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, preferably a self-expanding 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 retinoic acid and / or a synthetic retinoid, which 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 make them antithrombogenic and counteract hyperlasia. This should ensure rapid healing of the device and suppress side effects as much as possible. To date, no coating technology has been described that simultaneously has antithrombogenic, endothelialization-promoting and anti-inflammatory effects and inhibits intimal hyperplasia. Retinoic acid is a compound or group of compounds formed from isoprenoid carboxylic acids. Retinoic acids belong to the apocarotenoids and form a subgroup of retinoids, making them terpenoids. Non-aromatic retinoids include all-trans retinoic acid (tretinoin) and the isomer 13-cis-retinoic acid (isotretinoin), which are used both systemically and topically. Both are also naturally produced in relatively small amounts in the human vitamin A metabolism. 9-cis-retinoic acid (alitretinoin) has also been described for therapeutic use. All-trans retinoic acid is a metabolite of vitamin Al (all-trans retinol) that mediates the functions of vitamin Al required for growth and development. Retinoic acid has a wide range of biological effects. Retinoic acid is primarily used to treat disorders of cell proliferation. Retinoic acid has pleiotropic effects on vascular smooth muscle cells and macrophages: It influences the proliferation, migration, and conversion of smooth muscle cells into other cell types and modulates macrophage activation. However, the anti-inflammatory effects of retinoic acid are also receiving increasing attention. It is therefore not surprising that retinoic acids are proposed for the treatment of cardiovascular and inflammatory diseases. However, the anti-inflammatory effect and the inhibition of hyperplasia by retinoic acid are only fully effective when the retinoic acid reaches the lower cell layers of the smooth muscle cells. A further problem is that the effect usually does not extend beyond a persists for a longer period of time, necessitating prolonged therapy with the substances. The anticoagulant effect can also cause undesirable side effects, such as a general reduction in coagulation, which can be detrimental in the case of external injuries. Synthetic retinoids such as tamibarotene (AM80) and baxarotene (LGD1069) have an effect comparable to that of retinoic acid. Molecular and quantum mechanical calculations have shown that they can bind to the same receptors as retinoic acid (see Tsuji M. et al., FEBS Open Bio 7 (2017), pp. 391-96). AM80 has also been described to inhibit the expression and transcriptional function of KLF5, which is responsible for the formation of neointima after vascular injury (Fujiu K. et al., Circ. Res. (2005), 97(11), pp. 1132-41). For a therapy in which the retinoic acid and / or the synthetic retinoid act only directly at the site, it would be necessary to introduce the substances directly at the site. Since the insertion of stents or flow diverters creates positions with an increased susceptibility to thrombosis events, it would also be advisable to introduce the retinoic acid and / or the synthetic retinoid as close as possible to the stents and flow diverters. Furthermore, it is desirable to enclose the retinoic acid and / or the synthetic retinoid in a degradable compound to ensure that the retinoic acid can penetrate the lower cell layer. WO 2021 / 251712 A1 describes a drug-delivery stent and a method for its manufacture, wherein the stent is inserted into a narrowed area in the body where stenosis symptoms are observed or predicted to prevent narrowing of the narrowed area and enable the release of a drug, such as retinoic acid. Furthermore, a drug-delivery stent is described, consisting of a stent with mechanical strength to prevent narrowing of the narrowed area and a coating film formed on the surface of the stent to absorb and release the drug. US Pat. No. 9,211,363 B2 describes controlled-release vascular implants, such as vascular grafts, stents, wraps, and gels, containing a biocompatible polymer, such as polyester, polyurethane, polycarbonate, and all-trans retinoic acid or its derivatives. These vascular implants are said to be used to treat, prevent, or inhibit thrombosis and / or neointimal hyperplasia that could be caused by prosthetic implantation. WO 2000 / 010552 A2 describes the use of anti-angiogenic agents for inhibiting adverse reactions to vascular wall injuries, including stent neointima, dialysis graft neointima, and vascular graft-induced neointima, and for treating benign hypertrophic scarring, as well as for treating and passivating unstable atherosclerotic plaques. The use of catheter devices to enhance the local delivery of anti-angiogenic agents into the endothelial tissue of blood vessels in the living body is envisaged. A disadvantage of the approaches described in the prior art is that the coatings are formed only in comparatively small thickness, which can impair 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 consisting of Fibrin nanofibers are formed, and the nanostructure coating additionally contains retinoic acid. According to the invention, the nanostructure coating has a two-layer structure, wherein the first layer is formed by a matrix, in particular a 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 single-fiber structure, in particular a pile-like structure. The retinoic acid and / or the synthetic retinoid is integrated into the first layer and / or the second layer, e.g., embedded or bound. The invention differs from the previously known prior art in that the nanostructure coating is essentially formed in two layers and the retinoic acid 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 