Diels-Alder reaction and supramolecular interaction-based dual-network hydrogel dressing and preparation method thereof
The dual network hydrogel dressing constructed through Diels-Alder reaction and supramolecular action solves the insufficient care of traditional dressings on diabetic ulcer wounds, realizes self-healing, intelligent response and drug-sustaining delayed release. It is suitable for diabetic wound care, with good biocompatibility and economic benefits.
Patent Information
- Application Number
- CN202510606847.2
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-05-12
- Publication Date
- 2025-08-08
AI Technical Summary
Traditional dressings are difficult to effectively care for the wounds of stubborn ulcers caused by diabetes, which is prone to secondary damage. The existing new dressings have shortcomings in mechanical, self-repair, intelligent responsiveness and biocompatibility.
A dual network hydrogel dressing was constructed using Diels-Alder reaction and supramolecular action. By modifying hyaluronic acid, hydroxypropyl-β-cyclodextrin and soluble starch, a dual network hydrogel based on covalent bonds and supramolecular action was formed, and the drug was sustained release of curcumin, achieving self-healing, intelligent response and good biocompatibility.
It provides a hydrogel dressing suitable for diabetic wounds, which has good mechanical strength, self-healing, stimulation responsiveness and drug sustained release, promotes wound healing, reduces raw material costs and is easy to produce in an industrial manner.
Smart Images
Figure CN120437366A_ABST
Abstract
Description
Technical Field
[0001] The present invention relates to the technical field of medical dressings, and in particular to a double-network hydrogel dressing based on Diels-Alder reaction and supramolecular action and a preparation method thereof. Background Art
[0002] At present, traditional dressings such as gauze and sterile cotton can hardly meet the actual needs of some special wound care. Among them, the ulcer wounds caused by high blood sugar in diabetic patients are a special wound that is very difficult to care for. Diabetic wounds are stimulated by factors such as high blood sugar and local hypoxia for a long time, which can cause complications such as stubborn ulcers, tissue damage, and wound infection. The treatment is much more complicated than that of conventional wounds, and it is also one of the most stubborn complications in diabetic patients. The current treatment measures for chronic diabetic ulcer wounds are internal blood sugar control and external dressing treatment. Using traditional dressings to care for this special wound can easily cause secondary damage to the wound, making it difficult to meet the care needs.
[0003] With the continuous development of intelligent biomaterial technology, various new wound dressings have been developed to make up for the shortcomings of traditional dressings. New functional wound dressings not only meet the most basic coverage function, but also create a good biological environment for the wound to prevent bacterial growth during the recovery process. During the healing process, they will not adhere to the new tissue and cause secondary damage when changing the dressing. Hydrogel is a hydrophilic polymer with the characteristics of moisturizing, softness, and biodegradability. These characteristics are very consistent with the characteristics of dressings. In recent years, hydrogel materials have been widely used in the care of various wounds.
[0004] As a dressing material, hydrogels must possess excellent mechanical properties, ensuring reliable mechanical performance while effectively maintaining their structural characteristics. Furthermore, they must possess certain self-healing properties, intelligent responsiveness, sustained drug release, and good biocompatibility. These excellent mechanical and self-healing properties help maintain the wound's biological environment and promote tissue healing, while intelligent stimulus responsiveness and sustained drug release facilitate wound sterilization and prevent infection. Therefore, the development of novel, multifunctional hydrogel dressings is a scientific trend in this field. Summary of the Invention
[0005] The purpose of the present invention is to provide a double-network hydrogel dressing based on the Diels-Alder reaction and supramolecular action and a preparation method thereof. In addition to being able to effectively care for ordinary wounds, the auxiliary material is also particularly suitable for special skin wounds caused by diabetes. It can achieve a benign interaction with wound tissue to promote wound healing. The preparation process is simple, the required raw material cost is low, the economic benefit is high, and it is easy to realize industrial production.
