Source: https://patents.google.com/patent/WO2009155328A2/en
Timestamp: 2019-04-25 15:32:42+00:00

Document:
2009-06-17 Application filed by Boston Scientific Scimed, Inc. filed Critical Boston Scientific Scimed, Inc.
An endoprosthesis, e.g., a stent (e.g., a drug eluting stent), that includes a porous surface and hollow elements integrated with a coating on the surface and a method of making the same are disclosed.
This application claims priority under 35 USC §119(e) to U.S. Provisional Patent Application Serial No. 61/073,647, filed on June 18, 2008, the entire contents of which are hereby incorporated by reference.
This disclosure relates to coating endoprostheses.
Many endoprostheses be delivered inside the body by a catheter. Typically the catheter supports a reduced-size or compacted form of the endoprosthesis as it is transported to a desired site in the body, for example the site of weakening or occlusion in a body lumen. Upon reaching the desired site the endoprosthesis is installed so that it can contact the walls of the lumen. Stent delivery is further discussed in Heath, U.S. 6,290,721, the entire contents of which is hereby incorporated by reference herein.
It is sometimes desirable for an endoprosthesis to contain a therapeutic agent, or drag which can elute into the body fluid in a predetermined manner once the endoprosthesis is implanted.
In one aspect, the disclosure features an endoprosthesis, e.g., a stent (e.g., a drag eluting stent), that includes a surface having a porous structure of a first material and a coating of a second material. The second material defines a plurality of hollow elements. In some implementations, the hollow elements and the coating are made of non- polymeric material, for example, a ceramic material, a metal, an alloy, or a mixture thereof.
Implementations may include one or more of the following features. The endoprosthesis has a body formed of the first material. The first material is a metal. The metal is stainless steel, nitinol, tungsten, tantalum, rhenium, iridium, silver, gold, bismuth, platinum or alloys thereof. The second material is a ceramic material. The ceramic material is silicon oxide, titanium oxide, iridium oxide or a mixture thereof. The coating and hollow elements have a porous structure. The porous structure comprises a plurality of pores having a width of about 0.5 nm to about 500nm. The coating and hollow elements have a thickness of about 1 nm to about 1 μm. The hollow elements contain a drag. The porous structure of the first material includes a plurality of pores having a width and a depth of about 1 nm to about 25 μm. The surface has a porosity of about 90% or less (e.g., about 80%, about 70%, about 60%, about 50% or less). The hollow elements are hollow spheres. The hollow spheres have an outer diameter of about 10 nm to about 5 μm. The hollow spheres have an inner diameter of about 1 nm to about 5 μm. In another aspect, the disclosure features a method of making an endoprosthesis that includes applying a sacrificial template to a surface, applying a ceramic precursor over the template, treating the precursor to form a ceramic deposit, and removing the sacrificial template to form a hollow ceramic region.
