Medical device with improved antithrombotic effect

Abstract

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

Description

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

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

[0003] To form the biological coating of the known stent, fibrinogen is first provided, which is then converted to fibrin by the addition of thrombin. The fibrin forms threads that extend outwards from the surface of the network structure. This creates a loose fibrin network into which heparin can be incorporated.

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

[0005] Furthermore, the use of metal devices inserted into blood vessels carries a significant risk of thrombosis and hemolysis, which cannot be completely eliminated by fibrin coating. This is particularly true for flow diverters inserted into blood vessels, which have a higher metal wire density than stents, which are primarily intended for stabilizing the blood vessel. Therefore, there is also a need to modify existing stent and flow diverter coatings to make them antithrombogenic and counteract hyperplasia. This should ensure rapid osseointegration of the device and minimize side effects.

[0006] To date, no coating technology has been described that simultaneously acts as an antithrombotic, endothelialization-promoting and anti-inflammatory agent and inhibits intimal hyperplasia.

[0007] 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 the retinoids, thus classifying them as terpenoids. Non-aromatic retinoids include all-trans retinoic acid (tretinoin) and its isomer 13-cis-retinoic acid (isotretinoin), which are used both systemically and topically. Both are also naturally produced in relatively small amounts during human vitamin A metabolism. The therapeutic use of 9-cis-retinoic acid (alitretinoin) has also been described.

[0008] All-trans retinoic acid is a metabolite of vitamin A1 (all-trans retinol) that mediates the functions of vitamin A1 required for growth and development. Retinoic acid has a wide range of biological effects. It 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 transformation 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.

[0009] It is therefore not surprising that retinoic acid is proposed for the treatment of cardiovascular and inflammatory diseases. However, the anti-inflammatory effect and the inhibition of hyperplasia by retinoic acid only fully materialize if the retinoic acid reaches the lower cell layers of the vascular smooth muscle cells. A further problem arises from the fact that the effect usually does not last for an extended period, thus requiring prolonged therapy with these substances. Furthermore, the anticoagulant effect can cause undesirable side effects, such as a general reduction in coagulation, which can be detrimental in the case of external injuries.

[0010] Synthetic retinoids such as tamibarotene (AM80) and baxarotene (LGD1069) have an effect comparable to retinoic acid. Molecular and quantum mechanical calculations have shown that these retinoids 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 as inhibiting the expression and transcriptional function of KLF5, which is responsible for neointima formation after vascular injury (Fujiu K. et al. Circ. Res. (2005), 97(11), pp. 1132-41).

[0011] For a therapy in which retinoic acid and / or the synthetic retinoid act only directly at the site of the infection, it would be necessary to introduce the substances directly to the affected area. Since the insertion of stents or flow diverters creates positions with an increased susceptibility to thrombotic events, it would also be advantageous to introduce the retinoic acid and / or the synthetic retinoid as close as possible to the stents and flow diverters. Furthermore, it is desirable to encapsulate the retinoic acid and / or the synthetic retinoid in a degradable compound to ensure that the retinoic acid can penetrate into the lower cell layer.

[0012] WO 2021 / 251712 A1 describes a drug-release 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, in order to prevent further narrowing of the narrowed area and to enable the release of a drug, such as retinoic acid. Furthermore, a drug-release 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 for the absorption and release of the drug.

[0013] US 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. The specified vascular implants are intended for use in the treatment, prevention, or inhibition of thrombosis and / or neointimal hyperplasia that may result from prosthetic implantation.

[0014] WO 2000 / 010552 A2 describes the use of anti-angiogenic agents to inhibit adverse reactions to vascular wall injuries, including stent neointima, dialysis-graft neointima, vascular graft-induced neointima, and for the treatment of benign hypertrophic scarring, as well as for the treatment and passivation of unstable atherosclerotic plaques. The use of catheter devices to improve the local delivery of anti-angiogenic agents into the endothelial tissue of blood vessels in living patients is permitted.

[0015] One disadvantage of the approaches described in the prior art is that the coatings are only formed in a comparatively small thickness, which can impair the desired simulation of a biological environment for the attachment of endothelial cells.

