CN116139338A - Preparation method and application of self-fixing repair patch - Google Patents

Abstract

The invention relates to the field of medical instruments, in particular to a preparation method and application of a self-fixing repair patch. The application provides a self-fixing repairing piece, the self-fixing biological repairing piece comprises a repairing material layer, and the repairing material layer is loaded or coated with a glue film layer. The micropores on the surface of the self-fixing repair sheet adhesive film layer are mutually spaced by tens of micrometers, a uniform micropore array can be regularly formed on the surface of the adhesive film layer, and the surface roughness and the specific surface area of the tissue adhesive film layer are improved due to the existence of the micropore array, so that the self-fixing repair sheet adhesive film layer is easier to attach to tissues and has positive influence on adhesion, migration and differentiation of cells. The various micropore structures can adapt to complex tissue surfaces. The tissue adhesive film layer is kept stable by utilizing a microporous structure dissipation matrix, and the microporous structure is beneficial to strengthening the tissue adhesive performance.

Description

Preparation method and application of self-fixing repair patch

Technical Field

The invention belongs to the field of medical instruments, and particularly relates to a preparation method and application of a self-fixing repair patch.

Background

The regeneration and repair of human tissue injury is always a clinical problem, in recent years, along with the development of cell biology and tissue engineering technology, the appearance of a biological patch as an emerging wound repair material brings light to people, the biological patch is a three-dimensional bracket structure formed by taking off cells from natural matrixes such as dermis, pericardium, porcine small intestine submucosa or porcine bladder basement membrane, and the biological patch can repair tissue defects through space induction and tissue replacement as a biological engineering bracket, and has good tissue compatibility because of removing all components causing host immune rejection, and the biological patch has wide application in clinical fields of tissue repair such as hernia surgery (such as incision hernia, abdominal wall hernia and inguinal hernia repair reconstruction), bladder, ureter defect, gynaecology (such as vaginal reconstruction and pelvic floor repair), cardiovascular system diseases (such as valve repair and vascular repair), otorhinolaryngology diseases (such as tympanic membrane repair and nasal contour plastic repair), neurosurgery diseases (such as dura (such as peritoneal repair), abdominal diseases (such as peritoneal repair), colorectal surgery diseases and the like, and has good application prospect.

For many years, the application of the biological patch in various clinical fields is to suture or fix the patch by adopting materials such as suture, rivet and the like or instruments. The traditional suture fixing method is time-consuming in suture operation, and frequent dressing change and stitch removal increase pain of patients, and the wound is easy to be infected, suppuration, scar left after healing and even tissue function recovery are disturbed. With the advancement of medicine. Clinically, the requirements on the effect of surgical techniques and auxiliary materials are increasing. Modern medicine is designed to minimize the pain of the patient and to complete the operation in the shortest time while achieving the maximum functional recovery.

In the field of hernia repair, the concept of tension-free repair of inguinal hernias using repair meshes has been widely accepted by physicians in the clinic. In order to reduce chronic pain, besides standardizing operation and avoiding nerve injury, reducing or even not stitching the mesh has important significance in improving the postoperative treatment effect of patients. Kangxin et al in one term ProGrip ^TM The results of a comparative study of self-anchoring patch and UHS patch in inguinal hernia tension-free repair (journal of Chinese hernia and abdominal wall surgery (electronic version) 2021, 8, 15, 4) show that ProGrip ^TM The self-fixing patch group has no foreign body sensation, incision infection, incision hematoma and seroma; postoperative scrotal effusion 1, recurrence 1, chronic pain 8. The UHS patch group showed 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. Application of ProGrip ^TM The self-fixing patch can reduce complications such as chronic pain and the like of inguinal hernia patients after non-tension hernia repair operation. ProGrip described in the study ^TM The self-fixing patch is made of polyethylene terephthalate with knitted single fibers, one side of the self-fixing patch is provided with an absorbable contact pin made of polylactic acid, and the self-fixing patch is attached to tissues by taking the absorbable contact pin as an anchoring device. The clinical commercial-free self-fixing patch of the biological patch at the present stage can be used, the clinical use mode is suture suturing or bonding in medical glue operation, the medical glue is mainly alpha-cyanoacrylate adhesive, but the adhesive has the defects of poor shock resistance, low viscosity, poor water resistance and the like, is limited in clinical application to a certain extent, and the surgical operation is increased as the suture mode is adopted.

Disclosure of Invention

In order to overcome the problems in the prior art, the invention aims to provide a preparation method and application of a self-fixing repairing sheet. The adhesive film layer has no side effect on tissues, has good compatibility with tissues and can be completely degraded. The self-fixing and stitching-free purpose of the patch is realized, the operation time and the wound penetrating the tissue of the patient and the chronic pain caused by nerve pulling are reduced, and the other operation risks brought by stitching are reduced.

To achieve the above and other related objects, a first aspect of the present invention provides a self-fixing patch, which includes a repair material layer loaded or coated with a glue film layer.

In any embodiment of the present application, one side of the adhesive film layer is provided with a uniform micropore array; the other surface of the adhesive film layer corresponding to the micropore array is attached to the biological repair material layer or at least part of the adhesive film layer is embedded into the repair material layer.

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

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

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

In any embodiment of the present application, the pore diameter of each pore of the pore array of the adhesive film layer is 10-1000 μm.

In any embodiment of the present application, the repair material layer comprises one or more of pericardium, porcine small intestine submucosa, porcine bladder basement membrane dermis, peritoneum, collagen membrane, silk fibroin membrane, synthetic fiber membrane, synthetic mesh.

In any embodiment of the present application, the raw materials of the adhesive film layer include a polyhydric phenol compound and a prepolymer, and the prepolymer includes one or more of acrylic acid, polyvinyl alcohol, N-succinimidyl acrylate, a crosslinking agent, and a photoinitiator.

