A convenient cell adhesion blocking structure

Abstract

The application relates to a convenient cell adhesion blocking structure, which comprises a blocking body, the blocking body comprises a contraction section and an outer disc section, the contraction section and the outer disc section are connected with each other; in an unfolded state, the outer diameter of the contraction section is smaller than the outer diameter of the outer disc section, the outer surface of the outer disc section comprises a circular outer disc surface and a circular ring-shaped outer peripheral surface, the cross section of the outer peripheral surface is semicircular, the outer edge of the outer disc surface is connected with the first edge of the outer peripheral surface, the second edge of the outer peripheral surface is connected with one end of the contraction section, the first edge and the second edge are circular, the first edge is farther away from the contraction section than the second edge, and a hydrogel layer is formed on the outer peripheral surface. By forming the hydrogel layer on the outer peripheral surface, the adhesion of tissue cells is facilitated, and the endothelialization process is accelerated.

Description

Technical Field

[0001] This invention relates to the field of medical device technology, specifically to a sealing structure that facilitates cell adhesion. Background Technology

[0002] Traditional metal occluders have smooth surfaces and slow endothelialization (usually requiring 3-6 months). Biodegradable occluders, compared to traditional metal occluders, have a shorter endothelialization time (usually requiring 1-3 months). However, cardiac implantable devices immediately affect hemodynamics within the heart after implantation, subsequently influencing thrombus formation on the device surface and the endothelialization process. In recent years, research into promoting endothelialization has focused on several directions: First, optimizing device structural design to reduce the surface area remaining after implantation and to better conform to the surrounding tissue structure; second, using polymeric materials with good biocompatibility and biodegradability to provide a supportive path for cell climbing during the endothelialization stage, with no residue in the long term; third, surface modification of device or choline occluder materials, such as fluorinated coatings (polytetrafluoroethylene) choline occluders, drug-impregnated or bioactive coatings (heparin, albumin, phosphorylcholine). Current surface modifications and coatings can reduce platelet activation and inflammatory responses to some extent, but existing coating technologies (such as heparin coatings) lack durability and are prone to detachment in the early stages of implantation. They cannot provide a sustained endothelialization-promoting coating, and their long-term effects are unclear. Furthermore, the effects of drug-coated coatings are not entirely controllable for different patients and are influenced by the patient's blood environment. Therefore, there is still a need in the field for biodegradable cardiac occluders with long-term anticoagulation and more stable endothelialization-promoting functions. Summary of the Invention

[0003] In view of this, the present invention provides a sealing structure that facilitates cell adhesion by forming a hydrogel layer on the outer peripheral surface, thereby facilitating the adhesion of tissue cells and accelerating the endothelialization process.

[0004] The technical solution adopted in this invention: An occlusion structure facilitating cell adhesion includes an occlusion body comprising a contractile segment and an outer disc segment, the contractile segment and the outer disc segment being interconnected. In the unfolded state, the outer diameter of the contractile segment is smaller than the outer diameter of the outer disc segment. The outer surface of the outer disc segment includes a circular outer disc surface and an annular outer peripheral surface. The cross-section of the outer peripheral surface is semi-circular. The outer edge of the outer disc surface is connected to a first edge of the outer peripheral surface, and a second edge of the outer peripheral surface is connected to one end of the contractile segment. Both the first edge and the second edge are circular. The first edge is farther away from the contractile segment than the second edge. A hydrogel layer is formed on the outer peripheral surface.

[0005] Preferably, the outer peripheral surface includes a first region and a second region that are connected to each other. The first region and the second region are both annular and completely cover the outer peripheral surface. The first region is connected to the first edge, and the second region is connected to the second edge. The cross-section of the first region is arc-shaped with an arc of 120°-135°. A hydrogel layer is formed on the first region, but no hydrogel layer is formed on the second region.

[0006] Preferably, the first region is formed into a hydrogel layer by the following method: Solution A and solution B are applied to the first region respectively, so that a hydrogel layer is formed on the first region; Solution A is an Alg / HA-BP solution; Solution B is a CaSO4 solution containing YAP / TAZ activating peptide, wherein the concentration of YAP / TAZ activating peptide is 10 μM, and CaSO4 is... 2+ Concentration 80mM.

