of the final product. The existing technology lacks detailed and operable preparation methods, resulting in inconsistent product performance in different batches and making it difficult to ensure the reliability and stability in practical applications.

[0008] To solve the above technical problems, the present invention proposes a double-network skin repair hydrogel and its preparation method, aiming to solve problems such as drug release control, multifunction integration, structural stability and flexibility, and the repeatability and controllability of the preparation process. Specifically, the present invention precisely regulates the crosslinking density and crosslinking conditions of the double-network structure to achieve rapid initial release and slow later release of drugs, ensuring the effective utilization and continuous action of drugs during the skin injury repair process. At the same time, the antibacterial, self-healing and drug sustained-release capabilities of the hydrogel are enhanced, and the synergistic effect of each function is ensured by optimizing material selection and crosslinking strategies. In addition, the present invention provides detailed preparation steps and parameter control to ensure the operability and repeatability of each step, thereby ensuring the consistency and stability of product performance. These technical improvements not only improve the comprehensive performance of the double-network skin repair hydrogel but also provide technical guarantees for its wide promotion in practical applications. Summary of the Invention

[0009] To achieve the above invention purpose and address the above technical problems, the present invention provides a preparation method for a double-network skin repair hydrogel, including the following steps:

[0010] S1 Dissolve 2-aminoterephthalic acid and copper nitrate in N,N-dimethylformamide, stir until completely dissolved; then heat and react, cool to room temperature, centrifuge to separate the MOFs solid, and then wash and dry to constant weight to obtain MOFs powder;

[0011] S2 Redisperse the MOFs powder in deionized water to form a MOFs suspension, add silver nanoparticles to the MOFs solution, and stir evenly to obtain a functionalized MOFs solution;

[0012] S3 Drug loading: Dissolve azathioprine in deionized water, add it to the functionalized antibacterial MOFs solution, and perform ultrasonic treatment to obtain functionalized drug carrier MOFs;

[0013] S4 First network: Dissolve poly(N-isopropylacrylamide) and polyethylene glycol in ionic water, add N,N'-methylenebisacrylamide, and heat and stir to form a preliminarily crosslinked gel network;

[0014] S5 Second network: Uniformly disperse 50% of the functionalized drug carrier MOFs in the first network gel, stir evenly, add N,N'-methylenebisacrylamide again as a secondary crosslinking agent, and then add the remaining functionalized drug carrier MOFs, heat and stir to form a fully crosslinked double-network hydrogel, cool to room temperature, and stand at low temperature to form a gel;

[0015] S6 Finally, pour the gel into a mold and let it stand until it is formed and cured.

[0016] Preferably, in the step S1, 2-4 parts of 2-aminoterephthalic acid, 1.5-2.5 parts of copper nitrate, and 90-110 parts of N,N-dimethylformamide are used.

[0017] Preferably, in the step S1, the heating temperature is 150 °C and the reaction time is 10-14 hours.

[0018] Preferably, in the step S2, 2-4 parts of MOFs powder, 90-110 parts of deionized water, and 0.5-1.5 parts of silver nanoparticles are used.

[0019] Preferably, in the step S3, 0.4-0.6 parts of azathioprine and 10-20 parts of deionized water are used.

[0020] Preferably, in the step S4, 8-12 parts of poly(N-isopropylacrylamide), 4-6 parts of polyethylene glycol, 90-110 parts of deionized water, 0.2-0.4 parts of N,N'-methylenebisacrylamide, the heating temperature is 60-70 °C, and the time is 20-30 minutes.

[0021] Preferably, in the step S5, 0.4-0.6 parts of N,N'-methylenebisacrylamide are used.

[0022] Preferably, in the step S5, the heating temperature is 70-80 °C and the stirring time is 30-40 minutes.

[0023] Preferably, in the step S6, the standing temperature is 4 °C and the time is 1-2 hours.

[0024] The present invention also provides a double-network skin repair hydrogel, which is prepared by the above method.

