Medical device with improved antithrombotic effect

Abstract

Medical device, in particular stent or flow diverter, with a network structure, in particular with a self-expanding network structure, wherein the network structure comprises at least one network structure element (10) which is, in particular completely, encased by a nanostructure coating formed from fibrin nanofibers (11, 12), characterized in that the nanostructure coating comprises a first layer (L1) which forms a matrix, in particular felt-like or nonwoven-like, of interconnected fibrin fibers (11), 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 woven-like structure, wherein the nanostructure coating additionally contains a polynucleic acid KLF5 inhibitor, selected from the group consisting of aptamers and miRNA, which 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 network structure, which is at least partially tubular and can expand automatically from a compressed cross-sectional diameter to an expanded cross-sectional diameter. The network structure has at least one network element that is encased by a nanostructured coating. This nanostructured coating is made of fibrin nanofibers.

[0003] 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.

[0004] Although the medical device known so far shows good results in endothelialization, further improvement is desirable.

[0005] 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.

[0006] Inflammation is a fundamental immune response that protects blood vessels from injury; however, 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 endothelial 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 invade 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).

[0007] KLF5 (Kruppel-like factor 5) is an essential transcription factor that binds to the GC boxes of several gene promoters and regulates their transcription. KLF5 expression is frequently abnormal in human cancers and in vascular smooth muscle cells (SMCs) associated with cardiovascular disease. KLF5 has been shown to play a crucial role in controlling the SMC phenotype following vascular injury, meaning that modulating this phenotype directly influences neointima formation after vascular injury. By inhibiting the activity of the transcription factor KLF5, the phenotypic modulation of SMCs could be suppressed, and the formation of vascular lesions around the neointima could be prevented. Therefore, due to its function, KLF5 inhibition represents a promising approach to limiting intimal hyperplasia.

[0008] To date, no coating technology has been described that simultaneously acts as an antithrombogenic, endothelialization-promoting and anti-inflammatory agent, and inhibits the activity of the transcription factor KLF5 to suppress intimal hyperplasia.

[0009] Several classes of substances are known to inhibit the transcription factor KLF5. Possible KLF5 inhibitors include aptamers, retrons, miRNA, siRNA, and specifically binding nucleic acid or peptide sequences. These classes of substances share the characteristic that they can be selected to bind specifically to the transcription factor KLF5 and thereby selectively suppress the proliferation of SMCs, thus selectively suppressing hyperplasia without impeding endothelialization.

[0010] Aptamers are short, single-stranded DNA or RNA oligonucleotides or peptides that, due to their 3D structure, can bind to a specific molecule. If the aptamer is a peptide, it is called a peptide aptamer.

[0011] Retrons are various DNA sequences found in the genomes of many bacterial species that encode reverse transcriptase and a unique single-stranded DNA / RNA hybrid known as multicopy single-stranded DNA (msDNA).

[0012] MicroRNAs, abbreviated miRNAs, are short, highly conserved, non-coding ribonucleic acids that play an important role in the complex network of gene regulation, particularly in gene silencing. MicroRNAs regulate gene expression with high specificity at the post-transcriptional level.

[0013] Small interfering RNAs, abbreviated siRNAs, are short single- or double-stranded ribonucleic acid molecules with a length of 20 to 25 base pairs. They bind to complementary single-stranded ribonucleic acid molecules and thereby disrupt their function.

[0014] In the present application, specifically binding polynucleic acid or peptide sequences are understood to be those polynucleic acid or peptide sequences that bind specifically to the transcription factor KLF5 in order to inhibit its function.

[0015] For a therapy in which the KLF5 inhibitor acts only directly at the site where inhibition of intimal hyperplasia is desired, it would be necessary to deliver the substances directly to the site. Since the insertion of stents or flow diverters creates areas with increased neointima formation, it would also be advantageous to deliver the KLF5 inhibitor as close as possible to the stents and flow diverters. Furthermore, it is desirable to encapsulate the KLF5 inhibitor in a degradable compound to ensure that it can penetrate the lower cell layer.

[0016] WO 2023 / 070072 A1 describes retrons containing binding sites for transcription factors, so-called retron decoys. These retron decoys can reduce the activity of transcription factors and mitigate the negative effects of transcription factor-induced dynamic processes. Furthermore, methods for administering these artificial retrons are proposed. These methods offer potential therapies for a variety of diseases, including inflammatory conditions caused, for example, by surgical procedures.

[0017] US 2008 / 020014 A1 relates to implantable devices (e.g., drug delivery stents) containing nuclear receptor ligands. These nuclear receptor ligands may include, among others, PPAR ligands or retinoids. The patent also proposes a method for treating or preventing vascular diseases (e.g., restenosis) and related conditions using devices containing nuclear receptor ligands.

