Gradient self-crosslinking constructed asymmetric adhesive film as well as construction method and application thereof

Abstract

The invention discloses a method for constructing an asymmetric adhesive film through gradient self-crosslinking, which comprises the following steps: 1) preparation of a macromolecular solution: adding a macromolecular polymer with an adhesive group and an active group into a solvent to prepare the macromolecular solution; 2) forming a polymer film: concentrating the polymer solution at a certain temperature to form the polymer film with a predetermined thickness; and 3) gradient cross-linking construction: dissolving a high-molecular cross-linking agent to a certain concentration, feeding the dissolved high-molecular cross-linking agent to the surface of the high-molecular film, and controlling the diffusion and reaction time of the cross-linking agent to construct the high-molecular film with asymmetric adhesion performance. According to the asymmetric adhesive film prepared by the invention, the high adhesion of the high-adhesion layer is beneficial to sealing an operative incision and reducing liquid leakage; due to the low adhesion of the non-adhesive layer, the risk of tissue adhesion is reduced, and tissue adhesion is prevented. The asymmetric adhesive film is easy to cut and apply, the operation is simple and convenient, and the in-vivo safety of the asymmetric material is ensured by the biocompatibility of the asymmetric material.

Description

Technical Field

[0001] The present invention belongs to the technical field of biomedical materials, and in particular relates to a gradient self-crosslinking asymmetric adhesive patch and its construction method and application, especially its application in abdominal tissue repair. Background Art

[0002] After traditional abdominal surgery, patients may encounter a series of complex and challenging problems that seriously affect the postoperative recovery process and quality of life. Specifically, leakage problems may cause digestive fluid or blood to accumulate in the abdominal cavity, increasing the risk of infection and triggering an inflammatory response. Tissue adhesions may lead to restricted intestinal motility, causing serious complications such as chronic pain or intestinal obstruction. In addition, improper infection control will further delay wound healing, increase patients' dependence on antibiotics and possible drug resistance problems. Prolonged recovery time means that patients need longer medical monitoring and rehabilitation guidance, which not only limits the patient's ability to move, but also increases the demand for medical resources.

[0003] Abdominal intestinal fistula is a serious medical condition that commonly occurs after abdominal surgery, intestinal injury, inflammation, or infection. It causes intestinal contents to enter the abdominal cavity through abnormal channels, leading to a series of hazards, including abdominal infection, fluid and electrolyte loss, malnutrition, multi-organ dysfunction, psychological impact, treatment complexity, risk of complications, decreased quality of life, increased economic burden, and complexity of rehabilitation treatment, and may also lead to death. The commonly used methods are normal sutures, staples, and anastomotic clips for sealing and hemostasis.

[0004] In addition, the surgical process may also cause adhesions between tissues and implants. Adhesions are fibrous bands of scar tissue that form between internal organs and their surrounding tissues. They are the result of the natural healing process of wounds caused by surgery, physical injury, or inflammation. In most cases of in-vivo implant surgery, adhesions will occur regardless of the surgical site. In addition, abdominal adhesions are a common problem in surgical procedures, with an incidence rate of over 90%, which can easily cause intestinal obstruction, severe pain, or organ disorders. Clinically, the commonly used method for abdominal adhesions is a second surgery to release the adhesions. However, a second surgery may cause new adhesions, while also increasing medical costs and the degree of physical trauma to the patient. The problem of postoperative adhesions has not yet been solved in the medical community. Summary of the Invention

[0005] To address the above issues, the present invention provides an asymmetric adhesive patch constructed with gradient self-crosslinking, its construction method, and its application in abdominal tissue repair. The patch utilizes gradient self-crosslinking to achieve a gradually decreasing crosslinking density from top to bottom, thereby imparting adhesive properties to its asymmetric structure. The adhesive side effectively prevents post-suturing fluid leakage, while the non-adhesive side effectively prevents tissue adhesion. This patch is used for intra-abdominal tissue repair, preventing fluid leakage and adhesion. It can be effectively applied in areas such as assisting in the treatment of abdominal intestinal anastomoses and hemostasis of the liver.

