Patent Publication Number: US-2013238081-A1

Title: Molybdenum Endoprostheses

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
     This application is a continuation of and claims the benefit of priority under 35 U.S.C. §120 to U.S. application Ser. No. 11/771,731, filed Jun. 29, 2007, which will issue as U.S. Pat. No. 8,398,702, on Mar. 19, 2013, the entire contents of which is hereby fully incorporated by reference. 
    
    
     TECHNICAL FIELD 
     This invention relates to endoprostheses, and more particularly to stents. 
     BACKGROUND 
     The body includes various passageways such as arteries, other blood vessels, and other body lumens. These passageways sometimes become occluded or weakened. For example, the passageways can be occluded by a tumor, restricted by plaque, or weakened by an aneurysm. When this occurs, the passageway can be reopened or reinforced, or even replaced, with a medical endoprosthesis. An endoprosthesis is typically a tubular member that is placed in a lumen in the body. Examples of endoprostheses include stents, covered stents, and stent-grafts. 
     Endoprostheses can be delivered inside the body by a catheter that supports the endoprosthesis in a compacted or reduced-size form as the endoprosthesis is transported to a desired site. Upon reaching the site, the endoprosthesis is expanded, for example, so that it can contact the walls of the lumen. 
     The expansion mechanism can include forcing the endoprosthesis to expand radially. For example, the expansion mechanism can include the catheter carrying a balloon, which carries a balloon-expandable endoprosthesis. Balloon-expandable endoprostheses are commonly made of 316L stainless steel or L605 alloys. The balloon can be inflated to deform and to fix the expanded endoprosthesis at a predetermined position in contact with the lumen wall. The balloon can then be deflated, and the catheter withdrawn. 
     When the endoprosthesis is advanced through the body, its progress can be monitored, e.g., tracked, so that the endoprosthesis can be delivered properly to a target site. After the endoprosthesis is delivered to the target site, the endoprosthesis can be monitored to determine whether it has been placed properly and/or is functioning properly. Methods of monitoring a medical device include X-ray fluoroscopy, computed tomography (CT), and magnetic resonance imaging (MRI). 
     SUMMARY 
     In one aspect, an endoprosthesis is disclosed having a member that includes molybdenum and at least one metal selected from the group consisting of titanium, rhenium, yttrium, palladium, rhodium, ruthenium, tungsten, tantalum, iridium, zirconium, hafnium, niobium, chromium, and combinations thereof. The member having a microstructure characterized by: (a) a molybdenum-rich base region comprising at least 50 weight percent molybdenum, (b) a surface region comprising at least one metal selected from the group consisting of titanium, rhenium, yttrium, palladium, rhodium, ruthenium, tungsten, tantalum, iridium, zirconium, hafnium, niobium, chromium, and combinations thereof, and (c) an inter-diffusion region in which the concentration of molybdenum decreases in the thickness direction from the molybdenum-rich base region to the surface region of the member. 
     In some embodiments, the molybdenum base region can include no more than 10 weight percent of any of the following elements: titanium, rhenium, yttrium, palladium, rhodium, ruthenium, tungsten, tantalum, zirconium, hafnium, iridium, and chromium. In some embodiments, the molybdenum-rich base region can include at least 95 weight percent molybdenum. For example, the molybdenum-rich base region can include 1.25 weight percent titanium, 0.3 weight percent zirconium, 0.15 weight percent carbon, and a balance of molybdenum. The molybdenum-rich base region could also include between 0.25 and 1.0 weight percent titanium, between 0.04 and 2.0 weight percent zirconium, between 0.01 and 0.04 weight percent carbon, and a balance of molybdenum. In some embodiments, the molybdenum-rich base region can include 99.95% pure molybdenum doped with potassium silicate. 
     In some embodiments, the surface region can be essentially free of molybdenum. In other embodiments, the surface region can include less than 50 percent by weight molybdenum. In some embodiments, the surface region can include titanium. For example, the surface region can include a titanium-molybdenum alloy or can consist essentially of titanium. 
     In some embodiments, the inter-diffusion region can be at between 10 nanometers and 10 microns thick. In some embodiments, the inter-diffusion region is at least 1 micron thick. In some embodiments, the inter-diffusion region can include iridium. For example, inter-diffusion region can include a higher concentration of iridium than either the molybdenum-rich base region or the surface region. 
     In some embodiments, the member can further include oxides, carbides, nitrides, or a combination thereof overlying the surface region. For example, the oxides, carbides, and nitrides can be selected from the group consisting of zirconium oxide, hafnium oxide, chromium oxide, iridium oxide, titanium oxy-nitride, TiO2, Nb2O5, Ta2O5, and combinations thereof. In some embodiments, the member can include a coating of zirconium, hafnium, chromium, iridium, or combinations thereof overlying the surface region. In some embodiments, the member can include a drug-eluting polymer coating overlying the surface region. 
     In some embodiments, the member can have a modulus of between 44 and 50 msi, a 0.2% offset yield strength of at least 50 ksi, and/or an elongation to break of at least about 15%. In some embodiments, the molybdenum-rich base region can have a density of at least 9.5 g/cc. 
     In some embodiments, endoprosthesis can be a stent. For example, the endoprosthesis can be a balloon-expandable stent. 
     In another aspect, there is disclosed an endoprosthesis having a member that includes molybdenum and titanium. The member having a microstructure characterized by: (a) a molybdenum-rich base region including at least 50 weight percent molybdenum, and (b) a surface region including titanium. 
     In some embodiments, the surface region can consists essentially of titanium. In other embodiments, the surface region can include a titanium-molybdenum alloy. 
     In some embodiments, the member can further include an intermediate region comprising iridium. In some embodiments, the member can further include a coating of zirconium, hathium, chromium, iridium, or combinations thereof overlying the surface region. 
     In some embodiments, the endoprosthesis can be a stent. For example, the endoprosthesis can be a balloon-expandable stent. 
     Other features, objects, and advantages of the invention will be apparent from the description and drawings, and from the claims. 
    
