DE19916086B4 - Implantable prosthesis, especially vascular prosthesis (stent) - Google Patents

Abstract

prosthesis to implant into a lumen of the human body to keep the lumen open, preferably vascular prosthesis to keep a blood vessel (stent) open, the stent being an elongated, has an essentially hollow cylindrical shape with a side wall, which is provided with a plurality of openings or openings and the Stent in the lumen from a first smaller diameter to one second larger diameter is expandable by lying on the wall of the lumen and supports them and keep the lumen open, the side wall of the stent (15) having a rough surface (P) has, characterized in that the surface of the Stents (10) with a hard, brittle, ceramic-like material (40) made of iridium oxide or titanium nitride with a layer thickness between 0.05 and 5 microns is coated.

Description

The Invention relates to a prosthesis for implantation in a Lumens of the human body, to keep this lumen open, preferably a vascular prosthesis for keeping a blood vessel open, according to the preamble of claim 1.

such Stents have an elongated, essentially hollow cylindrical shape with a side wall on the with a large number of openings or openings is provided so that the stent in the lumen from a first minor Diameter to a second larger diameter is expandable until it lies against the wall of the lumen and this supported, which keeps the lumen open. The stent is removed using a Catheter with the first small diameter transported into the lumen and then expanded to the second diameter there.

In particular for stents for Blood vessels can go through the damage the vessel wall at removal of deposits the risk of restenosis, d. H. a narrowing, cannot be ruled out because of the damage Muscle cells in the corresponding region of the vascular wall rapidly spread out so often within a period between three and six months after the Treat the vessel in turn is narrowed.

Around In the meantime, to avoid such restenosis, it is common to have one Stent in the blood vessel after the primary Placing extension of the deposit using a balloon. Several types of stents are used here.

at a kind of stent is placed on the dilatation balloon Balloon catheters crimped on and then passed into the endangered blood vessel where it is inflated by inflating the balloon until it hits the inside wall of the vessel. Then will the balloon again removed. The stent must have sufficient rigidity with sufficient elasticity at the same time, so that it on the one hand can follow the movements of the vessel wall, on the other hand, it supports them sufficiently.

Other Stents are made of spring steel and are made on a small Diameter compressed and taken up in a catheter. This stent is released in the blood vessel, so that it expands due to its spring properties and supports the vessel wall.

Finally are still stents made of so-called memory materials known, which are essentially deformable and only in due to the blood vessel the conditions prevailing there, in particular the temperature in expand their given structure in which they support the vessel wall.

The However, the presence of the stent in the bloodstream can in turn prevent thrombus formation and favor other deposits; this can also lead to a slow slow narrowing of the blood vessel. The Thrombus formation, fibrosis and also restenosis of the treated Blood vessel can be significantly reduced if correspondingly acting drugs nearby of the stent are applied, e.g. B. by the stent with a biodegradable Layer is provided, in which the drugs are incorporated, so that they are slowly released when the coating degrades.

A Restenosis can also be caused by direct contact between the outer wall of the stent can be triggered on the inner wall of the vessel, causing this irritation of the tissue to fibrosis of the vascular wall and finally to leads to restenosis of the vessel. This Risk can be caused by the above Coating of the stent can be reduced, in which drugs are incorporated.

to Prevention, or at least to reduce the formation of restenosis attempts have been made to radioactively treat the treated blood vessel, by z. B. the stent itself has radioactive properties.

It is the object of the invention, the stent and in particular its surface modify that an irritation of the vessel and thus a traumatic Reaction with appropriate proliferation of tissue cells and generation is prevented by thrombi; the surface of the stent should also be designed so that an additional biodegradable coating is applied effectively z. B. delivers antifibrotic and antithrombotic drugs; this is to prevent the implantation Stop tissue irritation or restenosis of the stent.

This Object is according to the invention solved the features of claim 1.

So far, all stents in clinical use have a polished and smooth surface and a smooth surface has also been regarded as the cheapest property of a bioimplant worldwide, the surprisingly simple solution according to the invention is that the side wall of the stent or the elements of the side wall are one have a rough surface. For this purpose, the surface of the stent is made with a hard, brittle and ceramic-like material made of iridium oxide or titanium trid coated with a layer density between 0.05 and 5 micrometers.

It was found by the inventors that such a rough surface Catalytic effect is achieved, which is the oxidative counter reaction, which is mediated by the leukocytes in the inflammatory reaction, breaks down and thus the inflammatory reaction prevented. The rough surface also has the advantage that the tissue cells adhere better here. Likewise, the rough surface effectively a thin one Coating applied, incorporated into the drug are, which then successively in the biodegradation of the thin coating be released.

Additionally allowed the rough surface the stent adheres very well to the balloon of a Balloon catheter with which it is inserted into the lumen. Compared to conventional stents the stent's adhesion to the balloon is significantly improved.