Implementations may include one or more of the following features. The ceramic precursor includes a metal oxide precursor. The metal oxide precursor is tetraethylorthosilicate, titanium isopropoxide, or iridium acetylacetonate. The sacrificial template is removed by calcination or chemical removal. A plurality of pores are formed on a surface where the pores have a width and a depth of about 1 ran to about 25 μm. The pores of the spheres and ceramic are formed by calcination or chemical removal. The structure of the substrate is formed by a plasma treatment. A polyelectrolyte layer is applied before applying the sacrificial template. A polyelectrolyte layer is applied after applying the sacrificial template. One or more polyelectrolyte layers could be applied to the porous surface. The sacrificial template is applied to the polyelectrolyte layers. The sacrificial template is applied to the porous surface. One or more polyelectrolyte layers are applied to the sacrificial template. The sacrificial template is pretreated with a polyelectrolyte to be encapsulated by a polyelectrolyte coating. The polyelectrolyte layers are applied by LBL deposition. The sacrificial template is a sphere. The sacrificial template is a polymer particle. The polymer particle has a size of about 10 nm to about 10 μm. A sol-gel ceramic precursor is applied to the polyelectrolyte layers and the template. The sol-gel precursor reacts to form a ceramic gel deposit. The ceramic gel deposit is converted to an oxide or ceramic (e.g. by hydrolysis and condensation reactions). The polyelectrolyte layers and template are removed by heating or chemical etching. A drug is provided in the hollow ceramic region. The drug is loaded to the endoprosthesis after the coating is formed. The drug is loaded to the endoprosthesis before the coating is formed. Aspects and/or implementations may have one or more of the following additional advantages. The endoprosthesis, e.g., a drug eluting stent, can include a large number of porous hollow elements embedded in and/or on its porous surface to facilitate drug elution. For example, metallic materials are mechanically stable but often lack porosity or drug- loading capacity while ceramic materials are porous but lack sufficient mechanical strength. A composition of a pretreated metal surface with hollow ceramic elements to contain drugs can have both sufficient mechanical strength and drug-loading capacity (e.g. porosity). The wall thickness of hollow elements can be independently controlled to be thin enough to resist cracking, flaking or peeling from the underlying metal surface. The porosity of a drug eluting stent, can be controlled, e.g., increased, by embedding the hollow elements having porous walls without compromising mechanical strength of the stent. The enhanced porosity facilitates drug loading. The drug elution profile over time can be selected by controlling the porosity of the metal and/or the properties of the hollow elements. For example, hollow elements made of the same material with thicker walls will release drugs at slower rate than the ones with thinner walls. Thus, introducing hollow elements with different size, different wall thickness, wall composition, or a geometry allows building a variety of drug release profiles. Further, the drug load can be easily varied by controlling the number of hollow elements put in the stent. Additionally, pore size can be changed by altering salt, additives (i.e., glucose) and pH in the PEM layers. The endoprostheses may be fully endothelialized, and thus not need to be removed from a lumen after implantation.
Figs. 1 A-IC are longitudinal cross-sectional views, illustrating delivery of a stent in a collapsed state, expansion of the stent, and the deployment of the stent in a body lumen.
Fig. 2Ais a perspective view of an implementation of a stent; Fig. 2B is a schematic cross-sectional view of the surface of the stent; Fig. 2C is another schematic cross-sectional view of the surface; and Fig. 2D is a schematic cross-sectional view of a drug-containing hollow sphere.
Figs. 5A-5C are FESEM pictures of some implementations of the disclosure..
DETAILED DESCRIPTION Referring to Figs. 1 A-IC, during implantation of a stent 10, the stent is placed over a balloon 12 carried near a distal end of a catheter 14, and is directed through a lumen 15 (Fig. IA) until the portion carrying the balloon and stent reaches the region of an occlusion 18. The stent is then radially expanded by inflating 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. IB). The pressure is then released from the balloon and the catheter is withdrawn from the vessel (Fig. 1 C), leaving the stent 10 fixed within lumen 15. The stent can be balloon expandable, as illustrated above, or a self-expanding stent. Examples of stents are described in Heath '721, supra. Referring to Figs. 2A-2D, stent 10 is configured to include a releasable drug and to release the drug in a controlled and predetermined manner once it is implanted. Referring to Fig. 2 A, the stent 10 is a generally tubular member including a plurality of fenestrations 22. The stent body 23 is made of a first material 120, e.g., a metal, and has a surface 140. Referring to Fig. 2B, a schematic cross-sectional view of the surface 140, the surface is porous or corrugated. Referring to Fig. 2C, a schematic cross-sectional view of the surface, the surface 140 is further coated with a second material 180, e.g., a ceramic material, and includes drug-containing hollow spheres 160 made of the second material 180. Referring to Fig. 2D, a schematic cross-sectional views of a drug-containing hollow sphere, the hollow sphere 160 includes a wall 240 having pores 260 connecting the interior 220 and the exterior 200 of the sphere 160. The interior 220 is a cavity containing a drug. The drug from the interior 220 of the spheres passes through the pores 260 into the porous space of surface 140 and then into body.
