Occluder with topological microstructure on surface and preparation method thereof

Abstract

The present invention discloses an occluder having a topological microstructure on its surface, comprising an occluding disc, the occluding disc comprising an occluding frame and an occluding membrane covering the surface of the occluding frame, the surface of the occluding membrane having a topological microstructure, the topological microstructure being a continuous groove array composed of a number of continuous grooves arranged in a regular radial pattern, the radial center being located at the center of the occluding membrane; a single continuous groove being a continuous teardrop-shaped structure, the cross-section of a single teardrop-shaped structural unit being composed of a semicircle and a trapezoid. The occluder having a topological microstructure on its surface disclosed by the present invention has a topological microstructure on its surface being a continuous groove array in a continuous teardrop-shaped structure, the special structure can enhance the orientation of endothelial cells and accelerate endothelialization, thereby resisting the formation of surface thrombi, achieving anti-coagulation function, and reducing the risk of use; and the preparation of the topological microstructure is simple, the process is controllable, and the properties are stable.

Description

Technical Field

[0001] The present invention relates to the technical field of occluders, and in particular to an occluder with a topological microstructure on its surface and a preparation method thereof. Background Art

[0002] Transcatheter left atrial appendage occlusion devices are a treatment option for stroke prevention, particularly for patients who are not suitable for long-term anticoagulant therapy. Other transcatheter occluders include minimally invasive devices for congenital heart disease, such as atrial septal defect (VSD), ventricular septal defect (ASD), patent ductus arteriosus (PDA), and patent foramen ovale (PFO). However, implantation of the occluder often triggers a coagulation reaction, leading to the formation of thrombi on the occluder surface. If these thrombi are not treated with medication, they can break off and circulate throughout the body. If they become lodged in the brain, they can cause more serious side effects. Therefore, post-implantation anticoagulant therapy (1-3 months or even longer) is necessary. This can be a significant burden for patients who are not suitable for anticoagulant therapy. Endothelialization of the occluder surface to form a complete endothelial layer can effectively prevent surface thrombus formation. Therefore, research on occluders that accelerate endothelialization has important clinical significance and broad application prospects.

[0003] Existing coatings that accelerate endothelialization primarily rely on chemical modification or coating the substrate surface with chemical components, whereby the active components promote endothelial cell migration and proliferation. However, the coatings primarily bond to the substrate through chemical interactions or physical adsorption. Coating stability is relatively poor, and there is a risk of loss of active components during sterilization. These methods are unsuitable for devices with complex structures such as occluders.

[0004] Compared to chemical methods, directly constructing physical structures on the surface to guide cells is more stable and reliable. However, currently, no occluder surface has a topological structure that accelerates endothelialization. Therefore, physically constructing topological microstructures on the occluder surface to directly regulate endothelial cell behavior and accelerate endothelialization has clinical potential. Summary of the Invention

[0005] In response to the above-mentioned problems existing in the prior art, the present invention discloses an occluder with a topological microstructure on the surface. The special topological microstructure on the surface of the occluder can improve the orientation of endothelial cells, accelerate endothelialization, and be beneficial to anti-coagulation of the device surface, thereby reducing the risk of use. Moreover, the preparation of this topological microstructure is simple, the process is controllable, and the properties are stable.

[0006] The specific technical solutions are as follows:

[0007] An occluder having a topological microstructure on its surface, comprising an occluding disc, wherein the occluding disc comprises an occluding frame and an occluding membrane covering the surface of the occluding frame:

[0008] The surface of the blocking membrane has a topological microstructure, which is a continuous groove array composed of a plurality of continuous grooves arranged in a regular radial pattern, with the center of the radial pattern located at the center of the blocking membrane;

[0009] A single continuous groove presents a continuous teardrop-shaped structure. The cross-section of a single teardrop-shaped structural unit is composed of a semicircle and a trapezoid. The radius r of the semicircle is selected from 2 to 50 μm, the lower base of the trapezoid is 2r, the height l of the trapezoid is selected from 10 to 100 μm, and the upper base a of the trapezoid is selected from 1 to 80 μm.

