Medical device with improved antithrombotic effect

Abstract

Medical device, in particular stent or flow diverter, with a mesh structure, in particular with a self-expanding mesh structure, wherein the network structure has at least one network structure element (10) which is, in particular completely, encased by a nanostructure coating formed from fibrin nanofibers (11, 12), characterized by the fact that The nanostructured coating comprises a first layer (L1) forming a matrix of interconnected fibrin fibers (11), in particular a felt-like or nonwoven-like matrix, wherein some fibrin fibers (12) protrude freely over the first layer (L1) and form a second layer (L2) of a single-fiber structure, in particular a nap-like structure, and wherein the The nanostructured coating additionally contains an HO-1 activator that is integrated into the first layer (L1) and / or the second layer (L2).

Description

[0001] The invention relates to a medical device, in particular a stent or a flow diverter, according to the preamble of claim 1. Such a medical device is known, for example, from DE 10 2018 110 591 A1.

[0002] The aforementioned DE 10 2018 110 591 A1 describes, in particular, a stent that has a biological coating which promotes endothelialization, i.e., the attachment of endothelial cells to the stent. The stent is based on a self-expanding mesh structure that is at least partially tubular and can expand automatically from a compressed cross-sectional diameter to an expanded cross-sectional diameter.

[0003] The network structure has at least one network element that is encased by a nanostructured coating. This nanostructured coating is formed from fibrin nanofibers.

[0004] To form the biological coating of the known stent, fibrinogen is first provided, which is then converted to fibrin by the addition of thrombin. The fibrin forms threads that extend outwards from the surface of the network structure. This creates a loose fibrin network into which heparin can be incorporated.

[0005] Although the medical device known so far shows good results in endothelialization, further improvement is desirable.

[0006] Furthermore, the use of metal devices inserted into blood vessels carries a significant risk of thrombosis and hemolysis, which cannot be completely eliminated by fibrin coating. This is particularly true for flow diverters inserted into blood vessels, which have a higher metal wire density than stents, which are primarily intended for stabilizing the blood vessel. Therefore, there is also a need to modify existing stent and flow diverter coatings to make them antithrombogenic and counteract hyperplasia. This should ensure rapid osseointegration of the device and minimize side effects.

[0007] While inflammation is a fundamental immune response that protects blood vessels from injury, it is also associated with a variety of acute and chronic diseases, including atherosclerosis. Endothelial dysfunction is the first diagnosable stage of atherosclerosis and contributes significantly to the disease process. In this dysfunction, the endothelial cell layer cannot maintain its barrier function, allowing monocytes, among other cells, to invade the underlying cell layers and differentiate into macrophages. Furthermore, lipoproteins can also penetrate these layers, be taken up by the macrophages, and form foam cells. These are characteristic of atherosclerosis because the expansion of the intima narrows the vessel lumen (stenosis). In a healthy vessel, the production of nitric oxide (NO) in the endothelial cells counteracts this process.For this reason, coating technologies are already known that promote the release or formation of NO.

[0008] The membrane-bound enzyme eNOS catalyzes NO production and can exist in two states: coupled and uncoupled. When eNOS is in the uncoupled state, peroxynitrite is produced in increased amounts instead of NO, but peroxynitrite is cell-damaging. Therefore, increased NO production does not necessarily lead to an improvement or prevention of endothelial dysfunction or atherosclerosis. It would thus be desirable to avoid the external administration of NO and instead prevent or at least mitigate endothelial dysfunction via another mechanism.

[0009] There is growing evidence that the interplay between carbon monoxide (CO) and nitric oxide (NO) plays a crucial role in vascular homeostasis and regeneration by improving endothelial function. CO, produced by heme oxygenase (HO), is considered a signaling molecule in both the cardiovascular and central nervous systems. A molecular factor at the interface between inflammation and hemostasis is the enzyme heme oxygenase-1 (HO-1). Heme oxygenase-1 is an enzyme that catalyzes the breakdown of pro-oxidative heme to antithrombotic CO, biliverdin, and iron, and is a key modulator of host defense and inflammation. HO-1 has been shown to regulate vascular thrombotic inflammatory processes. HO-1 expression is strongly induced in vascular tissue under stress conditions and accelerates the breakdown of heme to iron and the antioxidants CO and biliverdin.

[0010] It is therefore desirable to provide a coating technology that incorporates an HO-1 activator to promote CO production. This approach has the advantage that no NO radicals are formed; instead, the formation of radicals is actually reduced by CO production and the crosstalk between CO and NO.

[0011] To date, no coating technology has been described that simultaneously acts as an antithrombotic, endothelialization-promoting and anti-inflammatory agent and inhibits intimal hyperplasia.

