Coated medical device and method for coating a medical device

Description

[0001] The invention relates to a coating for medical devices, wherein the coating has cell adhesion-promoting properties.

[0002] The use of medical devices to treat a wide variety of medical conditions is steadily increasing. Many of these medical devices are implants that are permanently inserted into the vascular system or the patient's body during treatment and remain there.

[0003] To prevent such an implant from being permanently perceived as a foreign body, it is advantageous for the implant to grow into the tissue as soon as possible after implantation. For this to happen, the body's own cells must adhere to the implant. Therefore, an implant with a coating that promotes cell adhesion is advantageous. At the same time, the implant should not have any inflammatory potential. In the case of stents and similar medical devices that are implanted into a blood vessel, restenosis must be prevented.

[0004] An amino acid sequence that promotes cell adhesion and mechanical anchoring of cells is the RGD sequence, which is composed of the amino acids arginine, glycine, and aspartic acid. This sequence is found in proteins of the extracellular matrix, such as fibronectin and vitronectin. With the help of integrins (cell surface receptors), cells are able to bind to this amino acid sequence. Other peptide sequences with integrin-binding motifs are also known.

[0005] A stent with improved re-endothelialization properties is described in WO 2008 / 143933 A1. Although the binding of integrin-selective peptides to integrins on the cell surface activates a signaling cascade that could induce cell proliferation and thus cause restenosis, the inventors discovered that, despite integrin activation, the RGD peptide actually counteracts restenosis. This is attributed to increased adhesion of endothelial cells to the stent, which ensures rapid endothelialization and ingrowth of the stent into the surrounding tissue, thus preventing the formation of restenosis.

[0006] However, for implants inserted into blood vessels, preventing blood clotting induced by the implant itself, i.e., preventing platelet adhesion and platelet aggregation, is crucial. This, and thus the formation of blood clots or thrombi, can occur with permanent or temporary implants, as well as with medical instruments that are only briefly inserted into the patient's body for treatment or diagnostic purposes. The platelets adhere to the surface of the inserted medical device, which is labeled by the body's own proteins (platelet adhesion), which can subsequently lead to the formation of a thrombus (platelet aggregation).

[0007] If such a thrombus breaks loose in the vascular system, for example, it can lead to serious and even fatal complications. This is especially the case if the detached thrombus is washed away and lodges as an embolus in smaller vessels, largely blocking them and thus jeopardizing the adequate supply to the adjacent areas. Resulting illnesses can include strokes, heart attacks, or thrombosis.

[0008] To minimize these risks for the patient, dual platelet inhibition is now commonly used during surgery or interventions to reduce the risk of thrombosis. The patient typically receives an initial dose of a combination of antiplatelet agents, particularly a combination of acetylsalicylic acid (ASA) and clopidogrel, before the procedure and must continue to take this regularly for a certain period after the procedure. Other antiplatelet agents listed in the relevant guidelines for dual platelet inhibition can also be used. These are usually used instead of clopidogrel in combination with ASA. Examples include prasugel or ticagrelor.

[0009] The disadvantage of dual platelet inhibition is that it is administered systemically and therefore has a systemic effect. For the duration of dual platelet inhibition, the patient's overall risk of bleeding is therefore increased.

[0010] A further disadvantage is that dual platelet inhibition is not possible for some patient groups because the risks associated with dual platelet inhibition, particularly the increased risk of bleeding, are so great that they outweigh the benefits from the outset. In extreme cases, certain treatment methods are not available to some patients simply because they cannot be adequately protected against the risk of thrombosis after a procedure. Dual platelet inhibition, for example, is standard practice after the implantation of endovascular prostheses (stents and the like). For this reason, WO 2018 / 210989 A1 proposed coating medical devices with saccharides that only oligomerize or polymerize upon binding to the substrate.These mimic the natural glycocalyx, which covers the cells of blood vessels with a kind of mucous layer and consists of various polysaccharides covalently bound to the membrane proteins (glycoproteins) and membrane lipids (glycolipids). This is thus a biomimetic effect.

[0011] The task therefore arises to provide medical devices that ensure rapid ingrowth of the medical device into the surrounding tissue by increasing cell adhesion or cell adherence, but at the same time prevent increased platelet adhesion and aggregation.

[0012] The object is achieved according to the invention by an endovascular medical device comprising an at least partial coating, wherein the medical device is an implant intended to remain permanently in the body and wherein the coating comprises a functional layer and the functional layer contains saccharides and peptide sequences with integrin-binding motifs.

