Plugging device based on plugging film with surface microstructure and anti-coagulation coating and preparation method of plugging device

Abstract

The invention discloses a plugging device based on a plugging film with a surface microstructure and an anti-coagulation coating and a preparation method of the plugging device. The preparation method comprises the following steps: (1) designing and processing a metal template with a convex shape consistent with the appearance of the microstructure; meanwhile, the surface of the unstructured plugging film is treated, and an epoxy phosphorylcholine-containing polymer is grafted by introducing amino; (2) the obtained blocking film is placed on a heating table, the protruding morphology side of a metal template is attached to the blocking film, pressurization is conducted, meanwhile, heating is conducted through the heating table, and the metal template is rapidly soaked in ethyl alcohol to be cooled, fix patterns and dried after heating is completed; 3) preparing the plugging film obtained in the step 2) into a plugging device; according to the method, the microstructure and the coating are formed on the plugging film at the same time through one-step treatment, the preparation process of the corresponding plugging device structure is greatly simplified, repeatability is good, and the property is stable.

Description

Technical Field

[0001] The present invention belongs to the technical field of medical device preparation, and relates to an occluder and a preparation method thereof, and in particular to an occluder based on an occluding membrane with both a surface microstructure and an anticoagulant coating and a preparation method thereof. Background Art

[0002] Catheter interventional occlusion can prevent cardiovascular diseases such as those associated with stroke and congenital heart disease. Although traditional anticoagulant therapy can reduce the risk of thromboembolism, long-term use of anticoagulants may lead to risks such as massive bleeding. Catheter interventional occlusion can not only reduce or avoid the need for long-term anticoagulant therapy and reduce the risk of bleeding, but is also suitable for patients who cannot take anticoagulants for a long time. However, existing cardiac occluders such as left atrial appendage occluders, foramen ovale occluders, atrial septal defect occluders, and ventricular septal defect occluders often have poor surface blood compatibility after implantation, which may trigger blood coagulation and cause thrombus formation on their surface. If these thrombi are not removed through drug treatment, they may fall off and flow with the blood, causing more serious complications. Therefore, these occluders usually require a period of anticoagulant therapy after implantation, which is a major challenge for patients who are not suitable for anticoagulant drugs. At the same time, endothelial cells have poor adhesion and migration on the surface of the occluder disc, resulting in long endothelialization time and incomplete endothelialization. Therefore, the development of an occluder that can prevent surface coagulation early and accelerate endothelialization has important value and huge market potential for clinical applications. Summary of the invention

[0003] The purpose of the present invention is to solve the problems of easy induction of coagulation reaction and slow endothelialization in existing occluder devices, and to provide an occluder based on an occluding membrane with both surface microstructure and anticoagulant coating and a preparation method thereof. The method realizes the one-step preparation of an occluding membrane with both surface topological microstructure and anticoagulant coating through process design and regulation, which can effectively improve the anticoagulant performance and accelerate the endothelialization performance of the occluder.

[0004] In order to achieve the above object, the technical solution adopted by the present invention is as follows:

[0005] A method for preparing an occluder based on an occluding membrane having both a surface microstructure and an anticoagulant coating, comprising the following steps:

[0006] 1) Designing the topological groove shape of the required surface microstructure, obtaining a microstructure design drawing, and processing a metal template having a convex morphology consistent with the topological groove shape according to the drawing; and treating the surface of the structureless plugging membrane by introducing an amino-grafted epoxy phosphorylcholine polymer;

[0007] 2) placing the obtained blocking film on a hot stage, ensuring that the surface in contact with the hot stage is the surface grafted with the epoxy phosphorylcholine polymer, placing the raised morphology side of the metal template on the blocking film, applying pressure on the back of the metal template, and heating the hot stage to make the metal template and the blocking film closely fit, and then quickly immersing it in ethanol to cool and fix the pattern, and drying it to obtain a blocking film with both surface microstructure and anticoagulation coating;

[0008] 3) The occluding membrane obtained in 2) is sewn into the occluding frame according to the occluding device manufacturing method to prepare an occluding disk, thereby obtaining an occluding device based on the occluding membrane with both surface microstructure and anticoagulant coating.

