Composite tissue bonding patch as well as preparation method and application thereof

Abstract

The invention provides a composite tissue bonding patch as well as a preparation method and application thereof. The composite tissue bonding patch comprises a base body and micro-nano fibers formed with the base body in a composite mode. Wherein the micro-nano fibers are continuously or discontinuously dispersed in the base body. The composite tissue bonding patch disclosed by the invention is low in swelling degree, good in mechanical property and lasting in adhesiveness. After the composite tissue bonding patch is in contact with a wet tissue surface, interface liquid existing between the bonding patch and the wet tissue surface can be rapidly absorbed and removed, and a large number of instant molecular bonds can be formed between carboxylic acid and / or amino groups in the composite tissue bonding patch and molecules on the wet tissue surface; and rapid adhesion to a wet surface is realized. Moreover, the swelling degree of the composite tissue bonding patch is low, so that the patch can be prevented from falling off due to deformation caused by excessive water absorption, and the long-time strong adhesiveness can be maintained.

Description

TECHNICAL FIELD

[0001] The present application relates to a composite tissue adhesive patch and a preparation method thereof, and belongs to the field of medical implant materials. BACKGROUND

[0002] At present, the closure treatment of human tissue wounds is usually handled by sutures, but the suture time is long, the operation is complicated, and infection may be caused by the wound not being tightly sealed. Compared with the traditional wound closure method (suture), the tissue adhesive material is relatively easy to use and can minimize tissue damage. An ideal tissue adhesive material should have the following characteristics: good biocompatibility and bioabsorbability, strong tissue adhesion in a wet environment, mechanical properties and acceptable swelling properties.

[0003] Most of the existing tissue adhesive materials are in the form of viscous liquid or wet hydrogel. Such materials are usually produced in the form of viscous liquid or gel, or prepared by mixing components just before use, and then applied to the tissue surface through devices such as syringes. Such materials have many disadvantages, including weak adhesion, poor mechanical matching with tissue, slow adhesion formation, and inconvenience of use.

[0004] Currently, there are tissue adhesive materials in the form of tablets, patches or films. Although such tissue adhesive materials have good initial adhesion, the adhesion decreases rapidly over time, such as often separating from the tissue only after a few seconds or minutes; and easily swells too much under wet conditions, resulting in reduced mechanical properties and adhesion.

[0005] Therefore, it is an urgent technical problem to develop a tissue adhesive material with good mechanical strength and strong adhesion in a wet environment. SUMMARY

[0006] Problems to be solved by the application

[0007] In view of the problem of easy swelling of the existing tissue adhesive material, which leads to reduced mechanical properties and adhesion, the present application first provides a composite tissue adhesive patch with low swelling, good mechanical properties and durable adhesion.

[0008] The present application also provides a preparation method of a composite tissue adhesive patch. The preparation method is simple and easy to operate, the raw materials are easy to obtain, the patch is easy to shape, and is suitable for large-scale industrial production.

[0009] Solution to the problem

[0010] The present application first provides a composite tissue adhesive patch, which comprises: a substrate and micro-nano fibers complexed with the substrate; wherein,

[0011] The micro-nano fibers are continuously or discontinuously dispersed inside the matrix.

[0012] Further, the thickness of the composite tissue-adhesive patch is 0.1-1mm, preferably 0.2-0.6mm; and / or,

[0013] The diameter of the micro-nano fibers is greater than 60nm, preferably 0.1-100μm.

[0014] Further, the swelling degree of the composite tissue-adhesive patch is less than 700%; and / or,

[0015] The breaking strength of the composite tissue-adhesive patch is greater than 45kPa.

[0016] Further, the raw materials for preparing the matrix include monomers, thickening agents, cross-linking agents and photoinitiators, and the monomers and the thickening agents do not react chemically with each other;

[0017] Preferably, the mass ratio of the monomers to the thickening agents is (1-8):(0.05-8), preferably (2-6):(0.1-5).

[0018] Further, the monomers include acrylic monomers and / or acrylamide monomers; and / or,

[0019] The thickening agents include one or more than two combinations of chitosan, sodium alginate, hyaluronic acid, hydroxymethyl cellulose, carboxymethyl cellulose, hydroxyethyl cellulose and glycerol.

[0020] Further, the raw materials for preparing the micro-nano fibers include hydrophobic synthetic polymer materials; preferably, the raw materials for preparing the micro-nano fibers further include natural polymer materials; further preferably, the content of the natural polymer materials is less than 50% based on the total mass of the raw materials for preparing the micro-nano fibers.

[0021] The application also provides a preparation method of the composite tissue-adhesive patch according to the application, which includes the step of combining the matrix with the micro-nano fibers.

[0022] Preferably, the step of combining includes combining the spinning process with the hydrogel preparation process.

[0023] Preferably, the composite tissue-adhesive patch is obtained by dispersing the micro-nano fibers in a hydrogel precursor solution, and then through a cross-linking reaction and drying; wherein the micro-nano fibers are prepared by a spinning process, and the hydrogel precursor solution is obtained by dissolving the raw materials for preparing the matrix in a first solvent.

[0024] Further, the preparation method comprises the following steps:

[0025] dissolving the preparation raw material of the substrate in a first solvent to obtain a hydrogel precursor solution;

[0026] dissolving the preparation raw material of the micro-nano fiber in a second solvent to obtain a spinning solution;

[0027] spinning the spinning solution by using a spinning process, so that the micro-nano fiber is dispersed in the hydrogel precursor solution to obtain a mixture;

[0028] making the hydrogel precursor solution in the mixture undergo a cross-linking reaction to obtain a cross-linking product;

[0029] drying the cross-linking product to obtain a composite tissue adhesive patch;

[0030] Preferably, the spinning process can include one or more than two combinations of electrospinning process, centrifugal force spinning process, hot melt spinning process and melt electrospinning process.

[0031] Preferably, the cross-linking reaction is performed under ultraviolet light irradiation.

[0032] Further, the hydrogel precursor solution is laid on the surface of the substrate, and the spinning solution is spun above the hydrogel precursor solution by using a spinning process.

[0033] Preferably, in the spinning solution, the mass-volume ratio of the preparation raw material of the micro-nano fiber to the second solvent is (1-10) g / 100 mL.

[0034] Preferably, the spinning process is an electrospinning process, and parameters of the electrospinning process include: controlling the electrospinning time to be 10-20 min, and adjusting the distance between the electrospinning nozzle and the liquid surface of the hydrogel precursor solution to be 10-20 cm.

[0035] The application further provides a use of the composite tissue adhesive patch according to the application for preparing a hemostatic product, a wound closure product, a dura seal product, a blood vessel sealing product, a lung sealing product, a kidney sealing product, a gastrointestinal anastomosis product, a cerebrospinal fluid leakage product.

[0036] Effects of the application

[0037] The composite tissue adhesive patch of the application has low swelling degree, good mechanical properties and durable adhesion.

[0038] Further, the composite tissue-adhesive patch of the present application can quickly absorb and remove the interfacial liquid between the adhesive patch and the wet tissue surface after the composite tissue-adhesive patch contacts the wet tissue surface, and the carboxylic acid and / or amino groups in the composite tissue-adhesive patch can form a large number of instant molecular bonds (such as hydrogen bonds, electrostatic interactions) with the molecules of the wet tissue surface, thereby achieving rapid adhesion to the wet surface. In addition, the composite tissue-adhesive patch has low swelling degree, which can prevent the patch from falling off due to excessive water absorption and deformation, thereby maintaining strong adhesion for a long time.

