Composite film of dual fiber structure and method of making and use thereof

Abstract

This invention provides a composite membrane with a dual-fiber structure, its preparation method, and its applications. The composite membrane with a dual-fiber structure comprises: a first fiber layer and a second fiber layer having a porous structure; the pore size of the first fiber layer is 0.5–15 μm, and the pore size of the second fiber layer is 20–500 μm; the first fiber layer has first fiber filaments with a diameter of 0.1–5 μm; the second fiber layer has second fiber filaments with a diameter of 2–100 μm; the diameter of the first fiber filaments is smaller than the diameter of the second fiber filaments; wherein at least a portion of the first fiber filaments fills the second fiber layer; and the composite membrane also contains an adhesive, which penetrates into the pores of the first and second fiber layers, bonding at least a portion of the first and second fiber filaments together. The composite membrane with the dual-fiber structure of this invention is not prone to delamination and has good mechanical properties.

Description

Technical Field

[0001] This invention relates to a composite membrane with a dual-fiber structure, its preparation method, and its applications, belonging to the field of biomaterials technology. Background Technology

[0002] With the rapid development of the medical industry and textile technology, the application of textile materials in the medical field is becoming increasingly widespread. Most medical textile materials are composed of polymer fibers and their modified fibers, and their preparation methods mainly include: electrospinning, melt spinning, and nonwoven fabrics (including spunbond, meltblown, thermal rolling, and hydroentangling; currently, most nonwoven fabrics on the market are produced using the spunbond method). Currently, textile materials are used in infection control, barrier materials, wound care, medical devices, and cardiovascular materials. In the cardiovascular field, medical materials such as cardiac occluder membranes, artificial blood vessels, and cardiac patches typically have requirements regarding membrane thickness, pore size, and mechanical strength.

[0003] Electrospun fiber membranes possess a large specific surface area, high porosity, and a three-dimensional porous structure, which is conducive to cell proliferation, differentiation, and growth, thus exhibiting excellent tissue repair properties. Current research indicates that most cardiovascular materials are prepared using electrospinning. However, the mechanical strength of electrospun fiber membranes is relatively weak, failing to adequately meet the requirements of cardiovascular materials (such as the flow-resistance membranes of artificial blood vessels and cardiac occluders, which require materials to withstand blood flow pressure), resulting in less than ideal clinical application outcomes. To improve the mechanical strength of fiber membranes, various improvement methods have been explored, such as heat treatment, chemical cross-linking, and solvent fumigation. These post-treatment methods increase operational complexity and production costs, hindering large-scale production and potentially damaging the three-dimensional mesh structure of the fiber membrane, which is detrimental to cell proliferation, differentiation, and growth.

[0004] Nonwoven fabric, also known as needle-punched cotton or needle-punched nonwoven fabric, is a type of nonwoven material. It is made by directly forming a web from polymer chips, short fibers, or filaments through airflow or mechanical means, followed by hydroentangling, needle punching, or thermal rolling for reinforcement, and finally finishing processes. It is a soft, breathable new type of fiber product. Due to its moisture-proof, breathable, flexible, lightweight, flame-retardant, non-toxic, odorless, inexpensive, and recyclable properties, nonwoven fabric is widely used in various industries, such as sound insulation, heat insulation, electric heaters, masks, clothing, medical applications, and as filling materials. In the medical field, nonwoven fabric is commonly used in masks, protective clothing, surgical caps, disposable surgical gowns, and disposable medical sheets. However, the fibers in nonwoven fabric are relatively coarse and have large pore sizes, resulting in poor effectiveness in blocking blood flow, and its application in the cardiovascular field is relatively limited.

[0005] Therefore, researching a membrane material with good mechanical properties, a simple and easy preparation method, and applicable to the cardiovascular field has become an urgent technical problem to be solved. Summary of the Invention

[0006] The problem the invention aims to solve

[0007] In view of the technical problems existing in the prior art, the present invention first provides a composite membrane with a dual-fiber structure. The composite membrane of the present invention comprises a first fiber layer and a second fiber layer with a porous structure. The first fiber layer has a fine fiber structure, which is flexible and dense, facilitating cell adhesion and growth. The second fiber layer has a coarse fiber structure, which helps to improve the mechanical strength of the composite membrane. Furthermore, some of the coarse and fine fibers in the composite membrane are bonded together with an adhesive, making the composite membrane less prone to delamination. Overall, it exhibits good mechanical properties and good biocompatibility, and has broad application prospects in the cardiovascular field.

[0008] The present invention also provides a method for preparing a double fiber structure composite membrane, which is simple and easy to implement, uses readily available raw materials, and is suitable for mass production.

[0009] Solution for solving the problem

[0010] This invention provides a composite membrane with a dual-fiber structure, comprising: a first fiber layer and a second fiber layer having a porous structure, wherein the pore size of the first fiber layer is 0.5–15 μm, and the pore size of the second fiber layer is 20–500 μm; the first fiber layer has first fiber filaments with a diameter of 0.1–5 μm; the second fiber layer has second fiber filaments with a diameter of 2–100 μm; the diameter of the first fiber filament is smaller than the diameter of the second fiber filament; wherein,

[0011] At least a portion of the first fiber filaments are filled into the second fiber layer; and...

[0012] The composite membrane also contains an adhesive that penetrates into the pores of the first fiber layer and the second fiber layer, and bonds at least a portion of the first fiber filaments to the second fiber filaments by the adhesive.

[0013] Further, the mass ratio of the first fiber layer, the second fiber layer, and the adhesive is 1:(0.2-3):(0.1-1), preferably 1:(0.5-2):(0.4-0.8); and / or

[0014] The adhesive does not completely cover the fibrous structure of the first fiber layer and / or the second fiber layer.

[0015] Furthermore, the composite membrane has at least one of the following characteristics:

[0016] The thickness of the composite membrane is 0.05–0.3 mm;

[0017] The tensile strength of the composite membrane is 14–25 MPa;

[0018] The maximum pull-out stress of the composite membrane is 3.5 to 7.0 N.

[0019] Furthermore, the material of the first fiber layer includes a hydrophobic material and a hydrophilic material; the mass ratio of the hydrophobic material to the hydrophilic material is 1:(0-1), preferably 1:(0.1-0.5);

[0020] Preferably, the hydrophobic material includes one or more of polylactic acid, poly-L-lactic acid, polycaprolactone, polylactic acid-glycolic acid copolymer, polytrimethylene carbonate, poly-L-lactide-caprolactone, and polyurethane.

[0021] More preferably, the hydrophilic material includes one or more of collagen, gelatin or its derivatives, polyethylene glycol, polyvinyl alcohol, sodium hyaluronate, and alginate.

[0022] Furthermore, the material of the second fiber layer includes one or more combinations of polylactic acid, polyethylene terephthalate, polypropylene, and polyamide.

[0023] Further, the adhesive includes a hydrophilic adhesive; preferably, the hydrophilic adhesive includes one or more of chitosan or its derivatives, alginate or its derivatives, gelatin or its derivatives, and sodium hyaluronate or its derivatives.

[0024] Furthermore, the composite membrane further includes a third fiber layer having third filaments. An adhesive penetrates into the pores of the third fiber layer, bonding at least a portion of the third filaments to the first or second filaments via the adhesive; wherein...

[0025] The third fiber layer is located on the side of the first fiber layer opposite to the second fiber layer, and the diameter of the third fiber filament is 2–100 μm; or,

[0026] The third fiber layer is located on the side of the second fiber layer opposite to the first fiber layer, and the diameter of the third fiber filament is 0.1 to 5 μm.