In any embodiment of the present application, the polyhydric phenol compound is selected from tannic acid, catechol derivatives, pyrogallol derivatives, dopamine derivatives, caffeic acid derivatives, gallic acid derivatives, catechins, combinations of one or more of catechin derivatives.

In any embodiment of the present application, the cross-linking agent comprises a combination of one or more of N, N' -methylenebisacrylamide, methacrylated gelatin, polyethylene glycol diacrylate, poloxamer diacrylate, and oxidized alginate methacrylate.

In any embodiment of the present application, the photoinitiator comprises α -ketoglutarate and/or Irgacure 2959.

In any of the embodiments herein, the concentration of the solution of the polyphenol compound is 0.5% to 8% (w/w).

In any of the embodiments herein, the concentration of acrylic acid in the solution of the prepolymer is 15 to 30% (w/w).

In any of the embodiments herein, the concentration of the polyvinyl alcohol in the solution of the prepolymer is 3% to 15% (w/w); the alcoholysis degree of the polyvinyl alcohol is more than 75%.

In any of the embodiments herein, the concentration of the N-succinimidyl acrylate in the solution of the prepolymer is 0.1% to 2% (w/w).

In any of the embodiments herein, the concentration of the crosslinking agent in the solution of the prepolymer is 0.1% to 1% (w/w).

In any of the embodiments herein, the concentration of the photoinitiator in the solution of the prepolymer is from 0.05% to 0.5% (w/w).

The second aspect of the present application provides a method for preparing the self-fixing repair patch, which includes the following steps:

1) Proportioning, stirring and mixing the polyvinyl alcohol, the acrylic acid N-hydroxysuccinimide ester, the cross-linking agent and the photoinitiator according to the proportion relation of the first aspect to obtain a prepolymer solution;

2) Performing post-treatment comprising any one or more of the following steps:

2a) Placing the prepolymer solution obtained in the step 1) into a mold, and sequentially performing photo-curing, light-shielding soaking and drying treatment to obtain a glue film layer; fixing the adhesive film layer on the surface of the repair material layer to obtain a self-fixing repair sheet;

2b) Immersing the repair material layer in the prepolymer solution in the step 1) to obtain a mixture, placing the mixture in a mold, and sequentially performing photo-curing, light-shielding soaking and drying treatment to obtain the self-fixing repair sheet.

In any embodiment of the present application, in step 1), the stirring time is 4 to 12 hours.

In any embodiment of the present application, in step 2), the mold surface is a uniform array of microwells; preferably, the shape of each microwell cross section in the microwell array comprises a triangle, rectangle or oval.

In any embodiment of the present application, in step 2), the reaction time of the photo-curing is 5 to 20 minutes.

In any embodiment of the present application, in step 2), the light-shielding soaking is soaking in an aqueous solution of the polyhydric phenol compound; the soaking treatment time is 12-48 h.

In any embodiment of the present application, in step 2), the drying process is freeze drying and/or vacuum drying.

In any embodiment of the present application, in step 2 a), the fixing method includes placing the adhesive film layer on the surface of the wet repair material, and drying and molding after pressing.

The beneficial effects of the invention are as follows:

1. when the self-fixing patch is applied, the patch is contacted with wet tissues (muscle tissues with body fluid on the surface, fascia tissues, internal organs and the like), so that the patch absorbs water rapidly and forms firm adhesion, the patch can replace the traditional suture line and a suture fixing mode in the rivet operation, a more effective patch fixing and repairing scheme is provided, the operation time is greatly shortened, the suture difficulty is reduced, the patch can be fixed at a special position which is difficult to suture, the chronic pain caused by the wound penetrating the tissue of a patient and the traction nerve is reduced, and other operation risks brought by the suture are reduced.

2. The adhesive film used in the invention is a fully degradable component, has good biocompatibility, can form quick and durable adhesion to the surface of wet tissues, and has high adhesive strength and low swelling rate. According to the invention, acrylic acid and polyvinyl alcohol are used as molecular frameworks, so that a three-dimensional porous gel topological network structure is constructed, the material can quickly absorb and moisten tissue surface liquid, and initial weak connection is formed through hydroxyl on the surface of the material and hydroxyl on the surface of the tissue. The first strong binding site which generates covalent reaction with amino groups on the surface of the tissue is constructed by carrying out N-hydroxysuccinimide surface grafting modification on the hydroxyl groups of acrylic acid and polyvinyl alcohol. The polyhydric phenol groups are introduced into the network structure to form multiple hydrogen bonding, so that the tissue adhesion gel topological network structure is stabilized, the biomechanical strength of the material is improved, and meanwhile, the introduced polyhydric phenol groups can react with amino groups and sulfhydryl groups on the surface of the tissue to generate Schiff base reaction and Michael addition reaction to form second strong bonding sites, so that the tissue bonding strength is further improved.

The invention adds the polyhydric phenol compound, has pyrogallol and catechol structure, can be easily crosslinked with protein, can be oxidized into o-quinone under alkaline environment, can form non-covalent bond with polymer skeleton through hydrogen bond, enhances the integral mechanical strength and obviously reduces the swelling rate of the tissue adhesive; at the same time, the adhesive property with various surfaces is enhanced by the actions of hydrogen bond, ionic bond, pi-pi accumulation and the like.

3. The microporous structure is advantageous for further enhancing tissue adhesion properties. The micropores on the surface of the self-fixing repair sheet adhesive film layer are mutually spaced by tens of micrometers, and a uniform micropore array can be regularly formed on the surface of the adhesive film layer. The various micropore structures can adapt to complex tissue surfaces. The tissue adhesive film layer is kept stable by utilizing a microporous structure dissipation matrix, and the microporous structure is beneficial to strengthening the tissue adhesive performance.

When the self-fixing patch is adhered to a tissue, water and air in micropores of the adhesive film layer can be discharged in a pressing mode or the like to cause pressure difference between the inside and the outside of the micropores, so that additional suction force is generated, relative sliding between the adhesive film layer at the initial stage of adhesion and the surface of the tissue is reduced, and the adhesive property of the adhesive film layer is improved.

