Coating for medical devices

Abstract

Medical device comprising at least one substrate with a coating, wherein the coating comprises a functional layer, characterized in that the functional layer comprises at least one monosaccharide, wherein reduction and oxidation products of monosaccharides are also considered to be monosaccharides, the monosaccharides can be bound directly or indirectly to the substrate by functionalization of the monosaccharides and only oligo- or polymerize upon binding to the substrate.

Description

The invention relates to a coating for medical products, wherein the coating essentially comprises biomimetic and / or biorepulseive properties. In addition, the invention also relates to a method for coating the medical products.The use of medical products for the treatment of a wide variety of disease patterns is constantly increasing. Many of these medical devices at least temporarily or permanently enter the vascular system or generally the patient's body during the treatment and thus come into direct contact with the patient's blood. In this case, reactions of the body also occur on a regular basis via the blood and its corresponding constituents, which reactions are generally undesirable, can compromise the success of the treatment and can lead to conditions which are in part life-threatening for the patient.One of these undesirable reactions relates to blood clotting induced in a patient by the medical products used in the treatment, and more particularly to platelet adhesion and platelet aggregation. Platelet adhesion and platelet aggregation and thus the formation of blood clots, so-called thrombi, can be observed in the case of permanent or temporary implants just as in the case of medical instruments which are introduced into the patient's body only briefly for treatment or for diagnostic purposes. Platelets adhere to the surface of the introduced medical product labeled by endogenous proteins (platelet adhesion), which can result in the formation of a thrombus (platelet aggregation).If such a thrombus dissolves, for example, in the vascular system, serious to fatal consequences can occur in some cases. This is the case above all when the released thrombus is rinsed away and becomes fixed as an embolus in smaller vessels, largely closing them and thus jeopardizing the sufficient supply of the adjoining regions. Resulting disease patterns can be, for example, stroke, myocardial infarction or thrombosis.In order to minimize these risks for the patient, nowadays dual platelet inhibition is generally used in the context of surgery or intervention in order to reduce the risk of thrombosis. In this case, the patient generally receives a first dose of a combination of platelet aggregation inhibitors, in particular a combination of acetylsalicylic acid (ASS) and clopidogrel, before the intervention, and must also assume this regularly for a specific time after the intervention. In addition, other platelet aggregation inhibitors may also be used, which are mentioned in the corresponding guidelines for dual platelet inhibition. As a rule, these are used in combination with ASS instead of the clopidogrel. Examples are prasugel or Tiegrelor.The disadvantage of dual platelet inhibition is that it takes place systemically and thus also acts systemically. For the duration of dual platelet inhibition, the risk of bleeding for the patient is thus increased overall.A further disadvantage is that dual platelet inhibition is not possible at all for some groups of patients, since for these the risks associated with dual platelet inhibition, in particular the increased risk of bleeding, are so great that they outdominate the advantages from the outset. In extreme cases, certain treatment methods are not available to some patients solely because they cannot be sufficiently protected against the risk of thrombosis after intervention. Dual platelet inhibition is, for example, standard after the implantation of endovascular prostheses (stents and the like).It would thus be desirable if it were possible to provide a medical product which the body would not recognize as foreign bodies or at least would not exhibit any reactions which are undesirable for the success of the treatment, such as blood coagulation reactions, for example, and thus would be possible to dispense with dual platelet inhibition in medical products of this type.It is therefore the object of the invention to provide a medical product which substantially does not have the disadvantages mentioned.It is a further object of the invention to provide a coating for medical products which imparts in particular biomimetic and / or bioreulsive properties to the surface of medical products and which substantially does not trigger platelet reactions, in particular platelet adhesion.This object is achieved by an invention having the features of independent claim 1. It should be pointed out that the features listed individually in the claims can also be combined with one another in any desired and technologically meaningful manner and thus indicate further embodiments of the invention.A medical device according to the invention essentially comprises at least one substrate and a functional layer. The functional layer preferably has biomimetic and / or biorepulseive properties.Drug-coated implants have been