Referring particularly to Figs. 2B and 2C, in some implementations, the first material 120 is a substantially pure metallic element, or an alloy (e.g., 316L stainless steel). The porous region of the surface 140 not only increases the effective area of the surface but also provides a more confined area to which the hollow spheres 160 can be attached, protecting the spheres from being dislodged during handling, delivery and deployment of the stent. In implementations, cross-sectional size or width of the pores 170 is large compared to the sphere size; in implementations, the width and depth of the pores provide a secondary control of drug release by diffusion of the drug through the pores 170 once the drug comes out of the hollow spheres 160. In other implementations, the pores are sized such that they provide a minor or no role in diffusion-limiting the drug release to body fluid or tissue. In implementations, the pore depth, La, is in the range of about 1 nanometer ("ran") to 250 micrometers ("microns" or "μm"), e.g., about 100 nm to 1 μm; the pore width, Lw, is in the range of about 1 nm to 25 μm, e.g., about 500 nm to 1 μm. hi implementations, the ratio of the volume of pores to the total volume of the surface region, or porosity of the surface 140 is about 90% or less (e.g., about 80%, about 70%, about 60%, about 50% or less). Alternatively or additionally, the inward surface 150 of stent body 23 can also have a porous structure. In some implementations, the porous surface 140 is formed by plasma treatment, such as plasma immersion ion implantation ("PIII") as is described in details below. Referring particularly to Figs 2C and 2D, in some implementations, the second material 180 and hollow spheres are a ceramic material (e.g., SiOx, or IrOx). The outer diameter of the hollow spheres 160 is preferably smaller than or comparable to the pore dimensions (width and depth) of the porous region of surface 140. For example, the outer diameter, D0, is about 10 nm to 5 μm, e.g., 100 nm to 1 μm. The inner diameter, D,, of the hollow spheres 160 ranges from about 1 nm to 5 μm, e.g., 20 nm to 500 nm. Thickness, D1, of the sphere wall 240 can range from 1 nm to 1 μm, e.g., 10 nm to 500 nm and it may or may not be uniform along the radial axes. In implementations, the wall 240 has a porous structure, hi preferred implementations, wall 240 has an open-cell porous structure, so that the pores 260 in wall 240 are interconnected and serve as passageways between the interior and the exterior of the hollow spheres 160. The width of pores 260, lw, varies from about 0.5 nm to 500nm, e.g., 1 nm to 100 nm. In implementations, the second material coating 180 has substantially the same porous structure as the sphere wall 240 described above, and thickness of the coating 180 varies from about 1 nm to 2 μm, e.g., 10 nm to 1500 nm. A particular ceramic is IROX, which can have therapeutic benefits such as enhancing endothelialization. IROX and other ceramics are discussed further in Alt et al., U.S. Patent No. 5,980,566.
Suitable ceramics also include metal oxides, oxides and transition metal oxides (e.g. oxides of titanium, zirconium, halnium, tantalum, molybdenum, tungsten, thenium, and iridium; silicon; silicon-based ceramics, such as those containing silicon nitrides, silicon carbides and silicon oxides (sometimes referred to as glass ceramics); calcium phosphate ceramics (e.g. hydroxyapatite); carbon and carbon-based, ceramic-like materials such as carbon nitrides. In implementations, the second material and sphere are provided through a sol-gel reaction assisted with the use of spherical sacrificial templates (described below).
