Coated Medical Devices

Abstract

The present invention relates to a device (1) having a stent structure (2) for insertion into a blood vessel of the human or animal body, the stent structure (2) having an expanded state in contact with the inner wall of the blood vessel and a reduced diameter state in which it is movable through the blood vessel in a microcatheter, the stent structure (2) being preferably connected at its proximal end to an insertion aid (3), the device (1) being deployable for the treatment of vasospasm, the stent structure (2) being designed to be removable from the insertion aid (3), at least a part of the stent structure (2) being provided with a coating, the coating comprising a functional layer, the said functional layer being formed by oligomerization or polymerization of monosaccharides comprising at least one sugar alcohol and / or functionalized with a polymerizable group. Moreover, the present invention also relates to a related method for the treatment of vasospasm.

Description

[Technical field]

[0001] The present invention relates to a device having a stent structure adapted for insertion into a blood vessel of the human or animal body, the stent structure having an expanded state in which it abuts the inner wall of the blood vessel and a reduced diameter state in which it is movable through the blood vessel within a microcatheter, the stent structure being preferably connected at its proximal end to an insertion aid. [Background technology]

[0002] Intravascular prostheses, or stents, are often used for the treatment of vascular stenosis and are permanently implanted at the site of vascular stenosis to keep the blood vessel open. Typically, stents have a tubular structure and are made by laser cutting to achieve a surface composed of struts with openings between them, or are composed of a wire mesh. The stent can be delivered to the target site by a catheter and expanded there; in the case of self-expanding stents composed of shape memory materials, this expansion and abutment with the inner vessel wall occurs autonomously. Alternatively, the stent can be expanded with the aid of a balloon onto which the stent is crimped, or by other mechanical methods. After final placement, only the stent remains at the target site; the catheter, the guidewire or pusher wire, and other auxiliary means are removed from the vasculature.

[0003] Implants of essentially similar design are also used for occlusion of aneurysms by being placed in front of the neck of the aneurysm. However, such flow diverters have a higher surface density than stents for removing stenoses. An example of a flow diverter is described in US Pat. No. 5,393,366.

[0004] Vasospasm is the spasmodic constriction of blood vessels. Vasospasm entails the risk that downstream vessels will not be supplied with a sufficient amount of blood (ischemia), which may result in necrosis of the tissues whose perfusion has been interrupted. Especially in the brain region, vasospasm can occur several days after subarachnoid hemorrhage (SAH), often as a result of the rupture of an aneurysm. Other causes of subarachnoid hemorrhage are brain trauma and hemorrhage from vascular malformations or tumors. The blood that has entered the subarachnoid space rinses the surroundings of the blood vessels located there and is considered to be the most important trigger of vasospasm. About 60% of all SAH patients suffer from more or less pronounced vasospasm between the 5th and 20th days after the hemorrhage. If the arterial vessels are severely constricted, the dependent brain tissues will be undersupplied, which may cause irreversible damage (cerebral infarction). About 15-20% of all patients who survive SAH mainly suffer permanent neurological damage and are left disabled as a result. Approximately 5% of patients who survive SAH subsequently die as a result of cerebral vasospasm. In this regard, vasospasm is one of the main causes of cerebral hemorrhage and death following the rupture of an aneurysm and / or bleeding from surgery in the same or this area.

[0005] Usually, the vascular system is treated with drugs, especially calcium channel blockers or drugs that increase NO levels in blood.An example of a calcium channel blocker is nimodipine, which is often used to prevent vasospasm after subarachnoid hemorrhage.However, such drug therapy is accompanied by significant side effects, and is also costly and time-consuming.

[0006] Other options for the treatment of vasospasm are intensive care measures such as increasing arterial blood pressure and increasing the circulating blood volume, dilating stenotic vessels with a balloon, blocking the stellate ganglion, and surgical removal of sympathetic fibers (sympatholysis). These treatment methods vary individually in their effectiveness, are sometimes very complicated, and the effect is often not sustained for a long enough time. Although blockade of the stellate ganglion and surgical sympatholysis are effective, since sympathetic fibers in the walls of the cerebral arteries are significantly involved in the development of cerebral vasospasm, these procedures are insufficient for the complete prevention and treatment of cerebral vasospasm, since blockade of the stellate ganglion lasts only a few hours, and surgical sympatholysis is limited to only a small range of vascular segments that must be surgically prepared for this purpose.

[0007] From US Pat. No. 5,399,633 a device for the treatment of vasospasm is known, which essentially comprises a stent structure, but which does not remain permanently in the vascular system, but is moved to the site of the vasospasm, expanded there and then withdrawn again, such treatments often having to be repeated at intervals of several days or weeks.

[0008] However, it would be desirable to provide a device for treating vasospasm that can remain permanently in the body as an implant to treat vasospasm and, in particular, prevent the recurrence of vasospasm.

[0009] Traditionally, it was thought that permanent implants were not suitable for the treatment of vasospasm, since the insertion of the implant entails the risk of platelet aggregation. Since platelets can adhere to the surface of the inserted implant marked by proteins in the body (platelet adhesion), resulting in the formation of a blood clot (platelet aggregation), not only platelet adhesion but also platelet aggregation and therefore the formation of a blood clot, the so-called thrombus, can be observed in permanent implants. In most cases, this is treated with platelet aggregation inhibitors, such as acetylsalicylic acid (ASA), clopidogrel, prasgel or ticagrelor. [Prior art documents] [Patent documents]

[0010] [Patent Document 1] International Publication No. 2008 / 107172 [Patent Document 2] International Publication No. 2017 / 207689 Summary of the Invention [Problem to be solved by the invention]

[0011] It is therefore an object of the present invention to provide a device suitable for the treatment of vasospasm, which preferably can remain permanently in the body as an implant, without the need for additional administration of platelet aggregation inhibitors. [Means for solving the problem]

[0012] According to the invention, this object is achieved by a device having a stent structure intended for insertion into a blood vessel of the human or animal body, the stent structure having an expanded state in which it abuts the inner wall of the blood vessel and a reduced diameter state in which the stent structure is movable through the blood vessel in a microcatheter, the stent structure being preferably connected at its proximal end to an insertion aid, said device being deployable for the treatment of vasospasm, the stent structure being designed to be removable from said insertion aid, at least a part of the stent structure being provided with a coating, this coating comprising a functional layer, said functional layer comprising at least one sugar alcohol and / or formed by oligomerization or polymerization of monosaccharides functionalized with polymerizable groups.