[0027] The present invention also provides a method for preparing a composite membrane according to the present invention, wherein the preparation method includes the step of compounding a first fiber layer and a second fiber layer, and then allowing an adhesive to permeate the first fiber layer and the second fiber layer;

[0028] Preferably, the preparation method includes the following steps:

[0029] A nonwoven fiber membrane is used as the second fiber layer;

[0030] Using one side of the second fiber layer as the receiving plane, the first fiber layer is prepared by electrospinning or melt spinning to obtain a double-layer fiber membrane.

[0031] An adhesive solution is prepared and allowed to permeate through the surface of the first fiber layer and / or the second fiber layer into the first fiber layer and the second fiber layer to obtain a composite membrane.

[0032] Furthermore, the preparation method further includes the following steps:

[0033] After obtaining the bilayer fiber membrane, a nonwoven fiber membrane is laid flat on the side of the first fiber layer opposite to the second fiber layer as a third fiber layer, resulting in a three-layer fiber membrane; an adhesive solution is prepared, and the adhesive solution is allowed to permeate through the surface of the second fiber layer and / or the third fiber layer into the first fiber layer, the second fiber layer, and the third fiber layer, resulting in a composite membrane; or,

[0034] After obtaining the bilayer fiber membrane, the side of the second fiber layer opposite to the first fiber layer is used as the receiving plane, and a third fiber layer is prepared by electrospinning or melt spinning to obtain a three-layer fiber membrane; an adhesive solution is prepared, and the adhesive solution is allowed to penetrate through the surface of the first fiber layer and / or the third fiber layer into the first fiber layer, the second fiber layer and the third fiber layer to obtain a composite membrane.

[0035] The present invention further provides the use of the composite membrane with the dual fiber structure described in the present invention in the preparation of artificial blood vessels, flow-blocking membranes for cardiac occluders, vascular mesh stents, or hemostatic umbrellas for vascular occluders.

[0036] The effects of the invention

[0037] The composite membrane with a dual fiber structure of the present invention includes a first fiber layer and a second fiber layer with a porous structure. The first fiber layer has a fine fiber structure, which is flexible and dense, and is conducive to cell adhesion and growth. The second fiber layer has a coarse fiber structure, which can help improve the mechanical strength of the composite membrane. Furthermore, some of the coarse and fine fibers in the composite membrane are bonded together by an adhesive, making the composite membrane less prone to delamination and giving it good overall mechanical properties.

[0038] In the composite membrane with a dual fiber structure of the present invention, since the adhesive does not completely cover the fiber structure of the composite membrane, the composite membrane still retains part of the three-dimensional fiber network structure, which is beneficial to cell adhesion, proliferation and growth, and has good biocompatibility.

[0039] The composite membrane with a dual-fiber structure of the present invention has a relatively thin thickness, which facilitates delivery and use via interventional methods. It also has good tensile strength and maximum suture pull-out stress, and has broad application prospects in the cardiovascular field, such as as a choke membrane for cardiac occluders, artificial blood vessels, vascular mesh stents, or hemostatic umbrellas for vascular occluders.

[0040] The preparation method of the dual-fiber composite membrane of the present invention is simple and easy to implement, the raw materials are readily available, and it is suitable for mass production. Attached Figure Description

[0041] Figure 1 A photograph is shown of the composite membrane of Example 1 of the present invention after being soaked in PBS buffer for 2 months.

[0042] Figure 2 A schematic diagram of the adhesion evaluation of the bilayer structure of the composite film of Embodiment 3 of the present invention is shown, wherein the left figure is before peeling and the right figure is after peeling.

[0043] Figure 3 A schematic diagram illustrating the adhesion evaluation of the PLLA electrospun fiber membrane-PLA spunbond fiber membrane of Comparative Example 3 of the present invention is shown.

[0044] Figure 4 The image shows scanning electron microscope (SEM) images of the composite membrane of Example 1, wherein the left image is an SEM image taken from one side of the second fiber layer (spunbond fiber membrane); and the right image is an SEM image taken from one side of the first fiber layer (electrospun fiber membrane).

[0045] Figure 5 The image shows scanning electron microscope (SEM) images of the composite membrane of Example 2, wherein the left image is an SEM image taken from one side of the second fiber layer (spunbond fiber membrane); and the right image is an SEM image taken from one side of the first fiber layer (electrospun fiber membrane).

[0046] Figure 6 The image shows scanning electron microscope (SEM) images of the composite membrane of Example 6, wherein the left image is an SEM image taken from one side of the second fiber layer (spunbond fiber membrane); and the right image is an SEM image taken from one side of the third fiber layer (spunbond fiber membrane).

[0047] Figure 7 A scanning electron microscope (SEM) image of the poly-L-lactic acid (PLLA) electrospun fiber membrane of Comparative Example 1 is shown.

[0048] Figure 8 A scanning electron microscope (SEM) image of the polylactic acid (PLA) spunbond fiber membrane of Comparative Example 2 is shown.

[0049] Figure 9The images show photographs of the composite membranes implanted subcutaneously on the backs of rats in Examples 3 and 6, with the left image showing composite membrane-3 of Example 3 and the right image showing composite membrane-6 of Example 6.

[0050] Figure 10 The images show the tissue section staining analysis of the composite membranes of Examples 3 and 6 implanted under the skin on the back of rats one month (1M), where the left image is the composite membrane-3 of Example 3 and the right image is the composite membrane-6 of Example 6.

[0051] Figure 11 The images show the tissue section staining analysis of the composite membranes of Examples 3 and 6 implanted subcutaneously on the back of rats three months (3M), with the left image showing the composite membrane-3 of Example 3 and the right image showing the composite membrane-6 of Example 6. Detailed Implementation

[0052] Various exemplary embodiments, features, and aspects of the present invention will be described in detail below. The term "exemplary" as used herein means "serving as an example, embodiment, or illustration." Any embodiment described herein as "exemplary" is not necessarily to be construed as superior to or better than other embodiments.

[0053] Furthermore, to better illustrate the present invention, numerous specific details are set forth in the following detailed embodiments. Those skilled in the art should understand that the present invention can be practiced without certain specific details. In other instances, methods, means, apparatus, and steps well known to those skilled in the art have not been described in detail in order to highlight the spirit of the present invention.

[0054] 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.

[0055] In this specification, the word "may" has two meanings: to perform a certain process and not to perform a certain process.

[0056] 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.

[0057] 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.

[0058] In this instruction manual, when "room temperature" or "room temperature" is used, the temperature can be 15-25℃.

[0059] <First Aspect>

[0060] A first aspect of the present invention provides a composite membrane with a dual-fiber structure, comprising: a first fiber layer and a second fiber layer having a porous structure, wherein the pore size of the first fiber layer is 0.5–15 μm, and the pore size of the second fiber layer is 20–500 μm; the first fiber layer has first fiber filaments with a diameter of 0.1–5 μm; the second fiber layer has second fiber filaments with a diameter of 2–100 μm; the diameter of the first fiber filaments is smaller than the diameter of the second fiber filaments; wherein,

[0061] At least a portion of the first fiber filaments are filled into the second fiber layer; and...

[0062] The composite membrane also contains an adhesive that penetrates into the pores of the first fiber layer and the second fiber layer, and bonds at least a portion of the first fiber filaments to the second fiber filaments by the adhesive.

[0063] The composite membrane of the present invention comprises a first fiber layer and a second fiber layer having a porous structure. The first fiber layer has a fine fiber structure, which is flexible and dense, and is conducive to cell adhesion and growth. The second fiber layer has a coarse fiber structure, which can help improve the mechanical strength of the composite membrane. Furthermore, some of the coarse and fine fibers in the composite membrane are bonded together by an adhesive, making the composite membrane less prone to delamination. Overall, it has good mechanical properties and good biocompatibility, and has broad application prospects in the cardiovascular field.