[0010] The present invention forms a specially shaped continuous groove array on the occluding membrane surface, inducing directional cell migration while simultaneously restricting its direction, significantly improving cell migration efficiency and accelerating endothelialization. Compared to microstructures without topological microstructures or using traditional parallel microgrooves, the unique topological microstructure disclosed in the present invention can significantly increase endothelial coverage on the occluding membrane surface.

[0011] In the topological microstructure disclosed in the present invention:

[0012] The minimum spacing s between adjacent continuous grooves is 5 to 50 μm, preferably 5 to 20 μm, and more preferably 5 μm.

[0013] Experiments have shown that the depth of the grooves in the topological microstructures disclosed herein affects the endothelial coverage of the occluding membrane surface. When the depth d of the continuous grooves is as low as 1 μm, the endothelial coverage is significantly lower. Preferably, the depth d of the continuous grooves is 2 to 50 μm; more preferably, the depth d of the continuous grooves is 3 to 10 μm; more preferably, the depth d of the continuous grooves is 3 to 7 μm; and even more preferably, the depth d of the continuous grooves is 3 to 5 μm.

[0014] Experiments have shown that, in the topological microstructure disclosed in the present invention, the value of the upper base a of the trapezoid and the ratio of a to r have a critical impact on the efficiency of directional cell migration.

[0015] Preferred:

[0016] The upper base a of the trapezoid is selected from 5 to 10 μm, the radius r of the semicircle is selected from 5 to 20 μm, and the ratio of a to r is 1:(1 to 4);

[0017] More preferably, the ratio of a to r is 1:(1-2);

[0018] More preferably, the upper base a of the trapezoid is selected from 5 μm, and the ratio of a to r is 1:1.

[0019] With the continuous optimization of the above parameters, the topological microstructure significantly improves the endothelial coverage of the occluding membrane surface.

[0020] Preferably, the height l of the trapezoid is selected from 40 to 100 μm, and more preferably is 80 μm.

[0021] The present invention also discloses a method for preparing the occluder having a topological microstructure on its surface, comprising the following steps:

[0022] Step 1: Design a topological microstructure drawing based on the above structure and dimensions, and obtain the corresponding photomask according to the drawing;

[0023] Step 2: Clean the silicon wafer and transfer the topological microstructure designed in step 1 onto the silicon wafer using a standard photolithography process to obtain a silicon template with a topological microstructure.

[0024] Step 3: Transfer the topological microstructure on the silicon template prepared in step 2 to the blocking membrane by hot pressing;

[0025] Step 4: According to the occluder manufacturing method, the occluding membrane prepared in step 3 is combined with the occluding frame to obtain an occluding disk.

[0026] Preferably, in step 3, the hot pressing treatment is performed at a temperature of 120 to 200° C. and a pressure of 1 to 10 MPa.

[0027] Preferably, the blocking membrane is circular with a diameter ranging from 10 to 50 mm.

[0028] Compared with the prior art, the present invention has the following beneficial effects:

[0029] The present invention discloses an occluder with a topological microstructure on its surface. The topological microstructure on the occluder surface is a continuous groove array in a continuous teardrop-shaped structure. This special structure can improve the orientation of endothelial cells and accelerate endothelialization, thereby resisting the formation of surface thrombi, achieving anti-coagulation function, and reducing the risk of use. The topological microstructure is simple to prepare, with a controllable process and stable properties. The structure is suitable for occluders for left atrial appendage occlusion and minimally invasive treatment of congenital heart diseases such as atrial septal defect (VSD), ventricular septal defect (ASD), patent ductus arteriosus (PDA), and patent foramen ovale (PFO). BRIEF DESCRIPTION OF THE DRAWINGS

