An organizational sealing film, its preparation method and application

Abstract

The present invention belongs to the technical field of medical devices, and particularly relates to a tissue sealing film, a preparation method thereof and an application. The tissue sealing film prepared by the present invention is a multi-layer composite structure, which is composed of an anti-adhesive layer and an adhesive layer. The anti-adhesive layer includes an anti-adhesive layer bottom layer and an anti-adhesive layer transition layer; the multi-layer composite structure specifically includes an anti-adhesive layer bottom layer, a first anti-adhesive layer transition layer, a second anti-adhesive layer transition layer, a first adhesive layer, a second adhesive layer and a third adhesive layer, which are sequentially arranged from bottom to top. By adjusting conditions such as the composition and proportion of the mixed solvent, designing the transition layer, the interlayer structure (pit / protrusion structure), and adjusting the composition proportion of the adhesive layer, the adhesive layer and the anti-adhesive layer are compounded and formed through physical and chemical actions, so as to increase the mechanical matching and compounding effect of the two polymers, improve the mechanical properties and adhesion properties of the tissue sealing film, and have broad application prospects.

Description

Technical Field

[0001] The present invention belongs to the technical field of medical devices, and in particular relates to a tissue sealing membrane and a preparation method and application thereof. Background Art

[0002] The information disclosed in this background technology section is only intended to enhance the understanding of the overall background of the invention, and should not necessarily be regarded as an admission or any form of suggestion that the information constitutes the prior art already known to a person skilled in the art.

[0003] During surgery, sutures are commonly used to close damaged internal organs. However, pinholes at the suture sites can easily lead to fluid / gas leakage, and sutures cannot address low-pressure leakage or slow bleeding from internal organs. Consequently, many synthetic and semi-synthetic tissue sealants, such as porcine fibrin sealants and polyethylene glycol-based polymeric synthetic sealants, are used to close internal wounds. These products require pre-prepared solutions and the use of spray tools, increasing complexity and surgical time.

[0004] In recent years, literature has reported the use of suitable sheets or substrates in combination with adhesives to prepare tissue sealing membranes for visceral wound closure. The combination of substrate and adhesive is a critical step in the sealing membrane preparation process, impacting its performance and effectiveness. For example, patent CN109821057A discloses a visceral hemostatic patch, its preparation method, and its use. The sample is prepared using a layer-by-layer stacking method, resulting in a flexibility that is insufficient for interventional surgery. Patent CN112716702A discloses a degradable medical film and its preparation method. The film comprises an alternating AB-type composite structure, which enhances the interaction between the AB components and adhesion to tissue by varying the coating direction. However, the resulting film has weak interlayer bonding and requires manual coating direction changes, making industrial production difficult. Patent CN115671406A discloses a tissue sealing membrane using polyacrylic acid as an adhesive, applied directly to a basement membrane. Polyacrylic acid is swellable and easily detaches from the basement membrane after swelling in vivo, resulting in sealing failure.

[0005] Furthermore, postoperative tissue adhesion is a common and challenging problem in surgery. Currently, commonly used anti-adhesion materials include polylactic acid (PLA) anti-adhesion membranes and hyaluronic acid gels. These products lack tissue adhesion and are susceptible to barrier detachment or fragmentation during tissue and organ peristalsis, reducing their effectiveness. Furthermore, with the increasing development of endoscopic surgery, anti-adhesion membranes must be folded or rolled into a compact structure before introduction into the body, placing higher demands on their flexibility.

[0006] Therefore, there is an urgent need for a tissue sealing membrane and a preparation method thereof that has a strong composite effect between the base and the adhesive, good flexibility and wet adhesion strength, an anti-adhesion function, a simple process and is suitable for magnification. Summary of the Invention

[0007] In view of the problems existing in the prior art, the present invention provides a tissue sealing film, a preparation method and an application thereof. The material prepared by the present invention solves the problems of the mismatch between the mechanical properties of the substrate and the adhesive of the existing tissue sealing film, the weak composite force between the two layers, the insufficient flexibility of the sealing film, the low wet state adhesion strength, and the easy curling and cracking of the sealing film during the preparation process.

[0008] In order to achieve the above object, the present invention adopts the following technical solutions:

[0009] In the first aspect of the present invention, a tissue sealing film is provided. The tissue sealing film is a multi-layer composite structure composed of an anti-adhesive layer and an adhesive layer. The anti-adhesive layer includes an anti-adhesive layer bottom layer and an anti-adhesive layer transition layer; the multi-layer composite structure specifically includes an anti-adhesive layer bottom layer, a first anti-adhesive layer transition layer, a second anti-adhesive layer transition layer, a first adhesive layer, a second adhesive layer, and a third adhesive layer arranged in sequence from bottom to top.

[0010] Preferably, the thickness of the anti-adhesive layer bottom layer is 5-50 μm; the thickness of the anti-adhesive layer transition layer is 2-20 μm; the thickness of the adhesive layer is 10-100 μm.

[0011] Preferably, the thickness of the first anti-adhesive layer transition layer and the second anti-adhesive layer transition layer is 1-10 μm, preferably 4-8 μm; the thickness of the first adhesive layer, the second adhesive layer, and the third adhesive layer is 4-40 μm, preferably 8-20 μm.

[0012] Preferably, the surface of the anti-adhesive layer transition layer is made into a concave pit, convex structure or grid structure through a customized mold to increase the composite effect with the adhesive layer; preferably a concave pit structure, and the concave pit structure is composed of a continuous stripe structure or a discontinuous dot matrix structure.

[0013] Preferably, the anti-adhesive layer bottom layer includes a film-forming polymer; the anti-adhesive layer transition layer includes a film-forming polymer, a tissue adhesive polymer, and an additive; the adhesive layer includes a tissue adhesive polymer, a film-forming polymer, and an additive.

[0014] More preferably, the film-forming polymer is selected from one or more of poly(lactide-co-glycolide) (PLGA), polylactic acid (PLA), polycaprolactone (PCL), poly(lactide-caprolactone) copolymer (PLCL); the tissue adhesive polymer is selected from one or more of acrylic resin adhesives with benzaldehyde or active ester.

