A vascular stent based on zoned coating and microporous gradient drug loading

Abstract

The application provides a vascular stent based on a partitioned coating and a micropore gradient drug loading, and relates to the technical field of vascular stents.The vascular stent comprises a stent base body, the outer surface of the stent base body is provided with a plurality of micropores, a first drug coating is attached to the pore wall of the micropores, wherein the first drug coating comprises a drug crystal layer composed of a fat-soluble anti-proliferative drug, and the adhesion density of the drug crystal layer in the micropores decreases in a gradient distribution from the pore bottom to the pore opening direction, so as to inhibit the burst release of the fat-soluble anti-proliferative drug in the early stage after the stent base body is implanted into a blood vessel; a second drug coating is arranged on the surface of the base body except the micropores, so that the first drug coating and the second drug coating are isolated from each other on the surface of the stent base body.The physical shielding effect and release interference effect between the anticoagulation functional layer and the drug controlled release functional layer are eliminated, and the burst release phenomenon of the drug in the early stage is inhibited.

Description

Technical Field

[0001] This application relates to the field of vascular stent technology, and in particular to a vascular stent based on partitioned coating and microporous gradient drug delivery. Background Technology

[0002] Vascular stent implantation is a core interventional procedure for the clinical treatment of atherosclerotic stenosis and occlusion. Currently, the most widely used vascular stents in clinical practice are mainly divided into two categories: bare-metal stents and drug-eluting stents. After bare-metal stent implantation, vascular smooth muscle cells are prone to excessive proliferation and migration into the lumen under the stimulation of the metallic foreign body, leading to a persistently high in-stent restenosis rate. Applying a drug-eluting coating to the surface of the metal stent can reduce the restenosis rate. Mainstream drug-eluting stents use permanent or biodegradable polymer coatings as drug carriers.

[0003] However, in existing drug-eluting stents, the drug coating is often randomly and uniformly distributed on the stent surface, which can easily lead to a significant drug burst release in the early stages of implantation. This makes it difficult to maintain a stable drug action cycle over a long period, reducing the inhibitory effect on the sustained proliferation of vascular smooth muscle cells. On the other hand, after vascular stent implantation, protein adsorption, platelet adhesion, and coagulation cascade reactions are easily induced, increasing the risk of thrombosis. Furthermore, the antithrombotic coating in drug-eluting stents is often placed in the same area as other functional coatings, or mixed with them on the stent surface. This interference between different functional drugs prevents them from effectively exerting their anticoagulant effect, leading to an increased risk of acute thrombosis in the early stages of stent implantation. Summary of the Invention

[0004] To address the aforementioned problems, one or more embodiments of the present invention provide a vascular stent based on partitioned coating and microporous gradient drug loading, thereby solving the problem that current drug-eluting stents have weak anti-proliferative and anti-thrombotic effects.

[0005] To achieve this objective, embodiments of the present invention provide a vascular stent based on a partitioned coating and microporous gradient drug delivery, the vascular stent comprising: The scaffold substrate has multiple micropores on its outer surface; A first drug coating is attached to the pore wall of the micropore; wherein the first drug coating includes a drug crystal layer composed of a lipid-soluble antiproliferative drug, and the drug crystal layer has a decreasing gradient distribution in the micropore along the direction from the bottom of the pore to the pore opening, so as to inhibit the burst release of the lipid-soluble antiproliferative drug in the early stage of implantation after the stent matrix is ​​implanted into the blood vessel. A second drug coating is disposed on the substrate surface other than the micropores, such that the first drug coating and the second drug coating are isolated from each other on the surface of the scaffold substrate.

[0006] Optionally, the second drug coating includes a nitrogen-rich modified layer and a heparin layer covalently bonded to the surface of the nitrogen-rich modified layer, and the nitrogen-rich modified layer covers the substrate surface except for the micropores.

[0007] Optionally, the micropore is a blind hole with a diameter that gradually decreases from the opening to the bottom.

[0008] Optionally, the second drug coating continuously covers the substrate surface except for the micropores, and the first drug coating continuously covers the pore walls of the micropores; and the pore walls of the micropores have a boundary region formed by femtosecond laser processing technology, the boundary region making the first drug coating and the second drug coating discontinuous on the surface of the scaffold substrate.

[0009] Optionally, the nitrogen-rich modified layer includes a nitrogen-enriched surface layer, which is prepared by covering the surface of the scaffold substrate with nitrogen using nitrogen plasma immersion ion implantation technology; And / or, the heparin layer comprises a monolayer of heparin molecules, wherein the heparin layer is formed by covalently grafting heparin molecules onto the surface of the nitrogen-rich modified layer via amide bonds through silane coupling agent activation combined with EDC / NHS coupling technology.

[0010] Optionally, the thickness of the nitrogen-rich modified layer is 100 nm to 300 nm, and the grafting amount of heparin molecules is 20 ng / cm. 2 ~40ng / cm 2 .

[0011] Optionally, the support base is a tubular mesh structure formed by arranging multiple ribs, and the cross-section of the ribs is a rounded flat rectangle.

[0012] Optionally, the width of the rib is 100μm~130μm and the thickness is 70μm~90μm.

[0013] Optionally, the pore diameter is 6μm~10μm, the bottom diameter is 3μm~5μm, the depth is 8μm~15μm, and the center-to-center distance between adjacent pores is 30μm~60μm.

[0014] Optionally, the lipid-soluble antiproliferative drug includes either rapamycin or everolimus.