[0006] In order to achieve the above object, the present invention provides the following technical solutions:

[0007] A method for constructing an asymmetric adhesive film by gradient self-crosslinking comprises the following steps:

[0008] 1) Preparation of polymer solution: adding a polymer having both adhesive groups and active groups to a solvent to prepare a polymer solution of a certain mass concentration;

[0009] 2) Formation of a polymer film: The polymer solution is concentrated at a certain temperature, and the solvent is gradually evaporated to form a polymer film with a predetermined thickness;

[0010] 3) Gradient cross-linking: The cross-linking agent is dissolved to a certain concentration and then evenly immersed into the surface of the polymer film. The diffusion and reaction time of the cross-linking agent are controlled so that the cross-linking density of the polymer film gradually decreases from the top surface to the bottom surface, thereby constructing a film with asymmetric adhesion properties.

[0011] In one embodiment of the present invention, the adhesive group is a group capable of enhancing adhesion performance; and the active group is a group containing an amino group or a carboxyl group.

[0012] In one embodiment of the present invention, the high molecular polymer having adhesion groups and active groups is selected from one or more of polymethylsiloxane (PDMS), dopamine grafted chitosan, dopamine grafted gelatin, dopamine grafted silk fibroin, dopamine grafted hyaluronic acid and dopamine grafted sodium alginate.

[0013] The present invention uses a gradient crosslinking method to crosslink high molecular weight polymers, creating a dual-layer film with varying crosslink densities. The upper surface has a higher crosslink density, and the high crosslink density region acts as a non-adhesive layer, exhibiting low or no adhesion and strong mechanical strength. The lower surface has a lower crosslink density, and the low crosslink density region acts as an adhesive layer, exhibiting differentiated high adhesion and greater flexibility.

[0014] In one embodiment of the present invention, the mass concentration of the polymer solution is 5%-50%, preferably 10%-30%, and more preferably 20%-30%.

[0015] In one embodiment of the present invention, the solvent used in step 1) is a solvent that can dissolve the high molecular weight polymer and is suitable for the subsequent cross-linking reaction.

[0016] Preferably, the solvent used in step 1) is an organic solvent or water, and the organic solvent is chloroform and / or ethanol.

[0017] In one embodiment of the present invention, in step 2), the polymer solution is introduced into a fixed mold and concentrated at 37-90° C. for 10-24 hours to gradually evaporate the solvent to obtain a polymer film.

[0018] In one embodiment of the present invention, the thickness of the polymer film is 1 to 5 cm, preferably 2 to 3 cm.

[0019] In one embodiment of the present invention, the cross-linking agent is selected from one or more of a silane coupling agent, glutaraldehyde, genipin and calcium chloride.

[0020] In one embodiment of the present invention, the silane coupling agent is used to crosslink polymethylsiloxane; the glutaraldehyde and genipin are used to crosslink polymers with amino groups; and the calcium chloride can form ionic bonds with carboxyl groups and is used to crosslink carboxyl-containing polymers.

[0021] In one embodiment of the present invention, the mass concentration of the cross-linking agent is 1%-20% (w / v), preferably 5%-10% (w / v);

[0022] For example, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10% or any value within the above numerical range.

[0023] In one embodiment of the present invention, the cross-linking time of the cross-linking agent is 6 to 24 hours, preferably 10 to 15 hours.

[0024] For example, 10h, 11h, 12h, 13h, 14h, 15h.

[0025] By controlling the reaction conditions such as the mass concentration of the polymer solution in the gradient cross-linking, the mass concentration of the cross-linking agent, the concentration time of the polymer solution, the concentration of the cross-linking agent, and the cross-linking time, the obtained asymmetric adhesive membrane can exhibit more excellent asymmetric adhesion properties while maintaining the overall structural integrity.

