MX2008005406A - A method for production of a coated endovascular device - Google Patents

Abstract

A method of coating a endovascular device that includes coating of a tubular body's surface by at least a thin layer (s) of a inert and biocompatible titanium based material. This method is performed by the following steps in succession:Deposition of a first Titanium layer (21). First nitrogen treatment of said first titanium layer (21) by transmission of high ionic currents on the substrate (Closed Field UnBalanced Magnetron Sputter Ion Plating) to obtain the transformation of at least a part of said first titanium layer (21) in a first layer of titanium nitride ceramic coating (210). Deposition on this said first layer of titanium nitride ceramic coating (210) of a second titanium layer (22). Second nitrogen treatment of said second titanium layer (22) by transmission of high ionic currents on the substrate (Closed Field UnBalanced Magnetron Sputter Ion Plating) to obtain the transformation of at least a part of said second titanium layer (22) in a second layer of titanium nitride ceramic coating (220).

Description

METHOD FOR THE PRODUCTION OF A ENDOVASCULAR DEVICE COVERED Field of the Invention The present invention relates to a method for the production of an endovascular device coated with the features in claim 1. A stent coated with the features in claim 13 is also a subject of this invention. to the cardiological medical field and more specifically refers to the realization of a medical-surgical device for the treatment and prevention of the ischemic heart condition. Background of the Invention Ischemic heart disease is the most common heart disease in western countries and is the leading cause of death. In the last decades several devices have been studied to try to fight against these diseases and the results obtained show that the stent implantation procedure is one of the most effective solutions. It is a simple technique that avoids the need to perform a more difficult surgery such as surgical revascularization. As is known, the stent is a substantially cylindrical prosthetic device with an expandable open structure, usually made of steel suitable for medical use, which is implanted at the site of the arterial lesion (stenosis or occlusion). The open structure is expanded to its desired dimension, according to the arterial diameter, by the well-known technique of the expansion balloon that requires the introduction of the balloon, in which the stent is folded, into the vessel and its subsequent inflation. The balloon, during its expansion, increases the diameter of the stent to the desired dimension, then it is deflated and withdrawn. The stent remains in the position where it is inserted due to the retraction of the tissues of the blood vessel. Applicants have noted that in the well-known art the stents have several problems and that it is possible to improve them with reference to several aspects. The most important problem of coronary angioplasty is intra-stent restenosis. This depends on several factors; the most important of these is the intimate hyperplasia, which manifests itself by the activation of the vasa vasorum of the tunica media of the soft muscle cells due to the damage caused during the implantation of the stent. To avoid this problem, generally, inhibitory drugs for the growth of cells and tissue are used and these are attached to the surface of the stent. The most commonly used technique is to coat the surface of the stent with a polymer whose role is to preserve the drug and slowly release it in time after stent implantation. The drug can be distributed on the polymer or it can be introduced between two polymeric layers, or it can be incorporated in the polymeric layer. However, in these cases, the drug is not released gradually and constantly from the surface of the stent, and this can reduce its effect. In particular, in the case of a metal stent without a polymer coating, a secondary cause of cell proliferation caused by the physico-chemical interaction between the vessel wall and the stent material (which includes nickel among its alloy components) has been noted. . In fact, it has been shown that in the well-known technique stainless steel stents in contact with organic liquids are subject to the corrosive phenomenon that produces the release of nickel, chromium and other substances that could cause an allergic reaction within the body. On the other hand, problems of blood biocompatibility increase the risk of thrombosis during the first days after implantation. For this reason the variations of the stents well known in the art have been developed, having a coating on their surface that will be in contact with the blood and which is made with analytical materials such as uranium, silicon carbide, carbon and depleted polymers. Metal stents with anallergic coatingHowever, they have other problems. In fact, the use of coating with materials that emit ionization radiation, such as depleted uranium, could produce a significant incidence of late thrombosis. The use of carbon as a coating material is not appropriate due to its detachment that occurs when the material is subjected to high mechanical stress due to its expansion during stent implantation. The recurrent use of silicon carbide, then, has proved not to be the most indicated due to its cytotoxicity in high concentrations. In the end, polymer coatings do not currently allow to obtain films of thickness less than 5 μm. Another problem of the well-known technique is that the methods currently used to produce stents does not make it possible to obtain a perfectly smooth stent surface, necessary to avoid blood flow turbulence that can worsen damage to the vessel wall and the incidence of restenosis. In the name of the same applicant a patent application was filed with the number MO2003A000238 to give a first solution to the above problems, and it refers to a stent with a titanium nitride layer, capable of not releasing allergic substances and of not interacting negatively with the body, thus guaranteeing corrosive resistance, chemical stability and high biocompatibility. Description of the Invention The purpose of the present invention is to improve the results of the previous invention, object of the patent application for industrial invention MO2003A000238, for the purpose of producing an endovascular device coated with a thinner coating layer, which does not modify the mechanical characteristics and functionality of the same stent. Another purpose of this invention is the realization of an endovascular device with a sufficiently smooth surface that avoids the turbulence of the blood flow and reduces the activation of platelets, in this way, avoiding or considerably reducing the risk of thrombosis. The endovascular device object of this invention, on the other hand, can be loaded with a drug and released at the planned times. These purposes and others, which will become clear with the following description, are achieved by an endovascular device with the features reported in claim 1. By the term endovascular device in the present invention it is preferably, but not limited to, one of The following types of devices: -a graft for the abdominal and thoracic aorta and / or the iliac arteries. - a coronary stent. -a peripheral stent. - a biliary stent - a renal stent. -a stent for the carotid and cerebral.