[0013] The invention is based on the idea of ​​promoting cell adhesion and ingrowth, while at the same time preventing the adhesion of a specific cell type, namely platelet adhesion. It has been shown that this is possible by not only applying peptide sequences with integrin-binding motifs to the medical device, but also by integrating saccharides into the functional layer.

[0014] The medical device according to the invention essentially comprises at least one substrate as the basis of the actual medical device and a functional layer. The functional layer imparts the desired properties to the medical device.

[0015] The RGD peptide sequence, whose mediation of cell adhesion has been well-studied, is particularly preferred as a peptide sequence with an integrin-binding motif. However, the use of other peptide sequences with an integrin-binding motif is also conceivable. References to peptides or peptide sequences in this application refer to peptides / peptide sequences that contain at least one integrin-binding motif, unless the context indicates otherwise.

[0016] To achieve binding of the saccharides and peptide sequences to the surface of the medical device, the saccharides are preferably polymerized and reacted with the peptides to form the functional layer. For this purpose, both the saccharides and the peptides are functionalized with polymerizable or reactive groups capable of binding to the surface of the medical device and inducing polymerization. The peptides do not necessarily have to be involved in the polymerization process themselves; it is sufficient if they possess reactive groups through which they can be linked to the saccharides. However, the polymerizable groups of the saccharides and the reactive groups of the peptides are often chosen to be identical.

[0017] For this purpose, saccharides on the one hand and peptides on the other hand can each be bound individually to polymerizable / reactive groups, whereby a reaction then takes place, which is usually at least partially a polymerization, to form the functional layer. The polymerizable / reactive groups with which saccharides or peptides are provided can be identical or at least be of such a nature that a reaction can take place between them. Accordingly, copolymerization is possible, in which reactions occur between them. However, separate reactions of functionalized saccharides and peptides on the surface of the medical device are also possible. To carry out polymerization, a solution containing both functionalized saccharides and functionalized peptides can be applied to the substrate, so that the functional layer is formed from a solution.Functionalized saccharides and functionalized peptides can be present in different ratios.

[0018] The polymerization or reaction of the polymerizable / reactive groups with which saccharides or peptides are provided does not have to occur simultaneously, however; it is also possible for one group of substances to react first before reactive units from the other group of substances are then applied. This involves two (or more) consecutive reactions of the various compounds equipped with polymerizable or reactive groups, namely saccharides on the one hand and peptides on the other. In this context, one also speaks of post-polymerization. In practice, the procedure is usually such that one first carries out a polymerization from a first solution with the first polymerizable group of substances, then changes the solutions and carries out a reaction from the second solution with the second polymerizable or reactive group of substances.In the postpolymerization principle described above, functionalized saccharides and functionalized peptides can also be used in different ratios.

[0019] When using separate molecules of p-saccharide on the one hand and p-peptide on the other, where p stands for any polymerizable or more generally reactive group, different variants result, some of which are listed here as examples: a) Simultaneous polymerization of p-saccharide and p-peptide b) First polymerization of p-saccharide, then exchange of the solutions and reaction with p-peptide c) First reaction with or polymerization of p-peptide, then exchange of the solutions and reaction with or polymerization of p-saccharide d) First polymerization of p-saccharide, then exchange of the solutions and reaction with p-peptide, then exchange of the solutions again and polymerization of or reaction with p-saccharide

[0020] In a corresponding manner, any other combinations of successive polymerizations or reactions are conceivable in principle.

[0021] Since the spatial extent of the peptide significantly exceeds that of a monosaccharide, a larger amount of functionalized saccharide must generally be polymerized or reacted than functionalized peptide. This applies to simultaneous polymerization as well as to sequential post-polymerizations. In this way, the positive properties of the saccharide and the peptide are equally noticeable on the surface of the coated medical device. Alternatively, as in example d above, an additional amount of p-saccharide can be applied to deliberately increase the amount of saccharide active on the surface.

[0022] An example of an RGD peptide that possesses a functional group for further reaction with polymers or polymerizable compounds is Acetyl-Cys-Doa-Doa-Gly-Arg-Gly-Asp-Ser-Pro-NH 2 , where Doa = 8-amino-3,6-dioxaoctanoic acid, which can be purchased from Cellendes GmbH, Reutlingen, Germany. Functionalization occurs via the thiol group. This can be used, for example, for coupling with polyvinyl alcohol, which in turn can be cross-linked with polyethylene glycol. The polyethylene glycol unit can also possess a polymerizable acrylate function.

[0023] Another RGD peptide that can be used according to the invention is GRGDSPK (Gly-Arg-Gly-Asp-Ser-Pro-Lys), which can have a reactive acrylate function. Coating with this peptide, which contains the RGD sequence, can be carried out in particular by first polymerizing p-saccharide on the surface to be coated, then exchanging the solutions for the RGD peptide solution, and then reacting with the functionalized GRGDSPK.