Referring to Fig. 3, a method 300 of making and coating porous surface 140 is described and illustrated. The left side of this figure provides a flow diagram of processing steps and the right side provides a cross-sectional schematic of a region of the stent at the corresponding processing steps. The method 300 includes forming a porous surface (step 302), applying a polyelectrolyte layer (step 304), applying sacrificial templates, e.g., templating polystyrene spheres (step 306), applying another polyelectrolyte layer (step 308), forming ceramic deposit within each polyelectrolyte layer (step 310), removing polyelectrolyte layers and sacrificial templates to form a porous ceramic coating integrated with hollow ceramic spheres which have porous walls and cavities on surface 140 (step 312), and loading the cavities with a therapeutic agent or drug (step 314). In some implementations, one or more polyelectrolyte layers are applied to the surface 140 and/ or sacrificial templates, and the thickness of the polyelectrolyte layers influence the final thickness of the ceramic coating. In step 302, the porous structure of surface 140 can be formed by plasma treatment, chemical etching, or electrochemical processes. In some implementations, plasma immersion ion implantation ("PIII") is applied. During PIII, one or more charged species in a plasma, such as an argon plasma, are accelerated at high velocity toward a substrate, e.g., a stent or a stent precursor ("pre-stent") such as a metal tube. Acceleration of the charged species, e.g., particles, of the plasma towards the pre-stent is driven by a pulsed electrical potential difference between the plasma and the pre-stent. Alternatively, the electrical potential difference can be applied between the plasma and an electrode that is underneath the pre- stent such that the pre-stent is in a line-of-sight. Upon impact with the outward surface and/or inward surface of the pre-stent, the charged species, due to their high velocity, penetrate a distance into the stent, interact with the first material, e.g., displace atoms and/or knock atoms out of the first material and form porous structures in the surface. The penetration depth is being controlled, at least in part, by the potential difference between the plasma and the stent. Other factors such as dose-rate, process temperature, and ion type can be selected to control the porous structure of the surface. An implementation of PIII system is described further below. hi steps 304, 306, and 308, after the porous surface is formed, charged layers containing polyelectrolytes and sacrificial templates are assembled upon the surface, using a layer-by-layer ("LBL") technique in which the layers electrostatically self-assemble. In the LBL technique, a first layer having a first net surface charge is deposited on an underlying substrate, followed by a second layer having a second net surface charge that is opposite in sign to the net surface charge of the first layer. Thus, the charge on the outer layer is reversed upon deposition of each sequential layer. Additional first and second layers can then be alternatingly deposited on the substrate to build multi-layered structure to a predetermined or targeted thickness. For example, in steps 304 and 308, deposited layers 141 and 143 can either be a polyelectrolyte monolayer or polyelectrolyte multilayers ("PEM") with thickness ranging from 0.3 nm to 1 μm, e.g., 1 ran to 500 ran. hi an intermediate layer between 141 and 143, charged sacrificial templates 142, e.g., polystyrene spheres, polymethylmethacrylate ("PMMA"), or silica templates , with net surface charges opposite in sign to those of layers 141 and 143, are deposited (step 306). hi certain implementations, the LBL assembly can be conducted by exposing a selected charged substrate (e.g., stent) to solutions or suspensions that contain species of alternating net charge, including solutions or suspensions that contain charged templates (e.g., polystyrene spheres), polyelectrolytes, and, optionally, charged therapeutic agents. The concentration of the charged species within these solutions and suspensions, which can be dependent on the types of species being deposited, can range, for example, from about 0.01 mg/mL to about 100 mg/mL (or to about 50 mg/niL, or to about 30 mg/mL). The pH of these suspensions and solutions can be such that the templates, polyelectrolytes, and optional therapeutic agents maintain their charge. Buffer systems can be used to maintain charge. The solutions and suspensions containing the charged species (e.g., solutions/suspensions of templates, polyelectrolytes, or other optional charged species such as charged therapeutic agents) can be applied to the charged substrate surface using a variety of techniques.