The Thought the surface designing the stent roughly runs contrary to the previous development in such stents. So far care was always taken to make the surface as smooth as possible, in particular in order to advance the stent through a body artery only slight friction and sliding resistance on the wall of the artery to have. Contrary to all fears it has been shown that a rough surface of a stent according to the invention the friction on the vessel wall is practical not deteriorated; it was found to be itself blood components when the stent is advanced through the arteries in the rough surface attach, which makes the surface quasi smoothed becomes.

In animal experiments, restenosis according to the invention was only discovered in about 4% of the cases, while about twice the value for conventional steel stents and an even higher value for stents with a gold coating. Obviously, the rough surface of the stent enables faster colonization with endothelial cells and smooth muscle cells. This was demonstrated in a shake model with cell cultures. Furthermore, the low value for restenoses is attributable to the catalyst action inherent in the rough stent surface, in particular if the rough surface of the stent is formed by an outer coating with the aforementioned iridium oxide or titanium nitrate. This catalyst effect can come about by decomposing H ₂ O ₂ , which is released by leukocytes when the counter-reaction is triggered, into water and oxygen. Since H ₂ O _{2 is} the most powerful stimulator of NFKB, an important signal transmitter for proliferation and restenosis development, the signaling cascade for the initiation of restenosis is interrupted at the beginning by the catalytic agent.

• – einen zentralen Bereich mit einer ersten Schichtdicke, der im wesentlichen die Grundform des Stents und dessen mechanische Eigenschaften festlegt und z. B. aus medizinischem 316L-Edelstahl gefertigt ist;
• – einen Zwischenbereich mit einer zweiten geringeren Schichtdicke, der die Grundstruktur bzw. die Elemente des Stents des zentralen Bereiches vollständig umgibt und aus einem Material besteht, das auch bei dem Aufweiten des Stents den zentralen Bereich weiterhin lückenlos umhüllt; dieser Zwischenbereich kann z. B. aus einem Edelmetall, wie z. B. Gold oder Platin bestehen oder aus einer Legierung aus Platin und Iridium; und
• – einen Außenbereich mit einer noch geringeren Schichtdicke, der auf den Zwischenbereich aufgebracht ist und der die raube Oberfläche des Stents bildet; das bevorzugte Material ist, wie erwähnt, Iridiumoxid oder Titannitrid.

According to a preferred embodiment of the invention, the side wall of the stent has three essentially concentric layer-like regions in cross section, namely

• - A central area with a first layer thickness, which essentially defines the basic shape of the stent and its mechanical properties and z. B. is made of medical grade 316L stainless steel;
• - An intermediate area with a second, smaller layer thickness, which completely surrounds the basic structure or the elements of the stent of the central area and consists of a material that continues to completely cover the central area even when the stent is expanded; this intermediate area can e.g. B. from a precious metal, such as. B. gold or platinum or an alloy of platinum and iridium; and
• An outer region with an even smaller layer thickness, which is applied to the intermediate region and which forms the rough surface of the stent; the preferred material, as mentioned, is iridium oxide or titanium nitride.

The Thickness of the side wall of the stent in the central area, i.e. usually a basic body made of 316L stainless steel, is usually between 50 and 130 microns, the thickness of the intermediate area between 4 and 15 microns and the thickness of the outside area between 0.05 micrometers and one micrometer and is preferred in the range of 0.5 microns.

The A homogeneous coating with e.g. B. one essentially smooth surface , but can also be carried out with surveys and which follow one another at regular intervals Indentations; who have elevations and recesses then preferably a size in the range between 20 and 500 nanometers. The intermediate area becomes this preferably from a particle material with particle sizes between 50 and 500 nanometers formed; this particle material can be in conventional Way, e.g. B by powder metallurgy, on the light roughened surface of the central body be applied. This consists of essentially spherical particles built-up intermediate area is ductile enough to expand the basic body of the stent or its elements completely to surround.

The material of the outer region of a stent according to the invention can either only actually be applied to the outer surface of the stent, ie to the side with which the stent on the inner wall of the vessel or

lumen is applied. However, an overall coating of all is preferred here Elements of the stent are made.

According to one preferred embodiment of the Invention, the central area of the stent is, as mentioned, from Made of 316L steel, the intermediate area made of gold and the outer area made of iridium oxide. An advantage of such a structure is that the iridium oxide layer the same potential as in the electrochemical series Gold, namely + 180 millivolts, whereas steel is 160 millivolts. Would the central area immediately hermetically coated with iridium oxide, because the iridium oxide is relatively brittle is and allows little plastic configuration changes in which Expansion of the stent shows hairline cracks in the range of 10 nanometers arise, although clinically, hemodynamically and mechanically have no relevance, a safe electrical No separation of the central stainless steel area from the environment guarantee would because of the different electostatic voltage values of steel and Iridium would become a battery source. First due to the ductile coating of the central area with gold or another noble metal or an alloy, this hermetic seal can be achieved become.