[0016] Therefore, there is a need for coatings that are both sufficiently stable and can closely mimic the natural cell environment and surface (glycolalyx). Furthermore, these surfaces should possess anticoagulant properties to suppress thrombotic events and hemolysis as much as possible.

[0017] DE 10 2021 106 472 A1 discloses an intravascular implant, e.g. in the form of a stent, with a base made of superelastic structural material and a mixed oxide layer of titanium oxynitride (TiO₂). x N y), which has a coating with an antithrombogenic material (e.g., heparin or heparan sulfate). DE 10 2021 128 698 A1 discloses a medical implant with lattice elements that, to increase the surface area of ​​the individual lattice elements, has a polymer nanostructure and an antithrombogenic coating. DE 10 2019 121 562 A1 describes medical devices and stents with a lattice structure, wherein the lattice structure is at least partially covered with a coating that has an antithrombogenic and / or endothelialization-promoting coating.

[0018] Moulas, A. et al Cardiovascular Revascularization Medicine. (2010) 11. 276=277.10.1016 / j.carrev.2010.03.027., Samara I. et al. Sci Rep. 2022 Aug 3; 12(1):13305. doi: 10.1038 / s41598-022-16025-5, and Samara I. et al. Hellenic journal of cardiology: HJC = Hellenike cardiologike epitheoresis, 76, 75-87. https: / / doi.org / 10.1016 / j.hjc.2023.08.003 describes the use of retinoic acid to prevent restenosis in drug-eluting stents, where the drug is applied to the stent using polylactide-co-glycolide (PLGA) as the drug-eluting matrix.

[0019] According to the invention, this problem is solved by the further development according to claim 1.

[0020] Accordingly, the invention is based on the concept of providing a medical device, in particular a stent or a flow diverter, with a network structure, and preferably with a self-expanding network structure, wherein the network structure comprises at least one network element which is, in particular completely, encased with a nanostructured coating formed from fibrin nanofibers and wherein the nanostructured coating additionally contains retinoic acid. According to the invention, the nanostructured coating has a two-layer structure, wherein the first layer is formed by a matrix, in particular a felt-like or nonwoven-like matrix, of interconnected fibrin fibers, and wherein some fibrin fibers protrude freely beyond the first layer and form a second layer of a single-fiber structure, in particular a woven one. The retinoic acid and / or the synthetic retinoid is integrated into the first layer and / or the second layer, e.g.stored or bound.

[0021] The invention differs from the prior art in that the nanostructure coating is essentially two-layered 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 network structure element, comprises a matrix of cross-linked fibrin fibers. This matrix is ​​particularly dense compared to the second layer. In this respect, the matrix can also be described as felt-like or non-woven. The fibrin fibers of the first layer are, in particular, cross-linked or matted together. A particularly dense fibrin structure is formed on this layer.

[0022] The second layer of the nanostructured coating is formed by a portion of the fibrin fibers that protrude from the first layer into the free space, forming a single-fiber structure. These protruding fibrin fibers are preferably uncrosslinked in the region of the second layer. The individual fibers or fractions of individual fibers essentially form a nap-like structure. Thus, the second layer exhibits a particularly loose fibrin fiber structure.

[0023] Essentially, the nanostructure coating is comparable to a velour carpet, in which the textile fibers are cross-linked or felted together in a first layer, and in an overlying layer individual textile fibers protrude freely, thus forming the pile of the velour.

[0024] It has been shown that this particular structure of the nanostructured coating provides an overall increased surface area for the adhesion of endothelial cells, thus significantly improving endothelialization. The first layer, which is more highly cross-linked, comes into direct contact with the cell surfaces (to which the cells adhere), while the protruding fibrin fiber ends at the cell edges ensure improved cell adhesion under flow stress (such as in blood vessels). Furthermore, the retinoic acid incorporated into the coating gives the surface provided by the coating enhanced antithrombotic and antihemolytic properties.

[0025] In the context of the invention described herein, retinoic acid is not subject to any relevant restrictions 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).

[0026] For the synthetic retinoid, it is preferred if it is in the form of tamibarotene (AM80) or baxarotene (LGD1069), although mixtures of the two specific substances mentioned may also be used.