12489 Berlin. Other suitable templates include melamine formaldehyde (MF), poly-DL-lactic acid (PLA), cubic sodium chloride and truncated rhombohedral sugar crystallites. The latter two are as well an example of template shapes that are not round, but in this case have the shape of crystals. Living cells such as red blood cells and bacteria can be used as templates. The template is burned away during a calcination step, similar to the removal of the simple polystyrene templates. Encapsulation of cells is discussed in Yu et al., Biomaterials 25 (2004) 3655-3802. In particular implementations, sacrificial templates can be pretreated with polyelectrolytes via LBL assembly to have a PEM coating. Next, the PEM-coated templates can be suspended or dissolved in a solvent and be applied to a substrate. When PEM-coated templates are used, step 308 is optional. In further implementations, sacrificial templates with different PEM coating and/or different thickness of PEM coating can be applied to a common stent, e.g., to create hollow structures at different portions of the stent with different wall thicknesses so that various drug eluting profiles at different portions of the stent can be achieved. Polyelectrolyte are polymers having charged (e.g., ionically dissociable) groups. The number of these groups in the polyelectrolytes can be so large that the polymers are soluble in polar solvents (including water) when in ionically dissociated form (also called polyions). Depending on the type of dissociable groups, polyelectrolytes can be classified as polyacids and polybases. When dissociated, polyacids form polyanions, with protons being split off. Polyacids include inorganic, organic and biopolymers. Examples of polyacids are polyphosphoric acids, polyvinylsulfuric acids, polyvinylsulfonic acids, polyvinylphosphonic acids and polyacrylic acids. Examples of the corresponding salts, which are called polysalts, are polyphosphates, polyvinylsulfates, polyvinylsulfonates, polyvinylphosphonates and polyacrylates. Polybases contain groups that are capable of accepting protons, e.g., by reaction with acids, with a salt being formed. Examples of polybases having dissociable groups within their backbone and/or side groups are polyallylamine, polyethylimine, polyvinylamine and polyvinylpyridine. By accepting protons, polybases form polycations. Some polyelectrolytes have both anionic and cationic groups, but nonetheless have a net positive or negative charge.
(e.g., polyelectrolytes having molecular weights of a few hundred Daltons up to macromolecular polyelectrolytes (e.g., polyelectrolytes of synthetic or biological origin, which commonly have molecular weights of several million Daltons). Still other examples of polyelectrolyte cations (polycations) include protamine sulfate polycations, poly(allylamine) polycations (e.g., poly(allylamine hydrochloride) (PAH)), polydiallyldimethylamrnonium polycations, polyethyleneimine polycations, chitosan polycations, gelatin polycations, spermidine polycations and albumin polycations. Examples of polyelectrolyte anions (polyanions) include poly(styrenesulfonate) polyanions (e.g., poly(sodium styrene sulfonate) (PSS)), polyacrylic acid polyanions, sodium alginate polyanions, eudragit polyanions, gelatin polyanions, hyaluronic acid polyanions, carrageenan polyanions, chondroitin sulfate polyanions, and carboxymethylcellulose polyanions.
Still more examples of polyelectrolytes and LBL assembly are disclosed in commonly assigned U. S. Serial No. 10/985,242, U.S. application publicly available through USPTO Public Pair, and Lefaux et al., "Polyelectolyte Spin Assembly: Influence of Ionic Strength on the Growth of Multilayered Films," J PoIm Sci Part B: Polym Phys 42, Wiley Periodicals, Inc.; 3654-3666, 2004, the entire disclosure of which is incorporated by reference herein.
In step 310, a precursor solution for a consequent in situ sol-gel reaction is applied to the stent surface with deposited layers 141, 142, and 143. The solution permeates the polyelectrolyte layers 141 and 143, and those of spheres 142 if they are pretreated with PEM. Then an in situ sol-gel reaction can take place within the interstices of polyelectrolytes.
Page U of 22 Application No. 60/884,471, filed September 14, 2006; Maehara et al, Thin Solid Films 438- 39:65-69, 2003; Kim et al, Thin Solid Films 499:83-89, 2003; and Bu et al, J. Europ. Cer. Soc. 25:673-79, 2005.
312 as discussed above is preferred. In particular implementations, a drug-polymer conjugate is applied instead of the drug itself, e.g. a conjugate of a polymer deposited in the LBL steps, hi some implementations, the drug can be loaded within the pores of the ceramic coating and the walls of hollow spheres. The stent can further include more than one therapeutic agent by having more than one drug within each hollow element, or by having different drugs in different hollow elements.