Drawings

Fig. 1 is a sectional view showing the structure of embodiment 1 of the present invention.

Fig. 2 is a cross-sectional view showing the structure of embodiment 3 of the present invention.

FIG. 3 is a schematic diagram of the process of photocrosslinking in accordance with the present invention.

FIG. 4 is a side cross-sectional view of the adhesive film layer of the present invention.

Fig. 5 is a front view of the adhesive film layer of the present invention.

Fig. 6 is a front view of the adhesive film layer of the present invention.

Description of element numbers:

1. adhesive film layer

11. Microporous structure on surface of adhesive film layer

2. Repair material layer

Detailed Description

Before the embodiments of the invention are explained in further detail, it is to be understood that the invention is not limited in its scope to the particular embodiments described below; it is also to be understood that the terminology used in the examples of the invention is for the purpose of describing particular embodiments only and is not intended to limit the scope of the invention; in the description and claims of the invention, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise.

The "range" disclosed herein is defined in terms of lower and upper limits, with a given range being defined by the selection of a lower and an upper limit, the selected lower and upper limits defining the boundaries of the particular range. Ranges that are defined in this way can be inclusive or exclusive of the endpoints, and any combination can be made, i.e., any lower limit can be combined with any upper limit to form a range. For example, if ranges of 60 to 120 and 80 to 110 are listed for a particular parameter, it is understood that ranges of 60 to 110 and 80 to 120 are also contemplated. Furthermore, if the minimum range values 1 and 2 are listed, and if the maximum range values 3,4 and 5 are listed, the following ranges are all contemplated: 1 to 3, 1 to 4, 1 to 5, 2 to 3, 2 to 4 and 2 to 5. In this application, unless otherwise indicated, the numerical ranges "a-b" represent shorthand representations of any combination of real numbers between a and b, where a and b are both real numbers. For example, the numerical range "0-5" means that all real numbers between "0-5" have been listed throughout, and "0-5" is only a shorthand representation of a combination of these values. When a certain parameter is expressed as an integer of 2 or more, it is disclosed that the parameter is, for example, an integer of 2, 3,4, 5, 6, 7, 8, 9, 10, 11, 12 or the like.

All steps of the present application may be performed sequentially or randomly, preferably sequentially, unless otherwise indicated. For example, the method comprises steps 1) and 2), meaning that the method may comprise steps 1) and 2) performed sequentially, or may comprise steps 2) and 1) performed sequentially.

Where numerical ranges are provided in the examples, it is understood that unless otherwise stated herein, both endpoints of each numerical range and any number between the two endpoints are significant both in the numerical range. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The present invention may be implemented using any method, apparatus and materials similar or equivalent to those described in the embodiments of the present invention, according to the knowledge of those skilled in the art and the description of the present invention, in addition to the specific methods, apparatus and materials used in the embodiments.

Unless otherwise indicated, the experimental methods, detection methods, and preparation methods disclosed in the present invention employ conventional techniques in the art, such as pharmacy, pharmacoanalytics, pharmaceutical chemistry, analytical chemistry, molecular biology, biochemistry, and related fields. These techniques are well described in the prior art.

As shown in fig. 1-2, a first aspect of the present application provides a self-fixing patch, where the self-fixing patch includes a repair material layer 2, and the repair material layer 2 is loaded or coated with a glue film layer 1. The load means that the adhesive film layer 1 is attached to the repairing material layer 2. The coating means that the adhesive film layer 1 wraps or permeates the repairing material layer 2.

As shown in fig. 1 to 2, one surface of the adhesive film layer 1 is provided with a uniform micropore array; the other surface of the adhesive film layer 1 corresponding to the micropore array is attached to the repair material layer 2 or at least part of the adhesive film layer 1 is embedded into the repair material layer 2. In the self-fixing repair patch provided by the application, the adhesive film layer 1 is kept stable by utilizing the dissipation matrix of the micropore 11 structure, and the micropore 11 structure is beneficial to strengthening the tissue adhesion performance. The adhesive film layer 1 has no side effect on tissues, has good compatibility with the tissues and can be completely degraded. The self-fixing and stitching-free purpose of the patch is realized, the operation time and the wound penetrating the tissue of the patient and the chronic pain caused by nerve pulling are reduced, and the other operation risks brought by stitching are reduced.

In the first embodiment of the present application, as shown in fig. 1, the other surface of the adhesive film layer 1 corresponding to the micropore array is attached to the repair material layer 2. In this case, the adhesive film layer 1 and the repair material layer 2 may be prepared separately, and then bonded by the adhesive action of the adhesive film layer 1.

In a second embodiment of the present application, as shown in fig. 2, at least a part of the adhesive film layer 1 is embedded in the repair material layer 2. In this case, the adhesive film layer 1 can be crosslinked and cured, and the repair material layer 2 and the adhesive film layer 1 can be fixed, so that the adhesive film layer 1 permeates into or completely wraps the repair material layer 2, and the two layers are combined into a stable integrated structure.

