Medical device having an improved antithrombotic effect

Abstract

The invention relates to a medical device, in particular a stent or flow diverter, comprising a mesh structure, in particular a self-expandable mesh structure, wherein the mesh structure comprises at least one mesh structure element (10) which is encased, in particular in its entirety, by a nanostructured coating formed from fibrin nanofibres (11, 12), wherein the nanostructured coating has a first layer (L1) which forms a matrix, in particular a felt-like or fleece-like matrix, of interconnected fibrin fibres (11), wherein some fibrin fibres (12) protrude freely beyond the first layer (L1) and form a second layer (L2) comprising a single-fibre structure, in particular a pile-like single-fibre structure, and wherein the nanostructured coating additionally contains a polynucleic acid-based or peptide-base KLF5 inhibitor that is integrated into the first layer (L1) and / or the second layer (L2).

Description

Medical device with improved antithrombotic effect Description The invention relates to a medical device, in particular a stent or a flow diverter, according to the preamble of patent claim 1. Such a medical device is known, for example, from DE 10 2018 110 591 A1. The aforementioned DE 10 2018 110 591 A1 describes, in particular, a stent with a biological coating that promotes endothelialization, i.e., the attachment of endothelial cells to the stent. The base of the stent is a self-expanding mesh structure that is at least partially tubular and can be automatically expanded from a compressed cross-sectional diameter to an expanded cross-sectional diameter. The mesh structure comprises at least one mesh element coated with a nanostructure coating. This nanostructure coating is formed from fibrin nanofibers. To form the biological coating in the known stent, fibrinogen is first introduced, which is then converted to fibrin by the addition of thrombin. The fibrin forms threads that extend outward from the surface of the mesh structure. This creates a loose fibrin network into which heparin can be incorporated. Although the medical device known so far shows good results in endothelialization, further improvement is desirable. Furthermore, the use of metal bodies inserted into a blood vessel carries a significant risk of thrombosis and hemolysis, which cannot be completely eliminated by the fibrin coating. This applies particularly to flow diverters inserted into blood vessels, which have a higher metal wire density than stents, which are primarily intended to stabilize the blood vessel. There is therefore a need to modify existing stent and flow diverter coatings to counteract thrombogenic effects and hyperlasia. This should ensure rapid healing of the device and minimize side effects. Inflammation is a fundamental immune response that protects blood vessels from injury, but inflammation 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 clinical picture. In endothelial dysfunction, the cell layer cannot maintain the barrier, allowing cells such as monocytes to penetrate the underlying cell layers and differentiate into macrophages. Lipoproteins can also penetrate the layers, be taken up by the macrophages, and form foam cells. These foam cells are characteristic of atherosclerosis because the expansion of the intima narrows the vascular lumen (stenosis). KLF5 (Kruppel-like factor 5) is an essential transcription factor that binds to the GC boxes of a number of 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 an important role in controlling the SMC phenotype after vascular injury, so modulating this phenotype has a direct impact on neointima formation after vascular injury. Inhibiting or blocking the activity of the transcription factor KLF5 could suppress the phenotypic modulation of the SMC and prevent the formation of vascular lesions around the neointima. Due to its function, inhibiting KLF5 therefore represents a promising approach to curb intimal hyperplasia. To date, no coating technology has been described that simultaneously has antithrombogenic, endothelialization-promoting and anti-inflammatory effects, and inhibits the activity of the transcription factor KLF5 to suppress intimal hyperplasia. Several classes of substances are known that are capable of inhibiting the transcription factor KLF5. Possible KLF5 inhibitors include aptamers, retrons, miRNA, siRNA, or specifically binding nucleic acid or peptide sequences. These classes of substances have in common that they can be selected to specifically bind to the transcription factor KLF5 and thereby selectively suppress SMC proliferation, allowing targeted suppression of hyperplasia without impeding endothelialization. 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. 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 called multicopy single-stranded DNA (msDNA) MicroRNAs, abbreviated to 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 highly specifically at the post-transcriptional level. Small interfering RNAs, abbreviated as 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, thereby disrupting their function. In the present application, specifically binding polynucleic acid or peptide sequences are understood to mean those polynucleic acid or peptide sequences that specifically bind to the transcription factor KLF5 in order to inhibit its function. 