[0007] Preferably, the Alg / HA-BP solution is obtained by the following method: S10, Obtain HA-BP and Alg-RGD-BP; S20. Dissolve Alg-RGD-BP and HA-BP in HEPES to obtain an Alg / HA-BP solution, wherein the mass ratio of Alg-RGD-BP to HA-BP is 4:1 and the mass ratio of Alg-RGD-BP to Alg / HA-BP is 1:100.

[0008] Preferably, the method for forming a hydrogel layer on the first region is as follows: S30. Cover the sealing body with silicone or PTFE, wherein the covering surface is all surfaces of the sealing body except for the first region; S40. Solution A and solution B are sequentially applied to the first region, and solutions A and B crosslink to form a hydrogel layer.

[0009] Preferably, HA-BP is obtained using the following method: MeHA was dissolved in triethanolamine buffer and stirred overnight to obtain solution number one. Add 5.5 eq of thiol-BP and 7.5 mM of tris(2-carboxyethyl)phosphine hydrochloride to solution No. 1, stir and react for 48 h to obtain solution No. 2; Solution No. 2 was dialyzed with deionized water for 3 days to obtain solution No. 3; Solution No. 3 was frozen overnight at -30°C, then transferred to a lyophilizer for lyophilization to obtain HA-BP, which was then stored at -20°C.

[0010] Preferably, Alg-RGD-BP is obtained using the following method: Dissolve 0.2 g of sodium alginate in 20 mL of L2-(N-morpholino)ethanesulfonic acid buffer, stir, and let stand overnight to obtain solution No. 4; Add excess N-hydroxysulfosuccinimide, excess 1-ethyl-(3-dimethylaminopropyl)carbodiimide and excess bisphosphate to solution No. 4, stir and react for 24 h to obtain solution No. 5; Solution No. 5 was dialyzed with deionized water for 3 days to obtain solution No. 6; Solution No. 6 was frozen overnight at -30°C, then transferred to a lyophilizer to obtain Alg-RGD-BP, which was stored at -20°C.

[0011] The beneficial effects of this invention are: The occlusion body of this invention has a hydrogel layer formed on its outer peripheral surface. In practical application, the contraction section of the occlusion structure is locked at the target position, and the outer disc section closes the target position from the outside. Most of the outer peripheral surface and the entire outer disc surface of the outer disc section are in contact with blood. The hydrogel layer facilitates the attachment of tissue cells, so tissue cells can attach along the hydrogel layer to the first edge, making it easier for tissue cells to cover the entire outer peripheral surface. In actual use, radially, from the outside to the inside, the outer disc surface gradually concaves towards the side of the contraction section, reducing the difficulty for tissue cells to attach on the outer disc surface. Therefore, tissue cells can more easily cover the entire occlusion structure, thereby achieving the purpose of accelerating the endothelialization process. Attached Figure Description

[0012] The above and other objects, features and advantages of the present invention will become clearer from the following description of embodiments of the invention with reference to the accompanying drawings, in which: Figure 1 This is a schematic diagram of the sealing structure; Figure 2 yes Figure 1 A cross-sectional view of the central sealing structure; Figure 3 This is a comparison of endothelial cell proliferation before and after dynamic hydrogel coating.

[0013] In the diagram: 1. Outer plate segment; 2. Contraction segment; 11. Outer plate surface; 12. Outer peripheral surface. Detailed Implementation

[0014] The present invention is described below based on embodiments, but the present invention is not limited to these embodiments. In the following detailed description of the present invention, some specific details are described in detail, but well-known methods, processes, procedures, and elements are not described in detail in order to avoid obscuring the essence of the present invention.

[0015] Furthermore, those skilled in the art should understand that the accompanying drawings provided herein are for illustrative purposes only and are not necessarily drawn to scale.

[0016] Unless the context explicitly requires it, the words "comprising," "including," and similar terms throughout the specification and claims should be interpreted as encompassing rather than being exclusive or exhaustive; that is, meaning "including but not limited to."