[0013] The device according to the invention essentially comprises at least one substrate, which serves as the base of the actual device, and a functional layer, which confers desired properties to the device, having a biomimetic or biorepellent effect.

[0014] Preferably, the functional layer substantially comprises a complex and highly branched hydrophilic matrix with a plurality of molecules each having a main chain as a polymer backbone and each having a plurality of side chains. The main chains and / or side chains can form bonds with other main chains and / or side chains. Other matrix forming mono-, oligo- and polymers can be incorporated into these main chains and side chains without being covalently bonded to the substrate. The sugars forming the functional layer, sugar alcohols also being considered as sugars in the sense of the present invention, are functionalized with polymerizable groups capable of binding to the surface of the stent structure and causing polymerization.

[0015] The polymerizable group with which the saccharide is functionalized can have a reactive multiple bond, in particular a reactive double bond. Polymerization can therefore take place via the double bond. In particular it can be an acrylic or methacrylic group known to those skilled in the art to be suitable for polymerization reactions. It is also possible to use other groups suitable for polymerization, for example vinyl or allyl. The backbone therefore exhibits at least partially polymerized vinyl, allyl, acrylic or methacrylic compounds or their derivatives and / or their isomers or combinations thereof. Thus, oligomerization or polymerization of the saccharide is usually carried out via the polymerizable group with which the saccharide is functionalized; on the other hand, new formation of glycosidic bonds usually does not take place.

[0016] The side chains include in particular monosaccharides and / or oligosaccharides, and also the reduction products of monosaccharides or oligosaccharides, in particular sugar alcohols (alditols), are to be understood as such. Apart from this, for the purposes of the present invention, oxidized monosaccharides and / or oligosaccharides may also occur, and the oxidized forms are also to be understood as monosaccharides or oligosaccharides.

[0017] Without wishing to be bound by a particular theory, the advantage of the coating proposed by the invention is found in the fact that the functional layer has biomimetic properties, respectively biorepellent properties, and is not recognized by the platelets as foreign to the body, but rather as endogenous, and therefore does not cause a reaction of the platelets, in particular an adhesion or aggregation reaction.

[0018] The biomimetic effect of the coating of the present invention is due to the fact that the functional layer of the present invention mimics the human glycocalyx, which covers the cells of blood vessels with a kind of mucus layer and is composed of various polysaccharides covalently bound to membrane proteins and membrane lipids, thus obtaining glycoproteins and glycolipids.

[0019] Due to the high biomimetic effect of the coatings proposed according to the invention, and in particular the functional layers, it is advantageous that polymerization of the reactants of the functional layer solution occurs essentially only after application of the functional layer solution onto the substrate, resulting in a composite layer that closely resembles the glycocalyx, such that platelet adhesion to surfaces that have been coated with the invention is significantly lower than to uncoated surfaces.

[0020] The biorepellent effect of the coating according to the invention is based on the principle of steric repulsion. Presumably, the space available for oligomers and polymers on the surface is reduced when the protein invades this space, i.e. the approaching protein is forced to adopt a conformation that is energetically unfavourable to the oligomers and polymers on the surface. This creates a repulsive force on the protein as a whole. It is also conceivable that the displacement of water molecules from the coating creates a repulsive penetration force on the protein.

[0021] With regard to platelet adhesion, this principle of action means that there are no or only very few proteins on the surface suitable for binding, preventing platelet adhesion and thus significantly reducing platelet adhesion.

[0022] The stent structure, which is cylindrical in at least some regions and preferably as a whole, generally has openings distributed around the circumference of the cylinder, in other words, a lattice or mesh structure made up of struts is created, with a plurality of openings or meshes formed around the circumference of a base cylindrical structure.

[0023] The stent structure, consisting of interconnected webs or struts, can be produced by laser cutting in a manner known per se; in this connection it is also referred to as a cut structure. In this way, a plurality of openings or mesh structures are produced in the stent structure, the openings being distributed over the circumference of the stent structure. Other production processes, such as galvanic or lithographic processes, 3D printing or rapid prototyping, may also be employed.

[0024] Alternatively, the stent structure may be a mesh-like structure comprising wires in the form of a braid. In this case, the wires typically extend helically along the longitudinal axis, with opposing intersecting wires extending above and below each other at the intersections, thereby forming honeycomb-like openings between the wires. The total number of wires is preferably between 8 and 64. The wires forming the mesh structure may be individual wires of metal, but may also be strands, i.e. multiple wires of small diameter arranged to form filaments that are preferably twisted together.

[0025] The term "aperture" or opening refers to the lattice structure, whether or not the aperture is separated from the surroundings by a membrane, i.e., even an aperture covered by a membrane is referred to as an aperture or opening. If necessary, the membrane can be applied to the outside or inside of the lattice structure. It is also possible to embed the lattice structure in the membrane. The membrane can be made of a polymer material such as polytetrafluoroethylene, polyester, polyamide, polyurethane, polyolefin or polysulfone. Polycarbonate urethane (PCU) is particularly preferred.

[0026] The advantage of a stent structure consisting of interconnected webs or struts, especially produced by laser cutting, is that during the expansion process, compared to a mesh structure including wires, the stent structure of struts is less prone to longitudinal contraction than a mesh structure. Since the stent structure exerts additional stress on the surrounding vessel wall during longitudinal contraction, longitudinal contraction should be minimized. Since vasospasm is caused by stimuli acting specifically on the blood vessels, any additional stress should be avoided in vasospasm treatment.

[0027] Stent structures of interconnected struts further provide the advantage that the radial force exerted by such stent structures of otherwise similar structure, strut / wire density and strut / wire thickness is higher than that of mesh structures including wires, because the struts are permanently attached at their intersections, whereas the wires of a mesh structure typically only extend above and below each other.

[0028] The struts or wires can have a circular, elliptical, square, rectangular or trapezoidal cross section, the edges of which are advantageously rounded. It may further be expedient to treat the stent structure by electropolishing to make it smoother and rounder and less traumatic. In addition, the risk of bacteria or other contaminants attaching is reduced. The use of flat struts / wires in the form of thin strips is also possible, in particular metal strips.

