Method for preparing a self-fixing patch and use thereof

Abstract

The present application relates to the field of medical devices, in particular to a preparation method of a self-fixing patch and application thereof. The present application provides a self-fixing patch, the self-fixing biological patch comprising a patch material layer, the patch material layer being loaded or coated with a glue film layer. The micropores on the surface of the glue film layer of the self-fixing patch of the present application are spaced apart from each other by tens of microns, and a uniform micropore array can be regularly formed on the surface of the glue film layer. Due to the existence of the micropore array, the surface roughness and specific surface area of the tissue-adhesive glue film layer are improved, the tissue-adhesive glue film layer is more easily combined with the tissue, and has a positive influence on the adhesion, migration and differentiation of cells. The various micropore structures can adapt to complex tissue surfaces. The tissue-adhesive glue film layer maintains stability by dissipating the matrix through the micropore structure, and the micropore structure is beneficial to strengthening the tissue adhesion performance.

Description

TECHNICAL FIELD

[0001] The application belongs to the field of medical devices, and particularly relates to a preparation method of a self-fixing repair patch and application thereof. BACKGROUND

[0002] Human tissue damage regeneration and repair has always been a difficult problem in clinical practice. In recent years, with the development of cell biology and tissue engineering technology, the emergence of biological patches as a new type of wound repair material has brought a glimmer of hope. Biological patches are three-dimensional scaffold structures formed by decellularization of natural matrices such as dermis, pericardium, porcine small intestinal submucosa or porcine bladder basement membrane. As a biological engineering scaffold, it can repair tissue defects through spatial induction and tissue replacement. Because all components that cause host immune rejection have been removed, it has good tissue compatibility and has been widely used in the repair of defects in various clinical fields such as hernia surgery (e.g., incisional hernia, abdominal wall hernia and inguinal hernia repair), bladder, urethral and ureteral defects, gynecology (e.g., vaginal reconstruction, pelvic floor repair), cardiovascular system diseases (e.g., valve repair, vascular repair), ear, nose and throat diseases (e.g., tympanic membrane repair, nasal contouring), neurosurgery diseases (e.g., dura mater repair), abdominal surgery diseases (e.g., peritoneal repair), colorectal and anorectal surgery diseases, and has achieved good application prospects.

[0003] For many years, biological patches have been used in various clinical fields and need to be sutured or fixed with materials or instruments such as sutures and rivets. The traditional suture fixation method is time-consuming, and repeated dressing and suture removal increases the pain of patients, and the wound is prone to infection, suppuration, scarring after healing, and even interference with the recovery of tissue function. With the progress of medicine, the requirements for surgical techniques and the effects of auxiliary materials in clinical practice are becoming higher and higher. The concept of modern medicine is to minimize the pain of patients and complete the surgery in the shortest possible time while achieving the maximum functional recovery.

[0004] In the field of hernia repair, the concept of using repair mesh for tension-free inguinal hernia repair has been widely recognized by physicians in clinical practice. In order to reduce chronic pain, in addition to standardizing surgical procedures to avoid nerve damage, reducing suture or even not suturing the mesh is of great significance to improve postoperative treatment effects. In a study by Kangxin et al. entitled "Comparison of self-fixing mesh and UHS mesh in tension-free repair of inguinal hernia" (Chinese Journal of Hernia and Abdominal Wall Surgery (Electronic Edition) Vol. 15 No. 4 August 2021), the results showed that ProGrip TM Self-fixing patch and UHS patch in tension-free repair of inguinal hernia TMThere were no foreign body sensation, incision infection, incision hematoma and seroma in the self-fixation patch group. There was 1 case of postoperative scrotal effusion, 1 case of recurrence and 8 cases of chronic pain. In the UHS patch group, there were 12 cases of postoperative foreign body sensation, 2 cases of incision infection, 3 cases of incision hematoma and seroma, 7 cases of scrotal effusion, 1 case of recurrence and 27 cases of chronic pain. The ProGrip TM The self-fixation patch can reduce chronic pain and other complications after tension-free hernia repair in patients with inguinal hernia. The ProGrip TM The self-fixation patch is made of knitted single-fiber polyethylene terephthalate, and is provided with an absorbable needle made of polylactic acid. The self-fixation is realized by the absorbable needle as an anchoring device and the tissue. There is no commercial self-fixation patch for the biological patch at present. The clinical use is sutured by suture or adhered by medical glue. The medical glue is mainly α-cyanoacrylate adhesive. However, the adhesive has defects such as poor impact resistance, low viscosity and poor water resistance, and the application in clinic is limited to a certain extent. Moreover, the suture method also increases the operation. SUMMARY

[0005] In order to overcome the problems in the prior art, the purpose of the present application is to provide a preparation method of a self-fixation patch and application thereof. The present application preforms a tissue adhesive film layer on the patch. The tissue adhesive film layer has no adhesion force in dry state, and after contacting with the wet tissue, the film layer reacts with the tissue rapidly to form strong adhesion, so that the patch is fixed at the repair position. The film layer has no side effect on the tissue, has good compatibility with the tissue, and can be completely degraded. The self-fixation of the patch is realized, the purpose of suture-free is achieved, the operation time is reduced, the trauma to the tissue of the patient and the chronic pain caused by pulling the nerve are reduced, and other operation risks caused by suture are reduced.

[0006] To achieve the above-mentioned purpose and other related purposes, the first aspect of the present application provides a self-fixation patch, which comprises a patch material layer, and the patch material layer is loaded or coated with a film layer.

[0007] In any embodiment of the present application, one side of the film layer is provided with a uniform micropore array; the other side of the film layer corresponding to the micropore array is attached to the biological patch material layer, or at least part of the film layer is embedded in the patch material layer.

[0008] In any embodiment of the present application, the thickness of the film layer is 200-400 μm.

[0009] In any embodiment of the present application, the depth of each micropore in the micropore array of the film layer is 20%-100% of the thickness of the film layer.

[0010] In any embodiment of the present application, the spacing between the micropore array of the adhesive film layer is 10-1000 μm; preferably, the spacing between the micropore array of the adhesive film layer is 10-100 μm.