[0027] The retinoic acid and / or the synthetic retinoid can be integrated into the coating in non-covalent form, for example, by impregnating the fibrin-fiber-coated medical device with a solution of the retinoic acid and / or the synthetic retinoid, or by adding the retinoic acid and / or the synthetic retinoid to the first layer before crosslinking the fibrin nanofibers, and then carrying out the crosslinking in the presence of the retinoic acid and / or the synthetic retinoid. Alternatively, the retinoic acid and / or the synthetic retinoid can be covalently bonded to components of the nanostructured coating, particularly to fibrin nanofibers within the 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 due to blood flow in adjacent blood vessels.

[0028] One method of covalent bonding involves attaching 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 hydroxyl 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 compound 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).

[0029] Accordingly, in a preferred embodiment, the retinoic acid and / or the synthetic retinoid is bound to components of the nanostructure coating 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.

[0030] In a particularly preferred embodiment, the citric acid polyester is selected from the group consisting of poly(1,10-decanediol-co-citric acid), poly(1,8-octanediol-co-citric acid), poly(1,6-hexanediol-co-citric acid), poly(1,12-dodecanediol-co-citric acid), poly(1,8-octanediol-co-citric acid-coglycerol), poly(1,8-octanediol-citric acid-co-polyethylene oxide), poly(1,12-dodecanediol-citric acid-co-polyethylene oxide), poly(1,8-octanediol-citric acid-co-N-methyldiethanoamine), poly(1,12-dodecanediol-citric acid-co-N-methyldiethanoamine) or mixtures thereof, wherein poly(1,8-octanediol-co-citric acid), also referred to as POC, is preferred.

[0031] In another embodiment, the binding occurs via the carboxylic acid group of the retinoic acid or the synthetic retinoid, which can be linked, for example, with EDC / NHS (EDC = 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide; NHS = N-hydroxysuccinimide) with NH₂ groups in components of the nanostructure coating. In a further embodiment, depending on requirements, the nanostructure coating and the retinoic acid and / or the synthetic retinoid can be modified in a first step with chemical functionalities suitable for click reactions, and in a second step, the retinoic acid and / or the synthetic retinoid can then be bound to the nanostructure coating via a reaction of these functionalities with each other.Examples of chemical functions suitable for click reactions include a primary amine on one of the reactants and a dialdehyde or epoxide on the other reactant, a CC triple bond and an azide group, or a thiol group and an alkene or epoxide group.

[0032] 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 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 encapsulated in liposomes or micelles, and wherein the nanostructured coating of the medical device according to the invention is impregnated or treated with a liquid formulation containing the liposomes or micelles.

[0033] In a preferred embodiment of the medical device according to the invention, the nanostructured coating has a fibrin content of at least 2 µg / cm². 2 , especially more than 2 µg / cm² 2 , especially more than 3 µg / cm²2 It has been shown that such a quantity of fibrin results in a sufficiently dense yet thin nanostructure coating. A thin nanostructure coating is advantageous for keeping the overall thickness of the network element within a specific range, allowing the entire medical device to be compressed to the smallest possible cross-sectional diameter. This is a prerequisite for guiding the medical device to the treatment site via small catheters. This also enables the treatment of small blood vessels, particularly in the cerebral region.

[0034] Furthermore, a thin nanostructured coating ensures that the overall wall thickness of the device remains small, thus preventing significant impairment of blood flow through a blood vessel. This avoids vascular narrowing (stenosis) caused by the device.

[0035] It is still preferred if the nanostructure coating contains an amount of retinoic acid and / or synthetic retinoid of at least 2 µg / cm². 2 , especially more than 2 µg / cm² 2 , especially more than 3 µg / cm² 2 exhibits such a quantity. It imparts favorable antithrombotic and antihemolytic properties.

[0036] In addition to retinoic acid and / or the synthetic retinoid, it may be advantageous to incorporate further antithrombotic agents or compounds into the nanostructured coating of the medical device according to the invention. Heparin is, for example, a particularly suitable agent for this purpose. The antithrombotic properties of the nanostructured coating can be further improved by incorporating heparin. Heparin can be incorporated into the first layer, and it is possible that the heparin may also bind to the second layer. In fact, the heparin can bond with the nanostructured coating across its entire thickness.