[0026] In one embodiment of the present invention, the gradient crosslinking in step 3) is performed by surface dripping, layer-by-layer infiltration or dipping, so that the crosslinking agent gradually infiltrates from top to bottom to form a crosslinking density from top to bottom, thereby constructing an asymmetric adhesive film.

[0027] In one embodiment of the present invention, the method for constructing an asymmetric adhesive patch by gradient self-crosslinking further comprises cutting the obtained asymmetric adhesive patch into a specific size for use in abdominal tissue repair.

[0028] The present invention also provides a gradient self-crosslinking asymmetric adhesive film with a double-layer film structure with different crosslinking densities. One side of the asymmetric adhesive film is an adhesive layer with a low crosslinking density, which is used to firmly adhere to the wet tissue interface; the other side is a non-adhesive layer with a high crosslinking density, which is used to prevent the adhesion of normal tissue and block foreign matter from adhering to the film.

[0029] In one embodiment of the present invention, the low cross-linking density adhesive layer refers to a cross-linking degree of 10 -2 ~10 - 1 mol / cm 3 .

[0030] In one embodiment of the present invention, the non-adhesive layer with high cross-linking density refers to a layer with a cross-linking density of 10 -5 ~10 -3 mol / cm 3 .

[0031] In one embodiment of the present invention, the thickness of the gradient self-crosslinking asymmetric adhesive film is 1 mm to 5 mm, preferably 2 to 3 mm.

[0032] In one embodiment of the present invention, the gradient self-crosslinking asymmetric adhesive patch has good flexibility, biocompatibility and mechanical stability, and can adapt to the irregular surface of abdominal tissue.

[0033] The present invention also provides a gradient self-crosslinking asymmetric adhesive patch for use in the medical field, especially in the treatment of abdominal cavity injuries.

[0034] Beneficial effects of the present invention:

[0035] 1) Gradient cross-linking technology

[0036] Gradient cross-linking technology precisely controls the concentration and penetration time of the cross-linker, creating a top-down gradient of cross-link density, thereby imparting different properties to the same material. Specifically, this technology employs a top-to-bottom cross-linker penetration strategy, gradually decreasing the cross-link density along the thickness, resulting in distinct material properties at the top and bottom layers. This design effectively optimizes the structural performance of the adhesive patch, providing a theoretical foundation and technical support for its application in the biomedical field.

[0037] 2) Design of asymmetric structure

[0038] The present invention adopts gradient cross-linking technology to allow the polymer cross-linking agent to penetrate from the top to the bottom of the film, forming a cross-linking density gradient, thereby giving the film asymmetric adhesion properties. The bottom molecular chains with low cross-linking density are free to move, showing high adhesion, and can be tightly attached to the surgical site, assisting in suturing and closing the incision, reducing the risk of leakage, and providing a stable healing environment; while the top molecular chains with high cross-linking density are restricted in movement, showing low adhesion or non-adhesion, effectively preventing tissue adhesion, reducing the risk of complications such as intestinal obstruction and chronic pain, while maintaining tissue mobility. The present invention achieves the functional zoning of surgical site closure and tissue non-adhesion, taking into account postoperative safety and physiological adaptability, and provides a new strategy for the optimization of biomedical adhesive materials.

[0039] 3) Advantages of asymmetric adhesive patches

[0040] The asymmetric adhesive patch offers excellent cutting adaptability and ease of operation, effectively conforming to irregular abdominal tissue surfaces. The biocompatibility imparted by its asymmetric structure ensures safety within the in vivo environment, thereby reducing the risk of postoperative adverse reactions. It effectively seals injuries while preventing adhesion to normal tissue. The asymmetric adhesive patch, constructed using gradient self-crosslinking technology, exhibits excellent flexibility, biocompatibility, and mechanical stability, making it widely clinically applicable in medical applications such as abdominal tissue repair and prevention of postoperative tissue adhesion. BRIEF DESCRIPTION OF THE DRAWINGS