[0015] Further preferably, the film-forming polymer is poly(lactide-co-glycolide) (PLGA); the tissue adhesive polymer is selected from poly(acrylic acid-co-hydroxybenzaldehyde acrylate) (abbreviated as PAA-PAA(BA)), poly(acrylic acid-co-N-hydroxysuccinimide acrylate) (abbreviated as PAA-PAA(NHS)).

[0016] Preferably, the additives include a plasticizer, a crosslinking agent, and also include one or more of an active drug, a preservative, and an antifoaming agent.

[0017] Further preferably, the plasticizer is selected from one or more of glycerol, triethyl citrate, triisopropyl palmitate, triethyl citrate, low molecular weight polyethylene glycol (PEG), and fibroin; the crosslinking agent is selected from one or more of sucrose, hydroxypropyl cellulose, polylysine, amino polyethylene glycol, low molecular weight chitosan, tannic acid, and trilysine; the active drug is selected from one or more of an antibacterial agent, an antibiotic, a growth factor, and an analgesic; the preservative is selected from one or more of benzoic acid, sodium benzoate, sorbic acid, and potassium sorbate.

[0018] In a second aspect of the present invention, a method for preparing the above tissue sealing film is provided, including the following steps:

[0019] S1. Dissolve the film-forming polymer in an organic solvent to obtain an anti-sticking layer solution, and coat it on the surface of the substrate to obtain an anti-sticking layer bottom layer;

[0020] S2. Dissolve the tissue adhesive polymer, the plasticizer, and the crosslinking agent in a mixed solvent to obtain an adhesive layer solution. Mix the anti-sticking layer solution and the adhesive layer solution in different volume ratios to obtain a first anti-sticking layer transition layer solution and a second anti-sticking layer transition layer solution, and coat them on the surface of the anti-sticking layer bottom layer in sequence to obtain an anti-sticking layer transition layer;

[0021] S3. Mix the anti-sticking layer solution and the adhesive layer solution in different volume ratios, coat them on the surface of the second anti-sticking layer transition layer in sequence to obtain an adhesive layer, and then obtain the tissue sealing film through post-treatment.

[0022] Preferably, in step S1, the mass concentration of the film-forming polymer is 5% - 25%, and the viscosity of the anti-sticking layer solution is 100 - 2000 mPa·s; the organic solvent is selected from one or more of dichloromethane, chloroform, hexafluoroisopropanol, acetone, and ethyl acetate.

[0023] Preferably, in step S1, the substrate is selected from one or more of a glass plate, a stainless steel plate, a tetrafluoroethylene plate, a release paper, and a release film; the height of the doctor blade for coating is 20 - 200 μm, and the coating speed is 100 - 2000 mm / min.

[0024] Preferably, in step S2, the mass ratio of the tissue adhesive polymer, plasticizer and crosslinking agent is 60-94:5-30:1-10, and the viscosity of the adhesive layer solution is 100-1000 mPa·s.

[0025] Preferably, in step S2, the mixed solvent includes a first solvent and a second solvent; the first solvent is selected from one or more of dichloromethane, chloroform, hexafluoroisopropanol, acetone, and ethyl acetate; the second solvent is selected from one or more of methanol, ethanol, and isopropanol; Further preferably, the mixed solvent is dichloromethane and methanol; Further preferably, the volume ratio of the first solvent to the second solvent is 1-6:1.

[0026] Preferably, in step S2, the height of the doctor blade of the coating setting is 10-80 μm, and the coating speed is 100-2000 mm / min.

[0027] Preferably, in step S2, the first anti-adhesive layer transition layer solution is obtained by mixing the anti-adhesive layer solution and the adhesive layer solution in a volume ratio of 7-9:1-3, and the second anti-adhesive layer transition layer solution is obtained by mixing the anti-adhesive layer solution and the adhesive layer solution in a volume ratio of 1-3:7-9. The solutions are sequentially coated on the surface of the bottom layer of the anti-adhesive layer to obtain the anti-adhesive layer transition layer.

[0028] Further preferably, the anti-adhesive layer solution and the adhesive layer solution are mixed in a volume ratio of 8:2 and coated on the surface of the bottom layer of the anti-adhesive layer to obtain the first anti-adhesive layer transition layer; the anti-adhesive layer solution and the adhesive layer solution are mixed in a volume ratio of 2:8 and coated on the surface of the bottom layer of the anti-adhesive layer to obtain the second anti-adhesive layer transition layer.

[0029] Preferably, in step S3, the height of the doctor blade used for coating is 40-400 μm, and the coating speed is 100-2000 mm / min.

[0030] Preferably, in step S3, the adhesive layer includes a first adhesive layer, a second adhesive layer and a third adhesive layer. The three layers are mixed with the anti-adhesive layer solution in an increasing trend of the volume ratio of the adhesive layer solution. The specific coating method is as follows: First, a mixed solution is coated on the surface of the second anti-adhesive layer transition layer in a volume ratio of 5-7:3-5 to obtain the first adhesive layer; then a mixed solution is coated on the first adhesive layer in a volume ratio of 7-9:1-3 to obtain the second adhesive layer; then a mixed solution is coated on the second adhesive layer in a volume ratio of 8-9:1-2 to obtain the third adhesive layer.

[0031] Further preferably, the specific coating method of the anti-adhesive layer transition layer is as follows: first, coat a mixed solution on the surface of the second anti-adhesive layer transition layer at a ratio of 6:4 to obtain a first adhesive layer; then coat a mixed solution on the first adhesive layer at a volume ratio of 8:2 to obtain a second adhesive layer; and then coat a mixed solution on the second adhesive layer at a volume ratio of 9:1 to obtain a third adhesive layer.

[0032] Preferably, in step S3, the post-treatment includes drying, cutting, packaging, and sterilizing the coated sample to obtain the tissue sealing film sample.

[0033] In the third aspect of the present invention, there is provided an application of the tissue sealing film described in the first aspect and / or the tissue sealing film prepared by the preparation method described in the second aspect in the field of medical devices.

