DE102010027124A1 - Medical implant and method of making such an implant - Google Patents

Abstract

The invention relates to a medical implant for intravascular use, comprising a body (10) made of a lattice structure that is compressible and expandable and has a biodegradable material made of a magnesium alloy. The invention is characterized in that the magnesium alloy is supersaturated with at least one alloy component, the magnesium alloy being obtainable by sputtering one or more targets, the material of which contains the components of the magnesium alloy, and depositing the target material converted into the gas phase on a substrate for formation a material structure such that the supersaturated alloy component is in solid solution.

Description

The invention relates to a medical implant and a method for producing such an implant. An implant with the features of the preamble of claim 1 is for example in the WO 2007/027251 A2 described.

It is known to make implants or endoprostheses from a resorbable material that dissolves at a material-specific rate so that the implant degrades after it has performed its function to prevent inflammatory reactions. For example, magnesium alloys are used which are both biocompatible and biodegradable. The disadvantage of these materials is that their absorption rate is relatively high, so there is a risk that the implant will dissolve too quickly before the treatment is completed.

To slow down the absorption rate, it is known from the publication mentioned above to coat the implant produced from a magnesium alloy with a biodegradable polymer. The absorption rate of the polymer coating is smaller than the absorption rate of the magnesium alloy of the main body, which reduces the overall absorption rate of the implant. Other examples of resorbable implants are in the DE 10 2005 018 356 A1 given, which also include polymeric coatings. To prepare such polymer-coated implants, spraying or dipping methods are used, in which a polymer is dissolved in a solvent and this solution is applied to the implant ( DE 10 2005 018 356 A1 ).

With the material combination metal / polymer there is the risk of detachment of the coating. If necessary, adhesion promoter layers must be used for this purpose. After degradation of the polymer occurs an uncontrolled absorption of the body or carrier, which can lead to the separation and detachment of stent areas. In addition, the polymer layers are susceptible to mechanical damage when crimped or discharged from a catheter. At the damaged areas, premature absorption of the body occurs. Certain polymer coatings can cause problems with the sterilization of the implant.

Conventional magnesium alloys for implants also have the disadvantage that hydrogen forms during the degradation of magnesium. This produces gas bubbles that cause tissue growth, d. H. in stents affect the growth of endothelium. Therefore, it may in the decomposition of the implants to side effects such. As come to hyperacidity, which hinder the healing and can lead to inflammation.

The invention has for its object to provide a medical implant that allows improved control and slowing down the rate of absorption. Moreover, the formation of hydrogen in the degradation of the implant should be avoided or at least reduced. The invention is also based on the object of specifying a method for producing such an implant.

With regard to the implant, the object is achieved by the subject matter of claim 1 and with regard to the method by the subject of claim 20.

The invention is based on the idea of addressing a medical implant for intravascular use comprising a body of lattice structure which is compressible and expansible and comprises a biodegradable magnesium alloy material. The magnesium alloy is supersaturated with at least one alloying component, wherein the magnesium alloy is obtainable by sputtering one or more targets whose material contains the components of the magnesium alloy and depositing the gaseous phase-transferred target material onto a substrate to form a material structure such that the supersaturated alloying component in solid solution is present.

The invention has the advantage that the properties of the implant, in particular the dissolution behavior, can be influenced in a targeted manner by the supersaturation of the magnesium alloy with at least one alloy component. For example. The supersaturation with the alloying component zinc can prevent or at least reduce the formation of hydrogen. However, achieving a supersaturation of the alloy by melt metallurgy has the problem that, as the melt cools, the alloying components concentrate at the grain boundaries, especially at the boundaries of the magnesium grains. As a result, the effect, in particular a homogeneous effect of the supersaturated alloy component is impaired. The degree of saturation of zinc is, for example, about 2.4 at.% In the case of a magnesium alloy produced by fusion metallurgy. The concentration of the supersaturated alloying component at the grain boundaries leads to a reduction of the mechanical stability by the occurrence of breakages. This accelerates the corrosion of the implant by creating preferential corrosion paths. In addition, the alloying component zinc is distributed inhomogeneously by the fusion metallurgical production, so that the formation Hydrogen is insufficiently prevented during degradation of the implant.

Although it is possible to produce a relatively high supersaturation of the magnesium alloy with zinc by very rapid cooling of the melt, whereby so-called metallic glasses are formed with an amorphous structure in which significantly more zinc is dissolved than in the conventional melt metallurgically produced material. However, it is not possible to produce medical implants for intravascular application, ie implants, such as stents, which have miniaturized structures. This procedure is unsuitable for small implants with small wall thicknesses.

In contrast, the invention has the advantage that on the one hand miniaturized implants, such as stents, from a supersaturated magnesium alloy, especially with zinc supersaturated magnesium alloy can be made at all. On the other hand, the invention has the advantage that the at least one alloying component, in particular the alloying component zinc in the supersaturated state, is homogeneously incorporated in the magnesium matrix, ie. H. essentially completely in solid solution. For this purpose, the invention provides that the magnesium alloy is obtainable by sputtering one or more targets, the material of which contains the components of the magnesium alloy and depositing the gaseous phase transferred target material on a substrate to form the lattice structure, such that the alloy component, in particular zinc in solid Solution exists.

In this case, the material may be in the amorphous or crystalline state. The supersaturation with an alloying component, in particular with zinc, can influence the structure formation and thus the corrosion behavior. The supersaturated state of the alloying component can lead to the formation of an amorphous structure rather than a crystalline structure. With an amorphous structure, corrosion is slowed down because corrosion does not proceed over preferred corrosion trenches. Forming hydrogen is better degraded by the body, because the process is slower.

Sputter-deposited magnesium tends to form crystals. When supersaturated with additives or alloying components, the sputtered magnesium can form an amorphous structure. An amorphous structure is advantageous for corrosion and has favorable mechanical properties, for example good elasticity. The invention therefore comprises amorphous structures.

It is also possible for crystalline lattice structures to be set in supersaturation with alloying elements, for example by a heat treatment. Also in this case, the dissolved alloying elements in the supersaturated state or the at least one alloying element in the supersaturated state can lead to a slowing down of the corrosion and / or to an improved homogeneity of the corrosion. The invention therefore comprises crystalline structures.