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 introduce the substances directly at the site. Since the insertion of stents or flow diverters creates positions with increased neointima formation, it would also be expedient to introduce the KLF5 inhibitor as close as possible to the stents and flow diverters. Furthermore, it is desirable to enclose the KLF5 inhibitor in a degradable compound to ensure that the KLF5 inhibitor can penetrate the lower cell layer. WO 2023 / 070072 A1 describes retrons containing binding sites for transcription factors, so-called retron decoys. Such retron decoys can reduce the activity of transcription factors and mitigate the negative effects of dynamic processes induced by transcription factors. Furthermore, methods for administering these artificial retrons are also proposed. These methods can be used to treat a variety of diseases, including inflammatory diseases caused, for example, by surgical interventions. US 2008 / 020014 A1 relates to implantable devices (e.g., drug-delivery stents) containing nuclear receptor ligands. The nuclear receptor ligands may include, among others, PPAR ligands or retinoids. A method for treating or preventing vascular diseases (e.g., restenosis) and related disorders using the devices containing nuclear receptor ligands is also proposed. Mondragon et al., Anti-Transcription Factor RNA Aptamers as Potential Therapeutics. Nucleic Acid Therapeutics. 2016, discusses 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). 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 upon local administration was investigated. In this context, the efficacy of a cell-specific RNA aptamer in promoting endothelial healing was demonstrated for the first time in a clinically relevant large animal model. None of the documents cited above describe a coating for a medical device that addresses the problem of insufficient layer thickness. A sufficient layer thickness is advantageous because it can influence the desired simulation of a biological environment for the attachment of endothelial cells. There is therefore a need for coatings that are both sufficiently stable and can mimic a natural cell environment and surface (glycocalyx) as closely as possible. Furthermore, these surfaces should be endowed with anticoagulant properties to suppress thrombosis and hemolysis as much as possible. According to the invention, this object is achieved by the further development according to patent claim 1. Accordingly, the invention is based on the idea of ​​specifying a medical device, in particular a stent or a flow diverter, with a mesh structure and preferably with a self-expanding mesh structure, wherein the mesh structure has at least one mesh structure element which is, in particular completely, coated with a nanostructure coating formed from fibrin nanofibers, and wherein the nanostructure coating additionally contains a polynucleic acid or peptide KLF5 inhibitor. According to the invention, the nanostructure coating has a structure with two layers, wherein the first layer is formed by a, in particular felt-like or fleece-like, matrix of interconnected fibrin fibers, and wherein some fibrin fibers protrude freely beyond the first layer and form a second layer of a, in particular pile-like, single-fiber structure. The polynucleic acid or Peptide KLF5 inhibitor is integrated into the first layer and / or the second layer, e.g. embedded or bound. The invention thus differs from the previously known prior art in that the nanostructure coating is essentially formed in two layers and the polynucleic acid or peptide KLF5 inhibitor is integrated into the layers. A first layer in the two-layer structure, which preferably lies directly on the surface of the mesh 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 with one another. A particularly dense fibrin structure is formed on this layer. The second layer of the nanostructure coating is formed by a portion of the fibrin fibers that protrude beyond the first layer into the open space, forming a single-fiber structure. The protruding fibrin fibers are preferably uncrosslinked in the second layer. The individual fibers, or individual fiber portions, essentially form a pile-like structure. Thus, the second layer has a particularly loose fibrin fiber structure. Essentially, the nanostructure coating is comparable to a velour carpet, in which the textile fibres are cross-linked or matted together in a first layer and individual textile fibres protrude freely in an overlying layer, thus forming the pile of the velour. It has been shown that this special structure of the nanostructured coating provides an overall 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 (the cells adhere to them), while the protruding fibrin fiber ends at the cell edges can improve cell adhesion under flow stress (such as in blood vessels). The KLF5 inhibitor incorporated into the coating, on the other hand, ensures that the surface area provided by the coating inhibits intimal hyperplasia. The polynucleic acid or peptide KLF5 inhibitor is not subject to any relevant restrictions in the context of the invention described here, as long as the desired KLF5-inhibiting properties can be provided. Therefore, in a preferred embodiment of the medical