[0041] Figure 1 Schematic diagram of the process of constructing a gradient self-crosslinking asymmetric adhesive film using gradient crosslinking in the present invention;

[0042] Figure 2 Schematic diagram of the gradient self-crosslinking asymmetric adhesive film prepared in Example 1 in use;

[0043] Figure 3 This is a physical picture of the gradient self-crosslinking asymmetric adhesive film prepared in Example 1;

[0044] Figure 4 is a scanning electron micrograph of the gradient self-crosslinking asymmetric adhesive film prepared in Example 1;

[0045] Figure 5 These are pictures of the gradient self-crosslinking asymmetric adhesive film prepared in Example 1 being attached to the wrist while moving; from left to right, the wrist is moved at 0°, 15°, 30°, 60°, and 0°, indicating good adhesion.

[0046] Figure 6 This is a photograph of the asymmetric adhesive patch prepared in Example 1 adhered to the liver;

[0047] Figure 7 A comparison chart of the mechanical properties test of the asymmetric adhesive film prepared in Example 1;

[0048] Figure 8 Schematic diagram comparing the adhesive properties of the sticky side of the asymmetric adhesive film prepared in Example 1;

[0049] Figure 9 This is a diagram showing the cytotoxicity test of the asymmetric adhesive film prepared in Example 1 in different concentrations of immersion solutions;

[0050] Figure 10 This is a comparison chart of the effects of the asymmetric adhesive patch in Example 1 and the control group in treating liver damage;

[0051] Figure 11 This is an H&E image of the asymmetric adhesive patch prepared in Example 1 for treating liver injury;

[0052] Figure 12 Schematic diagram of the adhesion force of the asymmetric adhesive film prepared in Example 2;

[0053] Figure 13 Schematic diagram of the interfacial adhesion force of the asymmetric adhesive film prepared in Example 3;

[0054] Figure 14 This is a diagram showing the effect of using the asymmetric adhesive film prepared in Example 4. DETAILED DESCRIPTION

[0055] The present invention will be described in further detail below with reference to specific examples. It should be understood that the following examples are merely illustrative and explanations of the present invention and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are encompassed within the scope of protection that the present invention is intended to protect.

[0056] Example 1

[0057] 1) Preparation of polymer solution: 10 g of polydimethylsiloxane was dissolved in chloroform to prepare a polymer solution with a mass concentration of 20%.

[0058] 2) The polymer solution prepared above was introduced into a fixed mold to form a certain shape, and then placed in an oven at 60°C for 12 hours to evaporate most of the solvent chloroform, forming a polymer film with a thickness of 2 cm.

[0059] 3) A silane coupling agent crosslinker was dissolved in chloroform to prepare a 5% (w / v) crosslinker solution. This solution was evenly applied to the polymer film using a surface-drip method. The polymer crosslinker penetrated downwards, and the crosslinking time was 10 hours, resulting in a gradient of density. The surface crosslinking density was higher, resulting in reduced molecular chain motion and thus lower adhesion. The bottom crosslinking density was lower, resulting in greater molecular chain motion, easier contact with the tissue interface, and thus higher adhesion. Thus, an asymmetric adhesive film was constructed using this method.

[0060] 4) Cut the obtained asymmetric adhesive film into a specific size for later use.

[0061] Figure 1 Schematic diagram of the process for constructing hydrogel films for gradient cross-linking.

[0062] Figure 2 This is a diagram of the adhesive patch applied to a liver wound.

[0063] The photo of the asymmetric adhesive film prepared in Example 1 is shown in FIG. Figure 3 As shown, it can be seen that the adhesive film is in the shape of a transparent film and can be cut into the required size and shape as needed.

[0064] The interface of the patch was scanned by scanning electron microscopy (SEM). Figure 4 As shown, it was found to have a clear gradient porosity.

[0065] When using, stick the asymmetrical adhesive patch on your wrist. Figure 5 As shown in the figure, from left to right, the wrist is adhered and then moves 0°, 15°, 30°, 60°, and 0°. It can be observed that when the wrist moves from 0 to 60°, it is found that the adhesive film can adhere to the wrist very well, indicating that it has good adhesion.