The crystalline lattice structure can form directly by sputtering. Alternatively, during sputtering, an amorphous lattice structure can be set, which can be converted by heat treatment into a crystalline lattice structure. In both cases, the mentioned advantages of supersaturation with additives or alloy components exist.

The at least one alloying component present in the supersaturated state may comprise zinc and / or calcium and / or elements from the group of rare earths. In particular, the at least one alloy component may comprise yttrium or neodymium or gadolinium.

The alloying component zinc can be present at a level of about 2.4 at.% To 35 at.%. Preferably, the magnesium alloy comprises zinc as a compulsory component with a content of 28 at% to 35 at%. In addition, as the optional component, calcium may be present at a level of from 1 at% to 5 at%, with the remainder being magnesium and unavoidable impurities. The content of the alloy components may change along the lattice structure such that different regions of the body have different dissolution rates, thereby affecting the dissolution behavior of the implant. For example, the rate of corrosion along the length of the stent or the implant length may change continuously, in particular gradually, or gradually, due to the changing composition. As a result, the implant or stent breaks down faster in one direction than in the other. The implant, in particular the stent, can degrade so that the ends corrode faster than the center of the implant. As a result, a stenosis in the central region, where the calcification is more developed, extended in time longer. In the case of an aneurysm, the central implant area, which decouples the aneurysm from the blood flow, advantageously remains longer in time. The edges or axial ends of the implant, which are already covered by endothelial tissue faster, are degraded faster. It is also possible that the corrosion rate changes in the circumferential direction. The implant can be positioned so that a lateral area, which is positioned in the region of an aneurysm, stops longer than the area arranged radially opposite, which supports the opposite side of the vessel. It is also possible the corrosion rate to influence so that an implant area at the height of a bifurcation or vessel branch dissolves faster than another implant area, so that the flow in the side vessel is ensured.

The advantage of the method according to the invention is that the alloy composition and the material properties, in particular the microstructural properties of the implant, can be very finely adjusted by the PVD method, that is to say by a method based on physical vapor deposition. Furthermore, the grain size of the crystalline material can be controlled well, so that a targeted grain refinement, in particular a targeted grain refining, can be set. With the method according to the invention, a high grain refining, d. H. small grain sizes are achieved, whereby the absorption rate of the implant is lowered. In addition, the production of the implant by means of a PVD method, in particular by means of sputtering, offers the possibility of changing the material properties in regions, so that the implant can be equipped with regionally different functions.

In a preferred embodiment, the body has at least two distinct first and second regions, wherein the crystalline material of the first region has a different grain size than the crystalline material of the second region. The advantage of the medical implant is that the properties of the implant can be selectively controlled as a function of the respective microstructure by setting different particle sizes in different regions of the implant. The setting of different grain sizes in different areas of the implant is particularly well by the use of PVD method, in particular by sputtering, feasible.

In this case, the at least one region of the implant forms a spatially extended material region which has substantially homogeneous physical properties, for example the dissolution properties of the material. The at least one other region of the implant forms another spatially extended material region which has substantially different homogeneous physical properties, in particular a different dissolution rate of the material. The different material areas are separated from each other in the sense that in one area a grain size and in the other area is a different grain size. They represent discrete regions, in contrast to a microstructure, in which different particle sizes, in particular different mean particle sizes, for example of different alloy components, are mixed in one and the same area. A material area forms a coherent massive fabric area. The fabric region forms, in particular macroscopically, the structure or a part of the structure of the implant, in particular of the implant body. The material areas in particular form part of the implant wall. Specifically, the material areas each form a separate part of the implant wall. The size, extent and shape of the respective region is not limited per se, but adapted such that a property set in the region, for example the dissolution rate, has an influence on the behavior of the implant. The size of the respective area required for this purpose depends on the wall thickness and / or the dimension of the implant or a structural element of the implant formed by the area and can thus be determined by the person skilled in the art, depending on the application and need. The delimitation of a region from another region, in particular from an adjacent other region, is effected in particular by the grain size, which differs in the different regions. Within a range, the material can be single-phase or multi-phase.

Preferred embodiments of the medical implant according to the invention are specified in the subclaims.

Thus, different areas of the body of the implant can form layers which are arranged on top of each other. The layers have different particle sizes; in concrete terms, the particle size present in one layer differs from the particle size present in another layer, so that different properties, for example different absorption rates, can be set in layers. In order to achieve greater layer thicknesses by the PVD method or sputtering, several layers are subsequently applied one above the other until the desired layer thickness has been reached. The individual material layers of a layer have the same grain size, so that the overall result is a greater layer thickness with a uniform (average) grain size. In this case, a plurality of such multi-layer sputtered layers can be combined with each other, wherein a different grain size is set per layer.

In this case, the layers may comprise at least one outer layer and one inner layer, wherein the grain size of the material of the outer layer is smaller than the grain size of the material of the inner layer. The outer layer of the implant comes in the body with the body fluid, in particular a vessel wall into contact. Due to the grain refining in the outer layer, the dissolution of the outer layer takes place relatively slowly. After the outer layer is completely dissolved, the Inner layer dissolved relatively quickly, since the grain size is greater than that of the outer layer.

It is also possible for two outer layers to be provided, of which one is arranged radially on the outside and one radially on the inside of the implant wall. The inner layer in this case forms a middle layer or a core layer, so that the overall result is a sandwich-like structure. The inner layer or middle layer is protected against bodily fluid on both sides by the outer layer, which is arranged radially inward and radially outward.

It is also possible to reverse the above-described dissolution behavior in that the grain size of the material of the at least one outer layer is greater than the grain size of the material of the inner layer.

This embodiment is suitable for influencing structural elements or web elements that initially exert a relatively high initial force on the vessel wall during implantation in such a way that the high initial force drops relatively quickly due to the rapidly degradable outer layer. After removal of the outer layer, a relatively thin, less rapidly absorbable layer remains, which, in contrast to the expansion function of the original stake element, essentially only assumes a supporting function.