[0011] In any embodiment of the present application, the pore size of each micropore of the micropore array of the adhesive film layer is 10-1000 μm.

[0012] In any embodiment of the present application, the patch material layer comprises one or more of a combination of pericardium, porcine small intestinal submucosa, porcine bladder basement membrane dermis, peritoneum, collagen membrane, silk fibroin membrane, synthetic fiber membrane, and synthetic mesh.

[0013] In any embodiment of the present application, the raw material of the adhesive film layer comprises a polyphenolic compound and a prepolymer, wherein the prepolymer comprises one or more of a combination of acrylic acid, polyvinyl alcohol, N-succinimidyl acrylate, a crosslinking agent, and a photoinitiator.

[0014] In any embodiment of the present application, the polyphenolic compound is selected from one or more of a combination of tannic acid, catechol, catechol derivatives, pyrogallol, pyrogallol derivatives, dopamine, dopamine derivatives, caffeic acid, caffeic acid derivatives, gallic acid, gallic acid derivatives, catechin, and catechin derivatives.

[0015] In any embodiment of the present application, the crosslinking agent comprises one or more of a combination of N,N'-methylenebisacrylamide, methacrylic anhydride gelatin, polyethylene glycol diacrylate, poloxamer diacrylate, and oxidized alginic acid ester methacrylate.

[0016] In any embodiment of the present application, the photoinitiator comprises α-ketoglutaric acid and / or Irgacure 2959.

[0017] In any embodiment of the present application, the concentration of the solution of the polyphenolic compound is 0.5%-8% (w / w).

[0018] In any embodiment of the present application, the concentration of the acrylic acid in the solution of the prepolymer is 15-30% (w / w).

[0019] In any embodiment of the present application, the concentration of the polyvinyl alcohol in the solution of the prepolymer is 3%-15% (w / w); and the alcoholysis degree of the polyvinyl alcohol is above 75%.

[0020] In any embodiment of the present application, the concentration of the N-succinimidyl acrylate in the solution of the prepolymer is 0.1%-2% (w / w).

[0021] In any embodiment of the present application, the concentration of the crosslinking agent in the solution of the prepolymer is 0.1%-1% (w / w).

[0022] In any embodiment of the present application, the concentration of the photoinitiator in the solution of the prepolymer is 0.05%-0.5% (w / w).

[0023] The second aspect of the present application provides a preparation method of the self-fixing patch, comprising the following steps:

[0024] 1) The polyvinyl alcohol, acrylic acid, N-hydroxysuccinimidyl acrylate, crosslinking agent and photoinitiator are mixed according to the proportion described in the first aspect, and a prepolymer solution is obtained;

[0025] 2) Post-treatment, comprising any one or more of the following steps:

[0026] 2a) The prepolymer solution in step 1) is placed in a mold, and sequentially subjected to light curing, light-avoiding soaking and drying treatment to obtain a film layer; the film layer is fixed on the surface of the repair material layer to obtain a self-fixing patch;

[0027] 2b) The repair material layer is immersed in the prepolymer solution in step 1) to obtain a mixture, and the mixture is placed in a mold, and sequentially subjected to light curing, light-avoiding soaking and drying treatment to obtain a self-fixing patch.

[0028] In any embodiment of the present application, in step 1), the stirring time is 4-12 h.

[0029] In any embodiment of the present application, in step 2), the surface of the mold is a uniform micropore array; preferably, the shape of the cross section of each micropore in the micropore array comprises a triangle, a rectangle or an ellipse.

[0030] In any embodiment of the present application, in step 2), the reaction time of the light curing is 5-20 min.

[0031] In any embodiment of the present application, in step 2), the light-avoiding soaking is soaking in an aqueous solution of the polyhydric phenolic compound; the soaking time is 12-48 h.

[0032] In any embodiment of the present application, in step 2), the drying treatment is freeze-drying and / or vacuum drying.

[0033] In any embodiment of the present application, in step 2a), the fixing mode comprises placing the film layer on the surface of the wet repair material, pressing and drying to form.

[0034] The present application has the following beneficial effects:

[0035] 1、The self-fixing patch of the present application can replace the traditional suture and rivet fixation method by contacting with wet tissue (muscle tissue, fascia tissue, internal organs, etc. with body fluid on the surface), quickly absorbing water and forming firm adhesion, thereby providing a more efficient patch fixation and repair scheme, greatly shortening the operation time and reducing the difficulty of suturing, and achieving the fixation of the patch in special positions that are difficult to suture, and reducing the trauma to the patient's tissue and chronic pain caused by the traction of the nerve, and reducing other surgical risks caused by sutures.

[0036] 2、The glue film used in the present application is completely degradable and has good biocompatibility, can form rapid and durable adhesion on the wet tissue surface, has high adhesion strength and low swelling rate. The present application uses acrylic acid and polyvinyl alcohol as the molecular skeleton to construct a three-dimensional porous gel topological network structure, which can quickly absorb the liquid on the wet tissue surface, and form an initial weak connection through the hydrogen bond between the hydroxyl groups on the surface of the material and the hydroxyl groups on the tissue surface. The first strong adhesion site is constructed by N-hydroxysuccinimide surface grafting modification of the hydroxyl groups of acrylic acid and polyvinyl alcohol to produce covalent reaction with the amino groups on the tissue surface. By introducing polyphenol groups into the network structure, multiple hydrogen bond interactions are formed to stabilize the tissue adhesion gel topological network structure and improve the biomechanical strength of the material itself. At the same time, the introduced polyphenol groups can react with the amino and sulfhydryl groups on the tissue surface to form Schiff base reaction and Michael addition reaction, thereby further improving the tissue adhesion strength.

[0037] The present application adds polyphenolic compounds with pyrogallol and catechol structures, which can easily crosslink with proteins and be oxidized to o-quinone in an alkaline environment, and form non-covalent bonds with the polymer skeleton through hydrogen bond interactions, thereby enhancing the overall mechanical strength and significantly reducing the swelling rate of the tissue adhesive. At the same time, the adhesion performance to various surfaces is enhanced through hydrogen bond, ionic bond, and π-π stacking interactions.