[0009] In the above technical solution, further, the surface of the structureless plugging membrane is treated, specifically including the following:

[0010] (1) Pretreatment of the surface of the structureless plugging membrane with oxygen plasma;

[0011] (2) subjecting the plugging membrane obtained in (1) to aminosilane chemical grafting, cleaning the surface of the plugging membrane, and then subjecting the surface of the plugging membrane to heat treatment to obtain a plugging membrane having amino-reactive functional groups on the surface;

[0012] (3) grafting the plugging membrane obtained in (2) with an epoxy phosphorylcholine polymer;

[0013] Furthermore, the parameters of the oxygen plasma pretreatment in (1) are power 100-600W, gas flow rate 2-300mL / min, and treatment time 1-60 minutes. More preferably, the parameters are power 100-300W, gas flow rate 100-300mL / min, and treatment time 10-30 minutes.

[0014] Furthermore, the epoxy phosphorylcholine polymer is an MPC (2-methacryloyloxyethyl phosphorylcholine)-GMA (glycidyl methacrylate) copolymer, and its preparation method is to prepare MPC into solution A; prepare GMA into solution B; dissolve the initiator AIBN into solution C for standby; fill the receiving tank and the reaction pipeline with inert gas, and allow solution A and solution B to enter the reaction pipeline through a three-dimensional plunger pump respectively, and merge at the first three-way mixer to form a mixed solution; allow solution C to enter the reaction pipeline through a three-dimensional plunger pump, and merge with the mixed solution at the second three-way mixer to form a reaction liquid, and the reaction liquid flows into the heating zone reaction pipeline, and then flows into the receiving tank to obtain a polymerization product, which is the purified and dried MPC-GMA polymer.

[0015] Further, the above (2) is specifically as follows: immersing the structureless plugging film after oxygen plasma pretreatment in an ethanol mixed solution of aminosilane for reaction for 1-24 hours; wherein the volume concentration of the ethanol aqueous solution of aminosilane is 10%-100%, the volume concentration of aminosilane is 1%-30%, and the reaction temperature is 10°C-120°C. The aminosilane is selected from one or more of 3-aminopropyltrimethylsilane, 3-aminopropyltriethoxysilane, N-(aminoethyl)-aminopropyltrimethoxysilane, N-(aminoethyl)-aminopropylmethyldimethoxysilane, N-(aminoethyl)-aminopropyltriethoxysilane, N-(aminoethyl)-aminopropyltriethoxysilane, and diethylenetriaminopropyltrimethoxysilane. More preferably, the structureless plugging membrane is immersed in an ethanol mixed solution of aminosilane for reaction for 1-3 hours, the volume concentration of ethanol is 50%-80%, the volume concentration of aminosilane is 5%-20%, and the reaction temperature is 60°C-80°C.

[0016] Furthermore, the cleaning liquid in (2) can be one or more of ethanol, toluene, deionized water, methanol, isopropanol, n-butanol, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), ethyl acetate, PM acetate, toluene, chloroform, and dichloromethane, and the cleaning is performed 1-5 times; the heat treatment is performed at 10°C-120°C for 5-120 minutes. More preferably, the cleaning liquid is ethanol, the heat treatment temperature is 60-80°C, and the treatment time is 15-30 minutes.

[0017] Furthermore, (3) is specifically as follows: placing the blocking membrane after grafting with amino groups into a solution containing epoxy phosphorylation choline polymer, wherein the solvent of the solution is one or more of ethanol, water, deionized water, methanol, isopropanol, n-butanol, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), ethyl acetate, PM acetate, toluene, chloroform, and dichloromethane, and the mass concentration of epoxy phosphorylation choline polymer in the solution is 0.1-20%, more preferably, the mass concentration of the polymer is 0.5-5%, and the solvent is ethanol.

