INCORPORATION BY REFERENCE TO ANY PRIORITY APPLICATIONS

Any and all applications for which a foreign or domestic priority claim is identified in the Application Data Sheet as filed with the present application are hereby incorporated by reference under 37 CFR 1.57.

FIELD

Embodiments of the present invention relate to nanostructures including metal oxide and methods of making and using the same.

BACKGROUND

Surface modifications have been explored to provide beneficial characteristics to a variety of devices. One of the methods that has been explored for preparing such surface modifications is electrochemical anodization. In electrochemical anodization, the surface being modified forms an anode electrode. The anode is generally then placed into electrical contact with at least one cathode through an electrolyte solution. A voltage is then applied across the anode and cathode for a period of time. Anodization often results in undesirable and uncontrollable amorphous material accumulating on the surface of the anode. Moreover, the resulting material may contain too high of a concentration of cytotoxic elements, such as nickel, rendering the resulting surface unusable for many potential applications. Accordingly, there is a need for reliable methods of preparing surface modifications with desirable structures and elemental compositions.

SUMMARY

The present invention relates to nanostructures comprising metal oxide and methods of forming the same on the surface of substrates. The substrates may be titanium or any titanium alloy, such as a nickel titanium alloy. The metal oxide nanostructures may have a lattice layer disposed on top of a nanotube layer disposed on top of the surface of a substrate. The lattice and nanotube layers may be formed during an anodization process. The distal surface of the lattice layer may or may not be enriched in titanium. Some embodiments of the present metal oxide nanostructures and methods of forming the nanostructures on surfaces have several features, no single one of which is solely responsible for their desirable attributes.

While some embodiments of the resulting metal oxide nanostructured surfaces provide numerous advantages over other known metal oxide layers, they may be particularly beneficial when used with implantable medical devices because they may promote healing by enhancing the integration of the medical device with the surrounding biological tissue. An example is the promotion of endothelial cell migration and proliferation and the inhibition of smooth muscle cell migration and proliferation in the cardiovascular and systemic vascular systems. With a medical device such as a stent, for example, some embodiments may promote the growth of a confluent endothelial layer while inhibiting the growth of the neointima, thus reducing restenosis and leading to long-term patency at the site of implantation. The medical device can also be an orthopedic implant, such as a knee implant, bone screw, or bone staple, such as those used for hand and foot bone fragments osteotomy fixation and joint arthrodesis.

In one embodiment, the nanostructure comprises two layers: a first layer of tubular structures, and a second layer comprising a lattice. The nanostructure can be arranged such that the first layer is situated between a substrate (e.g., a metal article) and the second layer. The substrate can be any suitable metal article, including an implantable medical device such as a stent. In some embodiments, the surface of the metal article comprises a titanium alloy, such as a nickel titanium alloy. The first layer can be formed at least in part from the surface of the substrate via anodization. The tubular structures comprise metal oxide(s). The tubular structures may or may not further comprise carbon, fluoride, or other elements. In some embodiments, the tubular structures comprise titanium oxide and nickel oxide. The composition of the tubular structures depends in part on the composition of the surface of substrate from which they are formed. The nanostructure can be formed on substantially (e.g. at least about 90%) all of the entire outer surface of a substrate, or it can be formed on a single or multiple discrete locations on the surface of a substrate.

Each of the tubular structures of the first layer has a cylindrical wall with an inner surface, a top surface, and an outer surface, the cylindrical wall defining a lumen therein. The geometry of a tubular structure generally defines an axis that further generally defines a direction of the tubular structure. If a tubular structure were a circular cylinder, then the axis is the locus of the centers of the circles defined by the tubular structure. With tubular structures having a polygonal or irregular cross section, the axis generally follows the center of the tubular structure. Collectively, the top surfaces of the tubular structures define a distal surface of the first layer. In some embodiments, the tubular structures can be aligned generally perpendicular to the substrate and generally parallel to one another (e.g. arranged vertically compared to a horizontal substrate). In other embodiments, at least some of the tubular structures can be formed at an angle other than 90° relative to the substrate. In some embodiments, the tubular structures are immediately adjacent to one another, such that there is no observable space between the outer surface of a cylindrical wall of one tubular structure and the outer surface(s) of the cylindrical wall(s) of the adjacent tubular structure(s). In some embodiments, the outer surface of the cylindrical wall of one tubular structure is in direct contact with the outer surface(s) of the cylindrical wall(s) of the adjacent tubular structure(s). In some embodiments, the outer surface of the cylindrical wall of one tubular structure is integrally connected with the outer surface(s) of the cylindrical wall(s) of the adjacent tubular structure(s). In other embodiments, the tubular structures can be arranged such that there is space between the cylindrical wall of one tubular structure and the cylindrical wall of the adjacent tubular structures. In some embodiments, tubular structures are not cylindrical and can define a variable cross-sectional area along the axial direction. In some embodiments, tubular structures can define polygonal or irregular openings that are approximately or generally perpendicular to the axial direction. The openings can be characterized by major and minor axes and a hydraulic diameter. A hydraulic diameter is a ratio of four times an area divided by a perimeter of a given opening.

