Asymmetric adhesive hydrogel and preparation method and application thereof

Abstract

The application discloses an asymmetric adhesive hydrogel and a preparation method and application thereof, and belongs to the technical field of biomedical materials. Firstly, acrylic acid (AA), nanoparticles and a crosslinking agent are added into water and stirred uniformly; then an initiator is added into the obtained solution, and after stirring, a hydrogel pre-polymer liquid is formed; the hydrogel pre-polymer liquid is solidified to obtain the asymmetric adhesive hydrogel; the nanoparticles are induced to be asymmetrically distributed in the cross section of the hydrogel through gravity sedimentation; the carboxyl of the adhesive group is effectively closed by the nanoparticles gathered on the lower surface, so that the lower surface is hydrophilic, thereby reducing the adhesion and wet adhesion performance of the lower surface; the upper surface has fewer nanoparticles, the upper surface is hydrophobic, and the upper surface has strong adhesion and wet adhesion performance.

Description

Technical Field

[0001] This invention belongs to the field of biomedical materials technology, and particularly relates to an asymmetric adhesive hydrogel, its preparation method and application. Background Technology

[0002] Currently, surgical suturing is the most common clinical method to promote wound healing, especially when internal tissues or organs that are difficult to treat have suffered significant trauma. However, the use of surgical sutures not only causes secondary damage to tissues, increasing patient suffering, but also leads to tissue adhesions, increasing postoperative risks. Commercially available clinical tissue adhesives, such as fibrin glue, cyanoacrylate, and polyethylene glycol, offer advantages such as portability, minimally invasiveness, and ease of use; however, these biological tissue adhesives generally suffer from poor wet adhesion strength, easy detachment, or poor biocompatibility. Hydrogels have attracted widespread attention due to their good mechanical compatibility and excellent biocompatibility with tissues, and have been widely used in the field of tissue engineering. In recent years, researchers have developed various adhesive hydrogels for tissue repair based on physical interactions such as hydrogen bonding and electrostatic coupling between the hydrogel surface and biological tissues. Although these hydrogels can form strong adhesion to dry biological tissue surfaces, their adhesion strength decreases significantly on moist surfaces, and they adhere to both sides, making them unsuitable for the effective repair of tissue trauma within organisms. Developing effective hydrogel bioadhesives for repairing internal soft tissue defects remains a significant challenge. Specifically, the greatest challenge in in vivo wound repair lies in the interaction between wet tissue surfaces and different organs within a continuously dynamic in vivo environment, such as the abdominal and thoracic cavities. This necessitates that the side of the hydrogel adjacent to the injured tissue possess excellent bioadhesion and bioactivity, providing mechanical support and a favorable microenvironment for tissue repair; while the other side should ideally be non-adhesive to surrounding tissues to physically prevent the formation of fibrotic scars. Therefore, how to provide an asymmetric adhesive hydrogel that meets the above requirements has been a persistent challenge for those skilled in the art. Summary of the Invention

[0003] To address the aforementioned technical problems, this invention proposes an asymmetric adhesive hydrogel, its preparation method, and its applications.

[0004] To achieve the above objectives, the present invention provides the following technical solution: This invention provides a method for preparing an asymmetric adhesive hydrogel, comprising the following steps: first, adding acrylic acid (AA), nanoparticles and a crosslinking agent to water and stirring until homogeneous; then adding an initiator to the resulting solution and stirring to form a hydrogel prepolymer; and finally, solidifying the hydrogel prepolymer to obtain the asymmetric adhesive hydrogel. The nanoparticles have a particle size of 150-300 nm.

[0005] This invention presents an asymmetric adhesive hydrogel induced by nanoparticles. This hydrogel patch exhibits different adhesive properties on both sides. The adhesive side can repel water from the surface of dynamically moist tissue within 5 seconds through hydrophobic interactions, rapidly achieving strong adhesion between the moist dynamic tissue and the hydrogel. This seals the tissue and improves the prevention of anastomotic leakage. Simultaneously, it possesses excellent anti-adhesion properties, providing postoperative tissue adhesion prevention. This invention is the first to utilize the asymmetric gradient distribution of nanoparticles across the hydrogel cross-section to effectively seal the adhesive groups, preparing a Janus hydrogel with adhesive asymmetry, which can then be used for dynamic wet tissue adhesion and anti-adhesion.

[0006] This invention prepares a hydrogel patch with different adhesion on two sides by inducing nanoparticles. The specific principle is as follows: the asymmetric gradient distribution of nanoparticles in the cross section of the hydrogel is induced by gravity sedimentation. The lower surface (bottom surface) has more nanoparticles that effectively seal the carboxyl groups of the adhesion group, making the lower surface hydrophilic, thereby reducing its adhesion and wet adhesion performance. The upper surface (top surface) has fewer nanoparticles, and the upper surface is hydrophobic and has strong adhesion and wet adhesion performance.

[0007] Furthermore, the nanoparticles have a particle size of 150 nm.