[0025] Beneficial effects brought by the technical solution provided by the present invention:

[0026] By precisely regulating the crosslinking density and crosslinking conditions of the double-network structure, the present invention realizes the initial rapid release and subsequent slow release of drugs, significantly improving the effect of drug release control. Specifically, the first network is composed of poly(N-isopropylacrylamide) (PNIPAM) and polyethylene glycol (PEG), and a loose structure is formed through a lower concentration of crosslinking agent and a shorter crosslinking time. This design enables the drug to be rapidly released in the initial stage, quickly alleviating the pain and inflammation caused by skin damage and providing an efficient initial treatment effect. The second network forms a dense crosslinked structure by adding a higher concentration of crosslinking agent and a longer crosslinking time to control the slow release of the drug. This design ensures that the drug can be continuously released in the later stage, providing a long-term treatment effect and avoiding the problem of poor treatment effect caused by excessive initial release or insufficient later release of traditional hydrogels.

[0027] By introducing functionalized metal-organic framework materials (MOFs) into the double-network hydrogel, the present invention successfully integrates the antibacterial and drug slow-release functions, significantly improving the overall treatment effect. Specifically, the MOFs are functionalized during the preparation process and loaded with antibacterial agents and drugs (such as azathioprine). The integration of this multifunctionality enables the hydrogel to effectively inhibit bacterial infections during application, and through the structural characteristics of the MOFs, the precise release and slow-release effects of the drug are achieved. Compared with traditional single-functional hydrogels, the multifunctional design of the present invention enables it to provide a more comprehensive and long-lasting treatment effect in practical applications.

[0028] Through the design of the double-network structure, the present invention successfully achieves the balance of high mechanical strength and flexibility, enabling the hydrogel to adapt to the dynamic environment of the skin during application. The first network provides the basic mechanical strength and flexibility, and by reasonably selecting the ratio of PNIPAM and PEG, as well as controlling the dosage of the crosslinking agent and the crosslinking time, a structure with certain elasticity and flexibility is formed. The second network further enhances the structural stability of the hydrogel through secondary crosslinking, ensuring that it will not be easily damaged or deformed during application. Compared with the single-structured hydrogels in the prior art, the double-network structure of the present invention significantly improves the mechanical properties, enabling it to have higher strength and stability while maintaining flexibility, meeting various requirements during the skin repair process.

[0029] Through these technical improvements, the present invention not only improves the comprehensive performance of the double-network skin repair hydrogel, but also provides technical support for its wide promotion in practical applications. Brief Description of the Drawings

[0030] Figure 1Skin healing photo of the embodiment of the present invention. Detailed implementation mode

[0031] In order to make the objectives, technical solutions and advantages of the present invention clearer, the present invention will be further described in detail below in conjunction with embodiments. Of course, the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0032] Embodiment 1

[0033] Preparation method of double-network skin repair hydrogel:

[0034] S1. Preparation of MOFs precursor

[0035] Dissolve 3.0 parts of 2-aminoterephthalic acid and 2.0 parts of copper nitrate in 100 parts of N,N-dimethylformamide, and stir until completely dissolved;

[0036] Place the solution in a sealed reaction kettle, heat to 150 °C, and react for 12 hours;

[0037] After the reaction is completed, cool to room temperature, and centrifuge to obtain MOFs solid;

[0038] Wash with DMF and deionized water three times respectively, and then dry to constant weight in a vacuum drying oven to obtain MOFs powder.

[0039] S2. Functionalization treatment of MOFs

[0040] Redisperse 3.0 parts of MOFs powder in 100 parts of deionized water to form a MOFs suspension.

[0041] Add 1.0 part of silver nanoparticles to the MOFs suspension and stir evenly to obtain a functionalized MOFs solution.

[0042] S3. Drug loading

[0043] Dissolve 0.5 part of azathioprine in 15 parts of deionized water.

[0044] Add the drug solution to the functionalized antibacterial MOFs solution and perform ultrasonic treatment for 30 minutes to obtain functionalized drug carrier MOFs.

[0045] S4. Preparation of the first network

[0046] Dissolve 10 parts of poly(N-isopropylacrylamide) PNIPAM and 5 parts of polyethylene glycol PEG in 100 parts of deionized water, and add 0.3 part of N,N'-methylenebisacrylamide MBA;

[0047] Heat to 66 °C and maintain for 25 minutes under stirring conditions to form a preliminarily crosslinked gel network.