[0038] 3、The microporous structure is beneficial to further enhancing the tissue adhesion performance. The micropores on the surface of the glue film layer of the self-fixing patch of the present application are spaced tens of microns apart, and can regularly form a uniform micropore array on the surface of the glue film layer. Due to the presence of the micropore array, the surface roughness and specific surface area of the tissue adhesion glue film layer are improved, which is more conducive to the adhesion of the tissue, and has a positive influence on the adhesion, migration, and differentiation of cells. The diverse microporous structure can adapt to complex tissue surfaces. The tissue adhesion glue film layer utilizes the microporous structure to dissipate the substrate and maintain stability, and the microporous structure is beneficial to enhancing the tissue adhesion performance.

[0039] When the self-fixing patch of the present application is adhered to the tissue, the water and air in the micropores of the glue film layer can be discharged by pressing or other methods to cause a pressure difference between the inside and outside of the micropores, thereby generating additional suction force, reducing the relative sliding between the glue film layer and the tissue surface in the initial adhesion stage, and improving the adhesion performance of the glue film layer. Attached Figure Description

[0040] Figure 1 This is a cross-sectional view of the structure in Embodiment 1 of the present invention.

[0041] Figure 2 This is a cross-sectional view of the structure in Embodiment 3 of the present invention.

[0042] Figure 3 A schematic diagram of the photocrosslinking process of this invention.

[0043] Figure 4 This is a side sectional view of the adhesive film layer of the present invention.

[0044] Figure 5 This is a front view of the adhesive film layer of the present invention.

[0045] Figure 6 This is a front view of the adhesive film layer of the present invention.

[0046] Component designation explanation:

[0047] 1. Adhesive film layer

[0048] 11. Microporous structure on the surface of the adhesive film layer

[0049] 2 Repair material layer Detailed Implementation

[0050] Before further describing specific embodiments of the present invention, it should be understood that the scope of protection of the present invention is not limited to the specific embodiments described below; it should also be understood that the terminology used in the embodiments of the present invention is for describing specific embodiments and not for limiting the scope of protection of the present invention; in the specification and claims of the present invention, unless otherwise expressly stated in the text, the singular forms "a", "an", and "this" include the plural forms.

[0051] "Range" endpoints disclosed by the present application are presented in the form of lower and upper limit values, and a given range is defined by selecting a lower limit and an upper limit, the selected lower and upper limits defining the boundaries of the particular range. Ranges defined by such endpoints can be either inclusive or exclusive of the end values, and can be arbitrarily combined in any manner, i.e., any lower limit can be combined with any upper limit to form a range. For example, if ranges of 60-120 and 80-110 are listed for a particular parameter, it is understood that ranges of 60-110 and 80-120 are also contemplated. In addition, if minimum range values of 1 and 2 are listed, and if maximum range values of 3, 4, and 5 are listed, then the following ranges are all contemplated: 1-3, 1-4, 1-5, 2-3, 2-4, and 2-5. In the present application, unless otherwise stated, a numerical range "a-b" indicates a shorthand way of describing each and every intervening real number, integer or combination of integers between the upper and lower limits of that range, wherein "a" and "b" are both real numbers. For example, the numerical range "0-5" indicates that all real numbers between "0-5" have been listed herein, "0-5" is merely a shorthand way of describing these numerical combinations. In addition, when a parameter is stated to be an integer > 2, it is equivalent to disclose that the parameter is, for example, an integer 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, etc.

[0052] Unless otherwise specified, all steps of the present application can be carried out in sequence or randomly, preferably in sequence. For example, the method comprises steps 1) and 2), indicating that the method can comprise steps 1) and 2) in sequence, or steps 2) and 1) in sequence.

[0053] When numerical ranges are given, it is understood that every numerical value between the upper and lower limits of that range is also implicitly disclosed. All technical and scientific terms used herein have, unless otherwise defined, the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. Any method, apparatus, material or substance similar or equivalent to those described herein, according to the knowledge of those skilled in the art, can be used in the practice of the present application.

[0054] Unless otherwise defined, all experimental methods, detection methods, preparation methods disclosed in the present application use conventional techniques in pharmaceutical science, pharmaceutical analysis, pharmaceutical chemistry, analytical chemistry, molecular biology, biochemistry and related fields. These techniques are well described in the prior art.

[0055] As Figures 1-2As shown in the first aspect of the present application, a self-fixing patch is provided, which comprises a patch material layer 2 loaded or coated with a film layer 1. The loading means that the film layer 1 is attached to the patch material layer 2. The coating means that the film layer 1 wraps or penetrates into the patch material layer 2.

[0056] As shown in the first aspect of the present application, Figures 1-2 one side of the film layer 1 is provided with an array of uniform micropores; the other side of the film layer 1 corresponding to the array of micropores is attached to the patch material layer 2 or at least part of the film layer 1 is embedded in the patch material layer 2. In the self-fixing patch provided by the present application, the film layer 1 is kept stable by the micropore structure 11, which is beneficial to the tissue adhesion performance. The film layer 1 has no side effects on the tissue, is well compatible with the tissue, and can be completely degraded. The self-fixing patch realizes the purpose of suture-free, reduces the operation time and the trauma of tissue penetration and chronic pain caused by pulling the nerve, and reduces other operation risks caused by sutures.

[0057] In the first embodiment of the present application, Figure 1 the other side of the film layer 1 corresponding to the array of micropores is attached to the patch material layer 2. In this case, the film layer 1 and the patch material layer 2 can be prepared respectively, and then attached by the adhesive effect of the film layer 1.

[0058] In the second embodiment of the present application, Figure 2 at least part of the film layer 1 is embedded in the patch material layer 2. In this case, the film layer 1 is cross-linked and solidified at the same time to fix the patch material layer 2 and the film layer 1, so that the film layer 1 penetrates or completely wraps the patch material layer 2, and the two are combined into a stable integrated structure.