device according to the invention, the polynucleic acid or peptide KLF5 inhibitor is selected from aptamers, retrons, miRNA, siRNA, and / or a specifically binding nucleic acid or peptide sequence. In a particularly preferred embodiment, the polynucleic acid or peptide KLF5 inhibitor is an aptamer. The polynucleic acid or peptide KLF5 inhibitor can be integrated into the coating in a non-covalent form, e.g., by impregnating the fibrin-coated medical device with a solution of the polynucleic acid or peptide KLF5 inhibitor, or by adding the polynucleic acid or peptide KLF5 inhibitor prior to crosslinking the fibrin nanothreads in the first layer, and performing the crosslinking in the presence of the polynucleic acid or peptide KLF5 inhibitor. Alternatively, the polynucleic acid or peptide KLF5 inhibitor can be covalently bound to components of the nanostructure coating, particularly to fibrin nanofibers of the nanostructure coating. Covalent binding has the advantage that the polynucleic acid or peptide KLF5 inhibitor cannot be significantly leached from the coating as a result of blood flow in adjacent blood vessels. In one embodiment, the attachment occurs via carboxylic acid groups containing NH2 groups present in the polynucleic acid or peptide KLF5 inhibitor with components of the nanostructure coating, e.g., when a peptide-based KLF5 inhibitor is used. For steric reasons, it is preferred if this attachment does not occur directly, but rather via a linker (i.e., a chemical structure without biological effect that increases the distance between the HO-l activator and the fibrin of the nanostructure coating). Such attachment via a linker is also possible with KLF5 inhibitors based on polynucleic acids; in this case, the linker can be bound to OH groups of the polynucleic acid and to OH or NH groups from the nanostructure coating. An alternative option for covalent bonding involves linking the polynucleic acid or peptide 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 or peptide KLF5 inhibitor to form an ester. The resulting ester bond has the advantage that the polynucleic acid or peptide KLF5 inhibitor is released in a controlled manner as soon as the medical device comes into contact with an aqueous medium (especially blood). Accordingly, in a preferred embodiment, the polynucleic acid or peptide KLF5 inhibitor is bound to components of the nanostructure coating via the carboxy group of the citric acid polyester, wherein the binding is preferably the reaction product of the polynucleic acid or peptide KLF5 inhibitor with a citric acid polyester and OH groups or amino groups from the nanostructure coating. In a particularly preferred embodiment, the citric acid polyester is selected from the group consisting of poly(l,10-decanediol-co-citric acid), poly(l,8-octanediol-co-citric acid), poly(l,6-hexanediol-co-citric acid), poly(l,12-dodecanediol-co-citric acid), poly(l,8-octanediol-co-citric acid-co-glycerol), poly(l,8-octanediol-citric acid-co-polyethylene oxide), poly(l,12-dodecanediol-citric acid-co-polyethylene oxide), poly(l,8-octanediol-citric acid-co-N-methyldiethanoamine), poly(l,12-dodecanediol-citric acid-co-N-methyldiethanoamine) or mixtures thereof, wherein poly(l,8-octanediol-co-citric acid), also known as POC referred to, is preferred. In a further preferred embodiment, the polynucleic acid or peptide KLF5 inhibitor is not integrated into the coating in covalent form, but is incorporated into the nanostructure coating in a nanoencapsulated form, and in particular in a form in which the polynucleic acid or peptide KLF5 inhibitor is present in degradable nanoparticles. A particularly suitable form is one in which the polynucleic acid or peptide KLF5 inhibitor is enclosed in liposomes or micelles, and wherein these form the nanostructure coating of the medical device according to the invention with a liquid formulation containing, impregnated or treated with the liposomes or micelles. In a further embodiment, as needed, the nanostructure coating and the polynucleic acid or peptide KLF5 inhibitor can be modified in a first step with chemical functions suitable for click reactions. In a second step, the polynucleic acid or peptide KLF5 inhibitor can then be linked to the nanostructure coating via a reaction of these functions. Chemical functions that can be used for click reactions include, for example, a primary amine on one of the reactants and a dialdehyde or epoxide on the other reactant, a C–C triple bond and an azide group, or a thiol group and an alkene or epoxide group. In a preferred embodiment of the medical device according to the invention, the nanostructure coating has a fibrin quantity of at least 2 pg / cm 2 , especially more than 2 pg / cm 2, especially more than 3 pg / cm 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 mesh element within a range, allowing the entire medical device to be easily compressed to the smallest possible cross-sectional diameter. This is the prerequisite for the medical device to be guided to the treatment site via small catheters. This allows even small blood vessels, particularly in the cerebral region, to be treated. In addition, a thin nanostructure coating ensures that the overall wall thickness of the device remains small, thus not significantly impairing blood flow through a blood