[0039] Further, the composite tissue-adhesive patch of the present application is a three-dimensional biomimetic structure, which enhances the mechanical properties of the tissue-adhesive patch and can also induce tissue regeneration and promote tissue repair.

[0040] In addition, the preparation method of the composite tissue-adhesive patch of the present application is simple and easy to operate, the raw materials are easy to obtain, and the gel is easy to shape, which is suitable for large-scale industrial production. BRIEF DESCRIPTION OF DRAWINGS

[0041] Figure 1 A product photo of the composite tissue-adhesive patch of Example 1 of the present application is shown.

[0042] Figure 2 An optical display microscope photo of the cross section of the composite tissue-adhesive patch of Example 1 of the present application is shown.

[0043] Figure 3 An optical display microscope photo of the cross section of the composite tissue-adhesive patch of Comparative Example 1 of the present application is shown.

[0044] Figure 4 A scanning electron microscope (SEM) photo of the upper and lower surfaces of the composite tissue-adhesive patch of Example 1 of the present application is shown. DETAILED DESCRIPTION

[0045] Various exemplary embodiments, features, and aspects of the present application will be described in detail below. The word "exemplary" is used herein to mean "serving as an example, instance, or illustration." Any implementation described herein as "exemplary" is not necessarily to be construed as preferred or advantageous over other implementations.

[0046] In addition, in order to better illustrate the present application, numerous specific details are given in the following detailed description. Those skilled in the art will understand that the present application can be practiced without certain specific details. In some instances, well-known methods, means, instruments and steps have not been described in detail in order to highlight the principles of the present application.

[0047] Unless otherwise stated, all units used in this specification are international standard units, and all numerical values ​​and ranges appearing in this invention should be understood to include systematic errors that are unavoidable in industrial production.

[0048] In this specification, the word "may" has two meanings: to perform a certain process and not to perform a certain process.

[0049] In this specification, references to "some specific / preferred embodiments," "other specific / preferred embodiments," "implementation," etc., refer to specific elements (e.g., features, structures, properties, and / or characteristics) related to that embodiment, which are included in at least one of the embodiments described herein and may or may not be present in other embodiments. Furthermore, it should be understood that these elements may be combined in any suitable manner in various embodiments.

[0050] In this specification, the range of values ​​referred to as "value A to value B" refers to the range including the endpoint values ​​A and B.

[0051] <First Aspect>

[0052] like Figure 1 As shown, a first aspect of the present invention provides a composite tissue adhesive patch. The composite tissue adhesive patch comprises: a substrate and micro / nanofibers composited with the substrate; wherein,

[0053] The micro / nanofibers are dispersed continuously or discontinuously within the matrix.

[0054] The composite tissue adhesive patch of the present invention has low swelling degree, good mechanical properties and durable adhesion.

[0055] Matrix

[0056] In this invention, the raw materials for preparing the matrix include monomers, thickeners, crosslinking agents, and photoinitiators, and the monomers and thickeners do not react chemically. The raw materials for preparing the matrix have good hydrophilicity.

[0057] In some specific embodiments, the mass ratio of the monomer to the thickener is (1-8):(0.05-8), preferably (2-6):(0.1-5). When the mass ratio of the monomer to the thickener is (1-8):(0.05-8), the desired matrix can be obtained.

[0058] In some specific embodiments, the content of the monomer is 25-95%, for example: 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, etc., based on the total mass of the preparation raw materials of the matrix being 100%; the content of the thickening agent is 2-70%, for example: 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, etc.; the content of the crosslinking agent is 0.5-2%, for example: 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, etc.; the content of the photoinitiator is 0.5-5%, for example: 0.8%, 1%, 1.2%, 1.5%, 1.8%, 2%, 2.2%, 2.5%, 2.8%, 3%, 3.2%, 3.5%, 3.8%, 4%, 4.2%, 4.5%, 4.8%, etc. When each component of the preparation raw materials of the matrix of the present application is within the above range, the required matrix can be obtained.

[0059] In the present application, the monomer includes an acrylic monomer and / or an acrylamide monomer. In the present application, the acrylic monomer can be acrylic acid, and the acrylamide monomer can be acrylamide.

[0060] In addition, the monomer of the present application can not be limited to the acrylic monomer and the acrylamide monomer, and preferably can also include a methacrylic monomer and / or a methacrylamide monomer. For example, the methacrylic monomer can exemplarily be one or a combination of two or more of methacrylic acid, carboxyethyl methacrylate, carboxyvinyl methacrylate, and crotonic acid, etc.; and the methacrylamide monomer can exemplarily be one or a combination of two or more of N-methyl acrylamide, N,N-dimethyl acrylamide, N-hydroxyethyl acrylamide, N-hydroxymethyl acrylamide, etc.

[0061] In the present application, dissolving the preparation raw materials of the matrix in a solvent can form a hydrogel precursor solution. By using a thickening agent, the flowability of the hydrogel precursor solution can be reduced, the hydrogel precursor solution can be more conveniently laid on a substrate, and the precursor solution can be prevented from flowing during the spinning process, thereby affecting the final thickness of the composite tissue adhesive patch. Without adding the thickening agent, the formed hydrogel precursor solution has greater flowability, so that the micro-nano fibers cannot be uniformly dispersed in the hydrogel precursor solution; in addition, the thickening agent also plays a suspending role on the micro-nano fibers in the hydrogel precursor solution, preventing the micro-nano fibers from settling and gathering, and affecting the adhesion and swelling degree of the final composite tissue adhesive patch. Specifically, the thickening agent includes one or a combination of two or more of chitosan, sodium alginate, hyaluronic acid, hydroxymethyl cellulose, carboxymethyl cellulose, hydroxyethyl cellulose, and glycerol.

[0062] In addition, the monomer and the thickening agent of the present application do not undergo chemical reactions. The inventors of the present application have found that acrylic acid and chitosan are easily formed into white flocculent substances due to electrostatic attraction, and similarly, acrylamide and sodium alginate are also easily formed into white flocculent substances. Therefore, in view of the application of the composite tissue-adhesive patch, the present application preferably does not use a combination of acrylic acid and chitosan, and a combination of acrylamide and sodium alginate.

[0063] For the cross-linking agent, the present application is not particularly limited, and can be a cross-linking agent commonly used in the art. Specifically, the cross-linking agent can include one or a combination of two or more of polyethylene glycol diacrylate (PEGDA), polyethylene glycol dimethacrylate (PEGDMA), N,N'-bis(acryloyl)cystamine, and gelatin methacryloyl (GelMA).

[0064] For the photoinitiator, the present application is not particularly limited, and can be a photoinitiator commonly used in the art. Specifically, the photoinitiator can include one or a combination of two or more of α-ketoglutaric acid, 2-hydroxy-4'-(2-hydroxyethoxy)-2-methylpropiophenone (Irgacure 2959), bis(pentafluorophenyl)titanocene, fluorinated diphenyltitanocene (Irgacure 784), and lithium phenyl-2,4,6-trimethylbenzoylphosphinate (LAP).