[0017] In the description of this invention, it should be understood that the terms "first," "second," etc., are used for descriptive purposes only and should not be construed as indicating or implying relative importance. Furthermore, in the description of this invention, unless otherwise stated, "a plurality of" means two or more.

[0018] See Figures 1-3 This invention provides a clogging structure that facilitates cell adhesion, comprising a clogging body, wherein the clogging body includes a contraction segment 2 and an outer disk segment 1, the contraction segment 2 and the outer disk segment 1 being interconnected; in the unfolded state, the outer diameter of the contraction segment 2 is smaller than the outer diameter of the outer disk segment 1, the outer surface of the outer disk segment 1 includes a circular outer disk surface 11 and an annular outer peripheral surface 12, the cross-section of the outer peripheral surface 12 is semi-circular, the outer edge of the outer disk surface 11 is connected to the first edge of the outer peripheral surface 12, the second edge of the outer peripheral surface 12 is connected to one end of the contraction segment 2, both the first edge and the second edge are circular, the first edge is farther away from the contraction segment 2 than the second edge, and a hydrogel layer is formed on the outer peripheral surface 12.

[0019] In this invention, the occlusion structure can be a left atrial appendage occluder or an atrial septum / ventricular septum occluder. In an embodiment where the occlusion structure is a left atrial appendage occluder, there is one contraction segment 2 and one outer disc segment 1. In an embodiment where the occlusion structure is an atrial septum / ventricular septum occluder, there is one contraction segment 2 and two outer disc segments 1. Each end of the contraction segment 2 is connected to an outer disc segment 1, making the overall occlusion structure dumbbell-shaped.

[0020] The explanation will take the left atrial appendage occluder as an example.

[0021] When the occlusion structure is implanted into the left atrial appendage, the constriction segment 2 is inserted into the left atrial appendage, and the radial dimension of the outer disc segment 1 is larger than the opening of the left atrial appendage, so that the outer disc segment 1 covers the entire opening of the left atrial appendage. Most of the outer surface of the outer disc segment 1 does not directly contact the left atrial appendage; only a portion of the outer peripheral surface 12 near the constriction segment 2 contacts the tissue near the left atrial appendage. Therefore, a hydrogel layer is provided on the outer peripheral surface 12, which reduces the difficulty of tissue cell attachment. Thus, tissue cells can attach along the outer peripheral surface 12 towards the outer disc surface 11, and tissue cells can more easily cover the entire outer peripheral surface 12. In actual use, radially, from the outside to the inside, the outer disc surface 11 gradually concaves towards one side of the constriction segment 2 (that is, the center of the outer disc surface 11 contracts inward), reducing the difficulty of tissue cell attachment on the outer disc surface 11. Therefore, tissue cells can more easily cover the entire occlusion structure, thereby achieving the purpose of accelerating the endothelialization process. Figure 3 The image shows the fluorescence of endothelial cells (blue nuclei, red actin filaments) obtained by confocal microscopy (model: Carl Zeiss LSM880, Germany); it clearly shows that the endothelial cell proliferation rate is increased by 3 times.

[0022] The occlusion body includes a braided occluder made of PDO (polydioxanone) filaments and a PLLA (poly-L-lactic acid) choke membrane sutured into the braided occluder. As mentioned earlier, tissue cells will climb onto the outer surface of the entire outer disc segment 1, allowing the tissue cells to naturally close the opening of the left atrial appendage. At the same time, the PDO filaments and PLLA choke membrane are also biodegradable, so the cellular tissue will eventually close the left atrial appendage, thereby achieving the purpose of the surgery.

[0023] The outer peripheral surface 12 includes a first region and a second region that are connected to each other. Both the first region and the second region are annular and completely cover the outer peripheral surface 12. The first region is connected to the first edge, and the second region is connected to the second edge. The cross-section of the first region is arc-shaped with an arc of 120°-135°. A hydrogel layer is formed on the first region, but no hydrogel layer is formed on the second region.