[0059] In the first and second embodiments of the present application, Figures 1-2The thickness of the adhesive film layer 1 is 200-400 μm; preferably, 200-300 μm, 300-350 μm, or 350-400 μm, etc. The depth of each micropore 11 in the micropore array of the adhesive film layer 1 is 20%-100% of the thickness of the adhesive film layer 1. In a specific embodiment of the present application, when the thickness of the adhesive film layer 1 is 200 μm, the depth of each micropore 11 can be 40-200 μm; preferably, 40-80 μm, 80-100 μm, or 100-200 μm, etc. The depth of each micropore 11 can be consistent with the thickness of the adhesive film layer 1, in which case each micropore 11 can penetrate the adhesive film layer 1. The spacing between the micropores 11 of the adhesive film layer 1 in the micropore array is 10-100 μm; preferably, 10-50 μm, 50-80 μm, or 80-100 μm. The spacing between the micropores 11 can be such that the surface of the adhesive film layer 1 regularly forms a uniform micropore array. Due to the presence of the micropore array, the surface roughness and specific surface area of the tissue-adhesive film layer 1 are improved, making it easier to adhere to tissue and having a positive effect on cell adhesion, migration, and differentiation. The pore size of each micropore 11 of the micropore array of the adhesive film layer 1 is 10-1000 μm; preferably, 10-100 μm, 100-500 μm, or 500-1000 μm, etc. The shape of the cross section of each micropore 11 of the micropore array of the adhesive film layer 1 is various, such as triangular, rectangular, elliptical, etc. The various micropore 11 structures can adapt to complex tissue surfaces. Although high surface tension at small sizes tends to cause the micropores 11 to collapse and retract, the adhesive film layer 1 uses its dissipation matrix to maintain the structure in a stable state, and the micropore 11 structure is conducive to strengthening tissue adhesion. When the self-fixing patch of the present application is adhered to tissue, water and air in the micropores 11 of the adhesive film layer 1 can be expelled by pressing or the like, causing a pressure difference between the inside and outside of the micropores 11, thereby generating additional suction, reducing the relative sliding of the adhesive film layer 1 and the tissue surface in the initial stage of adhesion, and improving the adhesion of the adhesive film layer 1.

[0060] In the self-fixing patch provided by the present application, the patch material layer 2 comprises a combination of one or more of pericardium, porcine small intestinal submucosa, porcine bladder basement membrane, dermis, peritoneum, collagen membrane, silk fibroin membrane, synthetic fiber membrane, and synthetic mesh. The synthetic mesh comprises polypropylene mesh, polyester mesh, polyvinylidene fluoride mesh, etc.

[0061] The raw material of the adhesive film layer 1 in the self-fixing patch provided in the present application comprises a polyphenol compound and a prepolymer, and the prepolymer comprises acrylic acid, polyvinyl alcohol, N-succinimidyl acrylate, a crosslinking agent and a photoinitiator. The raw material of the adhesive film layer 1 can be dissolved in deionized water, an aqueous solution or an organic solvent to form a polyphenol compound solution or a prepolymer solution. The aqueous solution comprises a physiological solution and a buffer solution, and the physiological solution comprises normal saline, Ringer's solution, Locke's solution and Tyrode's solution, etc., and the buffer solution comprises a phosphate buffer, a citric acid buffer, a carbonic acid buffer, an acetic acid buffer and a Tris buffer, etc. The organic solvent comprises a combination of one or more of methanol, ethanol, diethyl ether and cyclohexane, and those skilled in the art should understand that the solvent capable of dissolving the raw material described in the present application is within the protection scope.

[0062] The polyphenol compound in the self-fixing patch provided in the present application is selected from one or more of a combination of tannic acid, catechol, catechol derivative, pyrogallol, pyrogallol derivative, dopamine, dopamine derivative, caffeic acid, caffeic acid derivative, gallic acid, gallic acid derivative and catechin, and the concentration of the polyphenol compound solution is 0.5% to 8% (w / w). Preferably, the concentration is 0.5% to 1.0% (w / w), 1.0% to 1.5% (w / w), or 1.5% to 5% (w / w), 5% to 8% (w / w), etc. The polyphenol compound has been widely used in the biological field due to its physiological functions such as antioxidant, vascular protection and tumor prevention. The poor adhesion performance and excessive swelling behavior of the traditional tissue adhesive in the in vivo wet environment have become the main obstacle for many applications and functional researches. At present, different strategies have been reported to obtain strong and tough tissue glue.

[0063] In an embodiment of the present application, the polyphenol compound is tannic acid. Tannic acid is a naturally occurring antioxidant polyphenol with low cytotoxicity, antioxidant and antibacterial activity, etc. Tannic acid has pyrogallol and catechol structure, can be easily crosslinked with protein, and can be oxidized to o-quinone in alkaline environment, thereby forming non-covalent bond with the polymer backbone through hydrogen bond to enhance the overall mechanical strength.

[0064] In the prepolymer solution in the self-fixing patch provided in the present application, the concentration of the acrylic acid is 15% to 30% (w / w); preferably, the concentration is 15% to 18% (w / w), 18% to 25% (w / w), or 25% to 30% (w / w), etc. The use of acrylic acid monomer has stable reaction quality and strong industrial feasibility compared with high molecular polyacrylic acid.

[0065] The concentration of polyvinyl alcohol in the prepolymer solution is 3-15% (w / w); preferably, 3-7% (w / w), 7-8% (w / w), or 8-10% (w / w), 10-12% (w / w), 12-15% (w / w), etc. The alcoholysis degree of polyvinyl alcohol is more than 75%; preferably, 75-80%, 80-85%, or more than 85%, etc. The alcoholysis degree refers to the percentage of hydroxyl groups in the product obtained after alcoholysis.

[0066] Acrylic acid and polyvinyl alcohol are the molecular backbone to construct a three-dimensional porous gel topological network structure, which can quickly absorb the liquid on the surface of the wet tissue, and form an initial weak connection through the hydrogen bond between the hydroxyl groups on the surface of the material and the hydroxyl groups on the surface of the tissue. The film has carboxyl and hydroxyl groups, which can quickly absorb moisture and retain water on the surface of the moist and wet tissue, and quickly and durably adhere to the surface of the tissue, achieving the purpose of sutureless wound closure, and the clinical implementation conditions are simple and controllable.