[0012] Several substances are known to increase the enzyme activity of heme oxygenase-1 (HO-1) or to stimulate the activation of this biocatalyst. In this context, hyperforin (HPF) and finasteride have proven particularly effective as HO-1 activators.

[0013] Hyperforin (HPF) is an acylphloroglucinol compound found in extracts of Hypericum perforatum (St. John's wort) and possesses antidepressant, anti-inflammatory, antimicrobial, and antitumor properties. Recent studies have shown that hyperforin has a potent anti-melanoma effect by inhibiting the proliferation, motility, and colony formation of melanoma cells and inducing apoptosis. Furthermore, hyperforin has been found to stimulate the expression of oxygenase-1 (HO-1), thereby leading to increased CO production.

[0014] Finasteride is a synthetic 5α-reductase (5-AR) inhibitor that has attracted particular attention as a potential chemopreventive agent against prostate cancer. Indeed, it has been shown that finasteride, or durasteride, significantly reduces the incidence of prostate cancer in men. Furthermore, it has been observed that treatment with finasteride induces, among other effects, the expression of HO-1 proteins.

[0015] For a therapy in which the HO-1 activator acts only directly at the site where an anticoagulant effect is desired, it would be necessary to introduce the substances directly at that site. Since the insertion of stents or flow diverters creates positions with an increased susceptibility to thrombotic events, it would also be advantageous to introduce the HO-1 activator as close as possible to the stents and flow diverters. Furthermore, it is desirable to encapsulate the HO-1 activator in a degradable compound to ensure that it can penetrate the lower cell layer.

[0016] US 2018 / 369278 A1 concerns methods for treating arterial and venous thrombosis and vasculitis by administering carbon monoxide, a carbon monoxide-releasing molecule (CORM), or a combination thereof. Implantable devices capable of releasing carbon monoxide to treat microvascular arterial and venous thromboembolism and / or inflammation are also described.

[0017] US 8,597,720 B2 concerns medical devices with short-term body contact, such as balloon catheters, coated with at least one layer containing at least one antiproliferative, immunosuppressive, antiangiogenic, anti-inflammatory, fungicidal, and / or antithrombotic agent. It also proposes CO- or NO-synthesizing enzymes or activators for these enzymes, nucleotide sequences such as DNA and RNA that encode these enzymes and enhance their expression when introduced into cells, and / or inhibitors for CO- or NO-degrading enzymes.

[0018] US 2018 / 369278 A1 and US 8,597,720 B2 generally describe that NO and CO have various positive effects on wound healing and suggest, in this context, the introduction of CO or the addition of a carbon monoxide-releasing molecule (CORM), whereby the introduction of gaseous CO is impractical and imprecise and CORMs do release CO, but do not increase the activity of HO-1.

[0019] Furthermore, neither document US 2018 / 369278 A1 nor US 8,597,720 B2 describes the problem of insufficient coating thickness on medical devices, which can facilitate the desired simulation of a biological environment for the attachment of endothelial cells.

[0020] CN105727379 A describes a drug-eluting stent with a heme oxygenase absorbed onto the stent surface. This is intended to inhibit the proliferation of vascular endothelial cells and delay endothelialization on the stent surface.

[0021] US 2023 / 0398266 A1 describes a therapeutic agent for the inhibition of cytokines and / or inflammatory mediators for the treatment of patients suffering from inflammation-associated atherosclerosis and / or a thrombotic condition. For this purpose, the agent is administered into the blood vessel via an intravascular medical device.

[0022] US 6 203 991 B1 describes a procedure for inhibiting restenosis associated with mechanical injury to blood vessels, in which human heme oxygenase I (HO1) is delivered directly to the site of injury, for example via a catheter or a coated stent.

[0023] WO 2008 / 076708 A2 describes implantable devices, for example in the form of stents, with an outer and inner region, wherein a pharmaceutical active ingredient is present in at least one part of the outer and inner region.

[0024] German patent DE 10 2010022 589 A1 describes a felt coating made of PLGA, which is applied to vascular supports, particularly in the form of stents. The felt coating can then be loaded with an active ingredient.

[0025] There is a need for coatings that are both sufficiently stable and can closely mimic the natural cell environment and surface (glycolalyx). Furthermore, these surfaces should possess anticoagulant properties to suppress thrombotic events and hemolysis as much as possible.

[0026] According to the invention, this problem is solved by the further development according to claim 1.

[0027] The invention is based on the concept of providing a medical device, in particular a stent or a flow diverter, with a network structure, preferably a self-expanding network structure, wherein the network structure comprises at least one network element that is, in particular completely, encased with a nanostructured coating formed from fibrin nanofibers, and wherein the nanostructured coating additionally contains an HO-1 activator. According to the invention, the nanostructured coating has a two-layer structure, wherein the first layer is formed by a matrix, in particular a felt-like or nonwoven-like matrix, of interconnected fibrin fibers, and wherein some fibrin fibers protrude freely beyond the first layer and form a second layer of a single-fiber structure, in particular a nap-like matrix. The HO-1 activator is integrated into the first layer and / or the second layer, e.g., embedded or bound within it.