[0008] Furthermore, the nanoparticles are selected from one of lignin silver nanoparticles, tannic acid, and polysaccharides.

[0009] Furthermore, the polysaccharide is konjac glucomannan.

[0010] Furthermore, the crosslinking agent is polyether F127 diacrylate (F127DA).

[0011] Furthermore, the initiator is selected from one of photoinitiators, thermal initiators, and redox initiators.

[0012] Furthermore, the photoinitiator is photoinitiator I2959; the thermal initiator is ammonium persulfate (APS); and the redox initiator is a mixture of potassium persulfate (KPS) and N,N,N',N'-tetramethylethylenediamine (TEMED).

[0013] Furthermore, the curing method is photocuring or thermal curing.

[0014] The present invention also provides an asymmetric adhesive hydrogel prepared according to the above method, which is a hydrogel patch with different adhesion on both sides. The lower surface has a large number of nanoparticles that effectively seal the carboxyl groups of the adhesive groups, making the lower surface hydrophilic, thereby reducing its adhesion and wet adhesion properties. The upper surface has fewer nanoparticles, making the upper surface hydrophobic and having strong adhesion and wet adhesion properties.

[0015] The present invention also provides the application of the above-mentioned asymmetric adhesive hydrogel in the preparation of drugs for preventing anastomotic leakage and drugs for preventing postoperative adhesion, that is, the asymmetric adhesive hydrogel of the present invention can be used to prevent anastomotic leakage and prevent postoperative adhesion.

[0016] The asymmetric adhesive hydrogel of the present invention exhibits strong adhesion to biological tissues on wet surfaces.

[0017] Compared with the prior art, the present invention has the following advantages and technical effects: The asymmetric adhesive hydrogel preparation process provided by this invention is simple, convenient to operate, and uses inexpensive and readily available materials. The prepared asymmetric adhesive hydrogel can achieve strong adhesion to wet biological tissues through hydrogen bonds and covalent bonds between the material (hydrogel) and the tissue (body tissue). One side is hydrophobic and has strong wet adhesion, while the other side is hydrophilic and does not adhere. This not only effectively solves the problem of wound repair in biological tissues filled with tissue fluid, but also avoids the problem of the hydrogel adhering to other tissues while repairing wounded tissue.

[0018] This invention is the first to effectively seal the adhesive groups by simply adjusting the size of the nanoparticles in the hydrogel prepolymer or controlling the gradient distribution of the nanoparticles in the hydrogel prepolymer in the system, thereby controlling the differences in adhesion on the hydrogel surface. Attached Figure Description

[0019] The accompanying drawings, which form part of this invention, are used to provide a further understanding of the invention. The illustrative embodiments of the invention and their descriptions are used to explain the invention and do not constitute an undue limitation of the invention. In the drawings: Figure 1 The graph shows the adhesion energy test results of the upper and lower surfaces of the hydrogels prepared by lignin silver nanoparticles of different sizes in Examples 1-4. Figure 2 The graph shows the adhesion energy test results of the upper and lower surfaces of the hydrogels prepared by different types of nanoparticles in Examples 2 and 5-6. Figure 3 The graph shows the adhesion energy test results of the upper and lower surfaces of the hydrogels prepared with different initiators in Examples 2 and 7-8. Figure 4 The graph shows the adhesion energy test results of the upper and lower surfaces of the hydrogels prepared by different settling times of lignin silver nanoparticles in Examples 2 and 9-12. Figure 5 The adhesion diagrams for the hydrogel prepared in Example 2 and different wet tissues are shown, where a is pig intestine, b is pig skin, c is pig kidney, and d is pig liver; Figure 6This is a graph showing the cytotoxicity results of the gel material prepared in Example 2 after co-culturing with L929 cells; Figure 7 The graph shows the adhesion energy test results of the upper and lower surfaces of the hydrogel prepared in Example 2 to dry and wet tissues. Figure 8 The image shows the water contact angles of the upper and lower surfaces of the hydrogel prepared in Example 2, where a represents the upper surface and b represents the lower surface. Figure 9 SEM images of the upper and lower surfaces of the hydrogel prepared in Example 2; Figure 10 XPS results for the upper and lower surfaces of the hydrogel prepared in Example 2. Detailed Implementation

[0020] Various exemplary embodiments of the present invention will now be described in detail. This detailed description should not be considered as a limitation of the present invention, but rather as a more detailed description of certain aspects, features, and embodiments of the present invention.

[0021] It should be understood that the terminology used in this invention is merely for describing particular embodiments and is not intended to limit the invention. Furthermore, with respect to numerical ranges in this invention, it should be understood that each intermediate value between the upper and lower limits of the range is also specifically disclosed. Every smaller range between any stated value or intermediate value within a stated range, and any other stated value or intermediate value within said range, is also included in this invention. The upper and lower limits of these smaller ranges may be independently included or excluded from the range.