[0006] In order to solve the above-mentioned technical problems, the present invention adopts the following technical solution: a method for preparing a double-network hydrogel dressing based on Diels-Alder reaction and supramolecular action:
[0007] 2-Furfurylmethylamine is modified into hyaluronic acid to prepare a macromolecular diene (HA-FM-n), and the macromolecular diene (HA-FM-n) is dissolved in deionized water to obtain solution A for later use;
[0008] wherein n is the molar ratio of the number of repeating units of hyaluronic acid to 2-furylmethylamine, n=1, 2, 4, 6 (e.g., M of the HA repeating unit is 403, 2 g of HA (≈5 mmol of repeating unit) is added with 2-furylmethylamine (0.4856 g, 5 mmol) i.e. n=5 / 5=1);
[0009] 3-Maleimidopropionic acid is modified to hydroxypropyl-β-cyclodextrin to prepare a dienophile (HP-β-CD-MPA), and the dienophile (HP-β-CD-MPA) is dissolved in DMF to obtain solution B for later use;
[0010] Modifying 1-adamantanecarboxylic acid into soluble starch to prepare modified soluble starch (St-AD-n), dissolving the modified soluble starch (St-AD-n) in deionized water to obtain solution C for later use;
[0011] wherein n is the molar ratio of the pyranose repeating unit of St to 1-adamantanecarboxylic acid, n = 1, 2, 4, 6;
[0012] Mix solutions A, B, and C evenly to obtain a precursor solution, heat the precursor solution to 45-55° C. and keep it warm for 5-8 hours to form a gel, and continue to stand for 10-16 hours to complete the reaction to obtain a double network hydrogel (HA / DN-Gel).
[0013] As a further optimization of the preparation method of a double-network hydrogel dressing based on the Diels-Alder reaction and supramolecular action of the present invention, the preparation method of the macromolecular diene (HA-FM-n) is specifically as follows: hyaluronic acid, EDC and NHS are added to deionized water in sequence and magnetically stirred, then 2-furylamine is added and the pH of the solution is adjusted to 5, and the reaction is carried out at room temperature. After the reaction is completed, the reaction solution is dialyzed and freeze-dried to obtain HA-FM-n.
[0014] As a further optimization of the preparation method of the double-network hydrogel dressing based on the Diels-Alder reaction and supramolecular interaction of the present invention, the specific dialysis method is: the reaction solution is placed in a dialysis bag with a molecular weight cutoff of 3500 and dialyzed with deionized water for 3 days, and the water is changed every 8 hours.
[0015] As a further optimization of the preparation method of a double-network hydrogel dressing based on the Diels-Alder reaction and supramolecular action of the present invention, the preparation method of the dienophile (HP-β-CD-MPA) is specifically as follows: HP-β-CD is completely dissolved in deionized water, 3-maleimidopropionic acid is added, and after mixing evenly, the mixed solution is cooled to 0-5°C and slowly added dropwise to a mixed aqueous solution containing EDC and NHS. After the addition is completed, it is placed at room temperature to react. After the reaction is completed, the dienophile HP-β-CD-MPA is obtained after filtration and drying.
[0016] As a further optimization of the preparation method of a double-network hydrogel dressing based on the Diels-Alder reaction and supramolecular action of the present invention, the preparation method of the modified soluble starch (St-AD-n) is specifically as follows: the soluble starch St is heated and dissolved in DMSO, and after cooling, DMF is added and the temperature is lowered to 0-5°C to obtain a soluble starch solution for standby use; 1-adamantanecarboxylic acid, EDC and NHS are dissolved in DMF, and slowly stirred until the mixed solution is completely transparent, and then the transparent mixed solution is added to the soluble starch solution, reacted at room temperature, and after the reaction is completed, precipitated, rinsed, filtered and dried to obtain the modified soluble starch (St-AD-n).
[0017] As a further optimization of the preparation method of the double-network hydrogel dressing based on Diels-Alder reaction and supramolecular action of the present invention, the molar ratio of the added amounts of soluble starch St (pyranose repeating unit), 1-adamantanecarboxylic acid, EDC and NHS is 12:2:2:1.