[0064] In some specific embodiments, the mass ratio of the first fiber layer, the second fiber layer, and the adhesive is 1:(0.2-3):(0.1-1), preferably 1:(0.5-2):(0.4-0.8), for example: 1:(0.5-2.5):(0.2-0.9), 1:(0.8-2.2):(0.3-0.8), 1:(1-2):(0.4-0.7), 1:(1.2-1.8):(0.5-0.6), 1:(1.4-1.5):(0.5-0.6), etc. When the mass ratio of the first fiber layer, the second fiber layer, and the adhesive is 1:(0.2~3):(0.1~1), the adhesive can penetrate into the pores of the first and second fiber layers, thereby bonding the first and second fiber layers well. This makes the composite membrane less prone to delamination and gives it good mechanical strength. At the same time, the adhesive does not completely cover the fiber structure of the first and / or second fiber layers, so that the composite membrane still retains part of the three-dimensional fiber network structure, which is beneficial to cell adhesion, proliferation, and growth, and has good biocompatibility.

[0065] Furthermore, in this invention, the composite membrane has at least one of the following characteristics: the thickness of the composite membrane is 0.05–0.3 mm, for example: 0.08 mm, 0.1 mm, 0.12 mm, 0.15 mm, 0.18 mm, 0.2 mm, 0.22 mm, 0.25 mm, 0.28 mm, etc.; the tensile strength of the composite membrane is 14–25 MPa, for example: 16 MPa, 17 MPa, 18 MPa, 19 MPa, 20 MPa, 21 MPa, 22 MPa, 23 MPa, 24 MPa, etc.; the maximum pull-out stress of the composite membrane is 3.5–7.0 N, for example: 3.8 N, 4 N, 4.2 N, 4.5 N, 4.8 N, 5 N, 5.2 N, 5.5 N, 5.8 N, 6 N, 6.2 N, 6.5 N, 6.8 N, etc. The composite membrane of this invention has a relatively thin thickness, which makes it easier to deliver and use via interventional methods compared to thicker composite membranes. The composite membrane of this invention also exhibits good tensile strength and maximum suture pull-out stress, and has broad application prospects in the field of cardiovascular stents, such as as a choke membrane for cardiac occluders, artificial blood vessels, vascular mesh stents, or hemostatic umbrellas for vascular occluders.

[0066] First fiber layer

[0067] The first fiber layer of the present invention has a pore size of 0.5 to 15 μm, and the first fiber layer has a first fiber filament with a diameter of 0.1 to 5 μm. Preferably, the first fiber layer is an electrospun fiber membrane.

[0068] In some specific embodiments, the material of the first fiber layer of the present invention may include a hydrophobic material. Preferably, the material of the first fiber layer of the present invention may include a hydrophobic material and a hydrophilic material. The inventors of the present invention have discovered that when a hydrophobic material and a hydrophilic material are used to prepare the first fiber layer, it helps to make the first fiber layer and the second fiber layer bond more tightly under the action of the adhesive, and is beneficial to improving the tensile strength of the composite membrane material. Therefore, in the present invention, the material of the first fiber layer includes a hydrophobic material and a hydrophilic material; the mass ratio of the hydrophobic material to the hydrophilic material is 1:(0 to 1), preferably 1:(0.1 to 0.5), for example: 1:0.1, 1:0.2, 1:0.3, 1:0.4, 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, etc.

[0069] Specifically, the hydrophobic material includes one or more of the following: polylactic acid (PLA), poly-L-lactic acid (PLLA), polycaprolactone (PCL), polylactic acid-glycolic acid copolymer (PLGA), polytrimethylene carbonate (PTMC), poly-L-lactide-caprolactone (PLCL), and polyurethane; the hydrophilic material includes one or more of the following: collagen, gelatin or its derivatives, polyethylene glycol, polyvinyl alcohol, sodium hyaluronate, and alginate.

[0070] Second fiber layer

[0071] The second fiber layer of the present invention has a pore size of 20-500 μm and has second fiber filaments with a diameter of 2-100 μm; preferably, the second fiber layer is a nonwoven fiber membrane. The present invention improves the mechanical properties of the composite membrane by using coarser fibers with a larger diameter than the first fiber filaments.

[0072] The present invention does not impose any particular limitation on the material of the second fiber layer, and it can be a material commonly used in the art. Specifically, the material of the second fiber layer includes one or more of polylactic acid, polyethylene terephthalate, polypropylene, and polyamide.

[0073] Specifically, at least a portion of the first fiber filaments of the present invention are filled into the second fiber layer, thereby facilitating the tight bonding of the first fiber layer and the second fiber layer together.

[0074] adhesives

[0075] The composite membrane of the present invention further comprises an adhesive that penetrates into the pores of the first and second fiber layers, bonding at least a portion of the first and second fiber filaments together. By using an adhesive, the present invention obtains a composite membrane with a more tightly bonded bilayer fiber structure.

[0076] In some specific embodiments, the adhesive comprises a hydrophilic adhesive, which allows the adhesive to penetrate into the pores of the first and second fiber layers. Preferably, the hydrophilic adhesive comprises one or more of chitosan or its derivatives, alginate or its derivatives, gelatin or its derivatives, and sodium hyaluronate or its derivatives.

[0077] Other fiber layers

[0078] In this invention, the composite membrane may further include a third fiber layer, forming a three-layer composite membrane with the first fiber layer and the second fiber layer. The third fiber layer has third filaments, and an adhesive penetrates into the pores of the third fiber layer, bonding at least a portion of the third filaments to the first or second fiber filaments via the adhesive; wherein the third fiber layer is located on the side of the first fiber layer opposite to the second fiber layer, and the diameter of the third filament is 2–100 μm; or, the third fiber layer is located on the side of the second fiber layer opposite to the first fiber layer, and the diameter of the third filament is 0.1–5 μm.

[0079] Furthermore, in this invention, the third fiber layer may be the same as or similar to the first fiber layer, or it may be the same as or similar to the second fiber layer, which will not be elaborated further here. Specifically, when the third fiber layer is located on the side of the first fiber layer opposite to the second fiber layer, the third fiber layer is the same as or similar to the second fiber layer; when the third fiber layer is located on the side of the second fiber layer opposite to the first fiber layer, the third fiber layer is the same as or similar to the first fiber layer.

[0080] The inventors of this invention have discovered that by using a third fiber layer to form a three-layer composite membrane with the first and second fiber layers, and by filling the pores between the fiber layers with an adhesive to connect them, the overall fiber structure of the composite membrane becomes denser. This facilitates tighter adhesion between the fiber layers and prevents delamination. Furthermore, the adhesive does not completely cover the fiber structure of the first, second, and third fiber layers, preserving the three-dimensional fiber network structure that promotes cell adhesion and proliferation, thus giving it good biocompatibility.

[0081] When the composite membrane includes a third fiber layer, the mass ratio of the first fiber layer, the second fiber layer, the third fiber layer, and the adhesive can be 1:(0.2~3):(0.2~3):(0.1~1). For example: 1:(0.5~2.5):(0.5~2.5):(0.2~0.9), 1:(0.8~2.2):(0.8~2.2):(0.3~0.8), 1:(1~2):(1~2):(0.4~0.7), 1:(1.2~1.8):(1.2~1.8):(0.5~0.6), 1:(1.4~1.5):(1.4~1.5):(0.5~0.6), etc.

[0082] <Second aspect>

[0083] A second aspect of the present invention provides a method for preparing the composite membrane described in the first aspect, the method comprising the steps of compounding a first fiber layer and a second fiber layer, and then permeating the first fiber layer and the second fiber layer with an adhesive. The preparation method of the present invention is simple and easy to implement, the raw materials are readily available, and it is suitable for mass production.

[0084] In some specific implementations, the preparation method includes the following steps:

[0085] A nonwoven fiber membrane is used as the second fiber layer;

[0086] Using one side of the second fiber layer as the receiving plane, the first fiber layer is prepared by electrospinning or melt spinning to obtain a double-layer fiber membrane.