[0022] Unless otherwise stated, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. While only preferred methods and materials have been described herein, any methods and materials similar or equivalent to those described herein may be used in the implementation or testing of this invention. All references to this specification are incorporated by way of citation to disclose and describe methods and / or materials associated with those references. In the event of any conflict with any incorporated reference, the content of this specification shall prevail.

[0023] Various modifications and variations can be made to the specific embodiments described in this specification without departing from the scope or spirit of the invention, as will be apparent to those skilled in the art. Other embodiments derived from this specification will also be apparent to those skilled in the art. This specification and embodiments are merely exemplary.

[0024] The terms “include,” “including,” “have,” “contain,” etc., used in this article are all open-ended terms, meaning that they include but are not limited to.

[0025] An embodiment of the present invention provides a method for preparing an asymmetric adhesive hydrogel, comprising the following steps: first, adding acrylic acid (AA), nanoparticles and a crosslinking agent to water and stirring until homogeneous; then adding an initiator to the resulting solution and stirring to form a hydrogel prepolymer; and finally solidifying the hydrogel prepolymer to obtain an asymmetric adhesive hydrogel. The particle size of the nanoparticles is 100-300 nm.

[0026] The present invention provides an asymmetric adhesive hydrogel prepared by nanoparticle induction, which is a hydrogel patch with different adhesion on both sides. The specific principle is as follows: the asymmetric gradient distribution of nanoparticles in the cross section of the hydrogel is induced by gravity sedimentation. The lower surface has more nanoparticles that effectively seal the carboxyl groups of the adhesive groups, making the lower surface hydrophilic, thereby reducing its adhesion and wet adhesion properties. The upper surface has fewer nanoparticles, making the upper surface hydrophobic and having strong adhesion and wet adhesion properties.

[0027] In a preferred embodiment of the present invention, the mass ratio of AA, nanoparticles, crosslinking agent and initiator is (3-8):(0.002-0.007):(0.05-0.3):(0.025-0.026), preferably 5:0.005:0.1:(0.025-0.026).

[0028] For example, after adding AA, nanoparticles and crosslinking agent to water, the stirring time is 20 minutes.

[0029] For example, after adding the initiator, the stirring time is 10 minutes.

[0030] In a preferred embodiment of the present invention, after obtaining the hydrogel prepolymer, the method further includes a step of allowing the hydrogel prepolymer to settle and then solidifying it.

[0031] In a preferred embodiment of the present invention, the settling time of the hydrogel prepolymer is 0-20 min, preferably 0-5 min, and more preferably no settling, that is, the prepared hydrogel prepolymer is directly solidified.

[0032] In a preferred embodiment of the present invention, the particle size of the nanoparticles is 150 nm.

[0033] In a preferred embodiment of the present invention, the nanoparticles are selected from one of lignin silver nanoparticles, tannic acid, and polysaccharides.

[0034] In a preferred embodiment of the present invention, the polysaccharide is konjac glucomannan.

[0035] In a preferred embodiment of the present invention, the crosslinking agent is polyether F127 diacrylate (F127DA) with a weight-average molecular weight of 12000.

[0036] In a preferred embodiment of the present invention, the initiator is selected from one of photoinitiators, thermal initiators, and redox initiators.

[0037] This invention can use various initiators such as thermal initiators, photoinitiators, and redox initiators to initiate cross-linking of the system. When different initiators are used, it is only necessary to provide the corresponding conditions so that they can play the role of initiating cross-linking of the system.

[0038] In a preferred embodiment of the present invention, the photoinitiator is photoinitiator I2959; the thermal initiator is ammonium persulfate (APS); the redox initiator is a mixture of potassium persulfate (KPS) and N,N,N',N'-tetramethylethylenediamine (TEMED); and the preferred initiator is photoinitiator I2959.

[0039] In a preferred embodiment of the present invention, the curing method is photocuring or thermal curing.

[0040] In a preferred embodiment of the present invention, photocuring is performed under ultraviolet light.

[0041] For example, light curing is cross-linking and curing under 40W ultraviolet light for 10 minutes.

[0042] For example, thermosetting involves reacting at 60°C for 6 hours.

[0043] The embodiments of the present invention also provide an asymmetric adhesive hydrogel prepared according to the above method, which is a hydrogel patch with different adhesion on two sides. The lower surface (bottom surface) has a large number of nanoparticles that effectively seal the carboxyl groups of the adhesive groups, making the lower surface hydrophilic, thereby reducing its adhesion and wet adhesion properties. The upper surface (top surface) has fewer nanoparticles, and the upper surface is hydrophobic and has strong adhesion and wet adhesion properties.

[0044] Embodiments of the present invention also provide the application of the above-mentioned asymmetric adhesive hydrogel in the preparation of drugs for preventing anastomotic leakage and drugs for preventing postoperative adhesion, that is, the asymmetric adhesive hydrogel of the present invention can be used to prevent anastomotic leakage and prevent postoperative adhesion.

[0045] The asymmetric adhesive hydrogel of the present invention exhibits strong adhesion to biological tissues on wet surfaces.