[0018] As a further optimization of the preparation method of the double-network hydrogel dressing based on Diels-Alder reaction and supramolecular action of the present invention, curcumin is further added to the solution B, and the mass concentration of curcumin in the precursor solution is 10%.
[0019] As a further optimization of the preparation method of the double-network hydrogel dressing based on the Diels-Alder reaction and supramolecular action of the present invention, the mass concentration of HA-FM-n in the precursor solution A is 17-19%; the mass concentration of HP-β-CD-MPA in the precursor solution B without drug loading is 19-21%.
[0020] As a further optimization of the preparation method of the double-network hydrogel dressing based on Diels-Alder reaction and supramolecular action of the present invention, the mass concentration of St-AD-n in the precursor solution C is 7-8%.
[0021] The present invention also provides a double-network hydrogel dressing prepared by the above method. This functional hydrogel dressing exhibits multiple properties, including self-healing, intelligent stimulus responsiveness, sustained drug release, degradability, and biocompatibility. In addition to effectively caring for common wounds, this dressing is particularly suitable for special skin wounds caused by diabetes, achieving a benign interaction with wound tissue to promote wound healing. The preparation process is simple, the raw material cost is low, and the economic benefits are high, making it easy to industrialize.
[0022] The present invention has the following beneficial effects: 2-furylmethylamine, a diene molecule, is modified onto hyaluronic acid to obtain a macromolecular diene HA-FM. The enophile 3-maleimidopropionic acid is then modified onto hydroxypropyl-β-cyclodextrin to obtain the dienophile HP-β-CD-MPA. 1-adamantanic acid, a guest molecule with an adamantane structure specifically recognized by cyclodextrin, is then modified onto a soluble starch chain to obtain a soluble starch chain containing a guest molecule unit, St-AD. After mixing the three components, no additional crosslinking agent is required. The HP-β-CD-MPA component acts as a chemical / physical double crosslinker. The MPA groups of HP-β-CD-MPA react with HA-FM via a Diels-Alder (DA) reaction to form a chemical crosslinking network. Simultaneously, a supramolecular crosslinking network is formed through the host-guest interaction between the HP-β-CD-MPA cyclodextrin cavity and the adamantane-specific recognition of St-AD. Ultimately, a double-network hydrogel based on covalent and supramolecular interactions is formed. This ensures the hydrogel's mechanical strength while also imparting excellent self-healing and stimulus-responsive properties. By loading the hydrogel with anti-inflammatory drugs like curcumin, the sustained release of these drugs further accelerates wound healing. The materials used are low-cost, non-toxic, or have low toxicity, and exhibit excellent biocompatibility. These combined advantages make the hydrogel an excellent choice for wound care. BRIEF DESCRIPTION OF THE DRAWINGS
[0023] Figure 1 This is the SEM image of the double-network hydrogel prepared in Example 1;
[0024] Figure 2 This is a comparison chart of the repair effects of the hydrogel dressings prepared in Examples 1 and 4 on the wounds of high-sugar mice. DETAILED DESCRIPTION
[0025] In order to better understand the present invention, the content of the present invention is further illustrated below in conjunction with examples, but the content of the present invention is not limited to the following examples.
[0026] <Example 1>
[0027] (1) Synthesis of diene hyaluronic acid:
[0028] First, 2.0000g of hyaluronic acid, 1-(3-dimethylamino)carbodiimide (EDC) (0.7762g, 5mmol), and N-hydroxysuccinimide (NHS) (0.2877g, 2.5mmol) were added sequentially to a round-bottom flask containing 200mL of deionized water and magnetically stirred at 25°C for 2h to activate the -COOH group. 2-Furfurylamine (0.4856g, 5mmol) was then added, and HCl (0.2M) was added to adjust the solution's pH to approximately 5. The reaction was maintained at 25°C for 24h. After completion of the reaction, the reaction solution was placed in a dialysis bag (cut-off Mw = 3500) and dialyzed against deionized water for 3 days, with the water changed every 8h. Finally, the product was freeze-dried to obtain 1.5712g of a white flocculent product with a yield of 66%. The resulting product was named HA-FM-1.
