Composite membrane with double-fiber structure as well as preparation method and application of composite membrane

Abstract

The invention provides a composite membrane with a double-fiber structure as well as a preparation method and application of the composite membrane. The composite membrane with the double-fiber structure comprises a first fiber layer and a second fiber layer which are of a porous structure, the pore diameter of the first fiber layer is 0.5-15 microns, and the pore diameter of the second fiber layer is 20-500 microns; the first fiber layer is provided with first fiber yarns, and the diameter of the first fiber yarns is 0.1-5 [mu] m; the second fiber layer is provided with second fiber yarns, and the diameter of the second fiber yarns is 2-100 microns; the diameter of the first fiber yarn is smaller than that of the second fiber yarn; wherein at least part of the first fiber filaments are filled into the second fiber layer; and moreover, the composite membrane further contains an adhesive, the adhesive permeates into pores of the first fiber layer and the second fiber layer, and at least part of the first fiber filaments and the second fiber filaments are bonded through the adhesive. The composite membrane with the double-fiber structure is not easy to layer and has good mechanical properties.

Description

Technical Field

[0001] The present invention relates to a composite membrane with a dual fiber structure, a preparation method thereof and uses thereof, and belongs to the technical field of biomaterials. Background Art

[0002] With the rapid development of the medical industry and textile technology, the application scope of textile materials in the medical field is becoming wider and wider. Most medical textile materials are composed of polymer fibers and their modified fibers, and the main preparation methods thereof include: electrospinning, melt spinning, non-woven fabrics (including spunbonding, meltblowing, hot rolling, hydroentangling, and most of the non-woven fabrics on the market are produced by the spunbonding method), etc. At present, textile materials have been used in aspects such as infection control, barrier materials, wound care, medical devices, and cardiovascular materials. For the cardiovascular field, for example, medical materials such as the flow-blocking membrane of a cardiac occluder, artificial blood vessels, and cardiac patches usually have requirements for the thickness, pore size, and mechanical strength of the membrane material.

[0003] Electrospun fiber membranes have characteristics such as a large specific surface area and high porosity, and have a three-dimensional porous structure, which is beneficial to the proliferation, differentiation, and growth of cells, so they have good tissue repair performance. According to existing research, most cardiovascular materials are prepared by the electrospinning process. However, the mechanical strength of electrospun fiber membranes is weak and cannot well meet the requirements of cardiovascular materials (such as artificial blood vessels and the flow-blocking membrane of a cardiac occluder, which require the material to be able to withstand blood flow pressure), and the clinical application effect is not ideal. In order to improve the mechanical strength of the fiber membrane, various improvement methods have been tried, such as post-treatments such as heat treatment, chemical cross-linking, and solvent fumigation. These post-treatment methods increase the complexity of the operation and production costs, are not conducive to large-scale production, and may damage the three-dimensional mesh structure of the fiber membrane, which is not conducive to the proliferation, differentiation, and growth of cells.

[0004] Non-woven fabrics, also known as needle-punched cotton, needle-punched non-woven fabrics, etc., are a kind of non-woven fabrics. They are directly formed by using materials such as high polymer chips, staple fibers, or filaments through air laying or mechanical web formation, and then reinforced by hydroentangling, needle punching, or hot rolling, and finally formed into a non-woven fabric through post-treatment. It is a soft and breathable new fiber product. Since non-woven fabrics have characteristics such as moisture-proof, breathable, flexible, light, flame-retardant, non-toxic and odorless, low price, and recyclable, they are widely used in different industries, such as: sound insulation, heat insulation, electric heaters, masks, clothing, medical treatment, filling materials, etc. In the medical field, non-woven fabrics are often used in aspects such as masks, protective clothing, surgical caps, disposable surgical gowns, disposable medical sheets, etc. However, the fibers of non-woven fabrics are relatively thick and the fiber pore size is relatively large, and their effectiveness in blocking blood flow is poor, so they are less used in the cardiovascular field.

[0005] Therefore, it has become an urgent technical problem to study a membrane material with good mechanical properties, a simple and feasible preparation method, and which can be used in the cardiovascular field. Summary of the Invention

[0006] Problems to be Solved by the Invention

[0007] In view of the technical problems existing in the prior art, the present invention firstly provides a composite membrane with a dual fiber structure. The composite membrane with a dual fiber structure of the present invention simultaneously includes a first fiber layer and a second fiber layer with a porous structure. The first fiber layer has a fine fiber structure, good flexibility, and a dense fiber structure, which is beneficial to the adhesion and growth of cells. The second fiber layer has a thick fiber structure, and the thick fibers can help improve the mechanical strength of the composite membrane. Moreover, some of the thick fibers and fine fibers in the composite membrane are bonded by an adhesive, so that the composite membrane is not easy to delaminate, has good overall mechanical properties, good biocompatibility, and has a wide application prospect in the cardiovascular field.

[0008] The present invention also provides a preparation method of the composite membrane with a dual fiber structure. The preparation method is simple and feasible, the raw materials are easy to obtain, and it is suitable for mass production.

[0009] Solutions for Solving the Problems

[0010] The present invention provides a composite membrane with a dual fiber structure, which includes: a first fiber layer and a second fiber layer with a porous structure. The pore diameter of the first fiber layer is 0.5 - 15 μm, and the pore diameter of the second fiber layer is 20 - 500 μm; the first fiber layer has first fiber filaments, and the diameter of the first fiber filaments is 0.1 - 5 μm; the second fiber layer has second fiber filaments, and the diameter of the second fiber filaments is 2 - 100 μm; the diameter of the first fiber filaments is smaller than the diameter of the second fiber filaments; wherein,

[0011] at least part of the first fiber filaments are filled into the second fiber layer; and,

[0012] the composite membrane also has an adhesive, and the adhesive penetrates into the pores of the first fiber layer and the second fiber layer, and bonds at least part of the first fiber filaments and the second fiber filaments through the adhesive.