vessel. This prevents vascular constriction (stenosis) caused by the device. It is further preferred if the nanostructure coating contains an amount of polynucleic acid or peptide KLF5 inhibitor of at least 2 pg / cm 2 , especially more than 2 pg / cm 2 , especially more than 3 pg / cm 2 A Such an amount provides beneficial antithrombotic and antihemolytic properties. In addition to the polynucleic acid or peptide KLF5 inhibitor, it may be advantageous to incorporate additional antithrombotic agents or compounds into the nanostructure coating of the medical device according to the invention. A particularly suitable agent for this purpose is heparin, for example. The incorporation of heparin can further improve the antithrombogenicity of the nanostructure coating. Heparin can be incorporated into the first layer, although it is possible that the heparin will also bind to the second layer. Rather, the heparin can bond with the nanostructure coating across the entire layer thickness. The heparin can also be loosely or covalently bound into the nanostructure coating, whereby a covalent bond is associated with the same advantages as those stated above for the polynucleic acid or peptide KLF5 inhibitor. It is preferred if the heparin is covalently bound to fibrin fibers of the nanostructure coating. It is further advantageous if the first layer has a first amount of fibrin and the second layer has a second amount of fibrin, wherein the first amount of fibrin is greater than the second amount of fibrin. Specifically, it has been shown that a ratio between the first amount of fibrin and the second amount of fibrin of at least 2, in particular at least 3, in particular at least 4, is 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 or peptide KLF5 inhibitor or other substances, and, on the other hand, the second layer has a sufficiently loose structure to ensure improved adhesion of endothelial cells. Furthermore, it is advantageous if the first layer comprises a first amount of polynucleic acid or peptide KLF5 inhibitor and the second layer comprises a second amount of polynucleic acid or peptide KLF5 inhibitor, wherein the first amount is greater than the second amount. A ratio between the first amount of polynucleic acid or peptide KLF5 inhibitor and the second amount of KLF5 inhibitor of at least 2 is particularly advantageous. in particular at least 3, in particular at least 4. While the polynucleic acid or peptide KLF5 inhibitor can also covalently bind to the second layer and prevent blood clotting there through its antithrombogenic properties, it is expected that a larger amount of polynucleic acid or peptide KLF5 inhibitor will accumulate in the first layer due to the sponge-like structure of the fibrin nanothreads, which will then be successively released to the second layer. In this respect, the first layer can also form a drug reservoir. In the medical device according to the invention, in an advantageous embodiment, 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 nanostructure 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. The stability of the fibrin nanocoating is advantageously enhanced if the fibrin fibers are formed from cross-linked fibrin molecules. Cross-linking can be achieved by adding a special factor, factor XHIa, during the manufacturing process. Cross-linking significantly stabilizes the fibrin nanostructure and can improve the previously described benefits regarding endothelialization. With regard to cross-linking, it is particularly envisaged that the fibrin molecules each have two carboxyl termini (D domains) and one amino terminus (E domain), with the amino terminus of one fibrin molecule being linked to at least one carboxyl terminus of another fibrin molecule, particularly by a covalent bond. According to claim 17, the invention further relates to a medical device, in particular a stent or flow diverter, with a mesh structure, in particular with a self-expanding mesh structure, wherein the mesh structure comprises at least one mesh structure element that is, in particular completely, encased by a nanostructure coating formed from fibrin nanofibers. The nanostructure coating comprises a first layer that forms a matrix, in particular a felt-like or nonwoven-like matrix, of interconnected fibrin fibers, wherein the nanostructure coating additionally contains a polynucleic acid or peptide KLF5 inhibitor integrated into the first layer. The invention differs from the previously known prior art in that a polynucleic acid or peptide KLF5 inhibitor is integrated into the first, in particular the only, layer of the nanostructure coating. The first layer of the nanostructure coating preferably lies directly on the surface of the mesh element and comprises a matrix of cross-linked fibrin fibers. The matrix can be described as felt-like or fleece-like. The fibrin fibers of the first layer are, in particular, cross-linked or matted with one another. This forms a particularly dense fibrin structure. The polynucleic acid or peptide KLF5 inhibitor incorporated into the coating ensures that intimal hyperplasia is inhibited. Regarding the (further) advantages of the medical device according to claim 17, reference is made to the advantages explained in connection with the medical device according to claim 1. Furthermore, the medical device