[0018] Mondragón et al., Anti-Transcription Factor RNA Aptamers as Potential Therapeutics. Nucleic Acid Therapeutics. 2016, discuss several natural RNAs that modulate the activity of transcription factors and synthetic RNA aptamers for inhibiting the transcription factors Nuclear Factor KappaB (NF-κB), TATA-Binding Protein (TBP), Heat Shock Factor 1 (HSF1), and Runt-Related Transcription Factor 1 (RUNX1).

[0019] Lei et al., Smooth muscle cell-targeted RNA ligand promotes accelerated reendothelialization in a swine peripheral injury model, 2023, investigated the effect of luminal administration of a vascular smooth muscle cell (VSMC)-specific aptamer on endothelial healing. Furthermore, the effect of this aptamer on reendothelialization was examined upon local administration. In this context, the efficacy of a cell-specific RNA aptamer to promote endothelial healing was demonstrated for the first time in a clinically relevant large animal model.

[0020] US2011 / 0293674 A1 describes miRNAs that regulate the proliferation and differentiation of smooth muscle cells. These miRNAs can be used to coat medical devices, including stents. WO 2010 / 104796 describes methods for inducing the differentiation of smooth muscle cells in a stem cell or progenitor cell by introducing microRNA-143 or -145 into the cell, thereby generating a vascular smooth muscle cell. WO 2010 / 104796 A2 also describes implantable devices, such as coronary stents, in which the described miRNAs can be used as a coating.

[0021] None of the documents cited above describe a coating for a medical device that addresses the problem of insufficient layer thickness. Sufficient layer thickness is advantageous because it can influence the desired simulation of a biological environment for endothelial cell adhesion.

[0022] Therefore, 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.

[0023] According to the invention, this problem is solved by the further development according to claim 1.

[0024] The invention is based on the concept of providing a medical device, in particular a stent or a flow diverter, with a network structure, and preferably with a self-expanding network structure, wherein the network structure comprises at least one network element which is, in particular completely, encased with a nanostructured coating formed from fibrin nanofibers, and wherein the nanostructured coating additionally contains a polynucleic acid KLF5 inhibitor selected from the group consisting of aptamers and miRNAs. 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 woven one.The polynucleic acid KLF5 inhibitor is integrated into the first layer and / or the second layer, e.g. embedded or bound.

[0025] The invention differs from the prior art in that the nanostructure coating is essentially two-layered and the polynucleic acid KLF5 inhibitor 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.

[0026] 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.

[0027] 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.

[0028] This particular structure of the nanostructured coating has been shown to provide an increased surface area for endothelial cell adhesion, thus significantly improving endothelialization. The first layer, which is more highly cross-linked, comes into direct contact with the cell surfaces (leading to cell adhesion), while the protruding fibrin fiber ends at the cell edges ensure improved cell adhesion under flow stress (such as in blood vessels). Furthermore, the KLF5 inhibitor incorporated into the coating inhibits intimal hyperplasia.

[0029] The polynucleic acid KLF5 inhibitor in the invention described herein is selected from aptamers and miRNA. In a particularly preferred embodiment, the polynucleic acid KLF5 inhibitor is an aptamer.

[0030] The polynucleic acid KLF5 inhibitor 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 polynucleic acid KLF5 inhibitor, or by adding the polynucleic acid KLF5 inhibitor to the first layer before crosslinking the fibrin nanofibers, and then carrying out the crosslinking in the presence of the polynucleic acid KLF5 inhibitor. Alternatively, the polynucleic acid KLF5 inhibitor can be covalently bound to components of the nanostructured coating, particularly to fibrin nanofibers within the coating. Covalent bonding has the advantage that the polynucleic acid KLF5 inhibitor cannot be washed out of the coating to a significant extent due to blood flow in adjacent blood vessels.

[0031] In one embodiment, the linkage occurs via carboxylic acid groups present in the polynucleic acid KLF5 inhibitor with NH2 groups to 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). Linkage via a linker is possible with polynucleic acid-based KLF5 inhibitors in such a way that the linker can bind to OH groups of the polynucleic acid and to OH or NH groups from the nanostructure coating.

[0032] An alternative method of covalent bonding involves attaching the polynucleic acid KLF5 inhibitor to a citric acid polyester, which in turn can be covalently bonded to the fibrin fibers of the nanostructure coating. The carboxyl groups of the citric acid polyester, for example, react with OH or NH groups of the polynucleic acid KLF5 inhibitor to form an ester. The resulting ester compound has the advantage that the polynucleic acid KLF5 inhibitor is released in a controlled manner as soon as the medical device comes into contact with an aqueous medium (especially blood).