[0065] Further, in order to prepare the composite tissue-adhesive patch, a substrate can be used. For the material of the substrate, the present application is not particularly limited, and can be generally a glass material, for example, a glass plate, etc. Specifically, the raw material of the substrate can be dissolved in a solvent to obtain a hydrogel precursor solution, and then the hydrogel precursor solution can be placed on the surface of the substrate to form a viscous solution on the surface of the substrate, so that the micro-nano fibers can be well dispersed therein. For the method of placing the hydrogel precursor solution on the surface of the substrate, the present application is not particularly limited, and can use a method of casting, spraying, coating, etc., as long as the hydrogel precursor solution can continuously exist on the surface of the substrate.

[0066] Micro- and nanofibers

[0067] The micro-nano fibers of the present application mean fibers having a diameter in the range of 1 nm to 1000 μm. If the diameter of the micro-nano fibers is too small, the micro-nano fibers are easily floated in the hydrogel precursor solution, which affects the adhesion and mechanical properties of the patch. If the diameter of the micro-nano fibers is too large, the micro-nano fibers are easily sunk in the hydrogel precursor solution, which also affects the adhesion of the patch. In some specific embodiments, the diameter of the micro-nano fibers is greater than 60 nm, preferably 0.1-100 μm, and more preferably 0.1-25 μm.

[0068] In the present application, the preparation raw material of the micro-nanofiber comprises a hydrophobic synthetic polymer material. The inventors of the present application find that by adding the hydrophobic synthetic polymer material, the water absorption performance of the hydrogel is reduced, thereby further reducing the swelling degree of the composite tissue adhesive patch.

[0069] Specifically, the hydrophobic synthetic polymer material comprises one or a combination of two or more of polytrimethylcarbonate, polyglycolide, polylactic acid, polylactide, lactic acid-glycolic acid copolymer, and polyhydroxybutyrate.

[0070] For the forming method of the micro-nanofiber of the present application, the present application is not particularly limited, and the micro-nanofiber can be prepared by some common spinning processes in the art. Specifically, the micro-nanofiber in the composite tissue adhesive patch of the present application can be prepared by electrospinning, melt spinning, centrifugal force spinning, etc., and preferably prepared by using the electrospinning method.

[0071] The principle of electrospinning is that in the electrospinning process, a high voltage is applied to the liquid preparation raw material of the micro-nanofiber, so that the electric charge is introduced into the liquid. When the electric charge in the liquid accumulates to a certain amount, the liquid will form a Taylor cone at the nozzle, and then the liquid jet will be formed under the action of the external electric field force overcoming the surface tension. Then, under the joint action of the electrostatic repulsion, Coulomb force and surface tension, the polymer jet moves along an irregular spiral trajectory. The jet is stretched in a very short time, and the polymer jet solidifies to form a micro-nanofiber as the solvent volatilizes or heat is dissipated. In the electrospinning process, many parameters will affect the final micro-nanofiber, and by controlling the process parameters, micro-nanofibers of different sizes, morphologies and structures can be prepared.

[0072] The inventors of the present application find that by introducing the hydrophobic synthetic polymer material into the water-rich hydrogel material through the electrospinning process, on the one hand, the swelling performance of the composite tissue adhesive patch can be adjusted, and on the other hand, the micro-nanofiber network structure can be precisely controlled by using the electrospinning process, a three-dimensional biomimetic structure is constructed, and the mechanical properties and tissue regeneration inducing properties of the composite tissue adhesive patch are enhanced.

[0073] In the electrospinning process of the present application, the process parameters will affect the micro-nanofiber obtained by electrospinning, and by controlling the process parameters, micro-nanofibers of different sizes, morphologies and structures can be prepared. The present application does not have special requirements for the electrospinning method, which can be a common electrospinning method in the art. Specifically, the preparation raw material of the micro-nanofiber is dissolved in a suitable solvent to prepare a spinning solution, and then the spinning solution is spun into a micro-nanofiber by electrospinning.

[0074] In some specific embodiments, the raw materials for preparing the micro / nanofibers further include natural polymeric materials; more preferably, based on the total mass of the raw materials for preparing the micro / nanofibers (100%), the content of the natural polymeric materials is less than 50%. Specifically, the natural polymeric materials include one or more combinations of gelatin, collagen, silk fibroin, hyaluronic acid, and cellulose.

[0075] Composite tissue-adhesive patch

[0076] In the composite tissue adhesive patch of the present invention, the micro / nanofibers can be dispersed continuously or discontinuously in the matrix. In this invention, dispersing the micro / nanofibers in the matrix improves the mechanical properties of the composite tissue adhesive patch and reduces its swelling degree. In this invention, the micro / nanofibers are dispersed within the matrix and do not exist on the upper or lower surfaces of the matrix; if the micro / nanofibers are dispersed on the upper or lower surfaces of the matrix, i.e., suspended on the upper surface or deposited on the lower surface, it will affect the adhesion and swelling degree of the composite tissue adhesive patch.

[0077] In this invention, "continuous or discontinuous" means that the micro / nanofibers of this invention can be uninterrupted or discontinuous fibers; they can be a single continuous fiber obtained through a spinning process, or multiple discontinuous fibers obtained through a spinning process. This invention does not specifically limit the length of the micro / nanofibers; they can be either longer or shorter fibers depending on the spinning process. Furthermore, the micro / nanofibers of this invention are obtained directly through a spinning process without undergoing one or more of the following processes: shearing, grinding, pulverizing, or breaking.

[0078] Furthermore, in this invention, if the thickness of the composite tissue adhesive patch is too thin, the micro-nano fibers will be difficult to suspend uniformly in the prepolymer liquid, severely affecting the adhesion of the patch; if the thickness of the composite tissue adhesive patch is too thick, the swelling degree of the composite tissue adhesive patch will be high, resulting in a gradual decrease in adhesion.

[0079] To ensure the effective function of the composite tissue adhesive patch of the present invention, the thickness of the composite tissue adhesive patch is 0.1-1 mm, preferably 0.2-0.6 mm. When the thickness of the composite tissue adhesive patch is 0.1-1 mm, the composite tissue adhesive patch exhibits excellent mechanical properties, low swelling degree, and excellent adhesive performance.

[0080] Furthermore, such as Figure 2 As shown, the diameter of the micro / nanofiber is less than or equal to the thickness of the composite tissue adhesive patch. Preferably, the diameter of the micro / nanofiber is less than the thickness of the composite tissue adhesive patch. Additionally, as... Figure 4As shown, the surface of the composite tissue-adhesive patch does not have a fibrous form, i.e. the micro-nano fibers are continuously or discontinuously dispersed in the interior of the matrix.

[0081] Further, in the present application, the swelling degree of the composite tissue-adhesive patch is less than 700%, and / or the breaking strength of the composite tissue-adhesive patch is more than 45 kPa. The composite tissue-adhesive patch of the present application has a low swelling degree, good mechanical properties and long-lasting adhesion.

[0082] In some specific embodiments, the composite tissue-adhesive patch of the present application can further comprise a backing material layer disposed on the surface. The raw material used for the backing material layer is not particularly limited in the present application, as long as it can perform its function.

[0083] The composite tissue-adhesive patch of the present application has good adhesion on both sides after contacting with a wet surface. In the specific use process, it can be necessary to utilize the adhesive properties of only one side of the adhesive material. Therefore, the composite adhesive material can further be provided with a backing material layer to block the adhesive properties of the second side.

