WO2002094332A1

WO2002094332A1 - Medical device

Info

Publication number: WO2002094332A1
Application number: PCT/DE2002/001856
Authority: WO
Inventors: Manfred GÜLCHER; Martina Nissl; Andreas Mucha
Original assignee: Qualimed Innovative Medizinprodukte Gmbh
Priority date: 2001-05-21
Filing date: 2002-05-21
Publication date: 2002-11-28
Also published as: KR100613951B1; DE10292142D2; DE20220589U1; KR20040011506A; EP1389135A1

Abstract

The invention relates to a medical device for positioning in the body, in particular in a vessel of a patient. Said device consists of a substrate (1), which is suitable for long-term positioning, whose biocompatible characteristics have been modified by bombarding its surface (2) with foreign ions (3). The foreign ions (3) are thus embedded in the substrate (1) and form a barrier layer (5) that impedes the diffusion of substrate ions (4) between the surface (2) and the interior (6) of the substrate (1).

Description

Medical device

The invention relates to a medical device for placement in a patient's body vessel according to the features in the preamble of patent claim 1.

More particularly, the invention is related to vascular or cardiovascular stents.

In industrialized countries, vascular diseases are a major cause of disability and death. In the United States, more than half of all causes of death are cardiovascular diseases. The most common form of vascular disease is arteriosclerosis, which causes inadequate blood supply to organs. Heart attack, stroke and kidney failure can result. Atherosclerosis can result from a vascular injury in which the vascular smooth muscle cells of an arterial wall of a hyper undergo proliferation, penetrate into the inner vascular mucosa and spread. This can result in the vessels becoming completely blocked in the event of local blood clotting. This can lead to the death of the tissue supplied by this artery. If this is a coronary artery, this constipation can result in heart attack and death.

Coronary artery blockage can be treated with coronary artery bypass and / or angioplasty. Both procedures may initially be promising, but are practically useless if restenosis occurs after such treatment. It is suspected that hyperproliferation of vascular smooth muscle cells also occurs with restenosis. In a third of the patients treated by angioplasty, restenosis and closure occur within six months after treatment, whereby it has been proven that the restenosis rate is significantly increased in some patient groups (diabetics, smokers).

While the result of restenosis is the same (loss of intraluminal space), it is believed that the mechanism is different in the case of percutaneous transluminal coronary angioplasty (PTCA) and stenting. A main cause of restenosis after PTCA is a stenotic occlusion due to elastic reshaping of the vessel wall, whereas a loss of lumen due to non-growth of the tissue cells in the intraluminal space (intimal hyperplasia) is less dominant. In the case of stented vessels, restenosis is dominant due to intimal hyperplasia.

After a balloon injury from angioplasty or stenting, the vessel is exposed - exposed from the endothelial layer. This leads to increased leukocyte proliferation, separated into neutrophils and mononucleocytes, in order to remove the cellular debris (scavenge). The activation of these cells leads to the release of various mediating factors (cytokines) which have been shown to induce smooth muscle cell proliferation. Lowering these factors stops proliferation. However, if the injury persists, there is no decrease, which leads to vascular hyperplasia and restenosis. The extent and type of inflammation therefore correlate directly with the extent and severity of restenosis due to cellular hyperplasia (smooth muscle cell proliferation).

Only neutrophils were detected in vessels in which only PTCA was used alone, but no macrophages. This is a clear indication that no foreign body reaction is involved.

Other studies have shown that PTCA does not induce chronic injury compared to stenting. However, numerous foreign body reactions occurred in stented vessels. High concentrations of macrophages and tissue granulation were found. This indicates that a foreign body reaction has occurred in addition to wound healing. The cause may be the stent material.

One study found a close correlation between in-stent restenosis and contact allergies to metals. Given these findings, the choice of material used for stents and its negative property of causing both a local inflammatory response and a systemic allergic response becomes very important. For example, stents coated with a biocompatible layer are much more likely to cause inflammatory reactions and hyperplasia than uncoated stents.