[0015] Compared with the prior art, this application has the following advantages: The vascular stent provided in this application avoids chronic inflammation of the vascular wall, eosinophil infiltration, and poor stent apposition caused by polymer degradation products because neither the first nor the second drug coating contains a polymer carrier. This fundamentally eliminates the long-term safety hazard of in-stent thrombosis. By partitioning the first and second drug coatings on the surface of the stent substrate, the first drug coating on the inner wall of the micropores and the second drug coating on the substrate surface outside the micropores are spatially independent. This allows the drug release process and anticoagulation function to operate independently, fundamentally eliminating the physical shielding effect and release interference effect between the anticoagulation functional layer and the drug controlled-release functional layer. Simultaneously, the first drug coating exhibits a gradient distribution with decreasing density from the inside to the outside within the micropores, reducing the risk of lipid-soluble antiproliferative drugs being washed away in the early stages, effectively inhibiting the initial burst release of the drug, prolonging the duration of action of the antiproliferative drug, and ensuring a sustained and stable restenosis inhibition effect. Attached Figure Description

[0016] To more clearly illustrate the technical solution of this application, the drawings used in the description of this application will be briefly introduced below. Obviously, the drawings described below are only some embodiments of this application. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0017] Figure 1 This is a schematic diagram of the overall structure of a vascular stent based on partitioned coating and microporous gradient drug loading according to an embodiment of this application; Figure 2 This is a partial structural schematic diagram of the support substrate provided in one embodiment of this application.

[0018] Explanation of reference numerals in the attached figures: 1. Scaffold matrix; 2. Micropores; 3. First drug coating; 4. Nitrogen-rich modified layer; 5. Heparin layer. Detailed Implementation

[0019] The technical solutions of the embodiments of this application will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of this application, not all embodiments. Based on the embodiments of this application, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of this application.

[0020] To facilitate understanding of this article, a further explanation of the background technology is provided first. Current drug-eluting stents typically load anti-proliferative drugs onto the stent surface, allowing the drugs to be released after implantation to inhibit the proliferation of vascular smooth muscle cells, thereby reducing the probability of restenosis. With the continuous development of stent technology, further methods such as loading anticoagulants, hydrophilic materials, or biocompatible coatings onto the stent surface are used to improve blood compatibility. However, regardless of the type of drug-eluting stent, drug loading is achieved by forming a drug coating on the entire stent surface, and the drug coating is mostly a polymer carrier uniformly covering the stent surface. This drug coating structure has several shortcomings.

[0021] Firstly, the acidic products and microparticles generated during the degradation of the polymer coating in vivo can easily trigger chronic inflammatory reactions in the vascular wall, eosinophil infiltration, and poor positive remodeling of the vascular wall, which in turn leads to poor stent apposition and significantly increases the risk of late-stage in-stent thrombosis. Patients need to take dual antiplatelet drugs for a long time after the operation, which increases the risk of bleeding.

[0022] Secondly, to increase drug loading, a method exists to construct microporous structures on the stent surface to accommodate the drug. However, the drug is mostly uniformly deposited / covered on the entire outer surface of the stent. After stent implantation, the drug inside and outside the pores is released simultaneously by blood flushing and tissue fluid infiltration, easily causing a significant drug burst in the early stages of implantation. This leads to a rapid increase in drug concentration in a short period, with both inside and outside the pores exhibiting an initial concentration followed by insufficient release, thus shortening the drug release cycle. This is especially true for antiproliferative drugs, not only reducing drug utilization efficiency but also easily affecting the inhibitory effect on the sustained proliferation of vascular smooth muscle cells, thereby impacting long-term restenosis resistance.

[0023] Thirdly, to simultaneously achieve the dual therapeutic goals of antithrombosis and restenosis inhibition, researchers have proposed a multi-drug coating scheme that incorporates an anticoagulant layer (such as a heparin coating) and an anti-stenosis layer (such as an antiproliferative drug coating) on ​​the stent surface. However, heparin coatings are mostly immobilized using polymer carriers. In addition to the shortcomings mentioned in the first point, the polymer layer also has limited physical barrier capabilities against protein adsorption, focusing more on subsequent interventions in the coagulation cascade and having limited inhibitory effects on the initial adsorption phase of plasma proteins.

[0024] Fourthly, multiple drug-eluting layers are typically stacked from the inside out on the stent surface, with heparin layer 5 at the bottom and the remaining layers on top. This often leads to interference between different functional drugs, and the release kinetics, interfacial stability, and functional parameters of the drug coatings are mutually constrained. For example, beneath the stack, the thickness and grafting density of heparin layer 5 affect the bonding force between the remaining drug layers and the matrix. The drug loading and thickness of other drug layers simultaneously affect the contact efficiency between heparin layer 5 and the blood, limiting the maximum effectiveness of each layer. For instance, the anti-stenosis functional layer blocks the drug release behavior of the anticoagulant functional layer. In the early stages of drug release, it hinders the direct contact between heparin molecules and the blood, reducing the anticoagulant activity of heparin. Especially when the drug layer is thick or the drug loading is large, heparin layer 5 remains shielded for a considerable period, unable to effectively exert its anticoagulant effect, potentially leading to acute thrombosis risks in the early to late stages of stent implantation.

[0025] In addition, existing drug-eluting stents also suffer from insufficient local adhesion stability and are prone to delamination, cracking, or particle shedding during long-term service.

[0026] In view of this, how to reduce the initial burst release of drugs and prolong the stable release period of drugs while ensuring the anti-restenosis effect of the stent, and how to ensure that the anticoagulation function and the controlled release function do not interfere with each other after implantation, has become an urgent technical problem to be solved in the field of drug-eluting vascular stents.