Other features and advantages of the present invention will be described in the following detailed description of a preferred but not exclusive endovascular device, and of a method for producing it, according to the present invention. Brief Description of the Drawings This description is given with reference to the attached drawings, which are provided solely for the indicative purpose and therefore are not limiting. Figure 1 shows, a stent according to the present invention Figure 2 shows, on an enlarged scale, part of a stent section of figure 1, with highlighted coating layers Figures 3, 4, 5, 6, show , in a schematic manner, the same part of a cross-section of the wall of the stent during several operative phases of the coating production. Detailed Description of the Invention In the following the word stent will be used with the extended meaning defined above. Referring to the included drawings, a stent according to the present invention is indicated as 1. The stent 1 has a tubular, metallic, flexible and substantially indicidal body 2 which is made of, for example, a closed metallic net. As an indication, the metal net can be produced from a stainless steel tube with a circular section by a laser cut. The tubular body 2, is generally made of a processable material with a high resistance to fatigue, such as 316L stainless steel. Other types of materials can also be used, such as the following: -various inert and biocompatible metallic alloy, and in particular of CoCr alloy, such as L605 (Co-20Cr-15W-10NÍ), Co-28Cr-6Mo, Co-35Ni -20Cr-1 OMo, Co-20Cr-16Fe-15Ni-7Mo, due to its greater elasticity, which reduces the risk and the micro-fracture entity during the folding and expansion phases, and the possibility of maintaining the same characteristics with a smaller thickness. -various inert and biocompatible metallic alloy, and in particular pure Ti or its alloy, such as Ti-12Mo-6Zr-2Fe, Ti-15Mo Ti-3AI-2.5V, Ti-35Nb-7Zr-5Ta, Ti-6AI-4Va, Ti-6AI-7Nb, Ti-13Nb-13Zr. - Nickel-Titanium shape memory alloy (Nitinol). -various inert and biocompatible metallic alloy, and in particular the Cr alloy, such as Cr-14Ni-2,5Mo, Cr-13Ni-5Mn-2,5Mo, Cr-10Ní-3Mn-2,5Mo. The tubular body 2 is completely covered by at least one layer of inert and biocompatible coating 's', where by the term biocompatible a material is being indicated that is capable of interacting with the wall of the vessels of the tissues and the blood flow blood as little as possible, and not interact negatively with the human body. The thin biocompatible and inert titanium nitride based coating, which covers the complete stent, is obtained after preparation of the substantially cylindrical tubular body 2 made of an expandable metal net, generally of medical grade stainless steel, by a method comprising the following operations in succession: -deposition of a first layer of Titanium (21) -the first treatment of nitrogen (N) of the first layer of titanium (Ti) (21) by the transmission of high ionic currents in the substrate (Closed Field UnBalanced Magnetron Sputter Ion Plating) with the intention of obtaining the transformation of at least a part of the first titanium layer (21) into a first ceramic coating layer of titanium nitride (TiN) (210) -deposition in this first layer of ceramic coating of titanium nitride (TiN) (210) of a second layer of titanium (Ti) (22) -a second nitrogen treatment (N) of the second layer of titanium or (Ti) (22) by the transmission of high ionic currents in the substrate (Closed Field UnBalanced Magnetron Sputter Ion Plating) with the intention of obtaining the transformation of at least a part of the second layer of titanium (Ti) (22) ) in a second layer of titanium nitride ceramic coating (TiN) (220). The first titanium layer 21 preferably has a thickness of approximately 100 nm. The first nitrogen treatment of the first titanium layer 21 is with the intention of transforming at least a portion of the first titanium layer 21 into a compact ceramic coating made of titanium nitride 210. The second nitrogen treatment of the second layer of titanium (22) by the transmission of high ionic currents in the substrate (Closed Field UnBalanced Magnetron Sputter Ion Plating) is with the intention of obtaining the transformation of the entire second layer of titanium 22 into a second layer of ceramic coating completely made of titanium nitride 220. The first layer, formed at least in part by titanium nitride, makes the second treatment safe, preventing it from coming into direct contact with the outer surface of the cylindrical tubular body 2. The second treatment is made so that at least the outer part of all the ceramic coating made of titanium nitride (TiN) has a morphology that is in the same way as that shown in figure 2. In particular this morphology is characteristic of the entire ceramic lining made of porous titanium nitride 220. The thin Inert and biocompatible layer of titanium 's' (which is made of titanium nitride completely or almost completely) covering the stent has a thickness of approximately 1-2 μm, and preferably approximately 1.5 μm. The external surface of ceramic coating made of titanium nitride (TiN) is characterized by a pre-established porosity with the intention of increasing the retention of a layer, even if it is a monomolecular layer, of drug. More specifically, the mentioned nitrogen treatments are made using an ion deposition system made by at least one magnetron. The successive stage of this coating method is characterized by a deposition of an anti-restenosis drug on the external surface of the biocompatible material covering the tubular body 2. Prior to the implementation of this step, a preliminary phase with the intention of removing any contamination of the tubular body 2 that will be coated is necessary. In particular, treatment operations for the deposition of titanium are made by at least one magnetron and comprise the following steps: the insertion of the tubular body 2 in a vacuum chamber the insertion of at least one titanium element in the vacuum chamber - the insertion of a noble gas into the vacuum chamber - the bombardment by electrons generated by at least one magnetron of noble gas atoms to obtain ions of the noble gas - the ion bombardment of the noble gas of the element of titanium to obtain titanium ions - the induction of a potential difference between the tubular body 2 and the vacuum chamber to obtain deposition of the titanium ions on the tubular body. Subsequently, the deposition of the titanium nitride is produced by a successive phase during which the nitrogen gas is introduced into the vacuum chamber to obtain the titanium nitride. It is important to note that the titanium nitride coating of the stent has a lower wettability for the proteins than the stent stainless steel surface of the well known art. This coating ensures that there is no release of toxic ions from the same coating and the underlying steel. With the method described above it is possible to obtain coatings made of titanium compounds with a low average thickness (approximately 1.5 μm) and with a very thin and smooth structure that ensures a high resistance to the mechanical stress generated during the implantation of the stent, without modify the elastic deformability of the stent. At the end of the coating treatment, the stent is coated with a thin biocompatible inert layer based on titanium nitride which includes: a first layer of ceramic coating made of titanium nitride (210) which is in contact and limited with the surface external stent - a second titanium-based layer directly surrounded by the first ceramic coating layer made of titanium nitride (210) and the second layer is made of, at least in part, a second layer of nitride ceramic coating of titanium. The first ceramic coating layer of titanium nitride (210) is compact, contrary to the second layer that is directly surrounding it, which is composed entirely of titanium nitride and has a pre-established porosity and a columnar morphology. The thin inert biocompatible layer based on titanium nitride that covers the entire stent has a thickness of approximately 1-2 μm. Finally, the particular shape of the crystalline structure of deposited titanium nitride allows the application of drugs on the same coating, its release in the body according to the determined time and the possibility of using a thin layer of monomolecular polymer activation (for example polymeric micelles as liposomes). Another possibility is to place on the stent a layer of endothelial cells to facilitate a more rapid endothelialization of the blood vessel and to reduce the incidence of acute and sub-acute thrombosis after implantation, thus reducing the entity of restenosis. Optionally, the subject procedure of the invention optionally comprises a preliminary polishing step with the intention of eliminating any kind of contamination and / or superficial defects due to the laser cutting, as a side remelted material subsequent to the thermal explosion, of the tubular body that is will coat. In addition, the preliminary polishing stage can be operated by alumina powder (Al 203) and if this is not enough, it is possible to operate using a chemical attack with 3D photolithography methods and structures. In addition, this preliminary polishing step can also be a chemical, sand, electrolytic and / or electrochemical polishing.