In a preferred embodiment, the body comprises more than two layers arranged on top of each other, wherein the grain size of the material of the respective layer increases with increasing distance from the outer layer. This ensures that the absorption rate gradually increases with increasing dissolution of the implant. Again, it is possible to reverse this behavior by the grain size of the material of the respective layer decreases with increasing distance from the outer layer.

In the case of a sandwich-shaped implant wall or a sandwich-type implant, it is also possible to arrange the layers with the different grain sizes so that the layers on both sides of the middle or core layer have grain sizes which decrease or increase towards the core layer. Thus, the properties change layer by layer with increasing resolution.

The changes in the absorption rate with increasing dissolution of the implant, made possible by the above-explained embodiments, can be used as required and as a treatment objective and combined with one another by providing different regions of the implant with different absorption properties.

It can be provided that one or more medicaments are incorporated in at least one layer and / or in an intermediate layer. Thus, the invention or the embodiments mentioned above can be extended to drug-delivery implants.

In a further embodiment of the invention, the body has a plurality of structural elements, in particular lattice webs. The structural members may generally include stent members, such as the aforementioned grid bars, closed cells, connectors, end sheets, and the like, other functional elements. In this embodiment, at least one structural element comprises at least two different regions with different grain sizes and / or one structural element each consists of one region with one grain size and one further structural element each of a further region with a different grain size. In the latter case, this means that in this embodiment, whole structural elements differ in terms of their grain size, each structural element in itself having a substantially uniform grain size. Specifically, in each case there is an entire structural element, for example a grid web from the first region with a first grain size. Another structural element, for example a further grid web, forms a second area with a different grain size. The grain size of the first region or first structural element can be greater or smaller than the grain size of the second region or second structural element, depending on at which point of the implant a desired dissolution rate is to be set. It is also possible for a single structural element to have different regions with different particle sizes, so that different dissolution rates can be set within the same structural element. This makes it possible, for example, to cut through a structural element or a lattice web at a desired location in order to prevent the flow of force. In the region of the separation point, the grid web or the structural element has an area with a relatively large grain size, so that this area is degraded relatively quickly, whereas the remaining area of the structure element remains with a finer grain size.

In this case, first structural elements can be provided, which in the implanted state apply a greater supporting force than second structural elements, the material of the first structural elements having a smaller particle size than the material of the second structural elements. This means that the first structural elements mainly for the application of the supporting force, in the case of a stent for the Applying the radial force on the vessel wall, are responsible. The second structural elements have a retention function such that the second structural elements counteract an expansion of the diameter of the stent or another implant. The second structural elements therefore form bridges which limit an expansion movement of the implant, in particular of the stent.

With the adjustment of the grain size described above can be achieved that the second structural elements or bridges are resolved with larger grain sizes quickly. After dissolution of the retaining second structural elements, an increase in diameter occurs, so that the first structural elements can unfold their supporting force acting on the vessel wall. Overall, an implant can be realized that increases the radial force on the vessel wall with increasing duration of treatment. This can, for example, in so-called remodeling, d. H. be advantageous in the reconstruction of the vessel inner wall. Thereafter, the support force can be reduced by the first support elements are also degraded, but at a slower rate of dissolution than the second support elements.

It is also possible that the first and second structural elements both contribute to the application of the radial force or the expansion force acting on the vessel wall. In such an implant or stent, it is possible to reverse the dissolution rate such that the first structural elements with high support force are degraded faster than the second support elements. For this purpose, the first support elements on a larger grain size, as the second support elements.

In a further embodiment, the structural elements have layers with different grain sizes. This ensures that the dissolution behavior in the thickness direction, ie normal to the implant surface, changes.

The crystalline material may include corrosion trenches such that dissolution of the material in the implanted state occurs along the corrosion trenches, thereby enabling geometrically predetermined resolution of at least some areas of the implant or the complete implant.

The various regions may be web-shaped, with the grain size of at least one web-shaped region and the width of the web-shaped region in the ratio of 1:15 to 1: 100. This ensures that the grain size is in any case much smaller than the web width or generally the width of the regions or the structural elements.

As the biodegradable crystalline material or as the biodegradable crystalline materials, magnesium alloys and / or iron alloys may be used.

Preferably, the transition between the regions is discontinuous, wherein the grain size changes abruptly. Alternatively, the transition between the regions may be continuous, with the grain size continuously changing in a transition region between the two regions. Depending on the particular application, there may be advantages due to the discontinuous change in the particle size or due to the continuous changes in the particle size between the two regions. For example, the continuous change of the grain size in the transition region between the two regions having the different grain sizes has the advantage that the physical properties, in particular the dissolution speed, between the regions gradually change. By adjusting the size of the transition region, there is another possibility to control the resolution behavior, in particular to control time. The continuous transition (graded layers) also has a positive influence on the cohesion of the material. There is a particularly good adhesion between the layers when the material properties change continuously.

In a particularly preferred embodiment, the outer layer envelops the inner layer. The outer layer thus completely surrounds the inner layer or the inner region, that is to say also at the lateral edges of the inner layer or the inner region. The inner layer enveloped by the outer layer forms a core that is shielded from bodily fluid by the outer layer in use. This has the advantage that the dissolution behavior of the body or of the implant at the beginning of the dissolution of the structure of the outer layer and, after dissolution of the outer layer, only then from the structure of the inner layer or respectively of the corresponding grain size is determined. In contrast, in laminates where a laminate side is freely accessible, corrosion between the individual layers may be effective, with the result that the layers formed with the larger grains will corrode more rapidly than the layers with the finer grains. The corrosion of the laminated layers takes place at least in the edge region of the laminates, which are exposed to the body fluid, simultaneously.

The invention is explained in more detail below with reference to embodiments with further details with reference to the accompanying schematic drawings: In these show

1 the structure of a structural element, in particular a grid web according to the prior art;

1a the structure according to 1 in which intergranular corrosion occurs;

2 the structure of a structural element according to an embodiment of the invention;

3 the structure of a structural element according to a further embodiment of the invention;

3a the structure according to 3 in which intergranular corrosion occurs;

4 the structure of a structural element comprising two layers according to an embodiment of the invention; and

5 a view of a body of an implant according to an embodiment of the invention with different areas having different grain sizes.