nanostructure coating provides an increased surface area for the adhesion of endothelial cells, so that endothelialization can be significantly improved. The first layer, which is more strongly cross-linked, directly contacts the surfaces of the cells. Contact (they attach to them), while the protruding fibrin fiber ends at the cell edges can ensure improved cell adhesion under flow stress (such as in blood vessels). The retinoic acid incorporated into the coating, on the other hand, ensures that the surface provided by the coating has improved antithrombotic and antihemolytic properties. Retinoic acid is not subject to any relevant restrictions in the context of the invention described here, as long as the desired antithrombotic and antihemolytic properties can be provided. Therefore, in a preferred embodiment of the medical device according to the invention, the retinoic acid is selected from all-trans retinoic acid (tretinoin), 13-cis retinoic acid (isotretinoin), and / or 9-cis retinoic acid (alitretinoin), preferably all-trans retinoic acid (tretinoin). In a particularly preferred embodiment, the retinoic acid is all-trans retinoic acid (tretinoin). For the synthetic retinoid, it is preferred if it is present as tamibarotene (AM80) or baxarotene (LGD1069), although mixtures of the two specific substances mentioned can also be used. The retinoic acid and / or the synthetic retinoid can be integrated into the coating in a non-covalent form, e.g., by impregnating the medical device coated with fibrin threads with a solution of the retinoic acid and / or the synthetic retinoid, or by adding the retinoic acid and / or the synthetic retinoid prior to crosslinking the fibrin nanothreads in the first layer, and carrying out the crosslinking in the presence of the retinoic acid and / or the synthetic retinoid. Alternatively, it is possible for the retinoic acid and / or the synthetic retinoid to be covalently bound to components of the nanostructure coating, in particular to fibrin nanofibers of the nanostructure coating. Covalent bonding has the advantage that the retinoic acid and / or the synthetic retinoid cannot be washed out of the coating in an uncontrolled manner as a result of blood flow in adjacent blood vessels. One possible covalent bonding option is to bind the retinoic acid and / or the synthetic retinoid to a citric acid polyester, which in turn can be covalently bonded to the fibrin fibers of the nanostructure coating. The hydroxy groups of the citric acid polyester react with the carboxyl group of the retinoic acid or the synthetic retinoid to form an ester. The resulting ester bond has the advantage that the retinoic acid or the synthetic retinoid is released in a controlled manner when the medical device comes into contact with an aqueous medium (especially blood). Accordingly, in a preferred embodiment, the binding of the retinoic acid and / or the synthetic retinoid to components of the nanostructure coating occurs via the hydroxy group of the citric acid polyester, wherein the binding is preferably the reaction product of the retinoic acid and / or the synthetic retinoid 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 another embodiment, the linking takes place via the carboxylic acid group of the retinoic acid or the synthetic retinoid, which can be linked, for example, with EDC / NHS (EDC = l-ethyl-3-(3-dimethylaminopropyl)carbodiimide; NHS = N-hydroxysuccinimide) with NH2 groups in components of the nanostructure coating. In yet another embodiment, as required, the nanostructure coating and the retinoic acid and / or the synthetic retinoid can be modified in a first step with chemical functions that are suitable for click reactions and in a second step the retinoic acid and / or the synthetic Retinoid can be bonded to the nanostructure coating via a reaction between these functional groups. Chemical functions that can be used for click reactions include a primary amine on one of the reactants and a dialdehyde or epoxide on the other reactant, a carbon–carbon triple bond and an azide group, or a thiol group and an alkene or epoxide group. In an alternative embodiment, the retinoic acid and / or the synthetic retinoid is not integrated into the coating in covalent form, but is incorporated into the nanostructured coating in a nanoencapsulated form, and in particular in a form in which the retinoic acid and / or the synthetic retinoid is present in degradable nanoparticles. A particularly suitable form is one in which the retinoic acid and / or the synthetic retinoid is enclosed in liposomes or micelles, and the nanostructured coating of the medical device according to the invention is impregnated or treated with a liquid formulation containing the liposomes or micelles. 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 2It has been shown that such a quantity of fibrin results in a sufficiently dense yet thin nanostructure coating. A thin nanostructure coating is advantageous for keeping the overall thickness of the 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 retinoic acid and / or synthetic retinoid of at least 2 pg / cm 2 , especially more than 2 pg / cm 2 , especially more than 3 pg / cm 2 Such an amount provides beneficial antithrombotic and antihemolytic properties. In addition to retinoic acid and / or the synthetic retinoid, 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. 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 retinoic acid and / or the synthetic retinoid. 