[0034] The beneficial effects achieved by one or more of the above technical solutions of the present invention are as follows:

[0035] (1) By adjusting the composition and ratio of the mixed solvent, designing the transition layer, the interlayer structure (pit / protrusion structure), and adjusting the composition ratio of the adhesive layer, etc., the present invention enables the adhesive layer and the anti-adhesive layer to be compounded and formed through physical and chemical actions, increasing the mechanical matching and compounding effect of the two polymers, and improving the mechanical properties and adhesion properties of the tissue sealing film. At the same time, different additives, such as active drugs, can be incorporated into the adhesive layer and the anti-adhesive layer, and the drugs are slowly released at the use site, achieving the dual effects of tissue sealing and local drug release, and reducing the systemic toxicity of the drugs.

[0036] (2) The tissue sealing film prepared by the present invention can be used as a hemostatic material or wound dressing for visceral rupture, injury, or blood loss; it can be used as a tissue repair material for vascular sealing and dural repair in neurosurgery; it can be used as an anti-adhesion material for abdominal wall hernia, postoperative abdominal cavity, thoracic cavity, etc.; it can be used as a treatment and delivery device for sealing the tissue surface and releasing one or more drugs to the target site. Description of the Drawings

[0037] The specification drawings constituting a part of the present invention are used to provide a further understanding of the present invention. The schematic embodiments of the present invention and their descriptions are used to explain the present invention and do not constitute an improper limitation to the present invention.

[0038] Figure 1 It is a schematic diagram of the appearance and structure of the tissue sealing film sample prepared in Example 1 of the present invention, where A is the appearance diagram of the tissue sealing film sample; B is the schematic diagram of the structure of the tissue sealing film sample, where 1 - anti-adhesive bottom layer; 2 - anti-adhesive layer transition layer; 3 - anti-adhesive layer; 4 - adhesive layer;

[0039] Figure 2Appearance diagrams of the tissue sealing membranes prepared in Comparative Example 1, Comparative Example 6, and Comparative Examples 9-10 of the present invention, where (a) is the appearance diagram of the tissue sealing membrane of Comparative Example 1, (b) is the appearance diagram of the tissue sealing membrane of Comparative Example 6, (c) is the appearance diagram of the tissue sealing membrane of Comparative Example 9, and (d) is the appearance diagram of the tissue sealing membrane of Comparative Example 10;

[0040] Figure 3 Swelling results of the tissue sealing membranes prepared in Example 1 and Comparative Example 2 of the present invention, where (a) is the swelling result of the tissue sealing membrane of Example 1 and (b) is the swelling result of the tissue sealing membrane of Comparative Example 2;

[0041] Figure 4 Tensile strength and elongation at break test results of the tissue sealing membranes prepared in Examples 1-3 and Comparative Examples 2-10 of the present invention, where (a) is the test result diagram of the tensile strength of the tissue sealing membrane and (b) is the test result diagram of the elongation at break of the tissue sealing membrane;

[0042] Figure 5 Anti-sticking layer contact angle test results of the tissue sealing membranes prepared in Example 1 and Comparative Example 2 of the present invention, where (a) is the test result diagram of the anti-sticking layer contact angle of the tissue sealing membrane of Comparative Example 2 and (b) is the test result diagram of the anti-sticking layer contact angle of the tissue sealing membrane of Example 1;

[0043] Figure 6 Adhesion strength test results of the tissue sealing membranes prepared in Examples 1-3 and Comparative Examples 2-10 of the present invention; among them, (a) is a schematic diagram of the adhesion strength test process and (b) is the test result diagram of the adhesion strength of the tissue sealing membrane;

[0044] Figure 7 In vitro organ tissue adhesion results of the tissue sealing membrane prepared in Example 1 of the present invention, where (a) is the heart, (b) is the liver, (c) is the lung, (d) is the kidney, and (e) is the small intestine. Detailed Description of the Invention

[0045] It should be noted that the following detailed description is exemplary and is intended to provide further explanation of the present invention. Unless otherwise specified, all technical and scientific terms used in the present invention have the same meaning as commonly understood by those of ordinary skill in the technical field to which the present invention belongs.

[0046] The present invention will be further described in detail below in conjunction with specific examples. It should be noted that the specific examples are explanations of the present invention rather than limitations.

[0047] Example 1: This example provides a tissue sealing membrane and a preparation method thereof, including the following steps:

[0048] The tissue sealing membrane provided in this example is a multi-layer composite structure, and the appearance is asFigure 1 as shown at A in

[0049] such as Figure 1 as shown at B in, the tissue sealing film provided in this embodiment includes an anti - sticking layer 3 and an adhesive layer 4. Among them, the anti - sticking layer includes an anti - sticking layer bottom layer 1 and an anti - sticking layer transition layer 2;

[0050] The multi - layer composite structure specifically includes, from bottom to top in sequence, an anti - sticking layer bottom layer 1, a first anti - sticking layer transition layer, a second anti - sticking layer transition layer, a first adhesive layer, a second adhesive layer, and a third adhesive layer.

[0051] Among them, the thickness of the anti - sticking layer bottom layer is 15 μm; the thicknesses of the first anti - sticking layer transition layer and the second anti - sticking layer transition layer are 5 μm; the thicknesses of the first adhesive layer, the second adhesive layer, and the third adhesive layer are all 15 μm.

[0052] The specific preparation method is as follows:

[0053] (1) Weigh 1 g of PLGA and add it to 10 mL of dichloromethane to prepare an anti - sticking layer solution with a concentration of 0.1 g / mL. Using a small coater, add the PLGA solution onto the surface of the release paper for coating, and dry it at room temperature for 20 min to obtain the anti - sticking layer bottom layer.

[0054] (2) Mix dichloromethane and methanol in a volume ratio of 2.5:1 to obtain a mixed solvent. Weigh 3.0 g of PAA - PAA(BA), 0.3 g of glycerol, and 0.1 g of hydroxypropyl cellulose and add them to 10 mL of the mixed solvent to obtain a PAA - PAA(BA) solution. Mix the PAA - PAA(BA) solution and the PLGA solution prepared in step (1) evenly in a volume ratio of 8:2, and coat it on the anti - sticking layer bottom layer to obtain the first anti - sticking layer transition layer; mix the PAA - PAA(BA) solution and the PLGA solution evenly in a volume ratio of 2:8, and continue coating to obtain the second anti - sticking layer transition layer. Place a customized mold with embossments on the surface of the coating, dry it at room temperature for 20 min, and remove the mold to obtain an anti - sticking layer with indentations.