according to claim 17 may alternatively or additionally comprise individual features or a combination of several features previously mentioned with respect to the medical device according to claim 1. The nanostructure coating may further contain heparin, preferably heparin that is covalently bound to the fibrin fibers of the nanostructure coating. The heparin that is covalently bound to the first layer may be embedded in the fibrin layer. Embedded preferably means that the heparin that is covalently bound to the first layer forms an integral part of the nanostructure coating or is incorporated into the coating. The heparin that is covalently bound to the first layer may therefore be present both on the surface and inside the coating. In other words, heparin can be present throughout the entire thickness of the nanostructured coating. Heparin improves the anti-thrombogenicity of the nanostructured coating. Due to the covalent bonding of heparin to the fibrin fibers, heparin is advantageously stably immobilized in the nanostructured coating. This can prevent or at least slow down the degradation of heparin. Heparin remains longer or completely in the nanostructured coating, which inhibits or prevents thrombus formation in the long term. Furthermore, heparin is not only bound to the surface of the nanostructured coating, but also located within the nanostructured coating. Due to the covalent bond, the atoms of the heparin and the atoms of the fibrin share their valence electrons. This sharing of electrons makes the covalent bond very stable and robust, as the atoms essentially form a noble gas configuration. Therefore, the therapeutic effect of the heparin in the nanostructured coating is longer lasting and enables long-term treatment. The risk of thrombus formation and subsequent complications is thus reduced. The nanostructure coating can be between 5 and 50 ml / cm 2 , preferably between and 30 ml / cm 2 , more preferably between 10 and 20 ml / cm 2 , especially 12 to 18 mU / cm 2 , and most preferably about 15 ml / cm 2 Contains heparin. 180U heparin preferably corresponds to 1mg heparin. These amounts of heparin have been found to improve the stability of the nanostructured coating and enable low-friction guidance of the stent through a catheter. The amount of heparin can be measured using a colorimetric assay. Furthermore, some fibrin fibers can protrude freely beyond the first layer, forming a second layer consisting of a single-fiber structure, particularly a pile-like structure, with a polynucleic acid or peptide KLF5 inhibitor integrated into the second layer. This gives the nanostructured coating an overall increased surface area for endothelial cell adhesion, significantly improving endothelialization. Heparin can also be integrated into the second layer. The invention will be explained in more detail below using an exemplary embodiment with reference to the attached schematic drawings. Fig. 1 is a schematic cross-sectional view through a mesh structure element with a nanostructure coating of a medical device according to the invention according to a preferred embodiment; Fig. 2 is a schematic representation of the cross-linking of fibrin molecules to form a stabilized fibrin fiber; Fig. 3 is a perspective view of a stent made of a wire mesh in which the wires are formed of a radiopaque core material, and wire ends are formed at one stent end and loops are formed at the other stent end; Fig. 4 is 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 radiopacity than the sheath material; Fig. 5 A: a flow diverter with a radially self-expanding lattice structure, at least in sections tubular, made of several interwoven individual wires; B: a schematic representation of a mesh of the lattice structure of the medical device; Fig. 6 is a schematic cross-sectional view through a network structure element with a nanostructure coating of a medical device according to the invention according to a further preferred embodiment; and Fig. 7 is a schematic cross-sectional view through a network structure element with a nanostructure coating of a medical device according to the invention according to a further preferred embodiment. Figs. 1, 6, and 7 schematically show a mesh structural element 10 of a medical device, in particular a stent. Generally, the medical device includes a plurality of mesh structural elements 10 that form a mesh structure. The mesh structural elements 10 may be formed by wires that are interwoven to form a mesh structure. Alternatively, the mesh structural elements 10 may also form webs of a one-piece mesh structure. This is the case, for example, with stents that are cut in one piece from a tube. Such stents are often referred to as laser-cut stents. 