[0067] By introducing a polyphenol group into the network structure constructed by acrylic acid and polyvinyl alcohol as the molecular backbone, a multiple hydrogen bond stable tissue adhesion gel topological network structure is formed, and the biomechanical strength of the material itself is further improved.

[0068] The concentration of acrylic acid N-hydroxysuccinimide ester in the prepolymer solution is 0.1-2% (w / w); preferably, 0.1-0.5% (w / w), 0.5-1.0% (w / w), or 1.0-2% (w / w), etc. The acrylic acid N-hydroxysuccinimide ester can perform N-hydroxysuccinimide surface grafting modification on the hydroxyl groups of acrylic acid and polyvinyl alcohol, construct a first strong adhesion site for covalent reaction with the amino groups on the surface of the tissue, and make the tissue adhesive have strong adhesion strength.

[0069] The crosslinking agent includes one or more combinations of N,N'-methylenebisacrylamide, methacrylic anhydride gelatin (GelMA), polyethylene glycol diacrylate (PEGDA), poloxamer diacrylate (PoloxDA), and oxidized alginate methacrylate (OxAlgMA). The concentration of the crosslinking agent in the prepolymer solution is 0.1-1% (w / w); preferably, 0.1-0.3% (w / w), 0.3-0.5% (w / w), or 0.5-1% (w / w), etc.

[0070] The photoinitiator in the self-fixing patch provided by the present application includes α-ketoglutaric acid and / or Irgacure 2959. In the prepolymer solution, the concentration of the photoinitiator is 0.05%-0.5% (w / w); preferably, 0.05%-0.07% (w / w), 0.07%-0.09% (w / w), or 0.09%-0.5% (w / w), etc. The photoinitiator is also known as photosensitizer or photocuring agent, which is a kind of compound capable of absorbing energy of a certain wavelength in the ultraviolet region (250-420 nm) or visible region (400-800 nm) to generate free radicals, cations, etc., thereby initiating polymerization, crosslinking and curing.

[0071] In the self-fixing patch provided by the present application, the raw materials of the prepolymer include polyvinyl alcohol, acrylic acid, acrylic acid N-hydroxysuccinimide ester, crosslinking agent and photoinitiator. The prepolymer is a substance produced by the reaction of the above-mentioned five raw materials. The prepolymer needs to be photo-crosslinked to form a hydrogel, and the hydrogel is soaked in a polyphenol compound solution to react again to form a film 1.

[0072] The second aspect of the present application provides a preparation method of the self-fixing patch, which comprises the following steps:

[0073] 1) The polyvinyl alcohol, acrylic acid, acrylic acid N-hydroxysuccinimide ester, crosslinking agent and photoinitiator are mixed according to the proportion of the first aspect, and a prepolymer solution is obtained;

[0074] 2) Post-treatment, including any one or more of the following steps:

[0075] 2a) The prepolymer solution in step 1) is placed in a mold, and the light curing, light-avoiding soaking and drying treatment are sequentially performed to obtain a film layer 1. The film layer 1 is fixed on the surface of the repair material layer 2 to obtain a self-fixing patch.

[0076] 2b) The repair material layer 2 is immersed in the prepolymer solution in step 1) to obtain a mixed layer, and the mixed layer is placed in a mold, and the light curing, light-avoiding soaking and drying treatment are sequentially performed to obtain a self-fixing patch.

[0077] In the preparation method provided in this application, step 1) involves stirring and mixing the polyvinyl alcohol, acrylic acid, N-hydroxysuccinimide acrylate, crosslinking agent, and photoinitiator to obtain a prepolymer solution. The prepolymer solution, by mass percentage, comprises the following components: 15–30% (w / w) acrylic acid, 3%–15% (w / w) polyvinyl alcohol, 0.1%–2% (w / w) N-succinimide acrylate, 0.1%–1% (w / w) crosslinking agent, 0.05%–0.5% (w / w) photoinitiator, with the balance being a solution of polyphenolic compounds or a prepolymer solution in water, an aqueous solution, or an organic solvent. The aqueous solution includes physiological solutions and buffer solutions. Physiological solutions include physiological saline, Ringer's solution, Löwenstein's solution, and Tyrode's solution, etc., while buffer solutions include phosphate buffer, citrate buffer, carbonate buffer, acetate buffer, Tris buffer, etc. Organic solvents include one or more combinations of methanol, ethanol, diethyl ether, and cyclohexane. Those skilled in the art should understand that solvents capable of dissolving the raw materials described in this invention are all within the scope of protection. The stirring time is 4–12 h; preferably, 4–8 h, 8–10 h, or 10–12 h, etc. Acrylic acid and polyvinyl alcohol react to form a molecular backbone, constructing a three-dimensional porous gel topological network structure. N-hydroxysuccinimide acrylate is used to graft N-hydroxysuccinimide onto the hydroxyl groups of acrylic acid and polyvinyl alcohol, constructing a first strong adhesion site that covalently reacts with amino groups on the tissue surface. A crosslinking agent can crosslink the aforementioned compounds. A photoinitiator can cure the aforementioned compounds under ultraviolet light or other conditions.

[0078] In the preparation method provided in this application, step 2) involves placing the prepolymer solution described in step 1) in a mold and sequentially performing photocuring, light-protected immersion, and drying treatments to obtain the adhesive film layer 1. Wherein, as... Figures 4-6 As shown, the mold surface is a uniformly arranged array of micropores. Preferably, the cross-sectional shape of each micropore 11 in the micropore array includes triangles, rectangles, or ellipses. The diverse micropore 11 structures can adapt to complex tissue surfaces. The depth of each micropore 11 in the micropore array of the adhesive film layer 1 is 20% to 100% of the thickness of the adhesive film layer 1. The spacing between the micropores 11 in the micropore array of the adhesive film layer 1 is 10 to 1000 μm, which allows the adhesive film layer 1 surface to regularly form a uniform micropore array. Due to the presence of the micropore array, the surface roughness and specific surface area of ​​the tissue adhesive adhesive film layer 1 are improved, making it easier to adhere to tissues and positively influencing cell adhesion, migration, and differentiation. The pore size of each micropore 11 in the micropore array is 10 to 1000 μm. The micropore 11 structure is beneficial for enhancing tissue adhesion performance.

