Method for treatment medical devices made from nickel-titanium (NiTi) alloys

Abstract

The present invention improves the surface modification of NiTi alloys used for instance in medical devices through treatment with hydrogen particles in a suitable gaseous discharge and with oxygen atoms. The technique according to the present invention provides the formation of biocompatible solely titanium oxide layer thus preventing nickel to be present in the top surface layer. Furthermore this enables nanostructuring of the surface which depends on the treatment conditions. Devices made from NiTi alloys treated with the method according to the present invention have improved biocompatibility; platelets do not readily attach and activate on such surfaces and the thrombus formation rate is reduced in comparison with extensively used untreated NiTi alloys.

Claims

1. Method for treatment a medical device made from a NiTi alloy, comprising: mounting said device made from NiTi alloys into a reaction chamber; evacuating said reaction chamber to achieve pressure below atmospheric pressure; leaking hydrogen gas into said reaction chamber during continuous pumping of said reaction chamber so that the pressure in the said reaction chamber is between 1 and 100 000 Pa; establishing an electrical discharge in the said reaction chamber filled with said hydrogen; reacting said device made from NiTi alloys with gaseous particles created in hydrogen upon excitation of said hydrogen molecules by said electrical discharge until the native oxide is eliminated; introducing neutral oxygen atoms into said reaction chamber; simultaneously reacting said device made from NiTi alloys with said neutral oxygen atoms in said reaction chamber and with gaseous particles created in hydrogen upon excitation of said hydrogen by said electrical discharge until a titanium oxide film is established on the surface of said device made from NiTi alloys; and turning off said electrical discharge in said treatment chamber, closing inlet of said gases and venting said treatment chamber with essentially dry air.

2. Method according to claim 1, wherein said hydrogen gas leaking is amended with an additional gas.

3. Method according to claim 1, wherein said electrical discharge is selected from the list of discharges including DC (Direct Current), AC (Alternative Current), RF (Radio-Frequency) and MW (Micro Wave) discharges.

4. Method according to claim 1, further comprising increasing the concentration of said neutral oxygen atoms in said reaction chamber during parallel reacting of said device made from NiTi alloys with gaseous particles created in hydrogen upon excitation of said hydrogen gas by said electrical discharge.

5. Method according to claim 1, wherein said electrical discharge causes gas to transform into a non-equilibrium state.

6. Method according to claim 1, wherein said simultaneous reaction is maintained until said titanium oxide film with a thickness of 40 to 1000 nm.

7. Method according to claim 1, wherein the fluence of said neutral oxygen atoms onto said device made from NiTi alloys in said reaction chamber is between 1×10.sup.19 m.sup.−2 and 1×10.sup.25 m.sup.2.

8. Method according to claim 2, wherein said electrical discharge is selected from the list of discharges including DC (Direct Current), AC (Alternative Current), RF (Radio-Frequency) and MW (Micro Wave) discharges.

9. Method according to claim 2, further comprising increasing the concentration of said neutral oxygen atoms in said reaction chamber during parallel reacting of said device made from NiTi alloys with gaseous particles created in hydrogen upon excitation of said hydrogen gas by said electrical discharge.

10. Method according to claim 3, further comprising increasing the concentration of said neutral oxygen atoms in said reaction chamber during parallel reacting of said device made from NiTi alloys with gaseous particles created in hydrogen upon excitation of said hydrogen gas by said electrical discharge.

11. Method according to claim 2, wherein said electrical discharge causes gas to transform into a non-equilibrium state.

12. Method according to claim 3, wherein said electrical discharge causes gas to transform into a non-equilibrium state.

13. Method according to claim 4, wherein said electrical discharge causes gas to transform into a non-equilibrium state.

14. Method according to claim 6, wherein said simultaneous reaction is maintained until said titanium oxide film with a thickness of 60 to 800 nm is formed.

15. Method according to claim 7, wherein the fluence of said neutral oxygen atoms onto said device made from NiTi alloys in said reaction chamber is between 5×10.sup.23 m.sup.−2 and 5×10.sup.24m.sup.−2.