Claims (37)

1. Method for the realization of a coated endovascular device that includes at least the steps of: -preparation of a substantially cylindrical tubular body (2) made of an inert, biocompatible metal or a metal alloy selected from the group consisting of stainless steel, CoCr alloy, Ti or its alloy, Cr alloy; -covering the tubular surface of the body with at least one thin layer based on inert biocompatible titanium (s), the coating is produced according to the following stages: I. deposition of a first layer of titanium (Ti) (21); II. First treatment of nitrogen (N) of the first layer of titanium (Ti) (21) by the transmission of high ionic currents in the substrate (Closed Field UnBalanced Magnetron Sputter Ion Platting) with the intention of obtaining the transformation of at least one part of the first titanium layer (21) in a first ceramic coating layer of titanium nitride (TiN) (210); III. deposition in this first ceramic coating layer of titanium nitride (TiN) (210) of a second layer of titanium (Ti) (22); IV. a second treatment of nitrogen (N) of the second layer of titanium (Ti) (22) by the transmission of high ionic currents in the substrate (Closed Field UnBalanced Magnetron Sputter Ion Platting) with the intention of obtaining the transformation of at least a part of the second layer of titanium (Ti) (22) in a second ceramic coating layer of titanium nitride (TiN) (220).

2. Method according to claim 1, wherein the first nitrogen treatment (N) of the first titanium (Ti) layer (21) is with the intention of transforming at least a part of the first titanium layer ( 21) in a compact titanium nitride ceramic coating (210).

Method according to claim 1 or 2, wherein the second nitrogen treatment of the second titanium layer (22), made by the transmission of high ion currents in the substrate (Closed Field UnBalanced Magnetron Sputter Ion Platting) is with the intention of transforming the entire second titanium layer (22) into a second porous ceramic layer of titanium nitride (220).

4. Method according to claims 1 and 2, wherein the thickness of the first titanium (Ti) layer is approximately 100 nm.

5. Method according to claim 1, wherein the thin layer based on inert biocompatible titanium nitride (s) that fully coated the endovascular device has a thickness of about 1-2 μm.

6. Method according to claim 1, wherein at least the external part of the titanium nitride (TiN) ceramic coating has a columnar morphology.

The method according to claim 1, wherein at least the outer surface of the titanium nitride (TiN) ceramic coating is characterized by a predetermined porosity.

8. Method according to claim 1, wherein the nitrogen treatments are produced by the use of an ion deposition system made by at least one magnetron.

9. Method according to claim 1, characterized in that it also includes a subsequent step of deposition of an anti-restenosis drug on the external porous surface of the biocompatible layer (s) that coated the tubular body.

10. Method according to claim 1, wherein the endovascular device is a graft for the abdominal and thoracic aorta and / or the iliac arteries.

11. Method according to claim 1, wherein the endovascular device is a coronary stent.

12. Method according to claim 1, wherein the endovascular device is a peripheral stent.

13. Method according to claim 1, wherein the endovascular device is a biliary stent.

14. Method of compliance with claim 1, where the endovascular device is a renal stent.

15. Method according to claim 1, wherein the endovascular device is a stent for the carotid and cerebral.

16. Method according to claim 1, wherein in the endovascular device the substantially cylindrical tubular body (2) is made of an inert and biocompatible steel 316L.

Method according to claim 1, wherein in the endovascular device the substantially cylindrical tubular body (2) is made of an inert and biocompatible CoCr alloy, selected from the group consisting of L605 (Co-20Cr-15W-10N ), Co-28Cr-6Mo, Co-35Ni-20Cr-1 OMo, Co-20Cr-16Fe-15Ni-7Mo.

Method according to claim 1, wherein in the endovascular device the substantially cylindrical tubular body (2) is made of an inert and biocompatible Ti or its alloy, selected from the group consisting of Ti-12Mo-6Zr-2Fe , Ti-15Mo, Ti-3AI-2.5V, Ti-35Nb-7Zr-5Ta, Ti-6AI-4Va, Ti-6AI-7Nb, Ti-13Nb-13Zr.

19. Method according to claim 1, wherein in the endovascular device the substantially cylindrical tubular body (2) is made of the nickel-titanium shape memory alloy (Nitinol).