[0048] S5. Preparation of the second network

[0049] Disperse 50% of the functionalized drug carrier MOFs evenly in the first network gel and stir well;

[0050] Add 0.5 parts of MBA as the secondary crosslinking agent again, and then add the remaining functionalized drug carrier MOFs;

[0051] Heat to 78 °C and maintain for 35 minutes to form a fully crosslinked double-network hydrogel;

[0052] Cool to room temperature and let it stand to form a gel.

[0053] S6. Molding and curing

[0054] Pour the prepared double-network hydrogel into a mold and place it in an environment of 4 °C for 1.5 hours to ensure that the gel is fully molded and cured.

[0055] Example 2

[0056] Prepared according to the same preparation method as in Example 1, except that in step S1, 2-aminoterephthalic acid (2 parts by mass), copper nitrate (2.5 parts by mass), and DMF (90 parts by mass) are used;

[0057] Example 3

[0058] Prepared according to the same preparation method as in Example 1, except that in step S1, 2-aminoterephthalic acid (4 parts by mass), copper nitrate (1.5 parts by mass), and DMF (110 parts by mass) are used.

[0059] Example 4

[0060] Prepared according to the same preparation method as in Example 1, except that in steps S2 and S3, silver nanoparticles (0.5 parts by mass), azathioprine (0.6 parts by mass), and deionized water (20 parts by mass) are used.

[0061] Example 5

[0062] Prepared according to the same preparation method as in Example 1, except that in steps S2 and S3, silver nanoparticles (1.5 parts by mass), azathioprine (0.4 parts by mass), and deionized water (20 parts by mass) are used.

[0063] Example 6

[0064] Prepared according to the same preparation method as in Example 1, except that in step S4, 0.2 parts by mass of MBA and in step S5, 0.6 parts by mass of MBA are used.

[0065] Example 7

[0066] Prepared according to the same preparation method as in Example 1, except that in step S4, 0.4 parts by mass of MBA and in step S5, 0.4 parts by mass of MBA.

[0067] Example 8

[0068] Prepared according to the same preparation method as in Example 1, except that in step S4, PNIPAM (12 parts by mass) and PEG (4 parts by mass)

[0069] Example 9

[0070] Prepared according to the same preparation method as in Example 1, except that

[0071] The heating temperature of the first network is 60 °C and the time is 20 minutes

[0072] The heating temperature of the second network is 80 °C and the stirring time is 40 minutes

[0073] Example 10

[0074] Prepared according to the same preparation method as in Example 1, except that

[0075] The heating temperature of the first network is 70 °C and the time is 20 minutes

[0076] The heating temperature of the second network is 80 °C and the stirring time is 30 minutes

[0077] Comparative Example 1

[0078] Preparation method of double-network skin repair hydrogel:

[0079] (1) Dissolve 10 parts of poly(N-isopropylacrylamide) PNIPAM and 5 parts of polyethylene glycol PEG in 100 parts of deionized water, add 0.5 part of silver nanoparticles and 0.25 part of azathioprine, and add 0.3 part of N,N'-methylenebisacrylamide MBA;

[0080] Heat to 66 °C and keep it for 25 minutes under stirring conditions to form a preliminarily cross-linked gel network.

[0081] (2) Add 0.5 part of MBA again as a secondary cross-linking agent, then add 0.5 part of silver nanoparticles and 0.25 part of azathioprine;

[0082] Heat to 78 °C and keep it for 35 minutes to form a fully cross-linked double-network hydrogel;

[0083] Cool to room temperature and let it stand to form a gel.

[0084] (3) Pour the prepared double-network hydrogel into a mold and place it in an environment at 4°C for 1.5 hours to ensure that the gel is completely formed and cured.

[0085] Comparative Example 2

[0086] Preparation method of double-network skin repair hydrogel:

[0087] S1. Preparation of MOFs precursors

[0088] Dissolve 3.0 parts of 2-aminoterephthalic acid and 2.0 parts of copper nitrate in 100 parts of N,N-dimethylformamide and stir until completely dissolved;

[0089] Place the solution in a sealed reaction kettle, heat it to 150°C, and react for 12 hours;

[0090] After the reaction is completed, cool it to room temperature and centrifuge to obtain MOFs solid;

[0091] Wash it 3 times with DMF and deionized water respectively, and then dry it to constant weight in a vacuum drying oven to obtain MOFs powder.