1, 6 and 7 essentially shows a cross-section through the mesh structure element 10, wherein, for reasons of clarity, the nanostructure coating is only shown on one surface. However, the nanostructure coating extends over the entire outer surface of the mesh structure element 10, i.e., the mesh structure element 10 can be completely coated by the nanostructure coating. In particular, it is provided that the nanostructure coating extends only over the outer circumferential surface of the individual mesh structure elements 10. Cells or meshes of a mesh structure, i.e., openings delimited by the individual mesh structure elements 10, are preferably not covered by the nanostructure coating. However, it is advantageous if all mesh structure elements 10 of the mesh structure are completely coated with the nanostructure coating. The nanostructure coating has a first layer LI, which lies directly on the surface of the mesh element 10 (see Figs. 1, 6, and 7). The first layer LI is formed by fibrin fibers 11, which form a densely networked matrix. The fibrin fibers 11 thus interlock and are highly compacted, essentially resulting in a nonwoven-like first layer LI. The schematic representation according to Fig. 1 shows that individual fibrin fibers 12 protrude above the first layer LI. These protruding fibrin fibers 12 form a second layer L2 of the Nanostructure coating. The second layer L2 is formed by a single-fiber structure, i.e., the fibrin fibers 12 are present as free fibers, in particular with largely free ends. The second layer L2 thus essentially forms a pile of protruding fibrin fibers 12. The fibrin fibers 11 of the first layer LI and the protruding fibrin fibers 12 of the second layer L2 are bound to KLF5 inhibitor molecules 13 (in this case shown as polynucleic acid aptamer) via covalent bonds. According to Figures 6 and 7, the first layer LI is the only layer of the nanostructure coating. KLF5 inhibitor molecules 13 (shown here as a polynucleic acid aptamer) are covalently bound to the fibrin fibers 11 of the first layer LI. The individual fibrin fibers 11, 12 are formed from fibrin molecules 14, which bond together when thrombin is added, so that the fibrin fibers 11, 12. In a very simplified representation, as shown in Fig. 3, each fibrin molecule 14 has a central amino terminus, also referred to as the E domain 21. Individual monomers extend from the E domain 21, forming a so-called coiled-coil structure 24. On the outside of the molecule are carboxy termini, referred to as the D domain 22. By adding thrombin, fibrin peptides are cleaved, whereby the released fibrin monomers are linked by polymer bonds 23. By further adding a fibrin-stabilizing factor (factor XHIa), cross-linking bonds 13 are formed. The cross-linking bonds 13 are formed between the E domain 21 and at least one D domain 22 of another fibrin molecule 14. In particular, adjacent D domains 22 of two fibrin molecules 14 are connected by the covalent bond 13 to the E domain 21 of a third fibrin molecule 14. The covalent bonds 13 thus form a bridge that stabilizes the weaker polymerization bond 23. Overall, the entire fibrin fiber structure is thus stabilized. The two-layer nanostructure coating described in the present invention is particularly effective in binding endothelial cells. In experiments, the A nanostructured coating was applied to a glass substrate and immersed in an endothelial cell solution. It was shown that the nanostructured coating is designed in such a way that at least 60,000, and in particular between 60,000 and 90,000, endothelial cells per square centimeter attach to the nanostructured coating. This represents a significant increase in the number of endothelial cells per square centimeter compared to previous biological coatings. Not only is the number of endothelial cells per square centimeter increased with the nanostructured coating of the invention, but it has also been shown that cell viability is significantly increased 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 using a CCK-8 assay on a stent with the nanostructured coating described here after three days, resulting in an absorption value of significantly more than 0.2 at a wavelength of 450 nm. In Fig. 7 it can be seen that the nanostructure coating contains not only KLF5 inhibitor molecules (in this case shown as a polynucleic acid aptamer) 13 but also heparin molecules 19. The heparin 19 is covalently bound to the fibrin fibers 11 of the first layer LI. The nanostructure coating shown has between 5 and 50 ml / cm 2 Heparin 19. Heparin 19 improves the anti-thrombogenicity of the nanostructured coating. The advantages of the nanostructure coating described above are, as mentioned above, particularly evident in stents and flow diverters coated therewith, whereby the structure and design of these devices are not subject to any relevant restrictions. However, the corresponding stents and flow diverters preferably have a structure and dimensions that allow them to be used in human blood vessels. Since the stents should be usable in most cases through minimally invasive procedures, it is further preferred if the stents according to the invention are designed as an at least partially tubular stent and are surrounded by a compressed Cross-sectional diameters can be automatically expanded to an expanded cross-sectional diameter. In a special advantageous embodiment, the medical device according to the invention is designed as a stent with a mesh 20 of wires 21, each of which has an X-ray-visible core material and a superelastic sheath material and forms 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 as large as 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. The mesh 20 has in this embodiment 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 configuration is shown in Figure 3. More specific configurations of the stent are given in DE 20 2021 106 808 U1, in particular in