In the first and second embodiments of the present application, as shown in fig. 1 to 2, the thickness of the adhesive film layer 1 is 200 to 400 μm; preferably 200 to 300. Mu.m, 300 to 350. Mu.m, 350 to 400. Mu.m, 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 one embodiment of the present application, when the thickness of the adhesive film layer 1 is 200 μm, the depth of each micropore 11 may be 40 μm to 200 μm; preferably 40 to 80 μm, 80 to 100 μm, 100 to 200 μm, or the like. The depth of each of the micro-holes 11 may be identical to the thickness of the adhesive film layer 1, in which case each of the micro-holes 11 may penetrate the adhesive film layer 1. The spacing between the micropores 11 of the adhesive film layer 1 between the micropore arrays of the adhesive film layer 1 is 10-100 mu m; preferably 10 to 50 μm, 50 to 80 μm, or 80 to 100 μm. The spacing of the micropores 11 may be such that the surface of the adhesive film layer 1 forms a uniform array of micropores regularly. Due to the existence of the micropore array, the surface roughness and the specific surface area of the tissue adhesive film layer 1 are improved, the tissue adhesive film layer is easier to attach to tissues, and the adhesion, migration and differentiation of cells are positively influenced. The aperture of each micropore 11 of the micropore array of the adhesive film layer 1 is 10-1000 mu m; preferably 10 to 100 μm, 100 to 500 μm, 500 to 1000 μm, etc. The cross-section of each microwell 11 of the microwell array of the adhesive film layer 1 has various shapes, and may be triangular, rectangular, elliptical, etc. The diverse microwell 11 structure can accommodate complex tissue surfaces. Although high surface tension on a small size tends to collapse and retract the micropores 11, the adhesive film layer 1 maintains the stable existence of the structure with its dissipative matrix, and the micropore 11 structure is advantageous for enhancing tissue adhesion performance. When the self-fixing patch is adhered to a tissue, water and air in the micropores 11 of the adhesive film layer 1 can be discharged in a pressing mode or the like, so that pressure difference between the inside and the outside of the micropores 11 is caused, additional suction force is generated, relative sliding between the adhesive film layer 1 at the initial stage of adhesion and the surface of the tissue is reduced, and the adhesion performance of the adhesive film layer 1 is improved.

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

In the self-fixing repair patch provided by the application, the raw materials of the adhesive film layer 1 comprise a polyphenol compound and a prepolymer, wherein the prepolymer comprises acrylic acid, polyvinyl alcohol, N-succinimidyl acrylate, a crosslinking agent and a photoinitiator. The raw materials of the adhesive film layer 1 can be dissolved in deionized water, aqueous solution or organic solvent to form a polyphenol compound solution or prepolymer solution. The aqueous solution includes physiological solution including physiological saline, wilt's solution, le Shi solution, and tai's solution, and buffer solution including phosphate buffer, citrate buffer, carbonate buffer, acetate buffer, tris buffer, and the like. The organic solvent comprises one or more of methanol, ethanol, diethyl ether, and ethylene, and those skilled in the art will appreciate that solvents that dissolve the materials of the present invention are within the scope of protection.

In the self-immobilized patch provided by the application, the polyhydric phenol compound is selected from one or more of tannic acid, catechol derivatives, pyrogallol derivatives, dopamine derivatives, caffeic acid derivatives, gallic acid derivatives, catechin and catechin derivatives. The concentration of the polyhydric phenol compound solution is 0.5% -8% (w/w); preferably, it 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 wide application in biological fields because of its physiological functions of resisting oxidation, protecting blood vessels, preventing tumors, etc. The poor adhesive performance and excessive swelling behaviour of traditional tissue adhesives in wet in vivo environments has been a major impediment to numerous applications and functional studies. At present, different strategies have been reported to obtain tough tissue gels.

In one embodiment of the present application, the polyphenol compound is tannic acid. Tannic acid is a naturally occurring antioxidant polyphenol and has the characteristics of low cytotoxicity, antioxidation, antibacterial activity and the like. Tannic acid has pyrogallol and catechol structures, can be easily crosslinked with protein, can be oxidized into o-quinone under alkaline environment, can form non-covalent bonds with a polymer framework through hydrogen bonding, and enhances the overall mechanical strength.

In the self-fixing repair patch provided by the application, the concentration of acrylic acid in the prepolymer solution is 15% -30% (w/w); preferably, it is 15% -18% (w/w), 18% -25% (w/w), 25% -30% (w/w), etc. Compared with high molecular polyacrylic acid, the acrylic acid monomer has stable reaction quality and strong industrial feasibility.

In the self-fixing repair patch provided by the application, 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 the polyvinyl alcohol is more than 75%; preferably 75 to 80%, 80 to 85%, or more than 85%, etc. The alcoholysis degree refers to the percentage of hydroxyl groups in the original groups in the product obtained after alcoholysis.

Acrylic acid and polyvinyl alcohol are molecular skeletons, and a three-dimensional porous gel topological network structure is constructed, so that the material can quickly absorb liquid on the surface of a moist tissue, and initial weak connection is formed through hydroxyl on the surface of the material and hydroxyl on the surface of the tissue. The adhesive film has carboxyl and hydroxyl, can quickly absorb moisture and permanently retain water on the moist and wet tissue surface, can quickly and permanently adhere to the tissue surface, realizes the purpose of closing the wound without a suture, and has simple and controllable clinical implementation conditions.

By introducing polyphenol groups into a network structure constructed by taking acrylic acid and polyvinyl alcohol as molecular skeletons, a multiple hydrogen bond stable tissue adhesion gel topological network structure is formed, and the biomechanical strength of the material is further improved.

In the self-fixing repair patch provided by the application, the concentration of the N-hydroxysuccinimide acrylate in the prepolymer solution is 0.1% -2% (w/w); preferably, it is 0.1 to 0.5% (w/w), 0.5 to 1.0% (w/w), or 1.0 to 2% (w/w), etc. The N-hydroxysuccinimide acrylate can carry out N-hydroxysuccinimide surface grafting modification on hydroxyl groups of acrylic acid and polyvinyl alcohol, and a first strong bonding site which generates covalent reaction with amino groups on the surface of the tissue is constructed, so that the tissue adhesive has stronger bonding strength.

In the self-anchoring patch provided herein, the cross-linking agent includes a combination of one or more of N, N' -methylenebisacrylamide, methacrylic anhydride gelatin (GelMA), polyethylene glycol diacrylate (PEGDA), poloxamer diacrylate (PoloxDA), and oxidized alginate methacrylate (OxAlgMA). In the prepolymer solution, the concentration of the cross-linking agent is 0.1% -1% (w/w); preferably, it is 0.1 to 0.3% (w/w), 0.3 to 0.5% (w/w), or 0.5 to 1% (w/w), etc.