[0028] The invention differs from the prior art in that the nanostructure coating is essentially two-layered and the HO-1 activator is integrated into the layers. A first layer in the two-layer structure, which preferably lies directly on the surface of the network structure element, comprises a matrix of cross-linked fibrin fibers. This matrix is ​​particularly dense compared to the second layer. In this respect, the matrix can also be described as felt-like or nonwoven. The fibrin fibers of the first layer are, in particular, cross-linked or matted together. A particularly dense fibrin structure is formed on this layer.

[0029] The second layer of the nanostructured coating is formed by a portion of the fibrin fibers that protrude from the first layer into the free space, forming a single-fiber structure. These protruding fibrin fibers are preferably uncrosslinked in the region of the second layer. The individual fibers or fractions of individual fibers essentially form a nap-like structure. Thus, the second layer exhibits a particularly loose fibrin fiber structure.

[0030] Essentially, the nanostructure coating is comparable to a velour carpet, in which the textile fibers are cross-linked or felted together in a first layer, and in an overlying layer individual textile fibers protrude freely, thus forming the pile of the velour.

[0031] This unique nanostructured coating has been shown to provide an increased surface area for endothelial cell adhesion, thus significantly improving endothelialization. The first, more highly cross-linked layer makes direct contact with the cell surfaces (enabling cell adhesion), while the protruding fibrin fiber ends at the cell edges enhance cell adhesion under flow stress (such as in blood vessels). Furthermore, the HO-1 activator incorporated into the coating ensures that the surface provided by the coating exhibits improved antithrombotic and antihemolytic properties.

[0032] The HO-1 activator is not subject to any relevant limitations in the context of the invention described herein, as long as the desired HO-1 activity-enhancing properties can be provided. However, finasteride and hyperforin have proven advantageous. Therefore, in a preferred embodiment of the medical device according to the invention, the HO-1 activator is selected from finasteride, hyperforin, and a mixture thereof.

[0033] The HO-1 activator can be integrated into the coating in non-covalent form, for example, by impregnating the fibrin-fiber-coated medical device with a solution of the HO-1 activator, or by adding the HO-1 activator to the first layer before crosslinking the fibrin nanofibers, and then carrying out the crosslinking in the presence of the HO-1 activator. Alternatively, the HO-1 activator can be covalently bonded to components of the nanostructured coating, particularly to fibrin nanofibers within the coating. Covalent bonding has the advantage that the HO-1 activator cannot be washed out of the coating to a significant extent due to blood flow in adjacent blood vessels.

[0034] In one embodiment, the linkage occurs via carboxylic acid groups present in the HO-1 activator, which can be linked to NH2 groups in components of the nanostructure coating. For steric reasons, it is preferred if this linkage does not occur directly, but via a linker (i.e., a chemical structure without biological activity that increases the distance between the HO-1 activator and the fibrin of the nanostructure coating).

[0035] A particular and preferred method of covalent bonding involves attaching the HO-1 activator to a citric acid polyester, which in turn can be covalently bonded to the fibrin fibers of the nanostructure coating. The hydroxyl groups of the citric acid polyester react with the carboxyl group of the HO-1 activator to form an ester. The resulting ester compound has the advantage that the HO-1 activator is released in a controlled manner when the medical device comes into contact with an aqueous medium (especially blood).

[0036] Accordingly, in a preferred embodiment, the HO-1 activator is linked to components of the nanostructure coating via the hydroxy group of the citric acid polyester, wherein the linkage is preferably the reaction product of the HO-1 activator with a citric acid polyester and OH groups or amino groups from the nanostructure coating.

[0037] In a particularly preferred embodiment, the citric acid polyester is selected from the group consisting of poly(1,10-decanediol-co-citric acid), poly(1,8-octanediol-co-citric acid), poly(1,6-hexanediol-co-citric acid), poly(1,12-dodecanediol-co-citric acid), poly(1,8-octanediol-co-citric acid-coglycerol), poly(1,8-octanediol-citric acid-co-polyethylene oxide), poly(1,12-dodecanediol-citric acid-co-polyethylene oxide), poly(1,8-octanediol-citric acid-co-N-methyldiethanoamine), poly(1,12-dodecanediol-citric acid-co-N-methyldiethanoamine) or mixtures thereof, wherein poly(1,8-octanediol-co-citric acid), also referred to as POC, is preferred.