[0027] In order to overcome or at least partially solve the above problems, refer to Figure 1 and Figure 2 As shown, Figure 1 This is a diagram illustrating the overall structural composition of the vascular stent based on partitioned coating and microporous gradient drug loading according to the present invention. Figure 2 This is a partial schematic diagram of the scaffold substrate 1. (See attached diagram.) Figure 1 As shown, this embodiment of the invention provides a vascular stent based on a partitioned coating and microporous gradient drug loading. The vascular stent includes: a stent substrate 1, with a plurality of micropores 2 formed on the outer surface of the stent substrate 1; a first drug coating 3, which is attached to the pore walls of the micropores 2; wherein the first drug coating 3 includes a drug crystal layer composed of a lipid-soluble antiproliferative drug, and the drug crystal layer has a decreasing gradient distribution in the attachment density along the direction from the bottom to the opening of the micropores 2, so as to inhibit the burst release of the lipid-soluble antiproliferative drug in the early stage of implantation after the stent substrate 1 is implanted into the blood vessel; and a second drug coating, which is disposed on the substrate surface other than the micropores 2, so that the first drug coating 3 and the second drug coating are isolated from each other on the surface of the stent substrate 1; wherein the second drug coating includes an antithrombotic drug without polymers.

[0028] In this embodiment, the provided vascular stent includes a stent substrate 1, which can be a metal stent substrate. The metal stent substrate can be made of any one or more of stainless steel, cobalt-chromium alloy, platinum-chromium alloy, nickel-titanium alloy, magnesium alloy, zinc alloy, and iron-based biodegradable alloy. The stent substrate 1 is laser-engraved and electropolished, resulting in a smooth, burr-free surface. The stent substrate 1 has a radially compressible and expandable tubular mesh structure, composed of multiple axially arranged wave-shaped ribs connected by connecting rods. The cross-section of the ribs is a rounded, flat rectangle. The expanded diameter of the stent substrate 1 should be adapted to the target vessel size, and different nominal diameters and lengths can be manufactured according to clinical needs. In this embodiment, the stent substrate 1 is made of medical-grade cobalt-chromium alloy (L605).

[0029] Multiple micropores 2 can be formed on the inner surface, outer surface, and outer wall region of the stent substrate 1. Preferably, multiple uniformly distributed micropores 2 are formed on the outer surface of the ribs of the stent substrate 1 (i.e., the side surface that adheres to the blood vessel wall after stent implantation). The inner surface is the side surface opposite to the outer surface, or the side surface of the stent substrate 1 facing the center of the blood vessel. The micropores 2 can be formed on the outer surface of the stent substrate 1 from the outside in using techniques such as laser processing, electrochemical etching, and photolithography. Each micropore 2 is recessed into the surface of the rib, and the opening of the micropore 2 communicates with the external environment but does not penetrate the rib. In some embodiments, the micropores 2 can be circular, elliptical, polygonal, conical, stepped, or irregular. In some embodiments, multiple micropores 2 are distributed at intervals on the outer surface of the stent substrate 1. In some preferred embodiments, the micropores 2 form a gradient structure in diameter along the direction from the bottom to the opening. Preferably, the pore size of the micropore 2 near the bottom of the pore is smaller than that near the opening of the pore, so as to enhance the adhesion stability of the drug crystal layer in the bottom of the pore.

[0030] The first drug coating 3 is disposed on the surface of the pore wall of the micropore 2, thereby forming a first drug coating region on the surface of the stent substrate 1. The first drug coating 3 includes a drug crystal layer composed of a lipid-soluble antiproliferative drug, for example, composed of microcrystals of a lipid-soluble antiproliferative drug. This drug crystal layer is directly attached to the inner wall of the micropore 2, that is, the lipid-soluble antiproliferative drug is in direct contact with the bare metal substrate. Preferably, the lipid-soluble antiproliferative drug may include rapamycin and everolimus or their derivatives, etc., to inhibit the abnormal proliferation of vascular smooth muscle cells, thereby reducing the risk of restenosis.

[0031] like Figure 2As shown, as one improvement of this embodiment, the drug crystal layer forms a gradient distribution with decreasing adhesion density along the direction from the bottom to the opening of the micropore 2. This gradient distribution with decreasing adhesion density can be understood as at least one microcrystal aggregation parameter, such as coverage, packing density, thickness, crystal size, and crystal continuity of the lipid-soluble antiproliferative drug per unit area, decreasing from the bottom to the opening. The drug crystal layer is formed on the inner wall of the micropore 2 through a solution deposition combined with a drying crystallization process. During the gradient distribution drug loading process of the micropore 2, the desired gradient distribution morphology of the drug crystal layer inside the micropore 2 can be formed by controlling the structural parameters and drug loading parameters of the micropore 2. Exemplarily, the gradient distribution may include a continuous decreasing distribution towards the opening, a segmented decreasing distribution, a step-like decreasing distribution, a linear decreasing distribution, a non-linear decreasing distribution, and other gradient distributions. This can be achieved through multiple step-by-step deposition, masking, or zoned concentration control processes. This zoned control process is a common processing method, and will not be elaborated upon further in this embodiment.

[0032] By distributing the first drug coating 3 within the micropores 2 with a density gradient at the bottom of the pores compared to the opening, after the stent substrate 1 is implanted into the blood vessel, the scouring effect of blood flow on the stent surface mainly acts on the outer surface of the ribs and the shallow region of the micropore opening 2. The dense crystalline layer at the bottom of the pores, being deep within the narrow cavity and needing to overcome the frictional resistance of the pore wall and the geometric constraints of the pore bottom to migrate outwards, is not easily directly scoured away. Therefore, the thickness parameter of the first drug coating 3 is used to suppress the rapid release of the drug in the early stages of implantation, making the drug release process more gradual.