In the embodiments of the implant according to the invention or the manufacturing method according to the invention described below, the body is 10 or the body 10 forming lattice structure made of a zinc-supersaturated magnesium alloy. The supersaturation with other alloy components is possible. The alloying component zinc is present in solid solution, ie the alloying component zinc does not form a separate phase in the lattice structure of the magnesium. The homogeneous distribution of the alloying component zinc in the magnesium matrix achieved in this way ensures that the formation of hydrogen during the degradation of the magnesium alloy is uniformly or substantially completely prevented. The formation of a magnesium / zinc mixed crystal is achieved by the production of the magnesium alloy or lattice structure by a PVD process in which one or more targets are atomized and the gaseous phase-transferred target material is deposited on a substrate to form the lattice structure. It is possible to coat an existing support structure with the supersaturated magnesium alloy. Alternatively, self-supporting lattice structures or a self-supporting lattice structure can be produced by the PVD method. In the self-supporting structure is dispensed with a support structure and the material of this structure completely applied by the PVD process. In this case, layers are deposited on a substrate until the desired wall thickness of the grid structure is reached. A method for producing self-supporting lattice structures for medical implants is, for example, in DE 10 2006 029 831 as in DE 10 2001 018 541 disclosed, both to the applicant. The content of both applications is incorporated by reference in its entirety.

Due to the supersaturation also amorphous structures can be adjusted.

It is possible to vary the zinc content or in general the content of the individual alloy components of the magnesium alloy in the wall thickness direction of the lattice structure or the individual webs of the lattice structure, in particular to vary it continuously. This is possible by the layered structure of the grid structure resulting from the PVD process. Thus, due to the changing composition of the material, the implant properties may gradually change across the thickness of the structure. The change can be continuous so that there are no discrete layer transitions. Rather, the composition of the layers changes gradually, resulting in an overall continuous change in the composition of the magnesium alloy over the lattice structure. As part of the manufacturing process, the gradual change in the composition is achieved by a continuous change in the sputtering parameters or, in general, the production parameters in the PVD process. This is not possible with conventional melting processes. Specifically, for example, the distance of the target of the structure to be produced can be continuously changed, in particular reduced or increased. This results in different compositions, even in targets with homogeneous target materials. It is also possible to change other process parameters, such as the voltage. Furthermore, a plurality of targets, in particular movable targets, can be used in the context of the method. It is possible to use the targets simultaneously or alternately. By continuously changing the sputtering parameters for both targets, the change in the target composition of the alloy can be achieved. By one or more of the method measures described above, the zinc content of the magnesium alloy of the lattice structure can be continuously increased, so that the corrosion rate in different material areas of the lattice structure is gradually reduced. The different material regions can change in the direction of the wall thickness, ie in the radial direction and / or along the lattice structure, ie in the axial direction. In this case, the maximum zinc content may be present in the region of the inner wall of the implant and / or the outer wall of the implant. It is also possible, the innermost and / or outermost layer of the lattice structure, ie the composition in the edge region of the wall as Form zinc oxide layer, in particular partially or completely form. Such a zinc oxide layer significantly slows down the corrosion of the material. The formation of the zinc oxide layer can be achieved for example by reaction sputtering with oxygen content.

It is possible to form the lattice structure by the PVD method so that the zinc content on the sides of the ridges of the lattice structure increases. The core of the webs thus consists of a material with lower zinc concentration and is surrounded by material with a higher zinc content, in particular completely enclosed.

The continuously varying compositions of the layered layers (graded layer) have the significant advantage over a discrete layer structure with a sudden change in the properties of the individual layers or the composition of the individual layers, that the layers adhere better to each other, when the properties of the layers continuously change, as provided in inventive method or its embodiments.

The magnesium alloy mentioned in the introduction to the description with a zinc content of 28 to 35 at.% And an optional calcium content of 1 to 5 at.%, Residual magnesium and unavoidable impurities have proved to be particularly advantageous. Other magnesium alloys, for example magnesium alloys alloyed with aluminum, titanium or other alloying elements, are possible. These alloys are disclosed in connection with a supersaturated zinc content.

The above-mentioned features are disclosed and claimed both in connection with the implant and in connection with the production method. Moreover, the above-mentioned features are disclosed and claimed in connection with the exemplary embodiments described in more detail in particular with regard to the setting of different regions of the grating structure with different grain sizes.

The method according to the invention or its embodiments offer an excellent alternative to the conventional techniques used for the production of biologically degradable implants, in particular stents. The PVD methods according to the invention, in particular the sputtering processes, allow the setting of very small particle sizes, whereby the absorption rate of the implant material is greatly reduced in comparison to known implant materials. Moreover, PVD methods or sputtering processes have the advantage that the material properties, in particular the grain size, can be varied in regions, so that the absorption rate in different implant areas can be adjusted differently, so that special properties of the implant can be enhanced, attenuated or readjusted. Thus, the resolution of the implant is well controlled. In particular, sputtering has the advantage that the distribution of the elements in the alloy can be finely adjusted. Precipitations are avoided in contrast to conventional melting technologies, since the magnesium or the iron can be supersaturated with alloying elements, whereby the dissolution rates can be varied in other limits. The second phases can be better distributed. Furthermore, it is possible to reduce the dissolution rate by the fine, targeted adjustment of the alloys.

Sputtering also has the advantage that larger amounts of additional elements or a variety of different additional elements that slow down the resolution, for example, can be introduced into the material, as is possible with conventional melting technologies. In the case of the latter, precipitation processes often occur which adversely affect the mechanical properties of the implant.