[0013] Furthermore, 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 fiber structures 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 film is 0.05 to 0.3 mm;

[0017] The tensile strength of the composite film is 14 to 25 MPa;

[0018] The maximum pull-out stress of suture of the composite film 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 to 1), preferably 1:(0.1 to 0.5);

[0020] Preferably, the hydrophobic material includes one or more combinations of polylactic acid, poly-L-lactic acid, polycaprolactone, poly(lactic-co-glycolic acid), polytrimethylene carbonate, poly(L-lactide-caprolactone), polyurethane;

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

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

[0023] Furthermore, the adhesive includes a hydrophilic adhesive; preferably, the hydrophilic adhesive includes one or more combinations of chitosan or its derivatives, alginic acid or its derivatives, gelatin or its derivatives, sodium hyaluronate or its derivatives.

[0024] Furthermore, the composite film further includes a third fiber layer, the third fiber layer has third filaments, the adhesive penetrates into the pores of the third fiber layer, and at least part of the third filaments are bonded to the first filaments or the second filaments through 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 filaments is 2 to 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 filaments is 0.1 to 5 μm.

[0027] The present invention also provides a preparation method of the composite film according to the present invention, wherein the preparation method includes the step of making the adhesive penetrate the first fiber layer and the second fiber layer after the first fiber layer and the second fiber layer are composite-molded;

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

[0029] Take the non-woven fiber membrane as the second fiber layer;

[0030] Take one side of the second fiber layer as the receiving plane, and use electrospinning or melt spinning to prepare the first fiber layer to obtain a double-layer fiber membrane;

[0031] Prepare an adhesive solution, and make the adhesive solution penetrate into the first fiber layer and the second fiber layer through the surface of the first fiber layer and / or the second fiber layer to obtain a composite membrane.

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

[0033] After obtaining the double-layer fiber membrane, lay a layer of non-woven fiber membrane on the side of the first fiber layer opposite to the second fiber layer as the third fiber layer to obtain a three-layer fiber membrane; prepare an adhesive solution, and make the adhesive solution penetrate into the first fiber layer, the second fiber layer and the third fiber layer through the surface of the second fiber layer and / or the third fiber layer to obtain a composite membrane; or,

[0034] After obtaining the double-layer fiber membrane, take the side of the second fiber layer opposite to the first fiber layer as the receiving plane, and use electrospinning or melt spinning to prepare the third fiber layer to obtain a three-layer fiber membrane; prepare an adhesive solution, and make the adhesive solution penetrate into the first fiber layer, the second fiber layer and the third fiber layer through the surface of the first fiber layer and / or the third fiber layer to obtain a composite membrane.

[0035] The present invention also provides a use of the composite membrane with the double fiber structure according to the present invention in the preparation of artificial blood vessels, flow-blocking membranes for cardiac occluders, vascular mesh scaffolds or hemostatic umbrellas for vascular occluders.

[0036] Effects of the invention

[0037] The composite membrane with the double fiber structure of the present invention simultaneously includes a first fiber layer and a second fiber layer having a porous structure. The first fiber layer has a fine fiber structure, good flexibility, and a dense fiber structure, which is beneficial to cell adhesion and growth. The second fiber layer has a coarse fiber structure, and the coarse fibers can help improve the mechanical strength of the composite membrane. Moreover, some of the coarse fibers and fine fibers in the composite membrane are bonded by an adhesive, making the composite membrane not easy to delaminate and having good mechanical properties as a whole.

[0038] In the composite membrane with the double 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 a partial 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 is convenient for transportation and use through an interventional method, and has good tensile strength and maximum suture pull-out stress, and has broad application prospects in the cardiovascular field, such as being used as a flow-blocking membrane of a cardiac occluder, an artificial blood vessel, a vascular dense mesh stent or a hemostatic umbrella of a vascular occluder, etc.

[0040] The preparation method of the composite membrane with a dual-fiber structure of the present invention is simple and easy to implement, and the raw materials are easy to obtain, which is suitable for mass production. Description of the Drawings

[0041] Figure 1 Shows a photograph of the composite membrane of Example 1 of the present invention soaked in PBS buffer for 2 months.

[0042] Figure 2 Shows a schematic diagram for evaluating the adhesion degree of the double-layer structure of the composite membrane of Example 3 of the present invention, where the left figure is before peeling and the right figure is after peeling.

[0043] Figure 3 Shows a schematic diagram for evaluating the adhesion degree of the PLLA electrospun fiber membrane - PLA spunbond fiber membrane of Comparative Example 3 of the present invention.

[0044] Figure 4 Shows a scanning electron microscope image (SEM) of the composite membrane of Example 1, where the left figure is the SEM image taken from one side of the second fiber layer (spunbond fiber membrane); the right figure is the SEM image taken from one side of the first fiber layer (electrospun fiber membrane).

[0045] Figure 5 Shows a scanning electron microscope image (SEM) of the composite membrane of Example 2, where the left figure is the SEM image taken from one side of the second fiber layer (spunbond fiber membrane); the right figure is the SEM image taken from one side of the first fiber layer (electrospun fiber membrane).

[0046] Figure 6 Shows a scanning electron microscope image (SEM) of the composite membrane of Example 6, where the left figure is the SEM image taken from one side of the second fiber layer (spunbond fiber membrane); the right figure is the SEM image taken from one side of the third fiber layer (spunbond fiber membrane).

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

[0048] Figure 8 Shows a scanning electron microscope image (SEM) of the poly-lactic acid (PLA) spunbond fiber membrane of Comparative Example 2.

[0049] Figure 9Pictures showing the composite membranes of Example 3 and Example 6 implanted subcutaneously in the back of rats are presented. The left picture shows the composite membrane - 3 of Example 3, and the right picture shows the composite membrane - 6 of Example 6.

[0050] Figure 10 Pictures showing the histological section staining analysis of the composite membranes of Example 3 and Example 6 one month (1M) after being implanted subcutaneously in the back of rats are presented. The left picture shows the composite membrane - 3 of Example 3, and the right picture shows the composite membrane - 6 of Example 6.