[0055] (3) Mix the PAA-PAA(BA) solution and the PLGA solution evenly at a volume ratio of 6:4, and coat the surface of the second anti-adhesive layer transition layer to obtain the first adhesive layer; mix the PAA-PAA(BA) solution and the PLGA solution evenly at a volume ratio of 8:2, and coat the surface of the first adhesive layer to obtain the second adhesive layer; mix the PAA-PAA(BA) solution and the PLGA solution evenly at a volume ratio of 9:1, and coat the surface of the second adhesive layer to obtain the third adhesive layer. Dry the sealed film sample in a fume hood for 30 min, transfer the sample to an oven, perform high-temperature cross-linking and drying, and obtain the tissue sealing film sample after cutting, packaging, and sterilization.

[0056] Example 2: This example provides a tissue sealing film and a preparation method thereof, including the following steps:

[0057] (1) Weigh 1.0 g of PLGA and add it to 10 mL of dichloromethane to prepare an anti-adhesive layer solution with a concentration of 0.1 g / mL. Using a small coater, add the PLGA solution to the surface of the release paper, coat it, and dry it at room temperature for 20 min to obtain the bottom layer of the anti-adhesive layer.

[0058] (2) Mix dichloromethane and methanol at a volume ratio of 2.5:1 to obtain a mixed solvent. Weigh 3.0 g of PAA-PAA(NHS), 0.3 g of glycerol, and 0.1 g of hydroxypropyl cellulose and add them to 10 mL of the mixed solvent to obtain a PAA-PAA(NHS) solution. Mix the PAA-PAA(NHS) solution and the PLGA solution prepared in step (1) evenly at a volume ratio of 8:2, and coat it on the bottom layer of the anti-adhesive layer to obtain the first anti-adhesive layer transition layer; mix the PAA-PAA(NHS) solution and the PLGA solution evenly at a volume ratio of 2:8, continue to coat it, and obtain the second anti-adhesive layer transition layer. Place a customized mold with embossments on the surface of the coating, dry it at room temperature for 20 min, and remove the mold to obtain the anti-adhesive layer with depressions.

[0059] (3) Mix the PAA-PAA(NHS) solution and the PLGA solution evenly at a volume ratio of 6:4, and coat the surface of the second anti-adhesive layer transition layer to obtain the first adhesive layer; mix the PAA-PAA(NHS) solution and the PLGA solution evenly at a volume ratio of 8:2, and coat the surface of the first adhesive layer to obtain the second adhesive layer; mix the PAA-PAA(NHS) solution and the PLGA solution evenly at a volume ratio of 9:1, and coat the surface of the second adhesive layer to obtain the third adhesive layer. Dry the sealed film sample in a fume hood for 30 min, transfer the sample to an oven, perform high-temperature cross-linking and drying, and obtain the tissue sealing film sample after cutting, packaging, and sterilization. Among them, the thickness of the bottom layer of the anti-adhesive layer is 15 μm; the thicknesses of the first anti-adhesive layer transition layer and the second anti-adhesive layer transition layer are 5 μm; the thicknesses of the first adhesive layer, the second adhesive layer, and the third adhesive layer are all 15 μm.

[0060] Example 3: This example provides a tissue sealing film and its preparation method, including the following steps:

[0061] (1) Weigh 1.0 g of PLGA and add it to 10 mL of dichloromethane to prepare an anti-adhesive layer solution with a concentration of 0.1 g / mL. Weigh 1.0 g of PLGA and 0.1 g of rifampicin (RFP) and add them to 10 mL of dichloromethane to obtain a drug-loaded anti-adhesive layer solution with a drug mass fraction of 10%. Using a small coater, add the RFP / PLGA solution to the surface of the release paper, coat it, and dry it at room temperature for 20 min to obtain the bottom layer of the anti-adhesive layer loaded with RFP.

[0062] (2) Mix dichloromethane and methanol at a volume ratio of 2.5:1 to obtain a mixed solvent. Weigh 3.0 g of PAA-PAA(NHS), 0.3 g of glycerol, and 0.1 g of hydroxypropyl cellulose and add them to 10 mL of the mixed solvent to obtain a PAA-PAA(NHS) solution. Mix the PAA-PAA(NHS) solution and the PLGA solution evenly at a volume ratio of 8:2, coat it on the bottom layer of the anti-adhesive layer to obtain the first anti-adhesive layer transition layer; mix the PAA-PAA(NHS) solution and the PLGA solution evenly at a volume ratio of 2:8, continue to coat it to obtain the second anti-adhesive layer transition layer. Place a customized mold with embossments on the surface of the coating, dry it at room temperature for 20 min, and remove the mold to obtain the anti-adhesive layer with indentations.

[0063] (3) Weigh 0.15 g of doxorubicin hydrochloride (DOX) and add it to 5 mL of the PAA-PAA(NHS) solution to obtain a drug-loaded adhesive layer solution with a drug mass fraction of 10% (abbreviated as the DOX / PAA-PAA(NHS) solution). Mix the DOX / PAA-PAA(NHS) solution and the PLGA solution evenly according to a volume ratio of 6:4, and coat the solution on the surface of the second anti-adhesive layer transition layer to obtain the first adhesive layer; mix the DOX / PAA-PAA(NHS) solution and the PLGA solution evenly according to a volume ratio of 8:2, and coat the solution on the surface of the first adhesive layer to obtain the second adhesive layer; mix the DOX / PAA-PAA(NHS) solution and the PLGA solution evenly according to a volume ratio of 9:1, and coat the solution on the surface of the second adhesive layer to obtain the third adhesive layer. Dry the sealed film sample in a fume hood for 30 min, transfer the sample to an oven, perform high-temperature cross-linking and drying, and obtain the drug-loaded tissue sealing film sample after cutting, packaging, and sterilization. Among them, the thickness of the bottom layer of the anti-adhesive layer is 15 μm; the thicknesses of the first anti-adhesive layer transition layer and the second anti-adhesive layer transition layer are 5 μm; the thicknesses of the first adhesive layer, the second adhesive layer, and the third adhesive layer are all 15 μm.

[0064] Comparative Example 1: This comparative example provides a tissue sealing film and its preparation method.

