Preparation method of hydrogel film, obtained product and application

Abstract

The invention discloses a preparation method of a hydrogel film, an obtained product and application, polyethylene glycol, alpha-cyclodextrin, a cross-linking agent and water are uniformly mixed, then cross-linking reaction is performed to obtain hydrogel, functional monomers are embedded in the hydrogel, and then post-treatment is performed to obtain the hydrogel film. The hydrogel film not only has good mechanical properties such as high tensile strength and elongation at break, but also has various special functions such as bacteriostasis, good biocompatibility, promotion of wound repair and biodegradability, and can meet diversified requirements in different fields such as biology, medicine, environmental monitoring, intelligent wearing and the like.

Description

Technical Field

[0001] The present invention relates to a preparation method of a hydrogel film and the obtained product, specifically to a preparation method of a hydrogel film with multiple functions and the obtained product, and also to the application of the hydrogel film in the fields of biology, medicine, environmental monitoring, smart wear, etc., belonging to the technical field of biomaterials. Background Art

[0002] With the continuous development of technology, hydrogel films have shown great application potential in many fields, such as biomedicine, environmental monitoring, smart wear, etc. However, traditional hydrogel films often have problems such as single function, insufficient mechanical properties, slow response speed, etc., which limit their wider application. For example, in the field of biomedicine, hydrogel films used for wound dressings may lack sufficient antibacterial properties and the ability to promote tissue regeneration. Therefore, it is of great practical significance to develop a hydrogel film with multiple excellent properties. Summary of the Invention

[0003] The purpose of the present invention is to provide a preparation method of a hydrogel film and the obtained product. The preparation method is simple and easy to implement. The obtained hydrogel film has good mechanical properties, antibacterial properties, adsorption properties, the ability to respond to external stimuli, and good biocompatibility. It is biodegradable and can meet the diverse needs of different fields, having a good application prospect.

[0004] To achieve the above purpose, the present invention adopts the following technical solutions:

[0005] A preparation method of a hydrogel film, the method comprising the following steps:

[0006] (1) Mix polyethylene glycol, α-cyclodextrin, a cross-linking agent and water, and raise the temperature for cross-linking reaction to obtain a hydrogel;

[0007] (2) Cool the hydrogel, then add a functional monomer and stir to mix to obtain a hydrogel embedding the functional monomer;

[0008] (3) Pour the hydrogel embedding the functional monomer into a mold, dry, and then perform plasma treatment to obtain a hydrogel film.

[0009] Furthermore, α-cyclodextrin and polyethylene glycol have unique molecular structures, which can combine and provide a basic framework support for the hydrogel film. The total content of α-cyclodextrin and polyethylene glycol is 10-15% of the total raw material mass, such as 10%, 11%, 12%, 13%, 14%, 15%. The mass ratio of polyethylene glycol to α-cyclodextrin is 1-5:1, such as 1:1, 2:1, 3:1, 4:1, 5:1. The total raw materials refer to polyethylene glycol, α-cyclodextrin, functional monomer, cross-linking agent and water.

[0010] Furthermore, the weight-average molecular weight of the polyethylene glycol is 1500 - 2500.

[0011] Furthermore, the cross-linking agent is polyethylene oxide and polyvinylpyrrolidone. Polyethylene oxide and polyvinylpyrrolidone are used to construct the network structure of the hydrogel and enhance the mechanical properties of the film. The total content of polyethylene oxide and polyvinylpyrrolidone is 5 - 10% of the total mass of the raw materials, such as 5%, 6%, 7%, 8%, 9%, 10%. The mass ratio of polyethylene oxide to polyvinylpyrrolidone is 1 - 3:1, such as 1:1, 2:1, 3:1. The total raw materials refer to polyethylene glycol, α-cyclodextrin, functional monomer, cross-linking agent and water.

[0012] Furthermore, the weight-average molecular weight of the polyethylene oxide is 1.8 - 2.2 million, and the weight-average molecular weight of the polyvinylpyrrolidone is 50,000 - 70,000.