[0051] Figure 11 Pictures showing the histological section staining analysis of the composite membranes of Example 3 and Example 6 three months (3M) after being implanted subcutaneously in the back of rats are presented. The left picture shows the composite membrane - 3 of Example 3, and the right picture shows the composite membrane - 6 of Example 6. Detailed implementation manners

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

[0053] In addition, to better illustrate the present invention, numerous specific details are given in the following detailed implementation manners. Those skilled in the art should understand that the present invention can also be implemented without some specific details. In other instances, methods, means, equipment, and steps well-known to those skilled in the art are not described in detail to highlight the gist of the present invention.

[0054] Unless otherwise stated, the units used in this specification are all international standard units, and the numerical values and numerical ranges appearing in the present invention should be understood to include the systematic errors inevitable in industrial production.

[0055] In this specification, the meaning expressed by using "can" includes both the meaning of performing a certain process and the meaning of not performing a certain process.

[0056] In this specification, the so-called "some specific / preferred implementation manners", "other specific / preferred implementation manners", "implementation manners", etc. refer to the specific elements (for example, features, structures, properties, and / or characteristics) related to the implementation manner described, which are included in at least one of the implementation manners described here, and may or may not exist in other implementation manners. In addition, it should be understood that the elements can be combined in various implementation manners in any suitable way.

[0057] In this specification, the numerical range expressed by using "numerical value A to numerical value B" refers to the range including the endpoint numerical values A and B.

[0058] In this specification, when "normal temperature" or "room temperature" is used, the temperature can be 15 to 25 °C.

[0059] <First aspect>

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

[0061] At least part of the first fiber filaments are filled into the second fiber layer; and,

[0062] The composite film also has an adhesive, the adhesive penetrates into the pores of the first fiber layer and the second fiber layer, and bonds at least part of the first fiber filaments and the second fiber filaments through the adhesive.

[0063] The composite film of the present invention has a first fiber layer and a second fiber layer with a porous structure at the same time. The first fiber layer has a fine fiber structure, good flexibility, and a dense fiber structure, which is beneficial to cell adhesion and growth. The second fiber layer has a thick fiber structure, and the thick fibers can help improve the mechanical strength of the composite film. Moreover, some of the thick fibers and fine fibers in the composite film are bonded by an adhesive, so that the composite film is not easily delaminated, has good overall mechanical properties, 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 fiber layer and the second fiber layer, so as to well bond the first fiber layer and the second fiber layer, making the composite film not easy to delaminate and having good mechanical strength; at the same time, the adhesive does not completely cover the fiber structure of the first fiber layer and / or the second fiber layer, so that the composite film 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 the present invention, the composite film has at least one of the following characteristics: the thickness of the composite film 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 film 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 suture pull-out stress of the composite film 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 film of the present invention has a relatively thin thickness, and compared with a thicker composite film, it is more convenient to be transported and used by an interventional method. The composite film of the present invention has good tensile strength and maximum suture pull-out stress, and has a wide application prospect in the field of cardiovascular stents, such as being used as a flow-blocking film of a cardiac occluder, an artificial blood vessel, a vascular dense mesh stent or a hemostatic umbrella of a vascular occluder, etc.

[0066] First fiber layer

[0067] The pore size of the first fiber layer of the present invention is 0.5 - 15 μm, the first fiber layer has first fiber filaments, and the diameter of the first fiber filaments is 0.1 - 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 hydrophobic materials. Preferably, the material of the first fiber layer of the present invention may include hydrophobic materials and hydrophilic materials. The inventors of the present invention have found that when hydrophobic materials and hydrophilic materials are used to prepare the first fiber layer, it helps to make the first fiber layer and the second fiber layer adhere more closely under the action of the adhesive, and is beneficial to improving the tensile strength of the composite film material. Therefore, in the present invention, the material of the first fiber layer includes hydrophobic materials and hydrophilic materials; the mass ratio of the hydrophobic material to the hydrophilic material is 1:(0-1), preferably 1:(0.1-0.5), 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 a combination of two or more of polylactic acid (PLA), poly-L-lactic acid (PLLA), polycaprolactone (PCL), poly(lactic-co-glycolic acid) (PLGA), polytrimethylene carbonate (PTMC), poly(L-lactide-co-caprolactone) (PLCL), polyurethane; the hydrophilic material includes one or a combination of two or more of collagen, gelatin or its derivatives, polyethylene glycol, polyvinyl alcohol, sodium hyaluronate, alginate.

[0070] Second fiber layer

[0071] The pore size of the second fiber layer of the present invention is 20-500 μm, the second fiber layer has second fiber filaments, and the diameter of the second fiber filaments is 2-100 μm; preferably, the second fiber layer is a non-woven fiber membrane. By using coarser fibers with a larger diameter than the first fiber filaments, the mechanical properties of the composite film can be improved in the present invention.

[0072] Regarding the material of the second fiber layer, the present invention is not particularly limited and may be materials commonly used in the art. Specifically, the material of the second fiber layer includes one or a combination of two or more of polylactic acid, polyethylene terephthalate, polypropylene, polyamide.

[0073] Specifically, at least part of the first fiber filaments of the present invention are filled into the second fiber layer, which is beneficial to tightly combining the first fiber layer and the second fiber layer together.

[0074] Adhesive

[0075] The composite film of the present invention further has an adhesive, and the adhesive penetrates into the pores of the first fiber layer and the second fiber layer, and bonds at least part of the first filaments and the second filaments through the adhesive. By using the adhesive, the present invention obtains a composite film with a more tightly combined double-layer fiber structure.

[0076] In some specific embodiments, the adhesive includes a hydrophilic adhesive. By using the hydrophilic adhesive, the present invention enables the adhesive to penetrate into the pores of the first fiber layer and the second fiber layer. Preferably, the hydrophilic adhesive includes one or a combination of two or more of chitosan or its derivatives, alginic acid or its derivatives, gelatin or its derivatives, sodium hyaluronate or its derivatives.