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 retinoic acid and / or the synthetic retinoid 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 retinoic acid and / or synthetic retinoid and the second layer comprises a second amount of retinoic acid and / or synthetic retinoid, wherein the first Amount of the respective substance is greater than the second amount of the substance. A ratio between the first amount of retinoic acid and / or synthetic retinoid and the second amount of retinoic acid and / or synthetic retinoid of at least 2, in particular at least 3, in particular at least 4 is particularly advantageous. Retinoic acid and / or the synthetic retinoid can indeed also bind covalently to the second layer and prevent blood clotting there due to its anti-thrombogenic properties. However, it is to be expected that a larger amount of retinoic acid and / or synthetic retinoid will be stored 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 reservoir for active ingredients. 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. Through cross-linking, the fibrin nanostructure is significantly stabilized and can achieve the previously described advantages with regard to endothelialization. Regarding cross-linking, it is particularly intended that the fibrin molecules each have two carboxyl termini (D domains) and one amino terminus (E domain), whereby the amino terminus of a fibrin molecule is at least one carboxyl terminus of another fibrin molecule, in particular by a covalent bond. According to claim 18, 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 retinoic acid and / or a synthetic retinoid integrated into the first layer. The invention differs from the previously known prior art in that a retinoic acid and / or a synthetic retinoid is integrated into the first, in particular 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 retinoic acid and / or the synthetic retinoid incorporated into the nanostructure coating ensure that the nanostructure coating has improved antithrombotic and antihemolytic properties. Regarding the (further) advantages of the medical device according to claim 18, reference is made to the advantages explained in connection with the medical device according to claim 1. Furthermore, the medical device according to claim 18 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, which is covalently bound to the first layer, forms an integral component of the nanostructured coating or is incorporated into the coating. The heparin, which is covalently bound to the first layer, can therefore be present both on the surface and within 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 within the nanostructured coating. This can prevent or at least slow down its degradation. Heparin remains in the nanostructured coating for a longer period of time or completely, which inhibits or prevents thrombus formation in the long term. Furthermore, heparin is not only bound to the surface of the nanostructured coating but is also located within the nanostructured coating. Due to the covalent bond, the heparin atoms and the fibrin atoms 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, enabling long-term treatment. The risk of thrombus formation and subsequent complications is 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 above the first layer and form a second layer of a single-fiber structure, in particular a pile-like structure, wherein retinoic acid and / or a synthetic retinoid is integrated into the second layer. As a result, the nanostructure coating has an overall Increased surface area for endothelial cell adhesion, significantly improving endothelialization. Heparin can also be incorporated 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, 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 above the first layer LI. 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. Retinoic acid molecules 13 are covalently bound to the fibrin fibers 11 of the first layer L1 and the protruding fibrin fibers 12 of the second layer L2. Instead of retinoic acid molecules 13, analogous molecules of synthetic retinoid can be bound to the fibrin fibers 11, 12. According to Figures 6 and 7, the first layer LI is the only layer of the nanostructure coating. Retinoic acid molecules 13 and / or molecules of synthetic retinoid 13 are bound to the fibrin fibers 11 of the first layer LI via covalent bonds. 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 connection with the present invention is particularly effective with regard to the attachment of endothelial cells. In experiments, the nanostructure coating was applied to a glass substrate and immersed with the glass substrate in an endothelial cell solution. It was shown that the nanostructure coating is designed in such a way that at least 60,000, in particular between 60,000 and 90,000, endothelial cells per square centimeter attach to the nanostructure 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 retinoic acid molecules 13 and / or molecules of synthetic retinoid 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 coated stents and flow diverters, 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 are intended to be deployable through minimally invasive procedures in most cases, it is It is further preferred if the stents according to the invention are 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. 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, comprises a 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 Kern applies: d K 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 having 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 L2 second 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, coated 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 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 retinoic acid and / or a synthetic retinoid 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 retinoic acid is selected from the group consisting of all-trans retinoic acid, 13-cis-retinoic acid and / or 9-cis-retinoic acid, and is preferably in the form of all-trans retinoic acid.