[0046] This invention induces an asymmetric gradient distribution of nanoparticles in the cross-section of a hydrogel through gravity sedimentation. The side with more nanoparticles effectively seals the adhesive groups, making the lower surface hydrophilic and exhibiting weak adhesion and weak wet adhesion to biological tissues. The side with fewer nanoparticles is hydrophobic and exhibits strong adhesion and wet adhesion to biological tissues. The hydrogel prepared by the method of this invention not only achieves strong adhesion to wounded and wet tissues in vivo, but also effectively avoids the problem of adhesion between wounded tissues and other tissues.

[0047] In a preferred embodiment of the present invention, the method for preparing lignin silver nanoparticles is as follows: alkali lignin and sodium hydroxide are dissolved in water to obtain a lignin solution; silver nitrate is dissolved in water to form a silver nitrate solution; ammonia is added dropwise to the silver nitrate solution until it becomes clear and transparent, then the lignin solution is added dropwise, the reaction is carried out for 4 hours, washed, and dried to obtain lignin silver nanoparticles.

[0048] An exemplary method for preparing lignin-silver nanoparticles with a particle size of 100 nm is as follows: 1 g of alkali lignin is dissolved in 20 mL of 1.25 mol / L sodium hydroxide solution to obtain a lignin solution; 0.4 g of silver nitrate is dissolved in 60 mL of water to form a silver nitrate solution; 5 mol / L ammonia is added dropwise to the silver nitrate solution until it becomes clear and transparent, followed by the addition of the lignin solution. After reacting for 4 hours, the mixture is washed and dried to obtain lignin-silver nanoparticles with a particle size of 100 nm.

[0049] An exemplary method for preparing lignin-silver nanoparticles with a particle size of 150 nm is as follows: 1 g of alkali lignin is dissolved in 20 mL of 1.25 mol / L sodium hydroxide solution to obtain a lignin solution; 0.6 g of silver nitrate is dissolved in 60 mL of water to form a silver nitrate solution; 5 mol / L ammonia is added dropwise to the silver nitrate solution until it becomes clear and transparent, followed by the addition of the lignin solution. After reacting for 4 hours, the mixture is washed and dried to obtain lignin-silver nanoparticles with a particle size of 150 nm.

[0050] An exemplary method for preparing lignin-silver nanoparticles with a particle size of 230 nm is as follows: 1 g of alkali lignin is dissolved in 20 mL of 1.25 mol / L sodium hydroxide solution to obtain a lignin solution; 0.8 g of silver nitrate is dissolved in 60 mL of water to form a silver nitrate solution; 5 mol / L ammonia is added dropwise to the silver nitrate solution until it becomes clear and transparent, followed by the addition of the lignin solution. After reacting for 4 hours, the mixture is washed and dried to obtain lignin-silver nanoparticles with a particle size of 230 nm.

[0051] An exemplary method for preparing lignin-silver nanoparticles with a particle size of 300 nm is as follows: 1 g of alkali lignin is dissolved in 20 mL of 1.25 mol / L sodium hydroxide solution to obtain a lignin solution; 1 g of silver nitrate is dissolved in 60 mL of water to form a silver nitrate solution; 5 mol / L ammonia is added dropwise to the silver nitrate solution until it becomes clear and transparent, then the lignin solution is added dropwise, and after reacting for 4 hours, the mixture is washed and dried to obtain lignin-silver nanoparticles with a particle size of 300 nm.

[0052] Unless otherwise specified, the room temperature in this invention is 25±2℃.

[0053] All raw materials used in the embodiments of this invention were purchased commercially. For example, mouse fibroblast (L929) cells were purchased from Wuhan Pronosei Life Science Technology Co., Ltd.

[0054] It should be noted that any aspects not described in detail in this invention are conventional practices in the field and are not the focus of this invention.

[0055] The technical solution of the present invention will be further illustrated by the following embodiments.

[0056] Example 1 Preparation method of lignin silver nanoparticles with a particle size of 100 nm: 1 g of alkali lignin was dissolved in 20 mL of 1.25 mol / L sodium hydroxide solution to obtain a lignin solution; 0.4 g of silver nitrate was dissolved in 60 mL of water to form a silver nitrate solution; 5 mol / L ammonia water was added dropwise to the silver nitrate solution until it became clear and transparent, and then the lignin solution was added dropwise. After reacting for 4 hours, the mixture was washed and dried to obtain lignin silver nanoparticles with a particle size of 100 nm.

[0057] A method for preparing an asymmetric adhesive hydrogel, comprising the following steps: Weigh 5g of acrylic acid (AA), 0.1g of polyether F127 diacrylate (F127DA, weight average molecular weight of 12000, the same below), and 0.005g of lignin silver nanoparticles with a particle size of 100nm. Add them to 10mL of deionized water and stir for 20min. Then add 0.025g of initiator I2959 and continue stirring for 10min to finally form a hydrogel prepolymer. Add the prepolymer to a polytetrafluoroethylene mold, cover the upper surface with a glass slide, and crosslink and cure under 40W ultraviolet light for 10min. Do not treat the hydrogel after demolding. Finally, an asymmetric adhesive hydrogel is obtained, which is a hydrogel with different surface adhesion.