[0084] Further, the composite tissue-adhesive patch of the present application can rapidly absorb and remove the interfacial liquid existing between the adhesive patch and the wet tissue surface after contacting with the wet tissue surface, and the carboxylic acid and / or amino groups in the composite tissue-adhesive patch can form a large number of instant molecular bonds (such as hydrogen bonds, electrostatic interactions) with the molecules of the wet tissue surface, achieving rapid adhesion to the wet surface. Due to the low swelling degree of the composite tissue-adhesive patch, it can prevent the patch from falling off due to excessive water absorption and deformation, thereby maintaining strong adhesion for a long time.

[0085] Further, the composite tissue-adhesive patch of the present application is a three-dimensional biomimetic structure, which enhances the mechanical properties of the tissue-adhesive patch and can also induce tissue regeneration and promote tissue repair.

[0086] <Second aspect>

[0087] The second aspect of the present application provides a preparation method of the composite tissue-adhesive patch according to the first aspect of the present application, which comprises the step of compounding the matrix with the micro-nano fibers.

[0088] The preparation method of the composite tissue-adhesive patch of the present application is simple and easy to implement, the raw materials are easy to obtain, the patch is easy to form, and it is suitable for large-scale industrial production.

[0089] In some specific embodiments, the step of complex forming comprises combining a spinning process with a hydrogel preparation process; preferably, the complex tissue-adhesive patch is obtained by dispersing the micro-nano fibers in a hydrogel precursor solution, and then through a cross-linking reaction, drying; wherein the micro-nano fibers are prepared by a spinning process, and the hydrogel precursor solution is obtained by dissolving the preparation raw materials of the matrix in a first solvent.

[0090] In some specific embodiments, the preparation method comprises the following steps:

[0091] dissolving the preparation raw materials of the matrix in a first solvent to obtain a hydrogel precursor solution;

[0092] dissolving the preparation raw materials of the micro-nano fibers in a second solvent to obtain a spinning solution;

[0093] spinning the spinning solution by a spinning process to disperse the micro-nano fibers in the hydrogel precursor solution to obtain a mixture;

[0094] subjecting the hydrogel precursor solution in the mixture to a cross-linking reaction to obtain a cross-linking product;

[0095] drying the cross-linking product to obtain a complex tissue-adhesive patch.

[0096] Preferably, the spinning process can comprise one or more than two combinations of electrospinning process, centrifugal force spinning process, hot melt spinning process, and melt electrospinning process.

[0097] In the present application, the preparation raw materials of the matrix are dissolved in a first solvent to obtain a hydrogel precursor solution. The matrix is prepared by using the hydrogel precursor solution. The preparation raw materials of the matrix can specifically comprise monomers, thickening agents, cross-linking agents, and photoinitiators, as described in the first aspect. The mixing method is not particularly limited in the present application, and can be any feasible mixing method. During the mixing process, the viscosity of the hydrogel precursor solution can be controlled by controlling the mass ratio of the monomers to the thickening agents in the preparation raw materials of the matrix, so as to facilitate the uniform paving of the hydrogel precursor solution on the surface of the substrate and the suspension of the micro-nano fibers.

[0098] The first solvent is not particularly limited in the present application, and can be a polar solvent commonly used in the art, such as water and the like.

[0099] In the present application, the components in the hydrogel precursor solution do not undergo cross-linking reaction before spinning; in particular, no chemical reaction occurs between the monomers and the thickening agents. After the micro-nano fibers are dispersed in the hydrogel precursor solution, only the monomers undergo polymerization under the action of the photoinitiator and the cross-linking agent to form the hydrogel.

[0100] In the present application, the preparation raw material of the micro-nano fiber is prepared in advance, and the preparation raw material of the micro-nano fiber is dissolved in a suitable second solvent to prepare a spinning solution with a certain concentration. Preferably, in the spinning solution, the mass-volume ratio of the preparation raw material of the micro-nano fiber to the second solvent in the spinning solution is (1-10) g / 100 mL. Among them, the preparation raw material of the micro-nano fiber can be the hydrophobic synthetic polymer material of the first aspect and the optional natural polymer material. There is no special limitation on the type of the second solvent for forming a solution, as long as it can meet the requirements of the subsequent electrospinning process. For example, the suitable second solvent can be one or a combination of two or more of hexafluoroisopropanol, trifluoroethanol, trichloromethane, dichloromethane, tetrahydrofuran, N,N'-dimethylformamide, etc.

[0101] In some specific embodiments, the hydrogel precursor solution is laid on the surface of the substrate, and the spinning solution is spun above the hydrogel precursor solution by using a spinning process. Preferably, the spinning solution is spun above the hydrogel precursor solution by using an electrospinning process, so that the micro-nano fibers are gravity-settled and dispersed in the hydrogel precursor solution to obtain a mixture.

[0102] In the present application, the content of the micro-nano fiber in the hydrogel precursor solution is not particularly limited, as long as it can be continuously or discontinuously dispersed in the interior of the substrate. Specifically, considering that too many micro-nano fibers will affect the adhesion of the composite tissue adhesive patch, therefore, in the present application, 0.05-1 g of micro-nano fibers can be dispersed in 100 mL of the hydrogel precursor solution.

[0103] The required micro-nano fibers can be prepared by adjusting the spinning parameters in the electrospinning process. For example, voltage, extrusion flow rate and spinning environment, etc. Preferably, the parameters of the electrospinning process include: adjusting the voltage of the high-voltage generator to 24-32 kV; adjusting the extrusion flow rate of the micro-injection pump to 5-10 mL / h; controlling the temperature in the electrospinning process to 19-30°C, and the humidity to 50-65%; adjusting the distance between the electrospinning nozzle and the liquid level of the hydrogel precursor solution to 10-20 cm.

[0104] Further, in the present application, if the electrospinning time is too long, the content of the micro-nano fiber is high, and an opaque composite tissue adhesive patch is obtained, and the adhesion of the composite tissue adhesive patch is reduced; if the electrospinning time is too short, the content of the micro-nano fiber is low, and the mechanical properties of the composite tissue adhesive patch are weak and the swelling degree is high. Therefore, in the present application, the electrospinning time can be controlled to 10-20 min.

[0105] Next, the hydrogel precursor solution in the mixture is subjected to a cross-linking reaction to obtain a cross-linked product. In some embodiments, the cross-linking reaction is performed under irradiation of ultraviolet light; preferably, the wavelength of the ultraviolet light is 365-405 nm, and the cross-linking reaction is performed for 20-50 min.

[0106] Finally, the cross-linked product is dried in an oven at 30-40°C for 1-3 days to obtain a composite tissue adhesive patch. In the present application, before drying, a step of removing residual organic solvents and monomers is further included; preferably, the composite tissue adhesive patch is soaked in an alcohol solvent to remove residual organic solvents and monomers; more preferably, the soaking is performed for 1-10 times.

[0107] As for the alcohol solvent, the present application is not particularly limited and can be a commonly used solvent in the art. For example, methanol, ethanol, etc. Preferably, the present application uses ethanol with a concentration of 75-95%. By using ethanol with a concentration of 75-95%, residual solvents and monomers can be effectively removed after repeated soaking.

[0108] Finally, the obtained composite tissue adhesive patch can be cut and sealed for packaging, and then subjected to irradiation sterilization. For example, Co-60 γ-ray irradiation sterilization can be used.