[0024] Another possibility is to provide polymerizable molecules that carry both the saccharide and the peptide. This can also be done in such a way that the polymerizable group is linked to the saccharide and the saccharide to the peptide, or vice versa. Using an acrylate linker, an example would be: acrylate-saccharide-RGD-peptide

[0025] During polymerization to form the functional layer, a layer is automatically created that possesses both functionalities. However, even when using polymerizable molecules with saccharide and peptide units, additional p-saccharide or p-peptide can be applied simultaneously, subsequently, or beforehand to specifically influence the properties of the functional layer. Due to the steric relationships between peptide and saccharide mentioned above, it is generally advisable to use additional p-saccharide.

[0026] When using polymerizable molecules that carry both the saccharide and the peptide (p-saccharide peptide, where p stands for any polymerizable / reactive group, regardless of the functionality to which the polymerizable / reactive group is linked), various variants arise, some of which are listed here as examples: a) Simultaneous (co)polymerization of p-saccharide peptide and p-saccharide b) First polymerization of p-saccharide, then exchange of the solutions and polymerization of p-saccharide peptide c) First polymerization of p-saccharide peptide, then exchange of the solutions and polymerization of p-saccharide

[0027] A spacer may be present between the polymerizable group and the saccharide or peptide. For example, the use of a polyethylene glycol (PEG) unit is possible. The molecular weight of the PEG unit is preferably between 300 and 15,000 Da, especially between 1,000 and 10,000 Da or between 2,000 and 5,000 Da.

[0028] Where RGD peptides are mentioned in the context of this invention, this refers to peptides that have an RGD peptide sequence consisting of arginine, glycine, and aspartic acid (Arg-Gly-Asp). The peptide sequence can also be present in cyclized form (cRGD). The RGD peptide can be present as a tripeptide, but it can also consist of a larger number of amino acids overall; however, it is important that the sequence contains arginine, glycine, and aspartic acid, which is important for the binding of the integrins of the cells that are intended to attach to the medical device. Accordingly, the RGD peptide can, for example, have the sequence A p -RGD-B q, where A and B are independently natural or unnatural amino acids, and p and q can independently be 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. Both A and B can vary within the peptide chain.

[0029] Also possible is a cyclic peptide with an RGD sequence such as (-RGD-Z r -), where Z are identical or different, natural or unnatural amino acids and r = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

[0030] The amino acids are generally natural L-amino acids, although the use of individual or exclusively D-amino acids is not excluded by the invention. Peptides that carry an RGD group, where amino acids or the peptide backbone are functionalized or carry additional groups, are also considered RGD peptides within the meaning of the invention.

[0031] The surface coating with peptide sequences containing integrin-binding motifs is advantageously carried out in such a way that cell adherence is increased for the endothelial cells, but not for the significantly smaller platelets. While endothelial cells are approximately 10 to 25 µm in size, platelets are approximately 1 to 4 µm in size. Therefore, if the density of the peptides serving as anchor points is not too high, the endothelial cells already have a sufficient number of peptide contacts to trigger a cellular reaction that causes adherence, but not the platelets. If, for example, the platelets only come into contact with individual peptides, the transmitted signal is not yet sufficient to cause platelet adherence.Without wishing to be bound to a specific theory, this is probably due to the fact that at low anchor point density, initial adherence via the integrin receptor is theoretically still possible, but the distances are too large for cell activation mediated by integrin cluster formation.

[0032] Studies on surfaces coated with RGD peptides have shown that the distance between the immobilized peptide ligands is advantageously at least 40 nm, more advantageously at least 50 nm, and especially at least 60 nm. A distance between the peptide ligands of up to 500 nm has proven particularly advantageous. Such a distance between the peptide ligands ensures sufficient attachment and adherence of endothelial cells, while this is not yet observed for platelets. Accordingly, the goal of promoting the attachment of endothelial cells and the ingrowth of a medical device, particularly an implant, is achieved without increasing the risk of platelet aggregation. By appropriately selecting the reaction conditions used for the coating reactions, such as concentration, time, temperature, selection of the functionalized peptide, etc., the desired surface coverage can be precisely adjusted.This can be determined, for example, using scanning electron or atomic force microscopy.

[0033] Preferably, the saccharides linked to a polymerizable group are monosaccharides. In this context, saccharides also include reduction and oxidation products of saccharides, particularly sugar alcohols. Oligo- or polymerization only occurs upon binding to the substrate. The functionalized monosaccharides are covalently bound to the substrate, with the groups to which the monosaccharides are linked being designed in such a way that a covalent bond to the substrate can occur. The functional layer thus comprises a complex matrix created by the polymerization of the applied, functionalized monosaccharides and the reaction with the functionalized peptides.