[0033] Accordingly, in a preferred embodiment, the polynucleic acid KLF5 inhibitor is linked to components of the nanostructure coating via the carboxyl group of the citric acid polyester, wherein the linkage is preferably the reaction product of the polynucleic acid KLF5 inhibitor with a citric acid polyester and OH groups or amino groups from the nanostructure coating.

[0034] 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.

[0035] In a further preferred embodiment, the polynucleic acid KLF5 inhibitor is not integrated into the coating in covalent form, but is incorporated into the nanostructured coating in nanoencapsulated form, and in particular in a form in which the polynucleic acid KLF5 inhibitor is present in degradable nanoparticles. A particularly suitable form is one in which the polynucleic acid KLF5 inhibitor 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.

[0036] In another embodiment, depending on requirements, the nanostructured coating and the polynucleic acid KLF5 inhibitor can be modified in a first step with chemical functionalities suitable for click reactions, and in a second step, the polynucleic acid KLF5 inhibitor 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.

[0037] 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 2 It 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.

[0038] 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.

[0039] It is still preferred if the nanostructure coating contains an amount of polynucleic acid KLF5 inhibitor 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.

[0040] In addition to the polynucleic acid KLF5 inhibitor, it can be advantageous to incorporate antithrombotic agents or compounds into the nanostructure 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 nanostructure 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 nanostructure coating across its entire thickness.

[0041] 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 polynucleic acid KLF5 inhibitor. It is preferred that the heparin be covalently bound to fibrin fibers of the nanostructure coating.

[0042] 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 polynucleic acid KLF5 inhibitor or other substances, and, on the other hand, the second layer has a sufficiently loose structure to guarantee improved adhesion of endothelial cells.

[0043] Furthermore, it is advantageous if the first layer contains an initial amount of polynucleic acid KLF5 inhibitor and the second layer contains a second amount of polynucleic acid KLF5 inhibitor, the initial amount being greater than the second amount. A ratio of at least 2, particularly at least 3, and particularly at least 4 between the initial amount of polynucleic acid KLF5 inhibitor and the second amount of KLF5 inhibitor is especially advantageous. While the polynucleic acid KLF5 inhibitor 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 polynucleic acid KLF5 inhibitor will be deposited 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 drug reservoir.

[0044] 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.

[0045] 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.

[0046] 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

[0047] 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.

[0048] 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.

[0049] 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.

[0050] 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 nanostructured 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. KLF5 inhibitor molecules (in this case shown as polynucleic acid aptamers) are covalently bonded to the fibrin fibers of the first layer and to the fibrin fibers of the second layer that protrude above it.

[0051] 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.

[0052] 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.

[0053] 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.

[0054] 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.

[0055] 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.

[0056] 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.

[0057] 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) is 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.

[0058] 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.

[0059] 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.

[0060] 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.

[0061] 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°.

[0062] 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.

[0063] 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.

[0064] 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.

[0065] 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(x1)−COF(x2)]≥A where A = 10% and x2 > x1.

[0066] 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.

[0067] 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.

[0068] 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 mesh 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 mesh structure has at least one mesh 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 has a first layer (L1) forming a matrix of interconnected fibrin fibers (11), in particular a felt-like or nonwoven 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 flor-like structure, wherein the nanostructured coating additionally contains a polynucleic acid KLF5 inhibitor, selected from the group consisting of aptamers and miRNA, which is integrated into the first layer (L1) and / or the second layer (L2). [2] Medical device according to claim 1 characterized by that the polynucleic acid KLF5 inhibitor exists as an aptamer. [3] Medical device according to claim 1 or 2, characterized by that the polynucleic acid KLF5 inhibitor 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 binding of the polynucleic acid KLF5 inhibitor to components of the nanostructure coating is effected via an ester group, wherein the binding is preferably the reaction product of the reaction of the polynucleic acid KLF5 inhibitor 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 polynucleic acid KLF5 inhibitor is present in nanoencapsulated form, especially in degradable nanoparticles in the nanostructure coating. [6] Medical device according to any one of the preceding claims, characterized by that the nanostructure coating contains an amount of the polynucleic acid KLF5 inhibitor 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 amount of the polynucleic acid KLF5 inhibitor and the second layer (L2) has a second amount of the polynucleic acid KLF5 inhibitor, wherein a ratio between the first amount and the second amount of the polynucleic acid KLF5 inhibitor 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 one 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 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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