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U.S. Patent Aug. 16,2011 Sheet 4 615 US 7,998,192 B2
This invention relates to endoprostheses, and more particularly to bioerodible endoprostheses.
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 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, e.g., so that it can contact the walls of the lumen. Stent delivery is further discussed in Heath, U.S. Pat. No. 6,290,721, the entire contents of which is hereby incorporated by reference herein.
The expansion mechanism may 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 endopro sthesis at a predetermined position in contact with the lumen wall. The balloon can then be deflated, and the catheter withdrawn from the lumen.
In another delivery technique, the endopro sthesis 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.
Passageways containing endoprostheses can become reoccluded. Re-occlusion of such passageways is known as restenosis. It has been observed that certain drugs can inhibit the onset of restenosis when the drug is contained in the endoprosthesis. It is sometimes desirable for an endoprosthesis-contained therapeutic agent, or drug to elute into the body fluid in a predetermined manner once the endoprosthesis is implanted.
There is described an endoprosthesis that includes a body defining a flow passage therethrough and is capable of maintaining patency in a blood vessel. The body includes iron or an alloy thereof. The body has a nano-structured surface comprising iron oxide in which the individual nano-structures have a height to thickness aspect ratio of at least 5:1.
In some embodiments, the height to thickness aspect ratio is between 10:1 and 20:1. For example, the height of each individual nano-structure can be between about 50 nm and about 500 nm. In some embodiments, the individual nanostructures can have a flake structure each having a width of at least twice the thickness. For example, the thickness of each
individual flake nano-structure can be between about 5 nm to 50 nm and the width of each individual flake nano-structure can be between about 100 nm to 500 nm. In other embodiments, the individual nano-structures can have a rice grain structure. For example, an individual rice grain nano-structure can have a diameter of between about 5 nm to 50 nm. In some embodiments, an average separation distance between adjacent individual nano-structures can be between about 1 nm and 50 nm.
The nano-structured surface of the body can also be described by its roughness characteristics and/ or resistance to corrosion. For example, the surface of the body can have a S d, of between 120 and 200. A nano-structured surface can have a resistance to corrosion of less than 5 Kohms (e.g., about 2 Kohms).
In some embodiments, the endoprosthesis can further include a polymer coating over at least a portion of the nanostructured surface. For example, the polymer coating can include a co-block polymer of polyglutamic acid and one or more of the following polymers: poly(ethylene oxide), polycaprolactam, poly(lactic-co-glycolic acid), and polysaccharides. For example, the polymer can include a co-block polymer of polyglutamic acid and a non-ionic polysaccharide (e.g., pullulan). In some embodiments, the polymer coating can be a drug eluting coating that includes a therapeutic agent.
The endoprosthesis can, in some embodiments, be bioerodible. For example, the body can include a bioerodible metal, such as pure iron. A coating, if present, can also be a bioerodible polymer.
The endoprosthesis can, in some embodiments, be a stent.
In another aspect, an endoprosthesis is described that includes a body defining a flow passage therethrough that is capable of maintaining patency in a blood vessel. The body includes iron or an alloy thereof and has a surface comprising iron oxide. The endoprosthesis also includes a coating over the surface that includes a co-block polymer of polyglutamic acid.
In some embodiments, the co-block polymer of polyglutamic acid canbe a co-blockpolymer of polyglutamic acid and of a polysaccharide. The polysaccharide can be a nonionic polysaccharide such as pullulan.
The endoprosthesis can, in some embodiments, be bioerodible. For example, the body can include a bioerodible metal, such as pure iron, and the coating can also be a bioerodible polymer.
The endoprosthesis can, in some embodiments, be a stent.
In another aspect, a method of producing an endoprosthesis is described. The method includes exposing a portion of an endoprosthesis, or a precursor thereof, to an electrolytic solution and applying a plurality of current pulses to the endoprosthesis. The endoprosthesis includes iron or an alloy thereof. The application of the current pulses to the endoprosthesis while exposed to the electrolytic solution creates a nanostructured surface on the endoprosthesis having a plurality of individual nano-structures having a height to thickness aspect ratio of at least 5: 1.
In some embodiments, the applied current pulses can include cathodic pulses, anodic pulses, or a combination thereof. The applied current pulses can include galvanic square waves, potential square waves, or a combination thereof.
The method, in some embodiments, can further include applying a coating including a polymer to the nano-structured surface.
In some embodiments, the endoprosthesis can be a bioerodible stent.
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.
FIGS. 1A-1C are longitudinal cross-sectional views illustrating delivery of a stent in a collapsed state, expansion of the stent, and deployment of the stent.
FIG. 2 is a perspective view of an embodiment of an expanded stent.
FIGS. 3A-3F depict examples of a surface having nanostructures having height to thickness aspect ratios of at least 5:1.
FIG. 4A depicts a stent having corrosion enhancing regions on connectors between bands.
FIG. 4B depicts a stent after the erosion of the connectors between bands.
FIGS. 5A-5D depict how a stent strut erodes with and without spaced corrosion enhancing regions.