[0109] <Third aspect>

[0110] The third aspect of the present application provides a use of the composite tissue adhesive patch according to the first aspect of the present application for preparing a hemostatic product, a wound closure product, a dura seal product, a vascular sealing product, a lung sealing product, a kidney sealing product, a gastrointestinal anastomosis product, and a cerebrospinal fluid leakage product.

[0111] Examples

[0112] Embodiments of the present application will be described in detail below with reference to examples, but those skilled in the art will understand that the following examples are only for illustration of the present application and should not be regarded as limiting the scope of the present application. If no specific conditions are specified in the examples, the conditions are performed according to the conventional conditions or the conditions recommended by the manufacturer. If no manufacturer of the reagent or instrument is specified, it is a conventional product that can be obtained by purchase on the market.

[0113] Example 1

[0114] (1) Preparation of a hydrogel precursor solution

[0115] 100 mg of hyaluronic acid and 100 mg of sodium alginate were dissolved in 7 g of water, stirred and dissolved, 3 g of acrylic acid, 50 mg of methacrylated gelatin, 100 mg of α-ketoglutaric acid were added, stirred and dissolved to obtain solution A.

[0116] (2) Preparation of the spinning solution

[0117] 0.5 g of polyglycolide was dissolved in 50 mL of hexafluoroisopropanol, stirred overnight until completely dissolved to obtain liquid B.

[0118] (3) Electrospinning

[0119] 10 mL of liquid A was spread on a 12 cm x 12 cm glass plate and placed in an electrospinning box for electrospinning. The process parameters for electrospinning were: the extrusion flow of the microsyringe pump was adjusted to 10 mL / h, the voltage of the high-voltage generator was adjusted to 32 kV, the humidity during the electrospinning process was controlled to 63%, and the temperature was controlled to 21°C. The electrospinning nozzle containing liquid B was moved to 22 cm above the glass plate and electrospinning was performed for 10 minutes to obtain a mixture.

[0120] (4) Crosslinking treatment

[0121] The glass plate with the mixture was placed under 405 nm ultraviolet light for 40 minutes for crosslinking treatment to obtain a crosslinked product.

[0122] (5) Post-treatment

[0123] The crosslinked product was repeatedly soaked in 95% ethanol to remove residual solvents and acrylic acid residues, then dried in a 37°C oven for 2 days, sealed and packaged, and subjected to Co-60 gamma ray irradiation sterilization treatment to obtain a composite tissue adhesive patch.

[0124] Example 2

[0125] (1) Preparation of the hydrogel precursor solution

[0126] 3 g of water and 5 g of glycerol were mixed uniformly, then 2 g of acrylamide, 50 mg of polyethylene glycol diacrylate, 200 mg of 2-hydroxy-4'-(2-hydroxyethoxy)-2-methylpropiophenone were added, and stirred until dissolved to obtain liquid A.

[0127] (2) Preparation of the spinning solution

[0128] 1.5 g of polytrimethylcarbonate was dissolved in 50 mL of hexafluoroisopropanol, stirred overnight until completely dissolved to obtain liquid B.

[0129] (3) Electrospinning

[0130] 10 mL of the A solution was spread on a 12 cm x 12 cm glass plate and placed in an electrospinning box for electrospinning. The process parameters for electrospinning were as follows: the extrusion flow of the microsyringe pump was adjusted to 10 mL / h, the voltage of the high-voltage generator was adjusted to 32 kV, the humidity during the electrospinning process was controlled to 63%, and the temperature was controlled to 21°C. The electrospinning nozzle loaded with the B solution was moved to a position 22 cm above the glass plate, and electrospinning was performed for 20 minutes to obtain a mixture.

[0131] (4) Crosslinking treatment

[0132] The glass plate with the mixture was placed under 405 nm ultraviolet light for irradiation for 20 minutes for crosslinking treatment to obtain a crosslinked product.

[0133] (5) Post-treatment

[0134] The crosslinked product was repeatedly soaked in 95% ethanol multiple times to remove residual solvents and acrylamide residues, then dried in an oven at 37°C for 2 days, sealed and packaged, and subjected to Co-60 gamma ray irradiation sterilization treatment to obtain a composite tissue adhesive patch.

[0135] Example 3

[0136] (1) Preparation of a hydrogel precursor solution

[0137] 200 mg of chitosan was dissolved in 6 g of 0.5 mol / L hydrochloric acid solution, stirred to dissolve, 4 g of acrylamide, 40 mg of polyethylene glycol diacrylate, and 100 mg of α-ketoglutaric acid were added, stirred to dissolve, to obtain the A solution.

[0138] (2) Preparation of a spinning solution

[0139] 2.5 g of polytrimethylcarbonate was dissolved in 50 mL of hexafluoroisopropanol, stirred overnight until completely dissolved, to obtain the B solution.

[0140] (3) Electrospinning

[0141] 10 mL of the A solution was spread on a 12 cm x 12 cm glass plate and placed in an electrospinning box for electrospinning. The process parameters for electrospinning were as follows: the extrusion flow of the microsyringe pump was adjusted to 10 mL / h, the voltage of the high-voltage generator was adjusted to 32 kV, the humidity during the electrospinning process was controlled to 63%, and the temperature was controlled to 21°C. The electrospinning nozzle loaded with the B solution was moved to a position 22 cm above the glass plate, and electrospinning was performed for 20 minutes to obtain a mixture.

[0142] (4) Crosslinking treatment

[0143] The glass plate with the mixture was placed under 405 nm ultraviolet light for irradiation for 20 minutes for crosslinking treatment to obtain a crosslinked product.

[0144] (5) Post-treatment

[0145] The cross-linked product was repeatedly soaked in 95% ethanol to remove residual solvents and acrylamide residues, then dried in an oven at 37°C for 2 days, sealed and packaged, and subjected to Co-60 gamma ray irradiation sterilization treatment to obtain a composite tissue adhesive patch.

[0146] Example 4

[0147] (1) Preparation of hydrogel precursor solution

[0148] After 3 g of water and 3 g of glycerol were mixed uniformly, 2 g of acrylamide, 2 g of acrylic acid, 50 mg of polyethylene glycol diacrylate, and 100 mg of a-ketoglutaric acid were added, and stirred until dissolved to obtain solution A.

[0149] (2) Preparation of spinning solution

[0150] 5 g of polylactide was dissolved in 50 mL of hexafluoroisopropanol and stirred overnight until completely dissolved to obtain solution B.

[0151] (3) Electrospinning

[0152] 10 mL of solution A was spread on a 12 cm x 12 cm glass plate and placed in an electrospinning box for electrospinning. The process parameters for electrospinning were as follows: the extrusion flow rate of the microsyringe pump was adjusted to 10 mL / h, the voltage of the high-voltage generator was adjusted to 32 kV, the humidity during electrospinning was controlled to 63%, and the temperature was controlled to 21°C. The electrospinning nozzle containing solution B was moved to a position 22 cm above the glass plate and electrospinning was performed for 15 minutes to obtain a mixture.

[0153] (4) Cross-linking treatment

[0154] The glass plate with the mixture was placed under 405 nm ultraviolet light for 30 minutes for cross-linking treatment to obtain a cross-linked product.

[0155] (5) Post-treatment

[0156] The cross-linked product was repeatedly soaked in 95% ethanol to remove residual solvents and acrylamide residues, then dried in an oven at 37°C for 2 days, sealed and packaged, and subjected to Co-60 gamma ray irradiation sterilization treatment to obtain a composite tissue adhesive patch.