[0065] The difference between this comparative example and Example 1 lies in that: in step (2), 3.0 g of PAA-PAA(BA), 0.3 g of glycerol, and 0.1 g of hydroxypropyl cellulose are weighed and added to 10 mL of methanol to obtain a PAA-PAA(BA) solution.

[0066] The contents of other components, the preparation method, and the thicknesses of each layer are the same as those in Example 1.

[0067] Comparative Example 2: This comparative example provides a tissue sealing film and its preparation method.

[0068] The difference between this comparative example and Example 1 lies in that: in step (2), the preparation of the anti-adhesive layer transition layer is not carried out. That is, the PAA-PAA(BA) solution and the PLGA solution prepared in step (1) are directly mixed evenly according to a volume ratio of 6:4 and then coated on the surface of the bottom layer of the anti-adhesive layer to obtain the first adhesive layer; the PAA-PAA(BA) solution and the PLGA solution are mixed evenly according to a volume ratio of 8:2 and then coated on the surface of the first adhesive layer to obtain the second adhesive layer; the PAA-PAA(BA) solution and the PLGA solution are mixed evenly according to a volume ratio of 9:1 and then coated on the surface of the second adhesive layer to obtain the third adhesive layer. Dry the sealed film sample in a fume hood for 30 min, transfer the sample to an oven, perform high-temperature cross-linking and drying, and obtain the tissue sealing film sample after cutting, packaging, and sterilization.

[0069] The contents of other components and the preparation method are the same as those in Example 1. Among them, the thickness of the bottom layer of the anti-adhesive layer is 15 μm, and the thicknesses of the first adhesive layer, the second adhesive layer, and the third adhesive layer are all 15 μm.

[0070] Comparative Example 3: This comparative example provides a tissue sealing film and a preparation method thereof

[0071] The difference between this comparative example and Example 1 lies in that: in step (2), only one layer of the anti-adhesive layer transition layer is prepared, that is, the PAA-PAA(BA) solution and the PLGA solution prepared in step (1) are directly mixed evenly in a ratio of 8:2, and coated on the bottom layer of the anti-adhesive layer to obtain the anti-adhesive layer transition layer. A customized mold with embossments is placed on the surface of the coating, dried at room temperature for 20 min, and the mold is removed to obtain the anti-adhesive layer with indentations.

[0072] The contents of other components and the preparation method are the same as those in Example 1. Among them, the thickness of the bottom layer of the anti-adhesive layer is 15 μm, the thickness of the anti-adhesive layer transition layer is 5 μm; the thicknesses of the first adhesive layer, the second adhesive layer, and the third adhesive layer are all 15 μm.

[0073] Comparative Example 4: This comparative example provides a tissue sealing film and a preparation method thereof

[0074] The difference between this comparative example and Example 1 lies in that: in step (2), the coating slurries of the first anti-adhesive layer transition layer and the second anti-adhesive layer transition layer are the same, that is, the PAA-PAA(BA) solution and the PLGA solution prepared in step (1) are directly mixed evenly in a volume ratio of 8:2, and coated on the bottom layer of the anti-adhesive layer twice to obtain the anti-adhesive layer transition layer. A customized mold with embossments is placed on the surface of the coating, dried at room temperature for 20 min, and the mold is removed to obtain the anti-adhesive layer with indentations.

[0075] The contents of other components, the preparation method, and the thickness of each layer are the same as those in Example 1.

[0076] Comparative Example 5: This comparative example provides a tissue sealing film and a preparation method thereof

[0077] The difference between this comparative example and Example 1 lies in that: in step (2), the coating slurries of the first anti-adhesive layer transition layer and the second anti-adhesive layer transition layer are the same and are a single component (PAA-PAA(BA) solution), that is, the PAA-PAA(BA) solution is directly coated on the surface of the bottom layer of the anti-adhesive layer twice, the sealing film sample is dried in a fume hood for 30 min, the sample is transferred to an oven, crosslinked and dried at high temperature, and the tissue sealing film sample is obtained after cutting, packaging, and sterilization.

[0078] The contents of other components, the preparation method, and the thickness of each layer are the same as those in Example 1.

[0079] Comparative Example 6: This comparative example provides a tissue sealing film and a preparation method thereof.

[0080] The difference between this comparative example and Example 1 is as follows: In step (3), a single layer of coating is performed on the adhesive layer. That is, the PAA-PAA(BA) solution and the PLGA solution are directly mixed evenly according to a volume ratio of 9:1, and then coated on the surface of the second anti-sticking layer transition layer to obtain the adhesive layer. The sealing film sample is dried in a fume hood for 30 min, then transferred to an oven for high-temperature cross-linking and drying, and finally cut, packaged, and sterilized to obtain the tissue sealing film sample.

[0081] The contents of other components and the preparation method are the same as those in Example 1. Among them, the thickness of the bottom anti-sticking layer is 15 μm; the thicknesses of the first anti-sticking layer transition layer and the second anti-sticking layer transition layer are 5 μm; the thickness of the adhesive layer is 45 μm.

[0082] Comparative Example 7: This comparative example provides a tissue sealing film and a preparation method thereof.

[0083] The difference between this comparative example and Example 1 is as follows: In step (3), the volume ratios of the coating slurries of the three-layer adhesive layer are the same. That is, the PAA-PAA(BA) solution and the PLGA solution are directly mixed according to a volume ratio of 9:1, and then coated on the surface of the anti-sticking layer transition layer 3 times repeatedly to obtain the adhesive layer. The sealing film sample is dried in a fume hood for 30 min, then transferred to an oven for high-temperature cross-linking and drying, and finally cut, packaged, and sterilized to obtain the tissue sealing film sample.

[0084] The contents of other components, the preparation method, and the thicknesses of each layer are the same as those in Example 1.

[0085] Comparative Example 8: This comparative example provides a tissue sealing film and a preparation method thereof.

[0086] The difference between this comparative example and Example 1 is as follows: In step (3), the coating slurries of the three-layer adhesive layer are the same, all being a single-component PAA-PAA(BA) solution. That is, the PAA-PAA(BA) solution is directly coated on the surface of the anti-sticking layer transition layer 3 times repeatedly to obtain the adhesive layer. The sealing film sample is dried in a fume hood for 30 min, then transferred to an oven for high-temperature cross-linking and drying, and finally cut, packaged, and sterilized to obtain the tissue sealing film sample.