Most of the stent products currently used are made of stainless steel or nitinol. Extensive in-vivo and in-vitro studies have confirmed the good biocompatibility of these metal alloys. Conversely, inflammatory and allergic reactions associated with these metal implants have been adequately documented. Collected data on patients with a metal hip implant showed a direct correlation between an increased amount of chromium and nickel ions on the one hand, and a decrease on the other of white blood cells. The entire immune system has been weakened. Even 3 years after arthroplasty, patients found significantly higher concentrations of metal ions in both blood serum and urine.

Nitinol contains a high concentration of nickel. Stainless steel contains nickel, chrome and molybdenum. Acute toxicity and cytotoxicity of ions of these metals have been demonstrated. Several studies conducted to assess the effect of nitinol and stainless steel metal ion leakage confirmed the toxic effects of high ionic concentrations on various in vitro cell cultures, including fibroblasts, epithelial and smooth muscle cells. Studies show that while low concentrations of emerging Ni ions do not activate ICAM (Improved Chemical Agent Monitor / intercellular adhesion molecules) on the surface of endothelial cells, these values are sufficient to release IL-6 from monocytes cause, and this in turn indirectly leads to activation of ICAM. This fact is very important because activated endothelial cells are responsible for an increase in inflammatory blood cells. As a result, an increased amount of inflammatory cells remains in the stent area and enables further neointimal proliferation.

However, while all of these studies are done with different toxic concentrations for Ni ions and Cr ions, they all come to the same conclusion that the cause of these ions is a type of corrosion process that leads to leaching out of the alloy. Therefore, the question of long-term corrosion resistance of the stent material is an important point for the reduction of in-stent restenosis.

The corrosion resistance of metal implants is based on their passivation through a thin oxide layer. Several surface passivation techniques have been considered for stent use. The general final The conclusion of all these studies is that better surface passivation significantly affects / reduces the leakage of metal ions.

Another way to control the growth of the cells into the lumen of the vessel is to make the stent radioactive. Radioisotopes with high decay energy are used for this, so that the effect of the radiation is limited to the immediate vicinity of the stent. However, the problem is known that the restenosis can be almost completely suppressed within the radioactive stent, but there is still a strong proliferation of tissue at the ends of the stent. The negative behavior of the radioactive stents could be due to the radiation dose at the stent ends being too low due to the short range of the β radiation. This problem can only be solved by increased activity at the stent ends. Furthermore, a commonly used ball implantation catheter is approx. 2-3 mm longer on both ends than the stent, so that it is not lost when it is inserted into the stenosis. This can lead to injury to the artery wall at a relatively large distance from the stent.

Another approach to avoid restenosis is to introduce radioactivity before or after balloon distillation. It was shown that radiation of the vessel wall can significantly reduce cell growth after balloon distillation. The disadvantage of this is that a strong radioactive source has to be introduced into the patient's body in order to bring a correspondingly high radiation dose to the vessel wall in a short time. With this approach, the surgical team and patients are exposed to a higher radiation exposure than when using a radioactive stent with less activity.

Radioactive stents can be produced by the method of ion implantation, in which ions are shot into the material of the stent from a special ion source. The radioactivity is under the surface of the stent material. It is also known that stents passivate by applying layers. Certain metals, such as iron, chromium, nickel and possibly their alloys, react very slowly in the presence of a surface film that acts as a corrosion protection. Stainless steel, for example, is refined by the thin, protective chrome layer. The type of passive film depends primarily on the metal and the conditions under which the film is made.

In practice it has been shown that an implanted medical device, such as e.g. a stent placed in the patient's body, applied coatings, does not always have the desired adhesion to the substrate of the stent, so that the surface of the stent changes and metal alloys can be washed out with the substrate of the stent exposed, with those described above adverse consequences.

The application of passivating layers to stents is particularly problematic because the stents are subjected to considerable mechanical stress when placed in the body lumen. Due to the different material properties of the coating and the substrate, it cannot be ruled out that cracks will appear in the coating or that the coating might even flake off.