By sputtering any thin layers (multilayer interlayers) can be formed, which have different properties, especially with regard to the resolution of the implant. The production of bioabsorbierbarer implants by sputtering also has the advantage that the material properties along the implant, ie in the axial, radial and circumferential direction can be changed. Here are a variety of possibilities. For example, the direction of dissolution can be influenced from the inner diameter to the outer diameter, from the web edge to the web core, from the stent ends to the stent center or in each case inversely. For example, intermediate layers can be introduced, which reduce the dissolution rate, so that the faster dissolving core of the implant or of the individual structural elements only begins to dissolve when the intermediate layer has completely degraded. By sputtering corrosion trenches can be introduced, so that the resolution is initially directed along predefined paths. In this case, the sputtering process can be combined, for example, with a lithography process. It is also possible to integrate path-like areas in the implant wall with a relatively large grain size, so that these areas corrode before the surrounding material. It is also possible to subsequently introduce corrosion trenches by etching. The resolution can be controlled by the length of these paths. By Sputtering and subsequent structuring of the implant, for example by etching, web geometries can be determined with which the resolution is controllable.

It has been found that with grain sizes smaller than 200 microns, an effective reduction in the dissolution rate is achieved. It is possible to set grain sizes in the range of 2 μm by sputtering or other PVD methods. The setting of other grain sizes is possible by sputtering readily. For example, the upper limit for the corrosion-slowing grain size to 175 microns, 150 microns, 125 microns, 100 microns, 75 microns, 50 microns, 25 microns, 20 microns, 15 microns, 10 microns, 8 microns, 6 microns, 4 microns are adjusted. The lower limit depends on the process parameters and may be 2 μm or less, in particular at least 1.8 μm, in particular at least 1.6 μm, in particular at least 1.4 μm, in particular at least 1.2 μm, in particular at least 1 μm, in particular at least 0 , 8 μm, in particular at least 0.6 μm, in particular at least 0.4 μm, in particular at least 0.2 μm, in particular at least 0.1 μm. For the combination of different ranges with different particle sizes, all values mentioned above, including their intermediate values, come into consideration. For example, one area may have a grain size of 2 μm and another area may have a grain size of 20 μm. Other different regions with different grain sizes may be provided. For example, a third region may have a grain size of 100 μm. It is also possible that further additional regions have the grain sizes of 200 μm known and customary in the prior art, so that these regions have a particularly fast resolving power.

The method according to the invention is suitable for producing different medical implants which are at least partially biodegradable. Particularly preferred is the process for producing biodegradable stents. It is also possible to use the method of manufacturing filters which are removed after a predetermined time by dissolution. Such filters are used, for example, in the cerebral area to prevent blood particles from clogging cerebral vessels. A common reason for the formation of clots and subsequent particle detachment is the expansion of a stenosis in the carotid area or the implantation of a heart valve. In the first phase after appropriate treatment, the risk of blood clots is particularly high. At this stage a filter along with anti-clotting therapy is beneficial. After a few days / weeks / months, anti-coagulant agents may be discontinued if the risk of particle detachment decreases. In this case, it is advantageous to make the filter from a bioabsorbable material to prevent the filter from causing thrombus formation without anti-coagulation treatment. Such a filter can be produced particularly advantageously with the aid of the method according to the invention or an embodiment of the method.

In surgical brain surgery and in the following weeks, the risk of bleeding is high. To block or restrict blood flow in the affected vessels for that time, occlusion devices or devices that minimize blood flow or lead to other collateral vessels are used. After completion of the treatment, this device or the occlusion device is to be absorbed in order not to impair the physiological flow in the long term. Such occlusion devices or devices can advantageously be produced with an embodiment of the method according to the invention.

The method according to the invention is not restricted to the manufacture on the aforementioned medical implants, but may comprise further implants made of biodegradable materials.

It is also possible to combine the method according to the invention or the embodiments described above with other methods, for example with methods by means of which the surface of the implant or of the stent can be structured. In this case, for example, etching methods are used.

In one embodiment of the method, at least one biodegradable crystalline material is coated on a base body, in particular by sputtering. Suitable crystalline materials are metals and metal alloys which are biodegradable, for example magnesium or iron or magnesium alloys and / or iron alloys. It is also possible with the method to integrate different materials, in particular two, three or more than three materials, in regions in the implant. Thus, the method is also outstandingly suitable for connecting different materials in a materially bonded manner, so that an implant can be produced which is constructed in regions from different materials, in particular different biodegradable materials.

The grain size of the applied crystalline material is adjusted so that it is less than 200 microns. The base body, on which the crystalline material is sputtered, may be made at least partially of a biodegradable material. The main body can be replaced by other manufacturing processes be formed, for example by laser cutting of a solid material. The base body can have a different microstructure, in particular other particle sizes, than the bioabsorbable crystalline material applied by sputtering to the base body.

In a further embodiment of the method, it is provided that the crystalline material forms a self-supporting body of the implant, which is produced by sputtering. This means that the support structure of the body is made by sputtering. A main body, as in the previous embodiment, is not required for this purpose. Methods for producing such self-supporting implants, in particular self-supporting stents, are known per se.

Both methods have in common that at least part of the bioabsorbable implant material is applied by sputtering.

The product that can be produced by the method will be described below with reference to 1 to 5 explained in more detail.

In the 1 to 3 are fabric sections of implants shown, which are at least partially made of a biodegradable, crystalline material, in particular of a metallic material. In the figures, the grain boundaries 17 the grains 18 shown. As in 1 To recognize, the grain size of known implants is much larger than the grain size of the implants according to the 2 . 3 , the embodiments according to the invention.

The grain size is the mean grain size. This applies to the entire information in the application concerning the particle size. To determine the grain size, in particular the average grain size, various methods are available which are known to the person skilled in the art, for example the line cutting method in which the grains which are visible in a plane cut are cut from a measuring line and counted. From the length of the measurement line and the number of grains, the grain size can be determined in a conventional manner. The measurement of the cutting line can be done for example by laser interferometry.

Since it does not depend on the absolute average grain size in the determination of the different grain sizes of the different areas, but only on the relative difference between the mean grain sizes of the different areas, it is irrelevant with which method the respective grain size is determined. It is understood that the same procedure is used for both areas.

If the absolute mean grain size is to be determined, the line-cut method is used.

In the known implant materials, the grain size is 200 microns or more. In the implants according to the embodiments of the invention, the grain size is less than 200 microns.