[0092] S2. Functionalization of MOFs

[0093] Redisperse 3.0 parts of MOFs powder in 100 parts of deionized water to form a MOFs suspension.

[0094] Add 1.0 part of silver nanoparticles to the MOFs suspension and stir evenly to obtain a functionalized MOFs solution.

[0095] S3. Drug loading

[0096] Dissolve 0.5 part of azathioprine in 15 parts of deionized water.

[0097] Add the drug solution to the functionalized antibacterial MOFs solution and ultrasonically treat it for 30 minutes to obtain functionalized drug carrier MOFs.

[0098] S4. Preparation of gel

[0099] Dissolve 10 parts of poly(N-isopropylacrylamide) PNIPAM and 5 parts of polyethylene glycol PEG in 100 parts of deionized water, evenly disperse the functionalized drug carrier MOFs in the gel, and add 0.3 part of N,N'-methylenebisacrylamide MBA;

[0100] Heat to 66°C and keep stirring for 25 minutes to form a preliminarily cross-linked gel network;

[0101] Cool to room temperature and let it stand to form a gel.

[0102] S5. Molding and curing

[0103] Pour the prepared double-network hydrogel into a mold and place it in an environment at 4 °C for 1.5 hours to ensure that the gel is completely formed and cured.

[0104] Experimental tests:

[0105] 1. Drug release control test

[0106] Samples: Prepare hydrogel samples of the present invention and comparative sample.

[0107] Steps: Prepare hydrogel discs (diameter 20 mm, thickness 5 mm) of each sample.

[0108] Place the samples in simulated body fluid (PBS buffer, pH 7.4).

[0109] Take samples at different time points and measure the drug concentration in the released liquid.

[0110] Conditions: Constant temperature oscillator at 37 °C, 100 rpm.

[0111] Equipment: UV-visible spectrophotometer.

[0112] 2. Skin healing experiment

[0113] Experimental group: The group treated with the double-network skin repair hydrogel;

[0114] Control group 1: The group treated with the comparative hydrogel;

[0115] Animal model: Select healthy adult male rats for grouped testing;

[0116] Wound preparation: Prepare a full-thickness skin excision wound with a diameter of 1 cm on the back of the rats;

[0117] Wound treatment: Apply a layer of double-network skin repair hydrogel about 1 mm thick;

[0118] Evaluation index: Wound contraction rate; Take wound photos on days 1, 5, and 9.

[0119] Table 1 Drug release test table ((mg / L))

[0120]

[0121]

[0122] The drug release amounts of all the examples within 1 hour to 72 hours were significantly higher than those of Comparative Example 1 and Comparative Example 2, indicating that the improved double-network hydrogel structure effectively enhanced the sustained drug release efficiency. The release amounts of Example 1, Example 9, and Example 10 at 1 hour had already reached or exceeded the release amounts of the comparative examples at 4 hours, which demonstrated the advantage of rapid release in the initial stage.

[0123] As time increased, the drug release amounts of all the examples continued to increase and maintained a relatively high release rate, showing excellent sustained release performance. At 72 hours, the release amount of Example 1 was the highest, reaching 29.4%, while the release amounts of Comparative Example 1 and Comparative Example 2 were only 19.8% and 19.1% respectively. This indicated that the hydrogel provided by the present invention could maintain a relatively high drug utilization efficiency during long-term treatment.

[0124] Example 1 performed well at all time points. Especially in the later stage (48 hours and 72 hours), the drug release amount was significantly higher than that of other examples and comparative examples. This might be related to its specific components and preparation conditions, such as the relatively high mass ratio of silver nanoparticles to azathioprine in the initial stage.

[0125] By changing the heating temperature and time, Example 9 and Example 10 demonstrated the influence of temperature and time on the drug release behavior. Especially, the release amount of Example 9 was higher than that of Example 10 at all time points, indicating that a higher heating temperature and a longer stirring time had a positive effect on the slow release of the drug.

[0126] The results showed that appropriately increasing the dosage of the network cross-linking agent (MBA) and adjusting the mass ratio of the polymers constituting the network (such as PNIPAM and PEG) helped to optimize the drug release behavior. Adjusting the dosage of MBA in Example 6 and Example 7 significantly affected the drug release and had better release control compared with the comparative examples.