[0038] In another preferred embodiment, the HO-1 activator is not integrated into the coating in covalent form, but is incorporated into the nanostructured coating in a nanoencapsulated form, and in particular in a form in which the HO-1 activator is present in degradable nanoparticles. A particularly suitable form is one in which the HO-1 activator is encapsulated in liposomes or micelles, and wherein the nanostructured coating of the medical device according to the invention is impregnated or treated with a liquid formulation containing the liposomes or micelles.

[0039] In another embodiment, depending on requirements, the nanostructured coating and the HO-1 activator can be modified in a first step with chemical functionalities suitable for click reactions, and in a second step, the HO-1 activator can then be linked to the nanostructured coating via a reaction of these functionalities with each other. Examples of chemical functionalities suitable for click reactions include a primary amine on one of the reactants and a dialdehyde or epoxide on the other, a C-C triple bond and an azide group, or a thiol group and an alkene or epoxide group.

[0040] In a preferred embodiment of the medical device according to the invention, the nanostructured coating has a fibrin content of at least 2 µg / cm². 2 , especially more than 2 µg / cm² 2 , especially more than 3 µg / cm² 2It has been shown that such a quantity of fibrin results in a sufficiently dense yet thin nanostructure coating. A thin nanostructure coating is advantageous for keeping the overall thickness of the network element within a specific range, allowing the entire medical device to be compressed to the smallest possible cross-sectional diameter. This is a prerequisite for guiding the medical device to the treatment site via small catheters. This also enables the treatment of small blood vessels, particularly in the cerebral region.

[0041] Furthermore, a thin nanostructured coating ensures that the overall wall thickness of the device remains small, thus preventing significant impairment of blood flow through a blood vessel. This avoids vascular narrowing (stenosis) caused by the device.

[0042] It is still preferred if the nanostructure coating contains an amount of HO-1 activator of at least 2 µg / cm². 2 , especially more than 2 µg / cm² 2 , especially more than 3 µg / cm² 2 exhibits such a quantity. It imparts favorable antithrombotic and antihemolytic properties.

[0043] In addition to the HO-1 activator, it can be advantageous to incorporate antithrombotic agents or compounds into the nanostructured coating of the medical device according to the invention. Heparin is, for example, a particularly suitable agent for this purpose. The antithrombotic properties of the nanostructured coating can be further improved by incorporating heparin. Heparin can be incorporated into the first layer, and it is possible that the heparin may also bind to the second layer. In fact, the heparin can bond with the nanostructured coating across its entire thickness.

[0044] The heparin can also be incorporated into the nanostructure coating either loosely or covalently, with covalent binding offering the same advantages as those described above for the HO-1 activator. It is preferred that the heparin be covalently bound to fibrin fibers of the nanostructure coating.

[0045] Furthermore, it is advantageous if the first layer has a first amount of fibrin and the second layer has a second amount of fibrin, the first amount being greater than the second. Specifically, a ratio between the first and second fibrin amounts of at least 2, particularly at least 3, and especially at least 4, has been shown to be advantageous. This ensures that, on the one hand, the first layer is sufficiently dense to form a sponge-like structure for incorporating the HO-1 activator or other substances, and, on the other hand, the second layer has a sufficiently loose structure to guarantee improved adhesion of endothelial cells.

[0046] Furthermore, it is advantageous if the first layer contains an initial amount of HO-1 activator and the second layer contains a second amount of HO-1 activator, the initial amount being greater than the second. A ratio of at least 2, particularly at least 3, and particularly at least 4 between the initial and second amounts of HO-1 activator is especially advantageous. While the HO-1 activator can also bind covalently to the second layer and prevent blood clotting there through its antithrombogenic properties, it is expected that a larger amount of HO-1 activator will be stored in the first layer due to the sponge-like structure of the fibrin nanofilaments, and then successively released to the second layer. In this respect, the first layer can also act as a reservoir for the active ingredient.

[0047] In an advantageous embodiment of the medical device according to the invention, the first layer can have a height between 5 nm and 100 nm, in particular between 5 nm and 50 nm, in particular between 5 nm and 30 nm, in particular between 10 nm and 40 nm, in particular between 20 nm and 30 nm. The second layer can have a height between 5 nm and 200 nm, in particular between 5 nm and 100 nm, in particular between 5 nm and 50 nm, in particular between 5 nm and 30 nm, in particular between 10 nm and 40 nm, in particular between 20 nm and 30 nm. It is particularly preferred if the total height of the nanostructured coating is at most 300 nm, in particular at most 200 nm, in particular at most 150 nm, in particular at most 120 nm, in particular at most 100 nm, in particular at most 90 nm, in particular at most 80 nm, in particular at most 60 nm.