16. Method according to claim 1, wherein the medical device treated is a stent.

17. Method according to claim 1, wherein said leaking hydrogen gas into said reaction chamber during continuous pumping of said reaction chamber is performed such that the pressure in the said reaction chamber is between 10 and 1000 Pa.

18. Method according to claim 2, wherein said additional gas is a noble gas.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) The invention is herein described, by way of example only, with reference to the accompanying drawings, wherein:

(2) FIG. 1 shows ESCA profile of a virgin sample made from NiTi alloy used for vascular stents;

(3) FIG. 2 shows ESCA profile of a sample made from NiTi alloy after treatment by the method of invention, where the fluence of neutral oxygen atoms were set to 1×10.sup.24 m.sup.−2, while flux was set to 2×10.sup.23 m.sup.−2 s.sup.−1;

(4) FIG. 3 shows an SEM image of a virgin vascular stent made from NiTi alloy after incubation with whole blood (magnification 500×);

(5) FIG. 4 shows an SEM image of a virgin vascular stent made from NiTi alloy after incubation with whole blood (magnification 1.000×);

(6) FIG. 5 shows an SEM image of a vascular stent made from NiTi alloy after treatment by the method of invention, where the fluence of oxygen atoms was set to 4×10.sup.22 m.sup.−2 while the flux was set to 2×10.sup.23 m.sup.−2 s.sup.−1 (magnification 500×);

(7) FIG. 6 shows an SEM image of a vascular stent made from NiTi alloy after treatment by the method of invention, where the fluence of oxygen atoms was set to 1×10.sup.24 m.sup.−2 while the flux was set to 2×10.sup.23 m.sup.−2 s.sup.−1 and the sample was incubated with whole blood (magnification 1.000×);

(8) FIG. 7 shows an SEM image of a vascular stent made from NiTi alloy after treatment by the method of invention, where the fluence of oxygen atoms was set to 4×10.sup.24 m.sup.−2 while the flux was set to 2×10.sup.23 m.sup.−2 s.sup.−1 and the sample was incubated with whole blood (magnification 500×); and

(9) FIG. 8 shows an SEM image of a vascular stent made from NiTi alloy after treatment by the method of invention, where the fluence of oxygen atoms was set to 4×10.sup.24 m.sup.−2 while the flux was set to 2×10.sup.23 m.sup.−2 s.sup.−1 and the sample was incubated with whole blood (magnification 1.000×).

DETAILED DESCRIPTION OF THE INVENTION

(10) Vascular stents are commonly employed in case of cardiovascular diseases, where there is a need to enlarge the lumen wall and to restore the blood flow. A vascular stent is mounted into a human blood vessel by a physician using a catheter. The stent materials should have appropriate mechanical properties and satisfactory biocompatibility and hemocompatibility. Stents are made of titanium (Ti), 316L stainless steel (SS-medical grade), Nitinol (NiTi alloy) and Cobalt-Chromium (CoCr). However, the drawback connected with this type of vascular implants still remains due to high risk of restenosis and thrombosis. In case of NiTi and SS vascular stents, there is a risk of allergenic reactions due to release of Nickel. However, these materials are frequently employed due to their excellent mechanical properties and long-term durability. The mechanical properties of the NiTi alloys remain unchanged for ages.

(11) New generation of so-called drug eluting stents (DES) has been developed to overcome the above-mentioned limitations. Therefore, the bare metal stents (BMS) were coated with anti-cell-proliferative coatings in order to prevent uncontrolled proliferation of smooth muscle cells (reducing the risk of restenosis) or anti-thrombotic drugs that reduce the risk of thrombosis. Unfortunately, long-term studies of DES have shown to increase the risk of thrombosis, mainly due to insufficient proliferation of endothelial cells that line the inner side of our natural blood vessels and are thought to be an ideal anti-thrombogenic material. Thus, novel approach to improve surface properties of vascular stents is still needed and is solved by the method according to the present invention.