known for many years, following another approach to avoiding body defense reactions. In particular, anti-proliferative drug-coated stents are mentioned here which, in contrast to the invention described here, reduce neointimal hyperplasia.According to the present invention, there is usually also a carrier layer on the substrate itself, which carrier layer comprises adhesion promoters via which the functional layer can be connected to the substrate. Preferred adhesion promoters in the context of the invention are silane adhesion promoters. Alternatively, other adhesion promoters, for example polyolefinic adhesion promoters or adhesion promoters based on titanates or zirconates, can also be used.Further examples of adhesion promoters arethiols and dithio compounds particularly suitable for noble metal substratesamines and alcohols particularly suitable for platinum substratescarboxylic acids particularly suitable for silver substrates and aluminum substrates, where the aluminum may have an aluminum oxide surfacephosphonic acids (phosphonates), particularly suitable for iron, iron oxide, titanium and titanium dioxide substratescomplex-forming adhesion promoters, in particular chelates, which also partly bind non-covalently to substrates, are particularly suitable for various metal and metal oxide substratesIn all cases, the adhesion promoters should have functional groups, via which a reaction of the adhesion promoter with the functional layer and thus a generally covalent coupling is made possible.Preferably, the substrate is suitable for bonding with an adhesion promoter. Such substrates are to be referred to in the sense of this application as "coatable substrate". Coatable substrates accordingly comprise substrates whose surface is sufficiently reactive and / or sufficiently activatable to form bonds at least partially with an adhesion promoter or else directly with the functional layer. Preferably, the bonds between substrate and adhesion promoter comprise covalent bonds.Coatable substrates in the context of the invention can accordingly be a wide variety of, in particular oxidizable, substrates and combinations thereof. These include, for example, metals such as nickel, titanium, platinum, iridium, gold, cobalt, chromium, aluminum, iron or alloys and combinations thereof. For example, a metal can also be coated with another metal, wherein the carrier layer and the functional layer are in turn applied to the outer metal layer. Coatable metals are also understood to mean substrates in which the actual metal is covered by an oxide layer. Further coatable substrates are glasses.Coatable substrates in the context of the invention can also be a wide variety of plastics, such as, for example, polyamides (PA), polytetrafluoroethylene (PTFE), expanded polytetrafluoroethylene (ePTFE), polylactides (PLA), polyesters, polyethers, polyurethane, polyolefins, and also corresponding block copolymers. A large number of suitable plastics in the field of medical technology are known to the person skilled in the art. Whereas in the case of metallic or oxidic surfaces, an adhesion promoter is generally required, such an adhesion promoter is not always used as substrate in the case of polymers.A suitable bonding can be effected, for example, by silanization, i.e. a chemical bonding of silicon compounds, in particular silane compounds, to at least parts of their surface. Silicon and silane compounds bind to surfaces, for example, to hydroxy and carboxy groups.Polyolefins can also be used as adhesion promoters, including chlorinated polyolefins (CPO) or acrylated polyolefins (APO).However, the invention is not limited to coatings of the plastics and metals mentioned, but rather these are mentioned only by way of example. In principle, the invention is directed to coatings of all conceivable materials which constitute a coatable substrate in the sense of the invention.A silane compound in the context of the invention is to be understood as meaning all those compounds which follow the general formula R m SiX n (m, n=0-4, where R is organic radicals, in particular alkyl, alkenyl or aryl groups, and X is hydrolyzable groups, in particular OR, OH or halogen where R=alkyl, alkenyl or aryl. In particular, the silane can have the general formula RSiX 3. In addition, corresponding compounds having a plurality of silicon atoms belong to the silane compounds within the meaning of the invention. In particular, silane derivatives in the form of silicoorganic compounds are understood as silane compounds in the sense of the invention. Silane compounds in the context of the invention are accordingly not only to be understood as meaning those substances which consist of a silicon basic structure and hydrogen and which carry the designation silanes.The matrix of the functional layer is preferably covalently bonded to the carrier layer or the substrate and is preferably synthesized by means of graft polymerization, wherein the functional layer is produced on the carrier layer or the substrate. The polymerization of the applied monosaccharides, wherein also reduction and oxidation products of monosaccharides are understood as such, in particular sugar alcohols (alditols), takes place substantially only on the carrier layer / the substrate or within the functional layer.It is immaterial to the invention