[0029] (2) Synthesis of enophile hydroxypropyl-β-cyclodextrin:
[0030] First, HP-β-CD (5 g, 3.25 mmol) was completely dissolved in 40 mL of deionized water. 3-Maleimidopropionic acid (2.7484 g, 16.25 mmol) was then added and mixed thoroughly to obtain a clear solution. The mixture was then cooled to 0-5°C and slowly added dropwise to a mixed aqueous solution of EDC (2.5227 g, 16.25 mmol) and NHS (0.9351 g, 8.125 mmol). After the addition was complete, the mixture was allowed to react at room temperature for 6 hours, during which a large amount of white precipitate was observed. Finally, the product was collected by filtration. After vacuum drying at 45°C, 5.1555 g of a white solid powder was obtained with a yield of 69%. The resulting product was named HP-β-CD-MPA.
[0031] (3) Synthesis of adamantane-modified soluble starch
[0032] In the presence of a dehydrating agent, 1-adamantanecarboxylic acid (1-AD) and soluble starch (St) undergo an esterification reaction to synthesize St-AD-n. By varying the feed ratio, a series of products, St-AD-n, were synthesized, where n represents the molar ratio of the pyranose unit of St to 1-AD. St (1 g, 3.0864 mmol) was dissolved in 20 mL of DMSO by heating. After cooling, 15 mL of DMF was added and the mixture was cooled to 0-5°C for later use. Subsequently, 1-AD (0.0927 g, 0.5144 mmol), EDC (0.0799 g, 0.5144 mmol), and NHS (0.0296 g, 0.2572 mmol) were mixed and dissolved in 5 mL of DMF, with the ratio of St units: 1-AD = 6:1, EDC:-COOH = 1:1, and EDC:NHS = 2:1. The mixture was stirred slowly until the solution became completely transparent. The transparent mixed solution was then added to the clear soluble starch solution and reacted at 25°C for 12 hours. After the reaction, the mixture was precipitated with 60 mL of toluene, rinsed with 20 mL of acetone, filtered, and dried under vacuum at 40°C to obtain 0.8238 g of a white solid with a yield of 82%. The resulting product was named St-AD-6.
[0033] (4) HA-FM (200 mg) prepared in step (1) was heated and dissolved in 0.9 mL of deionized water to obtain solution A. HP-β-CD-MPA (200 mg) prepared in step (2) was dissolved in 0.8 mL of DMF to obtain solution B. St-AD (40 mg) prepared in step (3) was dissolved in 0.5 mL of deionized water to obtain solution C. After heating to completely dissolve the three solutions, B and C were poured into A, mixed evenly, and reacted at 50°C for about 6 hours to form a gel. The solution was allowed to stand for 12 hours to complete the reaction and stabilize the cross-linking of the gel network, thereby obtaining the hydrogel dressing HA / DN-Gel-1. Figure 1 The SEM image of HA / DN-Gel-1 is given. Due to the formation of a double network, the interaction between polymers is enhanced and HA / DN-Gel shows a denser porous structure. Figure 2 As shown. On the first day, the initial wound sizes of the three groups were basically the same. On the 4th to 10th days, the blank control group shrank slowly (~4%), and the wounds of the HA / DN-Gel group (~25%) and the HA / DN / CUR group (~37%) healed better, which was higher than the blank control group. On the 13th to 16th days, all the wounds in the sample groups began to scab, and the wounds shrank significantly. Among them, the drug-loaded gel group healed the best, showing the smallest scar area. The above results show that HA / DN-Gel can inhibit the activity of bacteria on the wound surface while promoting the healing of infected wounds.
[0034] <Example 2>
[0035] (1) Prepare hyaluronic acid diene according to the method of step (1) in Example 1.