[0066] Figure 6 This photograph shows the asymmetric adhesive patch prepared in Example 1 applied to the liver. As can be seen, when the asymmetric adhesive patch is picked up with forceps, it effectively adheres to the damaged liver tissue, sealing the lesion. It also remains attached to the liver tissue when pulled up, demonstrating its excellent adhesion.

[0067] According to the international standard: ASTM D3039 (Standard Test Method for Tensile Properties of Polymer-Based Composite Materials), the mechanical properties of the asymmetric adhesive film were tested using a universal tensile machine, and the stress-strain curve was calculated using the following formula.

[0068] Stress = F (force) / A (area of ​​force)

[0069] Strain = ΔL (deformation distance) / L (initial length)

[0070] The stress-strain curve is Figure 7 As shown in the figure, the mechanical properties of adhesive films with high cross-linking density, low cross-linking density and asymmetric structure were tested respectively. Figure 7 As can be seen in the figure, the film exhibits greater stress and smaller deformation at high cross-link density, indicating weak molecular chain motion. The film exhibits less stress and greater deformation at low cross-link density, indicating easier molecular chain motion. Therefore, the asymmetric adhesive film exhibits excellent adhesion at low cross-link density and no adhesion at high cross-link density.

[0071] According to the relevant provisions on peel strength test in the pharmaceutical industry standard YY / T 0148-2006 "General Requirements for Medical Adhesive Tapes", the adhesion of the sticky side of the asymmetric adhesive film prepared in Example 1 was tested.

[0072] Films with high and low cross-linking densities were prepared below for comparison with the adhesive film prepared in Example 1:

[0073] Preparation of polymer solution: 10 g of polydimethylsiloxane was dissolved in chloroform to prepare a polymer solution with a mass concentration of 20%.

[0074] The crosslinking agent silane coupling agent is dissolved in chloroform to prepare a crosslinking agent solution with a mass concentration of 5% (w / v), and then quickly mixed and stirred with the above-mentioned polymer solution to obtain a homogeneous solution. The solution is introduced into the mold to form a high crosslinking density hydrogel film.

[0075] The same method was used to obtain a low cross-linking density film by taking a cross-linking agent with a mass concentration of 0.5%.

[0076] from Figure 8 It can be seen that the adhesion of the film with high cross-linking density in dry or wet state is 50 J·m -2 and 25 J·m -2 , while the adhesion of the film with low cross-linking density in dry or wet state is 350 J·m -2 and 310 J·m -2The adhesive force of the adhesive side of the asymmetric adhesive film prepared in Example 1 in dry or wet state is 330 J·m -2 and 300 J·m -2 .

[0077] Construction of liver trauma model:

[0078] Reference: An off-the-shelf bioadhesive patch for sutureless repair of gastrointestinal defects. Sci Transl Med 2022, 14(630): eabh2857. The method is to place the rat in a small animal anesthesia induction box and induce anesthesia with 5% isoflurane (flow rate 600mL / min). After complete anesthesia, the rat is switched to 2% isoflurane (500mL / min) and maintained with a nose drop. The rat is fixed in a prone position on a heated operating table, the abdominal hair is removed, and the rat is disinfected three times with 75% alcohol. The rat's abdomen is dissected so that the liver is exposed on moist sterile gauze. A 10um incision is made on the colon or stomach using a surgical tool and repaired with a hydrogel patch (10×20um). The abdominal muscles are then sutured with 4-0 absorbable braided sutures, and the skin is sutured with 4-0 non-absorbable braided sutures. The surgical incision is disinfected with iodine swabs, and the rat is prevented from licking or biting the surgical incision. The left ear is disinfected with iodine swabs and marked with an ear tag. After the animals recovered from anesthesia, they were returned to their cages and given analgesic jelly. They were given normal water and food, and their surgical conditions were closely observed. Surgical sutures and commercial adhesives were used as controls in this experiment.