In the self-anchoring patches provided herein, the photoinitiator includes alpha-ketoglutarate and/or Irgacure 2959. In the prepolymer solution, the concentration of the photoinitiator is 0.05% -0.5% (w/w); preferably, it is 0.05 to 0.07% (w/w), 0.07 to 0.09% (w/w), or 0.09 to 0.5% (w/w), etc. The photoinitiator is also called a photosensitizer or a photo-curing agent, and is a compound capable of absorbing energy with a certain wavelength in an ultraviolet light region (250-420 nm) or a visible light region (400-800 nm) to generate free radicals, cations and the like so as to initiate polymerization, cross-linking and curing.

In the self-fixing repair patch provided by the application, the raw materials of the prepolymer comprise polyvinyl alcohol, acrylic acid, N-hydroxysuccinimide acrylate, a cross-linking agent and a photoinitiator, the prepolymer is a substance generated by the reaction of the 5 raw materials, the prepolymer needs to be photo-crosslinked to form hydrogel, and the hydrogel is soaked in a polyphenol compound solution to react again to form the adhesive film 1.

The second aspect of the present application provides a method for preparing the self-fixing repair patch, which includes the following steps:

1) Proportioning, stirring and mixing the polyvinyl alcohol, the acrylic acid N-hydroxysuccinimide ester, the cross-linking agent and the photoinitiator according to the proportion relation of the first aspect to obtain a prepolymer solution;

2) Performing post-treatment comprising any one or more of the following steps:

2a) Placing the prepolymer solution obtained in the step 1) into a mold, and sequentially performing photo-curing, light-shielding soaking and drying treatment to obtain a glue film layer 1; and fixing the adhesive film layer 1 on the surface of the repair material layer 2 to obtain the self-fixing repair sheet.

2b) Immersing the repairing material layer 2 in the prepolymer solution in the step 1) to obtain a mixed layer, and placing the mixed layer in a mould to sequentially perform photo-curing, light-shielding soaking and drying treatment to obtain the self-fixing repairing sheet.

In the preparation method provided by the application, the step 1) is to stir and mix the polyvinyl alcohol, the acrylic acid, the N-hydroxysuccinimide acrylate, the cross-linking agent and the photoinitiator to obtain a prepolymer solution. The prepolymer solution comprises the following components in percentage by mass: 15-30% (w/w) of acrylic acid, 3-15% (w/w) of polyvinyl alcohol, 0.1-2% (w/w) of N-succinimidyl acrylate, 0.1-1% (w/w) of cross-linking agent, 0.05-0.5% (w/w) of photoinitiator, and the balance of water, aqueous solution or organic solvent to form a polyphenol compound solution or prepolymer solution. The aqueous solution includes physiological solution including physiological saline, wilt's solution, le Shi solution, and tai's solution, and buffer solution including phosphate buffer, citrate buffer, carbonate buffer, acetate buffer, tris buffer, and the like. The organic solvent comprises one or more of methanol, ethanol, diethyl ether, and ethylene, and those skilled in the art will appreciate that solvents that dissolve the materials of the present invention are within the scope of protection. Wherein the stirring time is 4-12 h; preferably, the time is 4 to 8 hours, 8 to 10 hours, 10 to 12 hours, or the like. Acrylic acid and polyvinyl alcohol react to form a molecular skeleton, a three-dimensional porous gel topological network structure is constructed, N-hydroxysuccinimide ester of acrylic acid and polyvinyl alcohol carry out N-hydroxysuccinimide surface grafting modification on hydroxyl groups of the acrylic acid and the polyvinyl alcohol, a first strong bonding site which generates covalent reaction with amino groups on the surface of a tissue is constructed, and a cross-linking agent can cross-link the compound. The photoinitiator may cure the aforementioned compounds under ultraviolet light or the like.

In the preparation method provided by the application, step 2) is to place the prepolymer solution in step 1) in a mold, and sequentially perform photo-curing, light-shielding soaking and drying treatment to obtain the adhesive film layer 1. Wherein, as shown in fig. 4-6, the surface of the die is an array of uniformly arranged micropores, and preferably, the shape of the cross section of each micropore 11 of the array of micropores comprises a triangle, rectangle or ellipse. The diverse microwell 11 structure can accommodate complex tissue surfaces. 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. The spacing between the micropores 11 of the adhesive film layer 1 between the micropore arrays of the adhesive film layer 1 is 10-1000 mu m, and the spacing between the micropores 11 can enable the surface of the adhesive film layer 1 to form a uniform micropore array regularly. Due to the existence of the micropore array, the surface roughness and the specific surface area of the tissue adhesive film layer 1 are improved, the tissue adhesive film layer is easier to attach to tissues, and the adhesion, migration and differentiation of cells are positively influenced. The pore diameter of each microwell 11 of the microwell array is 10 to 1000 μm. The microporous 11 structure is advantageous for enhancing tissue adhesion properties.

In the preparation method provided by the application, in the step 2), the reaction time of the photo-curing is 5-20 min; preferably, it is 5 to 10 minutes, 10 to 15 minutes, 15 to 20 minutes, or the like. Photocuring refers to a reaction in which a compound undergoes photolysis upon exposure to light, or when a part of bonds are separated, activated molecules such as generated radicals bond to each other, resulting in the formation of a network structure of polymer chains. In the present application, as shown in fig. 3, the photoinitiator absorbs energy of a certain wavelength in ultraviolet light (250 to 420 nm), generates free radicals, cations, etc., and thus initiates crosslinking curing.