[0013] Furthermore, the functional monomer is vancomycin. The functional monomer endows the hydrogel film with special functions, such as antibacterial property, anti-inflammatory property, etc. Vancomycin has good antibacterial activity against Gram-positive bacteria (such as Staphylococcus aureus, etc.). It is encapsulated in the hydrogel film by the method of embedding and slow release, which has a smaller dosage than traditional intravenous injection and less side effects on the body. The content of the functional monomer is 0.1‰ - 0.5‰ of the total mass of the raw materials, such as 0.1‰, 0.2‰, 0.3‰, 0.4‰, 0.5‰. The total raw materials refer to polyethylene glycol, α-cyclodextrin, functional monomer, cross-linking agent and water.

[0014] Furthermore, water is used as the solvent, and its dosage ensures that the sum of all raw materials is 100wt%.

[0015] Furthermore, in step (1), there is no special requirement for the mixing order of each raw material. They can be mixed together, or some can be mixed first and then the other part. For example, polyethylene glycol, α-cyclodextrin, and water can be mixed and dissolved evenly first, and then the cross-linking agent is added and mixed evenly.

[0016] Furthermore, in step (1), in order to promote the mixing of each raw material or its dissolution in water, at least one of stirring, ultrasonic treatment, and heating can be used for assistance.

[0017] Furthermore, in step (1), the mixture undergoes a cross-linking reaction at 55 - 75°C to form a hydrogel with a certain degree of cross-linking. For example, the reaction temperature can be 55°C, 60°C, 65°C, 70°C, 75°C. The reaction time is controlled according to the actual situation. To ensure the full progress of the polymerization reaction, it is generally 2 - 4h. For example, 2h, 3h, 4h.

[0018] Further, in step (2), the functional monomer is embedded and mixed at 25 - 35°C, and the reaction time is controlled according to the actual situation. To ensure the full progress of the polymerization reaction, it is generally 1 - 2 h.

[0019] Further, in step (3), the hydrogel is dried under the conditions of vacuum, a temperature of 25 - 35°C, and a relative humidity of 20% - 30% for 4 - 6 h.

[0020] Further, in step (3), the power of the plasma treatment is 90 - 110 W, such as 90 W, 100 W, 110 W, and the treatment time is 1 - 10 minutes.

[0021] The present invention obtains a hydrogel film through solution polymerization and specific post - treatment. This hydrogel film has a micro - porous and three - dimensional grid structure, which is conducive to the transport and exchange of substances. It has been verified that the hydrogel film not only has good mechanical properties, such as high tensile strength and elongation at break, but also has a variety of special functions, such as rapid response to external stimuli, good biocompatibility, promotion of wound repair, antibacterial, and biodegradability, etc., which can meet the diverse needs of different fields such as biology, medicine, and smart wearables.

[0022] The present invention has the following beneficial effects:

[0023] 1. The method of the present invention is simple, efficient, and cost - controllable, ensuring that the hydrogel film can be mass - produced and applied.

[0024] 2. By selecting polyethylene glycol, α - cyclodextrin, polyethylene oxide, and polyvinylpyrrolidone and controlling their dosages, the mechanical properties of the hydrogel film are improved. The obtained hydrogel film has a high tensile strength and an excellent elongation at break, and can maintain its integrity and is not easily broken under different application scenarios.

[0025] 3. Vancomycin is introduced into the hydrogel film of the present invention, and the introduction of vancomycin endows the hydrogel film with a variety of special functions. For example, antibacterial experiments were carried out on the hydrogel film against common Gram - positive bacteria (such as Staphylococcus aureus, etc.), and obvious antibacterial zones appeared on the culture medium, indicating that the gel film has the function of inhibiting bacterial growth and preventing wound infection by bacteria; the hydrogel film has a promoting effect on the recovery of the wound, and it can recover to about 40% of the original wound in about 7 days, and can be used to promote wound recovery.

[0026] 4. The raw materials selected in the present invention have good biocompatibility, are non - toxic and non - irritating to human cells and tissues, and can be applied to the biomedical field. At the same time, the hydrogel film can gradually degrade in the natural environment or in the body and will not cause long - term pollution.