The second layer comprises a lattice disposed on top of the distal surface of the first layer. The lattice comprises metal oxide(s). The lattice may or may not further comprise carbon, fluoride, or other elements. This second layer can be in contact with or integrally connected to the distal surface of the first layer (e.g. the top surface of cylindrical walls of the plurality of tubular structures). Compared to the discrete tubular structures of the first layer, the second layer generally comprises a single integrated structure. In some embodiments, the distal surface of the second layer is significantly free of any amorphous material or particulate with dimensions greater than about 30 nm. In some embodiments, the lattice comprises metal oxides including but not limited to titanium oxide and nickel oxide. In some embodiments, the ratio of titanium oxide to nickel oxide on the distal surface (e.g. the top about 10 nm) of the second layer is greater than about 10:1, or about 17:1.

Methods of forming a nanostructure comprising metal oxide on the surface of a substrate are also disclosed herein. In one embodiment, the method comprises placing an anode and at least one cathode in electrical contact through a first electrolyte solution, applying a first voltage across the anode and cathode(s) through the first electrolyte solution for a first time period, modifying or replacing the first electrolyte solution to provide a second electrolyte solution containing an acid, and applying a second voltage across the anode and cathode(s) through the second electrolyte solution for a second time period. In some embodiments, the anode and cathode(s) are optionally provided. In some embodiments, the first electrolyte does not contain an acid or contains a very low amount of acid. The first electrolyte solution may be modified by adding an acid, resulting in the second electrolyte solution. Alternatively, the first electrolyte solution may be removed and replaced with a second electrolyte solution that contains an acid. In some embodiments, the first electrolyte solution may be modified by lowering the pH or increasing the acid concentration to achieve the second electrolyte solution. In some embodiments, the substrate is not modified to remove any portion of the oxide structure(s) formed during the first time period prior to the second time period. The first and second voltages can be the same or different. The first and second time periods can be the same or different. The temperature of the electrolyte solution in the first and second time periods can be the same or different.

In another embodiment, the method comprises placing an anode and at least one cathode in electrical contact through a first electrolyte solution, applying a first voltage across the anode and cathode(s) through the first electrolyte solution for a first time period, removing at least part of the oxide layer formed on the surface of the anode during the first time period, and applying a second voltage across the anode and cathode(s) through the second electrolyte solution for a second time period. In some embodiments, the anode and cathode(s) are optionally provided. The first and second voltages can be the same or different. The first and second time periods can be the same or different. The temperature of the electrolyte solution in the first and second time periods can be the same or different.

In another embodiment, the method comprises placing an anode and at least one cathode in electrical contact through a first electrolyte solution, applying a first voltage across the anode and cathode(s) through the first electrolyte solution for a first time period, removing at least part of the oxide layer formed on the surface of the anode during the first time period, modifying or replacing the first electrolyte solution to provide a second electrolyte solution containing an acid, and applying a second voltage across the anode and cathode(s) through the second electrolyte solution for a second time period. In some embodiments, the anode and cathode(s) are optionally provided. The first electrolyte solution may be modified by adding an acid. Alternatively, the first electrolyte solution may be removed and replaced with a second electrolyte solution that contains an acid. In some embodiments, the first electrolyte solution may be modified by lowering the pH or increasing the acid concentration to achieve the second electrolyte solution. The first and second voltages can be the same or different. The first and second time periods can be the same or different. The temperature of the electrolyte solution in the first and second time periods can be the same or different.

In some embodiments of the methods discussed above, the anode can be an implantable medical device, including but not limited to a stent. The medical device can also be an orthopedic implant, such as a knee implant, bone screw, or bone staple, such as those used for hand and foot bone fragments osteotomy fixation and joint arthrodesis. The cathode can be platinum, iron, stainless steel, graphite, or any other conductive material.

Methods of forming a biocompatible nanostructure on the surface of an implantable medical device are also disclosed herein. In some embodiments, the methods comprise placing an anode and cathode in electrical contact through a first electrolyte solution containing ethylene glycol, water, and ammonium fluoride, applying a first voltage across the anode and cathode through the first electrolyte solution for a first time period, modifying or replacing the first electrolyte solution resulting in a second electrolyte solution containing an acid, and applying a second voltage across the anode and cathode through the second electrolyte solution for a second time period. In some embodiments, an implantable medical device is optionally provided as the anode. In some embodiments, the cathode is optionally provided. In some embodiments, the first electrolyte solution does not contain an acid. In some embodiments, the first electrolyte solution can be modified by adding an acid, including but not limited to sulfuric acid or hydroiodic acid. In other embodiments, the first electrolyte solution can be removed and replaced with a second electrolyte solution that contains an acid, including but not limited to sulfuric acid or hydroiodic acid. The first and second voltages can be the same or different. The first and second time periods can be the same or different. The temperature of the electrolyte solution in the first and second time periods can be the same or different. In some embodiments, the first and second voltages are about 25V, the first and second time periods are about 5 minutes, and the temperature of the electrolyte solution in the first and second time periods is about 30 C. In some embodiments, the oxide material formed during the first time period is not removed or modified prior to the second time period.

These, as well as other components, steps, features, objects, benefits, and advantages, will now become clear from a review of the following detailed description of illustrative embodiments, the accompanying drawings, and the claims.