    
     
       DESCRIPTION OF DRAWINGS 
         FIG. 1  is a perspective view of an embodiment of an expanded stent. 
         FIG. 2  is a cross sectional view of a band or connector of a stent. 
         FIGS. 3A-3C  depict a process for producing a member having an inter-diffusion region between a molybdenum-rich base region and a surface region. 
         FIG. 4  is a flow chart of an embodiment of a method of making a stent. 
     
    
    
     Like reference symbols in the various drawings indicate like elements. 
     DETAILED DESCRIPTION 
     Referring to  FIG. 1 , a balloon-expandable stent  20  can have the form of a tubular member defined by a plurality of bands  22  and a plurality of connectors  24  that extend between and connect adjacent bands. During use, bands  22  can be expanded from an initial, smaller diameter to a larger diameter to contact stent  20  against a wall of a vessel, thereby maintaining the patency of the vessel. Connectors  24  can provide stent  20  with flexibility and conformability that allow the stent to adapt to the contours of the vessel. 
     The bands  22  and connectors  24  of the balloon-expandable stent  20  can include molybdenum and at least one of the following metals, alone or in combination with each other: titanium, rhenium, yttrium, palladium, rhodium, ruthenium, tungsten, tantalum, iridium, zirconium, hafnium, niobium, and chromium. Molybdenum has an advantageous combination of mechanical and physical properties, including a unique balance of modulus and yield strength. The modulus for molybdenum is higher than the modulus of 316L stainless steel and of L605 alloys, while molybdenum&#39;s yield strength is between the yield strengths of 316L stainless steel and of L605 alloys. This balance of properties would provide a lower diameter recoil for better securement on the delivery system and expanded diameter retention (apposition to the vessel wall) than 316L stainless steel and L605 alloys when used in the same stent configuration. A molybdenum stent could also be more MRI compatible because molybdenum has a lower magnetic susceptibility than iron and cobalt, which are ferromagnetic elements. Molybdenum also has higher radiopacity than 316L stainless steel and L605 alloys because molybdenum has a higher material mass absorption coefficient and a higher density. Molybdenum is commercially available in tubing form from Eagle Alloys, Goodfellow, and Minitubes. A comparison of the material properties of commercially pure molybdenum versus 316L stainless steel and L605 is presented in Table I, below. 
     