[0087] An adhesive solution is prepared and allowed to permeate through the surface of the first fiber layer and / or the second fiber layer into the first fiber layer and the second fiber layer to obtain a composite membrane.

[0088] The nonwoven fiber membrane can be obtained commercially or prepared. Specifically, the preparation process of the nonwoven fiber membrane can include one or more of the following: spunbonding, meltblowing, thermal bonding, stitch weaving, hydroentangling, needle punching, and air-laid pulp.

[0089] The first fiber layer can be prepared by using electrospinning or melt spinning as a receiving plane on one side of the second fiber layer to obtain a double-layer fiber membrane; preferably, an electrospun fiber membrane is prepared by electrospinning as the first fiber layer.

[0090] The principle of electrospinning is that a high voltage is applied to a polymer liquid during the electrospinning process, introducing charge into the liquid. When the charge in the liquid accumulates to a certain amount, the liquid forms a Taylor cone at the nozzle. Under the action of the applied electric field, it overcomes surface tension to form a liquid jet. Then, under the combined action of electrostatic repulsion, Coulomb force, and surface tension, the polymer jet moves along an irregular spiral trajectory. The jet is stretched and pulled in a very short time, and as the solvent evaporates or heat dissipates, the polymer jet solidifies to form micro / nanofibers. During the electrospinning process, many parameters affect the final electrospun fibers. By controlling the process parameters, micro / nanofibers of different sizes, morphologies, and structures can be prepared.

[0091] Furthermore, during electrospinning, fiber raw materials can be prepared in advance and dissolved in a first solvent to prepare a spinning solution of a certain concentration. The fiber raw material can be the raw material for the first fiber layer as described in the first aspect.

[0092] In the electrospinning process of this invention, the process parameters affect the first fiber layer obtained by electrospinning. By controlling the process parameters, support layers of different sizes, shapes, and structures can be prepared. This invention does not have special requirements for the electrospinning method; it can be any electrospinning method commonly used in the art. Specifically, the electrospinning conditions of this invention are as follows: the spinning solution is placed in an electrospinning syringe, the liquid propulsion speed of the micro-injection pump is adjusted to 6-10 mL / h, the voltage of the high-voltage generator is adjusted to 18-32 kV, the receiving distance of the receiving device is adjusted to 18-25 cm, and electrospinning is performed for 10-60 min to obtain an electrospun fiber membrane, which is the first fiber layer.

[0093] Furthermore, an adhesive solution can be obtained by dissolving the adhesive in a solvent. The present invention does not particularly limit the solvent, as long as it can dissolve the adhesive; specifically, it can be water and / or an acetic acid solution with a volume concentration of 0.1% to 5%. The present invention does not particularly limit the concentration of the adhesive in the adhesive solution, as long as it can penetrate the first and second fiber layers. The mass concentration is generally 5 to 100 mg / mL.

[0094] Specifically, one or more of the following methods can be used: paving, coating, casting, and spraying, so that the adhesive solution can penetrate through the surface of the first fiber layer and / or the second fiber layer into the first fiber layer and the second fiber layer to obtain a composite film.

[0095] In some specific implementations, the preparation method further includes the following steps:

[0096] After obtaining a bilayer fiber membrane, a nonwoven fiber membrane is laid flat on the side of the first fiber layer opposite to the second fiber layer as a third fiber layer, resulting in a three-layer fiber membrane; an adhesive solution is prepared, and the adhesive solution is allowed to permeate through the surface of the second fiber layer and / or the third fiber layer into the first fiber layer, the second fiber layer, and the third fiber layer, resulting in a composite membrane; or,

[0097] After obtaining the bilayer fiber membrane, the side of the second fiber layer opposite to the first fiber layer is used as the receiving plane, and the third fiber layer is prepared by electrospinning or melt spinning to obtain a three-layer fiber membrane; an adhesive solution is prepared, and the adhesive solution is allowed to permeate through the surface of the first fiber layer and / or the third fiber layer into the first fiber layer, the second fiber layer and the third fiber layer to obtain a composite membrane.

[0098] Finally, the composite membrane is post-processed, such as by drying, cleaning, etc., to obtain the desired composite membrane with a double-layer fiber structure.

[0099] <Third aspect>

[0100] A third aspect of the present invention also provides the use of the composite membrane with a dual-fiber structure according to the first aspect of the present invention in the preparation of artificial blood vessels, choke membranes for cardiac occluders, vascular mesh stents, or hemostatic caps for vascular occluders. The composite membrane with a dual-fiber structure of the present invention has broad application prospects in the cardiovascular field.

[0101] Example

[0102] The embodiments of the present invention will be described in detail below with reference to examples. However, those skilled in the art will understand that the following examples are for illustrative purposes only and should not be considered as limiting the scope of the invention. Unless otherwise specified in the examples, conventional conditions or conditions recommended by the manufacturer are followed. Reagents or instruments whose manufacturers are not specified are all commercially available conventional products.

[0103] Example 1

[0104] (1) A polylactic acid (PLA) spunbond fiber membrane with a size of 20cm×8cm (thickness: 0.08mm, mass: 0.25g, pore size: 30~120μm, fiber diameter: 5~30μm) is used as the second fiber layer and laid flat on a metal plate as the electrospinning receiving plane.

[0105] (2) Electrospinning is performed on the receiving plane described in step (1), wherein the spinning solution is a poly(L-lactic acid) (PLLA) solution in hexafluoroisopropanol with a concentration of 80 mg / mL. The spinning solution is placed in an electrospinning syringe, the voltage of the high voltage generator is adjusted to 21 kV, the liquid propulsion speed of the micro-injection pump is adjusted to 8 mL / h, the receiving distance of the receiving device is adjusted to 20 cm, and the electrospinning time is 30 min (the mass of the electrospun fiber membrane after removing the loss part is 0.30 g, pore size: 0.5~10 μm, fiber diameter: 0.2~2 μm), and an electrospun fiber membrane as the first fiber layer is obtained, resulting in a double-layer fiber membrane;

[0106] (3) Dissolve 0.1g of chitosan in 3mL of acetic acid-water (2%, v / v) solution to obtain an adhesive solution. Coat the adhesive solution evenly on one side of the spunbond fiber membrane in the double-layer fiber membrane described in step (2). Due to the large pore size of the spunbond fiber membrane, the adhesive can easily penetrate into the gap between the double-layer fiber membranes. After coating evenly, dry, clean, and bake to obtain composite membrane-1. After testing, the average thickness of the composite membrane is 0.13mm.

[0107] Example 2

[0108] (1) A polylactic acid (PLA) spunbond fiber membrane with a size of 20cm×8cm (thickness: 0.08mm, mass: 0.25g, pore size: 30~120μm, fiber diameter: 5~30μm) is used as the second fiber layer and laid flat on a metal plate as the electrospinning receiving plane.

[0109] (2) Electrospinning is performed on the receiving plane described in step (1), wherein the spinning solution is a hexafluoroisopropanol solution of poly-L-lactic acid (PLLA) / gelatin with a concentration of 80 mg / mL, wherein the mass ratio of poly-L-lactic acid to gelatin is 1:1. The spinning solution is placed in an electrospinning syringe, the voltage of the high voltage generator is adjusted to 28 kV, the liquid propulsion speed of the micro-injection pump is adjusted to 8 mL / h, the receiving distance of the receiving device is adjusted to 20 cm, and the electrospinning time is 30 min (the mass of the electrospun fiber membrane after removing the loss part is 0.30 g, the pore size is 0.5~10 μm, and the fiber diameter is 0.2~3 μm), and an electrospun fiber membrane as the first fiber layer is obtained, resulting in a double-layer fiber membrane;

[0110] (3) Dissolve 0.1g of chitosan in 3mL of acetic acid-water (2%, v / v) solution to obtain an adhesive solution. Coat the adhesive solution evenly on one side of the spunbond fiber membrane in the double-layer fiber membrane described in step (2). Due to the large pore size of the spunbond fiber membrane, the adhesive can easily penetrate into the gap between the double-layer fiber membranes. After coating evenly, dry, clean, and bake to obtain composite membrane-2. The average thickness of the composite membrane was tested to be 0.13mm.