[0029] The openings formed in the stent structure between the individual struts or wires have an inscribed circle diameter of 0.1-6 mm, where inscribed circle diameter refers to the diameter of the largest circle that can be placed within the opening. The data refers to the stent structure in an expanded state, i.e., the state that the stent structure assumes when it is not subject to external constraints or restrictions. Depending on the diameter of the vessel into which the implant is implanted, the implant may not be able to assume a fully expanded state, so that the expanded state within the vasculature may differ from the expanded state that exists in the absence of external constraints.

[0030] Openings having an inscribed circle diameter of 1 mm or greater are preferred because they represent a relatively coarse mesh stent structure, which is capable of exerting a radial force of an appropriate magnitude for treating vasospasm.

[0031] The openings created in the stent structure may be closed around the periphery, i.e., surrounded without interruption by struts or wires (so-called "closed cell designs"). However, "open cell designs" are preferred, in which at least some of the struts / wires have interruptions and the cells formed by the struts / wires are at least partially open, i.e., not completely closed. Such open cell designs exhibit greater flexibility, which may be advantageous in highly tortuous vessels. Furthermore, stent structures with closed cell designs tend to adopt a straightened configuration, which may exert some stress on the vessel, especially if the vessel itself has a more curved path.

[0032] Furthermore, in order to generate radial forces of suitable magnitude, it is considered expedient to use struts or wires with a relatively large cross section or diameter, i.e., relatively large struts / wires. For example, when using struts or wires with a substantially rectangular cross section, a height and width of the strut / wire of 30 to 300 μm has proven to be advantageous, and a rectangular cross section with rounded edges is also considered to be substantially rectangular. In the case of a circular cross section, the diameter should be 30 to 300 μm.

[0033] However, as already mentioned, the stent structure may also be a mesh of wires forming a braid, and in this connection is also referred to as a braided stent structure.

[0034] The proximal and distal ends of the stent structure may each be provided with loose wire ends, which are preferably atraumatic in order to avoid damaging the vessel. The atraumatic configuration of the wire ends can be achieved, for example, by rounding the wire ends. Another option is to make the wires form loops at one or both ends of the stent structure and guide them back into the braid again. Thus, the ends of the stent structure no longer have free wire ends, and the risk of damaging the vessel wall is reduced.

[0035] The density of the struts or wires of the stent structure can be similar to conventional stents used to open blood vessels, but can also be significantly higher, in which case the stent structure is very similar to a type of flow diverter that is placed in front of an aneurysm to block the aneurysm from blood flow. The flow diverter has a high surface coverage, often in the range of 20-65% in the expanded state, i.e., a fairly high percentage of the total surface area of ​​the flow diverter is made of material in the form of struts / wires with openings located between them. The comments above regarding the stent structure, the design of the struts and wires, and the routing or configuration of these, etc., apply whether the stent structure resembles a conventional stent or a flow diverter.

[0036] Even if the above-mentioned stent structure with the biomimetic coating described hereinbefore is intended to remain permanently in the blood vessel, the associated stent structure can also be used only for short-term insertion and expansion in the blood vessel. For stent structures that are not intended to remain permanently in the blood vessel and are removed after a few minutes at a time, a separation point between the stent structure and the insertion aid is not necessarily required. It is understood that such an embodiment of the device with the stent structure at least partially equipped with the described coating is also claimed according to the present invention. Nevertheless, the separation point can be advantageous to provide the treating physician with different options depending on the relevant situation, i.e. to pull back the stent structure or to separate the stent structure at the separation point if the pullback is problematic or if the physician decides for other reasons that the stent structure should remain permanently in the blood vessel.

[0037] Typically, the insertion aid is provided in the form of an insertion wire or pusher wire, known for use with implants. In the case of implants intended to remain permanently in the vasculature, the insertion aid is attached to the implant via a detachment point, which may be designed to allow mechanical, thermal or electrolytic disconnection. The device proposed by the invention has at least one such detachment point, with a single detachment point being preferred to facilitate disconnection / release. The insertion aid is preferably made of stainless steel, nitinol or cobalt-chromium alloy.

[0038] The insertion aid or insertion wire is preferably attached radially outwardly to the proximal end of the stent structure. In other words, the connection between the insertion aid and the stent structure is not located in the center of the stent structure but eccentrically at or near the inner vessel wall. In this way, blood flow is as unimpeded as possible. Furthermore, the eccentric location of the insertion aid facilitates the retraction of the device into the microcatheter, if necessary.

[0039] The separation point is preferably designed to be galvanically corrosive. In this case, at least partial dissolution of the separation point is achieved by applying a voltage to the separation point using a suitable voltage / power source. The electrolytic dissolution method galvanically corrodes the separation point by applying a voltage, so that the implant is separated from the insertion aid. Usually, a direct current is used, and low amperes (<3mA) are sufficient. The separation point is usually made of metal, which acts as an anode when a voltage is applied, causing oxidation and dissolution of the metal.

[0040] To avoid anodization of the implant, the implant needs to be electrically isolated from the separation point and the insertion aid. Electrolytic stripping of implants is a method well known in the prior art, for example of occlusion coils used to close aneurysms (see, for example, WO 2011 / 147567). The principle is based on the fact that, when a voltage is applied, appropriately designed separation points made of suitable materials, in particular metals, are dissolved, in principle by anodization, at least to such an extent that the area of ​​the implant located distal to the relevant separation point is released. The separation points may be made, for example, from stainless steel, magnesium, magnesium alloys or cobalt-chromium alloys. A particularly preferred magnesium alloy is Resoloy®, developed by Sarstedt / MeKo GmbH, Germany (see WO 2013 / 024125). It is an alloy consisting of magnesium and, in particular, lanthanides, in particular dysprosium. Another advantage of using magnesium and magnesium alloys is that magnesium residues remaining in the body are physiologically unproblematic.