[0030] Figure 1 Schematic diagram of the structure of the blocking membrane with a topological microstructure on the surface of the present invention, in which 11 is the blocking membrane, 111 is the topological microstructure;

[0031] Figure 2 is a cross-sectional schematic diagram of the topological microstructure;

[0032] Figure 3 A local schematic diagram of a water droplet-shaped groove in the topological microstructure;

[0033] Figure 4 This is a fluorescence microscopy image of endothelial cells cultured on the surface of the occlusion disk treated in Comparative Example 1 for 7 days;

[0034] Figure 5 This is a fluorescence microscopy image of endothelial cells cultured on the surface of the occluder disc treated in Example 1 for 7 days;

[0035] Figure 6 The migration distances of endothelial cells on the surface of the occluding disk after being treated in Example 1 and Comparative Example 1 on the first, second, and third days, respectively, are statistically shown. DETAILED DESCRIPTION

[0036] The present invention will be further described in detail below with reference to examples and comparative examples, but the embodiments of the present invention are not limited thereto.

[0037] The occluder disclosed in the present invention has a topological microstructure on its surface, including an occluding disk, which is composed of an occluding frame and an occluding membrane 11 covering the surface of the occluding frame, and the occluding membrane 11 has a topological microstructure 111 on its surface (the structural schematic diagram is shown in FIG. Figure 1 The topological microstructure is a continuous groove array composed of a number of continuous grooves arranged in a regular radial pattern. The blocking membrane is circular, and the radial center of the topological microstructure is located at the center of the blocking membrane. The depth of a single continuous groove is denoted as d, and the minimum spacing between adjacent continuous grooves is denoted as s (the cross-sectional schematic diagram is shown in FIG. Figure 2 As shown); a single continuous groove presents a continuous water drop-shaped structure, and the local schematic diagram is shown Figure 3 As shown, the cross section of a single teardrop-shaped structural unit is composed of a semicircle and a trapezoid, the radius of the semicircle is denoted as r, the lower base of the trapezoid is denoted as 2r, the upper base of the trapezoid is denoted as a, and the height of the trapezoid is denoted as l.

[0038] Example 1

[0039] Step 1: Design the topological microstructure. Draw a drawing of continuous narrow water droplet grooves using AutoCAD. Specific dimensions: minimum groove spacing s of 5 μm, groove depth d of 3 μm. Within a single water droplet-shaped unit, the radius r is 5 μm, the lower base 2r of the trapezoid is 10 μm, the height l of the trapezoid is 80 μm, and the upper base a of the trapezoid is 5 μm. The corresponding photomask is then processed according to the drawing.

[0040] Step 2: Preparation of a negative silicon template with a topological microstructure. The silicon wafer is cleaned and the design is transferred to the wafer using a standard photolithography process, resulting in a silicon wafer with a topological microstructure. The specific process involves using a spreader to evenly distribute the photoresist on the wafer, pre-baking the photoresist on a hot plate, and then placing the patterned mask into the photolithography machine for exposure and development. The resulting silicon template features continuous, narrow, water-droplet-like protrusions.

[0041] Step 3: Prepare the microtopology of the plugging membrane surface. Place the plugging membrane (30 mm in diameter) on a 150°C hot plate. Place a silicone template with a raised surface on the membrane. Apply pressure to the back of the template to ensure a tight fit between the template and the plugging device. Heat press for 1 hour at 10 MPa. Afterward, quickly immerse the membrane in water to cool and fix the pattern. This results in a plugging membrane with continuous, narrow, water-droplet-shaped grooves on its surface.

[0042] Step 4: Suturing the occlusion membrane and the occlusion frame: According to the occlusion device manufacturing method, the occlusion membrane with a narrow water droplet microstructure is sewn into the occlusion frame using nylon thread to prepare the occlusion disc.