Patent Application No. 2005/0216074. Polymers for drug elution coatings are also disclosed in U.S. Published Patent Application No. 2005/019265 A.
Referring to Fig. 4, an implementation of a PIII processing system is shown. System 80 includes a vacuum chamber 82 having a vacuum port 84 connected to a vacuum pump and a gas source 130 for delivering a gas, e.g., argon, helium, xenon, oxygen, or nitrogen, to chamber 82 to generate a plasma. System 80 includes a series of dielectric windows 86, e.g., made of glass or quartz, sealed by o-rings 90 to maintain a vacuum in chamber 82. Removably attached to some of the windows 86 are radio frequency ("RF") plasma sources 92, each source having a helical antenna 96 located within a grounded shield 98. The windows without attached RF plasma sources are usable, e.g., as viewing ports into chamber 82. Each antenna 96 electrically communicates with an RF generator 100 through a network 102 and a coupling capacitor 104. Each antenna 96 also electrically communicates with a tuning capacitor 106. Each tuning capacitor 106 is controlled by a signal D, D', D" from a controller 110. By adjusting each tuning capacitor 106, the output power from each RF antenna 96 can be adjusted to maintain homogeneity of the generated plasma.
In use, a plasma is generated in chamber 82 and accelerated to a pre-stent 13. Pre- stent 13 can be made, for example, by forming a tube including the conventional metallic material and laser cutting a stent pattern in the tube, or by knitting or weaving a tube from a metallic wire or filament. A gas, such as argon, is introduced from gas source 130 into chamber 82, where a plasma is generated. The charged species in the generated plasma, e.g., an argon plasma, are accelerated toward all portions of pre-stent 13, including exterior 131 and interior portions 132 of the pre-stent, and thus, bombard the surface of the pre-stent. PIII is described by Chu, U.S. Patent No. 6,120,660; Brukner , Surface and Coatings Technology, 103-104, 227-230 (1998); and Kutsenko, Acta Materialia, 52, 4329-4335 (2004), the entire disclosure of each of which is incorporated by reference herein. The configuration of the porous stent surface formed is controlled in the PIII process by tuning the ion penetration depth and ion concentration through selection of the type of ion, the ion energy and ion dose. For example, when the ions have a relatively low energy, e.g., 10 kiloelectronvolts ("keV") or less, penetration depth is relatively shallow when compared with the situation when the ions have a relatively high energy, e.g., greater than 40 keV. In some implementations, the potential difference can be greater than 10 kilovolts ("kV"), e.g., greater than 20 kV , greater than 40 kV , greater than 50 kV , greater than 60 kV, greater than 75 kV, or even greater than 100 kV. The ion dosage being applied to a surface can range from about 1 x 1014 ions/cm2 to about 1 x 1019 ions/cm2, e.g., from about 1 x 1015 ions/cm2 to about 1 x 1018 ions/cm2.
Page I5 of 22 (PAH/PSS/PAH/PSS). Each layer was deposited over 20 minutes and then rinsed three times with DI water. Subsequently, the PEM-coated coupon is placed into a sol-gel solution of 1 g TEOS in 5OmL ethanol, with 5mL water and 0.5mL 25 wt.% NH40H and kept there for ~16 hours before it is retrieved. The coupon was rinsed three times in DI water. As a final step, the gel/PEM-coated coupon is placed in a tube furnace and calcined in air at 5400C for 4.5 hours, ramping up at a rate of 360°C/hour from room temperature, total oven time ~6hrs. The sample was allowed to cool in the oven overnight until it reached room temperature. Referring to Figs. 5 A-5C, Field Emission Scanning Electron Microscopy ("FESEM") images of the surface of a 316L stainless steel coupon processed with the method disclosed in Fig.3 are shown. As shown in Fig 5 A, ceramic spheres are bound to a ceramic coating which almost conformally overlies the porous or corrugated surface of the coupon. Referring to Fig 5B, a further magnified FESEM image, porous features of the ceramic coating and ceramic spheres are move visible. Referring to Fig 5C, which was taken at a higher electron accelerating voltage (e.g., 15 kV), the ceramic spheres are hollow. In further implementations, the hollow elements and/or ceramic coating may incorporate magnetic particles, e.g., nanoparticles, loosely sitting in the cavities by applying sacrificial templates with magnetic kernels which remain in the ceramic material after templating material is removed. The implementations may have one or more additional following advantages, including that the release profile of a therapeutic agent from an endoprosthesis, e.g., a ceramic coated stent, can be controlled through non-invasive means, e.g., a magnetic field. The magnetic field can be used to selectively agitate the particles, to modify the porosity of the ceramic. Use of magnetic particles is described further in U.S. Provisional Application No. 60/845,136, filed September 15, 2006.