[0033] Preferably, the drug crystal layer in this application exhibits a continuously decreasing gradient distribution in adhesion density along the direction from the bottom to the opening of the micropore 2. This allows the drug release path to gradually change along the depth of the pore, reducing localized rapid dissolution caused by sudden changes in local drug accumulation. This makes the drug release process within the pore more stable and helps maintain the consistency of long-term anti-proliferation effects. Furthermore, the continuously decreasing structure can be formed by utilizing the enrichment pattern of the drug within the micropore 2, relying on the spontaneous migration of drug molecules to create a gradual density transition. This eliminates the need for multiple independent processing or zoned control of different depth regions, thereby reducing process complexity.

[0034] The second drug coating is then described. The second drug coating is applied to the substrate surface excluding the micropores 2, forming a second drug coating region on the surface of the stent substrate 1. This second drug coating region is separate from the first drug coating region by the boundary of the micropores 2, allowing the first drug coating 3 and the second drug coating to be located in different areas of the stent substrate 1. The second drug coating may partially or completely cover the non-microporous areas of the stent substrate 1. In this embodiment, the second drug coating specifically refers to an antithrombotic drug that does not contain a polymer. Preferably, the antithrombotic drug is heparin, i.e., heparin is not disposed on the stent substrate 1 via a polymer carrier. It is used to inhibit platelet activation and inactivate coagulation factors, thereby reducing the risk of thrombosis after stent implantation. Therefore, the first drug coating 3 and the second drug coating form non-overlapping functional zones, avoiding interference between the antiproliferative drug and the antithrombotic drug.

[0035] In summary, the vascular stents of one or more embodiments of this application are applicable to scenarios such as coronary artery stents, peripheral vascular stents, cerebral vascular stents, aortic branch stents, biodegradable stents, or drug-eluting stents. Since neither the first drug coating 3 nor the second drug coating contains a polymer carrier, chronic inflammation of the vascular wall, eosinophil infiltration, and poor stent apposition caused by polymer degradation products are avoided, fundamentally eliminating the long-term safety hazard of in-stent thrombosis. By partitioning the surface of the stent substrate 1 with the first drug coating 3 and the second drug coating, the first drug coating 3 on the inner wall of the micropore 2 and the second drug coating on the substrate surface outside the micropore 2 are spatially independent, allowing the drug release process and anticoagulation function to operate independently, fundamentally eliminating the physical shielding effect and release interference effect between the anticoagulation functional layer and the drug controlled-release functional layer. Simultaneously, the first drug coating 3 exhibits a gradient distribution with decreasing density from the inside to the outside within the micropore 2, reducing the risk of lipid-soluble antiproliferative drugs being washed away in the early stages, effectively inhibiting the initial burst release of the drug, prolonging the duration of action of the antiproliferative drug, and ensuring a sustained and stable restenosis inhibition effect.

[0036] As an extension of this embodiment, mutual isolation may include an isolation method where the edges of the micropores 2 are separated by boundaries. A gap may exist between the first drug coating 3 and the second drug coating, and the width of this gap may be set to be small. For example, the first drug coating 3 may be a certain distance from the pore opening, and / or the second drug coating may be a certain distance from the edge of the pore opening, such that the two coatings are spaced apart on the scaffold substrate 1. In some embodiments, mutual isolation between the two drugs may include an isolation method where the boundaries are directly adjacent. Specifically, the first drug coating 3 is disposed inside the micropores 2, and the second drug coating is disposed in the outer peripheral region of the micropores 2. The two are joined at the pore opening edge of the micropores 2 to form a stepped functional layer structure that extends continuously along the surface of the scaffold substrate 1. For example, the first drug coating 3 terminates just inside the pore opening, and the second drug coating just covers the substrate surface (including the pore opening edge) except for the micropores 2, to form a functional partition structure with the pore opening edge of the micropores 2 as the boundary. The two coatings are adjacent on the scaffold substrate 1 but do not overlap. By isolating the two coatings directly adjacent to each other, the two coatings can completely cover the entire surface of the stent substrate 1, ensuring the continuity of the two coatings in their respective coating areas, thereby maximizing the anti-restenosis function and anti-thrombotic function of the blood vessel respectively.

[0037] As a specific design of this embodiment, the second drug coating continuously covers the substrate surface except for the micropores 2, and the first drug coating 3 continuously covers the pore walls of the micropores 2; and there is a boundary region formed by femtosecond laser processing technology at the edge of the pore wall of the micropores 2, the boundary region making the first drug coating 3 and the second drug coating discontinuous on the surface of the scaffold substrate 1.

[0038] In this embodiment, the second drug coating is first loaded onto the scaffold substrate 1. Then, micropores are formed on the scaffold substrate 1 with the second drug coating using femtosecond laser processing technology. This allows the second drug coating in the micropore processing area to be removed simultaneously, resulting in exposed micropores 2 not covered by the second drug coating. Then, the first drug coating 3 is loaded into the micropores 2. Because the first drug coating 3 is separated by the substrate area between the micropores 2, the first drug coating 3 is discontinuous on the surface of the scaffold substrate 1. At the same time, the second drug coating is separated by the micropores 2, making the second drug coating discontinuous on the surface of the scaffold substrate 1. This results in a non-overlapping functional partition structure where the first drug coating 3 and the second drug coating are isolated from each other in the orifice area.