       
         
           
               
               
               
               
               
             
               
                 TABLE I 
               
               
                   
               
               
                   
                 Young&#39;s 
                   
                 % 
                   
               
               
                   
                 Modulus 
                 0.2% offset yield 
                 elongation 
                 Density, 
               
               
                 Alloy: 
                 (E), msi 
                 strength, ksi 
                 at fracture 
                 g/cc 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 Molybdenum 
                 44 
                 70 
                 20 
                 10.2 
               
               
                 316L stainless steel 
                 28 
                 45 
                 55 
                 8.0 
               
               
                 L605 
                 33 
                 89 
                 50 
                 9.3 
               
               
                   
               
            
           
         
       
     
       FIG. 2  depicts a cross section of a band  22  or connector  24  of a stent. The member can have a microstructure that includes a molybdenum-rich base region  32 , an inter-diffusion region  34 , and a surface region  36 . The molybdenum-rich base region  32  can include at least 50 weight percent molybdenum. The surface region  36  can include at least one of the following metals, alone or in combination with each other: titanium, rhenium, yttrium, palladium, rhodium, ruthenium, tungsten, tantalum, iridium, zirconium, hafnium, niobium, and chromium. The inter-diffusion region  34  can include a varying concentration of molybdenum, which decreases in the thickness direction from the molybdenum-rich base region to the surface region of the member. 
     The molybdenum-rich base region  32  can include at least 50 weight percent molybdenum, but can also include other metals, such as titanium, rhenium, yttrium, palladium, rhodium, ruthenium, tungsten, tantalum, zirconium, hafnium, iridium, and/or chromium. In some embodiments, the molybdenum-rich base region  32  can be limited to no more than 10 weight percent of any of these elements. The molybdenum-rich base region can have a density of at least 9.5 g/cc. 
     In some embodiments, the molybdenum-rich base region can have a molybdenum concentration of at least 95 weight percent. For example, the molybdenum-rich base region can include Mo TZM, Mo TZC, or Mo HCT alloys. Mo TZC alloy includes 1.25 weight percent titanium, 0.3 weight percent zirconium, 0.15 weight percent carbon, and a balance of essentially molybdenum. Mo TZM alloy includes between 0.25 and 1.0 weight percent titanium, between 0.04 and 2.0 weight percent zirconium, between 0.01 and 0.04 weight percent carbon, and a balance of essentially molybdenum. Mo HCT, from Elmet Technologies, includes 99.95% pure Mo doped with potassium silicate. Mo HCT can have a maximum of 150 ppm potassium, a maximum of 300 ppm silicon, and a maximum of 200 ppm oxygen. HCT stands for High reCrystallization Temperature. The properties for Mo HCT are essentially the same as for pure Mo, but the benefit of using Mo HCT is that it allows for diffusion heat treatment at higher temperatures than for pure Mo and thus it can allow for interdiffusion in shorter processing times. The material properties of Mo TZC and Mo TZM are included below in Table II. 
     
       
         
           
               
               
               
               
               
               
             
               
                 TABLE II 
               
               
                   
               
               
                   
                 Ultimate 
                 Yield 
                   
                   
                   
               
               
                   
                 Tensile 
                 Strength, 
                 Elongation, 
                 Modulus, 
                 Density, 
               
               
                 Alloy: 
                 Strength, ksi 
                 ksi 
                 % 
                 msi 
                 g/cc 
               
               
                   
               
             
            
               
                 Mo TZC 
                 144 
                 105 
                 22 
                 47 
                 10.1 
               
               
                 Mo TZM 
                 140 
                 125 
                 10 
                 47 
                 10.2 
               
               
                   
               
            
           
         
       
     