[0077] Other fiber layers

[0078] In the present invention, the composite film may further include a third fiber layer to form a three-layer composite film with the first fiber layer and the second fiber layer. The third fiber layer has third filaments, and the adhesive penetrates into the pores of the third fiber layer, and bonds at least part of the third filaments to the first filaments or the second filaments through 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 filaments is 2 to 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 filaments is 0.1 to 5 μm.

[0079] Further, in the present invention, the third fiber layer may be the same as or similar to the first fiber layer, or may be the same as or similar to the second fiber layer, which will not be elaborated herein. 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 the present invention have found that using a third fiber layer to form a three-layer composite film with the first fiber layer and the second fiber layer, and filling the adhesive in the pores between the fiber layers to connect the fiber layers, can make the overall fiber structure of the composite film more dense, which is beneficial to the closer fitting between the fiber layers and not easy to delaminate, and the adhesive does not completely cover the fiber structures of the first fiber layer and / or the second fiber layer and / or the third fiber layer, retaining the three-dimensional fiber network structure beneficial to cell adhesion and proliferation, so that it has good biocompatibility.

[0081] When the composite film 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] The second aspect of the present invention provides a method for preparing the composite film described in the first aspect. The preparation method includes the step of making the adhesive penetrate the first fiber layer and the second fiber layer after the first fiber layer and the second fiber layer are compounded and formed. The preparation method of the present invention is simple and easy to implement, the raw materials are easy to obtain, and it is suitable for mass production.

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

[0085] Use the non-woven fiber membrane as the second fiber layer;

[0086] Use one side of the second fiber layer as the receiving plane, and use electrospinning or melt spinning to prepare the first fiber layer to obtain a double-layer fiber membrane;

[0087] Prepare an adhesive solution, and make the adhesive solution penetrate into the first fiber layer and the second fiber layer through the surface of the first fiber layer and / or the second fiber layer to obtain a composite film.

[0088] For the non-woven fiber membrane, it can be obtained by purchasing commercially or prepared. Specifically, the preparation process of the non-woven fiber membrane can include one or a combination of two or more of spunbonding, meltblowing, thermal bonding, stitch bonding, hydroentangling, needling, and pulp air laying.

[0089] For the first fiber layer, it can be prepared on one side of the second fiber layer as the receiving plane by using electrospinning or melt spinning 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 during the electrospinning process, a high voltage is applied to the polymer liquid to introduce charges into the liquid. When the charges in the liquid accumulate to a certain amount, a Taylor cone will form at the nozzle. Under the action of the external electric field force, the surface tension is overcome 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 drawn in a very short time. As the solvent evaporates or heat dissipates, the polymer jet solidifies to form micro / nano fibers. During the electrospinning process, many parameters will affect the final electrospun fibers. By controlling the process parameters, micro / nano fibers with different sizes, morphologies, and structures can be prepared.

[0091] Furthermore, when performing electrospinning, the fiber raw material can be prepared in advance and dissolved in the first solvent to prepare a spinning dope of the fiber raw material with a certain concentration. Among them, the fiber raw material can be the raw material of the first fiber layer described in the first aspect.

[0092] During the electrospinning process of the present invention, the process parameters will affect the first fiber layer obtained by electrospinning. By controlling the process parameters, a support layer with different sizes, morphologies, and structures can be prepared. The present invention has no special requirements for the electrospinning method, and it can be a common electrospinning method in the art. Specifically, the conditions for electrospinning in the present invention are as follows: Place the spinning dope in an electrospinning syringe, adjust the liquid propulsion speed of the micro-injection pump to 6 - 10 mL / h, adjust the voltage of the high-voltage generator to 18 - 32 kV, adjust the receiving distance of the receiving device to 18 - 25 cm, perform electrospinning, and the electrospinning time is 10 - 60 min, thereby obtaining an electrospun fiber membrane, which is the first fiber layer.

[0093] Furthermore, the adhesive solution can be obtained by dissolving the adhesive in a solvent. The present invention does not make special limitations on the solvent, as long as it can dissolve the adhesive. Specifically, it can be water and / or acetic acid solution with a volume concentration of 0.1 - 5%. The present invention does not make special limitations on the concentration of the adhesive in the adhesive solution, as long as it can penetrate the first fiber layer and the second fiber layer. The mass concentration can generally be 5 - 100 mg / mL.

[0094] Specifically, one or a combination of two or more of spreading, coating, casting, spraying, etc. can be used, so that the adhesive solution penetrates into the first fiber layer and the second fiber layer through the surface of the first fiber layer and / or the second fiber layer to obtain a composite membrane.

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

[0096] After obtaining the double-layer fiber membrane, lay a layer of non-woven fiber membrane on the side of the first fiber layer opposite to the second fiber layer as the third fiber layer to obtain a three-layer fiber membrane; prepare an adhesive solution, and make the adhesive solution penetrate into the first fiber layer, the second fiber layer, and the third fiber layer through the surface of the second fiber layer and / or the third fiber layer to obtain a composite membrane; or,

[0097] After obtaining the double-layer fiber membrane, use the side of the second fiber layer opposite to the first fiber layer as the receiving plane, and use electrospinning or melt spinning to prepare the third fiber layer to obtain a three-layer fiber membrane; prepare an adhesive solution, and make the adhesive solution penetrate into the first fiber layer, the second fiber layer, and the third fiber layer through the surface of the first fiber layer and / or the third fiber layer to obtain a composite membrane.

[0098] Finally, perform post-treatment on the composite membrane, such as drying, cleaning, drying, etc., so as to obtain the required composite membrane with a double-layer fiber structure.

[0099] <Third aspect>

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

[0101] Examples

[0102] The following will describe the implementation schemes of the present invention in detail in conjunction with examples. However, those skilled in the art will understand that the following examples are only used to illustrate the present invention and should not be regarded as limiting the scope of the present invention. For those not specified in the examples, they are carried out under conventional conditions or conditions recommended by the manufacturer. Those reagents or instruments not specified in the manufacturer are all conventional products that can be obtained through commercial purchase.