Ln some implementations, after the forming hollow spheres inside of the porous surface generated by e.g. PIII and filling them with a drug, an additional material can be applied to fill the remaining space in the porous surface, for example, a bioerodible polymer (PLGA, PLLA) (with or without an additional drug load), or a highly porous sol-gel layer prepared at low temperature, e.g., at room temperature.
Any stent described herein can be dyed or rendered radio-opaque by addition of, e.g., radio-opaque materials such as barium sulfate, platinum or gold, or by coating with a radio- opaque material. In implementations, the porous structure can be formed directly on the stent body, as described above, or the porous structure can be formed in a coating over the stent body. The coating may be, e.g., a radio-opaque metal.
The stent can include (e.g., be manufactured from) metallic materials, such as stainless steel (e.g., 316L, BioDur® 108 (UNS S29108), and 304L stainless steel, and an alloy including stainless steel and 5-60% by weight of one or more radiopaque elements (e.g., Pt, Ir, Au, W) (PERSS®) as described in US-2003-0018380-A1, US-2002-0144757-A1, and US-2003- 0077200-A1), Nitinol (a nickel-titanium alloy), cobalt alloys such as Elgiloy, L605 alloys, MP35N, titanium, titanium alloys (e.g., Ti-6A1-4V, Ti-50Ta, Ti-IOIr), platinum, platinum alloys, niobium, niobium alloys (e.g., Nb-IZr) Co-28Cr-6Mo, tantalum, and tantalum alloys. Other examples of materials are described in commonly assigned U.S. Application No.
10/672,891, filed September 26, 2003; and U.S. Application No. 11/035,316, filed January 3, 2005. Other materials include elastic biocompatible metal such as a superelastic or pseudo- elastic metal alloy, as described, for example, in Schetsky, L. McDonald, "Shape Memory Alloys", Encyclopedia of Chemical Technology (3rd ed.), John Wiley & Sons, 1982, vol. 20. pp. 726-736; and commonly assigned U.S. Application No. 10/346,487, filed January 17, 2003.
The stent 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 implementations, a coronary stent can have an expanded diameter of from about 2 mm to about 6 mm. In some implementations, a peripheral stent can have an expanded diameter of from about 4 mm to about 24 mm. In certain implementations, a gastrointestinal and/or urology stent can have an expanded diameter of from about 6 mm to about 30 mm. In some implementations, 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., U.S. Patent No. 6,290,721).