[0111] Example 3

[0112] The composite membrane-3 was obtained by replacing the "polylactic acid (PLA) spunbond fiber membrane (thickness: 0.08 mm, mass: 0.25 g, pore size: 30-120 μm, fiber diameter: 5-30 μm)" described in step (1) of Example 1 with "polylactic acid (PLA) spunbond fiber membrane (thickness: 0.04 mm, mass: 0.15 g, pore size: 20-200 μm, fiber diameter: 5-30 μm)". All other steps were the same as in Example 1. After testing, the average thickness of the composite membrane was found to be 0.09 mm.

[0113] Example 4

[0114] The composite membrane-4 was obtained by replacing the "polylactic acid (PLA) spunbond fiber membrane (thickness: 0.08 mm, mass: 0.25 g, pore size: 30-120 μm, fiber diameter: 5-30 μm)" described in step (1) of Example 2 with "polylactic acid (PLA) spunbond fiber membrane (thickness: 0.04 mm, mass: 0.15 g, pore size: 20-200 μm, fiber diameter: 5-30 μm)". All other steps were the same as in Example 2. After testing, the average thickness of the composite membrane was found to be 0.09 mm.

[0115] Example 5

[0116] The only difference between Example 1 and Example 2 is that the spinning solution in step (2) is a poly(L-lactic acid) hexafluoroisopropanol solution with a concentration of 80 mg / mL, and the spinning solution in step (2) is a poly(L-lactic acid) hexafluoroisopropanol solution with a concentration of 80 mg / mL. The remaining steps are the same as in Example 1, resulting in composite membrane-5. After testing, the average thickness of the composite membrane is 0.11 mm.

[0117] Example 6

[0118] (1) A polylactic acid (PLA) spunbond fiber membrane with a size of 21cm×7cm (thickness: 0.04mm, mass: 0.15g, pore size: 20~200μm, fiber diameter: 5~30μm) is used as the second fiber layer and laid flat on a metal plate as the electrospinning receiving plane.

[0119] (2) Electrospinning of the spinning solution is performed on the receiving plane described in step (1), wherein the spinning solution is a poly(L-lactic acid) (PLLA) solution in hexafluoroisopropanol with a concentration of 80 mg / mL. The spinning solution is placed in an electrospinning syringe, the voltage of the high voltage generator is adjusted to 21 kV, the liquid propulsion speed of the micro-injection pump is adjusted to 8 mL / h, the distance between the needle and the receiving plane is 20 cm, and the spinning time is 20 min (the mass of the electrospun fiber membrane after removing the loss part is 0.20 g, the pore size is 0.5~10 μm, and the fiber diameter is 0.2~2 μm), and an electrospun fiber membrane as the first fiber layer is obtained, resulting in a double-layer fiber membrane;

[0120] (3) Dissolve 0.1g of chitosan in 3mL of acetic acid-water (2%, v / v) solution to obtain an adhesive solution. Take 2mL of the adhesive solution and coat it evenly on one side of the spunbonded fiber membrane in the double-layer fiber membrane described in step (2). Wait for the adhesive solution to penetrate the double-layer fiber membrane.

[0121] (4) Take a polylactic acid (PLA) spunbond fiber membrane of the same size as the second fiber layer as the third fiber layer, cover it on one side of the electrospun fiber membrane of the double fiber membrane, add 2 mL of the same adhesive solution as in step (3) for coating, wait for the adhesive solution to penetrate, dry, clean, and bake to obtain composite membrane-6. After testing, the average thickness of the composite membrane is 0.12 mm.

[0122] Example 7

[0123] (1) A polylactic acid (PLA) spunbond fiber membrane with a size of 21cm×7cm (thickness: 0.04mm, mass: 0.17g, pore size: 20~200μm, fiber diameter: 5~30μm) is used as the second fiber layer and laid flat on a metal plate as the electrospinning receiving plane.

[0124] (2) Electrospinning of the spinning solution is performed on the receiving plane described in step (1), wherein the spinning solution is a poly(L-lactic acid) (PLLA) solution in hexafluoroisopropanol with a concentration of 80 mg / mL. The spinning solution is placed in an electrospinning syringe, the voltage of the high voltage generator is adjusted to 21 kV, the liquid propulsion speed of the micro-injection pump is adjusted to 8 mL / h, the receiving distance of the receiving device is adjusted to 20 cm, and the electrospinning time is 20 min (the mass of the electrospun fiber membrane after removing the loss part is 0.20 g, pore size: 0.5~10 μm, fiber diameter: 0.2~2 μm), and an electrospun fiber membrane as the first fiber layer is obtained, resulting in a double-layer fiber membrane;

[0125] (3) Using the other surface of the polylactic acid (PLA) spunbond fiber membrane described in step (1) as the receiving plane, electrospinning is started. The experimental parameters and time of electrospinning are the same as in step (2). A third fiber layer is prepared to obtain a three-layer fiber membrane.

[0126] (4) Dissolve 0.2g of chitosan in 6mL of acetic acid-water (2%, v / v) solution to obtain an adhesive solution. Coat 2mL of the adhesive solution onto each of the two surfaces of the three-layer fiber membrane described in step (3). The adhesive solution penetrates into the gaps between the three-layer fiber membrane. After uniform coating, dry, clean, and bake to obtain composite membrane-7. After testing, the average thickness of the composite membrane is 0.13mm.

[0127] Example 8

[0128] (1) A polylactic acid (PLA) spunbond fiber membrane with a size of 20cm×8cm (thickness: 0.08mm, mass: 0.25g, pore size: 30~120μm, fiber diameter: 5~30μm) is used as the second fiber layer and laid flat on a metal plate as the electrospinning receiving plane.

[0129] (2) Electrospinning of the spinning solution is performed on the receiving plane described in step (1), wherein the spinning solution is a poly(L-lactic acid) (PLLA) solution in hexafluoroisopropanol with a concentration of 80 mg / mL. The spinning solution is placed in an electrospinning syringe, the voltage of the high voltage generator is adjusted to 21 kV, the liquid propulsion speed of the micro-injection pump is adjusted to 8 mL / h, the receiving distance of the receiving device is adjusted to 20 cm, and the electrospinning time is 30 min (the mass of the electrospun fiber membrane after removing the loss part is 0.3 g, the pore size is 0.5-10 μm, and the fiber diameter is 0.2-2 μm), and an electrospun fiber membrane as the first fiber layer is obtained, resulting in a double-layer fiber membrane;

[0130] (3) Dissolve 0.1g of chitosan in 3mL of acetic acid-water (2%, v / v) solution to obtain an adhesive solution, and coat it evenly on one side of the spunbonded fiber membrane in the double-layer fiber membrane described in step (2), and wait for the adhesive to penetrate the double-layer fiber membrane.

[0131] (4) Take a polylactic acid (PLA) spunbond fiber membrane of the same size as the second fiber layer as the third fiber layer, cover it on one side of the electrospun fiber membrane of the double fiber membrane, add 3 mL of the same adhesive solution as in step (3) for coating, wait for the adhesive to penetrate, dry, clean, and bake to obtain composite membrane-8. After testing, the average thickness of the composite membrane is 0.21 mm.

[0132] Example 9

[0133] (1) A polylactic acid (PLA) spunbond fiber membrane with a size of 20cm×8cm (thickness: 0.08mm, mass: 0.25g, pore size: 30~120μm, fiber diameter: 5~30μm) is used as the second fiber layer and laid flat on a metal plate as the electrospinning receiving plane.