[0034] Preferably, the saccharides in their non-functionalized form are at least partially sugar alcohols or corresponding derivatives or isomers. Sugar alcohols (alditols) are reduction products of sugars in which an aldehyde function has been reduced to an alcohol.

[0035] A preferred sugar alcohol for the functional layer, in its non-functionalized form, corresponds to a sugar alcohol with the molecular formula C 6 H 14 O 6 , for example, sorbitol (sorbitol) and / or its derivatives, for example, sorbitan. Other sugar alcohols can be mannitol, lactitol, xylitol, threitol, erythritol, or arabitol. The structure of sorbitol is shown below:

[0036] "In its non-functionalized form" means that the molecular formula given represents the molecular formula of the non-functionalized sugar alcohol, but may also include its derivatives and / or its isomers.

[0037] For the purposes of the invention, derivatives are understood to mean, in addition to the generally accepted chemical definition of "derived substance of similar structure," all cyclic and heterocyclic compounds derivable from the substance by dehydration. An example of this is sorbitan or sorbitan anhydride, which is formed by the elimination of a water molecule from sorbitol. It thus represents the anhydride of sorbitol. Another example is isosorbide, which is obtained by the elimination of an additional water molecule.

[0038] The polymerizable groups through which the saccharides and peptides are functionalized can have reactive multiple bonds, especially reactive double bonds. Polymerization can thus occur via the double bonds. In particular, it can be an acrylic or methacrylic group, the suitability of which for polymerization reactions is known to the person skilled in the art. The use of other groups suitable for polymerization, such as vinyl or allyl, is also possible. With regard to the peptide, the polymerizable group, especially a (meth)acrylate linker, can be attached, for example, to the N-terminus. The oligo- or polymerization of the saccharides thus normally occurs via the polymerizable groups through which the saccharides are functionalized; however, as a rule, no new glycosidic bonds are formed.

[0039] The solution from which the functional layer of the coating according to the invention is constructed can therefore comprise one or more of the following substances as saccharide components: (1) Sorbitol acrylates (with one or more acrylate groups), where the acrylate groups can be located at different positions. (2) Sorbitol acrylates (with one or more acrylate groups), wherein the sorbitol acrylates may be partially oxidized and may comprise an aldehyde, keto and / or a carboxy group. (3) Sorbitol acrylates (with one or more acrylate groups), which may comprise further reactive groups, for example carboxy groups. (4) Anhydrides, for example sorbitan (mono)acrylate with a polymerizable group. (5) Sorbitol with a non-polymerizable group, for example a carboxy group. (6) Complex sorbitol compounds that are not polymerizable but can be incorporated into the polymer matrix of the functional layer.

[0040] The structure of the functional layer can be varied by changing the specific composition of the materials. For example, it is possible to create more tightly meshed functional layers by increasing the proportion of crosslinkers, or to create less crosslinked functional layers with longer linear regions by reducing the proportion of crosslinkers.

[0041] According to the invention, the medical device itself, which represents the substrate, usually also has a carrier layer comprising adhesion promoters, via which the functional layer can be bonded to the substrate. Preferred adhesion promoters within the meaning of the invention are silane adhesion promoters. Alternatively, other adhesion promoters, such as polyolefinic adhesion promoters or adhesion promoters based on titanates or zirconates, can also be used.

[0042] Further examples of adhesion promoters are Thiols and dithio compounds, particularly suitable for precious metal substrates Amines and alcohols, particularly suitable for platinum substrates Carboxylic acids, particularly suitable for silver substrates and aluminum substrates, where the aluminum may have an aluminum oxide surface Phosphonic acids (phosphonates), particularly suitable for iron, iron oxide, titanium, and titanium dioxide substrates Complex-forming adhesion promoters, in particular chelates, some of which also bind non-covalently to substrates, particularly suitable for various metal and metal oxide substrates

[0043] The adhesion promoters should possess functional groups that enable the adhesion promoter to react with the functional layer, usually resulting in a covalent bond. Depending on the material of the medical device, the bond between the adhesion promoter and the medical device may also be covalent.

[0044] A suitable adhesion promoter can be achieved, for example, through silanization, i.e., the chemical bonding of silicon, particularly silane, compounds to at least parts of their surface. On surfaces, silicon and silane compounds bond to hydroxyl and carboxyl groups, for example.