[0037] Heparin can also be incorporated into the nanostructure coating either loosely or covalently, with covalent bonding offering the same advantages as those described above for retinoic acid and / or the synthetic retinoid. It is preferred that the heparin be covalently bonded to fibrin fibers of the nanostructure coating.

[0038] Furthermore, it is advantageous if the first layer has a first amount of fibrin and the second layer has a second amount of fibrin, the first amount being greater than the second. Specifically, a ratio of at least 2, particularly at least 3, and especially at least 4 between the first and second fibrin amounts has been shown to be advantageous. This ensures that, on the one hand, the first layer is sufficiently dense to form a sponge-like structure for the incorporation of retinoic acid and / or the synthetic retinoid or other substances, and, on the other hand, the second layer has a sufficiently loose structure to guarantee improved adhesion of endothelial cells.

[0039] Furthermore, it is advantageous if the first layer contains a first amount of retinoic acid and / or synthetic retinoid, and the second layer contains a second amount of retinoic acid and / or synthetic retinoid, wherein the first amount of the respective substance is greater than the second amount. 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, particularly at least 3, and particularly at least 4, is especially advantageous. Retinoic acid and / or the synthetic retinoid can also bind covalently to the second layer and prevent blood clotting there through its antithrombogenic properties.However, due to the sponge-like structure of the fibrin nanofilaments, it is expected that a larger amount of retinoic acid and / or synthetic retinoid will be deposited in the first layer, which will then be successively released to the second layer. In this respect, the first layer can also act as a drug reservoir.

[0040] In an advantageous embodiment of the medical device according to the invention, the first layer can have a height between 5 nm and 100 nm, in particular between 5 nm and 50 nm, in particular between 5 nm and 30 nm, in particular between 10 nm and 40 nm, in particular between 20 nm and 30 nm. The second layer can have a height between 5 nm and 200 nm, in particular between 5 nm and 100 nm, in particular between 5 nm and 50 nm, in particular between 5 nm and 30 nm, in particular between 10 nm and 40 nm, in particular between 20 nm and 30 nm. It is particularly preferred if the total height of the nanostructured coating is at most 300 nm, in particular at most 200 nm, in particular at most 150 nm, in particular at most 120 nm, in particular at most 100 nm, in particular at most 90 nm, in particular at most 80 nm, in particular at most 60 nm.

[0041] The stability of the fibrin nanocoating is advantageously enhanced if the fibrin fibers are formed from cross-linked fibrin molecules. This cross-linking can be achieved by adding a special factor, factor XIIIa, during the manufacturing process. Cross-linking significantly stabilizes the fibrin nanostructure and improves the previously described advantages regarding endothelialization. Specifically, the cross-linking is achieved by having each fibrin molecule possess two carboxyl terminals (D domains) and one amino terminal (E domain), with the amino terminal of one fibrin molecule being linked to at least one carboxyl terminal of another fibrin molecule, particularly by a covalent bond.

[0042] The invention is explained in more detail below using an exemplary embodiment with reference to the accompanying schematic drawings. These show Fig. 1 a schematic cross-sectional view through a mesh structure element with a nanostructure coating of a medical device according to the invention in a preferred embodiment; Fig. 2 A schematic representation of the cross-linking of fibrin molecules to form a stabilized fibrin fiber. Fig. 3 A perspective view of a stent made of a wire mesh in which the wires are formed from an X-ray visible core material, and wire ends are formed at one stent end and loops are formed at the other stent end. Fig. 4 A side view of a single-wire stent, wherein the wires are formed from a core-sheath material, and wherein the core material has a higher radiolucency than the sheath material Fig. 5 A: a flow diverter with a radially self-expanding lattice structure, at least partially tubular, made of several interwoven individual wires; B: a schematic representation of a mesh of the lattice structure of the medical device

[0043] Fig. Figure 1 shows a schematic representation of a mesh structure element 10 of a medical device, in particular a stent. Generally, the medical device comprises several mesh structure elements 10 that form a mesh structure. The mesh structure elements 10 can be formed by wires that are interwoven to create a mesh structure. Alternatively, the mesh structure elements 10 can also form webs of a single-piece mesh structure. This is the case, for example, with stents that are cut from a single piece of tubing. Such stents are often referred to as laser-cut stents.