[0039] Therefore, femtosecond laser processing technology enables the partitioned loading of the two functional coatings in the boundary region generated at the aperture edge, ensuring no coating overlap between the first and second drug coating areas. Compared to processing the micropores 2 first and then loading the two drug coatings separately, the method of loading the entire structure and then processing with laser avoids the process complexity brought about by traditional masking or area-selective loading processes. Since the second drug coating is formed as a whole first, it is easier to ensure the integrity and uniformity of the second drug coating in non-micropore areas. At the same time, the boundary region formed by laser processing technology is particularly suitable for micropore array structures. When there are many micropores 2 and the aperture is small, femtosecond laser can quickly form a large-scale micropore array through programmed scanning and simultaneously achieve functional layer region separation, which is more suitable for large-scale manufacturing. Moreover, the ultrashort pulse characteristics of femtosecond laser limit the damage to the coating around the aperture during processing to the boundary region, with a very small heat-affected zone, and does not cause thermal deformation of the substrate material (such as the second drug coating area) around the micropores 2.

[0040] As another improvement in this embodiment, the second drug coating includes a nitrogen-rich modified layer 4 and a heparin layer 5 covalently bonded to the surface of the nitrogen-rich modified layer 4, and the nitrogen-rich modified layer 4 covers the substrate surface except for the micropores 2. In this embodiment, the nitrogen-rich modified layer 4 and the heparin layer 5 are sequentially disposed on the scaffold substrate 1 from the inside to the outside, and the heparin layer 5 is covalently grafted to the substrate surface through the nitrogen-rich modified layer 4. The nitrogen-rich modified layer 4 is specifically an inorganic surface layer enriched with nitrogen, which is used to reduce the free energy of the metal surface, thereby weakening the physical adsorption tendency of the surface of the scaffold substrate 1 for plasma proteins such as fibrinogen. At the same time, no delamination or cracking occurs during the radial compression and expansion of the scaffold, significantly improving the mechanical durability of the coating. Preferably, the thickness of the nitrogen-rich modified layer 4 is 100nm~300nm. By controlling the thickness of the nitrogen-rich modified layer 4, the density of surface functional groups and the flexible deformation capability during the expansion process of the scaffold can be balanced.

[0041] The heparin molecules in heparin layer 5 have active sites that specifically bind to thrombin and coagulation factor Xa. Simultaneously, their negative charge generates electrostatic repulsion against platelets, thereby endowing the outer surface of the scaffold matrix 1 with anticoagulant function. Because the heparin molecules are fixed by covalent bonds, they do not detach in vivo, which helps maintain the long-term stability of the interfacial function, thus preserving the long-term anticoagulant effect of the heparin molecules.

[0042] Thus, by using the nitrogen-enriched modified layer 4 as a carrier for antithrombotic drugs, the nitrogen-enriched modified layer 4 on the outer surface of the stent works synergistically with the covalently fixed heparin monolayer to inhibit thrombus formation from two levels: physically blocking protein adsorption and chemically inactivating coagulation factors. Simultaneously, because the nitrogen-enriched modified layer 4 does not contain polymers, it completely eliminates the need for polymer coatings, preventing chronic inflammation of the vessel wall and late-stage apposition problems caused by polymer degradation products, thereby reducing the risk of very late-stage in-stent thrombosis.

[0043] Preferably, the nitrogen-rich modified layer 4 is formed using nitrogen plasma immersion ion implantation technology. The heparin layer 5 comprises a monolayer of heparin molecules, which is formed by covalently grafting heparin molecules onto the surface of the nitrogen-rich modified layer 4 via amide bonds using silane coupling agent activation combined with EDC / NHS coupling technology. In this embodiment of the invention, the nitrogen-rich modified layer 4 is prepared using nitrogen plasma immersion ion implantation technology. This process implants nitrogen ions into the surface of a metal substrate to form a nitrogen-rich surface layer. An inorganic diffusion interface is formed between the implanted nitrogen atoms and metal atoms, eliminating the delamination problem caused by insufficient adhesion between traditional organic polymer coatings and metal substrates.

[0044] Heparin layer 5 is formed by covalently grafting heparin molecules onto the surface of nitrogen-rich modified layer 4 via amide bonds using a silane coupling agent activation combined with EDC / NHS coupling technology, creating a monolayer. The silane coupling agent activates the surface of nitrogen-rich modified layer 4 through surface amination, introducing amino or active silane groups that can be used for subsequent coupling reactions. Subsequently, the EDC / NHS coupling system drives the reaction between heparin molecules and the amino groups on the surface of nitrogen-rich modified layer 4, forming an amide bond connection structure, thus achieving covalent grafting and fixation of heparin molecules on the surface of nitrogen-rich modified layer 4. Therefore, the covalent graft structure formed by amide bonds has high chemical stability, enabling heparin layer 5 to maintain a stable attachment state even under long-term blood flow, stent expansion deformation, and body fluid environments, further reducing the risk of heparin detachment. Simultaneously, the monolayer structure reduces the overall thickness of heparin layer 5, thereby reducing localized cracking, interlayer delamination, or particle detachment caused by the stretching of a thick coating during stent expansion.

[0045] Therefore, the nitrogen-enriched modified layer 4 and the heparin layer 5 together constitute a polymer-free antithrombotic functional layer. The nitrogen-enriched modified layer 4 acts as a carrier for the heparin layer 5 and can reduce protein adsorption. The heparin layer 5 is used to inactivate thrombin and coagulation factor Xa, thereby forming a surface antithrombotic structure with synergistic effects of physical anti-adsorption and chemical anticoagulation.