[0041] The cathode can be placed, for example, on the body surface, while the separation point functions as the anode. Alternatively, another area of ​​the device can be used as the cathode. Of course, the separation point must be conductively connected to a power source. The insertion aid, in particular the insertion wire, itself can also function as a conductor. If the cathode is placed on the body surface, the area of ​​the cathode should be selected significantly larger than the area of ​​the anode, since the corrosion current that occurs is controlled by the area of ​​the cathode. To a certain extent, the dissolution rate at which the separation point dissolves can be controlled by appropriately adjusting the size of the cathode surface relative to the anode surface. The device proposed by the present invention may therefore comprise a voltage source and, where applicable or appropriate, an electrode that can be placed on the body surface.

[0042] Instead of electrolytically dissolved separation points, other separation points known from the prior art can also be used, in particular mechanically, thermally or chemically separable separation points. In the case of mechanical separation / cutting, typically there is a form-fit, force-fit or friction-fit, which is released upon release of the stent structure to separate the stent structure from the insertion aid. In the case of thermal separation points, the connection is released by heating the separation point, softening or melting it, and cutting is achieved. Another option is to use chemical cutting, where the separation occurs due to a chemical reaction that takes place at the separation point.

[0043] It is also possible to combine different types of separation, for example electrolytic and mechanical separation. For this purpose, a mechanical connection, in particular brought about by a form fit, is established between the components, which connection is maintained until the components maintaining the mechanical connection are electrolytically corroded.

[0044] Preferably, the stent structure is of a self-expanding design, capable of autonomously transitioning to an expanded state upon release from the microcatheter. To achieve this, a stent structure made of a material with shape memory properties is advantageous, and in particular the use of a nickel-titanium alloy known under the trade name Nitinol has proven its worth. However, polymers or other alloys with shape memory properties are also conceivable.

[0045] The device proposed by the invention can be used in particular in the neurovascular field, but also in the cardiovascular or peripheral areas.

[0046] Typically, treatment is performed by advancing the device of the present invention within a microcatheter to the target site, i.e., the site where vasospasm occurs. Following this, the stent structure is released by pulling back the microcatheter proximally, which expands and abuts the inner wall of the blood vessel to treat the vasospasm. The stent structure is then left in place either permanently or, for temporary use, for a period of time, typically 1-10 minutes. If the stent structure is not to be permanently placed in the blood vessel, the microcatheter is then again moved distally to collapse the stent structure, and the microcatheter is pulled back with the device. This procedure can be repeated for several days in a row.

[0047] The terms "proximal" and "distal" should be understood to refer to the portion of the device that faces toward the treating physician when inserted as proximal and the portion that faces away from the treating physician as distal. Thus, the device is typically advanced distally by the microcatheter. The term "axial" refers to the longitudinal axis of the device extending from proximal to distal, and the term "radial" refers to the level / plane extending perpendicular thereto.

[0048] In parallel with this treatment carried out with the device of the invention, a drug treatment can also be carried out, for example by administration of nimodipine, which can be administered intra-arterially, especially at the site of vasospasm.

[0049] Generally, stent structures are designed to be open at both ends in order to prevent as little obstruction of blood flow as possible and to prevent undersupply of subsequent vessels and tissues supplied by them. Stent structures that are not intended to remain permanently in the vessel may be closed at the distal end; closed structures located at the distal end are more atraumatic. In this context, open is understood to mean that there are no struts or wires located at each end of the stent structure, and the struts / wires are limited to the outer periphery of the stent structure. However, when closed ends are provided, there are also struts or wires in the center of the stent structure. Even when the distal end is closed, there are openings between the struts or wires, so this end is not completely impermeable; blood flow can still pass through the respective openings.

[0050] The force exerted by the expandable stent structure radially outward on the inner vessel wall should be in the range of 2-30 N / m, preferably 5-10 N / m, based on a diameter of the stent structure of 2.00 mm. The radial forces indicated in this case refer to the force acting radially per unit length, i.e. are considered as relative radial forces. In this case, only the part of the stent structure that abuts on the inner vessel wall and is therefore able to exert a force on the inner vessel wall (effective length) is taken into account. Along the effective length, the stent structure must cover a minimum of 50% of the envelope arranged around the stent structure. In contrast, the absolute radial force indicates a value that is applicable to the entire stent structure.

[0051] The applied radial force (chronic outward force, COF) is determined by the vee block test as described below.

[0052] The vee block test setup includes two polymethylmethacrylate (PMMA) blocks, each with a 90° vee groove milled and polished smooth. The vee blocks are placed one on top of the other such that when they come into contact a hollow space of square cross section is formed between the blocks. One vee block is rigidly fixed while the other is equipped with a force sensor.

[0053] The COF represents the force that the stent structure exerts on the vessel or on the vee blocks in the test during self-expansion. To determine the radial force, the stent structure, located in the delivery hose or microcatheter, is centered between the vee blocks. The delivery hose / microcatheter is then pulled back and the stent structure is released. Due to its self-expanding properties, the structure collapses and the resulting radial force can be measured by a force sensor connected to one of the vee blocks and further evaluated. To be able to compare stent structures of different lengths, the relative radial force is calculated as follows:

number

[0054] [Figure 1] An uncoated Nitinol plate strip after 10 minutes of incubation with heparinized whole blood is shown under a fluorescent microscope at 10x magnification, with numerous attached CD61-positive platelets clearly visible. [Diagram 2] A coated nitinol plate strip after 10 min incubation with heparinized whole blood is shown under a fluorescent microscope at 10x magnification. Only a few attached CD61 positive platelets can be seen. [Diagram 3]An exemplary side view of a device 1 according to the invention is shown. The device comprises a stent structure 2 and an insertion aid 3 in the form of an insertion / pusher wire. In this example, the stent structure 2 is produced by laser cutting and comprises struts which together form a continuous honeycomb structure. The insertion aid 3 is connected eccentrically, i.e. in the edge region, to the stent structure 2 at its proximal end via a detachment point 4. By applying a voltage to the detachment point 4, the stent structure 2 can be detached from the insertion aid 3 and permanently embedded in the blood vessel. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0055] According to an advantageous embodiment, the radial force exerted by the stent structure in the expanded state is substantially constant along its length, i.e. in the proximal and distal portions the radial force is equal to that of the central portion. In contrast, in a conventional uniformly constructed stent, the radial force actually acting on the proximal and distal portions is usually weaker than that of the central portion. It is therefore expedient to selectively increase the radial force in the proximal and distal portions to create a stent structure in which the radial force in the expanded state is substantially constant over its effective length, the struts or wires that are typically no longer in full contact with the inner vessel wall being ignored when considering the radial force. The proximal end therefore refers to the portion of the stent structure that is located most proximally and is no longer part of the effective length, where the struts / wires taper towards the insertion aid. Typically, the length of this proximal end is 8-10 mm, i.e. the total length of the stent structure is approximately this amount longer than the effective length of the stent structure.