[0009] until

[0025] of this document, the relevant scope of which is hereby incorporated by reference into this application. 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, which has a core material and a sheath material, wherein the core material has a higher X-ray visibility 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 a, in particular polished, outer surface of the wire 31, in particular of the sheath material, Mixed oxide layer comprising TiCh and at least one nitride, in particular titanium oxynitride and / or titanium nitride. Such a design is shown in Figure 4. More specific designs of the stent are given in DE 20 2016 107 791 B4, in particular in

[0006] until

[0021] of this document, the relevant scope of which is hereby incorporated by reference into this application. In yet another 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 a plurality of interwoven individual wires 41 forming meshes 42 of the lattice structure 40, wherein at least some of the individual wires 41 have an X-ray visible core material 41a and a superelastic sheath material 41b, wherein a plurality of 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 has a mesh number n and the core material 41a has a core diameter d K em, and where the core diameter d Ke rn applies: dK ern = f ' (D eX p / n) where for a visibility factor f applies: 0.08 < f < 0.15. Such a configuration is shown in Figures 1 and 2. More specific configurations of the stent are given in DE 10 2019 104 828 B4, the relevant scope of which is hereby incorporated by reference into this application. In a further advantageous embodiment, the medical device according to the invention is designed as a stent with a self-expanding, tubular mesh structure made of meshes, wherein the mesh structure is formed by a single wire made of an X-ray visible core material and a sheath material, which has a braiding angle a relative to a central longitudinal axis M of the braid structure, wherein - both ends of the braided structure have closed loops which form an enlargement of the diameter of the braided structure with a flaring angle b relative to a central longitudinal axis M of the braided structure, - the loops and part of the meshes form a continuous increase in diameter of the braid structure, and - for the braiding angle a and the flaring angle b the following applies: 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°. Such an embodiment is specified in DE 10 2018 125 983 B4, the relevant scope of which is hereby incorporated into this application by reference. In a further advantageous embodiment, the medical device according to the invention is designed as a stent with a compressible and expandable lattice structure of webs which are integrally connected to one another by web connectors and which delimit diamond-shaped cells, each cell being delimited by two straight webs and two S-shaped curved webs which connect the straight webs to one another, and wherein - the lattice structure in a rest state has a fully expanded rest diameter D exp which is between 3.0 mm and 5.0 mm, - a ratio between a fully compressed diameter Dcomp of 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 is between the fully compressed diameter Dkomp and an insert diameter which is at most 90% of the rest diameter D exp has a radial force of at least 0.5 N, in particular at least 0.6 N. Such an embodiment is specified in DE 10 2022 113 422 A1, the relevant scope of which is hereby incorporated into this application by reference. In yet another advantageous embodiment, the medical device according to the invention is designed as a stent for implantation in a blood vessel, in particular a neurovascular blood vessel, with a substantially tubular, self-expanding lattice structure which can be converted 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 Xi to x2: [(RRF(XI)-RRF(X2))-(COF(XI)-COF(X2))] / [COF(XI)-COF(X2)] > A where A = 10% and x2> Xi. Such an embodiment is specified in DE 10 2016 110 410 A1, the relevant scope of which is hereby incorporated into this application by reference. 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 latticework of wires, each of which is wound helically around a longitudinal axis of the latticework and crosses over and under each other, wherein the latticework in a resting state has a proximal cylindrical section and a distal cylindrical section, which are connected to one another 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 with two cylindrical sections with different cross-sectional diameters is intended to ensure the most uniform porosity of the stent possible when it is placed in blood vessels with different cross-sectional diameters. Stents with such a configuration are particularly the subject of the description in WO 2022 / 136368 A1, the relevant content of which is hereby incorporated by reference into the present application. The medical devices according to the invention realize in particular several of the following advantages: - improved antithrombogenic properties; - improved anti-inflammatory properties; - improved endothelialization; - the suppression of intimal hyperplasia; - faster healing 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 fiber of the single fiber structure 13 covalent bond 14 fibrin molecules 15 E-domain 16 D-domain 17 Polymer bond 18 Coiled-coil structure 19 Heparin 20 braids 21 wire 22 first stent end 23 second stent end 24 loops 25 open wire end 30 mesh 31 wire 40 lattice structure 41 Lattice structure 41a Nuclear material 41b Sheath material 42 stitches 43 mesh ring LI first layer

Claims

Claims 1. A medical device, in particular a 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 in that the nanostructure coating has a first layer (LI) which forms a, in particular felt-like or fleece-like, matrix of interconnected fibrin fibers (11), wherein some fibrin fibers (12) protrude freely beyond the first layer (LI) and form a second layer (L2) of a, in particular pile-like, single-fiber structure, and wherein the nanostructure coating additionally contains a polynucleic acid or peptide KLF5 inhibitor which is integrated into the first layer (LI) and / or the second layer (L2).