3. A medical device according to claim 1, characterized in that the medical device contains a synthetic retinoid selected from tamibarotene, baxarotene and a mixture thereof.

4. Medical device according to one of claims 1 to 3, characterized in that the retinoic acid and / or the synthetic retinoid is covalently bound to components of the nanostructure coating, in particular to fibrin nanofibers of the nanostructure coating.

5. Medical device according to claim 4, characterized in that the bonding of the retinoic acid and / or the synthetic retinoid to components of the nanostructure coating takes place via an ester group, wherein the bond is preferably the reaction product of the reaction of the retinoic acid with a citric acid polyester, preferably poly(1,8-octanediol-co-citric acid), and OH groups or amino groups from the nanostructure coating.

6. Medical device according to one of claims 1 to 3, characterized in that the retinoic acid and / or the synthetic retinoid is present in nanoencapsulated form, in particular in degradable nanoparticles in the nanostructure coating.

7. Medical device according to one of the preceding claims, characterized in that the nanostructure coating contains an amount of the retinoic acid and / or the synthetic retinoid of at least 2 pg / cm 2 , especially more than 2 pg / cm2 , especially more than 3 pg / cm 2 , has.

8. 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.

9. Medical device according to one of the preceding claims, characterized in that the first layer (L1) has a first amount of the retinoic acid and / or the synthetic retinoid and the second layer (L2) has a second amount of the retinoic acid and / or the synthetic retinoid, wherein a ratio between the first amount and the second amount of the retinoic acid and / or the synthetic retinoid is at least 2, in particular at least 3, in particular at least 4.

10. 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).

11. 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.

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

13. Medical device according to claim 10, 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).

14. 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.

15. 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 connected to a first Stent end (22) loops (24) and at a second stent end (23) open wire ends (25), 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 braid (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.

16. 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.

17. 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 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 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 dKern, and wherein for 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.

18. 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, coated 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 cross-linked fibrin fibers (11), wherein the nanostructure coating additionally contains a retinoic acid and / or a synthetic retinoid which is integrated into the first layer (LI).

19. Medical device according to claim 18, characterized in that the nanostructure coating is between 5 and 50 mU / cm 2, preferably between and 30 mU / cm 2 , 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.

20. Medical device according to claim 18 or 19, characterized in that some fibrin fibers (12) protrude freely beyond the first layer (L1) and a second layer (L2) consists of a, in particular pile-like, single-fiber structure wherein a retinoic acid and / or a synthetic retinoid is integrated into the second layer (L2).

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