in what form the (graft) polymerization takes place. In particular, starting from a main chain, the growth of the side chains can start. This approach is also referred to as a "grafting from.". It is likewise possible for the side chains to have already begun the oligopolymerization or polymerization and for the already growing side chains to bond to the main chain ("grafting onto"). Finally, oligo- or polymerized main and side chains can also be located together ("grafting through").The functional layer preferably comprises essentially a complex, highly branched, hydrophilic matrix comprising a multiplicity of molecules each having a main chain as polymeric backbone and in each case a plurality of side chains. The main and / or side chains can form bonds with further main and / or side chains. Further matrix-forming mono-, oligo- and polymers can be bound into these main and side chains without itself being covalently bound to the carrier layer.The backbone may comprise at least partially polymerized vinyl, allyl, acrylic or methacrylic compounds or their derivatives and / or their isomers or also combinations thereof.The side chains comprise in particular mono- and / or oligosaccharides, wherein reduction products of mono- or oligosaccharides are also understood as such, in particular sugar alcohols (alditols). In addition, oxidized mono- and / or oligosaccharides can also occur, wherein the oxidized form is also understood as mono- or oligosaccharide in the sense of the invention.The medical device according to the invention comprises at least one 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 are usually bonded covalently to the substrate. In addition, non-covalently bonding adhesion promoters are also known, for example those which bond 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.A preferred sugar alcohol of the functional layer corresponds in its nonfunctionalized form to a sugar alcohol having the empirical formula C 6 H 14 O 6, for example sorbitol, and / or derivatives thereof, such as, for example, sorbitan, and / or isomers thereof, such as, for example, mannitol."In its nonfunctionalized form" means that the empirical formula given represents the empirical formula of the nonfunctionalized sugar alcohol, but is optionally also intended to comprise its derivatives and / or its isomers. Functionalization is understood here to mean the introduction of a function into the compound which allows linkage to the substrate, the carrier layer and / or compounds already previously connected to the carrier layer or the substrate.It is clear to the person skilled in the art that the functional layer according to the invention also comprises functionalized variants of the sugar alcohol having the empirical formula C 6 H 14 O 6 and / or derivatives thereof and / or isomers thereof. In particular, it is clear to the skilled person that the functional layer comprises a complex matrix which can be formed by the polymerization of the applied, functionalized sugar alcohols.In the context of the invention, in addition to the definition of the term "derived substance of similar structure" which is generally customary in chemistry, derivatives are to be understood as meaning in particular all cyclic and / or heterocyclic compounds which can be derived from the substance, and even more precisely to be understood as meaning all cyclic and heterocyclic compounds which can be derived from the substance by dehydration. Moreover, the oxidized form of a compound is also understood as a derivative.The sugar alcohol or the sugar alcohols are preferably functionalized via at least one reactive group, wherein the reactive group preferably comprises a reactive multiple bond, in particular a double bond, and wherein this reactive double bond is preferably an acrylic group. Other functional groups suitable for the polymerization, which do not necessarily have to have a reactive double bond, are known to the skilled person and comprise, for example, methacrylic groups, vinyl groups or else allyl groups.The sugar alcohols of the functional layer are preferably at least partially polymerized among one another.The medical device comprises at least one substrate with a coating, wherein the coating comprises a functional layer. The functional layer comprises at least one functionalized monosaccharide, wherein the monosaccharides can be covalently bonded to the carrier layer and only oligo- or polymerize upon bonding to the carrier layer.Preferably, the coating comprises a carrier layer located on the substrate, wherein the functional layer is in turn bonded to the carrier layer. The bonds formed can be, in particular, covalent bonds, but optionally also other bonds such as complex bonds. The carrier layer essentially comprises the adhesion promoters which are bonded to the substrate. Preferred adhesion promoters are silicon compounds and polyolefinic adhesion promoters.The monosaccharide of the functional layer preferably comprises at least one sugar alcohol and / or derivatives thereof and / or isomers thereof.A preferred sugar alcohol of the functional layer corresponds in its nonfunctionalized form to a sugar alcohol having the empirical formula C 6 H 14 O 6, for example sorbitol, and / or derivatives thereof, for example sorbitan, and / or isomers thereof, for example