[0045] A silane compound within the meaning of the invention is understood to mean all those compounds which follow the general formula R m SiX n (m, n = 0-4, where R stands for organic radicals, in particular alkyl, alkenyl or aryl groups, and X for hydrolyzable groups, in particular OR, OH or halogen with R = alkyl, alkenyl or aryl). In particular, the silane can have the general formula RSiX 3. In addition, corresponding compounds having several silicon atoms belong to the silane compounds within the meaning of the invention. In particular, silane derivatives in the form of organosilicon compounds are understood to be silane compounds within the meaning of the invention. Accordingly, silane compounds within the meaning of the invention are not only understood to mean substances which consist of a silicon backbone and hydrogen and are called silanes.

[0046] Polyolefins can also be used as adhesion promoters, including chlorinated polyolefins (CPO) or acrylated polyolefins (APO).

[0047] The medical device forming the coatable substrate can be made of various materials. These include, for example, metals such as nickel, titanium, platinum, iridium, gold, cobalt, chromium, aluminum, iron, or alloys, as well as combinations thereof. For example, a metal can be coated with another metal, with the coating according to the invention, preferably consisting of the carrier layer and the functional layer, being applied to the outer metal layer. Coatable metals also include substrates in which the actual metal is covered by an oxide layer. Other coatable substrates include glasses.

[0048] A particularly preferred embodiment relates to a medical device that is completely or partially coated with gold, which ensures X-ray visibility. In particular, the dilation of the medical device in the blood vessel can be observed in this way, so that the treating physician can determine whether the dilation is occurring in the desired manner. This is particularly advantageous, for example, in an implant for the treatment of vasoconstriction. The coating according to the invention is then applied to the gold coating, with the functional layer containing saccharides and peptide sequences with integrin-binding motifs. In most cases, a carrier layer is also used. The base material of the medical device to which the gold coating is applied can be a conventional metal or a conventional metal alloy for corresponding medical devices, for example a nickel-titanium alloy, a cobalt-chromium alloy, or stainless steel.

[0049] Medical devices can also be manufactured from various plastics, such as polyamides (PA), polytetrafluoroethylene (PTFE), expanded polytetrafluoroethylene (ePTFE), polylactides (PLA), polyesters, polyethers, polyurethanes, polyolefins, and corresponding block copolymers. Those skilled in the art are familiar with a wide variety of suitable plastics in the field of medical technology. While a bonding agent is generally required for metallic or oxide surfaces, one is not always used for polymer substrates.

[0050] However, the invention is not limited to coatings of the aforementioned plastics and metals; rather, these are mentioned only as examples. In principle, the invention is directed to coatings of all conceivable materials that could be used for corresponding medical devices.

[0051] The matrix of the functional layer is preferably covalently bonded to the carrier layer or substrate and is preferably synthesized by graft polymerization, whereby the functional layer is generated on the carrier layer or substrate. The polymerization of the applied polymerizable groups carrying the saccharides and peptides preferably occurs essentially only on the carrier layer / substrate or within the functional layer.

[0052] The invention encompasses various types of (graft) polymerization. In particular, the growth of side chains can begin from a main chain. This approach is also referred to as "grafting from." It is also possible for the side chains to have already begun oligomerization or polymerization, and for the already growing side chains to bond with the main chain ("grafting onto"). Finally, already oligomerized or polymerized main chains and side chains can also join together ("grafting through").

[0053] The functional layer preferably essentially comprises a complex, highly branched, hydrophilic matrix comprising a plurality of molecules, each with a main chain as the polymeric backbone and several side chains. The main and / or side chains can form bonds with other main and / or side chains. Additional matrix-forming mono-, oligo-, and polymers can be incorporated into these main and side chains without themselves being covalently bound to the carrier layer.

[0054] The main chain may comprise at least partially polymerized vinyl, allyl, acrylic or methacrylic compounds or their derivatives and / or their isomers or combinations thereof.

[0055] The side chains comprise, in particular, mono- and / or oligosaccharides, whereby reduction products of mono- or oligosaccharides are also considered as such, in particular sugar alcohols (alditols), as well as peptides. Oxidized mono- and / or oligosaccharides may also occur, whereby the oxidized form is also considered a mono- or oligosaccharide within the meaning of the invention.

[0056] The medical device according to the invention comprises the basic structure of the medical device as a substrate with a coating, wherein the coating preferably comprises a carrier layer located on the substrate and a functional layer located on the carrier layer. The carrier layer essentially comprises the adhesion promoters, which can be covalently bonded to the substrate. In addition, non-covalently bonding adhesion promoters are also known, for example, those that bind to the substrate via a complex bond. Preferred adhesion promoters are silicon compounds and polyolefinic adhesion promoters. According to a preferred embodiment, the functional layer comprises at least one functionalized sugar alcohol, via which the functional layer is covalently bonded to the carrier layer, and a functionalized peptide.