[0079] In the preparation method provided in this application, in step 2), the photocuring reaction time is 5–20 min; preferably, it is 5–10 min, 10–15 min, or 15–20 min, etc. Photocuring refers to the reaction in which a compound undergoes photolysis after being irradiated by light, or when part of a bond opens, and the generated free radicals and other activated molecules bond with each other, resulting in the formation of a network structure of polymer chains. In this application, such as Figure 3 As shown, photoinitiators can absorb energy of a certain wavelength in ultraviolet light (250-420nm) to generate free radicals, cations, etc., thereby initiating cross-linking and curing.

[0080] In the preparation method provided in this application, step 2) involves immersing the hydrogel in a solution of the polyphenolic compound, where immersion means the hydrogel is completely submerged in the polyphenolic compound solution. The concentration of the polyphenolic compound solution is 0.5%–1.5% (w / w); preferably, it is 0.5%–0.7% (w / w), 0.7%–0.9% (w / w), or 0.9%–1.5% (w / w). The solvent for the polyphenolic compound solution is selected from water, aqueous solutions, or organic solvents to form the polyphenolic compound solution or prepolymer solution. Aqueous solutions include physiological solutions and buffer solutions. Physiological solutions include physiological saline, Ringer's solution, Leucer's solution, and Tyrode's solution, etc. Buffer solutions include phosphate buffer, citrate buffer, carbonate buffer, acetate buffer, Tris buffer, etc. Organic solvents include one or more combinations of methanol, ethanol, diethyl ether, and cyclohexane. The soaking time is 12–48 h; preferably, it is 12–24 h, 24–36 h, or 36–48 h. The addition of polyphenolic compounds in this step is to introduce polyphenolic groups into the network structure, forming multiple hydrogen bonds, stabilizing the tissue adhesion gel topology network structure and improving the biomechanical strength of the material itself, while simultaneously forming a second strong adhesive site, thereby further improving the tissue adhesion strength.

[0081] In the preparation method provided in this application, step 2) involves drying, which is freeze drying and / or vacuum drying.

[0082] In the preparation method provided in this application, step 2a) involves fixing the adhesive film layer 1 to the surface of the repair material layer 2 to obtain a self-fixing repair patch, as shown below. Figure 1 As shown. The fixing method includes placing the adhesive film layer 1 on the surface of the moist repair material, pressing it together, and then drying it to form the desired shape.

[0083] In the preparation method provided in this application, step 2b) involves immersing the repair material layer 2 in the prepolymer solution described in step 1) to obtain a mixture. The mixture is then placed in a mold and sequentially subjected to light curing, light-protected soaking, and drying treatments to obtain a self-fixing repair patch. Figure 2As shown, at this time, the adhesive film layer 1 is cross-linked and cured, and the repair material layer 2 can be fixed with the adhesive film layer 1 at the same time, so that the raw material of the adhesive film layer 1 can penetrate into the repair material layer 2, and the two are combined into a stable integrated structure.

[0084] The third aspect of the present application provides the use of the self-fixing patch or the preparation method in the preparation of medical repair materials; preferably, the application scenarios of the medical repair materials include hernia surgery (such as incisional hernia, abdominal wall hernia, and inguinal hernia repair and reconstruction), bladder, urethral and ureteral defects, gynecology (such as vaginal reconstruction, pelvic floor repair), cardiovascular system diseases (such as valve repair, vascular repair), ear-nose-throat diseases (such as tympanic membrane repair, nasal contouring), neurosurgery diseases (such as dura mater repair), abdominal surgery diseases (such as peritoneal repair), colorectal and anorectal surgery diseases, and defect tissue repair in various clinical fields.

[0085] The present application will be further described by the following examples, but not limited to the scope of the present application. All reagents are commercially available analytical pure products.

[0086] Example 1

[0087] (1) Prepare a prepolymer solution, which includes a deionized water solution of polyvinyl alcohol with a concentration of 15% (w / w) and an alcoholysis degree of 75%, 20% (w / w) of acrylic acid, 0.1% (w / w) of N,N'-methylenebisacrylamide, 0.05% (w / w) of α-ketoglutaric acid, and 0.5% (w / w) of acrylic acid N-hydroxysuccinimide ester, and fully stir them to obtain a prepolymer solution. Pour the prepolymer solution into a mold with a thickness of 200 μm to prepare micropores 11 with a spacing of 50 μm, a depth of 100 μm, and a pore size of 60 μm, and cross-link under ultraviolet light for 20 min to form a hydrogel.

[0088] (2) Soak the gel prepared in step (1) in a 1.0% (w / w) tannic acid solution under light-proof conditions, and take it out after soaking for 24 h to obtain a tissue adhesive precursor. Perform in-situ freeze-drying on the tissue adhesive precursor to obtain the adhesive film layer 1.

[0089] (3) Fix the adhesive film layer 1 prepared in step (2) on the wet surface of the multi-layer porcine small intestinal submucosa of the repair material layer 2, and dry to obtain a self-fixing patch.

[0090] Comparative Example 1

[0091] (1) A prepolymer solution was prepared by dissolving 8% (w / w) polyvinyl alcohol with an alcoholysis degree of 85%, 30% (w / w) acrylic acid, 0.1% (w / w) N,N'-methylenebisacrylamide, 0.05% (w / w) α-ketoglutaric acid, and 1% (w / w) N-hydroxysuccinimidyl acrylate in deionized water, and stirring the solution thoroughly to obtain a prepolymer solution. The prepolymer solution was poured into a mold with a thickness of 200 μm, and micro-holes 11 with a pitch of 80 μm, a depth of 150 μm, and a diameter of 100 μm were formed. The prepolymer solution was cross-linked under UV light for 20 min to form a hydrogel.

[0092] (2) The gel prepared in step (1) was lyophilized in situ to obtain a gel film layer 1.