[0018] Furthermore, 2) the heating temperature of the medium heat stage is 30-200°C. More preferably, the temperature of the heat stage is 100-130°C. In fact, when the hot pressing temperature is lower than 100°C, the coating grafting amount is small, the water contact angle is relatively large, the stability is poor, and the coating falls off. At the same time, during the micro hot pressing molding process, if the heating temperature is insufficient, the hot pressing effect of the polymer will be limited, resulting in the inability to accurately replicate the microstructure on the substrate; when the temperature is too high, exceeding 130°C, the coating cannot be obtained or is extremely uneven.

[0019] Furthermore, the drying in 2) is carried out at a temperature of 10°C-120°C for 5-120 minutes, and more preferably at 60-80°C for 10-30 minutes.

[0020] Beneficial effects:

[0021] The present invention provides an occluder having a microstructure and a phosphorylcholine anticoagulant coating on its surface. The anticoagulant coating and the microstructure can inhibit early coagulation and accelerate endothelialization, thereby greatly reducing the side effects after device implantation. In particular, during its preparation process, the microstructure solidification temperature and the phosphorylcholine coating thermal curing temperature are regulated, and the microstructure and the coating are simultaneously formed on the occluding membrane in a one-step process. This method greatly simplifies the preparation process of the corresponding occluder structure, and has good repeatability and stable properties. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 The microstructure morphology used in the embodiments of the present invention;

[0023] Figure 2 for Figure 1 mesostructure detail spacing;

[0024] Figure 3 for Figure 1 mesostructure detail size;

[0025] Figure 4 The XPS data of the plugging films obtained in Example 1, Comparative Example 1 and Comparative Example 2;

[0026] Figure 5 for Figure 4 Contact angle data of the corresponding samples;

[0027] Figure 6 This is the appearance of the plugging membrane obtained in Example 1;

[0028] Figure 7 These are the SEM data of the plugging membranes obtained in Example 1 and Comparative Example 1. DETAILED DESCRIPTION

[0029] The technical solution of the present invention is further described in detail below in conjunction with the accompanying drawings and specific embodiments. Figures 1 to 3 The topological microstructure shown is used as an example for explanation, however, it has no limiting effect on the scheme of the present invention. The specific topological structure of the microstructure has no effect on the method of the present invention. The microstructure described in the scheme of the present invention can be designed and obtained as needed.

[0030] like Figures 1 to 3 , Microstructure design part:

[0031] Topological microstructure drawing design. Draw the continuous narrow water drop groove drawing using the computer drawing software AutoCAD. The specific dimensions are: the minimum spacing s of the groove arrangement is 50 microns, and the groove depth d is 200 microns. In a single water drop-shaped structural unit, the radius r is 100 microns, and the lower base 2r of the trapezoid is 200 microns. The height l of the trapezoid is 400 microns, and the upper base a of the trapezoid is 100 microns. The corresponding raised metal template is obtained by laser processing according to the drawing.

[0032] Embodiment 1:

[0033] (1) The surface of the structureless plugging membrane was pretreated with oxygen plasma, with the working parameters of power 300W, gas flow rate 200mL / min, and time 20min; the pretreated structureless plugging membrane was immersed in an ethanol solution of silane coupling agent KH550, and a chemical grafting reaction of aminosilane was carried out on the membrane surface, with the reaction temperature being 60°C and the reaction time being 2 hours. The volume concentration of the silane coupling agent KH550 was 10%, and the volume fraction of the ethanol solution was 60%;

[0034] (2) The structureless plugging membrane with an aminosilane grafted surface was washed with ethanol three times and then heat treated at a temperature of 80° C. for 30 min;