On Another reason is that the intermediate area is made of a precious metal or a precious metal alloy in the x-ray image during implantation of the stent, in contrast to steel, is very visible because of gold an approximately six times higher radiopacity as steel and thus has a thickness of the intermediate area of z. B. 10 micrometers is equally visible as steel with a thickness of about 60 microns. By combining both materials is thus the x-ray density corresponding to 120 microns of steel sufficient to perform the operation to be able to follow the placement of the stent very well.

The coating with iridium oxide also has the advantage that iridium, for example, by neutron bombardment. B. can be converted into a radioactive isotope in a reactor, namely ¹⁹² Ir. The isotope has a half-life of 74 days and emits both β and γ radiation, which, as already mentioned above, can prevent the formation of restenosis.

Of Furthermore, iridium is a precious metal with an atomic weight of 77 and thus bears when observing the implantation on an x-ray screen also for better Visibility of the stent at.

After all still noted that the presented features of the invention independently of the construction of the stent are: they can be applied to both stents that are expandable by a balloon catheter, as well for stents constructed from spring steel and after approval automatic expand, and finally, too for stents from memory materials like Nitinol etc.

The Invention is based on exemplary embodiments closer to the drawing explained. In this represent:

1 a perspective view of a stent mounted on a balloon catheter with a rough surface according to the invention, which is formed by a mesh of webs and openings;

2 a schematic cross section through a web of the stent in 1 ;

3 a schematic representation of a preferred three-layer structure of the stent; and

4 a detailed view of the layer structure of the stent according 3 ,

In 1 is a stent 10 shown conventional configuration, which consists of a metallic mesh 12 from jetties 15 and through the walkways 15 separate openings 16 consists.

The stent 10 is, as explained below, with a coating 25 provided that has a rough surface made of iridium oxide, and then on the balloon 20 a dilatation catheter 23 assembled. The balloon can then in a known manner in the corresponding lumen of the human body, for. B. inserted into a coronary artery and by inflating the balloon 20 be stretched so that it supports the wall of the vessel.

The coating 25 encloses, as schematically in 2 represented by the webs 15 Formed primary structure of the stent completely, so that no part of the metallic area 12 exposed.

On this coating 25 can still have a varnish-like layer 26 applied, in which medications are incorporated. The coating 25 contains the iridium isotope ¹⁹² Ir, the one indicated here and with 42 emits designated radioactive radiation.

In 4 the structure of the stent in the area of the side wall is shown in more detail. The metallic body 12 with the webs 15 is a with 30 designated central area on which the coating 25 is applied. The coating itself has an intermediate area 32 made of gold on which there is an outdoor area 40 made of iridium oxide. The gold area seals the central metallic area 30 hermetic, thus enveloping the webs 15 completely, as in 2 shown.

The intermediate area 32 on the slightly roughened surface of the metal central area 30 applied. For this purpose, the webs can be provided on all sides with a homogeneous gold coating, which has an essentially smooth surface, whereby this intermediate area can also be built up by depositing several thin gold layers.

The structure of the intermediate area ( 32 ) is, however, as in 4 shown from a variety of microspherical particles, ie microspheres 33 , possible, the diameter of which is approximately between 50 and 500 nanometers; the entire layer thickness of the intermediate area is approximately between 4 and 8 micrometers.

The Microspheres of the intermediate area can also be made of platinum, one Platinum-iridium alloy with a proportion between about 2% by weight up to about 10% by weight iridium or another noble metal alloy consist.

The microspheres are on the central area 30 z. B. applied by a technique that is well known from powder metallurgy. With this method, the surface of this intermediate area can be achieved 32 corrugated, ie to be designed with adjoining elevations and depressions, the profile P, ie the radial distance between elevations and depressions, being in the range of the particle size, ie approximately between 20 and 500 nanometers. To that extent 4 only very schematic.

On this corrugated surface of the intermediate area 32 becomes an iridium oxide layer 40 applied, which forms the outer region of the stent with the desired rough surface. This layer is also preferably applied to both the actual outside and the inside of the wall of the stent; see. 2 , This area does not have to completely cover the intermediate area; it is quite possible and sometimes also desirable to leave gaps here, like this one in 4 is indicated. This iridium oxide layer can also be built up by depositing several thin layers.

Through the manufacturing process of the intermediate area 32 touch the microspheres 33 at some points 35 , whereas in other places spaces 37 remain.