[0058] Example 2 Preparation method of lignin silver nanoparticles with a particle size of 150 nm: 1 g of alkali lignin was dissolved in 20 mL of 1.25 mol / L sodium hydroxide solution to obtain a lignin solution; 0.6 g of silver nitrate was dissolved in 60 mL of water to form a silver nitrate solution; 5 mol / L ammonia water was added dropwise to the silver nitrate solution until it became clear and transparent, and then the lignin solution was added dropwise. After reacting for 4 hours, the mixture was washed and dried to obtain lignin silver nanoparticles with a particle size of 150 nm.

[0059] A method for preparing an asymmetric adhesive hydrogel, comprising the following steps: Weigh 5g of AA, 0.1g of F127DA, and 0.005g of lignin silver nanoparticles with a particle size of 150nm, add them to 10mL of deionized water, stir for 20min, then add 0.025g of initiator I2959 and continue stirring for 10min to finally form a hydrogel prepolymer. Add the prepolymer to a polytetrafluoroethylene mold, cover the upper surface with a glass slide, and crosslink and cure under 40W ultraviolet light for 10min. The hydrogel after demolding is left untreated, and the asymmetric adhesive hydrogel is finally obtained.

[0060] Example 3 Preparation method of lignin silver nanoparticles with a particle size of 230 nm: 1 g of alkali lignin was dissolved in 20 mL of 1.25 mol / L sodium hydroxide solution to obtain a lignin solution; 0.8 g of silver nitrate was dissolved in 60 mL of water to form a silver nitrate solution; 5 mol / L ammonia water was added dropwise to the silver nitrate solution until it became clear and transparent, and then the lignin solution was added dropwise. After reacting for 4 hours, the mixture was washed and dried to obtain lignin silver nanoparticles with a particle size of 230 nm.

[0061] A method for preparing an asymmetric adhesive hydrogel, comprising the following steps: Weigh 5g of AA, 0.1g of F127DA, and 0.005g of lignin silver nanoparticles with a particle size of 230nm, add them to 10mL of deionized water, stir for 20min, then add 0.025g of initiator I2959 and continue stirring for 10min to finally form a hydrogel prepolymer. Add the prepolymer to a polytetrafluoroethylene mold, cover the upper surface with a glass slide, and crosslink and cure under 40W ultraviolet light for 10min. The hydrogel after demolding is left untreated, and finally an asymmetric adhesive hydrogel is obtained.

[0062] Example 4 Preparation method of lignin silver nanoparticles with a particle size of 300 nm: 1 g of alkali lignin was dissolved in 20 mL of 1.25 mol / L sodium hydroxide solution to obtain a lignin solution; 1 g of silver nitrate was dissolved in 60 mL of water to form a silver nitrate solution; 5 mol / L ammonia water was added dropwise to the silver nitrate solution until it became clear and transparent, and then the lignin solution was added dropwise. After reacting for 4 hours, the mixture was washed and dried to obtain lignin silver nanoparticles with a particle size of 300 nm.

[0063] A method for preparing an asymmetric adhesive hydrogel, comprising the following steps: Weigh 5g of AA, 0.1g of F127DA, and 0.005g of lignin silver nanoparticles with a particle size of 300nm, add them to 10mL of deionized water, stir for 20min, then add 0.025g of initiator I2959 and continue stirring for 10min to finally form a hydrogel prepolymer. Add the prepolymer to a polytetrafluoroethylene mold, cover the upper surface with a glass slide, and crosslink and cure under 40W ultraviolet light for 10min. The hydrogel after demolding is left untreated, and the asymmetric adhesive hydrogel is finally obtained.

[0064] Example 5 A method for preparing an asymmetric adhesive hydrogel, comprising the following steps: Weigh 5g of AA, 0.1g of F127DA, and 0.005g of hydrated tannic acid with a particle size of 130nm, add them to 10mL of deionized water, stir for 20min, then add 0.025g of initiator I2959 and continue stirring for 10min to finally form a hydrogel prepolymer. Add the prepolymer to a polytetrafluoroethylene mold, cover the upper surface with a glass slide, and crosslink and cure under 40W ultraviolet light for 10min. The hydrogel after demolding is left untreated, and the asymmetric adhesive hydrogel is finally obtained.

[0065] Example 6 A method for preparing an asymmetric adhesive hydrogel, comprising the following steps: Weigh 5g AA, 0.1g F127DA, and 0.005g hydrated konjac glucomannan (KGM) with a particle size of 120nm, add them to 10mL of deionized water, stir for 20min, then add 0.025g initiator I2959 and continue stirring for 10min to finally form a hydrogel prepolymer. Add the prepolymer to a polytetrafluoroethylene mold, cover the upper surface with a glass slide, and crosslink and cure under 40W ultraviolet light for 10min. The hydrogel after demolding is left untreated, and the asymmetric adhesive hydrogel is finally obtained.