[0044] The schematic representation according to Fig. Figure 1 essentially shows a cross-section through the network structure element 10, with the nanostructure coating depicted only on one surface side for clarity. The nanostructure coating extends over the entire outer surface of the network structure element 10, meaning the network structure element 10 can be completely encased by the nanostructure coating. In particular, the nanostructure coating is intended to extend only over the outer circumferential surface of the individual network structure elements 10. Cells or meshes of a network structure, i.e., openings bounded by the individual network structure elements 10, are preferably not covered by the nanostructure coating. However, it is advantageous if all network structure elements 10 of the network structure are completely encased by the nanostructure coating.

[0045] The nanostructured coating has a first layer L1 that lies directly on the surface of the network structure element 10. The first layer L1 is formed by fibrin fibers 11, which form a densely cross-linked matrix. The fibrin fibers 11 are therefore interlocked and highly compacted, so that essentially a nonwoven-like first layer L1 is present.

[0046] The schematic representation according to Fig. Figure 1 shows that individual fibrin fibers 12 protrude as single fibers above the first layer L1. These protruding fibrin fibers 12 form a second layer L2 of the nanostructured coating above the first layer L1. The second layer L2 is formed by a single-fiber structure, meaning that the fibrin fibers 12 are present here as free fibers, with largely free ends. The second layer L2 thus essentially forms a nap of protruding fibrin fibers 12. Retinoic acid molecules are covalently bonded to the fibrin fibers of the first layer and to the fibrin fibers of the second layer. Analogously, molecules of synthetic retinoid can be bonded to the fibrin fibers instead of retinoic acid molecules.

[0047] The individual fibrin fibers 11, 12 are formed from fibrin molecules 20, which bond together upon the addition of thrombin, thus forming the fibrin fibers 11, 12. In a very simplified representation, each fibrin molecule 20 exhibits the following structure: Fig. Figure 3 shows a central amino terminus, also known as E-domain 21. Individual monomers extend from E-domain 21 in a coiled-coil structure 24. Carboxy terminals, designated as D-domain 22, are located on the outer surface of the molecule.

[0048] The addition of thrombin cleaves fibrin peptides, causing the released fibrin monomers to be linked by polymer bonds 23. Further addition of a fibrin-stabilizing factor (factor XIIIa) leads to the formation of cross-linking bonds 13. These cross-linking bonds 13 form between the E domain 21 and at least one D domain 22 of another fibrin molecule 20. In particular, adjacent D domains 22 of two fibrin molecules 20 are linked by the covalent bond 13 to the E domain 21 of a third fibrin molecule 20. The covalent bonds 13 thus form a bridge that stabilizes the weaker polymerization compound 23. Overall, this stabilizes the entire fibrin fiber structure.

[0049] The two-layer nanostructured coating described in connection with the present invention is particularly effective with regard to the attachment of endothelial cells. In experiments, the nanostructured coating was applied to a glass substrate and immersed, along with the glass substrate, in an endothelial cell solution. It was found that the nanostructured coating is designed such that at least 60,000, and in particular between 60,000 and 90,000, endothelial cells per square centimeter adhere to the nanostructured coating. This represents a significant increase in the number of endothelial cells per square centimeter compared to previous biological coatings.

[0050] Not only is the number of endothelial cells per square centimeter increased by the nanostructured coating of the invention, but it has also been shown that cell viability is significantly higher after three days compared to previous biological coatings. Thus, after three days, more endothelial cells survive on the nanostructured coating of the medical device according to the invention than on other, previously known biological coatings. Specifically, cell viability was experimentally determined after three days using a CCK-8 assay on a stent with the nanostructured coating described herein, yielding an absorption value at a wavelength of 450 nm of significantly more than 0.2.

[0051] The advantages of the nanostructured coating described above are particularly evident in stents and flow diverters coated with it, as mentioned above, and the structure and design of these devices are not subject to any relevant limitations. However, the corresponding stents and flow diverters preferably have a structure and dimensions suitable for use in human blood vessels. Since the stents are intended to be implantable via minimally invasive procedures in most cases, it is further preferred that the stents according to the invention are designed as at least partially tubular stents and can expand automatically from a compressed cross-sectional diameter to an expanded cross-sectional diameter.