(12) According to the present invention, the improved biocompatibility/hemocompatibility is achieved by treatment of NiTi alloy with reactive hydrogen particles created in a suitable gaseous discharge and subsequent addition of neutral oxygen atoms. Such a treatment allows for the formation of high-quality titanium oxide layer on the surface of materials made from NiTi alloy, the oxide films containing only titanium oxide thus being free from nickel or nickel oxides. This significantly reduces adhesion and activation of platelets on the surface and reduces the risk of thrombosis.

(13) The simplest method for formation of oxide film on a metallic surface is thermal oxidation. Thermal oxidation stands for heating of a metal in an atmosphere containing oxygen. The thickness of the oxide film, achieved by thermal oxidation, depends on the nature of the metal, the treatment time at elevated temperature, the temperature of the metal during exposure to oxygen-containing atmosphere and the partial pressure of oxygen in said oxygen-containing atmosphere. Such a treatment therefore allows for achieving a practically arbitrary thickness of the oxide film on the metallic surface, depending on the chosen treatment conditions. A drawback of thermal oxidation is reflected from the fact that the oxide film usually contains a mixture of different oxides. In the case the metal is a NiTi alloy the oxide film contains both titanium and nickel oxides.

(14) According to the present invention, a uniform titanium oxide film is obtained by an alternative treatment. Instead of heating materials made from NiTi alloys in oxygen-containing atmosphere, the material made from NiTi alloys are treated using different gases in the right manner.

(15) In the first step, according to the present invention, the NiTi alloy is mounted into an appropriate reacting chamber, which is capable of withstanding evacuation. Once the reaction chamber is evacuated to a low pressure, preferably below few Pascal, it is filled with hydrogen. The purpose of hydrogen is to interact with the native nickel oxide layer and reduce it to oxygen-free nickel. Such reactions are unlikely to occur at reasonably low temperature in hydrogen gas under normal conditions. In order to facilitate reduction of the native nickel oxide, an appropriate gaseous discharge is created in hydrogen gas present in the reaction chamber. In the gaseous discharge, hydrogen is transferred into a state of non-equilibrium gas. In hydrogen discharge, neutral hydrogen molecules are dissociated to atoms and partially ionized. Both neutral hydrogen atoms as well as molecular and atomic hydrogen ions are chemically much more reactive at given temperature then hydrogen molecules under normal conditions and interact with metal oxides. The interaction is essentially selective: the neutral hydrogen atoms as well as molecular and atomic hydrogen ions will preferentially react chemically with oxides of lower binding energy. In the case of materials made from NiTi alloys, the neutral hydrogen atoms as well as molecular and atomic hydrogen ions will react preferentially with nickel oxide. The chemical interaction leads to reduction of nickel oxide to pure metallic nickel following the reaction, which could be schematically presented as NiO+2H.fwdarw.Ni+H.sub.2O. The resulting water molecule is desorbed from the surface and removed from the reaction chamber due to continuous pumping of said reaction chamber. The treatment with hydrogen discharge therefore leads to a modification of the original native oxide film: instead of a mixture of titanium and nickel oxides, a mixture of titanium oxides and metallic nickel is achieved. Such a surface condition is not stable and will immediately change to its original state when exposed to air. In order to avoid this effect, the materials made from NiTi alloys essentially remain in the reaction chamber according to the present invention.

