Patent Publication Number: US-2012029613-A1

Title: Bioerodible Endoprosthesis

Description:
CROSS-REFERENCE TO RELATED APPLICATION 
     This application claims priority under 35 USC §119(e) to U.S. Provisional Patent Application Serial No. 61/367,929, filed on Jul. 27, 2010, the entire contents of which are hereby incorporated by reference. 
    
    
     TECHNICAL FIELD 
     This disclosure relates to bioerodible endoprostheses. 
     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. 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 The balloon can then be deflated, and the catheter withdrawn. 
     In another delivery technique, the endoprosthesis is formed of an elastic material that can be reversibly compacted and expanded, e.g., elastically or through a material phase transition. During introduction into the body, the endoprosthesis is restrained in a compacted condition. Upon reaching the desired implantation site, the restraint is removed, for example, by retracting a restraining device such as an outer sheath, enabling the endoprosthesis to self-expand by its own internal elastic restoring force. 
     It is sometimes desirable for an implanted endoprosthesis to erode over time within the passageway. For example, a fully erodible endoprosthesis does not remain as a permanent object in the body, which may help the passageway recover to its natural condition. Bioerodible endoprostheses can be formed from, e.g., a polymeric material, such as polylactic acid, or from a metallic material, such as magnesium, iron or an alloy thereof. 
     Bioerodible metals can erode due to corrosion in vivo. The corrosion process, however, can be non-uniform due to localized attacks and difficult to control. In vivo corrosion rates are difficult to predict from in vitro data. Accordingly, it is difficult to design a bioerodible endoprosthesis having the desired structural integrity for a desired period of time. 
     SUMMARY 
     An endoprosthesis is disclosed that includes a composite including a matrix of a bioerodible iron or bioerodible iron alloy and a plurality of particles within the matrix. The particles include palladium, manganese oxide, one or more transition metal oxides, or a combination thereof. 
     The particles can have diameters of less than 50 micrometers. In some embodiments, the particles have diameters of between 0.5 micrometers and 10 micrometers. In other embodiments, the particles are nanoparticles having diameters of between 20 nm and 500 nm. 
     The particles can include a core and a shell. In some embodiments, the core can include iron, magnesium, cobalt, zinc, copper, or a combination thereof and the shell includes palladium. In other embodiments, the core comprises magnesium and the shell includes manganese oxide. 
     In some embodiments including palladium, the palladium can be at least 99 percent pure. In some embodiments, the composite includes between 0.5 and 5 weight percent of palladium. 
     In some embodiments including manganese oxide, the manganese oxide is selected from the group of MnO 2 , Mn 3 O 4 , and combinations thereof. In some embodiments, the manganese oxide is mixed with a transition metal oxide. 
     The bioerodible iron alloy can be an alloy including iron and manganese. In some embodiments, the alloy includes at least 90 weight percent iron and less than 10 weight percent manganese. In some embodiments, the alloy includes less than 5 weight percent manganese. 
     The endoprosthesis can be a stent. 
     The particles can act as an oxidation reduction catalyst that accelerates the corrosion rate of the bioerodible iron or bioerodible iron alloy when the endoprosthesis is within a physiological environment, 
     The details of one or more embodiments are set forth in the accompanying drawings and the description below. Other features, objects, and advantages will be apparent from the description and drawings, and from the claims. 
    
    
     
       DESCRIPTION OF DRAWINGS 
         FIG. 1  is an example of a stent. 
         FIG. 2  depicts a cross-section of a stent strut body including a matrix of bioerodible iron or a bioerodible iron alloy and a plurality of particles within the matrix. 
         FIG. 3  depicts the structure of a nanoparticle. 
         FIG. 4  is a perspective view of an artificial heart valve in an expanded configuration. 
       Like reference symbols in the various drawings indicate like elements. 
     
    
    