[0043] Example 2

[0044] The preparation process is basically the same as that in Example 1, except that the specific size of the single continuous groove designed in step 1 is changed, specifically:

[0045] The radius r of the semicircle is adjusted to 20 μm, and the lower base 2r of the trapezoid is now 40 μm.

[0046] Example 3

[0047] The preparation process is basically the same as that in Example 1, except that the specific size of the single continuous groove designed in step 1 is changed, specifically:

[0048] The minimum spacing s of the groove arrangement is adjusted to 20 μm.

[0049] Example 4

[0050] The preparation process is basically the same as that in Example 2, except that the specific size of the single continuous groove designed in step 1 is changed, specifically:

[0051] The upper base a of the trapezoid was adjusted to 10 μm.

[0052] Examples 5 to 8

[0053] The preparation process is basically the same as that in Example 1, except that the specific size of the single continuous groove designed in step 1 is changed, specifically:

[0054] The depth d of a single continuous groove was adjusted to 2 μm, 5 μm, 7 μm, and 10 μm in sequence.

[0055] Comparative Example 1

[0056] The occluding membrane of a common occluder is a plane without any topological microstructure.

[0057] Comparative Example 2

[0058] The preparation process is basically the same as that in Example 1, the only difference is the designed topological microstructure. This comparative example uses parallel grooves with a groove width a of 10 μm, a groove spacing s of 10 μm, and a groove-free water droplet design.

[0059] Comparative Example 3

[0060] The preparation process is basically the same as that in Example 1, except that the specific size of the single continuous groove designed in step 1 is changed, specifically, the depth d of the single continuous groove is adjusted to 1 μm. Performance Test Endothelial Coverage Determination:

[0061] Human umbilical vein endothelium was harvested and labeled with a live cell dye at 100,000 / cm 2 The density of the cells was uniformly seeded in the area within 5 mm of the edge of the occluding disk after treatment in each embodiment or comparative example. After culturing for 7 days, the endothelial cell coverage in the occluding disk surface area was scanned by fluorescence microscopy, and the endothelial coverage rate of the occluding disk surface was statistically calculated (coverage rate = 7-day coverage area * 100% / total disk area). The specific values ​​are listed in Table 1 below.

[0062] To measure the relationship between migration distance and time, fluorescence images were taken on the first, second, and third days. The distance that endothelial cells migrated on the occlusion disk surface was measured using image processing software (ImageJ).

[0063] Table 1

[0064] serial number Endothelial coverage (%) Example 1 92.8 Example 2 78.3 Example 3 84.7 Example 4 80.9 Example 5 74.2 Example 6 91.1 Example 7 83.4 Example 8 77.2 Comparative Example 1 55.6 Comparative Example 2 63.6 Comparative Example 3 60.9

[0065] Observation of the data in this table shows that the surface of the occluding disc treated in accordance with Example 1 and Example 6 has a higher endothelial coverage speed than the ordinary occluding disc without treatment (Comparative Example 1). Increasing the groove width (Example 2, Example 3) reduces the endothelial coverage speed, but is still better than the parallel grooves without special structural design (Comparative Example 2) and the ordinary occluding disc (Comparative Example 1). The endothelial coverage speed is affected when the microstructure depth exceeds 5 μm (Example 7, Example 8) or is less than 3 μm (Example 5, Comparative Example 3). The teardrop-shaped grooves designed by the present invention can significantly accelerate the coverage of endothelial cells on the occluding disc surface, and the effect is better than the parallel grooves without special design, which is conducive to accelerating the endothelialization of the occluder surface and effectively shortening the time for patients to take anticoagulants after surgery.

[0066] Figure 4 This is a fluorescence microscope image of endothelial cells cultured on the surface of the occluder disk treated in Comparative Example 1 for 7 days. Figure 5This is a fluorescence microscopy image of endothelial cells cultured for 7 days on the surface of the occluder disc treated in Example 1. A comparison reveals that the endothelial cells almost completely cover the surface of the occluder disc designed in Example 1, with densely packed endothelial cells. However, the occluder disc treated in Comparative Example 1 has less than half of its surface covered, and the endothelial cells are less densely packed.