[0057] A preferred sugar alcohol of the functional layer corresponds in its non-functionalized form to a sugar alcohol with the molecular formula C 6 H 14 O 6 , for example sorbitol, and / or its derivatives, such as sorbitan, and / or its isomers, such as mannitol.

[0058] "In its non-functionalized form" means that the stated molecular formula represents the molecular formula of the non-functionalized sugar alcohol, but may also include its derivatives and / or isomers. Functionalization is understood to mean the introduction of a function into the compound that allows for linking to the substrate, the carrier layer, and / or compounds already previously bonded to the carrier layer or substrate.

[0059] The functional layer according to the invention can also comprise functionalized variants of the sugar alcohol with the molecular formula C 6 H 14 O 6 and / or its derivatives and / or its isomers. In particular, the functional layer can comprise a complex matrix that can be formed by the polymerization of the applied, functionalized sugar alcohols.

[0060] The sugar alcohols of the functional layer can be at least partially polymerized with each other.

[0061] The coating preferably comprises a carrier layer located on the substrate, with the functional layer in turn being bonded to the carrier layer. The bonds formed can be, in particular, covalent bonds, but possibly also other bonds such as complex bonds. The carrier layer essentially comprises the adhesion promoters bonded to the substrate. Preferred adhesion promoters are silicon compounds and polyolefinic adhesion promoters.

[0062] Without wishing to be bound to any particular theory, the advantage of the coating according to the invention with regard to saccharides is seen in the fact that the functional layer exhibits biomimetic or biorepulsive properties and is recognized by platelets not as foreign, but rather as self. Accordingly, the functional layer according to the invention does not trigger any reaction from the platelets, in particular no adhesion or aggregation reactions.

[0063] The biomimetic effect of the coating according to the invention is attributed to the fact that the functional layer according to the invention mimics the human glycocalyx. The glycocalyx covers the cells of the blood vessels with a kind of mucous layer and consists of various polysaccharides that are covalently bound to the membrane proteins (glycoproteins) and membrane lipids (glycolipids).

[0064] An advantage for the biomimetic effect of the coating according to the invention—and in particular of the functional layer—is that the polymerization of the reactants in the functional layer solution essentially only occurs after the functional layer solution has been applied to the substrate or carrier layer. As a result, the polymerization of the reactants creates a complex layer that is so similar to the glycocalyx that the adhesion of platelets to surfaces coated with the coating according to the invention is significantly lower than to uncoated surfaces.

[0065] The biorepulsive effect of the coating according to the invention is attributed to the principle of steric repulsion. Presumably, the space available to the oligomers and polymers on the surface is reduced upon approach of a protein, i.e., an approaching protein forces the oligomers and polymers on the surface to adopt an energetically less favorable conformation. This results in an overall repulsive force toward proteins. The displacement of water molecules from the coating may also lead to a repulsive osmotic force toward proteins.

[0066] For platelet adhesion, this principle of action means that platelets cannot adhere because there are no or only few proteins on the surface suitable for binding, which significantly reduces platelet adhesion.

[0067] On the other hand, the presence of peptides in the functional layer increases endothelial cell adherence to the medical device, which is usually an implant intended to remain permanently in the body. This increased cell adherence ensures rapid endothelialization and ingrowth of the implant into the surrounding tissue.

[0068] Another advantage of the coating according to the invention is that, during the intermediate adhesion-promoting step, the coating only covers those surfaces and structures of the medical device that are activatable by the corresponding adhesion promoters and, in particular, have already been activated. This makes it possible to immerse the entire medical device in the functional layer solution when applying the functional layer solution without the need for additional protection of areas that are not to be coated.

[0069] Such a selective coating or a coating process selective in this way has the advantage described above for a large number of medical devices, at least for those that comprise different materials, but a coating is only to be applied to certain of these materials.

[0070] The coating according to the invention allows for the possibility of activating only those parts of the medical device that will later receive the functional layer during the coating process. It is also conceivable that the medical device is already designed in such a way that substances that can be activated to promote adhesion are selected for the parts to be coated.

[0071] Medical devices with a coating according to the invention are suitable for endovascular, in particular neurovascular, and cardiovascular use as well as for use in the peripheral area, but the coating according to the invention can in principle always be useful for a medical device when the corresponding medical device comes into contact with blood.