Like reference symbols in the various drawings indicate like elements.
Referring to FIGS. 1A-1C, a stent 20 is placed over a balloon 12 carried near a distal end of a catheter 14, and is directed through the lumen 16 (FIG. 1A) until the portion carrying the balloon and stent reaches the region of an occlusion 18. The stent 20 is then radially expanded by inflating the balloon 12 and compressed against the vessel wall with the result that occlusion 18 is compressed, and the vessel wall surrounding it undergoes a radial expansion (FIG. 1B). The pressure is then released from the balloon and the catheter is withdrawn from the vessel (FIG. 1C).
Referring to FIG. 2, a balloon-expandable stent 20 can have a stent body having 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 stent 20 defines a flow passage therethrough and is capable of maintaining patency in a blood vessel.
The stent 20 can include a body including iron or an alloy thereof. In some embodiments, the stent 20 can include a body including one or more bioerodible metals, such as magnesium, zinc, iron, or alloys thereof. The body can have a surface including iron oxide.
The stent body can have a surface having a morphology characterized by high-surface-area porous nano-structures. The nano-structured surface can provide a high surface area characterized by crevices between and around spaced individual nano-structures. For example, the individual nanostructures can be in the form of grains or flakes. The nanostructured surface can trigger and accelerate the rate of erosion or degradation of the bioerodible metal of the body of the stent. Additionally, select areas of a stent body can be treated to have the nano-structured surface to allow for select areas of stent degradation. Additionally, the nano-structured surface can allow for coatings to be deposited and interlock into the surface, enhancing adhesion. In some embodiments, the surface can also encourage endothelial growth to enhance endothelialization of the stent 20. The nano-structured sur
face may also allow for greater freedom of motion and a stent body that is less likely to fracture as the stent is flexed in use prior from the controlled bioerosion of the stent body. The stresses can be caused by flexure of the stent, during expansion or contraction of the stent or as the stent is delivered through a tortuously curved body lumen increase as a function of the distance from the stent axis. As a result, in some embodiments, the nano-structured surface can be on abluminal regions of the surface of the stent body or at other high stress points, such as the regions of the bands 22 adjacent to the connectors 24 which undergo greater flexure during expansion or contraction.
The nano-structured surface can be characterized by its visual appearance, the size and arrangement of individual nano-structures, its roughness and/or its resistance to corrosion. Examples of surfaces having the morphological features are shown in FIGS. 3A-3F. In some embodiments, the morphology of the surface can include “com flake” and/or “rice grain” microstructures.
FIGS. 3A-3C depict a nano-structured surface characterized by definable thin planar flakes resembling com flakes. The “com flake” surface structures can have a height, H, of about 50 to 500 nm, e.g., about 100-300 nm, a width, W, of about 100 to 500 nm, e.g., about 200-400 nm, and a thickness, T, ofabout 5 to 50 nm, e.g., about 10-15 nm. The “com flake” structures can have an aspect ratio of the height to the thickness ofabout 5:1 or more, e.g., 10:1 to 20:1. The “com flake” structures can overlap in one or more layers. The separation between adjacent “corn flake” structures can be about 1-50 nm. FIGS. 3D-3F depict a nano-structured surface characterized by definable sub-micron sized grains resembling rice grains. The “rice grains” surface structures can have a height, H, of about 50 to 500 nm, e.g. about 100-300 nm, and an average diameter, D, ofabout 5 nm to 50 nm, e.g. about 10-15 nm. The “rice grain” structures have an aspect ratio of the height to the diameter of about 5:1 or more, e.g. 10:1 to 20: 1. The “rice grain” structures can overlap in one or more layers. The separation between adjacent “rice grain” structures can be about 1-50 nm.
The roughness of the nano-structured surface can also be characterized by the average roughness, Sa, the root mean square roughness, S q, and/or the developed interfacial area ratio, S d,. The Sa and S q parameters represent an overall measure of the texture of the surface. Sa and S q are relatively insensitive in differentiating peaks, valleys and the spacing of the various texture features. Surfaces with different visual morphologies can have similar Sa and S q values. For a surface type, the Sa and S q parameters indicate significant deviations in the texture characteristics. S d, is expressed as the percentage of additional surface area contributed by the texture as compared to an ideal plane the size of the measurement region. S d, further differentiates surfaces of similar amplitudes and average roughness. Typically S d, will increase with the spatial intricacy of the texture whether or not Sa changes. In some embodiments, where the surface of the body has a nano-structured surface, the S d, canbe about 100 or more, e.g. about 120 to 200. For example, the surface can have an S d, of about 150. In addition or in the alternative, the morphology can have an Sq of about 20 or more, e.g. about 20 to 30.
The corrosion resistance of the high-surface-area porous nano-structures of iron, having iron oxide at the surface, can be less than 5 Kohms, e.g., about 2 Kohms. This represents a significantly reduced resistance to corrosion when compared to iron having a smooth surface finish, which has a corrosion resistance of about 20 Kohms. The resistance to corrosion can be calculated by Electrochemical Impedance Spectroscopy