[0036] (2) Prepare hydroxypropyl-β-cyclodextrin enophile according to the method of step (2) in Example 1.
[0037] (3) Prepare adamantane-modified soluble starch according to the method of step (3) in Example 1.
[0038] (4) HA-FM (200 mg) prepared in step (1) was heated and dissolved in 0.9 mL of deionized water to obtain solution A. HP-β-CD-MPA (100 mg) prepared in step (2) was dissolved in 0.9 mL of DMF to obtain solution B. St-AD (40 mg) prepared in step (3) was dissolved in 0.5 mL of deionized water to obtain solution C. After heating to completely dissolve the three solutions, B and C were poured into A, mixed evenly, and reacted at 50°C for about 6 hours to form a gel. The solution was allowed to stand for 12 hours to complete the reaction and stabilize the cross-linking of the gel network, thereby obtaining the hydrogel dressing HA / DN-Gel-2.
[0039] <Example 3>
[0040] (1) Prepare diene hyaluronic acid according to the method of step (1) in Example 1.
[0041] (2) Prepare enophile hydroxypropyl-β-cyclodextrin according to the method of step (2) in Example 1.
[0042] (3) Prepare adamantane-modified soluble starch according to the method of step (3) in Example 1.
[0043] (4) HA-FM (200 mg) prepared in step (1) was heated and dissolved in 0.9 mL of deionized water to obtain solution A. HP-β-CD-MPA (300 mg) prepared in step (2) was dissolved in 0.7 mL of DMF to obtain solution B. St-AD (40 mg) prepared in step (3) was dissolved in 0.5 mL of deionized water to obtain solution C. After heating to completely dissolve the three solutions, B and C were poured into A, mixed evenly, and reacted at 50°C for about 6 hours to form a gel. The solution was allowed to stand for 12 hours to complete the reaction and stabilize the cross-linking of the gel network, thereby obtaining the hydrogel dressing HA / DN-Gel-3.
[0044] <Example 4>
[0045] (1) Prepare diene hyaluronic acid according to the method of step (1) in Example 1.
[0046] (2) Prepare enophile hydroxypropyl-β-cyclodextrin according to the method of step (2) in Example 1.
[0047] (3) Prepare adamantane-modified soluble starch according to the method of step (3) in Example 1.
[0048] (4) The HA-FM (200 mg) prepared in step (1) was heated and dissolved in 0.9 mL of deionized water to obtain solution A. The HP-β-CD-MPA (100 mg) and curcumin (5 mg) prepared in step (2) were dissolved in 0.9 mL of DMF to obtain solution B. The St-AD (40 mg) prepared in step (3) was dissolved in 0.5 mL of deionized water to obtain solution C; after heating to completely dissolve the three solutions, B and C were poured into A, mixed evenly, and reacted at 50°C for about 6 hours to form a gel. The solution was allowed to stand for 12 hours to complete the reaction and stabilize the cross-linking of the gel network to obtain the drug-loaded hydrogel dressing HA / DN / CUR-Gel-1. The photos of its effect on wound repair in high-sugar mice are shown in the figure below. Figure 2 shown.
[0049] The above describes the specific embodiments of the present invention. It should be understood that the present invention is not limited to the above specific embodiments, and those skilled in the art may make various variations or modifications within the scope of the claims, which do not affect the essence of the present invention.