The diameter of the microspheres preferably increases 35 in the radial direction towards the outside, so that initially relatively large microspheres are applied to the metal basic structure of the stent and then these spheres are made ever smaller. In this way, this intermediate area succeeds 32 To be designed so that no metallic part of the central area 30 is exposed, and that towards the outer edge this intermediate area is still relatively porous, so that into these pores, ie the spaces 37 Medicines can be inserted into a biodegradable material like this through 43 is indicated. These drugs are then gradually released after the stent is implanted. Antiinfective, antithrombogenic and antiproliferative agents are used as medicinal products. B. dexamethasone or taxol, hirudin or iloprost, etc.

It is also possible in these spaces 37 or on the coating 25 Fabrics, e.g. B. a viral vector, which are suitable for gene transfer, in order to thereby influence cells of the treated tissue in such a way that proliferation or proliferation, in particular soft muscle cells, is prevented, which in turn could lead to restenosis. Such a gene transfer can e.g. B. are formed by viruses such as the adenovirus and herpes virus or their sub-areas. Through the viral transfer, which takes place via absorption and diffusion, part of the genetic information of interest is transferred to the target cell. In this way, the proliferation of cells and thus also the restenosis can be prevented. Growth factors can also be used as inhibitors for restenosis, thrombosis formation or a mechanical stress reaction.

The surface of the finished stent has a sufficient roughness, so that the above-mentioned biodegradable coating is also used here 26 can be applied with incorporated drugs or gene transfer substances, while at the same time the accumulation of cells is promoted by the rough surface.

Claims (15)

A prosthesis for implantation in a lumen of the human body to keep the lumen open, preferably a vascular prosthesis for keeping a blood vessel open (stent), the stent having an elongated, essentially hollow cylindrical shape with a side wall which has a multiplicity of openings or openings and the stent in the lumen can be expanded from a first smaller diameter to a second larger diameter by lying against the wall of the lumen and supporting it and keeping the lumen open, the side wall of the stent ( 15 ) a has a rough surface (P), characterized in that the surface of the stent ( 10 ) with a hard, brittle, ceramic-like material ( 40 ) is coated from iridium oxide or titanium nitride with a layer thickness between 0.05 and 5 micrometers. Stent according to claim 1, characterized in that both the inner and the outer surface of the stent ( 10 ) is coated with the ceramic-like material Stent according to one of the preceding claims, characterized characterized that when using iridium oxide as a coating with a rough surface at least part of the iridium is present as a radioactive isotope. Stent according to one of the preceding claims, characterized in that the side wall of the stent ( 10 ) in cross section ( 3 ) essentially three concentric layer-like areas ( 30 . 32 . 40 ), namely - a central area ( 30 ) with a first layer thickness, which essentially corresponds to the basic shape of the stent ( 12 ) and its mechanical properties; - an intermediate area ( 32 ) with a second smaller layer thickness, which the basic structure ( 15 ) of the central area ( 30 ) completely surrounds and consists of a material that is also used when the stent is expanded ( 10 ) envelops the basic structure of the central area; and - an outdoor area ( 40 ) with a third, even smaller layer thickness, which extends to the intermediate area ( 30 ) is applied and which the rough surface of the stent ( 10 ) forms. Stent according to claim 4, characterized in that the surface of the central region ( 30 ) is roughened to ensure better adhesion of the intermediate area ( 32 ) to obtain. Stent according to one of claims 4 and 5, characterized in that the intermediate region ( 32 ) and / or the outside area ( 40 ) each have several thin layers. Stent according to one of claims 4 to 6, characterized in that the surface of the intermediate region ( 32 ) is provided with elevations and depressions which are essentially adjacent to one another and to which the material of the outer region is applied. Stent according to claim 7, characterized in that the radial distance (P) between the elevations and depressions is between 20 nanometers and 500 nanometers. Stent according to one of claims 4 to 8, characterized in that the intermediate region ( 32 ) is formed from a particle material, in particular microspheres with particle sizes between 50 and 500 nanometers. Stent according to one of claims 4 to 9, characterized in that the intermediate region ( 32 ) consists of a precious metal or a precious metal alloy. Stent according to claim 10, characterized in that the intermediate region ( 32 ) consists of a material from the group of gold and platinum as well as gold iridium and platinum iridium. Stent according to claim 4, characterized in that the thickness of the central region ( 30 ) between 50 and 130 micrometers, the layer thickness of the intermediate area ( 32 ) between 4 and 15 micrometers and the layer thickness of the outer area ( 40 ) is between 0.05 and 5 micrometers. Stent according to one of the preceding claims, characterized in that in the surface of the stent ( 10 ) Pharmaceuticals ( 32 ) are incorporated. Stent according to one of the preceding claims, characterized characterized in that in the stent substances, in particular viral vectors, added are that for a transfer of genetic information to certain cells of the Tissue or the inner wall of the lumen supported by the stent are suitable to prevent tissue proliferation. Stent according to claim 14, characterized in that for gene transfer suitable substances in a biodegradable material are embedded.