[0027] 5. The micro-porous structure of the hydrogel film of the present invention enables it to have a rapid response ability to external stimuli, and can undergo changes in physical or chemical properties within a short time. It can be made into an intelligent sensor for monitoring human physiological parameters (such as body temperature, humidity, motion state, etc.) to achieve human-computer interaction and health monitoring.

[0028] 6. The hydrogel film of the present invention can be used as a wound dressing, which can promote wound healing and prevent infection; it can also be used as a drug sustained-release carrier to encapsulate and slowly release drugs, capable of controlling the drug release rate and dosage, and improving the drug efficacy. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 SEM electron micrographs of the hydrogel films of Example 1 and Comparative Example 1, A, Example 1; B, Comparative Example 1.

[0030] Figure 2 Tensile comparison diagrams of the hydrogel film of Example 1, A, before stretching; B, after stretching to 350%.

[0031] Figure 3 Bacteriostatic effect diagrams of the hydrogel film, A, Comparative Example 1; B, Example 1.

[0032] Figure 4 Effect diagrams of the wound recovery of mice implanted with the hydrogel film of Example 1, A, 0 days; B, 1 day; C, 3 days; D, 7 days; E, 14 days. DETAILED DESCRIPTION OF THE INVENTION

[0033] The following describes the exemplary embodiments of the present invention, including various details of the embodiments of the present invention to facilitate understanding. It should be considered that they are merely exemplary. Therefore, those of ordinary skill in the art should recognize that various changes and modifications can be made to the embodiments described herein without departing from the scope and spirit of the present invention. Similarly, for the sake of clarity and conciseness, the descriptions of well-known functions, operations, and structures are omitted below.

[0034] Unless otherwise defined, the technical and scientific terms in this specification have the same meaning as commonly understood by those skilled in the art. Although methods and materials similar or equivalent to those described herein can be used in experiments or practical applications, the materials and methods are described below in the present invention. In case of conflict, the present specification, including the definitions therein, shall prevail.

[0035] In the following embodiments, the molecular weight of the polyethylene glycol used is 1500 - 2500, the molecular weight of the polyethylene oxide used is 1.8 - 2 million, and the molecular weight of the polyvinylpyrrolidone used is 50,000 - 70,000.

[0036] Example 1

[0037] 1. Raw material preparation: Weigh 10 g of polyethylene glycol, 5 g of α-cyclodextrin, 5 g of poly(ethylene oxide), 5 g of polyvinylpyrrolidone, 50 mg of vancomycin, and 100 mL of deionized water respectively, and set aside.

[0038] 2. Solution preparation: Add polyethylene glycol and α-cyclodextrin into deionized water, and ultrasonically dissolve in an ultrasonic machine for 30 minutes until completely dissolved.

[0039] 3. Polymerization reaction: Transfer the prepared solution to a water bath, then add poly(ethylene oxide) and polyvinylpyrrolidone, heat up to 65 °C and continue stirring, and carry out a cross-linking reaction at 65 °C for 3 h to obtain a hydrogel with a certain degree of cross-linking.

[0040] 4. Embedding treatment: Cool the prepared hydrogel to 30 °C, add vancomycin, stir and mix evenly at a speed of 300 rpm for 1.5 h to embed vancomycin into the hydrogel, and obtain a hydrogel embedding vancomycin.

[0041] 5. Post-treatment: After the reaction is completed, pour the obtained hydrogel embedding vancomycin into a mold. Then, place the hydrogel in a vacuum drying oven and dry it under the conditions of vacuum, a temperature of 30 °C and a relative humidity of 25% for 5 h to obtain a hydrogel film. Finally, perform plasma treatment on the surface of the hydrogel film, put the hydrogel film into a plasma cleaner, and treat it at a treatment power of 100 W for 5 minutes to obtain the final hydrogel film.

[0042] Figure 1 A is the SEM image of the obtained hydrogel film. It can be seen from the figure that the hydrogel cross-links to form a three-dimensional network structure and embeds vancomycin therein.