[0079] A liver trauma model was constructed and the untreated group, suture group, FAL group and @ The control group and the asymmetric adhesive patch prepared in Example 1 were used as the experimental group. The liver injury model was treated for comparison. Figure 10 It can be seen from the results that the asymmetric adhesive patch constructed by the method of the present invention has a good therapeutic effect, and H&E staining also found that it has a good repair effect, such as Figure 11 shown.

[0080] Example 2

[0081] 1) Preparation of polymer solution: 5 g of dopamine-grafted chitosan was dissolved in deionized water to obtain a polymer solution with a mass concentration of 5% (w / v).

[0082] 2) The polymer solution prepared above was introduced into a fixed mold to form a certain shape, and then placed in an oven at 37°C for 12 hours to evaporate most of the solvent to form a polymer film with a thickness of 2 mm.

[0083] 3) Glutaraldehyde was dissolved in deionized water to prepare a crosslinker solution with a mass concentration of 5% (w / v). The solution was evenly coated on the polymer film by surface dropwise addition. The polymer crosslinker penetrated from top to bottom for 10 hours to form an asymmetric adhesive film with different gradient densities.

[0084] 4) Cut the obtained asymmetric adhesive film into a specific size for later use.

[0085] The adhesion of the asymmetric adhesive film prepared in Example 2 is as follows: Figure 12 shown.

[0086] Example 3

[0087] 1) Preparation of polymer solution: 10 g of dopamine-grafted silk fibroin was dissolved in deionized water to prepare a polymer solution with a mass concentration of 10%.

[0088] 2) The polymer solution prepared above was introduced into a fixed mold to form a certain shape, and then placed in an oven at 50° C. for 24 hours to evaporate most of the solvent, forming a polymer film with a thickness of 2 cm.

[0089] 3) Genipin was dissolved in an ethanol solution to prepare a crosslinker solution with a mass concentration of 10% (w / v), and the solution was evenly coated on the polymer film by an infiltration method. The polymer crosslinker infiltrated from top to bottom for 10 hours to form different gradients of crosslinking density. The asymmetric adhesive film was constructed by the above method.

[0090] 4) Cut the obtained asymmetric adhesive film into a specific size for later use.

[0091] The same method as in Example 1 was used to test the interfacial adhesion of the asymmetric adhesive film prepared in Example 3. Figure 13 As shown in the figure, it can be seen that the interfacial adhesion force of the low cross-linking density part at the bottom of the adhesive film (about 350 N·m -1 ) is much higher than the interfacial adhesion force of the high cross-linking density portion at the top of the adhesive film (about 50 N·m -1 ).

[0092] Example 4

[0093] 1) Preparation of polymer solution: 10 g of dopamine-grafted sodium alginate was dissolved in deionized water to obtain a polymer solution having a mass concentration of 50% (w / v).

[0094] 2) The polymer solution prepared above was introduced into a fixed mold to form a certain shape, and then placed in an oven at 90° C. for 10 hours to evaporate most of the solvent, forming a polymer film with a thickness of 5 mm.

[0095] 3) Calcium chloride, a polymer crosslinking agent, is dissolved in water to prepare a solution with a mass concentration of 2% (w / v). The solution is evenly coated on the polymer film by a surface dropwise method. The polymer crosslinking agent penetrates from top to bottom, thereby forming different density gradients. The asymmetric adhesive film is constructed by the above method.

[0096] 4) Cut the obtained asymmetric adhesive film into a specific size for later use.

[0097] Figure 14 Schematic diagram of the use of the asymmetric adhesive film prepared in Example 4.

[0098] The above describes the embodiments of the present invention. However, the present invention is not limited to the above embodiments. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention shall be included in the scope of protection of the present invention.