[0134] (2) Electrospinning of the spinning solution is performed on the receiving plane described in step (1), wherein the spinning solution is a poly(L-lactic acid) (PLLA) solution in hexafluoroisopropanol with a concentration of 80 mg / mL. The spinning solution is placed in an electrospinning syringe, the voltage of the high voltage generator is adjusted to 21 kV, the liquid propulsion speed of the micro-injection pump is adjusted to 8 mL / h, the receiving distance of the receiving device is adjusted to 20 cm, and the electrospinning time is 20 min (the mass of the electrospun fiber membrane after removing the loss part is 0.2 g, the pore size is 0.5~10 μm, and the fiber diameter is 0.2~2 μm), and an electrospun fiber membrane as the first fiber layer is obtained, resulting in a double-layer fiber membrane;

[0135] (3) Using the other surface of the spunbond fiber membrane described in step (1) as the receiving plane, electrospinning is started. The experimental parameters and time of electrospinning are the same as in step (2). A third fiber layer is prepared to obtain a three-layer fiber membrane.

[0136] (4) Dissolve 0.2g of chitosan in 6mL of acetic acid-water (2%, v / v) solution to obtain an adhesive solution. Coat 3mL of the adhesive solution onto each of the two surfaces of the three-layer fiber membrane described in step (3). The adhesive solution penetrates into the gaps between the three-layer fiber membrane. After uniform coating, dry, clean, and bake to obtain composite membrane-9. After testing, the average thickness of the composite membrane is 0.24mm.

[0137] Example 10

[0138] (1) A polylactic acid (PLA) spunbond fiber membrane with a size of 20cm×8cm (thickness: 0.08mm, mass: 0.25g, pore size: 30~120μm, fiber diameter: 5~30μm) is used as the second fiber layer and laid flat on a metal plate as the electrospinning receiving plane.

[0139] (2) Electrospinning is performed on the receiving plane described in step (1), wherein the spinning solution is a hexafluoroisopropanol composite solution of poly-L-lactic acid (PLLA) / gelatin with a concentration of 80 mg / mL, wherein the mass ratio of poly-L-lactic acid to gelatin is 1:1. The spinning solution is placed in an electrospinning syringe, the voltage of the high voltage generator is adjusted to 29 kV, the liquid propulsion speed of the micro-injection pump is adjusted to 8 mL / h, the receiving distance of the receiving device is adjusted to 20 cm, and the electrospinning time is 30 min (the mass of the electrospun fiber membrane after removing the loss part is 0.3 g, the pore size is 0.5~10 μm, and the fiber diameter is 0.2~3 μm), and an electrospun fiber membrane as the first fiber layer is obtained, resulting in a double-layer fiber membrane;

[0140] (3) Dissolve 0.1g of chitosan in 3mL of acetic acid-water (2%, v / v) solution to obtain an adhesive solution, and coat it evenly on one side of the spunbonded fiber membrane in the double-layer fiber membrane described in step (2), and wait for the adhesive solution to penetrate the double-layer fiber membrane.

[0141] (4) Take a polylactic acid (PLA) spunbond fiber membrane of the same size as the second fiber layer as the third fiber layer, cover it on one side of the electrospun fiber membrane of the double fiber membrane, add 3 mL of the same adhesive solution as in step (3) for coating, wait for the adhesive to penetrate, dry, clean, and bake to obtain composite membrane-10. After testing, the average thickness of the composite membrane is 0.19 mm.

[0142] Example 11

[0143] (1) A polylactic acid (PLA) spunbond fiber membrane with a size of 20cm×8cm (thickness: 0.08mm, mass: 0.25g, pore size: 30~120μm, fiber diameter: 5~30μm) is used as the second fiber layer and laid flat on a metal plate as the electrospinning receiving plane.

[0144] (2) Electrospinning is performed on the receiving plane described in step (1), wherein the spinning solution is a hexafluoroisopropanol solution of poly-L-lactic acid (PLLA) / gelatin with a concentration of 80 mg / mL, wherein the mass ratio of poly-L-lactic acid to gelatin is 1:1. The spinning solution is placed in an electrospinning syringe, the voltage of the high voltage generator is adjusted to 29 kV, the liquid propulsion speed of the micro-injection pump is adjusted to 8 mL / h, the receiving distance of the receiving device is adjusted to 20 cm, and the electrospinning time is 30 min (the mass of the electrospun fiber membrane after removing the loss part is 0.3 g, the pore size is 0.5~10 μm, and the fiber diameter is 0.2~3 μm), and an electrospun fiber membrane as the first fiber layer is obtained, resulting in a double-layer fiber membrane;

[0145] (3) Using the other surface of the spunbond fiber membrane described in step (1) as the receiving plane, start electrospinning. The experimental parameters and time of electrospinning are the same as in step (2). Prepare the third fiber layer and obtain a three-layer fiber membrane.

[0146] (4) Dissolve 0.2g of chitosan in 6mL of acetic acid-water (2%, v / v) solution to obtain an adhesive solution. Coat 3mL of the adhesive solution onto each of the two surfaces of the three-layer fiber membrane described in step (3). The adhesive solution penetrates into the gaps between the three-layer fiber membrane. After uniform coating, dry, clean, and bake to obtain composite membrane-11. After testing, the average thickness of the composite membrane is 0.20mm.

[0147] Example 12

[0148] The only difference between Example 8 and Example 9 is that the spinning solution in step (2) of Example 8, which is described as "a hexafluoroisopropanol solution of poly-L-lactic acid (PLLA) with a concentration of 80 mg / mL", is replaced with "a hexafluoroisopropanol solution of polycaprolactone (PCL) with a concentration of 80 mg / mL". The remaining steps are the same as in Example 8, resulting in composite membrane-12. After testing, the average thickness of the composite membrane was found to be 0.21 mm.

[0149] Example 13

[0150] The only difference between Example 9 and Example 9 is that the spinning solution described in step (2) as "a poly(L-lactic acid) hexafluoroisopropanol solution with a concentration of 80 mg / mL" was replaced with "a poly(caprolactone) hexafluoroisopropanol solution with a concentration of 80 mg / mL". The remaining steps were the same. After testing, the average thickness of the three-layer film was 0.20 mm.

[0151] Comparative Example 1

[0152] A poly-L-lactic acid (PLLA) solution with a concentration of 80 mg / mL in hexafluoroisopropanol was prepared and added to the syringe of the electrospinning apparatus for electrospinning. The voltage of the high-voltage generator was adjusted to 21 kV, the liquid propulsion speed of the micro-injection pump was adjusted to 8 mL / h, the receiving distance of the receiving device was adjusted to 20 cm, and the electrospinning time was 45 min. The fibers were received into a membrane structure using the receiver of the electrospinning apparatus, resulting in a poly-L-lactic acid (PLLA) electrospun fiber membrane with a pore size of 0.5–10 μm, a fiber diameter of 0.2–2 μm, and an average thickness of 0.07 mm.

[0153] Comparative Example 2

[0154] The purchased polylactic acid (PLA) spunbond fiber membrane has a pore size of 35–110 μm, a fiber diameter of 5–30 μm, and an average thickness of 0.16 mm.

[0155] Comparative Example 3

[0156] (1) A polylactic acid (PLA) spunbond fiber membrane with a size of 20cm×8cm (thickness: 0.04mm, mass: 0.15g, pore size: 20~200μm, fiber diameter: 5~30μm) is laid flat on a metal plate as an electrospinning receiving surface;

[0157] (2) Electrospinning of the spinning solution is performed on the receiving plane described in step (1). The spinning solution is a poly(L-lactic acid) (PLLA) solution in hexafluoroisopropanol with a concentration of 80 mg / mL. The spinning solution is placed in an electrospinning syringe. The voltage of the high voltage generator is adjusted to 21 kV, the liquid propulsion speed of the micro-injection pump is adjusted to 8 mL / h, the receiving distance of the receiving device is adjusted to 20 cm, and the electrospinning time is 30 min (the mass of the electrospun fiber membrane after removing the loss part is 0.3 g, the pore size is 0.5-10 μm, and the fiber diameter is 0.2-2 μm). A double-layer fiber membrane is obtained, denoted as: PLLA electrospun fiber membrane-PLA spunbond fiber membrane. Its average thickness is measured to be 0.10 mm.