2. Medical device according to claim 1, characterized in that the polynucleic acid or peptide KLF5 inhibitor is selected from the group consisting of aptamers, retrons, miRNA, siRNA and / or a specifically binding nucleic acid or peptide sequences, wherein the polynucleic acid KLF5 inhibitor is preferably present as an aptamer.

3. Medical device according to one of claims 1 or 2, characterized in that the polynucleic acid or peptide 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 in that the binding of the polynucleic acid or peptide KLF5 inhibitor to components of the nanostructure coating is effected via an ester group, wherein the binding preferably comprises the reaction product of the reaction of the polynucleic acid or peptide KLF5 inhibitor with a Citric acid polyester, preferably poly(l,8-octanediol-co-citric acid), and OH groups or amino groups from the nanostructure coating.

5. Medical device according to one of claims 1 to 3, characterized in that the polynucleic acid or peptide KLF5 inhibitor is present in nanoencapsulated form, in particular in degradable nanoparticles in the nanostructure coating.

6. Medical device according to one of the preceding claims, characterized in that the nanostructure coating contains an amount of the polynucleic acid or peptide KLF5 inhibitor of at least 2 pg / cm 2 , especially more than 2 pg / cm 2 , especially more than 3 pg / cm 2 , has.

7. Medical device according to one of the preceding claims, characterized in that the nanostructure coating further contains heparin, preferably heparin which is covalently bound to fibrin fibers of the nanostructure coating.

8. Medical device according to one of the preceding claims, characterized in that the first layer (LI) comprises a first amount of the polynucleic acid or peptide KLF5 inhibitor and the second layer (L2) comprises a second amount of the polynucleic acid or peptide KLF5 inhibitor, wherein a ratio between the first amount and the second amount of the polynucleic acid or peptide KLF5 inhibitor is at least 2, in particular at least 3, in particular at least 4.

9. Medical device according to one of the preceding claims, characterized in that the second layer (L2) has a greater height than the first layer (LI).

10. Medical device according to one of the preceding claims, characterized in that the first layer (LI) 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 one of the preceding claims, characterized in that the fibrin fibers (11) are formed from cross-linked fibrin molecules (14).

12. Medical device according to claim 11, characterized in 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. A medical device according to any one of the preceding claims, which is designed as an at least partially tubular stent and is automatically expandable 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 an X-ray-visible 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 as large as 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 having a wire diameter of 0.046 mm or 0.05 mm and an outer diameter of 7.18 mm or 8.20 mm.

15. Medical device according to one of the preceding claims, characterized in that it is designed as a stent with a substantially tubular latticework (30) made of a single wire (31) which has a core material and a sheath material, wherein the core material has a higher X-ray visibility 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 a, in particular polished, outer surface of the wire (31), in particular of the sheath material, comprises a mixed oxide layer which has TiCh and at least one nitride, in particular titanium oxynitride and / or titanium nitride.

16. Medical device according to one of the preceding claims, characterized in 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) which form meshes (42) of the lattice structure (40), wherein at least some of the individual wires (41) have 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 completely self-expanded state has an expansion diameter D exp , the mesh ring (43) has a mesh number n and the core material (41a) has a core diameter dKem, and where the core diameter d Ke rn applies: d K ern = f ' (D eXp / n) where for a visibility factor f applies: 0.08 < f < 0.

15.

17. 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 in that the nanostructure coating has a first layer (LI) which forms a, in particular felt-like or fleece-like, matrix of interlinked fibrin fibers (11), wherein the nanostructure coating additionally contains a polynucleic acid or peptide KLF5 inhibitor which is integrated into the first layer (LI).

18. Medical device according to claim 17, characterized in that the nanostructure coating is between 5 and 50 mU / cm 2 , preferably between and 30 mU / cm2 , more preferably between 10 and 20 mU / cm 2 , especially 12 to 18 mU / cm 2 , and most preferably about 15 mU / cm 2 Contains heparin.

19. Medical device according to claim 17 or 18, characterized in that some fibrin fibers (12) protrude freely beyond the first layer (LI) and form a second layer (L2) of a, in particular pile-like, single-fiber structure, wherein a polynucleic acid or peptide KLF5 inhibitor is integrated into the second layer (L2).

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