[0157] Example 5

[0158] (1) Preparation of hydrogel precursor solution

[0159] Dissolve 200 mg of hydroxymethyl cellulose in 4 g of water, add 6 g of acrylamide, 60 mg of polyethylene glycol dimethacrylate, 100 mg of lithium phenyl-2, 4, 6-trimethylbenzoylphosphinate, and stir until dissolved to obtain solution A.

[0160] (2) Preparation of the spinning solution

[0161] Dissolve 1.75 g of polylactide and 1.75 g of gelatin in 50 mL of hexafluoroisopropanol, and stir overnight until completely dissolved to obtain solution B.

[0162] (3) Electrospinning

[0163] Spread 10 mL of solution A on a 12 cm x 12 cm glass plate, and place it in an electrospinning box for electrospinning. The process parameters for electrospinning are as follows: adjust the extrusion flow rate of the microsyringe pump to 10 mL / h, adjust the voltage of the high-voltage generator to 32 kV, control the humidity during the electrospinning process to 63%, and control the temperature to 21°C. After moving the electrospinning nozzle containing solution B to a position 22 cm above the glass plate, spin for 15 minutes to obtain a mixture.

[0164] (4) Crosslinking treatment

[0165] Place the glass plate with the mixture on it under 405 nm ultraviolet light for irradiation for 40 minutes for crosslinking treatment to obtain a crosslinked product.

[0166] (5) Post-treatment

[0167] Repeatedly immerse the crosslinked product in 95% ethanol to remove residual solvents and acrylamide residues, then place it in a 37°C oven for drying for 2 days, seal it for packaging, and perform Co-60 gamma ray irradiation sterilization treatment to obtain a composite tissue adhesive patch.

[0168] Example 6

[0169] (1) Preparation of the hydrogel precursor solution

[0170] Dissolve 200 mg of chitosan in 6 g of 0.5 mol / L hydrochloric acid solution, stir until dissolved, add 4 g of acrylamide, 40 mg of polyethylene glycol diacrylate, and 100 mg of α-ketoglutaric acid, and stir until dissolved to obtain solution A.

[0171] (2) Preparation of the spinning solution

[0172] Dissolve 1.25 g of polytrimethylcarbonate and 1.25 g of gelatin in 50 mL of hexafluoroisopropanol, and stir overnight until completely dissolved to obtain solution B.

[0173] (3) Electrospinning

[0174] 10 mL of the A solution was spread on a 12 cm x 12 cm glass plate and placed in an electrospinning box for electrospinning. The process parameters for electrospinning were as follows: the extrusion flow of the microsyringe pump was adjusted to 10 mL / h, the voltage of the high-voltage generator was adjusted to 32 kV, the humidity during electrospinning was controlled to 63%, and the temperature was controlled to 21°C. After the electrospinning nozzle loaded with the B solution was moved to a position 22 cm above the glass plate, electrospinning was performed for 15 minutes to obtain a mixture.

[0175] (4) Crosslinking treatment

[0176] The glass plate with the mixture was placed under 405 nm ultraviolet light for irradiation for 30 minutes for crosslinking treatment to obtain a crosslinked product.

[0177] (5) Post-treatment

[0178] The crosslinked product was repeatedly soaked in 95% ethanol multiple times to remove residual solvents and acrylamide residues, then dried in an oven at 37°C for 2 days, sealed and packaged, and subjected to Co-60 gamma ray irradiation sterilization treatment to obtain a composite tissue adhesive patch.

[0179] Example 7

[0180] (1) Preparation of a hydrogel precursor solution

[0181] 100 mg of sodium alginate was dissolved in 7 g of water, stirred to dissolve, 3 g of acrylic acid, 30 mg of N,N'-bis(acryloyl)cystamine, and 100 mg of a-ketoglutaric acid were added, stirred to dissolve, and an A solution was obtained.

[0182] (2) Preparation of a spinning solution

[0183] 1.25 g of polytrimethylcarbonate and 1.25 g of gelatin were dissolved in 50 mL of hexafluoroisopropanol, stirred overnight until completely dissolved, and a B solution was obtained.

[0184] (3) Electrospinning

[0185] 10 mL of the A solution was spread on a 12 cm x 12 cm glass plate and placed in an electrospinning box for electrospinning. The process parameters for electrospinning were as follows: the extrusion flow of the microsyringe pump was adjusted to 10 mL / h, the voltage of the high-voltage generator was adjusted to 32 kV, the humidity during electrospinning was controlled to 63%, and the temperature was controlled to 21°C. After the electrospinning nozzle loaded with the B solution was moved to a position 22 cm above the glass plate, electrospinning was performed for 15 minutes to obtain a mixture.

[0186] (4) Crosslinking treatment

[0187] The glass plate with the mixture was placed under 405 nm ultraviolet light for irradiation for 30 minutes for crosslinking treatment to obtain a crosslinked product.

[0188] (5) Post-treatment

[0189] The cross-linked product was repeatedly soaked in 95% ethanol to remove residual solvent and acrylic acid, then dried in an oven at 37°C for 2 days, sealed, and sterilized by Co-60 γ-ray irradiation to obtain the composite tissue adhesive patch.

[0190] Comparative Example 1

[0191] (1) 4 g of acrylamide, 40 mg of polyethylene glycol diacrylate, and 100 mg of α-ketoglutaric acid were added to 6 g of water, and stirred until dissolved to obtain liquid A.

[0192] (2) 10 mL of liquid A was spread on a 12 cm x 12 cm glass plate, and the glass plate with the mixture was placed under 405 nm ultraviolet light for 30 minutes for cross-linking treatment to obtain a cross-linked product.

[0193] (3) The cross-linked product was repeatedly soaked in PBS to remove residual acrylamide, then dried in an oven at 37°C for 2 days, sealed, and sterilized by Co-60 γ-ray irradiation to obtain the tissue adhesive product.

[0194] Comparative Example 2

[0195] (1) 3 g of acrylic acid, 30 mg of N,N'-bis(acryloyl)cystamine, and 100 mg of α-ketoglutaric acid were dissolved in 7 g of water, and stirred until dissolved to obtain liquid A.

[0196] (2) 10 mL of liquid A was spread on a 12 cm x 12 cm glass plate, and the glass plate with the mixture was placed under 405 nm ultraviolet light for 30 minutes for cross-linking treatment to obtain a cross-linked product.

[0197] (3) The cross-linked product was repeatedly soaked in PBS to remove residual solvent and acrylic acid, then dried in an oven at 37°C for 2 days, sealed, and sterilized by Co-60 γ-ray irradiation to obtain the tissue adhesive product.

[0198] Comparative Example 3

[0199] (1) 200 mg of chitosan was dissolved in 6 g of 0.5 mol / L hydrochloric acid solution, and stirred until dissolved. 4 g of acrylamide, 40 mg of polyethylene glycol diacrylate, and 100 mg of α-ketoglutaric acid were added, and stirred until dissolved to obtain liquid A.

[0200] (2) 10 mL of the A solution was spread on a 12 cm x 12 cm glass plate, and the glass plate with the mixture was placed under 405 nm ultraviolet light for irradiation for 30 minutes for crosslinking treatment, to obtain a crosslinked product.