[0043] Example 2

[0044] 1. Raw material preparation: Weigh 10 g of polyethylene glycol, 5 g of α-cyclodextrin, 5 g of poly(ethylene oxide), 5 g of polyvinylpyrrolidone, 50 mg of vancomycin, and 100 mL of deionized water respectively, and set aside.

[0045] 2. Solution preparation: Add polyethylene glycol and α-cyclodextrin into deionized water, and ultrasonically dissolve in an ultrasonic machine for 20 minutes until completely dissolved.

[0046] 3. Polymerization reaction: Transfer the prepared solution to a water bath, then add poly(ethylene oxide) and polyvinylpyrrolidone, heat up to 55 °C and continue stirring, and carry out a cross-linking reaction at 55 °C for 4 h to obtain a hydrogel with a certain degree of cross-linking.

[0047] 4. Embedding treatment: Cool the prepared hydrogel to 25°C, add vancomycin, stir and mix evenly at a rotation speed of 200 rpm for 2 h, and embed vancomycin into the hydrogel to obtain a hydrogel embedded with vancomycin.

[0048] 5. Post-treatment: After the reaction is completed, pour the obtained hydrogel embedded with vancomycin into a mold. Then, place the hydrogel in a vacuum drying oven and dry it for 4 h under the conditions of vacuum, a temperature of 25°C, and a relative humidity of 20% to obtain a hydrogel film. Finally, perform plasma treatment on the surface of the hydrogel film. Put the hydrogel film into a plasma cleaner and treat it for 1 minute at a treatment power of 90 W to obtain the final hydrogel film.

[0049] Example 3

[0050] 1. Raw material preparation: Weigh 10 g of polyethylene glycol, 5 g of α-cyclodextrin, 5 g of polyethylene oxide, 5 g of polyvinylpyrrolidone, 50 mg of vancomycin, and 100 mL of deionized water respectively for standby.

[0051] 2. Solution preparation: Add polyethylene glycol and α-cyclodextrin to deionized water, and ultrasonically dissolve them in an ultrasonic machine for 40 minutes until completely dissolved.

[0052] 3. Polymerization reaction: Transfer the prepared solution to a water bath, then add polyethylene oxide and polyvinylpyrrolidone, raise the temperature to 75°C and continue stirring, and carry out a cross-linking reaction at 75°C for 2 h to obtain a hydrogel with a certain degree of cross-linking.

[0053] 4. Embedding treatment: Cool the prepared hydrogel to 35°C, add vancomycin, stir and mix evenly at a rotation speed of 400 rpm for 1 h, and embed vancomycin into the hydrogel to obtain a hydrogel embedded with vancomycin.

[0054] 5. Post-treatment: After the reaction is completed, pour the obtained hydrogel embedded with vancomycin into a mold. Then, place the hydrogel in a vacuum drying oven and dry it for 6 h under the conditions of vacuum, a temperature of 35°C, and a relative humidity of 30% to obtain a hydrogel film. Finally, perform plasma treatment on the surface of the hydrogel film. Put the hydrogel film into a plasma cleaner and treat it for 10 minutes at a treatment power of 110 W to obtain the final hydrogel film.

[0055] Comparative Example 1

[0056] Prepare a hydrogel film according to the method of Example 1, except that: omit step 4 and do not perform the embedding treatment of vancomycin.

[0057] Figure 1Figure B shows the SEM image of the obtained hydrogel film. It can be seen from the figure that although the hydrogel without embedding treatment has the same three-dimensional network structure as that in Example 1, it does not contain vancomycin.

[0058] Comparative Example 2

[0059] The hydrogel film was prepared according to the method of Example 1, except that: 50 mg of vancomycin was replaced by 50 ml of clove essential oil.

[0060] The experimental process showed that after adding clove essential oil, the hydrogel precipitated and agglomerated, and could not be poured into the mold to form a film.

[0061] Comparative Example 3

[0062] The hydrogel film was prepared according to the method of Example 1, except that: polyethylene oxide was replaced by an equal mass of chitosan, and polyvinylpyrrolidone was replaced by an equal mass of sodium alginate.

[0063] Comparative Example 4

[0064] The hydrogel film was prepared according to the method of Example 1, except that: 5 g of polyethylene oxide and 5 g of polyvinylpyrrolidone were replaced by 10 g of polyvinylpyrrolidone.