[0056] To increase the radial force in the proximal and distal portions, the struts or wires may be designed to have a larger cross-section than in the central portion, so that the struts / wires are more massive, fully or partially compensating for the inherent tendency of the stent structure to exert a higher radial force in the central portion.

[0057] Alternatively or additionally, the density of struts or wires in the proximal portion may be higher than that in the central portion, again fully or partially compensating for the reduction in proximal or distal radial force observed in conventional stents.

[0058] Another possibility is to provide the stent structure with slits that run helically around the circumference of the stent structure or longitudinally along the circumference of the stent structure, in which case individual struts or wires may span the slits to affect the radial force characteristics.

[0059] Typically, the diameter of the stent structure in the freely expanded state is in the range of 2 to 8 mm, preferably in the range of 4 to 6 mm. The total length of the stent structure in the expanded state is usually in the range of 5 to 50 mm, preferably 10 to 45 mm, more preferably 20 to 40 mm. The effective length, i.e. the length of the stent structure in the expanded state that actually exerts a radial force on the inner wall of the blood vessel, is usually about 8 to 10 mm shorter.

[0060] If the stent structure consists of struts, the structure can be cut from a tube with a wall thickness of, for example, 25-70 μm; for mesh structures including braided wires, the wire thickness is preferably 20-70 μm. For example, a microcatheter through which the device can be moved to the target location in a compressed state has an inner diameter of 0.4-0.9 mm.

[0061] Another possibility is to incorporate electrical conductors into the stent structure, which allows applying electrical, radio frequency or ultrasound pulses to the nerve fibers extending into the vessel wall, temporarily or permanently reducing their function and thus preventing or treating vasospasm. Such a principle is described in WO 2018 / 046592 and is based on the use of a stent structure for endovascular denervation of brain-supplying arteries.

[0062] Physically, pulses can be applied to the nerve fibers in the form of high frequency (HF) signals, direct current, alternating current or ultrasound. In principle, denervation is ultimately based on heating the vessel wall, which eliminates or damages the function of the nerve fibers. The use of high frequency or ultrasound pulses is preferred insofar as they generate maximum energy deep in the surrounding vessel wall, so that the nerve fibers are specifically damaged, and not the entire vessel wall. The nerve fibers in this case are those of the sympathetic nervous system.

[0063] To allow the treating physician to visualize the treatment, the device is advantageously equipped with one or more radiopaque markers. The radiopaque markers may be, for example, platinum, palladium, platinum-iridium, tantalum, gold, tungsten or other radiopaque metals. For example, radiopaque coils can be arranged at various points on the device. It is also possible to provide the stent structure, in particular the struts or wires of the stent structure, with a coating of radiopaque material, for example a gold coating. This coating can have a thickness of, for example, 1 to 6 μm. The coating with radiopaque material does not have to cover the entire stent structure; this is especially important in the area of ​​the stent structure that is in contact with the inner vessel wall, i.e. essentially in the cylindrical part of the stent structure. Nevertheless, even when providing a radiopaque coating, it is considered to be advantageous to additionally arrange one or more radiopaque markers in the device, in particular at the distal end of the stent structure.

[0064] An additional option is to use struts made of a metal with shape memory properties, in particular a suitable nickel-titanium alloy with an at least partially platinum core. Such struts are known as DFT (drawn filled tubing) wires. In this way, the advantageous properties of nickel-titanium, namely shape memory properties, on the one hand, are combined with the advantageous properties offered by platinum, namely X-ray visibility, on the other hand.

[0065] In addition to the device according to the invention, the invention also relates to a method for the treatment of vasospasm, in which a device of the above-mentioned type is used, in which the stent structure of the device is moved to the location of the vasospasm by means of an insertion aid and expanded there, usually by pulling back the microcatheter containing the device in the proximal direction, and then detached from the insertion aid, which can be done electrolytically, i.e. by applying a voltage to a separation point located between the stent structure and the insertion aid.

[0066] Before the stent structure is advanced to the target location by the microcatheter, a relatively large lumen guide catheter is often first used through which a smaller lumen microcatheter is advanced distally. In neurovascular applications, for example, advancement is made through the guide catheter from the groin to the carotid artery, followed by further advancement only through the microcatheter.

[0067] It is also conceivable to place the stent structure at the location of the vasospasm only temporarily. In this case, the stent structure remains at the location of the vasospasm in an expanded state for a few minutes, preferably 1 to 10 minutes. The stent structure is then removed from the blood vessel. For this, the microcatheter can be advanced distally and the stent structure can be collapsed again and accommodated within the microcatheter. The microcatheter and the device can then be withdrawn and removed from the vasculature. The above procedure is preferably repeated for several consecutive days to continue the treatment of the vasospasm.

[0068] The device design and respective coating as described above in relation to the treatment of vasospasm can also be used for other purposes, including in particular the treatment of stenosis (vasoconstriction) or the treatment of aneurysms. In the case of the treatment of stenosis, the device essentially functions as a normal stent, but the stent is provided with the coating described above to prevent the accumulation of platelets and thus the formation of thrombi that would compromise the success of the treatment. As described above, the stent structure can be (laser) cut using a closed cell design or at least a partially open cell design. Optionally, a braided stent structure with loose wire ends at the proximal and / or distal ends can also be used, but the wires at the proximal and / or distal ends of the stent structure must be folded back into the braid.

[0069] Another alternative application is as a flow diverter to treat aneurysms. While the above applies in terms of basic design and coating, the surface coverage and surface density of the flow diverter typically exceeds that of a regular stent. The flow diverter is placed in front of the neck of the aneurysm to ensure that blood flow is diverted away from the aneurysm, ultimately leading to aneurysm deterioration / shrinkage.