Proceeding from this, the object of the invention is to provide a medical device for placement in the body of a patient which improves the passivation of the surface of its substrate and thus has more favorable biocompatible / hemocompatible properties.

The invention solves this problem by providing a medical device with the features of claim 1.

The essence of the invention is that foreign ions are embedded in the substrate of the medical device, which ions are diffusion-resistant for substrates. forming boundary layer between the surface and the interior of the substrate.

Ion implantation is a vacuum process in which the charged elementary particles (ions) are shot with high energy at solid surfaces. The ions penetrate into the near-surface areas of the substrate in the form of metal ions, noble gas ions or as here in the form of reactive ions. In contrast to ion beam coating, the plasma ion implantation, no additional layer is "applied" to the substrate during ion implantation, but atomic building blocks are "introduced" under the substrate surface. One advantage is the excellent dimensional accuracy of the coated surfaces. In particular, there are no problems with adhesive strength, as are known from other coating processes.

Special advantages with which ion implantation differs from other thin-film technologies are also the maintenance of finish processing, the low process temperature and the variability of the substrate materials (metals, plastics, ceramics) and the type of foreign ions. Alloys can also be produced with high reproducibility outside of the thermodynamic equilibrium. The finish processing can, for example, be a smoothing of the surface by electrical or mechanical polishing.

Ion implantation is also an environmentally compatible process that is particularly harmless with regard to radiation problems, such as those that can occur with radioactive stents. Another advantage is the extremely low penetration depth of the introduced foreign ions into the substrate, so that the mechanical properties of the substrate remain largely unchanged.

In the claimed medical device, foreign ions with relatively high energy are shot under vacuum and penetrate into the entire surface of the substrate. This means that the foreign ions either replace the free places in the lattice structure of the substrate or displace other atoms from the near-surface places of the substrate and replace these places. There is no significant enrichment of the foreign ion concentration, since only vacant and vacant lattice sites are replaced by foreign ions.

Depending on the level of the energy dose, substrates, in particular nickel ions, are more or less pushed back towards the interior of the substrate. The diffusion-preventing boundary layer can therefore also be formed further away from the substrate surface inside the substrate. The diffusion-preventing boundary layer is therefore not necessarily located directly on or below the surface. A high energy dose is preferably selected so that substrates, in particular of the nickel element, are shifted into sufficiently deep layers.

By varying the implantation energy, it is also possible, in addition to the boundary layer formed in the interior of the substrate, to enrich the outer surface of the substrate with foreign ions such that the concentration of the foreign ions on the surface or in areas close to the surface is greater than 90%. The concentration can even be greater than 95%. The biocompatibility of the substrate is decisively improved by the choice of suitable foreign ions. The combination of a diffusion-preventing boundary layer in the deeper interior of the substrate with a biocompatible layer introduced directly below the surface is particularly advantageous.

Experiments with carbon ions as foreign ions, i.e. Carbonization of a substrate, in particular of a stent, has shown that heavy metals, in particular nickel, are preferably displaced and replaced by the body's own and thus very biocompatible carbon.

Depending on the substrate, the penetration depth of the carbon is between a few nanometers and up to approx. 20 micrometers, which is a very small penetration depth compared to the material thickness of a conventional stent that the substrate as a whole maintains its mechanical properties. The device according to the invention can therefore also have a substrate with very specific physical properties, such as nitinol.

Foreign ions can be ions of a single element such as carbon, oxygen, nitrogen or tantalum, the latter at the same time improving the X-ray visibility. Ions of the elements mentioned have the positive property of displacing metal ions, in particular heavy metal ions.

Advantageous refinements of the inventive concept result from the subclaims.

According to claim 2, the foreign ions can also be a mixture of ions of several elements, for example carbon and oxygen. The decisive factor here is that this mixture of foreign ions enables the composition of the diffusion-preventing boundary layer to be specifically influenced. If foreign ions of a first element were first introduced into the medical device by ion implantation and then foreign ions of a second element, this would have the consequence that the foreign ions of the second element displace the foreign ions of the first element into deeper layers, so that the desired properties of the medical device Device may not be reached. It is therefore crucial that ions of the desired elements are implanted simultaneously and not in succession.