[0065] Comparative Example 5

[0066] The hydrogel film was prepared according to the method of Example 1, except that: 5 g of polyethylene oxide and 5 g of polyvinylpyrrolidone were replaced by 10 g of polyethylene oxide.

[0067] Comparative Example 6

[0068] The hydrogel film was prepared according to the method of Example 1, except that: after the embedding reaction was completed, the obtained hydrogel embedding vancomycin was poured into the mold and air-dried naturally. The air-dried gel still could not form a film after two days.

[0069] The properties of the hydrogel films prepared in the above examples and comparative examples were tested as follows:

[0070] 1. Mechanical property test: A universal material testing machine was used to test the tensile strength and elongation at break of the hydrogel film according to the method described in GB / T GBT1040.1-2006. The experimental results are shown in Table 1:

[0071] Table 1

[0072] Hydrogel film Tensile strength Elongation at break Example 1 1.3 MPa 350％ Example 2 0.9 MPa 294％ Example 3 1.0 MPa 215％ Comparative Example 1 1.2 MPa 317％ Comparative Example 2 —— —— Comparative Example 3 0.3 MPa 39％ Comparative Example 4 0.5 MPa 63％ Comparative Example 5 0.9 MPa 274％ Comparative Example 6 —— ——

[0073] Figure 2 For the tensile test results of the hydrogel film of Example 1, from the above Table 1 and Figure 2Look, the hydrogel film of Example 1 has the best mechanical properties, with high tensile strength and elongation at break.

[0074] 2. Antibacterial performance test: The experiment was carried out by the inhibition zone method.

[0075] 2.1 Select Staphylococcus aureus, inoculate it onto a fresh slant medium under sterile conditions, and culture it at an appropriate temperature for 18 - 24 hours to activate the strain. Wash the activated strain with sterile normal saline or buffer solution, transfer it to a sterile test tube, and pipette or vortex it evenly to adjust the concentration of the bacterial suspension to 10 7 CFU / mL, and set it aside after preparation.

[0076] 2.2 Prepare beef extract peptone agar medium, and sterilize it by autoclaving at 121 °C and 103.4 kPa for 15 - 20 minutes. After sterilization, wait for the medium to cool to about 50 °C, pour it into a sterile petri dish in a sterile operating table, about 15 - 20 mL per dish, and set it aside after it solidifies. Use a sterile pipette to aspirate 0.1 mL of the prepared bacterial suspension, drop it onto the surface of the solidified medium plate, and spread the bacterial liquid evenly on the surface of the medium with a sterile spreading rod to ensure that the bacterial liquid covers the entire plate. Then place the plate in an incubator at 37 °C and incubate it upside down for about 30 minutes to allow the bacterial liquid to fully adsorb on the medium. Use sterile forceps to pick up the hydrogel films of Example 1 and Comparative Example 1 respectively, gently place them at the center position of the plate coated with the bacterial liquid, and then place the plate with the hydrogel film placed in an incubator at 37 °C and incubate it for 24 hours.

[0077] 2.3 The antibacterial effects of the hydrogel films of Example 1 and Comparative Example 1 are as Figure 3 shown. It can be seen from the figure that there is a large inhibition zone near the hydrogel film of Example 1, and the colony density is also sparser than that of the comparative example, showing a strong antibacterial effect, while the hydrogel film of Comparative Example 1 has no obvious antibacterial effect.

[0078] 3. Repair performance test:

[0079] Establishment of mouse wound model: Seven healthy male KM mice aged 6 - 7 weeks with similar body weights, purchased from Jinan Pengyue Laboratory Animal Breeding Co., Ltd., were fed adaptively for 1 week to ensure good condition. The mice were anesthetized with ether gas. After the anesthesia took effect, the hair on the back of the mice was removed with a razor, with the area larger than the expected wound size. Then the skin was disinfected with iodophor 2 - 3 times and rinsed with normal saline. Surgical scissors and a living perforator were used to make circular wounds of the same size on the back skin of the mice, with a diameter of 10 - 15 mm and a depth reaching the dermis layer. Attention was paid to keeping the wound shape regular and the depth uniform. After adding an appropriate amount of normal saline to the wound surface to keep it moist, a hydrogel film was picked up with sterile forceps, and different hydrogel films were implanted into the wounds of each mouse. After implantation, it was fixed with medical tape to ensure that the film was closely attached to the wound surface and would not fall off.