The accompanying with the smaller grain size or the grain refinement advantage of the invention is based on the 1a and 3a illustrated. There it is shown that the dissolution of the implant material takes place by intercrystalline corrosion or grain boundary corrosion. Out 1a It can be seen that the grain boundary decay progresses rapidly for large grains having a grain size of 200 μm or more, whereas the intergranular corrosion in the fine grain structure according to US Pat 3a an implant material according to the invention takes place much slower due to the fine crosslinking. The dissolution rate in the known implant materials with a relatively large particle size is therefore higher than the dissolution rate in an implant according to an embodiment of the invention, in which the material has a smaller particle size. The smaller in comparison to the prior art grain size is in the implant according to 3a respectively. 2 achieved by applying the material by sputtering. Another advantage of the fine-grained structure is found in other mechanical properties, such as improved tensile strength and improved fatigue behavior. In a microstructure with a particularly small grain size, such as in 3 shown (about 2 microns), it is conceivable for the case that the implant forms a stent, the web width of the stent greatly reduce without the grains reach the size of the web dimensions, in particular the web width.

The ratio between the grain size and the ridge width or generally the ratio between the grain size and the width or thickness of the structural element can be adjusted in a range from 1:15 to 1: 100. If required, the range limits can be varied as follows: On the one hand, range limits can be set starting from the 1:15 limit, which is 1:20, 1:25, 1:30, 1:35, 1:40, 1:45, 1 : 50, 1:55, 1:60, 1:65, 1:70, 1:75, 1:80. The above range limits may be combined with the other limit of 1: 100, respectively.

The other range limit can be varied or varied as follows, starting from the ratio 1: 100: 1:95, 1:90, 1:85, 1:80, 1:75, 1:70, 1:65, 1: 60, 1:55, 1:50, 1:45, 1:40, 1:35. The The range limits mentioned above can each be combined or combined with the other range limit 1:15 and, if appropriate, with the restricted range limits emanating from the range limit 1:15.

Another special feature of the sputtered implant is in 4 shown. There it can be seen that the body 10 of the implant at least two different first and second areas 11 . 12 having. A region is generally understood to mean a spatial or layered section of the implant which has essentially homogeneous properties and thereby delimits itself from another second region. This is done as in 4 shown in the body 10 due to the different grain sizes of the grains 18 of the first and second areas 11 . 12 , The areas formed by sputtering 11 . 12 are cohesively connected.

The different areas 11 . 12 can, for example, layers 13 . 14 form, which are arranged on each other, as in 4 shown. The individual layers differ by different grain sizes and / or by different materials. It can, as in 4 illustrated, two layers may be provided, which are prepared by coating a base body or as a cantilever structure by sputtering or another PVD method. The layer thickness of the individual layer 13 . 14 is set in a conventional manner in that during sputtering a suitable number of layers of material is applied one above the other until the desired layer thickness is reached. In this case, a substantially uniform average grain size is set per material layer, so that the resulting layer is distinguished by the grain size from another layer, which is also produced by sputtering and applying a suitable number of material layers.

The different layers 13 . 14 form at least a part of the wall of the implant or the complete wall of the implant. In a stent, the webs are constructed of such layers, which have different rates of dissolution. The structure in layers is possible with the sputtering technique unlike conventionally produced pipes. For example, the stent can apply a very high force immediately after implantation to dilate a stenosis. After dissolution of the first layer after a controlled time remains a stent structure, which applies a much lower force due to the material degradation. The remaining structure fulfills the function of gentle support of the vessel wall or prevents detaching particles from entering the bloodstream. The implant, in particular the stent, may comprise at least one layer or a basic structure of a material which is not bioabsorbable, so that a weaker implant structure, ie with a smaller wall thickness, remains in the body compared to the implant prior to implantation, if so desired. Alternatively, the complete implant, in particular the complete stent, can consist entirely of bioabsorbable materials or consist of a completely bioabsorbable material, so that a complete dissolution of the stent is achieved after a predetermined time.

As in 4 Further, the layers can be an outer layer 13 and an inner layer 14 or a first layer and a second layer, wherein the grain size of the material of the outer layer 13 smaller than the grain size of the material of the inner layer 14 is. The outer layer is arranged so that it comes in the implanted state with the vessel wall or generally with body fluid directly in contact. It can be provided that the inner layer is coated on both sides with an outer layer, so that the inner layer does not come into direct contact with body fluid at least until the outer layers are dissolved. It can have more than one inner layer 14 be provided, which have different grain sizes. In the embodiment according to 4 has the outer layer 13 a fine-grained structure and thus forms a relatively slow dissolving structure. It is also possible to reverse the dissolution behavior such that a layer having a coarse-grained texture is disposed as the outer layer, so that the dissolution rate is initially relatively fast until the outer layer is dissolved, and then slowed down when the finer-grained inner layer after dissolution of the outer layer comes in contact with the body fluid. Again, it is possible to form the inner layer as a core layer with a fine-grained structure, which is coated on both sides with outer layers of a relatively coarse-grained microstructure. It can also be provided more than one inner layer.

In a layer structure with more than two layers, the grain size of the material of the respective layer may increase with increasing distance from the outer layer. This means that the outer layer is relatively fine-grained, the first layer arranged further inside has a structure with a slightly larger grain size than the outer layer, a second layer arranged on the first layer has a structure whose grain size is greater than the grain size of the first layer is u. s. w ..

This layer structure can be reversed such that the grain size of the material of the respective layer decreases with increasing distance from the outer layer.

In the first case, ie as the grain size increases, the dissolution rate increases as the resolution progresses. In the second case, with decreasing grain size, the dissolution rate slows down with increasing resolution.

Another embodiment is in 5 shown showing a stent with a grid structure. The stent has a body 10 on with several structural elements 15 . 16 , Which in the present case are designed as grid bars. Different structural elements form different regions with different particle sizes, which are characterized by different line thicknesses.