[0103] Example 1

[0104] (1) Use a polylactic acid (PLA) spunbond fiber membrane with a size of 20 cm × 8 cm (thickness: 0.08 mm, mass: 0.25 g, pore size: 30 - 120 μm, fiber filament diameter: 5 - 30 μm) as the second fiber layer, and lay it flat on a metal plate as the electrospinning receiving plane;

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

[0106] (3) Dissolve 0.1 g of chitosan in 3 mL of acetic acid-water (2%, v / v) solution to obtain an adhesive solution, and uniformly coat one side of the spunbond fiber membrane in the double-layer fiber membrane described in step (2). Since the spunbond fiber membrane has a larger pore size, the adhesive easily penetrates into the gaps between the double-layer fiber membranes. After uniform coating, dry, wash, and bake to obtain composite film-1. After testing, the average thickness of the composite film is 0.13 mm.

[0107] Example 2

[0108] (1) Use a poly(lactic acid) (PLA) spunbond fiber membrane with dimensions of 20 cm × 8 cm (thickness: 0.08 mm, mass: 0.25 g, pore size: 30 - 120 μm, fiber diameter: 5 - 30 μm) as the second fiber layer, and lay it flat on a metal plate as the electrospinning receiving plane;

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

[0110] (3) Dissolve 0.1 g of chitosan in 3 mL of acetic acid-water (2%, v / v) solution to obtain an adhesive solution, and uniformly coat one side of the spunbond fiber membrane in the double-layer fiber membrane described in step (2). Since the spunbond fiber membrane has a larger pore size, the adhesive easily penetrates into the gaps between the double-layer fiber membranes. After uniform coating, dry, wash, and bake to obtain composite film-2. After testing, the average thickness of the composite film is: 0.13 mm.

[0111] Example 3

[0112] Only replace the "polylactic acid (PLA) spunbond fiber membrane (thickness: 0.08 mm, mass: 0.25 g, pore size: 30 - 120 μm, fiber filament 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 filament diameter: 5 - 30 μm)", and keep the other steps the same as those in Example 1 to obtain composite film - 3. After testing, the average thickness of the composite film is 0.09 mm.

[0113] Example 4

[0114] Only replace the "polylactic acid (PLA) spunbond fiber membrane (thickness: 0.08 mm, mass: 0.25 g, pore size: 30 - 120 μm, fiber filament 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 filament diameter: 5 - 30 μm)", and keep the other steps the same as those in Example 2 to obtain composite film - 4. After testing, the average thickness of the composite film is 0.09 mm.

[0115] Example 5

[0116] Only replace the "spinning dope is a hexafluoroisopropanol solution of poly(L - lactic acid) (PLLA) with a concentration of 80 mg / mL" described in step (2) of Example 1 with "spinning dope is a hexafluoroisopropanol solution of polycaprolactone (PCL) with a concentration of 80 mg / mL", and keep the other steps the same as those in Example 1 to obtain composite film - 5. After testing, the average thickness of the composite film is 0.11 mm.

[0117] Example 6

[0118] (1) Use a polylactic acid (PLA) spunbond fiber membrane with dimensions of 21 cm × 7 cm (thickness: 0.04 mm, mass: 0.15 g, pore size: 20 - 200 μm, fiber filament diameter: 5 - 30 μm) as the second fiber layer, and lay it flat on a metal plate as the electrospinning receiving plane;

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

[0120] (3) Dissolve 0.1 g of chitosan in 3 mL of acetic acid-water (2%, v / v) solution to obtain an adhesive solution. Take 2 mL of the adhesive solution and evenly coat one side of the spunbond 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;

[0121] (4) Take a poly(lactic acid) (PLA) spunbond fiber membrane with 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-layer fiber membrane, add 2 mL of the same adhesive solution as in step (3) for coating, wait for the adhesive solution to penetrate, dry, wash, and bake to obtain composite film - 6. After testing, the average thickness of the composite film is 0.12 mm.

[0122] Example 7

[0123] (1) Take a poly(lactic acid) (PLA) spunbond fiber membrane with dimensions of 21 cm × 7 cm (thickness: 0.04 mm, mass: 0.17 g, pore size: 20 - 200 μm, fiber filament diameter: 5 - 30 μm) as the second fiber layer, and lay it flat on a metal plate as the electrospinning receiving plane;

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

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

[0126] (4) Dissolve 0.2 g of chitosan in 6 mL of acetic acid-water (2%, v / v) solution to obtain an adhesive solution. Coat 2 mL of the adhesive solution on 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 membranes. After uniform coating, dry, wash, and bake to obtain composite membrane - 7. After testing, the average thickness of the composite membrane is 0.13 mm.

[0127] Example 8

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

[0129] (2) Perform electrospinning on the spinning dope on the receiving plane described in step (1). Among them, the spinning dope is a hexafluoroisopropanol solution of poly-L-lactic acid (PLLA) with a concentration of 80 mg / mL. Place the spinning dope in an electrospinning syringe, adjust the voltage of the high-voltage generator to 21 kV, adjust the liquid propulsion speed of the micro-injection pump to 8 mL / h, adjust the receiving distance of the receiving device to 20 cm, and the electrospinning time is 30 min (the mass of the electrospun fiber membrane excluding the loss part is 0.3 g, pore size: 0.5 - 10 μm, fiber filament diameter: 0.2 - 2 μm) to prepare an electrospun fiber membrane as the first fiber layer and obtain a double-layer fiber membrane.