(16) Once the nickel is reduced from oxide to metallic nickel an additional step is realized. Without breaking treatment with hydrogen discharge, neutral oxygen atoms (in the ground state and/or in the first excited state commonly referred to as O(.sup.1D) state) are introduced into the reaction chamber. The neutral oxygen atoms are chemically extremely reactive and will cause oxidation of almost all metals. In the case of NiTi alloys, both titanium and nickel oxidize upon exposure to neutral oxygen atoms. Nickel oxides, however, will be quickly reduced to metallic nickel due to reaction schematically presented as NiO+2H.fwdarw.Ni+H.sub.2O, while titanium oxide will be more stable. Simultaneous application of hydrogen discharge and neutral oxygen atoms therefore assures for oxidation of titanium while leaving nickel essentially in the metallic form. Due to extensive interaction between neutral oxygen atoms and materials made from NiTi alloys, the net effect of simultaneous application of hydrogen discharge and neutral oxygen atoms will be growth of titanium oxide film on the surface of said NiTi alloys. Titanium atoms will diffuse toward the surface and oxidize resulting in depletion of the surface layer from nickel. If the flux of neutral oxygen atoms is low, the oxide film will be thin but free of nickel. Once the very thin but uniform titanium oxide film is made due to interaction with neutral oxygen atoms, nickel will not be able to appear on the surface of treated materials made from NiTi alloys due to very poor mobility of nickel in titanium oxide materials. Increasing the flux of neutral oxygen atoms onto the samples will allow for thickening of the titanium oxide film free from nickel since the mobility of nickel in compact titanium oxide film is very poor. Upon treatment with appropriate fluence of neutral oxygen atoms, a rather thick pure titanium oxide film is formed on the surface of materials made from NiTi alloys. The film of titanium oxide grown on the NiTi alloys upon treatment according to present invention is extremely stable since interaction of materials with neutral oxygen atoms allow for synthesizing very compact and dense oxide films. The inertness and long-term stability of titanium oxide films grown on the NiTi alloys has a significant influence on biocompatibility/hemocompatibility of the surface. Moreover, by varying the fluence of neutral oxygen atoms, the thickness of titanium oxide layer and surface nanotopography can be controlled. The efficiency of the present invention will be shown in the following examples.

Example 1: A Virgin NiTi Alloy Used for Stent Application

(17) In the example disclosed herein, a virgin NiTi alloy used for stent was analyzed by Electron Spectroscopy for Chemical Analysis (ESCA) method in order to obtain information about chemical composition in-depth. To determine chemical composition in-depth, the Ar.sup.+ ion beam with 1 keV energy was used for sputtering at an incidence angle of 45° and a raster of 5 mm×5 mm. The sputtering rate was approximately 1 nm/min. Depth profile obtained from ESCA is presented in FIG. 1. The results indicate that Ni is also detected on the top surface (about 1 at. %) and its concentration is slowly increasing in depth. The analysis of depth profile spectra indicates that the natively formed titanium oxide is present on the top surface (about 5 nm thick) and an increase in concentration of nickel and its oxides is slowly observed. This indicates that a very thin native titanium oxide film is formed on NiTi alloy used for stent application.

(18) The adhesion and activation of platelets on a virgin NiTi alloy used for stent was done according to the following procedure. Prior to whole blood incubation virgin NiTi surfaces were cleaned with ethanol, dried and incubated with whole blood taken by vein puncture from a healthy human donor. Virgin NiTi samples were incubated for 30 min with whole blood. The blood was drawn into 9 ml tubes with tri sodium citrate anticoagulant (Sigma). Afterwards, the fresh blood was incubated with NiTi surfaces in 24 well plates for 1 hour at room temperature and at gentle shaking at 300 RPM. The sample was incubated with 1 ml of whole blood. After 1 h of incubation, 1 ml of phosphate-buffered saline (PBS) was added to the whole blood. The blood with PBS was then removed and the titanium surface was rinsed 5 times with 2 ml PBS in order to remove weakly adherent platelets. Adherent cells were subsequently fixed with 400 μl of 1 PFA (paraformaldehyde) solution for 15 min at room temperature. Afterwards, the surfaces were rinsed with PBS and then dehydrated using a graded ethanol series (50, 70, 80, 90, 100 and again 100 vol. % ethanol) for 5 min and in the last stage in the series (100 vol. % ethanol) for 15 min. Then the samples were placed in a Critical Point Dryer, where the solvent is exchanged with liquid carbon dioxide. By increasing the temperature in the drier, the liquid carbon dioxide passes the critical point, at which the density of the liquid equals the density of the vapour phase. This drying process preserves the natural structure of the sample and avoids surface tension, which could be caused by normal drying. The dried samples were subsequently coated with gold and examined by means of SEM (Carl Zeiss Supra 35 VP) at accelerating voltage of 1 keV. Evaluation of platelet adhesion and activation from SEM images was done according to the morphology and number of platelets. Morphological forms of platelets from the least activated to the most activated are as follows: round (R)>dendritic (D)>spread dendritic (SD)>spread (S)>fully spread (FS).