[0201] (3) The hydrogel patch was repeatedly soaked in PBS to remove acrylamide residues, and then dried in an oven at 37°C for 2 days, sealed and packaged, and subjected to Co-60 gamma ray irradiation sterilization treatment, to obtain a tissue adhesion product.

[0202] Comparative Example 4

[0203] (1) 100 mg of sodium alginate was dissolved in 7 g of water, stirred and dissolved, 3 g of acrylic acid, 30 mg of N,N'-bis(acryloyl) cystamine, 100 mg of alpha-ketoglutaric acid were added, stirred and dissolved, to obtain the A solution.

[0204] (2) 10 mL of the A solution was spread on a 12 cm x 12 cm glass plate, and the glass plate with the mixture was placed under 405 nm ultraviolet light for irradiation for 30 minutes for crosslinking treatment, to obtain a crosslinked product.

[0205] (3) The crosslinked product was repeatedly soaked in PBS to remove solvent residues and acrylic acid residues, and then dried in an oven at 37°C for 2 days, sealed and packaged, and subjected to Co-60 gamma ray irradiation sterilization treatment, to obtain a tissue adhesion product.

[0206] Comparative Example 5

[0207] (1) Preparation of the hydrogel composition: 200 mg of chitosan was dissolved in 6 g of 0.5 mol / L hydrochloric acid solution, stirred and dissolved, 4 g of acrylamide, 40 mg of polyethylene glycol diacrylate, 100 mg of alpha-ketoglutaric acid were added, stirred and dissolved, to obtain the A solution.

[0208] (2) Preparation of the spinning solution: 2.5 g of polytrimethyl carbonate was dissolved in 50 mL of hexafluoroisopropanol, stirred overnight until completely dissolved, to obtain the B solution.

[0209] (3) The A solution and the B solution were directly mixed and stirred, and the hydrophobic components in the spinning solution were separated out, and a tissue adhesion product could not be obtained.

[0210] Comparative Example 6

[0211] (1) Preparation of the hydrogel composition

[0212] 200 mg of chitosan was dissolved in 6 g of 0.5 mol / L hydrochloric acid solution, stirred and dissolved, 4 g of acrylamide, 40 mg of polyethylene glycol diacrylate, 100 mg of alpha-ketoglutaric acid were added, stirred and dissolved, to obtain the A solution.

[0213] (2) Preparation of electrospun fiber membrane

[0214] 1.25 g of polytrimethylene carbonate and 1.25 g of gelatin were dissolved in 50 mL of hexafluoroisopropanol, stirred overnight until completely dissolved to obtain liquid B; electrospinning was performed on liquid B to form a spinning product. The process parameters of electrospinning were as follows: the extrusion flow of the micro-injection pump was adjusted to 10 mL / h, the voltage of the high-voltage generator was adjusted to 32 kV, and the humidity and temperature during the electrospinning process were controlled to be 63% and 21°C, respectively. The spinning product was repeatedly soaked in 95% ethanol to remove residual solvent and dried to obtain a fiber membrane.

[0215] (3) Crosslinking treatment

[0216] 10 mL of liquid A was spread on a 12 cm x 12 cm glass plate, and then the fiber membrane was soaked in liquid A. The glass plate with the mixture was placed under 405 nm ultraviolet light for irradiation for 30 minutes for crosslinking treatment to obtain a crosslinked product.

[0217] (4) Post-treatment

[0218] The crosslinked product was repeatedly soaked in 95% ethanol to remove residual solvent and acrylamide, and then dried in a 37°C oven for 2 days. The product was sealed and packaged, and subjected to Co-60 γ-ray irradiation sterilization treatment to obtain a tissue adhesive product.

[0219] Performance tests

[0220] 1. Swelling degree test

[0221] About 1 g of the composite tissue adhesive patch of Examples 1-7 and the tissue adhesive product of Comparative Examples 1-6 was accurately weighed, and the mass was recorded as W i . Phosphate buffer solution was added in a ratio of 1 g:30 mL, and the condition of the composite tissue adhesive patch or the tissue adhesive product was observed during the soaking process. After soaking for 24 h, the composite tissue adhesive patch or the tissue adhesive product was taken out, the excess water on the surface was absorbed with filter paper, and then weighed, recorded as W t . The swelling degree was calculated according to formula (1), and the results are shown in Table 1.

[0222] SR = (W t -W i ) / W i x 100% (1)

[0223] In formula (1), SR represents the swelling degree of the composite tissue adhesive patch or the tissue adhesive product; W t represents the mass of the swollen composite tissue adhesive patch or tissue adhesive product; and W iThe swelling degree of the composite tissue-adhesive patch or tissue-adhesive product before swelling.

[0224] Table 1 Swelling degree test results

[0225] Test samples Swelling degree (%) Example 1 sample 602％ Example 2 sample 613％ Example 3 sample 598％ Example 4 sample 557％ Example 5 sample 626％ Example 6 sample 588％ Example 7 sample 590％ Comparative Example 1 sample Changed to a transparent viscous liquid, swelling degree could not be tested Comparative Example 2 sample Changed to a transparent viscous liquid, swelling degree could not be tested Comparative Example 3 sample Changed to a transparent viscous liquid, swelling degree could not be tested Comparative Example 4 sample Changed to a transparent viscous liquid, swelling degree could not be tested Comparative Example 6 sample Hydrogel part changed to a viscous liquid, fiber membrane unchanged

[0226] As can be seen from Table 1, the composite tissue-adhesive patches of Examples 1-7 of the present application have a lower swelling degree, and the swelling degree is less than 700%. The tissue-adhesive products of Comparative Examples 1-4 all become transparent viscous liquid, and the swelling degree cannot be tested, which indicates that the hydrogel obtained by photo-crosslinking of pure acrylic acid or acrylamide, and the tissue-adhesive product obtained after drying, (Comparative Example 1 and Comparative Example 2) is easy to absorb water and swell, and the composite tissue-adhesive patch of the present application can significantly reduce the swelling degree by dispersing the micro-nano fibers in the matrix.

[0227] The hydrogel part of the tissue-adhesive product of Comparative Example 6 becomes a viscous liquid, and the fiber membrane does not change, which indicates that the hydrogel of Comparative Example 6 dissolves out, and the overall stability of the product is poor. The composite tissue-adhesive patch prepared by the preparation method of the present application can better interpenetrate the micro-nano fibers in the matrix and more closely combine with the matrix, thereby reducing the swelling degree.

[0228] 2. Continuous adhesion test in a wet environment

[0229] The adhesion and sealing effect and the continuous sealing time of the tissue-adhesive patch are important in vitro performance evaluation, which indicates the minimum pressure required to cause the tissue sealed by the tissue-adhesive patch to rupture or burst and the time under the pressure. When the tissue-adhesive patch is used to prevent leakage of tissue wounds such as heart, lung or gastrointestinal tract, this property becomes particularly important.

[0230] Test method: The test is performed by using a gel pressure resistance test recording tool system instrument, and the specific method is as follows:

[0231] First, take a casing with a diameter of 4 cm, and prepare a hole with a diameter of 5 mm in the middle of the casing, and adhere the composite tissue-adhesive patches (15 mm x 15 mm) of Examples 1-7 and the tissue-adhesive product (15 mm x 15 mm) of Comparative Example 6 to the wound. When adhering, the center line of the composite tissue-adhesive patch and the tissue-adhesive product needs to be located exactly above the incision. Maintain the pressure at 4 Kpa, and use a push pump to drop PBS solution on the patch at an extrusion flow rate of 2 mL / min, and the test time is 14 days, and whether the sample can continuously maintain the pressure is observed. The experimental results are shown in Table 2.