[0024] The first and second regions together form the outer peripheral surface 12. The arc of the cross-section of the outer peripheral surface 12 is 180°. The arc of the first region is 120°-135°, and therefore the arc of the second region is 60°-45°. In practical applications, the first region does not directly contact the left atrial appendage, while the second region does. No hydrogel layer is formed on the second region, thereby avoiding the reduction of friction between the sealing structure and the left atrial appendage due to the presence of a hydrogel layer, and preventing detachment caused by insufficient friction between the structure and the left atrial appendage.

[0025] The first region is formed into a hydrogel layer by the following method.

[0026] Solution A and solution B are applied to the first region respectively, so that a hydrogel layer is formed on the first region; Solution A is an Alg / HA-BP solution (alginate modified with bisphosphanate (BP) and hyaluronic acid modified with bisphosphanate); Solution B is a CaSO4 (calcium sulfate) solution containing YAP / TAZ activating peptide, wherein the concentration of YAP / TAZ activating peptide is 10 μM. 2+ Concentration 80mM.

[0027] YAP / TAZ stands for YAP (Yes-associated protein): Yes-related protein (or "YAP transcriptional regulatory protein"); and TAZ (Transcriptional coactivator with PDZ-binding motif): TAZ (transcriptional coactivator with PDZ-binding domain).

[0028] Alg / HA-BP solution was obtained by the following method: S10, Obtain HA-BP (bisphosphate modified hyaluronic acid) and Alg-RGD-BP.

[0029] Alg-RGD-BP is a sodium alginate modified with bisphosphonate (BP) and a short peptide (RGD) composed of arginine (R), glycine (G) and aspartic acid (D) that promotes cell adhesion.

[0030] S20. Dissolve Alg-RGD-BP and HA-BP in HEPES (4-hydroxyethylpiperazine ethanesulfonic acid solution) to obtain Alg / HA-BP solution, wherein the mass ratio of Alg-RGD-BP to HA-BP is 4:1 and the mass ratio of Alg-RGD-BP to Alg / HA-BP is 1:100.

[0031] The method for forming a hydrogel layer on the first region is as follows: S30. Cover the sealing body with silicone or PTFE (polytetrafluoroethylene), wherein the covering surface is all surfaces of the sealing body except for the first region.

[0032] S40. Solution A and solution B are sequentially applied to the first region, and solutions A and B crosslink to form a hydrogel layer.

[0033] HA-BP is obtained using the following method: MeHA (methacrylated hyaluronic acid) was dissolved in triethanolamine buffer and stirred overnight to obtain solution number one.

[0034] Add 5.5 eq of thiol-BP (thiol-bisphosphate) and 7.5 mM of TCEP (tris(2-carboxyethyl)phosphine hydrochloride) to solution No. 1, stir and react for 48 h (stirring continuously for 48 h) to obtain solution No. 2.

[0035] Solution No. 2 was dialyzed with deionized water for 3 days to obtain solution No. 3.

[0036] Solution No. 3 was frozen overnight at -30°C, then transferred to a lyophilizer for lyophilization to obtain HA-BP, which was then stored at -20°C.

[0037] Alg-RGD-BP is obtained using the following method: Dissolve 0.2g of sodium alginate in 20mL of MES (L2-(N-morpholino)ethanesulfonic acid) buffer, stir, and let stand overnight to obtain solution No. 4.

[0038] Add excess Sulfo-NHS (N-hydroxysulfosuccinimide), excess EDC (1-ethyl-(3-dimethylaminopropyl)carbodiimide), and excess BP (bisphosphate) to solution No. 4, stir and react for 24 hours to obtain solution No. 5.

[0039] Solution No. 5 was dialyzed with deionized water for 3 days to obtain solution No. 6.

[0040] Solution No. 6 was frozen overnight at -30°C, then transferred to a lyophilizer to obtain Alg-RGD-BP, which was stored at -20°C.

[0041] In addition, in step S40, the hydrogel layer can be formed by spin coating or spray coating.

[0042] Spin coating method: Tilt the outer disk 11 of the plugger so that the first edge is rotated and immersed in Alg / HA-BP solution (45° angle, 5 seconds), then lifted; immerse in solution B, rotate 3 times to uniformly crosslink and form hydrogel, then lift.