     The surface region  36  can include at least one of the following metals, alone or in combination with each other: titanium, rhenium, yttrium, palladium, rhodium, ruthenium, tungsten, tantalum, iridium, zirconium, hafnium, niobium, and chromium. The surface region can enhance corrosion resistance and/or improve the biocompatibility of the stent. In some embodiments, the surface region can be essentially free of molybdenum. In other embodiments, the surface region can include molybdenum in amounts lower than 50 percent by weight. In some embodiments, the surface region can include titanium. For example, the surface region can include essentially pure titanium or can include a titanium-molybdenum alloy. 
     The microstructure can also include an inter-diffusion region in which the concentration of molybdenum decreases in the thickness direction from the molybdenum-rich base region to the surface region of the member. In some embodiments, the inter-diffusion region can be at least 1 micron thick. In some embodiments, the inter-diffusion region can be between 10 nanometers and 10 microns. The inter-diffusion region can include a mixture of the constituents of the surface region  36  and the molybdenum-rich base region  32  with a concentration gradient transitioning from a region of higher molybdenum concentration adjacent to the molybdenum-rich base region  32  to a lower molybdenum concentration adjacent to the surface region  36 . 
       FIGS. 3A-3C  depict an exemplary method for producing a member having a molybdenum-rich base region  32 , a surface region  36 , and an inter-diffusion region  34  therebetween. For example, as shown in  FIG. 3A , a molybdenum-rich substrate  32  having at least 50 weight percent molybdenum can be provided. The substrate  32  can be cleaned in a plasma vapor deposition coating chamber with an oxide reduction process using an argon-hydrogen plasma. 
     As shown in  FIG. 3B , a layer of a second metal  38  can be deposited onto the substrate  32 . The second material  38  can include titanium, rhenium, yttrium, palladium, rhodium, ruthenium, tungsten, tantalum, iridium, zirconium, hafnium, niobium, or chromium. The second material  38  can be deposited using conventional plasma deposition equipment. The second material  38  can form a deposit of up to about 20 microns thick (e.g., between 20 nanometers and 1 micron thick). The layer of second material  38  can also be deposited by other commercially available ion implantation, sputter coating, chemical vapor deposition, or electroplating methods. 
     As shown in  FIG. 3C , the inter-diffusion region can be created by applying a surface-alloying diffusion treatment. For example, a heat treatment can be performed in high vacuum at greater than about 10 −5  torr. The heat treatment can be performed at a temperature selected from the range of 100° C. below the molybdenum tubing recrystallization temperature to 100° C. above the recrystallization temperature for 30 to 240 minutes. During this thermal exposure, the molybdenum and second metal would interdiffuse and produce an alloy of the constituents of the molybdenum-rich substrate  32  and the second material  38 . The resulting surface region  36  can either be made up entirely of the second material  38  or can include molybdenum diffused from the molybdenum-rich substrate  32 . The surface of the stent can contain 0 to 50% molybdenum, which can be controlled by controlling the extent of inter-diffusion. For example, the diffusivity of molybdenum in titanium at 1,000° C. was calculated to be 5.852 μ 2 /second and at 1,200° C. was calculated to be 294.5 μ 2 /second. The diffusion treatment can also convert a work hardened molybdenum-rich substrate to a condition of lower strength and higher ductility. 
     The tensile properties of the diffusion treated surface alloyed stent material, such as that shown in  FIG. 2 , would be between 44 and 50 msi Young&#39;s modulus, between 50 and 80 ksi 0.2% offset yield strength, between 65 and 95 ksi ultimate tensile strength, and/or greater than 15 percent elongation to break. 
     In some embodiments, the surface region  36  can be essentially pure titanium. In other embodiments, the surface region  36  comprises a titanium-molybdenum alloy. A titanium-molybdenum alloy can include up to about 50 weight percent molybdenum, and in some embodiments can contain less than 40 weight percent molybdenum. In some embodiments, a titanium containing surface region  36  can also include rhenium, yttrium, palladium, rhodium, ruthenium, tungsten, tantalum, iridium, zirconium, hafnium, niobium, and/or chromium as additional alloying elements. 
     In some embodiments, the surface region  36  can further be converted to oxides, nitrides, carbides, or combinations thereof. In some embodiments, zirconium, hathium, iridium, or chromium can further be applied to the surface region  36  and converted to an oxide. If the surface region  36  includes titanium and the air atmosphere were supplemented with a partial pressure of nitrogen, titanium oxynitride can form on the surface region  36  instead of titanium oxide. Titanium oxynitride may have a pro-healing response to minimize restenosis. In some embodiments, the surface can include TiO 2 , Nb 2 O 5  and/or Ta 2 O 5 . An alternate method could be to use electrochemical anodizing to build an oxide layer rather than thermal treatment methods. 