[0066] Example 7 A method for preparing an asymmetric adhesive hydrogel, comprising the following steps: Weigh 5g of AA, 0.1g of F127DA, and 0.005g of lignin silver nanoparticles with a particle size of 150nm, add them to 10mL of deionized water, stir for 20min, then add 0.025g of initiator ammonium persulfate (APS) and continue stirring for 10min to finally form a hydrogel prepolymer. Add the prepolymer to a polytetrafluoroethylene mold, cover the upper surface with a glass slide, and react at 60℃ for 6h to obtain hydrogels with different surface adhesion.

[0067] Example 8 A method for preparing an asymmetric adhesive hydrogel, comprising the following steps: Weigh 5g of AA, 0.1g of F127DA, and 0.005g of lignin silver nanoparticles with a particle size of 150nm, add them to 10mL of deionized water, stir for 20min, then add a redox initiator (composed of 0.025g of potassium persulfate (KPS) and 0.0000345g of crosslinking promoter TEMED), and continue stirring for 10min to finally form a hydrogel prepolymer. Add the prepolymer to a polytetrafluoroethylene mold, cover the upper surface with a glass slide, and react at 60℃ for 6h to obtain hydrogels with different surface adhesion.

[0068] Examples 9-12 Same as Example 2, except that the sedimentation time of the nanoparticles was 5 min (Example 9), 10 min (Example 10), 15 min (Example 11) and 20 min (Example 12).

[0069] Comparative Example 1 Preparation method of acrylate-modified hyaluronic acid (HA-MA): Dissolve 10g of hyaluronic acid in 100mL of water. After complete dissolution, add 1mL of methacrylic anhydride. After reacting for 3h, dialyze to obtain acrylate-modified hyaluronic acid (HA-MA).

[0070] A method for preparing a hydrogel, comprising the following steps: Weigh 5g of HA-MA, 0.1g of F127DA, and 0.005g of 150nm lignin silver nanoparticles, add them to 10mL of deionized water, stir for 20min, then add 0.05g of initiator I2959 and continue stirring for 10min to finally form a hydrogel prepolymer. Add the prepolymer to a polytetrafluoroethylene mold, cover the upper surface with a glass slide, and crosslink and cure under 40W ultraviolet light for 10min. The hydrogel after demolding is left untreated to obtain the final hydrogel.

[0071] Comparative Example 2 A method for preparing a hydrogel, comprising the following steps: Weigh 5g of acrylamide (AM), 0.1g of F127DA, and 0.005g of 150nm lignin silver nanoparticles, add them to 10mL of deionized water, stir for 20min, then add 0.025g of initiator I2959 and continue stirring for 10min to finally form a hydrogel prepolymer. Add the prepolymer to a polytetrafluoroethylene mold, cover the upper surface with a glass slide, and crosslink and cure under 40W ultraviolet light for 10min. The hydrogel after demolding is left untreated to obtain the final hydrogel.

[0072] Comparative Example 3 A method for preparing a hydrogel, comprising the following steps: Weigh 5g of AA, 0.1g of F127DA, and 0.005g of sodium lignosulfonate with a hydrated particle size of 15nm. Add them to 10mL of deionized water and stir for 20min. Then add 0.025g of initiator APS and continue stirring for 10min to finally form a hydrogel prepolymer. Add the prepolymer to a polytetrafluoroethylene mold, cover the upper surface with a glass slide, and react at 60℃ for 6h to obtain the hydrogel.

[0073] Comparative Example 4 A method for preparing a hydrogel, comprising the following steps: Weigh 5g of AA, 0.1g of F127DA, and 0.005g of 80nm silver nanoparticles, add them to 10mL of deionized water, stir for 20min, then add 0.025g of initiator APS and continue stirring for 10min to finally form a hydrogel prepolymer. Add the prepolymer to a polytetrafluoroethylene mold, cover the upper surface with a glass slide, and react at 60℃ for 6h to obtain the hydrogel.

[0074] Comparative Example 5 Preparation method of acrylate-modified gelatin (Gel-MA): Dissolve 10g of gelatin in 100mL of water. After complete dissolution, add 1mL of methacrylic anhydride. After reacting for 3h, dialyze to obtain acrylate-modified gelatin (HA-MA).

[0075] A method for preparing a hydrogel, comprising the following steps: Weigh 5g of HA-MA, 0.1g of F127DA, and 0.005g of 150nm lignin silver nanoparticles, add them to 10mL of deionized water, stir for 20min, then add 0.05g of initiator I2959 and continue stirring for 10min to finally form a hydrogel prepolymer. Add the prepolymer to a polytetrafluoroethylene mold, cover the upper surface with a glass slide, and crosslink and cure under 40W ultraviolet light for 10min. The hydrogel after demolding is left untreated to obtain the final hydrogel.