In the preparation method provided by the application, in the step 2), the hydrogel is soaked in the solution of the polyphenol compound in a dark place, wherein the soaking means that the hydrogel is completely immersed in the solution of the polyphenol compound. The concentration of the polyphenol compound solution is 0.5% -1.5% (w/w); preferably, it is 0.5 to 0.7% (w/w), 0.7 to 0.9% (w/w), or 0.9 to 1.5% (w/w), etc. The solvent of the polyphenol compound solution is selected from water, an aqueous solution, or a solution of a polyphenol compound or a prepolymer formed in an organic solvent. The aqueous solution includes physiological solution including physiological saline, wilt's solution Le Shi solution, and tai's solution, etc., and the buffer solution includes phosphate buffer, citrate buffer, carbonate buffer, acetate buffer, tris buffer, etc. The organic solvent comprises one or more of methanol, ethanol, diethyl ether and cyclohexane. The soaking treatment time is 12-48 h; preferably, the time is 12 to 24 hours, 24 to 36 hours, 36 to 48 hours, or the like. The polyphenol compound is added in the step to introduce a polyphenol group into a network structure to form multiple hydrogen bonds, stabilize the tissue adhesion gel topological network structure and improve the biomechanical strength of the material, and simultaneously form a second strong adhesion site, so that the tissue adhesion strength is further improved.

In the preparation method provided by the application, in the step 2), the drying is freeze drying and/or vacuum drying.

In the preparation method provided by the application, step 2 a) the adhesive film layer 1 is fixed on the surface of the repair material layer 2, and the self-fixing repair sheet is obtained, as shown in fig. 1. The fixing mode comprises that the adhesive film layer 1 is placed on the surface of a wet repair material, pressed and dried to be formed.

In the preparation method provided by the application, step 2 b) submerges the repairing material layer 2 in the prepolymer solution in step 1) to obtain a mixture, placing the mixture in a mold, sequentially performing photo-curing, light-shielding soaking and drying treatment to obtain the self-fixing repairing sheet, and as shown in fig. 2, the repairing material layer 2 and the adhesive film layer 1 can be fixed while the adhesive film layer 1 is crosslinked and cured at the moment, so that the raw material of the adhesive film layer 1 can infiltrate into the repairing material layer 2, and the repairing material layer 2 and the adhesive film layer 1 are combined into a stable integrated structure.

A third aspect of the present application provides the use of the self-fixing patch described above or the preparation method described above in the preparation of a medical repair material; preferably, the application of the medical repair material includes hernia surgery (such as incisional hernia, abdominal wall hernia and inguinal hernia repair reconstruction), bladder and ureteral defects, gynaecology (such as vaginal reconstruction and pelvic floor repair), cardiovascular diseases (such as valve repair and vascular repair), otorhinolaryngology diseases (such as tympanic membrane repair and nasal contouring), neurosurgery diseases (such as dura mater (spinal) membrane repair), abdominal surgical diseases (such as peritoneal repair), colorectal and anus surgical diseases and other defective tissue repair in clinical fields.

The present application is further illustrated by the following examples, which are not intended to limit the scope of the present application. All reagents were commercially available as analytically pure products.

Example 1

(1) A prepolymer solution was prepared, which included a deionized water solution of polyvinyl alcohol having a concentration of 15% (w/w) and an alcoholysis degree of 75%, 20% (w/w) acrylic acid, 0.1% (w/w) N, N' -methylenebisacrylamide, 0.05% (w/w) alpha-ketoglutaric acid, and 0.5% (w/w) N-hydroxysuccinimide acrylate, and was sufficiently and uniformly stirred to obtain a prepolymer solution. The prepolymer solution was poured into a mold having a thickness of 200. Mu.m, micropores 11 having a pitch of 50. Mu.m, a depth of 100. Mu.m, and a pore diameter of 60. Mu.m were prepared, and crosslinked under an ultraviolet lamp for 20 minutes to form a hydrogel.

(2) Immersing the gel prepared in the step (1) in 1.0% (w/w) tannic acid solution under the dark condition, and taking out after 24 hours of immersion to obtain the tissue adhesive precursor. And carrying out in-situ freeze-drying on the tissue adhesive precursor to obtain the adhesive film layer 1.

(3) And (3) fixing the adhesive film layer 1 prepared in the step (2) on the surface of the multi-layer porcine small intestine submucosa moistened by the repair material layer 2, and drying to obtain the self-fixing repair sheet.

Comparative example 1

(1) A prepolymer solution was prepared, which included a deionized water solution of polyvinyl alcohol having a concentration of 15% (w/w) and an alcoholysis degree of 75%, 20% (w/w) acrylic acid, 0.1% (w/w) N, N' -methylenebisacrylamide, 0.05% (w/w) alpha-ketoglutaric acid, and 0.5% (w/w) N-hydroxysuccinimide acrylate, and was sufficiently and uniformly stirred to obtain a prepolymer solution. The prepolymer solution was poured into a mold having a thickness of 200. Mu.m, and the cells 11 were not prepared, and crosslinked under an ultraviolet lamp for 20 minutes to form a hydrogel.

(2) And (3) freeze-drying the gel prepared in the step (1) in situ to obtain the adhesive film layer 1.

(3) And (3) adhering and fixing the adhesive film layer 1 prepared in the step (2) on the surface of the multi-layer porcine small intestine submucosa moistened by the repair material layer 2 by using water, and drying to obtain the self-fixing repair patch.

Example 2

(1) Preparing a prepolymer solution, wherein the prepolymer solution comprises 8% (w/w) of polyvinyl alcohol with alcoholysis degree of 85%, 30% (w/w) of acrylic acid, 0.1% (w/w) of N, N' -methylene bisacrylamide, 0.05% (w/w) of alpha-ketoglutaric acid and 1% (w/w) of N-hydroxysuccinimide acrylate in deionized water, and fully and uniformly stirring the solution to obtain the prepolymer solution. The prepolymer solution was poured into a mold having a thickness of 200. Mu.m, micropores 11 having a pitch of 80. Mu.m, a depth of 150. Mu.m, and a pore diameter of 100. Mu.m were prepared, and crosslinked under irradiation of an ultraviolet lamp for 20 minutes to form a hydrogel.

(2) Immersing the gel prepared in the step (1) in 1% (w/w) tannic acid solution under the dark condition, and taking out after 24 hours of immersion to obtain the tissue adhesive precursor. And carrying out in-situ freeze-drying on the tissue adhesive precursor to obtain the adhesive film layer 1.