[0093] (3) The gel film layer 1 prepared in step (2) was adhered to the surface of a wet multi-layer porcine bladder basement membrane of a repair material layer 2 using water, and dried to obtain a self-adhesive patch.

[0094] Example 2

[0095] (1) A prepolymer solution was prepared by dissolving 8% (w / w) polyvinyl alcohol with an alcoholysis degree of 85%, 30% (w / w) acrylic acid, 0.1% (w / w) N,N'-methylenebisacrylamide, 0.05% (w / w) α-ketoglutaric acid, and 1% (w / w) N-hydroxysuccinimidyl acrylate in deionized water, and stirring the solution thoroughly to obtain a prepolymer solution. The prepolymer solution was poured into a mold with a thickness of 200 μm, and micro-holes 11 with a pitch of 80 μm, a depth of 150 μm, and a diameter of 100 μm were formed. The prepolymer solution was cross-linked under UV light for 20 min to form a hydrogel.

[0096] (2) The gel prepared in step (1) was immersed in a 1% (w / w) tannic acid solution under light- shielding conditions, and taken out after 24 h of immersion to obtain a tissue adhesive precursor. The tissue adhesive precursor was lyophilized in situ to obtain a gel film layer 1.

[0097] (3) The gel film layer 1 prepared in step (2) was adhered to the surface of a wet multi-layer porcine bladder basement membrane of a repair material layer 2 using water, and dried to obtain a self-adhesive patch.

[0098] Example 3

[0099] (1) A prepolymer solution was prepared by dissolving 8% (w / w) polyvinyl alcohol with an alcoholysis degree of 85%, 30% (w / w) acrylic acid, 0.1% (w / w) N,N'-methylenebisacrylamide, 0.05% (w / w) α-ketoglutaric acid, and 1% (w / w) N-hydroxysuccinimidyl acrylate in deionized water, and stirring the solution until it was homogeneous. The prepolymer solution was poured into a mold with a thickness of 400 μm, and a polypropylene synthetic mesh of layer 2 was immersed in the prepolymer solution to form micropores 11 with a pitch of 80 μm, a depth of 150 μm, and a pore diameter of 200 μm. The solution was crosslinked by irradiation under a UV lamp for 20 min to form a hydrogel.

[0100] (2) The gel prepared in step (1) was immersed in a 1% (w / w) catechol solution under light-protected conditions for 24 h, and then removed to obtain a self-fixing patch precursor. The tissue adhesive precursor was lyophilized in situ to obtain a film layer 1.

[0101] Example 4

[0102] (1) A prepolymer solution was prepared by dissolving 10% (w / w) polyvinyl alcohol with an alcoholysis degree of 75%, 25% (w / w) acrylic acid, 0.1% (w / w) polyethylene glycol bisacrylate, 0.05% (w / w) α-ketoglutaric acid, and 1% (w / w) N-hydroxysuccinimidyl acrylate in deionized water, and stirring the solution until it was homogeneous. The prepolymer solution was poured into a mold with a thickness of 200 μm to form micropores 11 with a pitch of 100 μm, a depth of 100 μm, and a pore diameter of 30 μm. The solution was crosslinked by irradiation under a UV lamp for 20 min to form a hydrogel.

[0103] (2) The gel prepared in step (1) was immersed in a 0.5% (w / w) tannic acid solution under light-protected conditions for 48 h, and then removed to obtain a tissue adhesive precursor. The tissue adhesive precursor was lyophilized in situ to obtain a film layer 1.

[0104] (3) The film layer 1 prepared in step (2) was adhered to the surface of a wet multi-layer pig bladder basement membrane of layer 2 using water, and then dried to obtain a self-fixing patch.

[0105] Comparative Example 2

[0106] (1) A prepolymer solution was prepared by dissolving 1% (w / w) polyvinyl alcohol with an alcoholysis degree of 75%, 25% (w / w) acrylic acid, 0.1% (w / w) polyethylene glycol bisacrylate, 0.05% (w / w) α-ketoglutaric acid, and 1% (w / w) N-hydroxysuccinimide acrylate in deionized water, and stirring the solution until it was uniform. The prepolymer solution was poured into a mold with a thickness of 200 μm to form micropores 11 with a pitch of 100 μm, a depth of 100 μm, and a pore diameter of 30 μm, and the solution was crosslinked under UV light for 20 min to form a hydrogel.

[0107] (2) The gel prepared in step (1) was immersed in a 0.5% (w / w) tannic acid solution under lightless conditions, and was removed after 48 h of soaking to obtain a tissue adhesive precursor. The tissue adhesive precursor was subjected to in-situ freeze-drying to obtain a gel film layer 1.

[0108] (3) The gel film layer 1 prepared in step (2) was adhered to the surface of a multi-layer pig bladder basement membrane of a wet repair material layer 2 using water, and was dried to obtain a self-fixing repair patch.

[0109] Comparative Example 3

[0110] (1) A prepolymer solution was prepared by dissolving 1% (w / w) polyvinyl alcohol with an alcoholysis degree of 75%, 25% (w / w) acrylic acid, 0.1% (w / w) polyethylene glycol bisacrylate, 0.05% (w / w) α-ketoglutaric acid, and 1% (w / w) N-hydroxysuccinimide acrylate in deionized water, and stirring the solution until it was uniform. The prepolymer solution was poured into a mold with a thickness of 200 μm to form micropores 11 with a pitch of 100 μm, a depth of 100 μm, and a pore diameter of 30 μm, and the solution was crosslinked under UV light for 20 min to form a hydrogel.

[0111] (2) The gel prepared in step (1) was immersed in a 0.5% (w / w) tannic acid solution under lightless conditions, and was removed after 48 h of soaking to obtain a tissue adhesive precursor. The tissue adhesive precursor was subjected to in-situ freeze-drying to obtain a gel film layer 1.

[0112] (3) The gel film layer 1 prepared in step (2) was adhered to the surface of a multi-layer pig bladder basement membrane of a wet repair material layer 2 using water, and was dried to obtain a self-fixing repair patch.