     DETAILED DESCRIPTION 
     Stent  20 , shown in  FIG. 1 , is discussed below as an example of one endoprosthesis according to the instant disclosure. Stent  20  includes a pattern of interconnected struts forming a structure that contacts a body lumen wall to maintain the patency of the body lumen. For example, 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, small 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. Other examples of endoprostheses can include covered stents, stent-grafts, and artificial heart valves. 
     Stent  20  is a composite of a matrix of a bioerodible iron or a bioerodible iron alloy and a plurality of particles with the matrix. The term “composite,” as used herein, requires the presence of two or more constituent materials that remain separate and distinct within the finished structure. A “composite” is not an alloy, i.e., a solid solution. Instead, the particles remain compositionally distinct from the bioerodible iron or bioerodible iron alloy of the matrix. The particles are not precipitates within a bioerodible iron alloy. 
     The particles include an oxidation reduction catalyst that increases the rate of corrosion of the matrix within a physiological environment. Under physiological conditions, the corrosion reaction of iron is cathodically controlled and the corrosion current is at least partially determined by the limiting diffusion current for the oxygen reduction reaction. The corrosion reaction is more likely to be limited by the diffusion current for the oxygen reduction reaction when the iron is within an acidic environment. The addition of an oxidation reduction catalyst to stent  20  as part of a composite structure can accelerate the corrosion of the iron and can ensure that the stent struts degrade in a controlled manner. 
       FIG. 2  depicts a cross-section of a stent strut (band  22  or connector  24 ). Exposed portions of the discrete particles  36  act as oxidation reduction catalyst sites  37  and adjacent areas of the bioerodible iron or bioerodible iron alloy act as anodic sites  39 . As the bioerodible iron or bioerodible iron alloy erodes within the physiological environment, discrete particles  36  are released and new particles  36  become exposed to the physiological environment. In some embodiments, endothelialization of the stent  20  can prevent the particles  36  from being released into the blood stream. The particles  36  can be sized such that the release of the particles into the blood stream does not result in embolisms. In some embodiments, the particles  36  can have a maximum diameter of 50 micrometers. For example, the particles  36  can have diameters of between 0.5 and 10 micrometers. In some embodiments, the particles are nanoparticles having a diameter of between 20 nm and 500 nm. The concentration and distribution of the particles  36  within the matrix  38  can be varied to impact the erosion rates of the iron in different portions of the stent  20 . As will be discussed below, the composite of an oxidation reduction catalysts and a matrix of bioerodible iron or a bioerodible iron alloy can be formed using a powder metal sintering process, which can be used to prevent the particles  36  from being alloyed with the iron or iron alloy. 
     The oxidation reduction catalyst is palladium in some embodiments. The palladium can be at least 95 percent by weight pure. In some embodiments, the palladium is at least 99 percent by weight pure. In some embodiments, the nanoparticles can consist solely of palladium. In other embodiments, the nanoparticles can have a shell of palladium over a core. The core can include iron, magnesium, cobalt, zinc, copper, or a combination thereof.  FIG. 3  depicts an example of a nanoparticle  36  having a core  42  and a shell of palladium  44 . The palladium  44  may be a single atomic layer or include multiple layers. In some embodiments, the nanoparticles  36  can include additional intermediate layers. For example, nanoparticles having a shell of palladium can be formed by forming an alloy of palladium with iron, cobalt, zinc, or copper and shaping the alloy into nanoparticles. The constituents of the alloy can then be segregated such that the palladium moves to the surface of the nanoparticle by elevating the temperature of the nanoparticles. An example of a similar process is described in K. Gong et al., J. Electroanal. Chem. (2010), doi:10.1016/j.jelechem.2010.04.011. Additional layers of palladium can be deposited by depositing molecular layers of copper using under potential deposition (“UPD”) and replacing the copper with palladium. 
     The oxidation reduction catalyst is manganese oxide in some embodiments. In some embodiments, the manganese oxide is Mn 3 O 4 , MnO 2 , or a combination thereof. Manganese metal and MnO do not have the same catalytic effect as Mn 3 O 4  or MnO 2  because the crystal structure of the manganese oxide affects the catalytic performance. The manganese oxide can overlie a body of bioerodible iron or a bioerodible iron alloy and/or can be in the form of particles within a matrix of a bioerodible iron or bioerodible iron alloy. In some embodiments, a matrix of a bioerodible iron or a bioerodible iron alloy can include nanoparticles of manganese oxide. The nanoparticles can have an average diameter of between 20 nm and 500 nm. In some embodiments, the manganese oxide is in the form of nanoparticles having a shell of manganese oxide overlying a core. The core, in some embodiments, can be a bioerodible metal that breaks down in the physiological environment to produce basic byproducts. In some embodiments, the core is magnesium. A shell of manganese oxide over a magnesium core can prevent the magnesium from galvanically polarizing the iron. 