[0076] Comparative Example 6 Weigh 5g of AA-NHS, 0.1g of F127DA, and 0.005g of 80nm silver nanoparticles, add them to 10mL of deionized water, stir for 20min, then add 0.025g of initiator APS and continue stirring for 10min to finally form a hydrogel prepolymer. Add the prepolymer to a polytetrafluoroethylene mold, cover the upper surface with a glass slide, and react at 60℃ for 6h to obtain the hydrogel.

[0077] Comparative Example 7 Weigh 5g of AA, 0.1g of F127DA, and 0.005g of enzymatically hydrolyzed lignin with a hydrated particle size of 30nm. Add them to 10mL of deionized water and stir for 20min. Then add 0.025g of initiator APS and continue stirring for 10min to finally form a hydrogel prepolymer. Add the prepolymer to a polytetrafluoroethylene mold, cover the upper surface with a glass slide, and react at 60℃ for 6h to obtain the hydrogel.

[0078] Effect verification The adhesion properties of the asymmetric adhesive hydrogels prepared in Examples 1-12 and Comparative Examples 1-7 (hereinafter referred to as hydrogel dressings) to porcine skin tissue were tested using the following method: A universal testing machine (model 2kN, CMT1203) was used. The hydrogel dressings prepared in Examples 1-12 and Comparative Examples 1-7 were cut into rectangular shapes (35mm long, 1mm wide, and 1.5mm thick). The upper and lower surfaces of the hydrogel dressings were then bonded to the porcine skin tissue. After pressing for 1 minute, the other side of the hydrogel dressing was bonded to a rigid polyethylene terephthalate (PET) film using Krazy Glue. The PET film served as the backing for the hydrogel dressing. The backing and the porcine skin tissue were connected to a fixture. All the work done by the machine was equivalent to the energy dissipated at the crack tip. The universal testing machine applied unidirectional tension, and the changes in force and displacement were recorded simultaneously. The loading rate was kept constant at 100 mm / min. The adhesion energy was twice the average force-to-width ratio. The adhesion energy test results for the hydrophilic and hydrophobic sides of each hydrogel are as follows: Figure 1-4 As shown in Table 1, where Figure 1 The figures show the adhesion energy test results of the upper and lower surfaces of hydrogel dressings prepared by lignin silver nanoparticles of different sizes in Examples 1-4. It can be seen that the size of the lignin nanoparticles affects the adhesion strength at the bottom of the hydrogel. As the size of the lignin nanoparticles increases from 100 nm to 150 nm, the adhesion strength of the lower surface decreases drastically. As the size of the nanoparticles increases, the adhesion strength of the lower surface increases again. Figure 2The figures show the adhesion energy test results of the upper and lower surfaces of the hydrogel dressings prepared by different types of nanoparticles in Examples 2 and 5-6. It can be seen that when the diameter of the nanoparticles is greater than 100 nanometers and less than 200 nanometers, the adhesion strength of the lower surface of the hydrogel is significantly different from that of the upper surface. Figure 3 The graph shows the adhesion energy test results of the upper and lower surfaces of the hydrogel dressings prepared with different initiators in Examples 2 and 7-8. It can be seen that the hydrogel prepared with the photoinitiator has the largest asymmetric adhesion difference. Figure 4 The graph shows the adhesion energy test results of the upper and lower surfaces of the hydrogel dressings prepared with different settling times of lignin silver nanoparticles in Examples 2 and 9-12. It can be seen that the settling time has no significant effect on the asymmetric adhesion of the hydrogel. Table 1 shows the adhesion energy test results of the upper and lower surfaces of the hydrogel dressings prepared in Comparative Examples 1-7.

[0079] Table 1 As shown in Table 1, changing the basic gelling matrix of the hydrogel makes the hydrogel almost asymmetric adhesion. This may be because the change in the gelling matrix hinders the gradient distribution of nanoparticles. Changing the type of nanoparticles and making their size less than 100 nm reduces the adhesion difference between the upper and lower surfaces of the hydrogel, thus worsening the asymmetric adhesion.

[0080] The adhesion layer of the asymmetric adhesive hydrogel prepared in Example 2 was brought into contact with the surfaces of different substrates (including porcine tissues (liver, skin, intestine, kidney)), and slight pressure was applied to ensure full adhesion between the gel and the substrate. The results are as follows: Figure 5 As shown, the asymmetric adhesive hydrogel prepared by this invention can be directly adhered to the surfaces of different substrates (pig liver, pig skin, pig intestines, and pig kidneys).