[0158] Comparative Example 4

[0159] (1) A polylactic acid (PLA) spunbond fiber membrane with a size of 20cm×8cm (thickness: 0.04mm, mass: 0.15g, pore size: 20~200μm, fiber diameter: 5~30μm) is laid flat on a metal plate as an electrospinning receiving surface;

[0160] (2) Electrospinning is performed on the receiving plane described in step (1), wherein the spinning solution is a hexafluoroisopropanol solution of poly-L-lactic acid (PLLA) / gelatin with a concentration of 80 mg / mL, wherein the mass ratio of poly-L-lactic acid to gelatin is 1:1. The spinning solution is placed in an electrospinning injector, the voltage of the high-voltage generator is adjusted to 28 kV, the liquid propulsion speed of the micro-injection pump is adjusted to 8 mL / h, the receiving distance of the receiving device is adjusted to 20 cm, and the electrospinning time is 30 min (the mass of the electrospun fiber membrane after removing the loss part is 0.3 g, pore size: 0.5~10 μm, fiber diameter: 0.2~3 μm), and a double-layer fiber membrane is obtained, denoted as: PLLA / gelatin fiber membrane-PLA spunbond fiber membrane, with an average thickness of 0.09 mm.

[0161] Performance testing

[0162] 1. Immersion test

[0163] The composite membrane-1 from Example 1 was immersed in PBS and placed in a 37°C incubator for 2 months. Afterwards, the changes in the composite membrane were observed, and the results were as follows: Figure 1As shown in the figure. The results showed that after soaking for two months, there were no obvious changes on the surface of the composite membrane, and no delamination occurred. The electrospun fiber membrane and the spunbond fiber membrane remained tightly bonded, indicating that the two fiber membranes were tightly bonded, and the possibility of separation of the composite membrane was small even with long-term contact with body fluids or blood.

[0164] 2. Adhesion assessment

[0165] An attempt was made by hand to completely peel off the spunbond fiber membrane and the electrospun fiber membrane of composite membrane-3 in Example 3. It was found that the two were tightly bonded and could not be completely separated. Figure 2 As shown.

[0166] By manually attempting to completely peel off the spunbond fiber membrane and electrospun fiber membrane of the composite membrane in other embodiments, the same result as described above was obtained.

[0167] By manually peeling the PLLA electrospun fiber membrane-PLA spunbond fiber membrane of Comparative Example 3, it was found that the two fiber membranes could be separated very well. Figure 3 As shown.

[0168] 3. Microscopic morphology characterization

[0169] The composite membrane-1 prepared in Example 1, the composite membrane-2 prepared in Example 2, the composite membrane-6 prepared in Example 6, the PLLA electrospun fiber membrane of Comparative Example 1, and the PLA spunbond fiber membrane of Comparative Example 2 were bonded to the surface of a conductive stage with conductive adhesive and subjected to gold sputtering treatment. The accelerating voltage was adjusted to 3-5 kV, and the surface morphology of the membrane materials was observed at a certain magnification. The results are as follows. Figure 4-8 As shown.

[0170] from Figure 4-6 As can be seen, the composite membranes prepared in Examples 1, 2, and 6 of this invention retain fibrous structures on both surfaces and are not completely covered by adhesives, which helps cell adhesion and proliferation. Therefore, the composite membranes have good cell compatibility.

[0171] from Figure 7 and Figure 8 It can be seen that the PLLA electrospun fiber membrane in Comparative Example 1 has a finer fiber diameter, while the PLA spunbond fiber membrane in Comparative Example 2 has a coarser fiber diameter.

[0172] 4. Mechanical properties

[0173] Fiber membrane tensile and stitching performance tests

[0174] Membrane material under test:

[0175] Composite membrane-3 of Example 3, composite membrane-4 of Example 4, composite membrane-8 of Example 8, PLLA electrospun fiber membrane of Comparative Example 1, PLA spunbond fiber membrane of Comparative Example 2, PLLA electrospun fiber membrane-PLA spunbond fiber membrane of Comparative Example 3, and PLLA / gelatin fiber membrane-PLA spunbond fiber membrane of Comparative Example 4.

[0176] Referring to GB / T 1040.3-2006 Part 3: Test conditions for films and sheets, the test film material was cut into strips of 60mm×10mm for tensile property testing. The test speed was 200mm / min and the gauge length was 40mm. The results are shown in Table 1 below.

[0177] The test method for suture pull-out stress is as follows: Cut the membrane material to be tested into a strip of 30mm × 10mm. Pass a nylon suture (4-0) through the strip 5-10mm from one end of the sample. Fix the suture and the other end of the strip. Start the tensile test; the maximum force tested is the maximum suture pull-out stress. The test results are shown in Table 1 below:

[0178] Table 1

[0179]

[0180] As can be seen from Table 1, the tensile strength and maximum pull-out stress of the composite membrane-3 of Example 3, the composite membrane-4 of Example 4, and the composite membrane-8 of Example 8 are all higher than those of the single PLLA electrospun fiber membrane and PLA spunbond fiber membrane.

[0181] Example 4, based on Example 3, added gelatin and PLLA to the electrospun fiber membrane preparation process. The tensile strength of the resulting composite membrane-4 was significantly higher than that of composite membrane-3, indicating that adding hydrophilic materials to the electrospun fiber membrane is beneficial to improving the tensile strength of the composite membrane.

[0182] The composite membranes of Comparative Examples 3 and 4 are obtained by electrospinning a double-layer fiber membrane on a spunbond fiber membrane without using an adhesive for bonding. As a result, the composite membranes cannot simultaneously have good tensile strength and maximum pull-out stress at the seam. However, Examples 3 and 4 of the present invention use an adhesive to bond the electrospun fiber membrane and the spunbond fiber membrane of Comparative Examples 3 and 4 respectively, and the composite membranes obtained have both good tensile strength and maximum pull-out stress at the seam.

[0183] In addition, other composite membranes prepared by this invention can also have good tensile strength and maximum pull-out stress at the seam, with tensile strength ranging from 14 to 25 MPa and maximum pull-out stress at the seam ranging from 3.5 to 7 N.

[0184] 5. Cytotoxicity test

[0185] The cytotoxicity of the composite membrane was evaluated according to GB / T 16886.5-2017 "Biological Evaluation of Medical Devices - Part 5: In Vitro Cytotoxicity Tests". Specifically, the test membrane materials (composite membrane-1 of Example 1 and composite membrane-8 of Example 8) were used in the experiment. The extraction ratio of composite membrane-1 of Example 1 and composite membrane-8 of Example 8 to cell culture medium was 6 cm⁻¹, respectively. 2 The extract was diluted to 100% high-density polyethylene (HDPE) and incubated for 72 hours. The diluted extract was then used to contact L929 cells (10,000 cells / well) and cultured for 48 hours. Cells were stained using the MTT assay kit and the optical density was measured using a UV spectrophotometer. Negative control group: 100% HDPE extract; positive control group: DMSO; blank control group: cell culture medium. The cell viability was calculated as follows:

[0186] Table 2

[0187]

[0188] As shown in Table 2, the cell viability of composite membrane-1 in Example 1 and composite membrane-8 in Example 8 is higher than that of the blank control group by 70%. Therefore, the composite membrane of the present invention is non-cytotoxic and meets the cell compatibility requirements of medical devices.