20. Method according to claim 1, wherein in the endovascular device the substantially cylindrical tubular body (2) is made of an inert and biocompatible Cr alloy selected from the group consisting of Cr-14Ni-2.5Mo, Cr-13Ni- 5Mn-2.5Mo, Cr-10Ni-3Mn-2.5Mo.

21. Method according to claim 1, wherein this further comprises a stage of preliminary polishing with the intention of eliminating any kind of surface contamination and defects due to laser cutting, as side re-melt material subsequent to the thermal explosion , of the tubular body that will be covered.

22. Method according to claim 21, wherein the preliminary polishing stage is operated by alumina powder (Al 203) and if this is not sufficient, it is possible to operate using a chemical etching with 3d photolithography methods and structures.

23. Method according to claim 21, wherein the preliminary polishing step can also be a chemical, sand, electrolytic and / or electrochemical polishing.

24. Method according to claim 1, wherein the treatment operations are made by the use of at least one magnetron and comprising the following steps: -the insertion of the tubular body (2) in a vacuum chamber; -the insertion of at least one element of titanium in the vacuum chamber -the insertion of a noble gas in the vacuum chamber -the bombardment by electrons generated by at least one magnetron of noble gas atoms to obtain ions of the noble gas - the bombardment by the noble gas ions of the titanium element to obtain titanium ions - the induction of a potential difference between the tubular body (2) and the vacuum chamber to obtain the deposition of the titanium ions on the tubular body.

25. Method according to claim 24, wherein the method further comprises a step of introducing nitrogen gas into the vacuum chamber with the intention of obtaining titanium nitride.

26. coated endovascular device comprising: - a substantially cylindrical tubular body (2) made of an inert and biocompatible metal or of a metallic alloy selected from the group consisting of stainless steel, CoCr alloy, Ti or its alloy, CR alloy , having the substantially cylindrical tubular body surrounded on its outer surface by at least one thin inert biocompatible layer based on titanium (s) comprising: - a first layer of ceramic coating made of, at least in part, titanium nitride (210) which is in contact and surrounded with the external surface of the stent; a second titanium-based layer directly surrounded with the first ceramic coating layer made of titanium nitride (210) and the second layer is made of, at least in part, a second coating layer of titanium nitride ceramic (220).

27. A coated endovascular device according to claim 26, wherein the first ceramic coating of titanium nitride is compact.

28. A coated endovascular device according to claim 26, wherein the second titanium-based layer directly surrounded in the first ceramic coating layer of titanium nitride (210) is entirely formed of titanium nitride.

29. A coated endovascular device according to claim 26, wherein the thickness of the first titanium (Ti) layer (21) is about 100 nm.

30. A coated endovascular device according to claim 26, wherein the second titanium-based layer has a columnar morphology and a preset porosity.

31. Endovascular coated device according to claim 26, wherein the thin coating layer based on inert biocompatible titanium nitride (s) has a thickness of about 1-2 μm.

32. A coated endovascular device according to claim 26, wherein the substantially cylindrical tubular body (2) is made of an inert and biocompatible 316L steel.

33. Endovascular coated device according to claim 26, wherein the substantially cylindrical tubular body (2) is made of an inert and biocompatible CoCr alloy selected from the group consisting of L605 (Co-20Cr-15W-10Ni), Co-28Cr -Mo, Co-35Ni-20Cr-1 OMo, Co-20Cr- 16Fe-15Ni-7Mo.

34. A coated endovascular device according to claim 26, wherein the substantially cylindrical body (2) is made of an inert and biocompatible Ti or its alloy selected from the group consisting of Ti-12Mo-6Zr-2Fe, Ti-15Mo, TÍ-3AI-2.5V, Ti-35Nb-7Zr-5Ta, Ti-6AI-4Va, TÍ-6AI-7Nb, Ti-13Nb-13Zr.

35. A coated endovascular device according to claim 26, wherein the substantially cylindrical tubular body (2) is made of a Nickel-Titanium shape memory alloy (Nitinol).

36. A coated endovascular device according to claim 26, wherein the substantially cylindrical tubular body (2) is made of an inert and biocompatible Cr alloy selected from the group consisting of Cr-14Ni- 2.5Mo, Cr-13Ni- 5Mn-2.5Mo, Cr-10Ni-3Mn-2.5Mo.

37. Coated endovascular device obtainable by the method of any of claims 1 to 25.