[0048] The stability of the fibrin nanocoating is advantageously enhanced if the fibrin fibers are formed from cross-linked fibrin molecules. This cross-linking can be achieved by adding a special factor, factor XIIIa, during the manufacturing process. Cross-linking significantly stabilizes the fibrin nanostructure and improves the previously described advantages regarding endothelialization. Specifically, the cross-linking is achieved by having each fibrin molecule possess two carboxyl terminals (D domains) and one amino terminal (E domain), with the amino terminal of one fibrin molecule being linked to at least one carboxyl terminal of another fibrin molecule, particularly by a covalent bond.

[0049] The invention is explained in more detail below using an exemplary embodiment with reference to the accompanying schematic drawings. These show Fig. 1 a schematic cross-sectional view through a mesh structure element with a nanostructure coating of a medical device according to the invention in a preferred embodiment; Fig. 2 A schematic representation of the cross-linking of fibrin molecules to form a stabilized fibrin fiber. Fig. 3 A perspective view of a stent made of a wire mesh in which the wires are formed from an X-ray visible core material, and wire ends are formed at one stent end and loops are formed at the other stent end. Fig. 4 A side view of a single-wire stent, wherein the wires are formed from a core-sheath material, and wherein the core material has a higher radiolucency than the sheath material Fig. 5 A: a flow diverter with a radially self-expanding lattice structure, at least partially tubular, made of several interwoven individual wires; B: a schematic representation of a mesh of the lattice structure of the medical device

[0050] Fig. Figure 1 shows a schematic representation of a mesh structure element 10 of a medical device, in particular a stent. Generally, the medical device comprises several mesh structure elements 10 that form a mesh structure. The mesh structure elements 10 can be formed by wires that are interwoven to create a mesh structure. Alternatively, the mesh structure elements 10 can also form webs of a single-piece mesh structure. This is the case, for example, with stents that are cut from a single piece of tubing. Such stents are often referred to as laser-cut stents.

[0051] The schematic representation according to Fig. Figure 1 essentially shows a cross-section through the network structure element 10, with the nanostructure coating depicted only on one surface side for clarity. The nanostructure coating extends over the entire outer surface of the network structure element 10, meaning the network structure element 10 can be completely encased by the nanostructure coating. In particular, the nanostructure coating is intended to extend only over the outer circumferential surface of the individual network structure elements 10. Cells or meshes of a network structure, i.e., openings bounded by the individual network structure elements 10, are preferably not covered by the nanostructure coating. However, it is advantageous if all network structure elements 10 of the network structure are completely encased by the nanostructure coating.

[0052] The nanostructured coating has a first layer L1 that lies directly on the surface of the network structure element 10. The first layer L1 is formed by fibrin fibers 11, which form a densely cross-linked matrix. The fibrin fibers 11 are therefore interlocked and highly compacted, so that essentially a nonwoven-like first layer L1 is present.

[0053] The schematic representation according to Fig. Figure 1 shows that individual fibrin fibers 12 protrude as single fibers above the first layer L1. These protruding fibrin fibers 12 form a second layer L2 of the nanostructure coating above the first layer L1. The second layer L2 is formed by a single-fiber structure, i.e., the fibrin fibers 12 are present here as free fibers with, in particular, largely free ends. The second layer L2 thus essentially forms a nap of protruding fibrin fibers 12. HO-1 activator molecules are covalently bonded to the fibrin fibers of the first layer and to the fibrin fibers of the second layer that protrude above it.

[0054] The individual fibrin fibers 11, 12 are formed from fibrin molecules 20, which bond together upon the addition of thrombin, thus forming the fibrin fibers 11, 12. In a very simplified representation, each fibrin molecule 20 exhibits the following structure: Fig. Figure 3 shows a central amino terminus, also known as E-domain 21. Individual monomers extend from E-domain 21 in a coiled-coil structure 24. Carboxy terminals, designated as D-domain 22, are located on the outer surface of the molecule.

[0055] The addition of thrombin cleaves fibrin peptides, causing the released fibrin monomers to be linked by polymer bonds 23. Further addition of a fibrin-stabilizing factor (factor XIIIa) leads to the formation of cross-linking bonds 13. These cross-linking bonds 13 form between the E domain 21 and at least one D domain 22 of another fibrin molecule 20. In particular, adjacent D domains 22 of two fibrin molecules 20 are linked by the covalent bond 13 to the E domain 21 of a third fibrin molecule 20. The covalent bonds 13 thus form a bridge that stabilizes the weaker polymerization compound 23. Overall, this stabilizes the entire fibrin fiber structure.

[0056] The two-layer nanostructured coating described in connection with the present invention is particularly effective with regard to the attachment of endothelial cells. In experiments, the nanostructured coating was applied to a glass substrate and immersed, along with the glass substrate, in an endothelial cell solution. It was found that the nanostructured coating is designed such that at least 60,000, and in particular between 60,000 and 90,000, endothelial cells per square centimeter adhere to the nanostructured coating. This represents a significant increase in the number of endothelial cells per square centimeter compared to previous biological coatings.