[0130] (3) Dissolve 0.1 g of chitosan in 3 mL of acetic acid-water (2%, v / v) solution to obtain an adhesive solution, and uniformly coat it on one side of the spunbond 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 with 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-layer fiber membrane, add 3 mL of the same adhesive solution as in step (3) for coating, wait for the adhesive to penetrate, dry, wash, 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) Use a polylactic acid (PLA) spunbond fiber membrane with dimensions of 20 cm × 8 cm (thickness: 0.08 mm, mass: 0.25 g, pore size: 30 - 120 μm, fiber diameter: 5 - 30 μm) as the second fiber layer, and lay it flat on a metal plate as the electrospinning receiving plane;

[0134] (2) Electrospin the spinning dope on the receiving plane described in step (1). Among them, the spinning dope is a hexafluoroisopropanol solution of poly-L-lactic acid (PLLA) with a concentration of 80 mg / mL. Place the spinning dope in an electrospinning syringe, adjust the voltage of the high-voltage generator to 21 kV, adjust the liquid propulsion speed of the micro-injection pump to 8 mL / h, adjust the receiving distance of the receiving device to 20 cm, and the electrospinning time to 20 min (the mass of the electrospun fiber membrane excluding the loss part is 0.2 g, pore size: 0.5 - 10 μm, fiber diameter: 0.2 - 2 μm), to obtain an electrospun fiber membrane as the first fiber layer, and obtain a double-layer fiber membrane;

[0135] (3) Use the other surface of the spunbond fiber membrane described in step (1) as the receiving plane, start electrospinning, and the electrospinning experimental parameters and time are the same as those in step (2), to prepare the third fiber layer and obtain a three-layer fiber membrane;

[0136] (4) Dissolve 0.2 g of chitosan in 6 mL of acetic acid - water (2%, v / v) solution to obtain an adhesive solution. Coat 3 mL of the adhesive solution on 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 membranes. After coating evenly, dry, wash, and bake to obtain composite membrane - 9. After testing, the average thickness of the composite membrane is 0.24 mm.

[0137] Example 10

[0138] (1) Use a polylactic acid (PLA) spunbond fiber membrane with dimensions of 20 cm × 8 cm (thickness: 0.08 mm, mass: 0.25 g, pore size: 30 - 120 μm, fiber diameter: 5 - 30 μm) as the second fiber layer, and lay it flat on a metal plate as the electrospinning receiving plane;

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

[0140] (3) Dissolve 0.1 g of chitosan in 3 mL of acetic acid-water (2%, v / v) solution to obtain an adhesive solution, and uniformly coat one side of the spunbond 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 poly(lactic acid) (PLA) spunbond fiber membrane with 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-layer fiber membrane, add 3 mL of the same adhesive solution as in step (3) for coating, wait for the adhesive to penetrate, dry, wash, and bake to obtain composite film - 10. After testing, the average thickness of the composite film is: 0.19 mm.

[0142] Example 11

[0143] (1) Take a poly(lactic acid) (PLA) spunbond fiber membrane with a size of 20 cm × 8 cm (thickness: 0.08 mm, mass: 0.25 g, pore size: 30 - 120 μm, fiber diameter: 5 - 30 μm) as the second fiber layer, and lay it flat on a metal plate as an electrospinning receiving plane;

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

[0145] (3) using the other surface of the spunbond fiber membrane in step (1) as a receiving plane, starting electrospinning, the experimental parameters and time of electrospinning are the same as those in step (2), preparing a third fiber layer, and obtaining a three-layer fiber membrane;

[0146] (4) 0.2 g of chitosan was dissolved in 6 mL of acetic acid-water (2%, v / v) solution to obtain an adhesive solution, and 3 mL of the adhesive solution was applied to the two surfaces of the three-layer fiber membrane in step (3) respectively. The adhesive solution penetrated into the gaps between the three-layer fiber membranes, and after being evenly applied, it was dried, cleaned, and dried to obtain a composite membrane-11. After testing, the average thickness of the composite membrane was 0.20 mm.

[0147] Example 12

[0148] Only the "spinning solution is a hexafluoroisopropanol solution of poly-L-lactic acid (PLLA) with a concentration of 80 mg / mL" in step (2) of Example 8 was replaced with "spinning solution is a hexafluoroisopropanol solution of poly-caprolactone (PCL) with a concentration of 80 mg / mL", and the remaining steps were the same as Example 8 to obtain composite membrane-12. After testing, the average thickness of the composite membrane was 0.21 mm.

[0149] Embodiment 13

[0150] Only the "spinning solution is a hexafluoroisopropanol solution of poly-L-lactic acid (PLLA) with a concentration of 80 mg / mL" in step (2) of Example 9 is replaced by "the spinning solution is a hexafluoroisopropanol solution of poly-caprolactone (PCL) with a concentration of 80 mg / mL", and the remaining steps are the same as Example 9. After testing, the average thickness of the three-layer film is 0.20 mm.

[0151] Comparative Example 1

[0152] Prepare a hexafluoroisopropanol solution of poly L-lactic acid (PLLA) with a concentration of 80 mg / mL and add it to the syringe of the electrospinning device for electrospinning. Adjust the voltage of the high-voltage generator to 21 kV, adjust the liquid propulsion speed of the microinjection pump to 8 mL / h, adjust the receiving distance of the receiving device to 20 cm, and the electrospinning time to 45 minutes. Use the receiver of the electrospinning device to receive the fiber into a membrane structure, and the obtained poly L-lactic acid (PLLA) electrospun fiber membrane has 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 to 110 μm, a fiber diameter of 5 to 30 μm, and an average thickness of 0.16 mm.

[0155] Comparative Example 3

[0156] (1) Lay a polylactic acid (PLA) spunbond fiber membrane with dimensions of 20 cm × 8 cm (thickness: 0.04 mm, mass: 0.15 g, pore size: 20 - 200 μm, fiber diameter: 5 - 30 μm) flat on a metal plate as the electrospinning receiving plane;

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

[0158] Comparative Example 4

[0159] (1) Lay a polylactic acid (PLA) spunbond fiber membrane with dimensions of 20 cm × 8 cm (thickness: 0.04 mm, mass: 0.15 g, pore size: 20 - 200 μm, fiber diameter: 5 - 30 μm) flat on a metal plate as the electrospinning receiving plane;

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

[0161] Performance test

[0162] 1. Immersion Test

[0163] Immerse the composite membrane - 1 of Example 1 in PBS, place it in an incubator at 37°C for 2 months, take it out, and observe the changes in the composite membrane. The results are as follows Figure 1As shown in the figure. The results show that there is no obvious change on the surface of the composite membrane after two months of immersion, and no delamination occurs. The electrospun fiber membrane and the spunbond fiber membrane still adhere tightly, indicating that the two fiber membranes are tightly bonded. Even when in long-term contact with body fluids or blood, the possibility of the composite membrane separating is relatively small.