[0052] In a particularly advantageous embodiment, the medical device according to the invention is designed as a stent with a mesh (20) of wires (21), each having a radiopaque core material and a superelastic sheath material, and forming loops (24) at a first stent end (22) and open wire ends (25) at a second stent end (23), wherein the number of wire ends (25) is twice the number of loops (24) and more than 10 vol%, in particular more than 20 vol%, in particular at least 25 vol%, in particular at least 30 vol%, of each wire (21) is formed by the core material. In this embodiment, the mesh (20) has - 48 wires (21) each with a wire diameter of 0.038 mm and an outer diameter of 3.65 mm or 4.15 mm or 4.65 mm; or - 52 wires (21) each with a wire diameter of 0.042 mm and an outer diameter of 5.17 mm or 5.67 mm or 6.17 mm; or - 64 wires (21) each with a wire diameter of 0.046 mm or 0.05 mm and an outer diameter of 7.18 mm or 8.20 mm; such a design is in Fig. 3 shown. More specific embodiments of the stent are described in DE 20 2021 106 808 U1, in particular in

[0009] to

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

[0053] In a further particularly advantageous embodiment, the medical device according to the invention is designed as a stent with a substantially tubular mesh (30) made of a single wire (31) comprising a core material and a sheath material, wherein the core material has a higher radiopaque quality than the sheath material, and wherein between 20 vol% and 40 vol%, in particular between 25 vol% and 35 vol%, preferably 27 vol%, of the wire (31) is formed by the core material, and an outer surface of the wire (31), in particular of the sheath material, which is polished, comprises a mixed oxide layer comprising TiO2 and at least one nitride, in particular titanium oxynitride and / or titanium nitride.

[0054] Such a design is in Fig. 4 shown. More specific embodiments of the stent are described in DE 20 2016 107 791 B4, in particular in

[0006] to

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

[0055] In a further particularly advantageous embodiment, the medical device according to the invention is designed as a flow diverter with an at least partially tubular, radially self-expanding lattice structure (40) made of several interwoven individual wires (41) forming meshes (42) of the lattice structure (40), wherein at least a part of the individual wires (41) comprise a radiopaque core material (41a) and a superelastic sheath material (41b), wherein several meshes (42) immediately adjacent in the circumferential direction of the lattice structure (40) form a mesh ring (43), and wherein the lattice structure (40) in a fully self-expanded state has an expansion diameter D exp, the mesh ring (43) a number of meshes n and the core material (41a) a core diameter d Kern exhibit, and wherein the core diameter d Kern applies: dKern=f⋅(Dexp / n) where the following holds for a visibility factor f: 0.08≤f≤0.15.

[0056] Such a design is found in the Fig. 1 and Fig. 2. More specific designs of the stent are described in DE 10 2019 104 828 B4, the relevant scope of which is hereby incorporated into this application by reference.

[0057] In a further advantageous embodiment, the medical device according to the invention is designed as a stent with a self-expanding, tubular mesh structure, wherein the mesh structure is formed by a single wire made of an X-ray visible core material and a sheath material, which has a braiding angle a with respect to a central longitudinal axis M of the mesh structure, wherein - both ends of the braided structure have closed loops that form a diameter increase of the braided structure with a flare 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 the diameter of the braided structure, and - The following applies to the braiding angle a and the flaring angle b: b ≤ a, where b is at most 20° smaller than a, or b > a, where b is at most 5° larger than a, and b = 45° to 75°.

[0058] Such a design is specified in DE 10 2018 125 983 B4, the relevant scope of which is hereby incorporated into this application by reference.

[0059] In a further advantageous embodiment, the medical device according to the invention is designed as a stent with a compressible and expandable grid structure of struts which are integrally connected to one another by strut connectors and which delimit diamond-shaped cells, wherein each cell is delimited by two straight struts and two S-shaped bent struts which connect the straight struts to one another, and wherein - the lattice structure in a rest state has a fully expanded rest diameter D exp exhibits a thickness between 3.0 mm and 5.0 mm, - a ratio between a fully compressed diameter D komp the lattice structure and the rest diameter D expthe lattice structure is between 1:7 and 1:12, the webs have a web height, measured in the radial direction, of at least 0.05 mm and at most 0.09 mm, so that the lattice structure between the fully compressed diameter D komp and an insertion diameter that is at most 90% of the rest diameter D exp is, has a radial force of at least 0.5 N, in particular at least 0.6 N.