[0070] Another possible function of the stent structure or flow diverter placed in front of the aneurysm is to prevent the escape of the occluding means, such as occlusion coils, incorporated in the aneurysm. Such escape or escape of the occluding means from the aneurysm may have undesirable consequences, for example, the occluding means being carried by the blood flow to a more distally located area, where it may result in occlusion of the vessel or damage to the vessel wall. For this purpose, the stent structure can be permanently implanted in the vessel, but it is also possible to temporarily place the device in front of the aneurysm after inserting into the aneurysm a microcatheter through which the occluding means can be introduced into the aneurysm. In this way, the device prevents the escape of the occluding means from the aneurysm. If a sufficient number of occluding means, usually coils, are introduced into the aneurysm, these occluding means interlock with each other, so that they mutually prevent escape from the aneurysm, i.e., after the aneurysm is completely filled, further occlusion of the aneurysm neck may not be necessary. Such a technique is also called "jailing". In the case of such stent structures that are only temporarily introduced, a separation point for connection to an insertion aid does not necessarily have to be located, and as long as the stent structure at least partially carries the coating described, such devices are also considered to be included in the present invention according to further embodiments.

[0071] Another type of flow diverter is the so-called bifurcated flow diverter, which is placed in front of an aneurysm located at a branching site (bifurcation) of a blood vessel. Such a bifurcated flow diverter or bifurcated implant is described, for example, in WO 2014 / 029835. The distal part of such an implant is radially expanded relative to a more proximally located part. The distal part is configured to at least partially occlude the neck of the aneurysm. The coatings described to prevent platelet adhesion and aggregation are also useful for such bifurcated implants.

[0072] Also for stenosis and aneurysm indications, the invention relates to related devices as well as related methods. During this procedure, the device is guided to the target location, usually by a microcatheter. The device is released and assumes an expanded shape. This is done by pulling back the microcatheter proximally or by pushing the device distally out of the microcatheter. The distal stent structure is then detached from the insertion aid, and the stent structure is released into the blood vessel where it can remain. The microcatheter can then be pulled back proximally and removed from the vasculature. Platelet accumulation and thrombus formation are effectively prevented when the stent structure intended to treat stenosis or occlude aneurysms remains in the blood vessel.

[0073] Regardless of the embodiment involved, an essential feature of the present invention is the biomimetic coating. In principle, the device serving as the substrate is covered by a carrier layer containing an adhesion promoter, through which the functional layer can be bonded to the substrate. Within the scope of the present invention, preferred adhesion promoters are silane adhesion promoters. Alternatively, other adhesion promoters can be used, for example polyolefin adhesion promoters or adhesion promoters based on titanates or zirconates.

[0074] Further examples of adhesion promoters are: - Thiol and dithio compounds, particularly suitable for precious metal substrates -Amines and alcohols, especially suitable for platinum substrates - Carboxylic acid, which is particularly suitable for silver and aluminum substrates; the aluminum substrate may have an aluminum oxide surface - Phosphonates, which are particularly suitable for iron, iron oxide, titanium and titanium dioxide substrates - Complexed adhesion promoters, especially chelates, which are particularly suitable for various metal and metal oxide substrates and which to some extent covalently bond to the substrate.

[0075] The adhesion promoter should in principle contain functional groups, so that a covalent bond is possible, via which the adhesion promoter can react with the functional layer. Depending on the material of the device involved, the bond between the adhesion promoter and the device may also be covalent.

[0076] For example, suitable adhesion promotion can be achieved by silanization, i.e., chemically bonding silicon compounds, especially silane compounds, to at least a portion of the surface, where the silicon and silane compounds are bonded, for example, to hydroxy- and carboxy groups.

[0077] Preferably, the substrate is one that will bond with the adhesion promoter. For the purposes of this application, such substrates are referred to as "coatable substrates." Coatable substrates thus include substrates whose surface is sufficiently reactive and / or sufficiently activatable to bond at least partially with the adhesion promoter or directly with the functional layer.

[0078] Thus, in the sense of the present invention, coatable substrates may be of a wide variety of natures, and in particular include oxidizable substrates and combinations thereof. These include, for example, metals such as nickel, titanium, platinum, indium, gold, cobalt, chromium, aluminum, iron or alloys, and combinations thereof. For example, one metal can be coated with another metal, in which case the coating claimed by the present invention is preferably applied on the outer metal layer, which includes the carrier layer and the functional layer. Coatable metals also include substrates in which the base metal is covered by an oxide layer. Another coatable substrate is glass.

[0079] A particularly preferred embodiment relates to a device that is entirely or partially gold-coated, which ensures X-ray visibility. In particular, this allows the expansion of the device in the blood vessel to be visualized, and the treating physician to know whether the expansion is as desired. This is particularly advantageous when the implant is intended to treat vasospasm. The coating proposed by the present invention is then applied to the gold coating, which includes a functional layer and in most cases a carrier layer. The base material of the device to be gold-coated can be a conventional metal or a conventional metal alloy for the relevant medical device, such as a nickel-titanium alloy, a cobalt-chromium alloy or stainless steel.

[0080] Coatable substrates in the sense of the present invention may be various plastics such as polyamide (PA), polytetrafluoroethylene (PTFE), expanded polytetrafluoroethylene (ePTFE), polylactic acid (PLA), polyester, polyether, polyurethane, polyolefin, as well as related block copolymers. In the field of medical engineering, many suitable plastics are known to those skilled in the art. Adhesion promoters are usually required for metal or oxide surfaces, but are not necessarily required for polymers used as substrates.

[0081] For example, suitable adhesion promotion can be achieved by silanization, i.e., by chemical bonding of silicon compounds, especially silane compounds, to at least a portion of the surface, where the silicon and silane compounds are bonded, for example, to hydroxy and carboxy groups.

[0082] Polyolefins, including chlorinated polyolefins (CPO) or acrylated polyolefins (APO), may also be used as adhesion promoters.