Claims

1. A method for constructing an asymmetric adhesive film by gradient self-crosslinking, characterized in that: The following steps are involved: 1) Preparation of polymer solution: adding a polymer having both adhesive groups and active groups to a solvent to prepare a polymer solution of a certain mass concentration; 2) Formation of a polymer film: The polymer solution is concentrated at a certain temperature, and the solvent is gradually evaporated to form a polymer film with a predetermined thickness; 3) Gradient cross-linking: Dissolve the polymer cross-linking agent to a certain concentration, then evenly immerse it into the surface of the polymer film. Control the diffusion and reaction time of the cross-linking agent so that the cross-linking density of the polymer film gradually decreases from the top surface to the bottom surface, thereby constructing a film with asymmetric adhesion properties.

2. The method according to claim 1, characterized in that The adhesion group is a group that can enhance adhesion performance; Preferably, the active groups include groups containing amino groups and carboxyl groups; Preferably, the high molecular polymer is selected from one or more of polymethylsiloxane, dopamine grafted chitosan, dopamine grafted gelatin, dopamine grafted silk fibroin, dopamine grafted hyaluronic acid, and dopamine grafted sodium alginate; Preferably, the solvent used in step 1) is a solvent that can dissolve the high molecular weight polymer and is suitable for the subsequent cross-linking reaction; for example, an organic solvent or water; the organic solvent is chloroform and / or ethanol.

3. The method according to claim 1, characterized in that The mass concentration of the polymer solution is 5%-50%, preferably 10%-30%, more preferably 20%-30%.

4. The method according to claim 1, wherein In the step 2), the polymer solution is introduced into a fixed mold and concentrated at 37-90° C. for 10-24 hours to allow the solvent to evaporate gradually, thereby obtaining a polymer film; Preferably, the thickness of the polymer film is 1 to 5 cm, preferably 2 to 3 cm.

5. The method according to claim 1, wherein The cross-linking agent is selected from one or more of a silane coupling agent, glutaraldehyde, genipin and calcium chloride; Preferably, the silane coupling agent is used to cross-link polymethylsiloxane; the glutaraldehyde and genipin are used to cross-link polymers with amino groups; the calcium chloride can form ionic bonds with carboxyl groups and is used to cross-link carboxyl-containing polymers; Preferably, the mass concentration of the cross-linking agent is 1%-20%, preferably 5%-10%; For example, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10%; The cross-linking time of the cross-linking agent is 6 to 24 hours, preferably 10 to 15 hours.

6. The method according to claim 1, wherein The gradient cross-linking in step 3) is carried out by surface dripping, layer-by-layer spraying or dipping, so that the cross-linking agent gradually penetrates from top to bottom, forming a cross-linking density from top to bottom, thereby constructing an asymmetric adhesive film.

7. The method according to claim 1, characterized in that The method also includes cutting the obtained asymmetric adhesive patch into a specific size for use in abdominal tissue repair.

8. An asymmetric adhesive film constructed by gradient self-crosslinking, characterized in that: The asymmetric adhesive patch is obtained by using the method for constructing an asymmetric adhesive patch by gradient self-crosslinking according to any one of claims 1 to 7. Preferably, the gradient self-crosslinking asymmetric adhesive film has a thickness of 1 mm to 5 mm, preferably 2 to 3 mm.

9. The asymmetric adhesive film according to claim 8, characterized in that: The asymmetric adhesive film is a double-sided structured film, one side of which is an adhesive layer with a low cross-linking density for firmly adhering to the wet tissue interface; the other side is a non-adhesive layer with a high cross-linking density for preventing normal tissue adhesion and preventing foreign matter from adhering to the film. Preferably, the low cross-linking density adhesive layer refers to a cross-linking degree of 10 -2 ~10 -1 mol / cm 3 The non-adhesive layer with high cross-linking density is a layer with a cross-linking density of 10 -5 ~10 -3 mol / cm 3 .

10. Use of an asymmetric adhesive patch prepared by the method for constructing an asymmetric adhesive patch by gradient self-crosslinking according to any one of claims 1 to 7 in medical treatment, especially in the treatment of damaged abdominal tissue.

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