[0046] Preferably, the grafting amount of heparin molecules is controlled to be 20 ng / cm using silane coupling agent activation combined with EDC / NHS coupling technology. 2 ~40ng / cm 2The grafting amount can be adjusted by controlling process parameters such as the density of the silane coupling agent, the concentration of the EDC / NHS coupling system, the concentration of the heparin molecule solution, and the reaction time. The process steps and parameter adjustment methods of the silane coupling agent activation technology and the EDC / NHS coupling technology can be understood from known technologies or the examples below. If the grafting amount is too low, the heparin coverage on the surface of the scaffold matrix 1 will be insufficient, potentially exposing some matrix areas and reducing the inactivation capacity for thrombin and coagulation factor Xa. If the grafting amount is too high, heparin molecules will undergo multilayer stacking, potentially obscuring some active sites and reducing the effective utilization rate of heparin molecules. Therefore, the grafting amount of heparin molecules is controlled at 20 ng / cm³. 2 ~40ng / cm 2 This allows heparin molecules to form a relatively uniform monomolecular distribution on the surface of the nitrogen-rich modified layer 4, taking into account anticoagulant activity, surface stability, and interfacial integrity during scaffold expansion.

[0047] As a further explanation of this embodiment, micropore 2 is a frustum-shaped blind aperture with a diameter that tapers from the opening to the bottom. In this embodiment, micropore 2 is a blind aperture with a diameter that tapers from the opening to the bottom. The tapering blind aperture forms a cavity with a large opening and a small bottom. The narrow area at the bottom of the aperture provides geometric constraint and mechanical protection for dense drug crystallization, making it less likely for the high-density drug layer located deep at the bottom of the aperture to be directly washed away and peeled off by blood flow after stent implantation. At the same time, the wider opening area of ​​the aperture facilitates the full wetting and filling of the cavity by the drug solution during drug loading and provides a channel for solvent evaporation during drying. This tapering micropore configuration can also provide mechanical anchoring points for endothelial cells, guiding the directional migration and spreading of cells. Meanwhile, the polymer-free clean surface eliminates the toxic inhibition of chronic inflammation on endothelial cells, accelerating the endothelial integrity process within the stent lumen.

[0048] Then, by controlling the micropores 2 to have a tapered configuration, the formation of a gradient distribution pattern of the drug crystal layer can be promoted. During the loading process of the first drug coating 3, the drug solution used in the first drug coating 3 can also be driven by capillary action to flow and accumulate towards the bottom of the pore along the inclined inner wall of the frustum-shaped micropores 2. After drying, a gradient distribution is naturally formed in which the density of the bottom region is higher than that of the opening region. This gradient distribution pattern is adapted to the frustum-shaped structure of the micropores 2, which has a larger opening and a smaller bottom. Since the diameter of the bottom of the pore is smaller than the diameter of the opening, the dense drug crystal layer is mainly concentrated in the narrowest space at the bottom of the pore.

[0049] Preferably, the pore diameter of the micropore 2 is 6μm~10μm, the bottom diameter is 3μm~5μm, the depth is 8μm~15μm, and the center-to-center distance between adjacent micropores 2 is 30μm~60μm. The micropore array covers the main area of ​​the outer surface of the ribs. In this embodiment, a larger pore size facilitates the entry of the drug solution into the micropore 2 and improves the drug deposition efficiency, while a smaller bottom size enhances the mechanical embedding ability of the drug crystal layer in the bottom region. Simultaneously, the pore diameter and bottom diameter determine the taper range of the micropore 2, which promotes a gradient distribution of drug crystal layer density decreasing from the bottom to the pore opening within the pore cavity. The pore depth provides sufficient longitudinal distribution space for the gradient crystal layer, ensuring that the drug loading meets therapeutic requirements. The center-to-center distance between the micropores 2 allows sufficient rib material to be retained between adjacent micropores 2 to maintain the overall mechanical strength and expansion support capacity of the scaffold ribs, while simultaneously forming a second drug coating of sufficient width on the surface of the ribs between the micropores 2. Therefore, the above parameter combination achieves synergistic optimization between drug loading capacity, gradient distribution scale, and structural strength.

[0050] In some embodiments, the micropore array is arranged periodically along the length of the ribs. More preferably, the width of the ribs in this invention is 100μm~130μm and the thickness is 70μm~90μm. This embodiment further designs the dimensional parameters of the ribs, which can provide sufficient arrangement space for the micropore array, ensuring that one or more rows of micropores 2 can be opened on a single rib to achieve an effective anti-proliferation drug loading. At the same time, within this size range, the ribs can still maintain sufficient radial support strength. The scaffold substrate 1 is a tubular mesh structure formed by arranging multiple ribs, and the cross-section of the ribs is a rounded flat rectangle. The rounded corners of the cross-section of the flat rectangle eliminate stress concentration at right-angle corners and reduce the risk of cracking or plastic deformation at the corners of the ribs during radial compression and expansion of the scaffold. The flat rectangular cross-section shape gives the ribs a large surface area in the width direction, providing sufficient surface area for the opening of the micropore array and the bearing of the second drug coating.

[0051] The embodiments of this application are described in detail below with reference to the accompanying drawings.

[0052] Example 1: A vascular stent based on partitioned coating and microporous gradient drug delivery includes a stent substrate 1. The stent substrate 1 is made of medical-grade cobalt-chromium alloy, laser-engraved and electropolished to achieve a smooth, burr-free surface. The stent substrate 1 has a radially compressible and expandable tubular mesh structure. The stent substrate 1 is composed of multiple axially arranged corrugated ribs connected by connecting rods. The cross-section of the ribs is a rounded, flat rectangle, with a width of 120 μm and a thickness of 80 μm. Multiple uniformly distributed micropores 2 are formed on the outer surface of the ribs of the stent substrate 1. Each micropore 2 is a frustum-shaped blind hole with a diameter gradually decreasing from the opening to the bottom. The opening diameter is 8 μm, the bottom diameter is 4 μm, the depth is 12 μm, and the center-to-center distance between adjacent micropores 2 is 45 μm.