[0232] Table 2 Adhesion performance test results

[0233]

[0234] As shown in Table 2, the adhesive properties of the composite tissue adhesive patches of Examples 1-7 of the present application are excellent, and the pressure maintaining can still be sustained on the 14th day, indicating that the composite tissue adhesive patches of the present application have a longer lasting adhesive property. The adhesive properties of the tissue adhesive products of Comparative Examples 1-4 and Comparative Example 6 are poor, and swelling occurs, and the samples lose the pressure maintaining state within one day.

[0235] 3. Burst strength test

[0236] Burst pressure is an important mechanical property of a tissue adhesive patch, which indicates the minimum pressure required to cause the tissue sealed by the adhesive to rupture or burst. This property becomes particularly important when the tissue adhesive patch is used to prevent leakage from a wound of tissue such as the heart, lung or gastrointestinal tract. Generally, the burst strength required to prevent leakage of cerebrospinal fluid is 6.7 KPa, the burst strength required to prevent lung leakage is 20 KPa, and the burst strength required to prevent bleeding from a blood vessel is 18.8 KPa.

[0237] The test method is as follows:

[0238] (1) The detection equipment is composed of a base (containing a water tank), a fixed hollow cover, a water delivery system, and a pressure detection system. A casing with a diameter of not less than 4 cm is taken, and a hole with a diameter of 5 mm is prepared in the middle of the casing. An oily pen is used to draw a point on the test table, and the hole is placed at the center of the point. The composite tissue adhesive patch of Example 1-7 is taken, and a circular test sample with a diameter of 1.5 cm is cut out using a skin biopsy punch with a diameter of 1.5 cm. The sample is placed on the casing with the hole as the center, and is made to adhere to the casing and form a seal. Then, it is placed on the test base and fixed using the hollow cover, and then the pressure is increased externally, and the burst strength is measured. The burst strength is the effect of the elasticity and toughness of the tissue adhesive patch itself and its adhesion.

[0239] (2) Burst strength detection: the water delivery system is opened, and PBS solution is injected at an extrusion flow rate of 2 mL / min to increase the pressure, and the maximum pressure at which the sample fails to rupture is recorded. The test results are shown in Table 3.

[0240] Table 3 Burst strength detection results

[0241] Test samples Breaking strength Example 1 sample 58 kPa Example 2 sample 59 kPa Example 3 sample 53 kPa Example 4 sample 61 kPa Example 5 sample 63 kPa Example 6 sample 66 kPa Example 7 sample 65 kPa

[0242] As shown in Table 3, the mechanical properties of the composite tissue adhesive patches of the present application are excellent, and can be used to prevent leakage from a wound of tissue such as the lung, blood vessel or gastrointestinal tract.

[0243] It should be noted that although the technical solutions of the present application are introduced with specific examples, those skilled in the art can understand that the present application should not be limited thereto.

[0244] Having described various embodiments of the application, it is to be understood that the above description is meant not to limit and not to encompass all of the possible embodiments covered by the claims. Many modifications and variations of this application can be apparent to those of ordinary skill in the art without departing from the spirit and scope of the described embodiments. It is intended that the scope of the application should only be limited by the appended claims.

Claims

1. A composite tissue-adhesive patch, characterized by, The composite tissue-adhesive patch comprises: a base and micro-nanofibers complexed with the base; the micro-nanofibers are continuously or discontinuously dispersed in the interior of the base.

2. The composite tissue-adhesive patch of claim 1, wherein, The thickness of the composite tissue-adhesive patch is 0.1-1 mm, preferably 0.2-0.6 mm; and / or, the diameter of the micro-nanofibers is greater than 60 nm, preferably 0.1-100 μm.

3. The composite tissue-adhesive patch of claim 1 or 2, wherein, The swelling degree of the composite tissue-adhesive patch is less than 700%; and / or, the breaking strength of the composite tissue-adhesive patch is greater than 45 kPa.

4. The composite tissue-adhesive patch of any one of claims 1-3, wherein, The raw materials for preparing the base include monomers, thickening agents, cross-linking agents and photoinitiators, and the monomers and the thickening agents do not chemically react with each other; Preferably, the mass ratio of the monomers to the thickening agents is (1-8):(0.05-8), preferably (2-6):(0.1-5).

5. The composite tissue-adhesive patch of claim 4, wherein, The monomers include acrylic monomers and / or acrylamide monomers; and / or, The thickening agents include one or more than two combinations of chitosan, sodium alginate, hyaluronic acid, hydroxymethyl cellulose, carboxymethyl cellulose, hydroxyethyl cellulose and glycerol.

6. The composite tissue-adhesive patch of any one of claims 1-5, wherein, The raw materials for preparing the micro-nanofibers include hydrophobic synthetic polymer materials; preferably, the raw materials for preparing the micro-nanofibers further comprise natural polymer materials; further preferably, the content of the natural polymer materials is less than 50% based on the total mass of the raw materials for preparing the micro-nanofibers.

7. A method of producing the composite tissue-adhesive patch according to any one of claims 1 to 6, characterized by, The step of complexing the base with the micro-nanofibers includes: Preferably, the step of complexing includes combining a spinning process with a hydrogel preparation process; Preferably, the composite tissue-adhesive patch is obtained by dispersing the micro-nanofibers in a hydrogel precursor solution, followed by a cross-linking reaction and drying; wherein the micro-nanofibers are prepared by a spinning process, and the hydrogel precursor solution is obtained by dissolving the raw materials for preparing the base in a first solvent.

8. The preparation method according to claim 7, characterized in that, The steps include: dissolving the raw materials for preparing the base in a first solvent to obtain a hydrogel precursor solution; dissolving the raw materials for preparing the micro-nanofibers in a second solvent to obtain a spinning solution; spinning the spinning solution by a spinning process to disperse the micro-nanofibers in the hydrogel precursor solution to obtain a mixture; subjecting the hydrogel precursor solution in the mixture to a cross-linking reaction to obtain a cross-linking product; drying the cross-linking product to obtain a composite tissue-adhesive patch; Preferably, the spinning process can include one or more than two combinations of an electrospinning process, a centrifugal force spinning process, a hot melt spinning process and a melt electrospinning process. Preferably, the cross-linking reaction is performed under ultraviolet light irradiation.

9. The production method according to claim 8, characterized by, The hydrogel precursor solution is laid on the surface of a substrate, and the spinning solution is spun above the hydrogel precursor solution by a spinning process; Preferably, in the spinning solution, the mass-volume ratio of the raw materials for preparing the micro-nanofibers to the second solvent is (1-10) g / 100 mL. Preferably, the spinning process is an electrospinning process, parameters of the electrospinning process include: controlling the time of electrospinning to be 10-20 min, adjusting the distance between the electrospinning nozzle and the liquid level of the hydrogel precursor solution to be 10-20 cm.

10. Use of the composite tissue-adhesive patch according to any one of claims 1-6 for the preparation of a hemostatic product, a wound closure product, a dura seal product, a vessel sealing product, a lung sealing product, a kidney sealing product, a gastrointestinal anastomosis product, a cerebrospinal fluid leakage product.

Images