[0035] (3) ultrasonically spraying the aminosilanized structureless plugging membrane material with an epoxy phosphorylation choline polymer solution for chemical grafting reaction, wherein the mass concentration of the epoxy phosphorylation choline polymer is 3%, the solvent is ethanol, the ultrasonic spraying flow rate is 60 μL / min, the distance between the liquid inlet needle and the vibration column is 0.2 mm, the spraying height is 20 mm, the power of the ultrasonic nozzle is 1.0 W, the carrier gas pressure is 12 kPa, and the number of spraying passes is 10 times;

[0036] (4) The obtained plugging membrane material containing epoxy phosphorylcholine polymer is placed on a hot stage at 120°C, and a metal template with a convex surface is buckled on the plugging membrane. Pressure is applied to the back of the template to tightly combine the template and the plugging membrane to form a phosphorylcholine coating topological microstructure plugging membrane. The hot pressing time is 2 hours and the pressure is 20 MPa. After the end, it is quickly immersed in ethanol to cool and fix the pattern. After baking at 80°C for 20 minutes, a phosphorylcholine coating microstructure plugging membrane with good anticoagulation and biocompatibility is obtained.

[0037] (5) According to the occluder manufacturing method, the phosphorylcholine coated microstructured occluding membrane is sewn into the occluding frame using nylon thread to prepare an occluding disk.

[0038] Embodiment 2:

[0039] (1) The surface of the microstructure plugging membrane was pretreated with oxygen plasma, with the working parameters of power 300W, gas flow rate 200mL / min, and time 20min; the pretreated microstructure plugging membrane was immersed in an ethanol solution of silane coupling agent KH550, and a chemical grafting reaction of aminosilane was carried out on the membrane surface, with the reaction temperature being 60°C and the reaction time being 2 hours. The volume concentration of the silane coupling agent KH550 was 10%, and the volume fraction of the ethanol solution was 60%;

[0040] (2) The microstructured plugging membrane with an aminosilane grafted surface was washed with ethanol three times and then heat treated at a reaction temperature of 80° C. for 30 min;

[0041] (3) immersing the microstructured plugging membrane with the aminosilane coating into an epoxy phosphorylation choline polymer solution for 3 minutes; wherein the epoxy phosphorylation choline polymer has a mass concentration of 5% and the solvent is ethanol;

[0042] (4) The obtained plugging membrane material containing epoxy phosphorylcholine polymer is placed on a hot stage at 110°C, and a metal template with a convex surface is buckled on the plugging membrane. Pressure is applied to the back of the template so that the template and the plugging membrane are tightly combined to form a phosphorylcholine coating topological microstructure plugging membrane. The hot pressing time is 3 hours and the pressure is 30 MPa. After the end, it is quickly immersed in ethanol to cool and fix the pattern. After baking at 80°C for 20 minutes, a phosphorylcholine coating microstructure plugging membrane with good anticoagulation and biocompatibility is obtained.

[0043] (5) According to the occluder manufacturing method, the phosphorylcholine coated microstructured occluding membrane is sewn into the occluding frame using nylon thread to prepare an occluding disk.

[0044] Comparative Example 1: The non-microstructured plugging film was cleaned and dried without any further treatment.

[0045] Comparative Example 2:

[0046] (1) The surface of the microstructure plugging membrane was pretreated with oxygen plasma, with the working parameters of power 300W, gas flow rate 200mL / min, and time 20min; the pretreated microstructure plugging membrane was immersed in an ethanol solution of silane coupling agent KH550, and a chemical grafting reaction of aminosilane was carried out on the membrane surface, with the reaction temperature being 60°C and the reaction time being 2 hours. The volume concentration of the silane coupling agent KH550 was 10%, and the volume fraction of the ethanol solution was 60%;

[0047] (2) The microstructured plugging membrane with an aminosilane grafted surface was washed with ethanol three times and then heat treated at a reaction temperature of 80° C. for 30 min;