[0053] The surface of the scaffold substrate 1, excluding the inner walls of the micropores 2, is covered with a nitrogen-rich modified layer 4. This nitrogen-rich modified layer 4 is a nitrogen-enriched surface layer formed by nitrogen plasma immersion ion implantation, and has a thickness of 200 nm. A heparin layer 5 is immobilized on the surface of the nitrogen-rich modified layer 4. The heparin layer 5 is a monolayer of heparin molecules formed by covalent bonding, and is firmly bonded to the surface of the nitrogen-rich modified layer 4 through activation with a silane coupling agent and EDC / NHS-mediated covalent bonding. The heparin grafting amount is 30 ng / cm³. 2 .

[0054] The inner wall of micropore 2 is directly attached with a rapamycin crystal layer composed of microcrystals of rapamycin. Inside a single micropore 2, the distribution of rapamycin exhibits a non-uniform gradient pattern. The closer to the bottom of the pore, the denser the drug crystal accumulation; the closer to the pore opening, the sparser the drug crystal distribution. By controlling drug loading parameters such as drug concentration, temperature, and time during the drug impregnation and drying process, and by ensuring that the drug solution flows and accumulates along the inclined inner wall towards the bottom of the pore due to capillary action during the impregnation and drying process, a gradient distribution is formed after drying, where the density at the bottom of the pore is higher than that at the pore opening. This gradient distribution pattern is adapted to the frustum-shaped structure of micropore 2, which has a larger opening and a smaller bottom. Because the diameter of the bottom of the pore is smaller than that of the opening, the dense drug crystal layer is mainly concentrated in the narrowest area at the bottom of the pore. After the stent is implanted into the blood vessel, the scouring effect of blood flow on the stent surface mainly acts on the outer surface of the rib and the shallow area of ​​the opening of the micropore 2. The dense crystals located at the bottom of the pore are located deep in the narrow cavity and need to overcome the frictional resistance of the inclined inner wall and the geometric constraints of the bottom of the pore to migrate outward. Therefore, the structure can inhibit the rapid release of drugs in the early stage of implantation and make the drug release process more gradual.

[0055] Furthermore, the edges and inclined inner walls of micropore 2 provide a favorable mechanical anchoring interface for the pseudopodia extension and adhesion focal formation of endothelial cells, which helps guide the endothelial cells to spread and migrate directionally along the scaffold direction. At the same time, the absence of a polymer coating avoids the potential inhibition of endothelial cell proliferation by coating degradation products and reduces the interference of the chronic inflammatory microenvironment on the endothelial repair process, creating favorable conditions for the rapid migration and coverage of endothelial cells after scaffold implantation.

[0056] The vascular stent of this embodiment can be obtained through the following procedure: S1. A cobalt-chromium alloy support substrate 1, laser-engraved and electrolytically polished, is provided. The support substrate 1 is placed in the chamber of a nitrogen plasma immersion ion implantation device. After evacuation, high-purity nitrogen gas is introduced, and a high-voltage pulse is applied for nitrogen ion implantation. The preferred implantation parameters are: implantation voltage of 20kV~40kV, and implantation dose of 1×10⁻⁶. 17 ions / cm 2 The processing time is 60 min to 120 min. After processing, a nitrogen-rich modified layer 4 with a thickness of about 200 nm is formed on the surface of the scaffold substrate 1. This layer covers the entire surface of the scaffold substrate 1.

[0057] S2. The scaffold substrate 1 obtained in S1 was immersed in an ethanol / water solution of a silane coupling agent (such as 3-aminopropyltriethoxysilane, APTES) and reacted at room temperature for 2 hours to activate surface amination. After removal, it was washed sequentially with ethanol and deionized water, and dried with nitrogen. Subsequently, the scaffold substrate 1 was immersed in MES buffer (pH 5.5) containing sodium heparin, EDC (1-ethyl-(3-dimethylaminopropyl)carbodiimide), and NHS (N-hydroxysuccinimide) and reacted at room temperature for 4 hours to covalently graft heparin molecules onto the surface of nitrogen-rich modified layer 4 via amide bonds. After the reaction, it was thoroughly washed with deionized water and dried to obtain heparin layer 5, with a heparin grafting amount of approximately 30 ng / cm. 2 .

[0058] S3. Next, a micropore array is fabricated on the outer surface of the ribs of the scaffold obtained in S2 using a femtosecond laser processing system. The laser wavelength is 1030 nm, the pulse width is 400 fs, and the repetition frequency is 100 kHz. The laser beam is focused by the objective lens to a spot with a diameter of approximately 5 μm. By controlling the laser energy density and pulse number, frustum-shaped blind holes with a large opening and a small base are formed point by point on the outer surface of the ribs. During the processing, the nitrogen-rich modified layer 4 and the heparin layer 5 in the micropore area are ablated and removed by the laser, exposing the fresh metal substrate. At the same time, an inclined inner wall with a certain roughness is formed. After processing, the scaffold substrate 1 is ultrasonically cleaned in ethanol to remove processing debris.

[0059] S4. First, dissolve rapamycin in anhydrous ethanol to prepare a drug solution with a concentration of 10 mg / mL. Immerse the stent obtained in S3 in the drug solution at a certain temperature. Place it in a vacuum drying oven and evacuate to -0.08 MPa for 30 minutes. The drug solution fully fills the inner cavity of micropore 2 under capillary action. Remove the stent and dry it at room temperature in a clean environment for 12 hours. During the drying process, the drug solution accumulates along the inclined pore wall towards the bottom of the pore, and rapamycin crystallizes and precipitates in the pore, forming a gradient drug layer with a dense bottom and sparse opening, finally obtaining the vascular stent of this embodiment.