Carbon ions or carbon, analogs and / or derivatives thereof have been shown to be particularly advantageous as foreign ions, as well as oxygen ions which, because of their ability to displace heavy metal ions, can be referred to as metal ion displacers in the sense of the invention. Depending on the substrate, foreign ions can be implanted to a depth of approximately 20 μm, but significantly smaller penetration depths can also suffice to form a sufficiently diffusion-preventing boundary layer between the surface and the interior of the substrate.

It is essential for the function of the boundary layer that the surface is impermeable to ions of metals with a density higher than 4.5 g / cm ³ (heavy metals), regardless of the position of the boundary layer. Metals with a density higher than 4.5 g / cm ³ (e.g. iron, zinc, copper, manganese, tin, chromium, cadmium, lead, mercury, nickel) can, as described in the beginning, be inflammatory and, if necessary, toxic to the body human organism.

While heavy metals can basically occur in various substrates of medical devices within the meaning of claim 6, this is particularly the case when the substrate is a metal. Suitable metals, especially for stents, are medical stainless steels, nitinol, but also cobalt alloys with a high nickel content.

As an additional measure to reduce the proliferation in the area of the device introduced into the patient's body, therapeutic agents can be used.

The cytostatic paclitaxel is known to be particularly effective in inhibiting some types of cancer and in effectively combating restenosis if necessary. Systematic administration of paclitaxel can cause undesirable side effects. This makes local application the preferred treatment. Local paclitaxel treatment can be more effective if administered over a long period of time. This period is preferably at least as long as the normal response time of the body after angioplasty. Trials have shown that topical administration of paclitaxel over a period of days or even months can most effectively prevent restenosis. Such a long period of time can be replaced by a timed release from the stent.

However, if a stent is in contact with the bloodstream for an extended period of time, this can cause thrombus formation, which can also narrow the inner vessel diameter. A substrate surface that releases a therapeutic agent such as paclitaxel can therefore prevent restenosis, but not prevent thrombus formation. It is therefore desirable to have a stent with restenosis-inhibiting properties that can remain in the body for a longer period of time without a thrombus forming at this point.

By impregnating a restenosis-inhibiting substance into a stent, in contrast to a coating applied to the stent, i.e. If it is placed under the surface, the problems of breakage, peeling and poor adhesion of the coating and thus loss of the substance that inhibits restenosis are avoided. At the same time, a binding agent can be provided on the substrate which inhibits the binding of anticoagulants, e.g. Heparin, to the binding agent and thus to the substrate. This combination of restenosis-inhibiting substances and anticoagulants assigned to the substrate via a binding agent makes it possible to effectively prevent both restenosis and thrombus formation. It is of course also possible within the scope of the invention to assign other therapeutic agents to the substrate via a binding agent, such as cytostatics such as paclitaxel, if this makes sense from a therapeutic point of view.

Advantageously, not only the therapeutic agent is releasably assigned to the binding agent. The binding agent can also be releasably assigned to the substrate. It is therefore possible within the scope of the invention that the bond detaches itself from the substrate either after the release of the therapeutic agent or simultaneously with the release of the therapeutic agent. After detachment of the binding agent, for example after a body reaction to a z. B. caused by stenting local injury, it is primarily important to avoid allergic reactions of the body to the substrate, especially restenosis. The device according to the invention fulfills this function solely through the implanted diffusion-preventing boundary layer. A binding agent, such as a polymeric coating, has fulfilled its intended task with the complete release of the therapeutic agent. The process of detaching or dissolving is not limited to a certain period of time, but can also be long-term.

A preferred area for using a medical device that is provided with a restenosis-inhibiting substance is stents for coronary arteries, made of a metallic material such as, for example, nitinol or stainless steel.

The difference between a coating process and an ion implantation is explained below on the basis of the schematic illustration in FIGS. 1a and 1b.