(3) And (3) adhering and fixing the adhesive film layer 1 prepared in the step (2) on the surface of the multi-layer porcine bladder basement membrane moistened by the repair material layer 2 by using water, and drying to obtain the self-fixing repair sheet.

Example 3

(1) Preparing a prepolymer solution, wherein the prepolymer solution comprises 8% (w/w) of polyvinyl alcohol with alcoholysis degree of 85%, 30% (w/w) of acrylic acid, 0.1% (w/w) of N, N' -methylene bisacrylamide, 0.05% (w/w) of alpha-ketoglutaric acid and 1% (w/w) of N-hydroxysuccinimide acrylate in deionized water, and fully and uniformly stirring the solution to obtain the prepolymer solution. Pouring the prepolymer solution into a mold with the thickness of 400 mu m, immersing the repair material layer 2 polypropylene synthetic mesh into the prepolymer solution to prepare micropores 11 with the distance of 80 mu m, the depth of 150 mu m and the aperture of 200 mu m, and crosslinking under the irradiation of ultraviolet light for 20min to form the hydrogel.

(2) Immersing the gel prepared in the step (1) in a catechol solution of 1% (w/w) under the dark condition, and taking out the gel after 24 hours of immersion to obtain the self-fixing repair patch precursor. And carrying out in-situ freeze-drying on the tissue adhesive precursor to obtain the adhesive film layer 1.

Example 4

(1) Preparing a prepolymer solution, wherein the prepolymer solution comprises a deionized water solution of 10% (w/w) of polyvinyl alcohol with alcoholysis degree of 75%, 25% (w/w) of acrylic acid, 0.1% (w/w) of polyethylene glycol diacrylate, 0.05% (w/w) of alpha-ketoglutaric acid and 1% (w/w) of N-hydroxysuccinimide acrylate, and fully and uniformly stirring the deionized water solution to obtain the prepolymer solution. The prepolymer solution was poured into a mold having a thickness of 200. Mu.m, micropores 11 having a pitch of 100 μm, a depth of 100 μm and a pore diameter of 30 μm were prepared, and crosslinked under an ultraviolet lamp for 20 minutes to form a hydrogel.

(2) Immersing the gel prepared in the step (1) in 0.5% (w/w) tannic acid solution under the dark condition, and taking out after immersing for 48 hours to obtain the tissue adhesive precursor. And carrying out in-situ freeze-drying on the tissue adhesive precursor to obtain the adhesive film layer 1.

(3) And (3) adhering and fixing the adhesive film layer 1 prepared in the step (2) on the surface of the multi-layer porcine bladder basement membrane moistened by the repair material layer 2 by using water, and drying to obtain the self-fixing repair sheet.

Comparative example 2

(1) Preparing a prepolymer solution, wherein the prepolymer solution comprises deionized water solution of 1% (w/w) polyvinyl alcohol with alcoholysis degree of 75%, 25% (w/w) acrylic acid, 0.1% (w/w) polyethylene glycol diacrylate, 0.05% (w/w) alpha-ketoglutaric acid and 1% (w/w) N-hydroxysuccinimide acrylate, and fully and uniformly stirring the deionized water solution to obtain the prepolymer solution. The prepolymer solution was poured into a mold having a thickness of 200. Mu.m, micropores 11 having a pitch of 100 μm, a depth of 100 μm and a pore diameter of 30 μm were prepared, and crosslinked under an ultraviolet lamp for 20 minutes to form a hydrogel.

(2) Immersing the gel prepared in the step (1) in 0.5% (w/w) tannic acid solution under the dark condition, and taking out after immersing for 48 hours to obtain the tissue adhesive precursor. And carrying out in-situ freeze-drying on the tissue adhesive precursor to obtain the adhesive film layer 1.

(3) And (3) adhering and fixing the adhesive film layer 1 prepared in the step (2) on the surface of the multi-layer porcine bladder basement membrane moistened by the repair material layer 2 by using water, and drying to obtain the self-fixing repair sheet.

Comparative example 3

(1) Preparing a prepolymer solution, wherein the prepolymer solution comprises 10% (w/w) of polyvinyl alcohol with alcoholysis degree of 75%, 10% (w/w) of acrylic acid, 0.1% (w/w) of polyethylene glycol diacrylate, 0.05% (w/w) of alpha-ketoglutaric acid and 1% (w/w) of N-hydroxysuccinimide acrylate in deionized water, and fully and uniformly stirring the solution to obtain the prepolymer solution. The prepolymer solution was poured into a mold having a thickness of 200. Mu.m, micropores 11 having a pitch of 100 μm, a depth of 100 μm and a pore diameter of 30 μm were prepared, and crosslinked under an ultraviolet lamp for 20 minutes to form a hydrogel.

(2) Immersing the gel prepared in the step (1) in 0.5% (w/w) tannic acid solution under the dark condition, and taking out after immersing for 48 hours to obtain the tissue adhesive precursor. And carrying out in-situ freeze-drying on the tissue adhesive precursor to obtain the adhesive film layer 1.

(3) And (3) adhering and fixing the adhesive film layer 1 prepared in the step (2) on the surface of the multi-layer porcine bladder basement membrane moistened by the repair material layer 2 by using water, and drying to obtain the self-fixing repair sheet.

The ingredients of the above examples and comparative examples are shown in Table 1:

TABLE 1 composition of film layers

The performances of the self-fixing repair patch prepared by the embodiment of the invention are respectively measured:

(1) Adhesive Strength test

The self-fixing patch of the above example was taken to have an area of 10mm×25mm, and the perforated side thereof was adhered to the surface of wet pigskin having a width of 25mm, so that the overlapping area of the pigskin and the self-fixing patch was 10mm×25mm, i.e., the adhesive area. The tissue adhesive bonding performance test method according to YY/T0729.1 part 1: lap-shear tensile load strength was tested.