[0072] The medical device according to the invention can, for example, be a stent (vascular endoprosthesis), such as those used to treat vascular constrictions and permanently implanted at the site of the vascular constriction to keep the vessel open. The coating causes the implant to rapidly grow into the tissue, so that after a certain period of time, the body no longer perceives it as a foreign body. Stents typically have a tubular structure and are either laser-cut, creating a surface of struts with openings between them, or consist of a wire mesh. Stents can be delivered to the target site via a catheter and expanded there.

[0073] Stent-like implants can also be implanted into a blood vessel to treat vasospasm. Vasospasm is a spasmodic narrowing of a blood vessel. This carries the risk that subsequent vessels will no longer receive sufficient blood supply (ischemia), which can lead to necrosis of the tissue supplied by the vessels. By placing a vasospasm stent, the blood vessel is dilated.

[0074] Another application for the coating is flow diverters, which are used to treat aneurysms. The basic structure and coating are similar to those described above, but a flow diverter typically has a greater surface coverage or surface density than a conventional stent. The flow diverter is placed in front of the aneurysm neck to ensure that blood flow is bypassed. This ultimately ensures the aneurysm's destruction.

[0075] Another possible function of a stent structure or flow diverter placed in front of an aneurysm is to prevent occlusion agents, such as occlusion coils, from escaping from the aneurysm. Such leakage of occlusion agents from the aneurysm can have undesirable consequences, for example, if the occlusion agent is carried by the bloodstream to more distal areas, causing occlusion of the blood vessel or injury to the blood vessel wall. For this purpose, the stent structure can be permanently implanted in the blood vessel.

[0076] A subgroup of flow diverters are so-called bifurcation flow diverters, which are placed in front of aneurysms located at a vascular bifurcation. Such a bifurcation flow diverter or bifurcation implant is described, for example, in WO 2014 / 029835 A1. Such an implant has a distal section that is radially expanded compared to a more proximal section. The distal section is designed to at least partially close the neck of the aneurysm. The described coating is also useful for such a bifurcation implant to prevent platelet adhesion and aggregation.

[0077] The terms "proximal" and "distal" are to be understood in such a way that, during insertion of the device, parts facing toward the attending physician are referred to as proximal, and parts facing away from the attending physician are referred to as distal. The device is thus typically advanced distally through a microcatheter. The term "axial" refers to the longitudinal axis of the implant, running from proximal to distal, while the term "radial" refers to planes perpendicular to this axis.

[0078] The described implants can be composed of interconnected webs or struts. Such a structure can be manufactured by laser cutting in a generally known manner; in this context, they are also referred to as cut structures. In this way, a multitude of openings or a mesh structure are created on the implant, with the openings distributed over the circumference of the stent structure.

[0079] Other manufacturing processes are also conceivable, such as galvanic or lithographic production, 3D printing or rapid prototyping.

[0080] Alternatively, corresponding implants can also be constructed from a mesh structure of wires that form a braid. The wires typically run helically along the longitudinal axis, with opposing wires running over and under each other at the intersection points, forming honeycomb-like openings between the wires. The total number of wires is preferably 8 to 64. The wires that form the mesh structure can be individual metal wires, but it is also possible to provide strands, i.e., several small-diameter wires that together form a filament and are preferably twisted together.

[0081] Usually at the proximal end, an implant can be connected to an insertion aid, in particular an insertion wire, via a detachment point. The detachment point can, for example, be designed to be electrolytically corrodible, so that the implant is detached when an electrical voltage is applied. Other detachment points known from the prior art can also be used, in particular mechanically, thermally or chemically separable detachment points. With a mechanical detachment there is typically a positive, force or frictional connection, which is broken when the implant is released, so that the implant detaches from the insertion aid. With a thermal detachment point the connection can be broken by heating the detachment point, whereupon it becomes so soft or melts that separation occurs.Finally, chemical detachment is also possible, in which the detachment is brought about by a chemical reaction at the detachment site.

[0082] The implant can be self-expanding, meaning it automatically assumes an expanded state after release. For this purpose, the implant is made of materials with shape memory properties, such as nickel-titanium alloys known as Nitinol. Other stent-like implants are expanded using a balloon; the coating according to the invention can also be used for such implants.

[0083] It is advisable for the medical device to have one or more radiopaque markers to enable visualization by the treating physician. The radiopaque markers can be made of platinum, palladium, platinum-iridium, tantalum, gold, tungsten or other radiopaque metals. For example, radiopaque coils can be attached to various points on the medical device. It is also possible to provide the stent structure, in particular the struts or wires of the stent structure, with a coating made of a radiopaque material, for example a gold coating. This can have a thickness of 1 to 6 µm, for example. The coating with a radiopaque material does not have to cover the entire medical device; it is particularly important in the areas that come into contact with the inner vessel wall, i.e. essentially in the cylindrical part of a stent structure.However, even when providing a radiopaque coating, it may be useful to additionally apply one or more radiopaque markers, particularly at the distal end of the medical device.