In the case of a coating (FIG. 1a), for example, C atoms are additionally supplied to the surface. The arrow P indicates the original surface. Since the substrate 1 and the coating B are two different materials with different physical properties, problems with the adhesiveness of the coating B can arise. This can mean that a carbonized stainless steel stent suffers damage during the balloon distillation in the transition area between the coating B and the substrate 1, whereby the coating B can crack or possibly even chip off. In contrast, foreign ions 3 (for example C ions) are implanted directly into a surface 2 of a substrate 1 (for example stainless steel) during the ion implantation (FIG. 1b). There can be no problem with the adhesiveness if the substrate 1 or the stent is carbonized by the previously described method of ion implantation. The method described above creates an inert surface 2 by firmly integrating the foreign ions 3, which prevents diffusion of substrates 4, in particular heavy metal ions. This provides protection against allergies and inflammatory reactions and helps to avoid restenosis.

FIG. 2 shows the relative concentration K of implanted foreign ions 3 (C ions) and the relative concentration of Fe ions and Ni ions as a function of the depth T. The depth T is measured starting from the surface 2 of the substrate 1.

It can be seen that the concentration K of the foreign ions 3 at a short distance from the surface 2 initially increases to a maximum and decreases in the further course. It is striking that the concentration of Ni ions in areas near the surface tends to zero. The concentration of Ni ions tends towards zero even at a distance from the surface, so that apart from a narrow overlap zone between C ions and Ni ions, a boundary layer 5 formed by the increased C ion concentration represents a diffusion barrier for Ni ions , Ni ions can penetrate into the boundary layer up to a certain limit value of the concentration of foreign ions 3, but cannot penetrate it, so that at least some of the substrates, namely the Ni ions, which are representative of all heavy metal ions, cannot be penetrated by the Diffuse green layer through to the surface 2 of the substrate 1. The process parameters for the ion implantation are chosen in each case in such a way that a diffusion of certain substrates is avoided. Sufficient enrichment of the interface with foreign ions and a certain minimum thickness of the interface are essential. Immediately on the surface 2 in this example there are only Fe ions and C ions in approximately the same distribution. The Fe-ion concentration then increases with increasing depth and, following the boundary layer, the concentration of the Ni-ions also increases to the concentration ratios prevailing in the interior 6 of the substrate 1.

REFERENCE NUMBERS

1 - substrate

2 - surface of 1

3 - foreign ions

4 - Substrations

5 - boundary layer

6 - Interior of 1

B coating

K - relative concentration

T - depth

Claims

claims

1. Medical device for placement in the body, in particular in a patient's body vessel, consisting of a substrate (1) suitable for long-term placement, the biocompatible properties of which have been changed by bombarding its surface (2) with foreign ions (3), characterized in that that the foreign ions (3) are embedded in the substrate (1) and form a boundary layer (5) which prevents diffusion for substrates (4) between the surface (2) and the interior (6) of the substrate (1).

2. Medical device according to claim 1, characterized in that the foreign ions are a mixture of ions of several elements.

3. Medical device according to claim 1 or 2, characterized in that the foreign ions (3) are at least partially carbon ions.

4. Medical device according to one of claims 1 to 3, d ad u rch characterized in that the foreign ions are at least partially oxygen ions.

5. Medical device according to one of claims 1 to 4, characterized in that foreign ions (3) are introduced to a depth of approximately 20 μm into the surface (2) of the substrate (1).

6. Medical device according to one of claims 1 to 5, characterized in that the surface (2) is impermeable to ions of metals with a density higher than 4.5 g / cm ³ (heavy metals).

7. Medical device according to one of claims 1 to 6, characterized in that the substrate (1) is a metal.

8. Medical device according to one of claims 1 to 7, characterized in that the surface (2) is polished.

9. Medical device according to one of claims 1 to 8, characterized in that on the surface (2) of the substrate (1) a binding agent is provided, to which a medical agent is releasably assigned.

10. Medical device according to claim 9, characterized in that the binding agent is releasably assigned to the substrate (1).

11. Medical device according to claim 9, characterized in that the medicinal active substance is an anticoagulant

12. Medical device according to claim 9, characterized in that the medicinal active substance is a cytostatic.