In a further embodiment, which is not shown in the figures, form the various areas 11 . 12 so-called graded layers, in which the grain size, in particular the mean grain size between the layers changes continuously. Between two juxtaposed or stacked layers with different grain sizes, a transition layer or a transition region is arranged, in which the mean grain size changes continuously. The continuously changing grain size of the transition region leads to a continuous transition of the two layers. As a result, the physical properties between the two layers change continuously. This particularly concerns the dissolution rate. The distance between the two regions or layers having the different particle sizes, ie the transition region, is designed such that at least one mean grain size is present in the transition region, which lies between the different average particle sizes of the two regions or layers which are connected by the transition region are. The larger the transition region is formed, ie the greater the distance between the two layers is formed with the different grain sizes, the more gradual, ie the more uniform, the change in the average grain size can be set in the transition region. The distance between the layers can be selected by the skilled person depending on the application. All features of the other embodiments disclosed in this application, in particular all grain size features, are also disclosed and claimed in the context of this embodiment.

Since the determination of the mean grain size does not depend on the determination of absolute values, but only the differences in the mean grain size are recorded, any measuring method can be used to determine the grain size, provided that the grain size is determined by a uniform method. Preferably, the per se known line-cutting method is used to determine the mean grain size.

The transition region with the continuously changing average grain size can be produced by a PVD method, in particular by sputtering, by continuously changing the process parameters of the sputtering method that determine the mean grain size.

Likewise, it is possible to provide the different regions or layers with the different grain sizes directly adjacent to each other without a transition region such that the average grain size between the two regions or layers is abrupt, ie. H. discontinuous changes. All features of the other embodiments disclosed in this application, in particular all grain size features, are also disclosed and claimed in the context of this embodiment.

Another preferred embodiment, which may be combined with the graded layers and / or with the abruptly merging layers, relates to an implant in which the outer layer 13 the inner layer 14 wrapped, especially completely wrapped. The layers may, for example, be realized in the form of lattice structures, in particular in the form of webs of a stent which have radially inward a first region of a first grain size and radially outward in the form of a cladding a second region of a second different grain size. The radially outwardly disposed second area completely encloses the first area. The outer and inner regions or layers have different grain sizes. Seen in cross-section, correspondingly embodied grid structures have a core area (first area) which is enveloped on the outside by a second area, the two areas having different grain sizes. It is also possible to arrange several outer layers around the core area, each having different grain sizes. All features of the other embodiments disclosed in this application, in particular all grain size features, are also disclosed and claimed in the context of this embodiment.

In particular, the embodiment with the fully enclosed inner region of the web or the lattice structure can also be advantageous in combination with graded layers, that is, with continuous material transitions.

The cladding of a core layer or a core region has the advantage, in contrast to laminated layers in which the sides of the layers are accessible, that a uniform Corrosion behavior and thus sets a controllable dissolution rate. For laminates that are open on one side (laminate), corrosion can take place between the layers.

The concept of the coated regions or layers having different particle sizes is generally applicable to latticed implants in which a part of the lattice structure or a part of the elements forming the lattice structure is designed as explained above. The elements may include lands, connectors, bridges or other elongated, curved or straight elements of the grid structure.

The production of the coated layers, for example, by the method for producing structured layers according to DE 10 2006 029 831 whose content is incorporated by reference in its entirety into this application. Here, instead of or in addition to the different materials areas are set with different grain sizes. Specifically, a first layer having a first grain size is applied, inter alia, to a substrate or to a composite of sacrificial layers. On the first layer, a second layer is applied with a different grain size, which is patterned for example by etching such that only the second layer is partially removed on both sides. As a result, the first lower layer projects laterally beyond the second upper layer on both sides. By applying a third layer having, for example, the same grain size as the first lower layer, the second layer with the one grain size can be completely enveloped by an outer layer with a different grain size, wherein the first and the third layer (= outer layer) laterally of connect the second (inner) layer in the free areas materially fluid. The corresponding method according to DE 10 2006 029 831 is in 12 to 17 shown.

Further, the method according to DE 10 2009 023 371 referenced by the applicant. The above application is also fully incorporated by reference into the present application.

The abovementioned processes are in each case PVD processes, in particular sputtering processes, which are particularly suitable for producing the different layers having the different particle sizes.

In connection with all exemplary embodiments or generally in connection with the invention, it is disclosed that at least two regions of crystalline material with different particle sizes, in particular at least two biodegradable regions of crystalline material with different particle sizes, are provided for setting different dissolution rates of the different regions. There may be 3, 4, 5 or more areas, each having different dissolution rates.

In the case of elongate elements of the implant body, such as in the case of the elements of a grid structure, for example the webs, the different areas in the radial direction of the elements, i. H. generally in the thickness direction, and / or longitudinally arranged.

The different regions with the different grain sizes may consist of the same material, in particular magnesium or a magnesium alloy. Suitable magnesium alloys are known to the person skilled in the art. It is also possible to use different materials for the different areas. Both alternatives are disclosed in connection with all embodiments and in connection with the invention in general.

All embodiments of the invention are generally disclosed in the context of vascular or cardiac implants. For example, the implant may comprise stents or stent-like implants, filters, in particular filters with a stent-like holding section, flow dividers, occluders, coils, or devices which minimize the blood flow or guide it to other collateral vessels, for example umbrellas. The body of the implant may have a lattice structure. The grid structure may comprise a laser-cut or a braided grid structure. In the latter case, wires form the body of the implant. The body of the implant can also form a functional element of the implant, for example a filter section. The grid structure or the body can form a wall of the implant. The implant wall can be curved and, in particular, can be adapted to come into contact with a vessel wall, at least in regions, when the implant is inserted into a vessel. The implant can also be a graft in which either the cover or the grid structure or both consist of the biodegradable material. It may also be that the cover and the grid structure have different grain sizes. However, it may also be that the different area both occur in the coverage area or in the grid structure. It is also possible to use the invention in orthopedic implants. The invention can be applied to the entire implant or to a part of the implant. For example. For a stent combined with a filter, it is possible to control the dissolution rate so that only the Filter, or generally only the functional element dissolves after completion of the application purpose.