[0087] The contents of other components, the preparation method, and the thicknesses of each layer are the same as those in Example 1.

[0088] Comparative Example 9: This comparative example provides a tissue sealing film and a preparation method thereof.

[0089] The difference between this comparative example and Example 1 lies in that: in step (2), the surface of the anti-sticking layer transition layer was not embossed with a embossed die; the contents of other components, the preparation method, and the thickness of each layer are the same as those in Example 1.

[0090] Comparative Example 10: This comparative example provides a tissue sealing film and a preparation method thereof, including the following steps:

[0091] (1) Weigh 1.0 g of PLGA and add it to dichloromethane to prepare an anti-sticking layer solution with a concentration of 0.1 g / mL (abbreviated as PLGA solution). Using a small coater, add the PLGA solution to the surface of the release paper for coating, and dry it at room temperature for 20 min to obtain the first anti-sticking layer.

[0092] (2) Mix dichloromethane and methanol in a volume ratio of 2.5:1 to obtain a mixed solvent. Weigh 3.0 g of PAA-PAA(BA), 0.3 g of glycerol, and 0.1 g of hydroxypropyl cellulose and add them to the mixed solvent to obtain a PAA-PAA(BA) solution. Use the PAA-PAA(BA) solution to coat on the first anti-sticking layer and dry it at room temperature for 20 min to obtain the first adhesive layer.

[0093] (3) Repeat steps (1) and (2) to obtain a four-layer sealing film sample with alternating anti-sticking layers and adhesive layers. Dry the sample in a fume hood for 30 min, transfer the sample to an oven for high-temperature cross-linking and drying, and obtain a tissue sealing film sample after cutting, packaging, and sterilization. Among them, the thicknesses of both the anti-sticking layer and the adhesive layer are 15 μm.

[0094] Test Example 1: In this test example, the appearance and swelling of the tissue sealing films prepared in the examples and comparative examples were tested

[0095] Experimental process: Swelling and delamination test of the sample in PBS buffer

[0096] Take the sealing film sample, accurately weigh the mass of the sample as 0.05 g using a ten-thousandth balance, place it in a reagent bottle, add 2 mL of phosphate buffer solution (pH = 7.4) preheated to 37°C ± 1°C, seal the reagent bottle and place it in a constant temperature shaker at 37°C ± 1°C and 60 rpm. After 24 hours, take out the sample and observe its swelling situation. The results are shown in Table 1 and Table 2:

[0097] Table 1

[0098]

[0099] Table 2

[0100]

[0101] As can be seen from Tables 1 to 2, the samples prepared by the present invention (Examples 1 to 3) have a flat appearance, swell in PBS buffer without delamination. The results of Example 1 are as shown in Figure 3 Figure (a) in; Comparative Example 2 has no anti-sticking transition layer, swells and delaminates in PBS buffer, and detaches from the anti-sticking layer, unable to ensure lasting adhesion strength. The results are as shown in Figure 3 Figure (b) in.

[0102] For the sample prepared by Comparative Example 1 using a single solvent, the adhesive layer detaches from the anti-sticking layer and is incomplete, and the appearance is as shown in Figure 2 Figure (a) in, and it is impossible to conduct tensile strength and adhesion strength tests; for the sample obtained by one-layer coating with an adhesive layer in Comparative Example 6, there are many surface bubbles and large bubbles, and the appearance is as shown in Figure 2 Figure (b) in, resulting in uneven thickness of the sample and making it unusable; for the samples of Comparative Example 9 and Comparative Example 10, no embossing die was used for embossing during the preparation process, resulting in film curling, which is not conducive to subsequent packaging and use. The appearances are as shown in Figure 2 Figure (c) and (d) in.

[0103] Test Example 2: In this test example, the tensile strength and elongation at break of the tissue sealing films prepared in the examples and comparative examples were tested.

[0104] Experimental process: Cut the sealing film sample into dumbbell-shaped specimens with a test length of 10.0 mm and a width of 2.0 mm. Use a universal tensile machine to conduct tests at a tensile rate of 5 mm / min, observe the fracture situation of the specimens, and calculate the tensile strength and elongation at break.

[0105] As shown in Figure 4 Figure (a) in, the tensile strength values of the tissue sealing films of Examples 1 to 3 and Comparative Examples 2 to 10 are 17.37 ± 2.14 MPa, 16.15 ± 1.01 MPa, 15.44 ± 0.71 MPa, 6.64 ± 0.19 MPa, 10.33 ± 0.26 MPa, 12.15 ± 1.22 MPa, 4.64 ± 0.19 MPa, 4.91 ± 0.59 MPa, 11.10 ± 0.57 MPa, 5.71 ± 0.26 MPa, 14.88 ± 0.47 MPa, 10.94 ± 0.66 MPa, respectively.

[0106] As shown in Figure 4As shown in (b) of the figure, the elongation at break of the tissue sealing films of Examples 1 to 3 and Comparative Examples 2 to 10 were 79.34 ± 3.43%, 64.34 ± 5.64%, 60.33 ± 3.39%, 40.81 ± 0.84%, 42.67 ± 3.74%, 43.67 ± 3.23%, 21.83 ± 1.16%, 21.73 ± 2.14%, 53.88 ± 3.96%, 27.20 ± 0.65%, 59.21 ± 5.11%, and 39.95 ± 2.31%, respectively.

[0107] From the comparison between the above values, it can be seen that Example 1 has relatively high tensile strength and elongation at break. When there is no anti-adhesive transition layer (Comparative Example 2) or the anti-adhesive transition layer is one layer (Comparative Example 3), the flexibility of the sample decreases. This is because the addition of the anti-adhesive transition layer increases the hydrophilicity of the anti-adhesive layer, which is beneficial to the coating of the adhesive layer and the interlayer bonding. Among them, the results of the contact angles of the anti-adhesive layers of Example 1 and Comparative Example 2 are as Figure 5 shown. It can be seen that the contact angle of the anti-adhesive layer of Example 1 of the present invention is 56° (as shown in Figure 5 Figure (b) therein), while the contact angle of the anti-adhesive layer of Comparative Example 2 is 73° (as shown in Figure 5 Figure (a) therein). Therefore, the anti-adhesive layer of the tissue sealing film of Example 1 has stronger hydrophilicity, which is beneficial to the spreading of the adhesive layer.