[0057] Not only is the number of endothelial cells per square centimeter increased by the nanostructured coating of the invention, but it has also been shown that cell viability is significantly higher after three days compared to previous biological coatings. Thus, after three days, more endothelial cells survive on the nanostructured coating of the medical device according to the invention than on other, previously known biological coatings. Specifically, cell viability was experimentally determined after three days using a CCK-8 assay on a stent with the nanostructured coating described herein, yielding an absorption value at a wavelength of 450 nm of significantly more than 0.2.

[0058] The advantages of the nanostructured coating described above are particularly evident in stents and flow diverters coated with it, as mentioned above, and the structure and design of these devices are not subject to any relevant limitations. However, the corresponding stents and flow diverters preferably have a structure and dimensions suitable for use in human blood vessels. Since the stents are intended to be implantable via minimally invasive procedures in most cases, it is further preferred that the stents according to the invention are designed as at least partially tubular stents and can expand automatically from a compressed cross-sectional diameter to an expanded cross-sectional diameter.

[0059] In a particularly advantageous embodiment, the medical device according to the invention is designed as a stent with a mesh (20) of wires (21), each having a radiopaque core material and a superelastic sheath material, and forming loops (24) at a first stent end (22) and open wire ends (25) at a second stent end (23), wherein the number of wire ends (25) is twice the number of loops (24) and more than 10 vol%, in particular more than 20 vol%, in particular at least 25 vol%, in particular at least 30 vol%, of each wire (21) is formed by the core material. In this embodiment, the mesh (20) has - 48 wires (21) each with a wire diameter of 0.038 mm and an outer diameter of 3.65 mm or 4.15 mm or 4.65 mm; or - 52 wires (21) each with a wire diameter of 0.042 mm and an outer diameter of 5.17 mm or 5.67 mm or 6.17 mm; or - 64 wires (21) each with a wire diameter of 0.046 mm or 0.05 mm and an outer diameter of 7.18 mm or 8.20 mm; such a design is in Fig. 3 shown. More specific embodiments of the stent are described in DE 20 2021 106 808 U1, in particular in

[0009] to

[0025] of this document, the relevant scope of which is hereby incorporated into this application by reference.

[0060] In a further particularly advantageous embodiment, the medical device according to the invention is designed as a stent with a substantially tubular mesh (30) made of a single wire (31) comprising a core material and a sheath material, wherein the core material has a higher radiopaque quality than the sheath material, and wherein between 20 vol% and 40 vol%, in particular between 25 vol% and 35 vol%, preferably 27 vol%, of the wire (31) are formed by the core material, and an outer surface of the wire (31), in particular of the sheath material, which is polished, comprises a mixed oxide layer comprising TiO2 and at least one nitride, in particular titanium oxynitride and / or titanium nitride.

[0061] Such a design is in Fig. 4 shown. More specific embodiments of the stent are described in DE 20 2016 107 791 B4, in particular in

[0006] to

[0021] of that document, the relevant scope of which is hereby incorporated into this application by reference.

[0062] In a further particularly advantageous embodiment, the medical device according to the invention is designed as a flow diverter with an at least partially tubular, radially self-expanding lattice structure (40) made of several interwoven individual wires (41) forming meshes (42) of the lattice structure (40), wherein at least a part of the individual wires (41) comprise a radiopaque core material (41a) and a superelastic sheath material (41b), wherein several meshes (42) immediately adjacent in the circumferential direction of the lattice structure (40) form a mesh ring (43), and wherein the lattice structure (40) in a fully self-expanded state has an expansion diameter D exp, the mesh ring (43) a number of meshes n and the core material (41a) a core diameter d Kern exhibit, and wherein the core diameter d Kern applies: dKern=f⋅(Dexp / n) where the following holds for a visibility factor f: 0.08≤f≤0.15.

[0063] Such a design is found in the Fig. 1 and Fig. 2. More specific designs of the stent are described in DE 10 2019 104 828 B4, the relevant scope of which is hereby incorporated into this application by reference.

[0064] In a further advantageous embodiment, the medical device according to the invention is designed as a stent with a self-expanding, tubular mesh structure, wherein the mesh structure is formed by a single wire made of a radiopaque core material and a sheath material, which has a braiding angle a with respect to a central longitudinal axis M of the mesh structure, wherein both ends of the mesh structure have closed loops that form a diameter increase of the mesh structure with a flare angle b with respect to a central longitudinal axis M of the mesh structure. - the loops and part of the meshes form a continuous increase in the diameter of the braided structure, and - The following applies to the braiding angle a and the flaring angle b: b ≤ a, where b is at most 20° smaller than a, or b > a, where b is at most 5° larger than a, and b = 45° to 75°.