[0113] The components of the above examples and comparative examples are shown in Table 1:

[0114] Table 1 Components of the gel film layer

[0115]

[0116] The properties of the self-fixing repair patches prepared in the examples were measured as follows:

[0117] (1) Adhesion strength test

[0118] The self-fixing patch of the above example was taken, with an area of 10 mm x 25 mm, and the hole side was adhered to the surface of a wet pigskin with a width of 25 mm, so that the pigskin and the self-fixing patch had an overlapping area of 10 mm x 25 mm, i.e. the adhesion area. The test was performed according to YY / T 0729.1 Tissue Adhesive Bonding Performance Test Method Part 1: Lap-Shear Tensile Load Strength.

[0119] (2) Peeling strength test

[0120] The self-fixing patch of the above example was taken, with an area of 100 mm x 20 mm, and the hole side was adhered to the surface of a wet pigskin and intestine tube with a width of 20 mm, so that the pigskin and intestine tube and the self-fixing patch had an overlapping area of 100 mm x 20 mm, i.e. the adhesion area. The test was performed according to YY / T 0729.2-2009 Tissue Adhesive Bonding Performance Test Method Part 2: T-Peel Tensile Load Strength.

[0121] (3) Swelling test

[0122] The self-fixing patch of the above example was taken, and the thickness was measured and recorded as V0. The self-fixing patch was immersed in a PBS solution, and after 7 days, the swollen self-fixing patch was taken out, the surface water was wiped off with filter paper, the thickness of the gel was measured, and recorded as V1. The swelling rate Q = (V1-V0) / V0.

[0123] Table 2 Test data

[0124]

[0125] The above examples are only illustrative of the principles and effects of the present application, and are not intended to limit the present application. Any person skilled in the art can modify or change the above examples without departing from the spirit and scope of the present application. Therefore, all equivalent modifications or changes made by those skilled in the art without departing from the spirit and technical thought disclosed by the present application should be covered by the claims of the present application.

Claims

1. A self-fixating patch, characterized in that, The self-fixing patch comprises a patch material layer (2) loaded or coated with a film layer (1), one side of the film layer (1) is provided with a uniform micropore array; the other side of the film layer (1) corresponding to the micropore array is attached to the patch material layer (2) or at least part of the film layer (1) is embedded in the patch material layer (2), the raw material of the film layer (1) comprises a polyphenolic compound and a prepolymer, the prepolymer is composed of acrylic acid, polyvinyl alcohol, acrylic acid N-succinimidyl ester, a crosslinking agent and a photoinitiator, and the polyphenolic compound is selected from tannic acid; the raw material of the film layer (1) is dissolved in deionized water, an aqueous solution or an organic solvent to form a polyphenolic compound solution or a prepolymer solution, and in the prepolymer solution, the concentration of the polyvinyl alcohol is 3%-15% w / w, and the concentration of the acrylic acid is 15-30% w / w. The self-fixing patch is prepared by the following steps: 1) stirring and mixing polyvinyl alcohol, acrylic acid, acrylic acid N-hydroxysuccinimidyl ester, a crosslinking agent and a photoinitiator to obtain a prepolymer solution; 2) placing the prepolymer solution in step 1) in a mold, the surface of the mold is a uniform micropore array, and after photocuring, the film layer (1) is obtained by soaking in a tannic acid solution in the dark and drying treatment, and the film layer (1) is fixed on the surface of the patch material layer (2) to obtain the self-fixing patch.

2. The self-fixating patch of claim 1, wherein, The thickness of the film layer (1) is 200-400 μm; and / or the depth of each micropore (11) in the micropore array of the film layer (1) is 20%-100% of the thickness of the film layer (1).

3. The self-fixating patch of claim 1, wherein, The spacing between the micropore arrays of the film layer (1) is 10-1000 μm; And / or the pore size of each micropore (11) in the micropore array of the film layer (1) is 10-1000 μm; And / or the patch material layer (2) comprises a combination of one or more of pericardium, pig small intestinal submucosa, pig bladder basement membrane, dermis, peritoneum, collagen membrane, silk fibroin membrane, synthetic fiber membrane and synthetic mesh.

4. The self-fixating patch of claim 3, wherein, The spacing between the micropore arrays of the film layer (1) is 10-100 μm.

5. The self-fixating patch of claim 1 wherein, The crosslinking agent comprises a combination of one or more of N,N'-methylenebisacrylamide, methacrylic anhydride gelatin, polyethylene glycol diacrylate, poloxamer diacrylate and oxidized alginic acid ester methacrylate; And / or the photoinitiator comprises α-ketoglutaric acid and / or Irgacure 2959.

6. The self-fixating patch of claim 1 wherein, One or more of the following features are included: A) The concentration of the polyphenolic compound solution is 0.5%-8% w / w; B) In the solution of the prepolymer, the alcoholysis degree of the polyvinyl alcohol is above 75%; C) In the solution of the prepolymer, the concentration of the acrylic acid N-succinimidyl ester is 0.1%-2% w / w; D) In the solution of the prepolymer, the concentration of the crosslinking agent is 0.1%-1% w / w; E) In the solution of the prepolymer, the concentration of the photoinitiator is 0.05%-0.5% w / w.

7. The self-fixating patch of claim 1 wherein, One or more of the following features are also included: a) in step 1), the stirring time is 4-12h; b) in step 2), the photocuring reaction time is 5-20min; c) in step 2), the soaking time is 12-48h; d) in step 2), the drying treatment is freeze-drying and / or vacuum drying; e) in step 2), the fixing method comprises placing the adhesive film layer (1) on the surface of the wet repair material layer (2), and drying after pressing to form.

8. The self-fixating patch of claim 7, wherein, The shape of the cross section of each micropore (11) in the micropore array comprises a triangle, a rectangle or an ellipse.

9. Use of the self-fixing patch according to any one of claims 1-8 in the preparation of a medical repair material.

10. The use according to claim 9, characterized in that, The application scenarios of the medical repair material include bladder, urethral and ureter defects, gynecological diseases, cardiovascular system diseases, ear-nose-throat diseases, neurosurgery diseases, abdominal surgery diseases or colorectal and anorectal surgery diseases.

11. Use according to claim 9, characterized in that, The application scenarios of the medical repair material include hernia surgery.

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