(19) Differences in adhesion of platelets were observed from SEM images as seen in FIG. 3 and FIG. 4. Platelet adhesion and activation can be determined by counting the number of attached cells as well as by observing the morphological changes of platelets on the surface. Results from SEM analysis clearly indicate that platelets attach and activate on the surface of the NiTi alloy used for stent application. In FIG. 4, taken at higher magnification, the morphology of platelets can be studied. It can be observed that platelets on the surface are in dendritic, spread and fully spread form, which is correlated with high platelet activation on the surface. Such morphology of platelets has high potential to cause thrombosis and reduces the life of such virgin NiTi alloy used for stent application.

Example 2: NiTi Alloy Used for Stent Application after Treatment According to the Method of the Present Invention where the Fluence of Neutral Oxygen Atoms was Set to 1×10.SUP.24 .m.SUP.−2

(20) NiTi alloy used for stent application was treated according to the present invention where the fluence of neutral oxygen atoms was set to 1×10.sup.24 m.sup.−2, while the flux was set to 2×10.sup.23 m.sup.−2 s.sup.−1. The surface was analyzed by Electron Spectroscopy for Chemical Analysis (ESCA) method in order to obtain information about chemical composition in-depth. To determine chemical composition in-depth, the Ar.sup.+ ion beam with 1 keV energy was used for sputtering at an incidence angle of 45° and a raster of 5 mm×5 mm. The sputtering rate was approximately 1 nm/min. Depth profile obtained from ESCA is presented in FIG. 2, whereby no nickel was detected on the top surface layer.

(21) The sample was mounted into the reaction chamber, the chamber was evacuated to a pressure below the detection limit of the pressure gauge (the pressure limit was about 1 Pa), the reaction chamber was filled with hydrogen during continuous pumping so the hydrogen pressure in the system was 30 Pa. A radiofrequency discharge of power 500 W was established in the reaction chamber filled with hydrogen at the pressure of 30 Pa. The sample was left to react with reactive hydrogen particles created in hydrogen gas under discharge conditions for 10 s. After the period of 10 s, neutral oxygen atoms were slowly but continuously leaked into the reaction chamber during further continuous operation of the electrical discharge. The fluence of neutral oxygen atoms on the surface of the sample made from NiTi surface used for vascular stents was set to 1×10.sup.24 m.sup.−2.

(22) Results of chemical composition in-depth are presented in FIG. 2. The results indicate that Ni was not detected on the top surface (less than 0.2 at. %). It could be evaluated that after treatment by the method of invention about 80 nm thick titanium oxide films is formed on the surface.

(23) The studies on adhesion and activation of platelets were conducted on NiTi alloy surface used for stent application immediately after treatment according to the present invention where the fluence of neutral oxygen atoms was set to 1×10.sup.24 m.sup.−2. The incubation procedure with whole blood was the same as the one described in Example 1. The images of SEM analysis at lower and higher magnification are presented in FIG. 5 (where only a few platelets were observed on the surface and they were preferentially in the round non-activated state) and FIG. 6, respectively. With reference to FIG. 6 it was hard to detect platelets on the surface, however, those that were detected, were in round non-activated form. The surface morphology after treatment by the method of invention is altered and grain-like morphology is formed on the surface.