[0084] In addition to the medical device according to the invention, the invention also relates to a method for producing such a medical device, namely a method for coating a medical device with a functional layer, wherein the functional layer is produced by reaction of saccharides functionalized with reactive groups and peptides functionalized with reactive groups, wherein the reaction is generally at least partially a polymerization.

[0085] All statements and described combinations of features relating to the medical device also apply accordingly to the method according to the invention and vice versa. Try

[0086] There were in vitro A series of tests was conducted with the coating according to the invention to investigate the influence on the adhesion of endothelial cells on the one hand and platelets on the other. The Nitinol sample plates tested were divided into three groups: 1) Uncoated Nitinol platelets (A + D) 2) Nitinol platelets with a coating of sugar alcohols polymerizing on the surface and functionalized with polymerizable groups (B + E) 3) Nitinol platelets corresponding to the 2nd group, which have additionally been coated with the peptide GRGDSPK (C + F).

[0087] The result is in Fig. 1 Platelets A to C were seeded with human umbilical vein endothelial cells (HUVEC) and stained with a specific fluorescent dye. Platelets D to F were incubated with human whole blood. Adherent platelets were stained with a specific fluorescent dye.

[0088] It can be seen that the uncoated plates A and D show strong cell attachment, both endothelial cells (A) and platelets (D). In contrast, plates B and E, which only had a saccharide layer applied, show almost no cell attachment, neither endothelial cells (B) nor platelets (E). The absence of platelets is, on the one hand, positive to prevent recurrent thrombus formation; on the other hand, endothelial cell adherence would be desirable to promote implant ingrowth.

[0089] The latter is demonstrated by platelets C and F. Endothelial cell colonization (C) is strong and of a comparable magnitude to that of the uncoated platelets. Platelet deposition, however, remains negligible (F).

Claims

1. Endovascular medical device, wherein at least parts of the medical device are coated and the coating comprises a functional layer containing saccharides and wherein the medical device is an implant intended to remain in the body permanently, characterised in that the functional layer contains peptide sequences with integrin-binding motifs.

2. Medical device according to claim 1, in that the functional layer contains an RGD peptide sequence.

3. Medical device according to claim 1 or 2, characterised in that the functional layer is formed by a reaction of saccharides functionalised with polymerisable groups and peptides functionalised with reactive groups with integrin-binding motifs.

4. Medical device according to claim 3, characterised in that the functional layer is formed by a copolymerisation of saccharides functionalised with polymerisable groups and peptides functionalised with reactive groups with integrin-binding motifs.

5. Medical device according to claim 3, characterised in that the functional layer is formed by successive reactions of saccharides functionalised with polymerisable groups and peptides functionalised with reactive groups with integrin-binding motifs.

6. Medical device according to claim 3, characterised in that the functional layer is formed by successive reactions of peptides functionalised with reactive groups with integrin-binding motifs and saccharides functionalised with polymerisable groups.

7. Medical device according to claim 3, characterised in that the functional layer is formed by a polymerisation of polymerisable molecules carrying a saccharide unit and a peptide unit, wherein the peptide has at least one integrin-binding motif.

8. Medical device according to any one of claims 1 to 7, characterised in that the saccharides are monosaccharides.

9. Medical device according to any one of claims 1 to 8, characterised in that the saccharides in their non-functionalised form are at least partly sugar alcohols or cyclic or heterocyclic compounds derivable from sugar alcohols by dehydration.

10. Medical device according to any one of claims 3 to 9, characterised in that the polymerisable groups comprise reactive multiple bonds, in particular double bonds, wherein the double bonds are in particular components of (meth)acrylic, allyl or vinyl groups.

11. Medical device according to any one of claims 1 to 10, characterised in that the coating comprises a carrier layer with an adhesion promoter and the functional layer is bonded to the carrier layer.

12. Medical device according to claim 11, characterised in that the bonding of the adhesion promoter to the medical device and / or the bonding of the functional layer to the carrier layer is a covalent bond.

13. Medical device according to claim 11 or 12, characterised in that the adhesion promoter comprises a silicon compound, in particular a silane compound.

14. Medical device according to any one of claims 3 to 13, characterised in that a spacer is provided between the polymerisable group and the saccharide and / or peptide.

15. Method for producing a medical device according to any one of claims 1 to 14 by coating a medical device with a functional layer, wherein the functional layer is produced by the reaction of saccharides functionalised with reactive groups and peptides functionalised with reactive groups with integrin-binding motifs.