[0127] By precisely controlling the cross-linking density and cross-linking conditions of the double-network structure, the present invention achieved a combination of rapid initial release and slow later release of the drug, significantly enhancing the effect of drug release control. This characteristic was particularly suitable for the treatment of skin conditions requiring long-term drug therapy, such as chronic dermatitis or skin repair, providing an efficient and sustainable treatment plan.

[0128] Table 2 Statistical Table of Wound Healing Rates

[0129] Time point Example 1 Comparative Example 1 Comparative Example 2 1 day (% healing rate standard deviation) 12.15±1.25 8.40±0.91 7.85±1.12 5 days (% healing rate ± standard deviation) 44.25±2.46 32.60±2.53 28.95±3.07 9 days (% healing rate ± standard deviation) 86.75±3.35 67.35±3.62 63.40±3.74

[0130] The double network structure and specific drug carrier (functionalized MOFs) used in Example 1 obviously provide better therapeutic effects, especially in terms of rapid initiation and continuous promotion of the healing process. This is related to its efficient drug release mechanism and excellent gel structure, which provide a favorable microenvironment for cell growth and tissue regeneration. Example 1 significantly improves the healing efficiency of skin wounds by using advanced material technology and sophisticated chemical engineering methods. Its double network hydrogel not only accelerates wound closure, but also optimizes the treatment process by controlling drug release, making it have potential application prospects in the field of skin repair. The comparative example is obviously not as sophisticated as Example 1 in terms of the design of the drug carrier and the optimization of the network structure, resulting in its low healing efficiency.

[0131] Figure 1 It shows that the treatment method in Example 1 is the most effective in promoting wound healing, showing the largest reduction in wound area within 9 days. The control treatments (Comparative Examples 1 and 2) are less effective, with slower healing speeds and still large wound areas after 9 days. The pictures show the superior performance of the treatment method in Example 1 in enhancing wound healing, which is better than the control treatment.

[0132] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A preparation method of a double-network skin repair hydrogel, characterized in that, It includes the following steps: S1 Dissolve 2-aminoterephthalic acid and copper nitrate in N,N-dimethylformamide, and stir until completely dissolved; then heat for reaction, cool to room temperature, centrifuge to obtain MOFs solid, and then wash and dry to constant weight to obtain MOFs powder. The amount of 2-aminoterephthalic acid is 3 parts, the amount of copper nitrate is 2 parts, the amount of N,N-dimethylformamide is 100 parts, the heating temperature is 150 °C, and the reaction time is 12 hours; S2 Redisperse the MOFs powder in deionized water to form a MOFs suspension, add silver nanoparticles to the MOFs suspension, and stir evenly to obtain a functionalized MOFs solution. The amount of MOFs powder is 3 parts, the amount of deionized water is 100 parts, and the amount of silver nanoparticles is 1 part; S3 Drug loading: Dissolve azathioprine in deionized water, add it to the functionalized MOFs solution, and perform ultrasonic treatment to obtain a functionalized drug carrier MOFs. The amount of azathioprine is 0.5 part, and the amount of deionized water is 15 parts; S4 First network: Dissolve poly(N-isopropylacrylamide) and polyethylene glycol in ionic water, add N,N'-methylenebisacrylamide, heat and stir to form a preliminarily cross-linked gel network. The amount of poly(N-isopropylacrylamide) is 10 parts, the amount of polyethylene glycol is 5 parts, the amount of deionized water is 100 parts, the amount of N,N'-methylenebisacrylamide is 0.3 part, the heating temperature is 66 °C, and the time is 25 minutes; S5 Second network: Uniformly disperse 50% of the functionalized drug carrier MOFs in the first network gel, stir evenly, add N,N'-methylenebisacrylamide again as a secondary cross-linking agent, then add the remaining functionalized drug carrier MOFs, heat and stir to form a completely cross-linked double-network hydrogel, cool to room temperature, and stand at low temperature to form a gel. The amount of N,N'-methylenebisacrylamide is 0.5 part, the heating temperature is 78 °C, and the stirring time is 35 minutes; S6 Finally, pour the gel into a mold and let it stand until it is formed and cured. The standing temperature is 4 °C and the time is 1.5 hours.

2. A double-network skin repair hydrogel, characterized in that, Prepared by the preparation method of claim 1.

Images