[0189] 6. Subcutaneous implantation experiment

[0190] Experimental animals: SD rats

[0191] Samples: Composite membrane-3 prepared in Example 3; Composite membrane-6 prepared in Example 6.

[0192] Experimental protocol: Subcutaneous implantation experiments were conducted in accordance with GB / T 16886.11-2011.

[0193] Specific procedure: Two to three sacs were created subcutaneously on each side of the rat's back, spaced approximately 1 to 2 cm apart. A composite membrane measuring 1.0 cm × 0.5 cm was implanted into each sac. The animals were dissected at two time points, 1 and 3 months after implantation, and the degradation of the material and the condition of the rat's subcutaneous tissue were observed. The results are shown in Figures 9-11.

[0194] Results analysis:

[0195] Depend on Figure 9 and 10As can be seen, one month after implantation under the skin of rats, composite membrane-3: the material is relatively intact, with a layer of coarse fibrous filaments and a layer of red fine fibrous filaments visible, without obvious thickening of fibrous tissue, macrophages and multinucleated giant cells are seen next to it, and a dense collagen fiber layer is formed around it; composite membrane-6: the material is relatively intact, with a layer of coarse fibrous filaments and a layer of red fine fibrous filaments visible, without obvious thickening of fibrous tissue, macrophages and multinucleated giant cells are seen next to it, and a collagen fiber layer and newly formed small blood vessels are formed around it.

[0196] Depend on Figure 9 and 11 It can be seen that 3 months after implantation under the skin of rats, the composite membrane-3 and composite membrane-6 are relatively intact in appearance, the composite membranes do not become brittle, are not easily broken when stretched, and new tissues are present on the surface of both membranes.

[0197] Therefore, it is evident that composite membranes-3 and-6 exhibit good tissue compatibility, and their structures remain relatively intact three months after implantation, without becoming brittle or easily broken under tension. Thus, the composite membranes of this invention have significant application potential in cardiovascular materials (such as artificial blood vessels and flow-blocking membranes).

[0198] It should be noted that although the technical solution of the present invention has been described with specific examples, those skilled in the art will understand that the present invention should not be limited thereto.

[0199] The various embodiments of the present invention have been described above. These descriptions are exemplary and not exhaustive, nor are they limited to the disclosed embodiments. Many modifications and variations will be apparent to those skilled in the art without departing from the scope and spirit of the described embodiments. The terminology used herein is chosen to best explain the principles, practical application, or technical improvements to the embodiments in the market, or to enable others skilled in the art to understand the embodiments disclosed herein.

Claims

1. A medical composite film of a dual fiber structure, characterized by, include: The system comprises a first fiber layer and a second fiber layer with a porous structure. The pore size of the first fiber layer is 0.5~15 μm, and the pore size of the second fiber layer is 20~500 μm. The first fiber layer has a first fiber filament with a diameter of 0.1~3 μm. The second fiber layer has a second fiber filament with a diameter of 5~100 μm. The diameter of the first fiber filament is smaller than the diameter of the second fiber filament. At least a portion of the first fiber filaments are filled into the second fiber layer; and... The medical composite membrane also contains an adhesive, which penetrates into the pores of the first fiber layer and the second fiber layer and bonds at least a portion of the first fiber filaments to the second fiber filaments by the adhesive, wherein the adhesive does not completely cover the fiber structure of the first fiber layer and / or the second fiber layer; The material of the first fiber layer includes a hydrophobic material, which includes one or more of polylactic acid, polycaprolactone, polylactic acid-glycolic acid copolymer, polytrimethylene carbonate, poly-L-lactide-caprolactone, and polyurethane. The second fiber layer is a spunbond fiber layer, and the material of the second fiber layer includes one or more of polylactic acid, polyethylene terephthalate, polypropylene, and polyamide.

2. The medical composite film according to claim 1, characterized in that, The polylactic acid in the hydrophobic material is poly-L-lactic acid.

3. The medical composite film according to claim 1, characterized in that, The mass ratio of the first fiber layer, the second fiber layer, and the adhesive is 1:(0.2~3):(0.1~1).

4. The medical composite film according to claim 3, characterized in that, The mass ratio of the first fiber layer, the second fiber layer, and the adhesive is 1:(0.5~2):(0.4~0.8).

5. The medical composite film according to any one of claims 1 to 4, characterized in that, The medical composite membrane has at least one of the following characteristics: The thickness of the medical composite membrane is 0.05~0.3mm; The tensile strength of the medical composite membrane is 14~25MPa; The maximum pull-out stress of the medical composite membrane is 3.5~7.0N.

6. The medical composite film according to any one of claims 1 to 4, characterized in that, The material of the first fiber layer includes a hydrophobic material and a hydrophilic material; the mass ratio of the hydrophobic material to the hydrophilic material is 1:(0~1).

7. The medical composite membrane according to claim 6, characterized in that, The mass ratio of the hydrophobic material to the hydrophilic material is 1:(0.1~0.5).

8. The medical composite membrane according to claim 6, characterized in that, The hydrophilic material includes one or more of collagen, gelatin or its derivatives, polyethylene glycol, polyvinyl alcohol, sodium hyaluronate, and alginate.

9. The medical composite film according to any one of claims 1 to 4, characterized in that, The adhesive includes a hydrophilic adhesive.

10. The medical composite film according to claim 9, characterized in that, The hydrophilic adhesive includes one or more of the following: chitosan or its derivatives, alginate or its derivatives, gelatin or its derivatives, and sodium hyaluronate or its derivatives.

11. The medical composite film according to any one of claims 1 to 4, characterized in that, The medical composite membrane further includes a third fiber layer having third fiber filaments. An adhesive penetrates the pores of the third fiber layer, bonding at least a portion of the third fiber filaments to the first or second fiber filaments via the adhesive. The third fiber layer is located on the side of the first fiber layer opposite to the second fiber layer, and the diameter of the third fiber filament is 2~100μm; or, The third fiber layer is located on the side of the second fiber layer opposite to the first fiber layer, and the diameter of the third fiber filament is 0.1~5μm.

12. A method for preparing a medical composite membrane according to any one of claims 1-11, characterized in that, The preparation method includes the steps of compounding a first fiber layer and a second fiber layer, and then allowing an adhesive to penetrate the first fiber layer and the second fiber layer.

13. The preparation method according to claim 12, characterized in that, The preparation method includes the following steps: Use spunbond fiber membrane as the second fiber layer; Using one side of the second fiber layer as the receiving plane, the first fiber layer is prepared by electrospinning or melt spinning to obtain a double-layer fiber membrane. An adhesive solution is prepared and allowed to permeate through the surface of the first fiber layer and / or the second fiber layer into the first fiber layer and the second fiber layer to obtain a medical composite membrane.

14. The method of claim 13, wherein, The preparation method further includes the following steps: After obtaining the bilayer fiber membrane, a spunbond fiber membrane is laid flat on the side of the first fiber layer opposite to the second fiber layer as a third fiber layer, resulting in a three-layer fiber membrane; an adhesive solution is prepared, and the adhesive solution is allowed to permeate through the surface of the second fiber layer and / or the third fiber layer into the first fiber layer, the second fiber layer, and the third fiber layer, to obtain a medical composite membrane; or, After obtaining the bilayer fiber membrane, the side of the second fiber layer opposite to the first fiber layer is used as the receiving plane, and a third fiber layer is prepared by electrospinning or melt spinning to obtain a three-layer fiber membrane; an adhesive solution is prepared, and the adhesive solution is allowed to permeate through the surface of the first fiber layer and / or the third fiber layer into the first fiber layer, the second fiber layer and the third fiber layer to obtain a medical composite membrane.

15. The use of a medical composite membrane with a dual-fiber structure according to any one of claims 1-11 in the preparation of artificial blood vessels, cardiac occluder choke membranes, vascular mesh stents, or vascular occluder hemostatic umbrellas.

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