     The oxidation reduction catalyst can include a transition metal oxide, such as ruthenium dioxide. For example, manganese oxide can be mixed with a transition metal oxide. In some embodiments, stent  20  include a combination of different types of oxidation reduction catalysts. For example, a stent  20  can include multiple particles of palladium, manganese oxide, and ruthenium dioxide within a matrix of bioerodible iron or a bioerodible iron alloy. 
     Stent  20  includes a matrix featuring a bioerodible iron or bioerodible iron alloy. In some embodiments, the matrix includes substantially pure iron (e.g., greater than 99% pure iron). Bioerodible iron alloys can include at least 65% by weight iron. For example, the bioerodible metal portion can include a bioerodible iron alloy that includes up to twenty percent manganese, up to 10 percent silver, and up to five percent carbon. For example, in some embodiments, a bioerodible iron alloy can include at least 90 weight percent iron and less than 10 weight percent manganese. In some embodiments, the alloy includes less than 5 weight percent manganese. In some embodiments, the alloy includes at least 1 weight percent manganese. For example, a stent can include a matrix of an iron-manganese alloy having 95-99 weight percent iron and 1-5 weight percent manganese and a plurality of nanoparticles of palladium within the matrix, the composite comprising a total of 0.5 to 5 weight percent palladium. 
     The composite can be produced using conventional techniques. In some embodiments, the composite is formed to include between 0.1 and 30 percent by weight of the oxidation reduction catalyst. In some embodiments, the composite includes between 0.5 and 20 weight percent of the oxidation reduction catalyst. The composite can include less than 10 weight percent of the oxidation reduction catalyst. For example, a composite of palladium and a bioerodible iron or bioerodible iron alloy can include between 0.5 and 5 weight percent palladium. A composite of manganese oxide and a bioerodible iron or bioerodible iron alloy can include between 0.5 and 5 weight percent manganese oxide. 
     The composite can be formed by powder sintering methods. Particles of the oxidation reduction catalyst can be mixed with powder of the bioerodible iron or bioerodible iron alloy. The mixture of powders can then be pressed and heated to a temperature below the melting point of the oxidation reduction catalyst, but sufficient to cause the bioerodible iron or bioerodible iron alloy particles to adhere. Because the powders are not heated above the melting point of the oxidation reduction catalyst, the oxidation reduction catalyst does not alloy with the iron. A sintered bar or tube can then be further worked and shaped into the desired dimensions of a stent by press rolling and other mechanical shaping techniques. In some embodiments, the oxidation reduction catalysts are in the form of nanoparticles having a core and shell structure, with the shell containing the oxidation reduction catalyst. 
     Stent  20  can be configured for vascular, e.g., coronary and peripheral vasculature or non-vascular lumens. For example, they can be configured for use in the esophagus or the prostate. Other lumens include biliary lumens, hepatic lumens, pancreatic lumens, urethral lumens. 
     Stent  20  can be of a desired shape and size (e.g., coronary stents, aortic stents, peripheral vascular stents, gastrointestinal stents, urology stents, tracheal/bronchial stents, and neurology stents). Depending on the application, the stent can have a diameter of between, e.g., about 1 mm to about 46 mm. In certain embodiments, a coronary stent can have an expanded diameter of from about 2 mm to about 6 mm. In some embodiments, a peripheral stent can have an expanded diameter of from about 4 mm to about 24 mm. In certain embodiments, a gastrointestinal and/or urology stent can have an expanded diameter of from about 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. The stent can be balloon-expandable, self-expandable, or a combination of both (e.g., see U.S. Pat. No. 6,290,721). 
     Stent  20  can also be part of a covered stent, a stent-graft and/or other endoprostheses. The endoprosthesis, in some embodiments, can an artificial heart valve. For example, an artificial heart valve  50  is depicted in  FIG. 4 . The heart valve  50  has a generally circular shape. A stent member  52  is formed of a wire including a composite of bioerodible iron or a bioerodible iron alloy with an oxidation reduction catalyst. The stent member  52  is formed in a closed zig-zag configuration. In other embodiments, the stent member of the artificial heart valve can include a plurality of bands with connectors in between. The valve member  55  is flexible and includes a plurality of leaflets  56 . The leaflet portion of the valve member  55  extends across or transverse of the cylindrical stent member  52 . The leaflets  56  are the actual valve and allow for one-way flow of blood. Extending from the periphery of the leaflet portion is a cuff portion  57 . The cuff portion is attached to the stent by sutures  58 . Sutures  53  can be used to attach the artificial heart valve  50  to heart tissue. The valve member  55  can be formed of polymer such as polytetrafluoroethylene or a polyester. In other embodiments, the valve member  55  can be a bioerodible polymer. 
     All publications, patent applications, patents, and other references mentioned herein are incorporated by reference herein in their entirety. 
     A number of embodiments have been described. Nevertheless, it will be understood that various modifications may be made without departing from the spirit and scope of this disclosure. Accordingly, other embodiments are within the scope of the following claims.