[0108] The anti-adhesive transition layers of Comparative Example 4 and Comparative Example 5 are both two layers of the same composition. The two transition layers of Comparative Example 4 are mainly composed of PLGA, and the sealing film has relatively high tensile strength. The two transition layers of Comparative Example 5 are tissue adhesive polymers, and the sealing film is relatively brittle with low tensile strength.

[0109] For Comparative Example 6, the adhesive layer was coated once, and a large number of bubbles were generated on the film surface, resulting in structural defects and having relatively low tensile strength and elongation at break.

[0110] The adhesive layers of Comparative Example 7 and Comparative Example 8 are both three layers of the same composition. A certain amount of PLGA was incorporated into the adhesive layer of Comparative Example 7, and its tensile strength is higher than that of the sample of Comparative Example 8.

[0111] Test Example 3: In this test example, the adhesion strength of the tissue sealing films prepared in the examples and comparative examples was tested.

[0112] Experimental process: Use cyanoacrylate glue to fix 2.5×2.5 cm pigskin on a T-shaped plate. Cut the sealing film into 2.5×2.5 cm samples, and use double-sided tape to fix them on another T-shaped plate. After aligning the directions of the pigskin and the samples, apply a force of 1 - 2 N to bond the two together as the sample to be tested. Place the clamping rod of the T-shaped plate of the sample to be tested into the fixture, and load the specimen at a speed of 2 mm / min until it breaks. The schematic diagram of the test process is as Figure 6As shown in Figure (a) therein, the adhesion strength was calculated.

[0113] As Figure 6 shown in (b) therein, the adhesion strengths of the tissue sealing films of Examples 1 to 3 and Comparative Examples 2 to 10 were 0.71±0.11 MPa, 0.68±0.15 MPa, 0.67±0.11 MPa, 0.35±0.11 MPa, 0.44±0.12 MPa, 0.38±0.17 MPa, 0.61±0.08 MPa, 0.43±0.04 MPa, 0.52±0.19 MPa, 0.39±0.06 MPa, 0.65±0.21 MPa, and 0.32±0.05 MPa, respectively.

[0114] It can be seen from the figure that the adhesion strength of Example 1 is higher than that of Comparative Example 7. The introduction of the gradient-decreasing hydrophobic component PLGA in the adhesive layer increases the composite effect of the adhesive layer and the anti-adhesive layer and improves the adhesion strength. At the same time, the test results of the sample of Example 3 show that the introduction of the drug has basically no effect on the tensile strength and adhesion strength of the sealing film. The adhesive layer of Comparative Example 8 uses a single-component PAA-PAA(BA) solution, resulting in a strong hydrophilicity on the surface of the adhesive layer, which cannot discharge a small amount of moisture on the tissue surface, reducing the adhesion strength. Comparative Example 10 uses an alternating coating method, with a weak bonding force between the adhesive layer and the anti-adhesive layer and a low cohesive strength of the sealing film, resulting in a low adhesion strength.

[0115] Test Example 4: In this test example, the adhesion test of the tissue sealing films prepared in the examples and comparative examples on in vitro organ tissues was carried out.

[0116] Experimental procedure: Through the in vitro organ tissue adhesion experiment, the adhesion effect of the tissue sealing film on different organs was evaluated. Take the excised organ tissues of the heart, liver, lung, kidney, small intestine, etc. of New Zealand rabbits for the adhesion test. Use a 27G needle to punch holes on the tissue surface, take a square sealing film with a side length of 10 mm and attach it to this hole. After pressing for 10 s, observe the adhesion to the tissue and check for any sample detachment and liquid leakage. Place the adhered organ tissue in 37°C physiological saline and soak for 24 h, then observe the adhesion to the tissue and check for any sample detachment and liquid leakage.

[0117] As Figure 7 shown in Figures (a)-(e) therein, the tissue sealing film has good adhesion and anti-leakage effects on different organs (heart, liver, lung, kidney, small intestine) of New Zealand rabbits. After the sample was soaked in physiological saline for 24 h, the sealing film could still adhere to the tissue surface, and no sample detachment from the tissue was observed, indicating that the sealing film has good adhesion effect in a wet environment.

[0118] The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. For those skilled in the art, various modifications and variations can be made to the present invention. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included within the protection scope of the present invention.

Claims

1. An organizational sealing film, characterized in that, The tissue sealing film is a multi-layer composite structure composed of an anti-adhesive layer and an adhesive layer. The anti-adhesive layer includes an anti-adhesive layer bottom layer and an anti-adhesive layer transition layer; the multi-layer composite structure specifically includes, from bottom to top in sequence, an anti-adhesive layer bottom layer, a first anti-adhesive layer transition layer, a second anti-adhesive layer transition layer, a first adhesive layer, a second adhesive layer, and a third adhesive layer; The anti-adhesive layer bottom layer is obtained by coating a poly(lactide-co-glycolide) solution on a substrate; The first anti-adhesive layer transition layer is obtained by uniformly mixing a poly(acrylic acid-co-acrylic acid N-hydroxysuccinimide ester) solution and a poly(lactide-co-glycolide) solution in a volume ratio of 8:2 and coating the mixture on the anti-adhesive layer bottom layer; The second anti-adhesive layer transition layer is obtained by uniformly mixing a poly(acrylic acid-co-acrylic acid N-hydroxysuccinimide ester) solution and a poly(lactide-co-glycolide) solution in a volume ratio of 2:8 and coating the mixture on the surface of the first anti-adhesive layer transition layer; The first adhesive layer is obtained by uniformly mixing a poly(acrylic acid-co-acrylic acid N-hydroxysuccinimide ester) solution and a poly(lactide-co-glycolide) solution in a volume ratio of 6:4 and coating the mixture on the surface of the second anti-adhesive layer transition layer; The second adhesive layer is obtained by uniformly mixing a poly(acrylic acid-co-acrylic acid N-hydroxysuccinimide ester) solution and a poly(lactide-co-glycolide) solution in a volume ratio of 8:2 and coating the mixture on the surface of the first adhesive layer; The third adhesive layer is obtained by uniformly mixing a poly(acrylic acid-co-acrylic acid N-hydroxysuccinimide ester) solution and a poly(lactide-co-glycolide) solution in a volume ratio of 9:1 and coating the mixture on the surface of the second adhesive layer; The concentration of the poly(lactide-co-glycolide) solution is 0.1 g / mL; the concentration of the poly(acrylic acid-co-acrylic acid N-hydroxysuccinimide ester) solution is 0.3 g / mL; The surface of the anti-adhesive layer transition layer is made into a pit, convex structure or grid structure through a mold; 2. The tissue sealing film according to claim 1, wherein The substrate is selected from one or more of a glass plate, a stainless steel plate, a polytetrafluoroethylene plate, a release paper, and a release film; The poly(lactide-co-glycolide) solution is obtained by dissolving poly(lactide-co-glycolide) in an organic solvent, and the organic solvent is selected from one or more of dichloromethane, chloroform, hexafluoroisopropanol, acetone, and ethyl acetate; The poly(acrylic acid-co-acrylic acid N-hydroxysuccinimide ester) solution is obtained by dissolving poly(acrylic acid-co-acrylic acid N-hydroxysuccinimide ester) and an additive in a mixed solvent; the mixed solvent includes a first solvent and a second solvent; the first solvent is selected from one or more of dichloromethane, chloroform, hexafluoroisopropanol, acetone, and ethyl acetate; the second solvent is selected from one or more of methanol, ethanol, and isopropanol; the volume ratio of the first solvent to the second solvent is 1 to 6:

1.

3. The tissue sealing film according to claim 1, wherein, The thickness of the bottom layer of the anti-adhesive layer is 5-50 μm; the thickness of the transition layer of the anti-adhesive layer is 2-20 μm; the thickness of the adhesive layer is 10-100 μm; among them, the thickness of the first anti-adhesive layer transition layer and the second anti-adhesive layer transition layer is 1-10 μm; the thickness of the first adhesive layer, the second adhesive layer and the third adhesive layer is 4-40 μm.

4. The tissue sealing film according to claim 2, wherein, The additive includes a plasticizer, a cross-linking agent, and also includes one or more of an active drug, a preservative, and an antifoaming agent; the plasticizer is selected from one or more of glycerol, triethyl citrate, triisopropyl palmitate, triethyl citrate, low molecular weight polyethylene glycol, and silk fibroin; the cross-linking agent is selected from one or more of sucrose, hydroxypropyl cellulose, polylysine, amino polyethylene glycol, low molecular weight chitosan, tannic acid, and trilysine; the active drug is selected from one or more of an antibacterial agent, an antibiotic, a growth factor, and an analgesic; the preservative is selected from one or more of benzoic acid, sodium benzoate, sorbic acid, and potassium sorbate.

5. A method for preparing an organizational sealing film according to any one of claims 1 to 4, characterized in that, It includes the following steps: S1. Dissolve the film-forming polymer in an organic solvent to obtain an anti-adhesive layer solution, and coat it on the surface of the substrate to obtain the bottom layer of the anti-adhesive layer; S2. Dissolve the tissue adhesive polymer, plasticizer and cross-linking agent in a mixed solvent to obtain an adhesive layer solution, mix the anti-adhesive layer solution and the adhesive layer solution in different volume ratios to obtain the first anti-adhesive layer transition layer solution and the second anti-adhesive layer transition layer solution, and coat them on the surface of the bottom layer of the anti-adhesive layer in sequence to obtain the transition layer of the anti-adhesive layer; S3. Mix the anti-adhesive layer solution and the adhesive layer solution in different volume ratios, coat them on the surface of the second anti-adhesive layer transition layer in sequence to obtain the adhesive layer, and then obtain the tissue sealing film through post-treatment; The mass concentration of the film-forming polymer in the anti-adhesive layer solution is 5%-25%; The mass ratio of the tissue adhesive polymer, plasticizer and cross-linking agent is 60-94:5-30:1-10; The anti-adhesive layer transition layer includes a first anti-adhesive layer transition layer and a second anti-adhesive layer transition layer. The specific coating method is: first coat a mixed solution on the bottom layer of the anti-adhesive layer at a volume ratio of 7-9:1-3 to obtain the first anti-adhesive layer transition layer, and then coat a mixed solution on the first anti-adhesive layer transition layer at a volume ratio of 1-3:7-9 to obtain the second anti-adhesive layer transition layer; The adhesive layer includes a first adhesive layer, a second adhesive layer and a third adhesive layer. The specific coating method is: first coat a mixed solution on the surface of the second anti-adhesive layer transition layer at a volume ratio of 5-7:3-5 to obtain the first adhesive layer; then coat a mixed solution on the first adhesive layer at a volume ratio of 7-9:1-3 to obtain the second adhesive layer; then coat a mixed solution on the second adhesive layer at a volume ratio of 8-9:1-2 to obtain the third adhesive layer; The surface of the anti-adhesive layer transition layer is made into a concave, convex or grid structure through a mold.

6. The preparation method according to claim 5, characterized in that, In step S1, the viscosity of the anti-adhesive layer solution is 100-2000 mPa·s; The organic solvent is selected from one or more of dichloromethane, chloroform, hexafluoroisopropanol, acetone, and ethyl acetate; the substrate is selected from one or more of a glass plate, a stainless steel plate, a tetrafluoroethylene plate, a release paper, and a release film.

7. The preparation method according to claim 5, characterized in that In step S2, the viscosity of the adhesive layer solution is 100~1000 mPa·s; The mixed solvent includes a first solvent and a second solvent; the first solvent is selected from one or more of dichloromethane, chloroform, hexafluoroisopropanol, acetone, and ethyl acetate; the second solvent is selected from one or more of methanol, ethanol, and isopropanol; the volume ratio of the first solvent to the second solvent is 1~6:

1.

8. The preparation method according to claim 5, characterized in that, In step S3, the post-treatment includes drying, cutting, packaging, and sterilizing the coated sample to obtain a tissue sealing film sample.

9. Application of the tissue sealing film according to any one of claims 1~4 and / or the tissue sealing film prepared by the preparation method according to any one of claims 5~8 in the field of medical devices.

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