[0060] Such a design is specified in DE 10 2022 113 422 A1, the relevant scope of which is hereby incorporated into this application by reference.

[0061] In a further advantageous embodiment, the medical device according to the invention is designed as a stent for implantation into a blood vessel, in particular a neurovascular vessel, with a substantially tubular, self-expanding lattice structure which can be transformed from a radially fully expanded expansion diameter to a radially fully compressed compression diameter, wherein the radial pressure exerted by the lattice structure forms a hysteresis with a compression pressure RRF and an expansion pressure COF, and wherein the following applies to the compression pressure RRF and the expansion pressure COF in a diameter range from x1 to x2: [(RRF(x1)−RRF(x2))−(COF(x1)−COF(x2))] / [COF(x1)−COF(x2)]≥A where A = 10% and x2 > x1.

[0062] Such a design is specified in DE 10 2016 110 410 A1, the relevant scope of which is hereby incorporated into this application by reference.

[0063] In a further advantageous embodiment, the medical device according to the invention is designed as a stent, in particular for the treatment of diseases of the carotid artery, wherein the stent has a tubular mesh of wires, each of which is wound helically around a longitudinal axis of the mesh and crosses over and under each other, wherein the mesh in a resting state has a proximal cylindrical section and a distal cylindrical section which are connected to each other by a transition section, and wherein the proximal cylindrical section has a different cross-sectional diameter and a different porosity than the distal cylindrical section.The design, comprising two cylindrical sections with different cross-sectional diameters, is intended to ensure the most uniform possible porosity of the stent when it is placed in blood vessels with different cross-sectional diameters. Stents with this design are specifically described in WO 2022 / 136368 A1, the relevant content of which is hereby incorporated into the present application by reference.

[0064] The medical devices according to the invention realize several advantages, in particular those listed below: - improved antithrombogenic properties; - improved anti-inflammatory properties; - improved endothelialization; - the suppression of intimal hyperplasia; - faster integration of the device into a blood vessel; - the possibility of discontinuing anticoagulant medication more quickly; and - a reduction in complications and side effects. Reference symbol list 10 Network structure element 11 Fibrin fiber of the fiber matrix 12 Fibrin fibers of the single fiber structure 13 covalent bonds 14 fibrin molecules 15 E-domain 16 D-domain 17 Polymer bond 18 Coiled-coil structure 20 mesh 21 wire 22 first stent end 23 second stent end 24 loops 25 open wire end 30 mesh panels 31 wire 40 Grid structure 41 Grid structure 41a Core material 41b Coating material 42 stitches 43 mesh rings L1 first layer L2 second layer