[0083] Silane compounds in the sense of the present invention are compounds of the general formula R m Six n(m, n=0-4, where R represents an organic radical, in particular an alkyl, alkenyl or aryl group, X represents a hydrolyzable group, in particular OR, OH or halogen, and R=alkyl, alkenyl or aryl). In particular, silanes are all compounds according to the general formula RSiX 3 Moreover, for the purpose of the present invention, related compounds having several silicon atoms are also counted as silane compounds. In particular, silane derivatives in the form of organosilicon compounds are considered as silane compounds according to the present invention. Thus, silane compounds in the sense of the present invention are not only substances that have a silicon skeleton and hydrogen and are designated as silanes.

[0084] Preferably, the matrix of the functional layer is covalently bonded to the carrier layer or substrate, preferably synthesized by graft polymerization, and the functional layer is produced on the carrier layer or substrate. The polymerization of the applied monosaccharides, also understood as such to be the reduction and oxidation products of monosaccharides, especially sugar alcohols (alditols), essentially occurs preferably only on the carrier layer / substrate or in the functional layer. Sugar alcohols (alditols) are the reduction products of sugars in which the aldehyde functional group is reduced to alcohol.

[0085] For the purposes of the present invention, it is irrelevant in which form the (graft) polymerization takes place. The growth of the side chains can therefore especially be initiated from the main chain. This approach is also called "grafting from". It is likewise possible for the side chains to already start oligomerizing or polymerizing, and for the already growing side chains to be attached to the main chain ("grafting onto"). Furthermore, the oligomerized or polymerized main chain and the side chains can also associate ("grafting through").

[0086] Preferably, the functional layer substantially comprises a complex and highly branched hydrophilic matrix, comprising a plurality of molecules, each having a main chain as a polymer backbone and a plurality of side chains. The main chains and / or side chains may form bonds with other main chains and / or side chains. Other matrix-forming monomers, oligomers and polymers may be incorporated into these main chains and side chains without themselves being covalently bonded to the carrier layer.

[0087] The backbone may comprise at least partially polymerized vinyl, allylic, acrylic or methacrylic compounds, or derivatives thereof and / or isomers thereof or combinations thereof.

[0088] The side chains include in particular monosaccharides and / or oligosaccharides, the reduction products of the monosaccharides or oligosaccharides being understood as such as well, in particular sugar alcohols (alditols).Furthermore, oxidized monosaccharides and / or oligosaccharides may occur, the oxidized forms also being understood as monosaccharides or oligosaccharides for the purposes of the present invention.

[0089] The device proposed by the present invention comprises at least a coated substrate, said coating preferably comprising a carrier layer located on the substrate and a functional layer located on the carrier layer. The carrier layer essentially comprises an adhesion promoter, which in most cases is covalently bonded to the substrate. Furthermore, non-covalent adhesion promoters are also known, for example adhesion promoters that are bonded to the substrate via complex bonds. Preferred adhesion promoters are silicon compounds and polyolefin-based adhesion promoters. According to a preferred embodiment, the functional layer comprises at least one functionalized sugar alcohol, via which it is covalently bonded to the carrier layer.

[0090] The preferred sugar alcohol of the functional layer, in its non-functionalized form, has the molecular formula C 6 H 14 O 6The sugar alcohol corresponds to a sugar alcohol having the structure, for example, 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: [ka]

[0091] "In non-functionalized form" means that the molecular formula mentioned represents the molecular formula of the sugar alcohol that is not functionalized, but also includes, where appropriate, its derivatives and / or isomers. Functionalization is understood to denote the introduction of functional groups into the compound that allow binding to the substrate, the carrier layer and / or to compounds already attached to the carrier layer or substrate.

[0092] The functional layer according to the present invention has the molecular formula C 6 H 14 O 6 and / or its derivatives and / or its isomers. The functional layer may in particular comprise a composite matrix which may result from the polymerization of the applied functionalized sugar alcohols.

[0093] In addition to the definition of the term "derivatives of similar structure" commonly used in chemistry, for the purposes of the present invention, derivatives should be understood to be all cyclic and heterocyclic compounds that can be derived from a substance by dehydration. An example of this is sorbitan or anhydrosorbitan, which is formed by the separation of a water molecule from sorbitol. It therefore represents the anhydride of sorbitol. Another example is isosorbide, which is obtained by further separation of a water molecule.

[0094] Preferably, the sugar alcohol is functionalized via at least one reactive group, which preferably contains a reactive multiple bond, in particular a double bond, and which is preferably an acrylic group. Other functional groups suitable for polymerization, which do not necessarily have a reactive double bond, are known to those skilled in the art and include, for example, methacrylic, vinyl or allyl groups.

[0095] Preferably, the sugar alcohols of the functional layer are at least partially polymerized with one another.

[0096] The device preferably comprises at least one substrate provided with a coating, the coating comprising a functional layer. The functional layer comprises at least one functionalized monosaccharide, which can be covalently bound to the carrier layer, and oligomerization or polymerization occurs only upon binding to the carrier layer. In this way, it has been found that a functional layer is formed that is particularly similar to the natural glycocalyx. The structure of the coating of the invention, in which oligomerization or polymerization of the saccharides occurs only upon binding to the substrate, differs significantly from coatings in which preformed polymers are applied onto the surface. In particular, the coating formed differs from prior art coatings in that it has a particularly low layer thickness, which is usually below 100 nm. In most cases, the thickness of the coating is in the range of 10-100 nm. This is also associated with the advantage that the mechanical properties of the coated medical device are only slightly affected, i.e. elasticity, ability to expand after release, ability to apply radial forces to the blood vessel, etc. are all preserved.

[0097] Preferably, the coating comprises a carrier layer located on the substrate, and then the functional layer is bonded to the carrier layer. The bond formed may be a covalent bond, in particular, but may also be other bonds, such as complex bonds. The carrier layer essentially comprises an adhesion promoter bonded to the substrate. Preferred adhesion promoters are silicon compounds and polyolefin-based adhesion promoters.

[0098] The monosaccharide of the functional layer preferably comprises at least one sugar alcohol and / or its derivative and / or its isomer.