[0164] 2. Adhesion evaluation

[0165] When trying to completely peel off the spunbond fiber membrane and the electrospun fiber membrane of the composite membrane - 3 in Example 3 by hand, it was found that the two adhered tightly and could not be completely separated, as Figure 2 shown.

[0166] When trying to completely peel off the spunbond fiber membrane and the electrospun fiber membrane of the composite membranes in other examples by hand, the same results as above were obtained.

[0167] When peeling off the PLLA electrospun fiber membrane - PLA spunbond fiber membrane of Comparative Example 3 by hand, it was found that the two fiber membranes could be well separated, as Figure 3 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 glued tightly to the surface of the conductive stage with conductive adhesive, and then sputter-coated with gold. 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 Figures 4 - 8 shown.

[0170] From Figures 4 - 6 it can be seen that the fiber structures are clearly retained on both surfaces of the composite membranes prepared in Examples 1, 2, and 6 of the present invention, and are not completely covered by the adhesive, which is helpful for cell adhesion and proliferation. Therefore, the composite membranes have good cell compatibility.

[0171] From Figure 7 and Figure 8 it can be seen respectively that the fiber diameter of the PLLA electrospun fiber membrane of Comparative Example 1 is relatively thin, and the fiber diameter of the PLA spunbond fiber membrane of Comparative Example 2 is relatively thick.

[0172] 4. Mechanical properties

[0173] Tensile property and suture property tests of the fiber membranes

[0174] Membrane materials to be tested:

[0175] Composite film - 3 of Example 3, Composite film - 4 of Example 4, Composite film - 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, PLLA / gelatin fiber membrane - PLA spunbond fiber membrane of Comparative Example 4.

[0176] Referring to the test conditions of the third part of GB / T 1040.3 - 2006: Films and sheets, the film material to be tested was cut into strip - shaped samples of 60 mm×10 mm for tensile property testing. The test speed was 200 mm / min and the gauge length was 40 mm. The results are shown in Table 1 below.

[0177] The test method for the suture pull - out stress was as follows: The film material to be tested was cut into strip - shaped samples of 30 mm×10 mm. A nylon suture (4 - 0) was passed through a position 5 - 10 mm from one end of the strip - shaped sample, and the other end of the suture and the strip - shaped sample were fixed. The stretching program was started, and the maximum force measured was the maximum suture pull - out stress. The test results are shown in Table 1 below:

[0178] Table 1

[0179]

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

[0181] On the basis of Example 3, in Example 4, gelatin was added to the electrospun fiber membrane for blending with PLLA. The tensile strength of the obtained Composite film - 4 was significantly higher than that of Composite film - 3, indicating that adding hydrophilic materials to the electrospun fiber membrane is beneficial to improving the tensile strength of the composite film.

[0182] For the composite films of Comparative Examples 3 and 4, only double - layer fiber membranes were electrospun on the spunbond fiber membrane without using adhesives for bonding. The obtained composite films could not simultaneously have good tensile strength and maximum suture pull - out stress; while in Examples 3 and 4 of the present invention, adhesives were used to bond the electrospun fiber membranes and spunbond fiber membranes of Comparative Examples 3 and 4 respectively, and the obtained composite films simultaneously had good tensile strength and maximum suture pull - out stress.

[0183] In addition, other composite films prepared by the present invention can also simultaneously have good tensile strength and maximum suture pull - out stress. The tensile strength is 14 - 25 Mpa, and the maximum suture pull - out stress is 3.5 - 7 N.

[0184] 5. Cytotoxicity experiment

[0185] The cytotoxicity of the composite film was evaluated according to GB / T 16886.5-2017 "Biological evaluation of medical devices - Part 5: Tests for in vitro cytotoxicity". Specifically, the test film materials (the composite film-1 of Example 1 and the composite film-8 of Example 8) were used for the experiment. The extraction ratios of the composite film-1 of Example 1 and the composite film-8 of Example 8 to the cell culture medium were 6 cm 2 / mL, and the extraction was carried out for 72 h. The extracted solution diluted by a certain multiple was contacted with L929 cells (10,000 cells / well), and cultured for 48 h. After staining the cells with an MTT kit, the optical density was measured with an ultraviolet spectrophotometer. Negative control group: 100% extracted solution of high-density polyethylene; positive control group: DMSO, and the blank control group was the cell culture medium. Through calculation, the results of the cell survival rate are as follows:

[0186] Table 2

[0187]

[0188] It can be seen from the data in Table 2 that the cell survival rates of the composite film-1 of Example 1 and the composite film-8 of Example 8 are higher than 70% of the blank control group. Therefore, the composite film of the present invention has no cytotoxicity and meets the cell compatibility requirements of medical devices.

[0189] 6. Subcutaneous implantation experiment

[0190] Experimental animals: SD rats

[0191] Samples: The composite film-3 prepared in Example 3; the composite film-6 prepared in Example 6.

[0192] Experimental protocol: Refer to GB / T 16886.11-2011 for the subcutaneous implantation experiment.

[0193] Specific protocol: Two to three cavities were made on each side of the subcutaneous area on the back of the rats, with an interval of about 1-2 cm. A composite film with a size of 1.0 cm × 0.5 cm was implanted into each cavity. After implantation, the animals were dissected at two time points of 1 and 3 months, and then the degradation of the material and the condition of the subcutaneous tissue of the rats were observed. The results are shown in Figures 9-11.