Medical articles include articles for exterior application to the body such as patches for delivery of therapeutic agent to intact skin and broken skin (including wounds) and implantable or insertable devices, for example, stents (including coronary vascular stents, peripheral vascular stents, cerebral, urethral, ureteral, biliary, tracheal, gastrointestinal and esophageal stents), stent coverings, stent grafts, vascular grafts, abdominal aortic aneurysm (AAA) devices (e.g., AAA stents, AAA grafts), vascular access ports, dialysis ports, catheters (e.g., urological catheters or vascular catheters such as balloon catheters and various central venous catheters), guide wires, balloons, filters (e.g., vena cava filters and mesh filters for distil protection devices), embolization devices including cerebral aneurysm filler coils (including Guglilmi detachable coils and metal coils), septal defect closure devices, drug depots that are adapted for placement in an artery for treatment of the portion of the artery distal to the device, myocardial plugs, patches, pacemakers, leads including pacemaker leads, defibrillation leads, and coils, ventricular assist devices including left ventricular assist hearts and pumps, total artificial hearts, shunts, valves including heart valves and vascular valves, anastomosis clips and rings, cochlear implants, tissue bulking devices, and tissue engineering scaffolds for cartilage, bone, skin and other in vivo tissue regeneration, sutures, suture anchors, tissue staples and ligating clips at surgical sites, cannulae, metal wire ligatures, urethral slings, hernia "meshes", artificial ligaments, orthopedic prosthesis such as bone grafts, bone plates, fins and fusion devices, joint prostheses, orthopedic fixation devices such as interference screws in the ankle, knee, and hand areas, tacks for ligament attachment and meniscal repair, rods and pins for fracture fixation, screws and plates for craniomaxillofacial repair, dental implants, or other devices that are implanted or inserted into the body.
Still further implementations are in the following claims.
1. An endoprosthesis, comprising: a surface, the surface comprising a porous structure of a first material; and a coating of a second material, the second material defining a plurality of hollow elements.
2. The endoprosthesis of claim 1, wherein the first material is a metal.
3. The endoprosthesis of claim 1, wherein the second material is a ceramic material.
4. The endoprosthesis of claim 3, wherein the ceramic material is silicon oxide, titanium oxide, iridium oxide or a mixture thereof.
5. The endoprosthesis of claim 1, wherein the coating and hollow elements have a porous structure.
6. The endoprosthesis of claim 5, wherein the porous structure comprises a plurality of pores having a width of about 0.5 nm to about 500nm.
7. The endoprosthesis of claim 1, wherein the hollow elements contain a drug.
8. The endoprosthesis of claim 1, wherein the porous structure of the first material comprises a plurality of pores having a width and a depth of about 1 nm to about 25 μm.
9. The endoprosthesis of claim 1, wherein the hollow elements are hollow spheres.
10. The endoprosthesis of claim 9, wherein the hollow spheres have an outer diameter of about 10 nm to about 5 μm.
11. The endoprosthesis of claim 1 , wherein the coating and hollow elements have a thickness of about 1 ran to about 1 μm.
12. The endoprosthesis of claim 1, wherein the endoprosthesis has a body formed of the first material.
13. A method of making an endoprosthesis, the method comprising: applying a sacrificial template to a surface; applying a ceramic precursor over the template; treating the precursor to form a ceramic deposit; and removing the sacrificial template to form a hollow ceramic region.
14. The method of claim 13, further comprising providing a drug in the hollow ceramic region.
15. The method of claim 13, further comprising forming a plurality of pores on a surface, said pores having a width and a depth of about 1 nm to about 25 μm; and applying said sacrificial template to said porous surface.
16. The method of claim 13, further comprising applying a polyelectrolyte layer to the sacrificial template, applying a sol-gel ceramic precursor to the polyelectrolyte and reacting the sol-gel precursor to form a ceramic gel deposit.
17. The method of claim 16, further comprising removing the polyelectrolyte and template by heating.
18. The method of claims 16 or 17, further comprising converting the ceramic gel deposit to an oxide or ceramic.
19. The method of claim 18, further comprising converting the ceramic gel deposit by firing.
20. The method of claim 16, further comprising applying a polyelectrolyte layer before applying said sacrificial template.
22. The method of claim 13, further comprising loading a drug to the endoprosthesis before the coating is formed.
23. The method of claim 13, wherein the sacrificial template is a polymer particle.
24. The method of 23, wherein the particle has a size of about 10 run to about 10 μm.
25. The method of 13, wherein the sacrificial template is pretreated with a polyelectrolyte to be encapsulated by a polyelectrolyte coating.

References: §119
 Application No. 60
 Application No. 2005
 Application No. 2005
 Application No. 60
 Application No.
10
 Application No. 11
 Application No. 10