Claims

[1] Medical device, in particular stent or flow diverter, with a mesh structure, in particular with a self-expanding mesh structure, wherein the network structure has at least one network structure element (10) which is, in particular completely, encased by a nanostructure coating formed from fibrin nanofibers (11, 12), characterized by , that The nanostructured coating comprises a first layer (L1) forming a matrix of interconnected fibrin fibers (11), in particular a felt-like or non-woven matrix, wherein some fibrin fibers (12) protrude freely over the first layer (L1) and form a second layer (L2) of a single-fiber structure, in particular a flor-like structure, and wherein the nanostructured coating additionally contains a retinoic acid and / or a synthetic retinoid that is integrated into the first layer (L1) and / or the second layer (L2). [2] Medical device according to claim 1, characterized by 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] Medical device according to claim 1, characterized by that the medical device contains a synthetic retinoid selected from timbarotene, baxarotene and a mixture thereof. [4] Medical device according to any one of claims 1 to 3, characterized by 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 by , that The binding of retinoic acid and / or the synthetic retinoid to components of the nanostructure coating occurs via an ester group. wherein the bond is preferably the reaction product of the reaction of 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 any one of claims 1 to 3, characterized by 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 any one of the preceding claims, characterized by that the nanostructured coating contains an amount of retinoic acid and / or synthetic retinoid of at least 2 µg / cm² 2 , especially more than 2 µg / cm² 2 , especially more than 3 µg / cm² 2 , exhibits. [8] Medical device according to any one of the preceding claims, characterized bythat the nanostructure coating continues to contain heparin, preferably heparin that is covalently bound to fibrin fibers of the nanostructure coating. [9] Medical device according to any one of the preceding claims, characterized by , that the first layer (L1) comprises a first amount of retinoic acid and / or the synthetic retinoid and the second layer (L2) comprises a second amount of retinoic acid and / or the synthetic retinoid, wherein a ratio between the first amount and the second amount of 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 any of the preceding claims, characterized by that the second layer (L2) has a greater height than the first layer (L1). [11] Medical device according to any one of the preceding claims, characterized by , that the first layer (L1) has a height between 5 nm and 100 nm, in particular between 5 nm and 50 nm, in particular between 5 nm and 30 nm, in particular between 10 nm and 40 nm, in particular between 20 nm and 30 nm, and the second layer (L2) has a height between 5 nm and 200 nm, in particular between 5 nm and 100 nm, in particular between 5 nm and 50 nm, in particular between 5 nm and 30 nm, in particular between 10 nm and 40 nm, in particular between 20 nm and 30 nm. [12] Medical device according to any one of the preceding claims, characterized by , that the fibrin fibers (11) are formed from cross-linked fibrin molecules (14). [13] Medical device according to claim 10, characterized by, that the fibrin molecules (14) each have two carboxyl termini (D domains (16)) and one amino terminus (E domain (15)), wherein the amino terminus of one fibrin molecule (14) is connected to at least one carboxyl terminus of another fibrin molecule (14), in particular by a covalent bond (13). [14] Medical device according to one of the preceding claims, which is designed as an at least partially tubular stent and can be automatically expanded from a compressed cross-sectional diameter to an expanded cross-sectional diameter. [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 forming loops (24) at a first stent end (22) and open wire ends (25) at a second stent end (23), wherein the number of wire ends (25) is twice the number of loops (24) and more than 10 vol%, in particular more than 20 vol%, in particular at least 25 vol%, in particular at least 30 vol%, of each wire (21) is formed by the core material, and wherein the mesh (20) - 48 wires (21) each with a wire diameter of 0.038 mm and an outer diameter of 3.65 mm or 4.15 mm or 4.65 mm; or - 52 wires (21) each with a wire diameter of 0.042 mm and an outer diameter of 5.17 mm or 5.67 mm or 6.17 mm; or - 64 wires (21) each with a wire diameter of 0.046 mm or 0.05 mm and an outer diameter of 7.18 mm or 8.20 mm; has. [16] Medical device according to one of the preceding claims, characterized in that it is designed as a stent with a substantially tubular mesh (30) made of a single wire (31) comprising a core material and a sheath material, wherein the core material has a higher radiolucency than the sheath material, and wherein between 20 vol% and 40 vol%, in particular between 25 vol% and 35 vol%, preferably 27 vol%, of the wire (31) is formed by the core material and an outer surface of the wire (31), in particular of the sheath material, which is in particular polished, comprises a mixed oxide layer comprising TiO2 and at least one nitride, in particular titanium oxynitride and / or titanium nitride. [17] Medical device according to any one of the preceding claims, characterized by, that it is designed as a flow diverter, with an at least partially tubular, radially self-expanding lattice structure (40) made of several interwoven individual wires (41) forming meshes (42) of the lattice structure (40), wherein at least a part of the individual wires (41) comprise an X-ray visible core material (41a) and a superelastic sheath material (41b), wherein several meshes (42) immediately adjacent in the circumferential direction of the lattice structure (40) form a mesh ring (43), wherein the lattice structure (40) in a fully self-expanded state has an expansion diameter D exp , the mesh ring (43) a number of meshes n and the core material (41a) a core diameter d Kern exhibit, and wherein the core diameter d Kern applies: dKern=f⋅(Dexp / n) where the following holds for a visibility factor f: 0.08≤f≤0.15.

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