[0065] Such a design is specified in DE 10 2018 125 983 B4, the relevant scope of which is hereby incorporated into this application by reference.

[0066] In a further advantageous embodiment, the medical device according to the invention is designed as a stent with a compressible and expandable grid structure of struts which are integrally connected to one another by strut connectors and which delimit diamond-shaped cells, wherein each cell is delimited by two straight struts and two S-shaped bent struts which connect the straight struts to one another, and wherein - the lattice structure in a rest state has a fully expanded rest diameter D exp exhibits a thickness between 3.0 mm and 5.0 mm, - a ratio between a fully compressed diameter D komp the lattice structure and the rest diameter D expthe lattice structure is between 1:7 and 1:12, the webs have a web height, measured in the radial direction, of at least 0.05 mm and at most 0.09 mm, so that the lattice structure between the fully compressed diameter D komp and an insertion diameter that is at most 90% of the rest diameter D exp is, has a radial force of at least 0.5 N, in particular at least 0.6 N.

[0067] Such a design is specified in DE 10 2022 113 422 A1, the relevant scope of which is hereby incorporated into this application by reference.

[0068] In a further advantageous embodiment, the medical device according to the invention is designed as a stent for implantation into a blood vessel, in particular a neurovascular vessel, with a substantially tubular, self-expanding lattice structure which can be transformed from a radially fully expanded expansion diameter to a radially fully compressed compression diameter, wherein the radial pressure exerted by the lattice structure forms a hysteresis with a compression pressure RRF and an expansion pressure COF, and wherein the following applies to the compression pressure RRF and the expansion pressure COF in a diameter range from x1 to x2: [(RRF(x1)−RRF(x2))−(COF(x1))−(COF(x2))] / [COF(x1)−COF(x2)]≥Awhere A=10% and x2>x1.

[0069] Such a design is specified in DE 10 2016 110 410 A1, the relevant scope of which is hereby incorporated into this application by reference.

[0070] In a further advantageous embodiment, the medical device according to the invention is designed as a stent, in particular for the treatment of diseases of the carotid artery, wherein the stent has a tubular mesh of wires, each of which is wound helically around a longitudinal axis of the mesh and crosses over and under each other, wherein the mesh in a resting state has a proximal cylindrical section and a distal cylindrical section which are connected to each other by a transition section, and wherein the proximal cylindrical section has a different cross-sectional diameter and a different porosity than the distal cylindrical section.The design, comprising two cylindrical sections with different cross-sectional diameters, is intended to ensure the most uniform possible porosity of the stent when it is placed in blood vessels with different cross-sectional diameters. Stents with this design are specifically described in WO 2022 / 136368 A1, the relevant content of which is hereby incorporated into the present application by reference.

[0071] The medical devices according to the invention realize several advantages, in particular those listed below: - improved antithrombogenic properties; - improved anti-inflammatory properties; - improved endothelialization; - the suppression of intimal hyperplasia; - faster integration of the device into a blood vessel; - the possibility of discontinuing anticoagulant medication more quickly; and - a reduction in complications and side effects. Reference symbol list 10 Network structure element 11 Fibrin fiber of the fiber matrix 12 Fibrin fibers of the single fiber structure 13 covalent bonds 14 fibrin molecules 15 E-domain 16 D-domain 17 Polymer bond 18 Coiled-coil structure 20 braids 21 wire 22 first stent end 23 second stent end 24 loops 25 open wire end 30 mesh panels 31 wire 40 Grid structure 41 Grid structure 41a Core material 41b Coating material 42 stitches 43 mesh rings L1 first layer L2 second layer