(2) Peel strength test

The self-fixing patch of the above embodiment is taken, the area is 100mm×20mm, and the surface with holes is adhered to the surface of wet pigskin and intestinal canal with the width of 20mm, so that the overlapping area of the pigskin, intestinal canal and the self-fixing patch is 100mm×20mm, namely the adhesive area. The adhesive property test method of YY/T0729.2-2009 tissue adhesive is as described in part 2: the T-peel tensile load strength was tested.

(3) Swelling test

Taking the self-fixing repair sheet of the above example, measuring the thickness as V0, immersing in PBS solution, taking out the swelled self-fixing repair sheet after 7 days, wiping off the water on the surface of the filter paper, measuring the colloid thickness as V1. Swelling ratio q= (V1-V0)/V0.

Table 2 test data

The above embodiments are merely illustrative of the principles of the present invention and its effectiveness, and are not intended to limit the invention. Modifications and variations may be made to the above-described embodiments by those skilled in the art without departing from the spirit and scope of the invention. Accordingly, it is intended that all equivalent modifications and variations of the invention be covered by the claims, which are within the ordinary skill of the art, be within the spirit and scope of the present disclosure.

Claims (10)

1. The self-fixing repair patch is characterized by comprising a repair material layer (2), wherein the repair material layer (2) is loaded or coated with a glue film layer (1).

2. The self-fixing repair patch according to claim 1, wherein one side of the adhesive film layer (1) is provided with a uniform micropore array; the other surface of the adhesive film layer (1) corresponding to the micropore array is attached to the repair material layer (2) or at least part of the adhesive film layer (1) is embedded into the repair material layer (2).

3. The self-fixing patch according to claim 1, wherein the thickness of the adhesive film layer (1) is 200 to 400 μm; and/or 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).

4. The self-fixing patch according to claim 1, wherein the spacing between the micropore arrays of the adhesive film layer (1) is 10 to 1000 μm; preferably, the spacing between the micropore arrays of the adhesive film layer (1) is 10-100 mu m;

and/or the aperture of each micropore (11) of the micropore array of the adhesive film layer (1) is 10-1000 mu m;

and/or the repair material layer (2) comprises one or more of pericardium, porcine small intestine submucosa, porcine bladder basement membrane, dermis, peritoneum, collagen membrane, silk fibroin membrane, synthetic fiber membrane, synthetic mesh.

5. The self-fixing patch according to claim 1, wherein the raw material of the adhesive film layer (1) comprises a polyhydric phenol compound and a prepolymer, and the prepolymer comprises one or more of acrylic acid, polyvinyl alcohol, N-succinimidyl acrylate, a crosslinking agent and a photoinitiator.

6. The self-anchoring patch according to claim 5, wherein the cross-linking agent comprises a combination of one or more of N, N' -methylenebisacrylamide, methacrylated gelatin, polyethylene glycol diacrylate, poloxamer diacrylate, and oxidized alginate methacrylate;

And/or, the photoinitiator comprises alpha-ketoglutaric acid and/or Irgacure 2959;

and/or the number of the groups of groups, the polyphenol compound is selected from one or more of tannic acid, catechol derivative, pyrogallol derivative, dopamine derivative, caffeic acid derivative, gallic acid derivative, catechin and catechin derivative.

7. The self-anchoring patch according to claim 5, comprising one or more of the following features:

a) The concentration of the solution of the polyphenol compound is 0.5% -8% (w/w);

b) In the solution of the prepolymer, the concentration of the acrylic acid is 15-30% (w/w);

c) In the solution of the prepolymer, the concentration of the polyvinyl alcohol is 3% -15% (w/w); the alcoholysis degree of the polyvinyl alcohol is more than 75%;

d) In the solution of the prepolymer, the concentration of the N-succinimidyl acrylate is 0.1% -2% (w/w);

e) In the solution of the prepolymer, the concentration of the cross-linking agent is 0.1% -1% (w/w);

f) The concentration of the photoinitiator in the solution of the prepolymer is 0.05% -0.5% (w/w).

8. The method of manufacturing a self-anchoring patch according to any one of claims 1 to 7, comprising the steps of:

1) Stirring and mixing the polyvinyl alcohol, the acrylic acid N-hydroxysuccinimide ester, the cross-linking agent and the photoinitiator to obtain a prepolymer solution;

2) Performing post-treatment comprising any one or more of the following steps:

2a) Placing the prepolymer solution obtained in the step 1) into a mold, and sequentially performing photocuring, light-shielding soaking and drying treatment to obtain a glue film layer (1); fixing the adhesive film layer (1) on the surface of the repair material layer (2) to obtain a self-fixing repair sheet;

2b) Immersing the repairing material layer (2) in the prepolymer solution in the step 1) to obtain a mixture, placing the mixture in a mold, and sequentially performing photo-curing, light-shielding soaking and drying treatment to obtain the self-fixing repairing sheet.

9. The method of manufacturing of claim 8, further comprising one or more of the following features:

a) In the step 1), the stirring time is 4-12 h;

b) In the step 2), the surface of the die is a uniform micropore array; preferably, the shape of the cross section of each microwell (11) in the microwell array comprises a triangle, rectangle or oval;

c) In the step 2), the reaction time of the photo-curing is 5-20 min;

d) In the step 2), the light-shielding soaking is soaking in the solution of the polyphenol compound; the soaking treatment time is 12-48 hours;

e) In the step 2), the drying treatment is freeze drying and/or vacuum drying;

f) In the step 2 a), the fixing mode comprises the steps of placing the adhesive film layer (1) on the surface of the wet repair material layer (2), pressing, and drying and forming.

10. Use of a self-anchoring patch according to any one of claims 1 to 7 or a method of preparation according to any one of claims 8 to 9 for the preparation of a medical repair material; preferably, the application of the medical repair material includes hernia surgery, bladder, ureteral defect, gynecological, cardiovascular system diseases, otorhinolaryngological diseases, neurosurgery diseases, abdominal surgery diseases or colorectal anus surgery diseases.

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