[0080] Measurement of wound area: The day when the wound was created was set as the 0th day of the experiment. After that, the wound area of the mice was observed and measured every day until the wounds of all mice healed, and the complete healing was defined as the scab falling off.

[0081] The wound healing conditions of the mice using different hydrogel films are shown in Table 2 below. The healing condition of the mice using the hydrogel film of Example 1 is as Figure 4 shown.

[0082] Table 2

[0083] Hydrogel film Days required for wound healing Example 1 14 Example 2 14 Example 3 15 Comparative Example 1 20 Comparative Example 3 23 Comparative Example 4 18 Comparative Example 5 16

[0084] From Table 2 and Figure 4 it can be seen that the hydrogel film of the embodiment of the present invention has a better function of promoting wound healing compared with each comparative example. Through the combined action of vancomycin, polyethylene glycol, α - cyclodextrin, and cross - linker, the wound healing speed is greatly improved.

[0085] Through the above verification, it can be fully proved that the hydrogel film of the present invention has diverse functions and excellent performance, providing a solid foundation for its wide application in multiple fields.

Claims

1. A method for preparing a hydrogel film, characterized in that The following steps are involved: (1) mixing polyethylene glycol, α-cyclodextrin, a cross-linking agent and water and heating the mixture to perform a cross-linking reaction to obtain a hydrogel; (2) cooling the hydrogel, and then adding the functional monomer and stirring and mixing to obtain a hydrogel encapsulating the functional monomer; (3) The hydrogel encapsulating the functional monomer is poured into a mold, dried, and then plasma treated to obtain a hydrogel film.

2. The preparation method according to claim 1, characterized in that: The mass ratio of polyethylene glycol to α-cyclodextrin is 1-5:

1.

3. The preparation method according to claim 1, characterized in that: The cross-linking agent is polyethylene oxide and polyvinyl pyrrolidone; preferably, the mass ratio of polyethylene oxide to polyvinyl pyrrolidone is 1-3:

1.

4. The preparation method according to claim 1, characterized in that: The functional monomer is vancomycin.

5. The preparation method according to any one of claims 1 to 4, characterized in that: Taking the sum of polyethylene glycol, α-cyclodextrin, functional monomer, crosslinking agent and water as 100wt%, the total content of α-cyclodextrin and polyethylene glycol is 10-15% of the total raw material mass, the content of the crosslinking agent is 5-10% of the total raw material mass, the content of the functional monomer is 0.1‰-0.5‰ of the total raw material mass, and water makes up to 100wt%.

6. The preparation method according to any one of claims 1 to 5, characterized in that: The molecular weight of the polyethylene glycol is 1500-2500; preferably, the molecular weight of the polyethylene oxide is 1.8-2.2 million, and the molecular weight of the polyvinyl pyrrolidone is 50,000-70,000.

7. The preparation method according to claim 1, characterized in that: In step (1), the mixture is subjected to a cross-linking reaction at 55-75° C. for 2-4 hours. Preferably, in step (1), the mixing of the raw materials is promoted by at least one of stirring, ultrasound and heating.

8. The preparation method according to claim 1, characterized in that: In step (2), the hydrogel is cooled to 25-35° C., and then the functional monomer is added and stirred for 1-2 hours.

9. The preparation method according to claim 1, characterized in that: In step (3), the hydrogel is dried for 4-6 hours under vacuum, at a temperature of 25-35° C. and a relative humidity of 20%-30%; preferably, in step (3), the power of the plasma treatment is 90-110 W, and the treatment time is 1-10 minutes.

10. A hydrogel film prepared by the preparation method according to any one of claims 1 to 9 and applications of the hydrogel film in the fields of biology, medicine, environmental monitoring and smart wear.

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