[0099] Thus, the solution from which the functional layer of the coating proposed by the invention is constituted may contain one or more of the following substances: (1) Sorbitol-acrylate (consisting of one or more acrylate groups), where the acrylate groups may be located at different positions. [ka]

[0100] (2) Sorbitol acrylates, which may be partially oxidized and may contain aldehyde, keto and / or carboxy groups. [ka]

[0101] (3) Sorbitol acrylates (having one or more acrylate groups), which may contain additional reactive groups such as carboxy groups. [ka]

[0102] (4) Anhydrides, such as sorbitan (mono)acrylate having polymerizable groups. [ka]

[0103] (5) Sorbitol having a non-polymerizable group, such as a carboxy group. [ka]

[0104] (6) Complex sorbitol compounds that are not polymerizable but can be incorporated into the polymer matrix of the functional layer. [ka]

[0105] The structure of the functional layer can be varied depending on the specific composition of matter: for example, by increasing the proportion of crosslinker, it is possible to produce a more tightly meshed functional layer, or by decreasing the proportion of crosslinker, to produce a less crosslinked functional layer with longer linear regions.

[0106] Another advantage of the coating according to the invention is that, via an intermediate stage of adhesion promotion, the coating can be activated for the associated adhesion promoter and covers only those surfaces and structures of the device that have been specifically activated, so that when applying the functional coating solution, it is possible to immerse the entire device in the functional coating solution without the need for additional protection of areas that should not be coated.

[0107] Such selective coatings, respectively selectively performed coating methods, provide the above-mentioned advantages for a number of devices, at least for devices made of different materials (in which case the relevant coating is applied to only some of these materials).

[0108] The coating proposed by the present invention allows the coating method to activate only those parts / areas of the device that are intended to later carry a functional layer. It is also conceivable that the device is already designed such that the parts to be coated contain activatable substances for adhesion promotion.

[0109] Devices provided with the coating according to the invention are particularly suitable for applications in the intravascular, neurovascular and cardiovascular fields; however, the coating for devices according to the invention may always be conveniently applied to all devices that come into contact with blood.

[0110] Any and all statements made with respect to the apparatus apply equally to the associated method and vice versa.

[0111] test To evaluate the effectiveness of the coatings proposed by the present invention, the coatings of the present invention were subjected to a series of in vitro tests. For this purpose, small nitinol plate specimens, uncoated and silanized according to the present invention and then coated with polymerized sorbitol acrylate, were incubated with heparinized whole blood for 10 minutes for each test series. Platelet adhesion was then measured by fluorescence microscopy using a fluorescently labeled CD61 antibody.

[0112] Platelet adhesion to Nitinol plate specimens coated in accordance with the present invention was found to be significantly lower compared to uncoated Nitinol plates.

Claims

1. A device having a stent structure (2) for insertion into a blood vessel of the human or animal body, the stent structure (2) has an expanded state in which it abuts against an inner wall of a blood vessel, and a contracted state in which it is movable through the blood vessel within a microcatheter; The stent structure (2) is connected to an insertion aid (3), the device is deployable for the treatment of vasospasm; The stent structure (2) is designed to be removable from the insertion aid (3), and at least a part of the stent structure (2) is provided with a coating, the coating comprising a functional layer, the functional layer being formed by oligomerization or polymerization of monosaccharides containing at least one sugar alcohol and / or functionalized with a polymerizable group. An apparatus comprising:

2. 2. The device according to claim 1, characterized in that the stent structure (2) is composed of wires which are connected to each other to form a strut or mesh structure.

3. 3. The device according to claim 1 or 2, characterized in that the stent structure (2) is self-expanding and transitions autonomously to the expanded state after being released from the microcatheter.

4. 3. The device according to claim 2, characterized in that the struts or wires have a height and width of 30 to 300 μm when of substantially rectangular cross section and a diameter of 30 to 300 μm when of circular cross section.

5. A device according to any one of claims 2 to 4, characterized in that in the middle of the stent structure (2) there are no struts or wires arranged at the proximal and / or distal ends.

6. 6. The device according to any one of claims 1 to 5, characterized in that the force exerted radially outward by the expanded stent structure (2) is in the range of 2 to 30 N / m, based on a diameter of the stent structure (2) of 2.00 mm.

7. 7. The device according to any one of claims 1 to 6, characterized in that the stent structure (2) has a proximal portion, a central portion and a distal portion, the proximal portion including a proximal end at which the stent structure (2) is connected to the insertion aid (3), and the expanded stent structure (2) exerts a substantially constant radial force along its entire length outside the proximal end.

8. A device having a stent structure (2) for insertion into a blood vessel of a human or animal body, comprising: the stent structure (2) has an expanded state in which it abuts against an inner wall of a blood vessel, and a contracted state in which it is movable through the blood vessel within a microcatheter; The stent structure (2) is connected to an insertion aid (3), the device is deployable for the treatment of vasospasm; The stent structure (2) is designed to be removable from the insertion aid (3), at least a part of the stent structure (2) is provided with a coating, the coating comprising a functional layer, the functional layer being formed by oligomerization or polymerization of monosaccharides containing at least one sugar alcohol and / or functionalized with a polymerizable group, the stent structure (2) is composed of wires that are connected to each other to form a strut or mesh structure, the stent structure (2) has a proximal portion, a central portion, and a distal portion, the proximal portion including a proximal end where the stent structure (2) is connected to the insertion aid (3), the expanded stent structure (2) exerts a substantially constant radial force along its entire length outside the proximal end; A device, wherein the struts or wires have a larger cross-section at the proximal and distal portions than at the central portion.

9. The device of claim 8 , wherein the density of the struts or wires is greater in the proximal and distal portions than in the central portion.

10. 10. The device according to claim 1, wherein the monosaccharides of the functional layer are functionalized in a form not bound to the device via at least one reactive multiple bond.

11. 11. The device according to claim 10, characterized in that the reactive multiple bond is a component of a methacryl group.

12. The device according to any one of the preceding claims, characterized in that the stent structure (2) comprises a gold coating underneath the functional layer.

13. The device according to any one of claims 1 to 12, characterized in that the coating comprises a carrier layer located on the stent structure (2) by means of an adhesion promoter, and the functional layer is bonded to the carrier layer.

14. 14. The device of claim 13, wherein the adhesion promoter is a silicon compound or a polyolefin.

15. The device of claim 14, wherein the silicon compound is a silane compound.

16. An apparatus as described in any one of claims 1 to 15, characterized in that the stent structure (2) is connected to the insertion aid (3) at the proximal end of the stent structure (2).

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