LIST OF REFERENCE NUMBERS

10

body

11

first areas

12

second areas

13

outer layer

14

inner layer

15, 16

structural elements

17

grain boundaries

18

grains

QUOTES INCLUDE IN THE DESCRIPTION

This list of the documents listed by the applicant has been generated automatically and is included solely for the better information of the reader. The list is not part of the German patent or utility model application. The DPMA assumes no liability for any errors or omissions.

Cited patent literature

• WO 2007/027251 A2 [0001]
• DE 102005018356 A1 [0003, 0003]
• DE 102006029831 [0049, 0093, 0093]
• DE 102001018541 [0049]
• DE 102009023371 [0094]

Claims (25)

Medical implant for intravascular application comprising a body ( 10 of a lattice structure which is compressible and expandable and comprises a biodegradable material of a magnesium alloy, characterized in that the magnesium alloy is supersaturated with at least one alloying component, the magnesium alloy being obtainable by sputtering one or more targets whose material comprises the components of the Containing magnesium alloy, and depositing the gaseous phase-transferred target material on a substrate to form a material structure such that the supersaturated alloy component is in solid solution. Implant according to claim 1, characterized in that the alloying component comprises zinc with a content of 2.4 at.% To 35 at.%. Implant according to claim 1 or 2 characterized in that comprising the magnesium alloy Zn 28 at% to 35 at% optional Ca 1 to 5 at .-% Remaining Mg and unavoidable impurities. Implant according to at least one of claims 1 to 3, characterized in that the content of the alloying component along the lattice structure changes such that different areas of the body ( 10 ) have different dissolution rates. Implant according to at least one of claims 1 to 4, characterized in that the body ( 10 ) at least two different first and second regions ( 11 . 12 ), wherein the crystalline material of the first region ( 11 ) has a different grain size than the crystalline material of the second region ( 12 ). Implant according to claim 5, characterized in that the different regions ( 11 . 12 ) of the body layers ( 13 . 14 ), which are arranged on top of each other. Implant according to claim 6, characterized in that the layers ( 13 . 14 ) at least one outer layer ( 13 ) and an inner layer ( 14 ), wherein the grain size of the material of the outer layer is smaller than the grain size of the material of the inner layer. Implant according to claim 6, characterized in that the layers ( 13 . 14 ) comprise at least an outer layer and an inner layer, wherein the grain size of the material of the outer layer is greater than the grain size of the material of the inner layer. Implant according to at least one of claims 6 to 8, characterized in that the body ( 10 ) more than two layers ( 13 . 14 ), wherein the grain size of the material of the respective layer with increasing distance from the outer layer ( 13 ) increases. Implant according to at least one of claims 6 to 8, characterized in that the body ( 10 ) more than two layers ( 13 . 14 ), wherein the grain size of the material of the respective layer with increasing distance from the outer layer ( 13 ) decreases. Implant according to at least one of claims 6 to 10, characterized in that in at least one layer ( 13 . 14 ) and / or one or more drugs are stored in an intermediate layer. Implant according to at least one of claims 5 to 11, characterized in that the body ( 10 ) several structural elements ( 15 . 16 ), in particular grid webs, wherein at least one structural element ( 15 . 16 ) at least two different areas ( 11 . 12 ) comprising different particle sizes and / or in each case one structural element ( 13 ) from one area ( 11 ) with a grain size and in each case a further structural element ( 14 ) from another area ( 12 ) with a different particle size. Implant according to claim 12, characterized in that first structural elements are provided, which apply a larger supporting force in the implanted state than second structural elements, wherein the material of the first structural elements has a smaller grain size than the material of the second structural elements. Implant according to claim 12, characterized in that first structural elements are provided, which apply a greater supporting force in the implanted state than second structural elements, wherein the material of the first structural elements has a larger grain size than the material of the second structural elements. Implant according to at least one of claims 12 to 14, characterized in that the structural elements ( 15 . 16 ) Layers ( 13 . 14 ) having different grain sizes. Implant according to at least one of claims 5 to 15, characterized in that the crystalline material has corrosion trenches such, that a dissolution of the material in the implanted state takes place along the corrosion trenches. Implant according to at least one of claims 5 to 16, characterized in that the regions ( 11 . 12 ) are web-shaped, wherein the grain size of at least one web-shaped area ( 11 . 12 ) and the width of the web-shaped area ( 11 . 12 ) in the ratio 1:15 to 1: 100. Implant according to at least one of claims 5 to 17, characterized in that the transition between the regions ( 11 . 12 ) is discontinuous, the grain size between the regions ( 11 . 12 ) changes abruptly, or the transition between the areas ( 11 . 12 ) is formed continuously, wherein the grain size in a transition region between the areas ( 11 . 12 ) changes continuously. Implant according to at least one of claims 7 to 18, characterized in that the outer layer ( 13 ) the inner layer ( 14 ) wrapped. A method of making an intravascular medical device by physical vapor deposition of a biodegradable material, wherein a magnesium alloy is supersaturated with at least one alloying component, wherein the material is atomized and deposited on a substrate to form the device, such that the supersaturated alloy component is in solid solution is present. Process according to claim 20, characterized in that at least two different first and second crystalline regions ( 11 . 12 ), wherein the crystalline material of the first region ( 11 ) has a different grain size than the crystalline material of the second region ( 12 ). Method according to claim 20 or 21, characterized in that at least two layers ( 13 . 14 ) are formed, which have different grain sizes. Method according to at least one of claims 20 to 22, characterized in that a plurality of structural elements ( 15 . 16 ) of the body ( 10 ) are formed, in particular grid webs, such that at least one structural element ( 15 . 16 ) at least two different areas ( 11 . 12 ) comprising different particle sizes and / or in each case one structural element ( 13 ) from one area ( 11 ) with a grain size and in each case a further structural element ( 14 ) from another area ( 12 ) with a different particle size. Method according to claim 20 or 21, characterized in that the body ( 10 ) is structured after the application of the layers of the crystalline material such that web geometries are formed by which the dissolution of the body ( 10 ) is controllable. Method according to at least one of claims 20 to 24, characterized in that a base body coated with at least one biodegradable crystalline material or at least one biodegradable crystalline material layers to form a cantilevered body ( 10 ) is applied to a substrate.

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