[0060] Example 2: The structure is basically the same as that of Example 1, except for the following characteristic parameters: The scaffold substrate 1 is made of medical-grade nickel-titanium alloy, with a rib width of 130 μm and a rib thickness of 90 μm. The micropores 2 have an opening diameter of 10 μm, a bottom diameter of 5 μm, and a depth of 15 μm. The center-to-center distance between adjacent micropores 2 is 60 μm. The nitrogen-rich modified layer 4 has a thickness of 150 nm, and the heparin grafting amount of the heparin layer 5 is 20 ng / cm. 2 The active ingredient in the first drug coating 3 is everolimus.

[0061] Example 3: The structure is basically the same as that of Example 1, except for the following characteristic parameters: The scaffold substrate 1 has a rib width of 100 μm and a rib thickness of 70 μm. The micropores 2 have an opening diameter of 6 μm, a bottom diameter of 3 μm, and a depth of 8 μm. The center-to-center distance between adjacent micropores 2 is 30 μm. The nitrogen-rich modified layer 4 has a thickness of 100 nm. The heparin grafting amount of the heparin layer 5 is 40 ng / cm³. 2 .

[0062] It should be noted that the various embodiments in this specification are described in a progressive manner, with each embodiment focusing on the differences from other embodiments. The same or similar parts between the various embodiments can be referred to each other.

[0063] It should also be noted that, in this document, the terms "upper," "lower," "left," "right," "inner," and "outer," etc., indicate the orientation or positional relationship based on the orientation or positional relationship shown in the accompanying drawings, and are only for the convenience of describing the invention and simplifying the description, and do not indicate or imply that the device or element referred to must have a specific orientation, or be constructed and operated in a specific orientation, and therefore should not be construed as a limitation of the invention. Furthermore, relational terms such as "first" and "second" are only used to distinguish one entity or operation from another entity or operation, and do not necessarily require or imply any such actual relationship or order between these entities or operations, nor should they be construed as indicating or implying relative importance. Moreover, the term "comprising" or any other variation thereof is intended to cover non-exclusive inclusion, such that a process, method, article, or terminal device that comprises a list of elements includes not only those elements, but also other elements not expressly listed, or elements inherent to such a process, method, article, or terminal device.

Claims

1. A vascular stent based on partitioned coating and microporous gradient drug delivery, characterized in that, Vascular stents include: The scaffold substrate has multiple micropores on its outer surface; A first drug coating is attached to the pore wall of the micropore; wherein the first drug coating comprises a drug crystal layer composed of a lipid-soluble antiproliferative drug, and the adhesion density of the drug crystal layer in the micropore is distributed in a decreasing gradient from the bottom to the opening, so as to inhibit the burst release of the lipid-soluble antiproliferative drug in the early stage of implantation after the stent matrix is ​​implanted into the blood vessel; wherein the decreasing gradient distribution of adhesion density means that at least one of the following microcrystal aggregation parameters per unit area of ​​lipid-soluble antiproliferative drug decreases from the bottom to the opening; A second drug coating is disposed on the surface of the scaffold substrate, excluding the micropores, such that the first drug coating and the second drug coating are isolated from each other on the surface of the scaffold substrate. The second drug coating includes a nitrogen-rich modified layer and a heparin layer fixed to the surface of the nitrogen-rich modified layer by covalent bonds, and the nitrogen-rich modified layer covers the substrate surface except for the micropores; the nitrogen-rich modified layer includes a nitrogen-enriched surface layer, and the nitrogen-rich modified layer is prepared by covering the surface of the scaffold substrate with nitrogen element by nitrogen plasma immersion ion implantation technology. The heparin layer comprises a monolayer of heparin molecules, which is formed by covalently grafting heparin molecules onto the surface of the nitrogen-rich modified layer via amide bonds through a silane coupling agent activation combined with EDC / NHS coupling technology.

2. The vascular stent based on partitioned coating and microporous gradient drug loading according to claim 1, characterized in that, The micropores are blind holes whose diameter gradually decreases from the opening to the bottom.

3. A vascular stent based on partitioned coating and microporous gradient drug loading according to claim 1, characterized in that, The second drug coating continuously covers the substrate surface except for the micropores, and the first drug coating continuously covers the pore walls of the micropores; and the pore walls of the micropores have boundary regions formed by femtosecond laser processing technology at their edges, the boundary regions causing the first drug coating and the second drug coating to be discontinuous on the surface of the scaffold substrate.

4. A vascular stent based on partitioned coating and microporous gradient drug loading according to claim 1, characterized in that, The thickness of the nitrogen-rich modified layer is 100nm~300nm, and the grafting amount of heparin molecules is 20ng / cm. 2 ~40ng / cm 2 .

5. A vascular stent based on partitioned coating and microporous gradient drug loading according to claim 1, characterized in that, The support base is a tubular mesh structure formed by multiple ribs, and the cross-section of each rib is a rounded flat rectangle.

6. A vascular stent based on partitioned coating and microporous gradient drug loading according to claim 5, characterized in that, The width of the rib is 100μm~130μm and the thickness is 70μm~90μm.

7. A vascular stent based on partitioned coating and microporous gradient drug delivery according to claim 5 or 6, characterized in that, The pores have an opening diameter of 6μm to 10μm, a bottom diameter of 3μm to 5μm, a depth of 8μm to 15μm, and a center-to-center distance of 30μm to 60μm between adjacent pores.

8. A vascular stent based on partitioned coating and microporous gradient drug loading according to claim 1, characterized in that, The lipid-soluble antiproliferative drug includes either rapamycin or everolimus.

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