     In some embodiments, the stent can include iridium and/or iridium oxide. For example, iridium can be applied to a molybdenum base metal and converted into an iridium oxide. Iridium can also be present as an intermediate alloying constituent present in the inter-diffusion region  34 . In some embodiments, a stent can include a molybdenum base metal, a concentration gradient transitioning from the molybdenum base metal to iridium or an alloy thereof, and a concentration gradient transitioning from iridium or an alloy thereof to titanium or an alloy thereof. The intermediate iridium or iridium alloy can be between about 5 to 10 microns thick in order to prevent small cracks from reaching the molybdenum base metal. 
     In some embodiments, a drug eluting polymer coating can also be applied to the surface region  36 . For example, drug eluding polymer coatings include those described in U.S. Pat. No. 5,674,242, U.S. Ser. No. 09/895,415, filed Jul. 2, 2001, and U.S. Ser. No. 10/232,265, filed Aug. 30, 2002. The therapeutic agents, drugs, or pharmaceutically active compounds can include, for example, anti-thrombogenic agents, antioxidants, anti-inflammatory agents, anesthetic agents, anti-coagulants, and antibiotics. 
       FIG. 4  shows an example of a method  40  of making a stent  20 . As shown, method  40  can include forming a tube (step  42 ) that includes molybdenum or a molybdenum alloy. The tube can be subsequently cut to form bands  22  and connectors  24  (step  44 ) to produce an unfinished stent. Areas of the unfinished stent affected by the cutting can be subsequently removed (step  46 ). The unfinished stent can be finished by applying a second material and heat treating to form a stent  20  having a molybdenum-rich base region  32 , a surface region  36 , and an inter-diffusion region  34  (step  48 ). 
     For example, a stent can be made from a hollow rod of molybdenum or a molybdenum alloy. The hollow rod can have an outer diameter of 0.8 to 1.2 inches and an inner diameter of 0.4 to 0.6 inches and a length of 6 to 9 inches. The hollow rod could be conventionally canned and hot-extruded to reduce the wall thickness to about 0.05 inches. The tube can be reduced in size via fixed mandrel or floating plug tube drawing operations with intermediate stress relieving steps to the final configuration of a 0.060 to 0.080 inch outer diameter and a 0.050 to 0.070 inch inner diameter (depending on the desired finished stent size). The stent tubing can be subjected to laser machining to cut the stent bands  22  and connectors  24  in the wall. Electrochemical etching and polishing can be used to remove the laser-affected layer of material, to produce the final dimensions of the stent substrate  32 , and to produce a smooth surface texture. The stent substrate  32  would then be subject to the deposition and diffusion treatments as discussed above in regard to  FIGS. 3A-3C  to produce a stent having bands  22  and/or connectors  24  having a molybdenum-rich base region  32 , a surface region  36 , and an inter-diffusion region  34  as shown in  FIG. 2 . The finished molybdenum containing stent can be crimped onto a balloon catheter, packaged, and sterilized. 
     Stent  20  can be of a desired shape and size (e.g., coronary stents, aortic stents, peripheral vascular stents, gastrointestinal stents, urology stents, and neurology stents). Depending on the application, stent  20  can have a diameter of between, for example, 1 mm to 46 mm. In certain embodiments, a coronary stent can have an expanded diameter of from 2 mm to 6 mm. In some embodiments, a peripheral stent can have an expanded diameter of from 5 mm to 24 mm. In certain embodiments, a gastrointestinal and/or urology stent can have an expanded diameter of from 6 mm to about 30 mm. In some embodiments, a neurology stent can have an expanded diameter of from about 1 mm to about 12 mm. An abdominal aortic aneurysm (AAA) stent and a thoracic aortic aneurysm (TAA) stent can have a diameter from about 20 mm to about 46 mm. 
     For example, a molybdenum-containing bare-metal balloon-expandable coronary stent can have a wall thickness of 0.0030 inches. Such a balloon-expandable stent can have a diameter recoil of less than 6 percent upon balloon expansion to 3.2 mm diameter. The stent can require between 0.20 and 0.40 Newtons force per millimeter of stent length to compress it from an initial balloon expanded diameter of 3.2 mm to 2.75 mm diameter oval within a V-shaped platens compression tester. 
     In use, stent  20  can be used, e.g., delivered and expanded, using a catheter delivery system. Catheter systems are described in, for example, Wang U.S. Pat. No. 5,195,969, Hamlin U.S. Pat. No. 5,270,086, and Raeder-Devens, U.S. Pat. No. 6,726,712. Stents and stent delivery are also exemplified by the Sentinol system, available from Boston Scientific Scimed, Maple Grove, Minn. 
     In some embodiments, a stent can be fabricated by forming a wire including a molybdenum-rich base region  32 , a surface region  36 , and an inter-diffusion region  34 , and knitting and/or weaving the wire into a tubular member. 
     Stent  20  can also be a part of a covered stent or a stent-graft. For example, stent  20  can include and/or be attached to a biocompatible, non-porous or semi-porous polymer matrix made of polytetrafluoroethylene (PTFE), expanded PTFE, polyethylene, urethane, or polypropylene. 
     The molybdenum containing members described herein can be used to form other endoprostheses. For example, the molybdenum containing members can be used to form a guidewire or a hypotube. The molybdenum members can also be used to form metal staples and wires used for wound closure. 
     All publications, references, applications, and patents referred to herein are incorporated by reference in their entirety. 
     Other embodiments are within the claims.