[0081] The biocompatibility of the asymmetric adhesive hydrogel prepared in Example 2 was tested as follows: 1 g of the asymmetric adhesive hydrogel was dispersed in 10 mL of MEM medium and soaked at 37°C for 24 h to obtain a dispersion. The cytotoxicity of the hydrogel dispersion was detected using a CCK-8 assay kit. The dispersion was diluted to 10 mg / mL and co-cultured with mouse fibroblast (L929) cells for 24 h, 72 h, and 120 h. After removing the medium, 100 μL of MEM medium (containing 10 μL of CCK-8) was added to each well, and the cells were incubated for 2 h. The absorbance at 450 nm was measured using a microplate reader, and the relative cell viability was calculated. Three parallel experiments were set up, with L929 cells cultured in high-glucose complete medium used as a control group. The experimental results are as follows: Figure 6As shown, after culturing for 24h, 72h, and 120h, the survival rates of both cell types reached over 90%, exhibiting high cell viability and indicating that the hydrogel has good biocompatibility. To investigate the wet adhesion performance of the tissue patch of this invention, the adhesion performance of the upper and lower surfaces of the asymmetric adhesive hydrogel prepared in Example 2 to dry and wet tissues was tested. The specific testing procedure was as follows: the hydrogel dressing was cut into rectangular shapes, and then the upper and lower surfaces of the hydrogel dressing were bonded to dried pigskin tissue and moistened pigskin tissue removed after being soaked in water. After pressing for 1 minute, the other side of the hydrogel dressing was bonded to a PET film using Krazy Glue. The PET film served as the backing for the hydrogel dressing. The backing for the hydrogel dressing and the pigskin tissue were connected to a fixture. All the work done by the machine is equal to the energy dissipated at the crack tip. A universal testing machine applied unidirectional tension, while simultaneously recording changes in force and displacement. The loading rate was kept constant at 100 mm / min. Figure 7 It can be seen that the adhesion performance of the top and bottom surfaces of the asymmetric adhesive hydrogel prepared in Example 2 to dry and wet tissues is not significantly different. Therefore, the asymmetric adhesive provided by the present invention has excellent wet tissue adhesion performance when used as an asymmetric adhesive patch.

[0082] To investigate the asymmetry of adhesion of the asymmetric adhesive hydrogel of this invention, the contact angles of the upper and lower surfaces of the asymmetric adhesive hydrogel of Example 2 were measured using a contact angle meter. Figure 8 It can be seen that the contact angle of the strong adhesion surface on the upper surface is 115° (>90° indicates hydrophobicity); the contact angle of the weak adhesion surface on the lower surface is 66° (<90° indicates hydrophilicity). Therefore, the asymmetric adhesive hydrogel provided by this invention possesses asymmetric hydrophilic-hydrophobic interface properties and can be used as an asymmetric adhesive patch. Simultaneously, the elemental distribution of the upper and lower surfaces and cross-section of the hydrogel was observed using scanning electron microscopy, such as... Figure 9 It can be seen that the silver content on the upper surface of the hydrogel is significantly lower than that on the lower surface, indicating that the lignin silver nanoparticles are deposited on the lower surface under gravity. The elemental distribution in its cross-section verifies this result. This invention also used X-ray electron spectroscopy to test the group distribution on the upper and lower surfaces of the hydrogel. Figure 10 It can be seen that the content of carboxyl groups, the adhesion groups, on the upper surface is significantly higher than that on the lower surface, which is consistent with its adhesion results. The above are merely preferred embodiments of the present invention, but the scope of protection of the present invention is not limited thereto. Any variations or substitutions that can be easily conceived by those skilled in the art within the scope of the technology disclosed in the present invention should be included within the scope of protection of the present invention.

Claims

1. A method for preparing an asymmetric adhesive hydrogel, characterized in that, Includes the following steps: First, acrylic acid, nanoparticles and crosslinking agent are added to water and stirred evenly; then, an initiator is added to the resulting solution and stirred to form a hydrogel prepolymer; the hydrogel prepolymer is then solidified to obtain the asymmetric adhesive hydrogel. The nanoparticles have a particle size of 100-300 nm.

2. The method for preparing the asymmetric adhesive hydrogel according to claim 1, characterized in that, The nanoparticles have a particle size of 150 nm.

3. The method for preparing the asymmetric adhesive hydrogel according to claim 1, characterized in that, The nanoparticles are selected from one of lignin silver nanoparticles, tannic acid, and polysaccharides.

4. The method for preparing the asymmetric adhesive hydrogel according to claim 3, characterized in that, The polysaccharide is konjac glucomannan.

5. The method for preparing the asymmetric adhesive hydrogel according to claim 1, characterized in that, The crosslinking agent is polyether F127 diacrylate.

6. The method for preparing the asymmetric adhesive hydrogel according to claim 1, characterized in that, The initiator is selected from one of photoinitiators, thermal initiators, and redox initiators.

7. The method for preparing the asymmetric adhesive hydrogel according to claim 6, characterized in that, The photoinitiator is photoinitiator I2959; the thermal initiator is ammonium persulfate; and the redox initiator is a mixture of potassium persulfate and N,N,N',N'-tetramethylethylenediamine.

8. The method for preparing the asymmetric adhesive hydrogel according to claim 1, characterized in that, The curing method is either photocuring or thermocuring.

9. An asymmetric adhesive hydrogel, characterized in that, It is prepared according to any one of claims 1-8.

10. The use of the asymmetric adhesive hydrogel as described in claim 9 in the preparation of drugs for preventing anastomotic leakage and drugs for preventing postoperative adhesion.

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