Claims
1. A method for preparing a double-network hydrogel dressing based on Diels-Alder reaction and supramolecular interaction, characterized in that: 2-Furfurylmethylamine is modified into hyaluronic acid to prepare a macromolecular diene (HA-FM-n), and the macromolecular diene (HA-FM-n) is dissolved in deionized water to obtain solution A for later use; Wherein, n is the molar ratio of the number of repeating units of hyaluronic acid to 2-furylmethylamine, n=1, 2, 4, 6; 3-Maleimidopropionic acid is modified to hydroxypropyl-β-cyclodextrin to prepare a dienophile (HP-β-CD-MPA), and the dienophile (HP-β-CD-MPA) is dissolved in DMF to obtain solution B for later use; Modifying 1-adamantanecarboxylic acid into soluble starch to prepare modified soluble starch (St-AD-n), dissolving the modified soluble starch (St-AD-n) in deionized water to obtain solution C for later use; Wherein, n is the molar ratio of the hydroxyl group on the pyranose unit of St to 1-adamantanecarboxylic acid, n = 1, 2, 4, 6; Mix solutions A, B, and C evenly to obtain a precursor solution, heat the precursor solution to 45-55° C. and keep it warm for 5-8 hours to form a gel, and continue to stand for 10-16 hours to complete the reaction to obtain a double network hydrogel (HA / DN-Gel).
2. The method for preparing a double-network hydrogel dressing based on Diels-Alder reaction and supramolecular interaction according to claim 1, characterized in that: The specific preparation method of the macromolecular diene (HA-FM-n) is as follows: hyaluronic acid, EDC and NHS are added to deionized water in sequence and magnetically stirred, then 2-furylamine is added and the pH of the solution is adjusted to 5, and the reaction is carried out at room temperature. After the reaction is completed, the reaction solution is dialyzed and freeze-dried to obtain HA-FM-n.
3. The method for preparing a double-network hydrogel dressing based on Diels-Alder reaction and supramolecular interaction according to claim 1, characterized in that: The specific method of dialysis is as follows: the reaction solution is placed in a dialysis bag with a molecular weight cut-off of 3500 and dialyzed with deionized water for 3 days, with the water being changed every 8 hours.
4. The method for preparing a double-network hydrogel dressing based on Diels-Alder reaction and supramolecular interaction according to claim 1, characterized in that: The preparation method of the dienophile (HP-β-CD-MPA) is specifically as follows: HP-β-CD is completely dissolved in deionized water, 3-maleimidopropionic acid is added, the mixed solution is cooled to 0-5°C, and the mixed solution is slowly added dropwise to a mixed aqueous solution containing EDC and NHS. After the addition is completed, the mixture is allowed to react at room temperature. After the reaction is completed, the mixture is filtered and dried to obtain the dienophile HP-β-CD-MPA.
5. The method for preparing a double-network hydrogel dressing based on Diels-Alder reaction and supramolecular interaction according to claim 1, characterized in that: The preparation method of the modified soluble starch (St-AD-n) is specifically as follows: soluble starch St is heated and dissolved in DMSO, and after cooling, DMF is added and the temperature is lowered to 0-5°C to obtain a soluble starch solution for standby use; 1-adamantanecarboxylic acid, EDC and NHS are dissolved in DMF, and slowly stirred until the mixed solution is completely transparent, and then the transparent mixed solution is added to the soluble starch solution, reacted at room temperature, and after the reaction is completed, the modified soluble starch (St-AD-n) is obtained by precipitation, rinsing, filtering and drying.
6. The method for preparing a double-network hydrogel dressing based on Diels-Alder reaction and supramolecular interaction according to claim 5, characterized in that: The molar ratio of the added amount of pyranose repeating units of soluble starch St, 1-adamantanediate, EDC and NHS is 12:2:2:
1.
7. The method for preparing a double-network hydrogel dressing based on Diels-Alder reaction and supramolecular interaction according to claim 1, characterized in that: Curcumin is also added to the solution B, and the mass concentration of curcumin alone in the solution B is 10%.
8. The method for preparing a double-network hydrogel dressing based on Diels-Alder reaction and supramolecular interaction according to claim 1, characterized in that: The mass concentration of HA-FM-n in the solution A is 17-19%, and the mass concentration of HP-β-CD-MPA in the solution B is 19-21%.
9. The method for preparing a double-network hydrogel dressing based on Diels-Alder reaction and supramolecular interaction according to claim 1, characterized in that: The mass concentration of St-AD-n in the solution C is 7-8%.
10. A double-network hydrogel dressing prepared by the method according to any one of claims 1 to 9.