[0048] (3) immersing the microstructured plugging membrane with the aminosilane coating into an epoxy phosphorylation choline polymer solution for 3 minutes; wherein the epoxy phosphorylation choline polymer has a mass concentration of 5% and the solvent is ethanol;

[0049] (4) The obtained plugging membrane material containing epoxy phosphorylcholine polymer is placed on a hot stage at 80°C, and the metal template with a convex surface is buckled on the plugging membrane. The back of the template is pressed to make the template and the plugging membrane tightly combined to form a phosphorylcholine coating topological microstructure plugging membrane. The hot pressing time is 1 hour and the pressure is 10MPa. After the end, it is quickly immersed in ethanol to cool and fix the pattern. After baking at 80°C for 20 minutes, a phosphorylcholine coating microstructure plugging membrane with good anticoagulation and biocompatibility is obtained.

[0050] (5) According to the occluder manufacturing method, the phosphorylcholine coated microstructured occluding membrane is sewn into the occluding frame using nylon thread to prepare an occluding disk.

[0051] Phosphorylcholine (PC) is a hydrophilic zwitterion with good biocompatibility and blood compatibility. It can resist protein and cell adhesion, reduce thrombosis caused by protein aggregation, and play an anti-coagulation role. The material containing PC is surrounded by water molecules, and these water molecule layers effectively cover the substrate to which it is applied, providing a biological "non-stick" surface, playing an anti-adhesion and anti-crystallization role. The occluding membrane with topological microstructure and phosphorylcholine coating prepared in Example 1 of the present invention is detected by X-ray photoelectron spectroscopy (XPS) (e.g. Figure 4 ), the peak of the P element in the phosphorylcholine molecule appears at around 133 eV, which indicates that the phospholipid polymer is successfully fixed on the surface of the blocking membrane. Although the blocking membrane obtained in Comparative Example 2 also has the peak of the P element in the phosphorylcholine molecule, its grafting amount is low, its stability is poor, it is easy to fall off, and it is not easy to accurately replicate the microstructure; the prepared blocking membrane with topological microstructure and phosphorylcholine coating is tested for contact angle (such as Figure 5 ), the blocking membrane changed from a hydrophobic surface to a hydrophilic surface, and the contact angle of Example 1 was reduced to about 30°, while the contact angle of Comparative Example 2 was reduced to about 60°, further indicating that the phosphorylcholine coating was successfully grafted and that Example 1 more effectively changed the hydrophilic properties of the blocking membrane surface. The surface structure of the blocking membrane with topological microstructure and phosphorylcholine coating (such as Figure 7 ), the surface of the comparative example and the embodiment did not change, and the results showed that the thickness of the phosphorylcholine coating was thin and the surface structure of the membrane was not changed, which helped to maintain the original performance of the device.

[0052] In summary, in the present invention, the coating and the microstructure are simultaneously prepared on the occluding membrane through a one-step operation, the process is simple, and it is easy to repeat the implementation; in addition, the PC coating and the microstructure can promote the growth of endothelial cells and inhibit the proliferation of smooth muscle cells, which is crucial for the long-term stability and function of implants such as occluders.

Claims

1. A method for preparing an occluder based on an occluder having both a surface microstructure and an anticoagulant coating occluding membrane, characterized in that: These include: 1) designing the topological groove shape of the required surface microstructure, obtaining a microstructure design drawing, and processing a metal template having a convex morphology consistent with the topological groove shape according to the drawing; and treating the surface of the structureless plugging membrane by introducing an amino-grafted epoxy phosphorylcholine polymer; 2) placing the obtained blocking film on a hot stage, ensuring that the surface in contact with the hot stage is the surface grafted with the epoxy phosphorylcholine polymer, placing the raised morphology side of the metal template on the blocking film, applying pressure on the back of the metal template, and heating the hot stage to make the metal template and the blocking film closely fit, and then quickly immersing it in ethanol to cool and fix the pattern, and drying it to obtain a blocking film with both surface microstructure and anticoagulation coating; 3) The occluding membrane obtained in 2) is sewn into the occluding frame according to the occluding device manufacturing method to prepare an occluding disk, thereby obtaining an occluding device based on the occluding membrane with both surface microstructure and anticoagulant coating.