mannitol. The structure of sorbitol is shown below: "In its nonfunctionalized form" is intended to mean that the empirical formula given represents the empirical formula of the nonfunctionalized sugar alcohol, but is optionally intended to also comprise derivatives thereof and / or isomers thereof.It is clear to the person skilled in the art that the functional layer according to the invention comprises functionalized variants of the sugar alcohol having the empirical formula C 6 H 14 O 6 and / or derivatives thereof and / or isomers thereof. In particular, it is clear to the skilled person that the functional layer comprises a complex matrix which has formed by the polymerization of the applied, functionalized monosaccharides.The monosaccharides of the functional layer are at least partially polymerizable with respect to one another.The monosaccharide is preferably functionalized via at least one reactive group, wherein the reactive group preferably comprises a reactive multiple bond, in particular a double bond, and wherein this reactive double bond is preferably an acrylic group. Other functional groups suitable for the polymerization, which do not necessarily have to have a reactive double bond, are known to the skilled person and comprise, for example, methacrylic groups, vinyl groups or else allyl groups.The solution from which the functional layer of the coating according to the invention is constructed can accordingly comprise individual substances or a plurality of the following substances: (1) sorbitol acrylates (having one or a plurality of acrylate group / s), it being possible for the acrylate group / s to be located at different positions. (2) sorbitol acrylates (having one or more acrylate group / s), wherein the sorbitol acrylates can be partially oxidized and can comprise an aldehyde, keto and / or a carboxy group. (3) sorbitol acrylates (having one or more acrylate group / s), wherein these can comprise further reactive groups, for example carboxy groups. (4) anhydrides, for example sorbitan (mono)acrylate having a polymerisable group. (5) sorbitol having a non-polymerisable group, for example a carboxy group. (6) Complex sorbitol compounds, which are not polymerisable but can be incorporated into the polymer matrix of the functional layer The structure of the functional layer can be varied via the specific composition of the substances. It is thus possible, for example, to produce more narrow-mesh functional layers by an increased proportion of crosslinkers or to produce functional layers with relatively low crosslinking properties with longer linear regions by a lower proportion of crosslinkers.Without wishing to be bound by a particular theory, the advantage of the coating according to the invention is seen in the fact that the functional layer has biomimetic or biorepulseive properties and is not recognized by platelets as being nonbody, but rather as being endogenous. Accordingly, the functional layer according to the invention does not trigger any reaction of the platelets, in particular no adhesion reactions and also no aggregation reactions.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 glycokallyx. The glycokallyx coats the cells of the blood vessels with a type of mucous layer and consists of various polysaccharides which are covalently bonded to the membrane proteins (glycoproteins) and membrane lipids (glycolipids).It is advantageous for the high biomimetic effect of the coating according to the invention-and in particular of the functional layer-that the polymerization of the reactants of the functional layer solution takes place substantially only after the application of the functional layer solution to the substrate or the carrier layer. As a result, polymerization of the reactants produces a complex layer which has such a high similarity to glycokallyx that the adhesion of platelets to surfaces provided with the coating according to the invention was significantly less than to uncoated surfaces.The bioreulsive effect of the coating according to the invention is attributed to the principle of steric repulsive action. Presumably, the space available to the oligo- and polymers on the surface is reduced as a protein approaches, i.e. an approaching protein forces the oligo- and polymers on the surface to assume an energy-less conformation. This results in a force repelling to proteins overall. The displacement of water molecules from the coating may also lead to a repulsive osmotic force with respect to proteins.For platelet adhesion, this principle of action means that platelets cannot adhere because no or only few proteins suitable for binding are present on the surface, whereby platelet adhesion is significantly reduced.Another advantage of the coating according to the invention is that, via the intermediate step of promoting adhesion, the coating covers only surfaces and structures of the medical product which can be activated for the corresponding adhesion promoters and in particular have also been activated. Thus, when applying the functional layer solution, it is possible to introduce the complete medical product into the functional layer solution without the need to additionally protect regions which are not to be coated.Such a selective coating or a coating method selective in this way has the advantage described above in