[0067] Figure 6 The figure below compares the migration distance of endothelial cells over time on the occluder disc surfaces treated in Comparative Example 1 and Example 1, respectively. It can be seen that the migration efficiency and speed of endothelial cells on the occluder disc surface treated in Example 1 are significantly higher than those on the untreated surface. This demonstrates that the teardrop-shaped grooves designed in the present invention significantly promote close coverage of endothelial cells on the occluder disc surface, helping to prevent surface thrombosis and reduce side effects after occluder implantation.

[0068] The applicant declares that the present invention illustrates the detailed method of the present invention through the above embodiments, but the present invention is not limited to the above detailed method.

Claims

1. An occluder having a topological microstructure on its surface, comprising an occluding disc, the occluding disc comprising an occluding frame and an occluding membrane covering the surface of the occluding frame, characterized in that: The surface of the blocking membrane has a topological microstructure, which is a continuous groove array composed of a plurality of continuous grooves arranged in a regular radial pattern, with the center of the radial pattern located at the center of the blocking membrane; A single continuous groove presents a continuous teardrop-shaped structure. The cross-section of a single teardrop-shaped structural unit is composed of a semicircle and a trapezoid. The radius r of the semicircle is selected from 2 to 50 μm, the lower base of the trapezoid is 2r, the height l of the trapezoid is selected from 10 to 100 μm, and the upper base a of the trapezoid is selected from 1 to 80 μm.

2. The occluder having a topological microstructure on the surface according to claim 1, characterized in that: The minimum spacing s between adjacent continuous grooves is 5 to 50 μm; The depth d of the continuous groove is 2 to 50 μm.

3. The occluder having a topological microstructure on the surface according to claim 1, characterized in that: In the single water drop-shaped structural unit, the radius r of the semicircle is selected from 5 to 20 μm, the upper base a of the trapezoid is selected from 5 to 10 μm, and the ratio of a to r is 1:(1 to 4).

4. The occluder having a topological microstructure on the surface according to claim 3, characterized in that: The depth d of the continuous groove is 3 to 10 μm; The height l of the trapezoid in the single water drop-shaped structural unit is selected from 40 to 100 μm.

5. The occluder having a topological microstructure on the surface according to claim 4, characterized in that: The minimum spacing s between adjacent continuous grooves is 5 to 20 μm; The depth d of the continuous groove is 3-7 μm.

6. The occluder having a topological microstructure on the surface according to claim 5, characterized in that: In the single water droplet-shaped structural unit, the ratio of a to r is 1:(1-2).

7. The occluder having a topological microstructure on the surface according to claim 6, characterized in that: The depth d of the continuous groove is 3-5 μm.

8. The occluder having a topological microstructure on the surface according to claim 7, characterized in that: In the single water droplet-shaped structural unit, a is selected from 5 μm, and the ratio of a to r is 1:1; The minimum spacing s between adjacent continuous grooves is 5 μm.

9. A method for preparing an occluder having a topological microstructure on its surface according to any one of claims 1 to 8, characterized in that: The steps include: Step 1: Design a topological microstructure drawing based on the above structure and dimensions, and process the corresponding photomask according to the drawing; Step 2: Clean the silicon wafer and transfer the topological microstructure designed in step 1 onto the silicon wafer using a standard photolithography process to obtain a silicon template with a topological microstructure. Step 3: Transfer the topological microstructure on the silicon template prepared in step 2 to the blocking membrane by hot pressing; Step 4: According to the occluder manufacturing method, the occluding membrane prepared in step 3 is combined with the occluding frame to obtain an occluding disk.

10. The method for preparing an occluder having a topological microstructure on its surface according to claim 9, characterized in that: In step 3, the hot pressing treatment is performed at a temperature of 120 to 200° C. and a pressure of 1 to 10 MPa.

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