2. The method for preparing an occluder based on an occluding membrane having both a surface microstructure and an anticoagulant coating according to claim 1, characterized in that: The surface of the structureless plugging membrane is processed, specifically including the following: (1) Pretreatment of the surface of the structureless plugging membrane with oxygen plasma; (2) subjecting the plugging membrane obtained in (1) to aminosilane chemical grafting, cleaning the surface of the plugging membrane, and then subjecting the surface of the plugging membrane to heat treatment to obtain a plugging membrane having amino-reactive functional groups on the surface; (3) The plugging membrane obtained in (2) is grafted with an epoxy phosphorylcholine polymer.

3. The method for preparing an occluder based on an occluding membrane having both a surface microstructure and an anticoagulant coating according to claim 2, characterized in that: The parameters of the oxygen plasma pretreatment in (1) are power 100-600 W, gas flow rate 2-300 mL / min, and treatment time 1-60 minutes.

4. The method for preparing an occluder based on an occluding membrane having both a surface microstructure and an anticoagulant coating according to claim 2, characterized in that: The method (2) is specifically as follows: immersing the structureless plugging film after oxygen plasma pretreatment in an ethanol mixed solution of aminosilane for reaction for 1-24 hours; wherein the volume concentration of the ethanol aqueous solution of aminosilane is 10%-100%, the volume concentration of aminosilane is 1%-30%, and the reaction temperature is 10-120°C.

5. The method for preparing an occluder based on an occluding membrane having both a surface microstructure and an anticoagulant coating according to claim 4, characterized in that: The aminosilane is selected from one or more of 3-aminopropyltrimethylsilane, 3-aminopropyltriethoxysilane, N-(aminoethyl)-aminopropyltrimethoxysilane, N-(aminoethyl)-aminopropylmethyldimethoxysilane, N-(aminoethyl)-aminopropyltriethoxysilane, N-(aminoethyl)-aminopropyltriethoxysilane, and diethylenetriaminopropyltrimethoxysilane.

6. The method for preparing an occluder based on an occluding membrane having both a surface microstructure and an anticoagulant coating according to claim 2, characterized in that: The cleaning solution described in (2) is one or more combinations of ethanol, toluene, deionized water, methanol, isopropanol, n-butanol, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), ethyl acetate, PM acetate, toluene, chloroform, and dichloromethane; the heat treatment is performed at 10°C-120°C for 5-120 minutes.

7. The method for preparing an occluder based on an occluding membrane having both a surface microstructure and an anticoagulant coating according to claim 2, characterized in that: (3) Specifically, the plugging membrane after grafting with amino groups is placed in a solution containing epoxy phosphorylcholine polymer, wherein the epoxy phosphorylcholine polymer is MPC (2-methacryloyloxyethyl phosphorylcholine)-GMA (glycidyl methacrylate) copolymer, and the solvent of the solution is one or more of ethanol, water, deionized water, methanol, isopropanol, n-butanol, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), ethyl acetate, PM acetate, toluene, chloroform, and dichloromethane, and the mass concentration of the epoxy phosphorylcholine polymer in the solution is 0.1-20%.

8. The method for preparing an occluder based on an occluding membrane having both a surface microstructure and an anticoagulant coating according to claim 1, characterized in that: 2) The heating temperature of the medium heat stage is 100-130℃.

9. The method for preparing an occluder based on an occluding membrane having both a surface microstructure and an anticoagulant coating according to claim 1, characterized in that: 2) The drying is carried out at a temperature of 10-120° C. for 5-120 min.

10. An occluder based on a occluding membrane with both surface microstructure and anticoagulant coating, characterized in that: The method is prepared by the method according to any one of claims 1 to 9.

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