[0043] Spraying method: First spray solution A onto the first area, then spray solution B to cross-link and form a hydrogel layer.

[0044] The hydrogel layer has a hardness of 8-10 kPa and a relaxation time of 20 s.

[0045] It should be understood that the above embodiments are merely exemplary and not restrictive. Various obvious or equivalent modifications or substitutions that can be made by those skilled in the art regarding the above details without departing from the basic principles of the present invention will be included within the scope of the claims of the present invention.

Claims

1. A sealing structure that facilitates cell adhesion, characterized in that, The device includes a sealing body comprising a contraction section and an outer disc section, the contraction section and the outer disc section being interconnected. In the deployed state, the outer diameter of the contraction section is smaller than the outer diameter of the outer disc section. The outer surface of the outer disc section includes a circular outer disc surface and an annular outer peripheral surface. The cross-section of the outer peripheral surface is semi-circular. The outer edge of the outer disc surface is connected to a first edge of the outer peripheral surface, and a second edge of the outer peripheral surface is connected to one end of the contraction section. Both the first edge and the second edge are circular. The first edge is farther away from the contraction section than the second edge. A hydrogel layer is formed on the outer peripheral surface. The outer peripheral surface includes a first region and a second region that are connected to each other; a hydrogel layer is formed on the first region, and no hydrogel layer is formed on the second region. The first region is formed into a hydrogel layer by the following method: Solution A and solution B are applied to the first region respectively, so that a hydrogel layer is formed on the first region; Solution A is an Alg / HA-BP solution; Solution B is a CaSO4 solution with added YAP / TAZ activating peptide, wherein the concentration of YAP / TAZ activating peptide is 10 μM and the concentration of Ca2+ is 80 mM. The Alg / HA-BP solution was obtained by the following method. S10, Obtain HA-BP and Alg-RGD-BP; S20. Dissolve Alg-RGD-BP and HA-BP in HEPES to obtain an Alg / HA-BP solution, wherein the mass ratio of Alg-RGD-BP to HA-BP is 4:1 and the mass ratio of Alg-RGD-BP to Alg / HA-BP is 1:

100. HA-BP is obtained using the following method: MeHA was dissolved in triethanolamine buffer and stirred overnight to obtain solution number one. Add 5.5 eq of thiol-BP and 7.5 mM of tris(2-carboxyethyl)phosphine hydrochloride to solution No. 1, stir and react for 48 h to obtain solution No. 2; Solution No. 2 was dialyzed with deionized water for 3 days to obtain solution No. 3; Solution No. 3 was frozen overnight at -30°C, then transferred to a lyophilizer for lyophilization to obtain HA-BP, which was then stored at -20°C. Alg-RGD-BP is obtained using the following method: Dissolve 0.2 g of sodium alginate in 20 mL of L2-(N-morpholino)ethanesulfonic acid buffer, stir, and let stand overnight to obtain solution No. 4; Add excess N-hydroxysulfosuccinimide, excess 1-ethyl-(3-dimethylaminopropyl)carbodiimide and excess bisphosphate to solution No. 4, stir and react for 24 h to obtain solution No. 5; Solution No. 5 was dialyzed with deionized water for 3 days to obtain solution No. 6; Solution No. 6 was frozen overnight at -30°C, then transferred to a lyophilizer to obtain Alg-RGD-BP, which was stored at -20°C.

2. The sealing structure for facilitating cell adhesion according to claim 1, characterized in that, Both the first region and the second region are annular, and the first region and the second region completely cover the outer peripheral surface. The first region is connected to the first edge, and the second region is connected to the second edge. The cross-section of the first region is arc-shaped with an arc of 120°-135°.

3. The sealing structure for facilitating cell adhesion according to claim 2, characterized in that, The method for forming a hydrogel layer on the first region is as follows: S30. Cover the covering surface of the sealing body with silicone or PTFE, wherein the covering surface is all surfaces of the sealing body except for the first region; S40. Solution A and solution B are sequentially applied to the first region, and solutions A and B crosslink to form a hydrogel layer.

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