Claims

[1] Medical device, in particular stent or flow diverter, with a mesh structure, in particular with a self-expanding mesh structure, wherein the network structure has at least one network structure element (10) which is, in particular completely, encased by a nanostructure coating formed from fibrin nanofibers (11, 12), characterized by , that The nanostructured coating comprises a first layer (L1) forming a matrix of interconnected fibrin fibers (11), in particular a felt-like or nonwoven-like matrix, wherein some fibrin fibers (12) protrude freely over the first layer (L1) and form a second layer (L2) of a single-fiber structure, in particular a nap-like structure, and wherein the The nanostructured coating additionally contains an HO-1 activator that is integrated into the first layer (L1) and / or the second layer (L2). [2] Medical device according to claim 1, characterized bythat the HO-1 activator is selected from the group consisting of hyperforin, finasteride and a mixture thereof. [3] Medical device according to claim 1 or 2, characterized by that the HO-1 activator is covalently bound to components of the nanostructure coating, in particular to fibrin nanofibers of the nanostructure coating. [4] Medical device according to claim 3, characterized by that the HO-1 activator is bound to components of the nanostructure coating via an ester group, wherein the binding is preferably the reaction product of the reaction of the HO-1 activator with a citric acid polyester, preferably poly(1,8-octanediol-co-citric acid), and OH groups or amino groups from the nanostructure coating. [5] Medical device according to any one of claims 1 to 3, characterized bythat the HO-1 activator is present in nanoencapsulated form, in particular in degradable nanoparticles in the nanostructure coating. [6] Medical device according to any one of the preceding claims, characterized by that the nanostructured coating has an HO-1 activator quantity of at least 2 µg / cm² 2 , especially more than 2 µg / cm² 2 , especially more than 3 µg / cm² 2 , exhibits. [7] Medical device according to any one of the preceding claims, characterized by that the nanostructure coating continues to contain heparin, preferably heparin that is covalently bound to fibrin fibers of the nanostructure coating. [8] Medical device according to any one of the preceding claims, characterized by, that the first layer (L1) has a first quantity of HO-1 activator and the second layer (L2) has a second quantity of HO-1 activator, wherein a ratio between the first quantity and the second quantity is at least 2, in particular at least 3, in particular at least 4. [9] Medical device according to any one of the preceding claims, characterized by that the second layer (L2) has a greater height than the first layer (L1). [10] Medical device according to any of the preceding claims, characterized by, that the first layer (L1) has a height between 5 nm and 100 nm, in particular between 5 nm and 50 nm, in particular between 5 nm and 30 nm, in particular between 10 nm and 40 nm, in particular between 20 nm and 30 nm, and the second layer (L2) has a height between 5 nm and 200 nm, in particular between 5 nm and 100 nm, in particular between 5 nm and 50 nm, in particular between 5 nm and 30 nm, in particular between 10 nm and 40 nm, in particular between 20 nm and 30 nm. [11] Medical device according to any one of the preceding claims, characterized by , that the fibrin fibers (11) are formed from cross-linked fibrin molecules (14). [12] Medical device according to claim 11, characterized by, that the fibrin molecules (14) each have two carboxyl termini (D domains (16)) and one amino terminus (E domain (15)), wherein the amino terminus of one fibrin molecule (14) is connected to at least one carboxyl terminus of another fibrin molecule (14), in particular by a covalent bond (13). [13] Medical device according to one of the preceding claims, which is designed as an at least partially tubular stent and can be automatically expanded from a compressed cross-sectional diameter to an expanded cross-sectional diameter. [14] Medical device according to one of the preceding claims, characterized in that it is designed as a stent with a mesh (20) of wires (21), each having a radiopaque core material and a superelastic sheath material, and forming loops (24) at a first stent end (22) and open wire ends (25) at a second stent end (23), wherein the number of wire ends (25) is twice the number of loops (24) and more than 10 vol%, in particular more than 20 vol%, in particular at least 25 vol%, in particular at least 30 vol%, of each wire (21) is formed by the core material, and wherein the mesh (20) - 48 wires (21) each with a wire diameter of 0.038 mm and an outer diameter of 3.65 mm or 4.15 mm or 4.65 mm; or - 52 wires (21) each with a wire diameter of 0.042 mm and an outer diameter of 5.17 mm or 5.67 mm or 6.17 mm; or - 64 wires (21) each with a wire diameter of 0.046 mm or 0.05 mm and an outer diameter of 7.18 mm or 8.20 mm; has. [15] Medical device according to one of the preceding claims, characterized in that it is designed as a stent with a substantially tubular mesh (30) made of a single wire (31) comprising a core material and a sheath material, wherein the core material has a higher radiopaque quality than the sheath material, and wherein between 20 vol% and 40 vol%, in particular between 25 vol% and 35 vol%, preferably 27 vol%, of the wire (31) are formed by the core material and an outer surface of the wire (31), in particular of the sheath material, which is in particular polished, comprises a mixed oxide layer comprising TiO2 and at least one nitride, in particular titanium oxynitride and / or titanium nitride. [16] Medical device according to any one of the preceding claims, characterized by, that it is designed as a flow diverter, with an at least partially tubular, radially self-expanding lattice structure (40) made of several interwoven individual wires (41) forming meshes (42) of the lattice structure (40), wherein at least a part of the individual wires (41) comprise an X-ray visible core material (41a) and a superelastic sheath material (41b), wherein several meshes (42) immediately adjacent in the circumferential direction of the lattice structure (40) form a mesh ring (43), wherein the lattice structure (40) in a fully self-expanded state has an expansion diameter D exp , the mesh ring (43) a number of meshes n and the core material (41a) a core diameter d Kern exhibit, and wherein the core diameter d Kern applies: dKern=f⋅(Dexp / n) where the following holds for a visibility factor f: 0.08≤f≤0.15.

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