[0194] Result analysis:

[0195] From Figure 9 and 10It can be seen that after 1 month of subcutaneous implantation in rats, Composite Membrane-3: The material is relatively intact, with visible coarse fiber layers and red fine fiber layers, no obvious thickening of fibrous tissue, macrophages and multinucleated giant cells can be seen beside it, and a dense collagen fiber layer forms around it for wrapping; Composite Membrane-6: The material is relatively intact, with coarse fiber layers and red fine fiber layers visible, no obvious thickening of fibrous tissue, macrophages and multinucleated giant cells can be seen beside it, and a collagen fiber layer forms around it for wrapping and there are newly formed small blood vessels.

[0196] It can be seen from Figure 9 and 11 that after 3 months of subcutaneous implantation in rats, the appearances of Composite Membrane-3 and Composite Membrane-6 are relatively intact, the composite membranes are not significantly embrittled, and they are not easily broken when stretched, and there is newly formed tissue on the surfaces of both membranes.

[0197] Thus, it can be seen that Composite Membrane-3 and Composite Membrane-6 have good biocompatibility, and their structures are relatively intact after 3 months of implantation, and they are not embrittled and not easily broken when stretched. Therefore, the composite membrane of the present invention has great application potential in cardiovascular materials (such as artificial blood vessels, flow-blocking membranes).

[0198] It should be noted that although the technical solutions of the present invention are introduced with specific examples, those skilled in the art can understand that the present invention should not be limited thereto.

[0199] The above has described the embodiments of the present invention. The above description is exemplary, not exhaustive, and is not limited to the disclosed embodiments. Many modifications and variations are obvious to those of ordinary skill in the art in the technical field without departing from the scope and spirit of the described embodiments. The choice of terms used herein is intended to best explain the principles of the embodiments, practical applications, or improvements to technologies in the market, or to enable other ordinary skilled persons in the technical field to understand the embodiments disclosed herein.

Claims

1. A composite membrane with a dual-fiber structure, characterized in that, Comprising: A first fiber layer and a second fiber layer having a porous structure, the pore size of the first fiber layer being 0.5 to 15 μm, and the pore size of the second fiber layer being 20 to 500 μm; the first fiber layer having first filaments with a diameter of 0.1 to 5 μm; the second fiber layer having second filaments with a diameter of 2 to 100 μm; the diameter of the first filaments being smaller than the diameter of the second filaments; wherein, At least a part of the first filaments is filled into the second fiber layer; and, The composite film further has an adhesive, the adhesive penetrating into the pores of the first fiber layer and the second fiber layer, and bonding at least a part of the first filaments and the second filaments through the adhesive.

2. The 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 to 3):(0.1 to 1), preferably 1:(0.5 to 2):(0.4 to 0.8); and / or The adhesive does not completely cover the fiber structure of the first fiber layer and / or the second fiber layer.

3. The composite film according to claim 1 or 2, characterized in that, The composite film has at least one of the following characteristics: The thickness of the composite film is 0.05 to 0.3 mm; The tensile strength of the composite film is 14 to 25 MPa; The maximum pull-out stress of suture of the composite film is 3.5 to 7.0 N.

4. The composite film according to any one of claims 1 to 3, 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 to 1), preferably 1:(0.1 to 0.5); Preferably, the hydrophobic material includes one or more combinations of polylactic acid, poly-L-lactic acid, polycaprolactone, poly(lactic-co-glycolic acid), polytrimethylene carbonate, poly(L-lactide-co-caprolactone), polyurethane; More preferably, the hydrophilic material includes one or more combinations of collagen, gelatin or its derivatives, polyethylene glycol, polyvinyl alcohol, sodium hyaluronate, alginate.

5. The composite film according to any one of claims 1-4, characterized in that, The material of the second fiber layer includes one or more combinations of polylactic acid, polyethylene terephthalate, polypropylene, polyamide.

6. The composite film according to any one of claims 1-5, characterized in that, The adhesive includes a hydrophilic adhesive; preferably, the hydrophilic adhesive includes one or more combinations of chitosan or its derivatives, alginic acid or its derivatives, gelatin or its derivatives, sodium hyaluronate or its derivatives.

7. The composite film according to any one of claims 1-6, characterized in that, The composite film further includes a third fiber layer having third filaments, the adhesive penetrating into the pores of the third fiber layer, and bonding at least a part of the third filaments to the first filaments or the second filaments through 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 filaments is 2 to 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 filaments is 0.1 to 5 μm.

8. A method for preparing a composite film according to any one of claims 1-7, characterized in that, The preparation method includes the steps of laminating and molding the first fiber layer and the second fiber layer, and then allowing the adhesive to penetrate the first fiber layer and the second fiber layer; Preferably, the preparation method comprises the following steps: Using the non-woven fiber membrane as the second fiber layer; Using one side of the second fiber layer as the receiving plane, and preparing the first fiber layer by electrospinning or melt spinning to obtain a double-layer fiber membrane; Preparing an adhesive solution, and allowing the adhesive solution to penetrate into the first fiber layer and the second fiber layer through the surface of the first fiber layer and / or the second fiber layer to obtain a composite membrane.

9. The preparation method according to claim 8, wherein The preparation method further comprises the following steps: After obtaining the double-layer fiber membrane, laying a layer of non-woven fiber membrane on the side of the first fiber layer opposite to the second fiber layer as the third fiber layer to obtain a three-layer fiber membrane; preparing an adhesive solution, and allowing the adhesive solution to penetrate into the first fiber layer, the second fiber layer and the third fiber layer through the surface of the second fiber layer and / or the third fiber layer to obtain a composite membrane; or After obtaining the double-layer fiber membrane, using the side of the second fiber layer opposite to the first fiber layer as the receiving plane, and preparing the third fiber layer by electrospinning or melt spinning to obtain a three-layer fiber membrane; preparing an adhesive solution, and allowing the adhesive solution to penetrate into the first fiber layer, the second fiber layer and the third fiber layer through the surface of the first fiber layer and / or the third fiber layer to obtain a composite membrane.

10. Use of the composite membrane with a dual fiber structure according to any one of claims 1-7 for preparing an artificial blood vessel, a flow-blocking membrane of a cardiac occluder, a vascular dense mesh stent or a hemostatic umbrella of a vascular occluder.

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