the case of a multiplicity of medical products, at least in the case of those which comprise different materials, but coating is intended to take place only on certain of these materials.The coating according to the invention allows options during the coating process for activating only those parts of the medical device which are later also intended to carry the functional layer. It is also conceivable that the medical product is already designed such that substances which can be activated for promoting adhesion are selected for the parts to be coated.Medical products with a coating according to the invention can be used in particular for endovascular, neurovascular use and cardiovascular use, but the coating according to the invention can in principle always be useful for a medical product when the corresponding medical product comes into contact with blood.Experiments I have shown that experiments are carried outIn vitro experimental series were carried out with the coating according to the invention in order to test the effectiveness of the coating according to the invention. For this purpose, an uncoated nitinol plate and a nitinol plate silanized according to the invention and subsequently coated with polymerized sorbitol acrylate were incubated for 10 minutes with heparinized whole blood. The adhesion of platelets was then determined by fluorescence microscopy via fluorescently labeled CD61 antibodies.There was a significantly lower adhesion of platelets to the nitinol platelets coated according to the invention compared to the uncoated nitinol platelets. Figure 1 shows an uncoated nitinol plate after 10 minutes incubation time with heparinized whole blood at 10x magnification under the fluorescence microscope. The adhesion of a large number of CD61 positive platelets is clearly evident. Figure 2 shows a coated nitinol plate after 10 minutes incubation time with heparinized whole blood at 10x magnification under the fluorescence microscope. Only a few attached CD61 positive platelets are seen.

Claims

Medical product comprising at least one substrate with a coating, wherein the coating comprises a functional layer, characterized in that the functional layer comprises at least one monosaccharide, wherein reduction and oxidation products of monosaccharides are also understood as monosaccharides, the monosaccharides can be bonded directly or indirectly to the substrate by functionalization of the monosaccharides and only oligo- or polymerise upon bonding to the substrate.Medical device according to claim 1, characterised in that the coating comprises a carrier layer with an adhesion promoter located on the substrate and the functional layer is bonded to the carrier layer.Medical device according to claim 2, characterised in that the bond of the adhesion promoter to the substrate and / or the bond of the functional layer to the carrier layer is a covalent bond.Medical device according to claim 2 or 3, characterised in that the adhesion promoter comprises a silicon compound, in particular a silane compound.Medical product according to one of Claims 1 to 4, characterized in that the monosaccharide of the functional layer comprises a sugar alcohol and / or derivatives thereof in its nonfunctionalized form.Medical product according to claim 5, characterised in that the sugar alcohol of the functional layer in its non-functionalised, oxidized or dehydrated form comprises at least one sugar alcohol of empirical formula C 6 H 14 O 6 and / or derivatives thereof.Medical device according to one of claims 1 to 6, characterised in that the monosaccharide of the functional layer in a form not bound to the carrier layer or the substrate is functionalised via at least one reactive multiple bond, in particular a double bond.Medical device according to claim 7, characterised in that the reactive double bond is part of a (meth)acryl group.Medical device according to any one of claims 1 to 8, characterised in that the substrate comprises at least one metal selected from the group comprising nickel, titanium, platinum, iridium, gold, cobalt, chromium, aluminium, iron and / or an alloy thereof.Medical device according to any one of claims 1 to 8, characterised in that the substrate comprises at least one plastic selected from the group comprising polyamides (PA), polytetrafluoroethylene (PTFE), expanded polytetrafluoroethylene (ePTFE), polylactides (PLA), polyesters, polyethers, polyurethane, polyolefins, further corresponding block copolymers.Medical device according to one of claims 1 to 10, characterised in that it is a medical device for endovascular use.Medical device according to one of claims 1 to 11, characterised in that it is a medical device for neurovascular use.Medical device according to one of claims 1 to 12, characterised in that it is a medical device for cardiovascular use.Method for coating a medical product having a substrate with a coating having a functional layer, wherein the functional layer comprises at least one monosaccharide, wherein reduction and oxidation products of monosaccharides are also understood as monosaccharides, and the monosaccharides are bonded directly or indirectly to the substrate by functionalization of the monosaccharides and only oligo- or polymerise upon bonding to the substrate.

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