(24) SEM analysis clearly showed that less platelets adhere on NiTi alloy used for stent application after treatment of the surface by the method of invention, where the fluence of neutral oxygen atoms was set to 1×10.sup.24 m.sup.−2. There are almost no platelets detected on the surface, while those that can be found are mainly in less active form—round and dendritic as seen at higher magnification (FIG. 6). Such surfaces will, to a lesser extent, elicit undesired thrombus formation in comparison to the samples prepared in Example 1. Moreover, the altered surface morphology obtained according to the present invention can be observed in FIG. 6. The surface seems to be nanostructured and small nano-grooves are uniformly formed on the surface, which may also influence on platelet adhesion and activation.

Example 3: NiTi Alloy Used for Stent Application after Treatment by the Method of Invention where the Fluence of Neutral Oxygen Atoms was Set to 4×10.SUP.24 .m.SUP.−2

(25) NiTi alloy used for stent application was treated according to the present invention where the fluence of neutral oxygen atoms was set to 4×10.sup.24 m.sup.−2, while the flux was set to 2×10.sup.23 m.sup.−2 s.sup.−1. In this case, a sample was mounted into the reaction chamber, the chamber was evacuated to a pressure below the detection limit of the pressure gauge (the pressure limit was about 1 Pa), the reaction chamber was filled with hydrogen during continuous pumping so the hydrogen pressure in the system was 30 Pa. A radiofrequency discharge of power 500 W was established in the reaction chamber filled with hydrogen at the pressure of 30 Pa. The sample was left to react with reactive hydrogen particles created in hydrogen gas under discharge conditions for 10 s. After the period of 10 s, neutral oxygen atoms were slowly but continuously leaked into the reaction chamber during further continuous operation of the electrical discharge. The fluence of neutral oxygen atoms on the surface of the sample made from NiTi surface used for vascular stents was set to 4×10.sup.24 m.sup.−2.

(26) The studies on adhesion and activation of platelets were conducted on NiTi alloy surface used for stent application immediately after treatment by the method of invention where the fluence of neutral oxygen atoms was set to 4×10.sup.24 m.sup.−2. The incubation procedure with whole blood was the same as the one described in Example 1.

(27) The images of SEM analysis at lower and higher magnification are presented in FIGS. 7 and 8, respectively. The images at higher magnification shows that the surface has grain-like surface morphology, which increases surface area and surface roughness, hence no platelets were detected on the surface.

(28) According to SEM analysis of samples treated by the method according to the invention where the fluence of neutral oxygen atoms was set to 4×10.sup.24 m.sup.−2, platelet adhesion was prevented, no platelets could be detected on the surfaces prepared by this method as seen from lower magnification image in FIG. 7.

(29) At higher magnification image shown in FIG. 8, the nano-structured surface can be observed. Compared to surface in Example 2 presented in FIG. 6 it can be clearly seen that nano-groves in FIG. 8 are much more pronounced, which could further reduce adhesion and activation of platelets on such surfaces. Surfaces treated according to the present invention, where the fluence of neutral oxygen atoms was set to 4×10.sup.24 m.sup.−2, could serve as blood connecting devices or medical devices to be implanted and having direct contact with blood of a host, such as vascular stents with superior properties.

(30) Finally, it can be stated that the present invention optimizes the biocompatibility of materials and products or devices made from NiTi alloys in contact with blood, especially vascular stents for instance. Against the background, the method allows for formation of pure titanium oxide film on the surface of NiTi alloys, which significantly reduces activation and adhesion of platelets and reduces the risk of thrombosis.

(31) Although specific embodiments have been illustrated and described herein, it will be appreciated by those of ordinary skill in the art that a variety of alternate and/or equivalent implementations may be substituted for the specific embodiments illustrated and described without departing from the scope of the present invention. This application is intended to cover any adaptations or variations of the specific embodiments discussed herein.

(32) Moreover, although the foregoing descriptions and the associated drawings describe example embodiments in the context of certain example combinations of elements and/or functions, it should be appreciated that different combinations of elements and/or functions may be provided by alternative embodiments without departing from the scope of the appended claims. In this regard, for example, different combinations of elements and/or functions than those explicitly described above are also contemplated as may be set forth in some of the appended claims. Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation.