CA2694686A1 - Articles having ceramic coated surfaces - Google Patents

Articles having ceramic coated surfaces Download PDF

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Publication number
CA2694686A1
CA2694686A1 CA2694686A CA2694686A CA2694686A1 CA 2694686 A1 CA2694686 A1 CA 2694686A1 CA 2694686 A CA2694686 A CA 2694686A CA 2694686 A CA2694686 A CA 2694686A CA 2694686 A1 CA2694686 A1 CA 2694686A1
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CA
Canada
Prior art keywords
ceramic
coating
coated article
shells
substrate
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
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CA2694686A
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French (fr)
Inventor
Jan Weber
Michele Zoromski
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Boston Scientific Scimed Inc
Original Assignee
Boston Scientific Scimed, Inc.
Jan Weber
Michele Zoromski
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Publication date
Application filed by Boston Scientific Scimed, Inc., Jan Weber, Michele Zoromski filed Critical Boston Scientific Scimed, Inc.
Publication of CA2694686A1 publication Critical patent/CA2694686A1/en
Abandoned legal-status Critical Current

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Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61FFILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02Prostheses implantable into the body
    • A61F2/04Hollow or tubular parts of organs, e.g. bladders, tracheae, bronchi or bile ducts
    • A61F2/06Blood vessels
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/08Materials for coatings
    • A61L31/082Inorganic materials
    • A61L31/088Other specific inorganic materials not covered by A61L31/084 or A61L31/086
    • CCHEMISTRY; METALLURGY
    • C23COATING METALLIC MATERIAL; COATING MATERIAL WITH METALLIC MATERIAL; CHEMICAL SURFACE TREATMENT; DIFFUSION TREATMENT OF METALLIC MATERIAL; COATING BY VACUUM EVAPORATION, BY SPUTTERING, BY ION IMPLANTATION OR BY CHEMICAL VAPOUR DEPOSITION, IN GENERAL; INHIBITING CORROSION OF METALLIC MATERIAL OR INCRUSTATION IN GENERAL
    • C23CCOATING METALLIC MATERIAL; COATING MATERIAL WITH METALLIC MATERIAL; SURFACE TREATMENT OF METALLIC MATERIAL BY DIFFUSION INTO THE SURFACE, BY CHEMICAL CONVERSION OR SUBSTITUTION; COATING BY VACUUM EVAPORATION, BY SPUTTERING, BY ION IMPLANTATION OR BY CHEMICAL VAPOUR DEPOSITION, IN GENERAL
    • C23C18/00Chemical coating by decomposition of either liquid compounds or solutions of the coating forming compounds, without leaving reaction products of surface material in the coating; Contact plating
    • C23C18/02Chemical coating by decomposition of either liquid compounds or solutions of the coating forming compounds, without leaving reaction products of surface material in the coating; Contact plating by thermal decomposition
    • C23C18/12Chemical coating by decomposition of either liquid compounds or solutions of the coating forming compounds, without leaving reaction products of surface material in the coating; Contact plating by thermal decomposition characterised by the deposition of inorganic material other than metallic material
    • C23C18/1204Chemical coating by decomposition of either liquid compounds or solutions of the coating forming compounds, without leaving reaction products of surface material in the coating; Contact plating by thermal decomposition characterised by the deposition of inorganic material other than metallic material inorganic material, e.g. non-oxide and non-metallic such as sulfides, nitrides based compounds
    • C23C18/1208Oxides, e.g. ceramics
    • CCHEMISTRY; METALLURGY
    • C23COATING METALLIC MATERIAL; COATING MATERIAL WITH METALLIC MATERIAL; CHEMICAL SURFACE TREATMENT; DIFFUSION TREATMENT OF METALLIC MATERIAL; COATING BY VACUUM EVAPORATION, BY SPUTTERING, BY ION IMPLANTATION OR BY CHEMICAL VAPOUR DEPOSITION, IN GENERAL; INHIBITING CORROSION OF METALLIC MATERIAL OR INCRUSTATION IN GENERAL
    • C23CCOATING METALLIC MATERIAL; COATING MATERIAL WITH METALLIC MATERIAL; SURFACE TREATMENT OF METALLIC MATERIAL BY DIFFUSION INTO THE SURFACE, BY CHEMICAL CONVERSION OR SUBSTITUTION; COATING BY VACUUM EVAPORATION, BY SPUTTERING, BY ION IMPLANTATION OR BY CHEMICAL VAPOUR DEPOSITION, IN GENERAL
    • C23C18/00Chemical coating by decomposition of either liquid compounds or solutions of the coating forming compounds, without leaving reaction products of surface material in the coating; Contact plating
    • C23C18/02Chemical coating by decomposition of either liquid compounds or solutions of the coating forming compounds, without leaving reaction products of surface material in the coating; Contact plating by thermal decomposition
    • C23C18/12Chemical coating by decomposition of either liquid compounds or solutions of the coating forming compounds, without leaving reaction products of surface material in the coating; Contact plating by thermal decomposition characterised by the deposition of inorganic material other than metallic material
    • C23C18/125Process of deposition of the inorganic material
    • C23C18/1254Sol or sol-gel processing
    • CCHEMISTRY; METALLURGY
    • C23COATING METALLIC MATERIAL; COATING MATERIAL WITH METALLIC MATERIAL; CHEMICAL SURFACE TREATMENT; DIFFUSION TREATMENT OF METALLIC MATERIAL; COATING BY VACUUM EVAPORATION, BY SPUTTERING, BY ION IMPLANTATION OR BY CHEMICAL VAPOUR DEPOSITION, IN GENERAL; INHIBITING CORROSION OF METALLIC MATERIAL OR INCRUSTATION IN GENERAL
    • C23CCOATING METALLIC MATERIAL; COATING MATERIAL WITH METALLIC MATERIAL; SURFACE TREATMENT OF METALLIC MATERIAL BY DIFFUSION INTO THE SURFACE, BY CHEMICAL CONVERSION OR SUBSTITUTION; COATING BY VACUUM EVAPORATION, BY SPUTTERING, BY ION IMPLANTATION OR BY CHEMICAL VAPOUR DEPOSITION, IN GENERAL
    • C23C18/00Chemical coating by decomposition of either liquid compounds or solutions of the coating forming compounds, without leaving reaction products of surface material in the coating; Contact plating
    • C23C18/02Chemical coating by decomposition of either liquid compounds or solutions of the coating forming compounds, without leaving reaction products of surface material in the coating; Contact plating by thermal decomposition
    • C23C18/12Chemical coating by decomposition of either liquid compounds or solutions of the coating forming compounds, without leaving reaction products of surface material in the coating; Contact plating by thermal decomposition characterised by the deposition of inorganic material other than metallic material
    • C23C18/125Process of deposition of the inorganic material
    • C23C18/1262Process of deposition of the inorganic material involving particles, e.g. carbon nanotubes [CNT], flakes
    • C23C18/127Preformed particles
    • CCHEMISTRY; METALLURGY
    • C23COATING METALLIC MATERIAL; COATING MATERIAL WITH METALLIC MATERIAL; CHEMICAL SURFACE TREATMENT; DIFFUSION TREATMENT OF METALLIC MATERIAL; COATING BY VACUUM EVAPORATION, BY SPUTTERING, BY ION IMPLANTATION OR BY CHEMICAL VAPOUR DEPOSITION, IN GENERAL; INHIBITING CORROSION OF METALLIC MATERIAL OR INCRUSTATION IN GENERAL
    • C23CCOATING METALLIC MATERIAL; COATING MATERIAL WITH METALLIC MATERIAL; SURFACE TREATMENT OF METALLIC MATERIAL BY DIFFUSION INTO THE SURFACE, BY CHEMICAL CONVERSION OR SUBSTITUTION; COATING BY VACUUM EVAPORATION, BY SPUTTERING, BY ION IMPLANTATION OR BY CHEMICAL VAPOUR DEPOSITION, IN GENERAL
    • C23C26/00Coating not provided for in groups C23C2/00 - C23C24/00
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2400/00Materials characterised by their function or physical properties
    • A61L2400/12Nanosized materials, e.g. nanofibres, nanoparticles, nanowires, nanotubes; Nanostructured surfaces
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10TTECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T428/00Stock material or miscellaneous articles
    • Y10T428/24Structurally defined web or sheet [e.g., overall dimension, etc.]
    • Y10T428/24802Discontinuous or differential coating, impregnation or bond [e.g., artwork, printing, retouched photograph, etc.]
    • Y10T428/24926Discontinuous or differential coating, impregnation or bond [e.g., artwork, printing, retouched photograph, etc.] including ceramic, glass, porcelain or quartz layer
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10TTECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T428/00Stock material or miscellaneous articles
    • Y10T428/29Coated or structually defined flake, particle, cell, strand, strand portion, rod, filament, macroscopic fiber or mass thereof
    • Y10T428/2913Rod, strand, filament or fiber
    • Y10T428/2918Rod, strand, filament or fiber including free carbon or carbide or therewith [not as steel]

Abstract

According to an aspect of the invention, articles are provided which comprise a substrate and a ceramic coating which covers at least a portion of the substrate surface. The ceramic coating includes raised ceramic shells connected by a ceramic layer that is conformal with the substrate. According to another aspect of the present invention, carbon nanotubes are provided, which comprise a ceramic coating covering at least a portion of the carbon nanotubes.

Description

ARTICLES HAVING CERAMIC COATED SURFACES

FIELD OF THE INVENTION
[0001] The present invention relates to articles, including medical articles, which have ceramic coated surfaces.

BACKGROUND OF THE INVENTION
[0002] Articles are provided with ceramic surfaces for use in myriad applications.
Accordingly there is continuing demand for novel ceramic-coated articles and for methods of making the same.

SUMMARY OF THE INVENTION
[0003] According to an aspect of the present invention, articles are provided which comprise a substrate and a ceramic coating that covers at least a portion of the substrate surface. The ceramic coating includes raised ceramic shells connected by an underlying ceramic layer that is conformal with the substrate. The shells may be partially or completely filled, or they may be hollow.
[0004] According to another aspect of the present invention, carbon nanotubes are provided, which comprise a ceramic coating covering at least a portion of the carbon nanotubes.
[0005] The above and other aspects, as well as various embodiments and advantages of the present invention will become immediately apparent to those of ordinary skill in the art upon review of the Detailed Description and Claims to follow.

BRIEF DESCRIPTION OF THE DRAWINGS
[0006] Fig. 1A is a schematic perspective view of a stent in accordance with the prior art.
Fig. 1B is a schematic cross-sectional view taken along line b--b of Fig. 1A.
[0007] Figs. 2A and 2B are schematic cross sectional views of stent struts, in accordance with two embodiments of the present invention.
[0008] Fig. 3A is a schematic cross-sectional view of an article with a ceramic coating, in accordance with an embodiment of the present invention.
[0009] Figs. 3B and 3C are SEM images of ceramic coatings in accordance with the present invention.
[0010] Figs. 4A and 4B are schematic cross-sectional views of articles with ceramic coatings, which are further comprise polymeric layers, in accordance with two embodiments of the present invention.
[0011] Fig 4C is schematic cross-sectional view illustrating a process for forming a polymeric layer like that of Fig. 4B.
[0012] Figs. 5A-5G are schematic cross-sectional views illustrating articles with ceramic coatings, and processes for forming the same, in accordance with various embodiments of the present invention.
[0013] Figs. 6A and 6B are schematic cross-sectional views of articles in accordance with two embodiments of the present invention.
[0014] Figs. 7A-7H, 8A-8C and 9A-9D are schematic cross-sectional views illustrating articles in accordance with various embodiments of the present invention and processes for forming the same.
[0015] Figs. l0A-lOC are schematic cross-sectional views illustrating a process for forming a ceramic coated carbon nanotube, in accordance with the present invention.
[0016] Fig. 11 is an SEM image of a ceramic coating in accordance with an embodiment of the present invention.

DETAILED DESCRIPTION OF THE INVENTION
[0017] According to an aspect of the present invention, articles are provided which comprise a substrate and a ceramic coating that covers at least a portion of the substrate surface. The ceramic coating includes raised ceramic shells connected by an underlying ceramic layer that is conformal with the substrate. The shells may partially or completely filled, or they may be hollow. As discussed in more detail below, in certain embodiments, the ceramic coating constitutes a single ceramic structure extending over the entire substrate surface.
[0018] As used herein a "layer" of a given material is a region of that material whose thickness is smaller than both its length and width. For example, the length and width may each be at least 5 times the thickness, for instance, independently ranging from 5 to to 30 to 100 to 300 to 1000 or more times the thickness. As used herein a layer need not be planar, for example, taking on the contours of an underlying substrate.
Thus, the ceramic shells described herein are layers. A layer can be discontinuous (e.g., patterned).
[0019] As used herein a "ceramic" region, for example, a ceramic layer or a ceramic shell, is a region of material that contains a single ceramic species or a mixture of two or more different ceramic species. For example, a ceramic region in accordance with the invention will typically comprise, for example, from 10 wt% or less to 25 wt%
to 50 wt%
to 75 wt% to 90 wt% to 95 wt% to 95 wt% or more of one or more ceramic species. A
ceramic region in accordance with the invention can thus comprise species other than ceramic species, for example, in some embodiments, comprising from 1 wt% or less to 2 wt% to 5 wt% to 10 wt% to 25 wt% to 50 wt% or more polymeric species.
[0020] Ceramic species for use in ceramic regions include metal and semi-metal oxides, metal and semi-metal nitrides, and metal and semi-metal carbides, among others.
Examples of metal and semi-metal oxides, nitrides and carbides include oxides nitrides and carbides of Periodic Table Group 14 semi-metals (e.g., Si, Ge), and oxides nitrides and carbides of transition and non-transition metals such as Group 3 metals (e.g., Sc, Y), Group 4 metals (e.g., Ti, Zr, Hf), Group 5 metals (e.g., V, Nb, Ta), Group 6 metals (e.g., Cr, Mo, W), Group 7 metals (e.g., Mn, Tc, Re), Group 8 metals (e.g., Fe, Ru, Os), Group 9 metals (e.g., Co, Rh, Ir), Group 10 metals (e.g., Ni, Pd, Pt), Group 11 metals (e.g., Cu, Ag, Au), Group 12 metals (e.g., Zn, Cd, Hg), Group 13 metals (e.g., Al, Ga, In, Tl), Group 14 metals (e.g., Sn, Pb), Group 15 metals (e.g., Bi). Carbides and nitrides of metal and semi-metal oxides may be formed, for example, using high-temperature carbothermal reduction and nitridation processes, among others.
[0021] One example of an article in accordance with the invention is illustrated schematically in the cross-section of Fig. 3A, in which is shown a substrate 3 10, covered with a ceramic coating 320 that includes raised ceramic shells 320s connected by a conformal ceramic layer 320c. The interiors 350 of the ceramic shells 320s are hollow as shown. The conformal ceramic layer 320c can be made very thin (e.g., 100 nm or less), and therefore able to readily deform (e.g., flex or bend) with the underlying substrate.
Moreover, the ceramic shells 320 can be evenly spaced (see Fig. 3) such that they do not engage each other during moderate bending/flexing. The height of the ceramic shells 320s can vary by several orders of magnitude and depends on the size of the particles that are used as templates to form the shells, as discussed further below.
[0022] Fig. 3B is an SEM of a structure like that illustrated schematically in Fig. 3A.
Fig. 3C is an SEM of a single raised ceramic shell. It is broken, demonstrating that it is hollow. Differences in surface roughness from sample to sample may arise from several parameters, including roughness of the underlying substrate as well as processing variations. Although it is not obvious upon viewing the SEM's, the ceramic layer covering the substrate and the ceramic shell of the spheres is one continuous structure, as schematically illustrated in Fig. 3A.
[0023] In Figs. 3A-3C, the ceramic shells are spherical. However, as discussed further below, the ceramic shells can take on a near infinite range of shapes, depending on the template particles that are used to form the shells. In Figs. 3A-3C, the interiors ceramic shells are hollow. However, the interiors of the ceramic shells can be partially or wholly filled with a near infinite array of substances, including metals, polymers, ceramics and combinations (hybrids) of the foregoing, among other materials, depending upon the template particle that is used to form the shells, and upon whether or not the template particle is wholly or partially removed during processing. As one specific example, the ceramic shells may comprise carbon nanotubes (e.g., providing mechanical reinforcement, etc.), among many other possibilities.
[0024] The present invention is applicable to virtually any article for which a ceramic coating is useful, so long as the substrate being coated is compatible with the processing conditions employed. Coated articles include articles with ceramic coatings that are either provided with or without shell structures, and where shell structures are provided, which shell structures may be hollow or contain reinforcing particles (e.g., carbon nanotubes, etc.). Such coatings may be provided for various reasons, including corrosion resistance, wear resistance, optical properties, anti-viral and anti-bacterial properties (e.g., anatase TiOx coatings, etc.) and photoactive behavior, among others. Example of articles include the following: automobile components, including complete car frames, may be coated with ceramic layers, the inside of transport pipes for gas, oil, other aggressive chemical media, photocatalytic and photovoltaic articles (e.g., by forming photoactive ceramic coatings, such as anatase coatings, on polymer substrates), aerospace articles (e.g., exterior panels of planes, space shuttles, rockets, etc), metallic firearm components, windows (e.g., nanometer-thick coatings formed in accordance with the invention may act as reflective coatings, etc.), doorknobs and door handles, telephones, floor tiles, vinyl wall paper, plastic banknotes (e.g., such as those used in certain countries such as Australia), coins, furniture, including furniture found in public places, seats (e.g., in cars, trains and buses), railings including stairway railings and the rubber hand belts of escalators, polymer based children toys (including those used in schools, daycare, etc.), and keypads on ATM machines, among many other articles.
[0025] In certain embodiments, the coated articles are medical articles.
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.
[0026] The devices of the present invention include, for example, implantable and insertable medical devices that are used for systemic treatment, as well as those that are used for the localized treatment of any tissue or organ of a subject. Non-limiting examples are tumors; organs including the heart, coronary and peripheral vascular system (referred to overall as "the vasculature"), the urogenital system, including kidneys, bladder, urethra, ureters, prostate, vagina, uterus and ovaries, eyes, ears, spine, nervous system, lungs, trachea, esophagus, intestines, stomach, brain, liver and pancreas, skeletal muscle, smooth muscle, breast, dermal tissue, cartilage, tooth and bone. As used herein, "treatment" refers to the prevention of a disease or condition, the reduction or elimination of symptoms associated with a disease or condition, or the substantial or complete elimination of a disease or condition. "Subjects" include vertebrate subjects, for example, humans, livestock and pets.
[0027] Medical devices of the present invention include a variety of implantable and insertable medical devices for insertion into and/or through a wide range of body lumens, several of which are recited above, including lumens of the cardiovascular system such as the heart, arteries (e.g., coronary, femoral, aorta, iliac, carotid and vertebro-basilar arteries) and veins, lumens of the genitourinary system such as the urethra (including prostatic urethra), bladder, ureters, vagina, uterus, spermatic and fallopian tubes, the nasolacrimal duct, the eustachian tube, lumens of the respiratory tract such as the trachea, bronchi, nasal passages and sinuses, lumens of the gastrointestinal tract such as the esophagus, gut, duodenum, small intestine, large intestine, rectum, biliary and pancreatic duct systems, lumens of the lymphatic system, and the major body cavities (peritoneal, pleural, pericardial), among others.
[0028] Medical device substrates which can be provided with ceramic coatings in accordance with the invention may correspond, for example, to an entire medical device (e.g., a metallic stent) or to only a portion of a medical device (e.g., corresponding to a component of a medical device, a material that is adhered to a medical device or device component, etc.).
[0029] Several exemplary embodiments of the present invention will now be described in conjunction with vascular stents for purposes of illustrating the invention.
However, the invention is in no way limited to stents, or even medical articles, as seen from the above.
[0030] By way of background, coronary stents such as those commercially available from Boston Scientific Corp. (TAXUS and PROMUS), Johnson & Johnson (CYPHER), and others are frequently prescribed for use for maintaining blood vessel patency, for example, after balloon angioplasty. These products are based on metallic balloon expandable stents with biostable polymer coatings, which release antiproliferative therapeutic agents at a controlled rate and total dose, for preventing restenosis of the blood vessel. One such device is schematically illustrated, for example, in Figs. lA and 1B. Fig. lA is a schematic perspective view of a stent 100 which contains a number of interconnected struts 101. Fig. 1B is a cross-section taken along line b--b of strut 101 of stent 100 of Fig. lA, and shows a stainless steel strut substrate 110 and a therapeutic-agent-containing polymeric coating 120, which encapsulates the entire stent strut substrate 110, covering the luminal surface 1101 (blood side), abluminal surface 110a (vessel side), and side 110s surfaces thereof.
[0031] While it is desirable to provide the abluminal surface of such a stent with a polymeric coating that is capable of releasing an antiproliferative drug to combat restenosis, such a drug may not be equally desirable on the luminal surface of the stent. If a polymeric coating were to be applied only to the abluminal surface of the stent, good adhesion between the stent surface and the polymeric coating is desired, because the polymeric coating is no longer secured to the stent merely by virtue of the fact that it surrounds the stent struts. Without sufficient adhesion, delamination of the coating from the stent surface may occur, for example, during delivery of the stent.
[0032] Moreover, even with good adhesion between the stent surface and the polymeric coating, in the case of a soft polymeric coating, the coating might nonetheless be rubbed from the surface of a self-expanding stent as a result of the high shear forces associated with the sliding removal of the stent from its delivery tube.
[0033] What is desired on the luminal surface of the stent, on the other hand, is a surface that promotes the rapid formation of a functional endothelial cell layer, which is known to be effective for purposes of reducing or eliminating inflammation and thrombosis that can occur in conjunction with the implantation of a foreign body in the vasculature. See, e.g., J. M. Caves et al., J. Vasc. Surg. (2006) 44: 1363-8.
[0034] One or more of the above goals, among others, may be achieved using ceramic coatings in accordance with the invention, which as noted above, in some embodiments, include raised ceramic shells (which may be hollow, or partially or wholly filled with a variety of solid materials) connected by a ceramic layer.
[0035] For example, referring now to Fig. 2A, which is a schematic cross sectional view of a stent strut 201, a ceramic coating 220 in accordance with the invention is provided over the luminal surface 2101, the abluminal surface 210a, and the side surfaces 210s of the stent strut substrate 210. A drug-eluting polymeric layer 230 is provided on the ceramic coating 220, but only over the abluminal surface 210a of the stent strut substrate 210 (and not over the lumina12101 and side 210s surfaces). As another example, and with reference to Fig. 2B, a ceramic coating 220 in accordance with the invention is again provided over the lumina12101, ablumina1210a and side 210s surfaces of the stent strut substrate 210, whereas the drug-eluting polymeric layer 230 is provided over the abluminal surface 210a and side 210s surfaces of the stent strut substrate 210, but not over the lumina12101 surface. Note that in either embodiment, if the polymer used in the polymeric coating 230 is biodisintegrable, one is ultimately left in vivo with a ceramic coating, which can be selected from various materials that are biologically inert or bioactive (e.g., titanium oxide, zirconium oxide, iridium oxide, etc.).
[0036] With respect to addressing the above-mentioned goals, ceramic coatings 220 in accordance with the present invention, particularly those embodiments where the ceramic structure comprises a plurality of ceramic shells, promote polymer coating adhesion, for example, by increasing the interfacial surface area between the polymeric coatings 230 and the underlying ceramic coating 220 (i.e., relative to the interfacial surface area that would otherwise exist between the between the polymeric coating 230 and the substrate 210, in the absence of the ceramic structure 220). In addition, ceramic coatings in accordance with the invention interlock with the adjacent polymeric coating 230 to a lesser or greater degree.
[0037] This can be better seen with reference to Fig. 4A, which is a schematic illustration of a substrate 410 (e.g., a stent strut, among innumerable other possibilities), having disposed thereon a ceramic coating 420 in accordance with the invention. The coating 420 includes raised ceramic shells 420s connected by a ceramic layer 420c that is conformal with the substrate 410. As previously noted, the raised ceramic shells 420s and ceramic layer 420c constitute a single ceramic structure. A polymeric coating 430 is shown, disposed over the ceramic coating 420. Due to the undercut beneath the ceramic shells 420s, the polymeric coating 430 interlocks to a degree with the ceramic coating 420. As seen from Figs. 7H and 8C (discussed further below), more complex, ceramic coatings can be formed which are capable of creating even greater degrees of interlock between the ceramic coatings of the invention and polymeric layers overlying them.
[0038] With regard to the ability of the ceramic coatings of the invention to protect polymeric coatings (e.g., against shear forces, abrasion, etc.), one such embodiment can be seen with reference to Fig. 4B, which like Fig. 4A is a schematic illustration of a substrate 410, having disposed thereon a ceramic coating 420 in accordance with the invention, which includes raised ceramic shells 420s connected by a ceramic layer 420c that is conformal with the substrate 420. A polymeric coating 430 is shown, disposed over the ceramic coating 420. Unlike Fig. 4A, however, the polymeric coating 430 does not extend substantially beyond the height of the raised ceramic shells 420s.
Consequently, the ceramic shells 420s are able to protect the polymeric coating 430 from being rubbed off, for example, as a result of abrasion, shear forces, and so forth.
[0039] One example of a process for producing a polymeric coating 4301ike that of Fig.
4B is schematically illustrated in Fig. 4C. After covering the ceramic coating 420c,420s with a viscous polymer solution 430v, a blade is run over the structure (three blades 450 are illustrated in Fig. 4C, arranged in a manner analogous to a triple-edge razor). The ceramic shells 420s act to limit the extent to which the blades 450 can approach the ceramic layer 420c. Consequently, a polymeric layer is created that is essentially of the same height as the ceramic shells 420s. Because the viscous polymer solution 430v will loose volume upon evaporation of the solvent contained therein, one may repeat the process, as desired, to increase the thickness of the final polymeric layer.
Of course other liquid polymeric compositions can be employed in the polymeric coating process, including polymer melts and curable polymeric compositions.
[0040] Thus, where employed in conjunction with a stent, a ceramic coating like that shown in Fig. 4B allows a soft polymeric coating to be protected against mechanical forces, without affecting the mechanical qualities of the stent. With respect to the latter advantage, another option for protecting a polymer coating from mechanical forces would be to form depressions within the stent surface, which would shield the polymeric coating. However, the amount polymeric coating (and thus therapeutic agent) that can be loaded within these depressions is limited to the amount of material that is removed, with significant removal of material potentially weakening the stent.
[0041] Another advantage of a ceramic coating like that shown in Fig. 4B, is that the coating allows for very good control over the height and total volume of any therapeutic-agent-containing polymer layer, and therefore over therapeutic agent content.
More particularly, the coating height is dependent on the height of the spherical shell, and this is defined by the size of the original template particles (e.g., polystyrene balls) which one can obtain with a variance in size of better than 2.0%. One has to take into account the volume taken up by the spheres. However, this can be done by taking into account the diameter and average density of the spherical shells, which are uniformly dispersed on the surface, as can be seen from Fig. 3B.
[0042] With respect to the goal of providing a stent surface that promotes the rapid formation of a functional endothelial cell layer, ceramic coatings of the invention are readily formed with micron-scale and/or nanometer-scale features, which have been widely reported to promote cell attachment and/or cell proliferation as discussed below.
In this regard, ceramic coatings can be produced with topographical features having a wide variety of shapes and sizes. The surface features generally have widths that are less than 100 microns ( m), ranging, for example, from 100 microns or more to 50 microns to 25 microns to 10 microns to 5 microns to 2 microns to 1 micron to 500 nm to 250 nm to 100 nm to 50 nm to 25 nm or less. As discussed below, the shapes and sizes of the surface features are dictated by the particles that are used as templates for the creation of the ceramic shells.
[0043] As noted above, cell attachment and cell growth (proliferation) on surfaces have both been reported to be influenced by the texturing found on the surface. For instance, literature has shown that endothelial cells cultured on textured surfaces spread faster and appear more like cells in native arteries. See R.G. Flemming et al., Biomaterials 20 (1999) 573-588. It has been reported that textured surfaces promote stabilized pseudo-neointima formation. In this regard, N. Fujisawa et al., Biomaterials 20 (1999) 955-962 found that, upon implantation in ovine carotid arteries, textured polyurethane surfaces consisting of regularly spaced, protruding micro-fibers on a smooth base plane (length, pitch and diameter at the base of the fibers were 250, 100 and 25 m, respectively) promoted the formation of a stabilized thrombus base onto which subsequent cellular migration and tissue healing occurred more rapidly than onto a smooth surface.
Others have noted that by creating well-defined micro-textured patterns on a surface, fluid flow at the surface is altered to create discrete regions of low shear stress, which may serve as sanctuaries for cells such as endothelial cells and promote their retention.
See S.C.

Daxini et al. "Micropatterned polymer surfaces improve retention of endothelial cells exposed to flow-induced shear stress," Biorheology 2006 43(1) 45-55.
[0044] Texturing in the sub-100 nm range has been observed to increase cell attachment and/or proliferation. See, e.g., the review by E.K.F Yim et al., "Significance of synthetic nanostructures in dictating cellular response," Nanomedicine: Nanotechnology, Biology, and Medicine 1 (2005) 10- 21, which reported that smooth muscle cells and endothelial cells have improved cell adhesion and proliferation on nanopatterned surfaces.
Both types of cells were sensitive to nanotopography. Without wishing to be bound by theory, feature sizes less than 100 nm are believed to allow adhesion of proteins such as fibronectin, laminin, and/or vitronectin to the nanotextured surface, and to provide a conformation for these proteins that better exposes amino acid sequences such as RGD
and YGSIR which enhance endothelial cell binding. See, e.g., Standard handbook of biomedical engineering and design, Myer Kutz, Ed., 2003 ISBN 0-07-135637-1, p.
16.13.
Moreover, nanotexturing increases surface energy, which is believed to increases cell adhesion. See, e.g., J.Y. Lim et al., J. Biomed. Mater. Res. (2004) 68A(3):
504-512. In this regard, submicron topography, including pores, fibers, and elevations in the sub-100 nm range, has been observed for the basement membrane of the aortic valve endothelium as well as for other basement membrane materials. See R.G. Flemming et al., Biomaterials 20 (1999) 573-588, S. Brody et al., Tissue Eng. 2006 Feb; 12(2):
413-421, and S.L. Goodman et al., Biomaterials 1996; 17: 2087-95. Goodman et al.
employed polymer casting to replicate the topographical features of the subendothelial extracellular matrix surface of denuded and distended blood vessels, and they found that endothelial cells grown on such materials spread faster and appeared more like cells in their native arteries than did cells grown on untextured surfaces.
[0045] An example of a process that may be used to create structures like those shown in Figs. 3A-3C will now be described. This process is based on a combination of layer-by-layer processing and sol-gel processing. Information on layer-by-layer/sol-gel processing can be found, for example, in "Colloids and Colloid Assemblies," Wiley-VCH, edited by Frank Caruso, ISBN 3-527-30660-9, pp. 266-269; D. Wang and F. Caruso, "Polyelectrolyte-Coated Colloid Spheres as Templates for Sol-Gel Reactions,"
Chem.
Mater. 2002, 14, 1909 - 1913; D. Wang et al., "Synthesis of Macroporous Titania and Inorganic Composite Materials from Coated Colloidal Spheres A Novel Route to Tune Pore Morphology," Chem. Mater. 2001, 13, 364-371; and WO 02/074431 to Caruso.
[0046] By way of background, it is well known that multilayer coatings can be formed on substrates based on electrostatic self-assembly of charged materials, commonly referred to as the layer-by-layer (LBL) method. In the LBL method, a first layer having a first surface charge is typically deposited on an underlying substrate (in the present invention, a medical device substrate or portion thereof), followed by a second layer having a second surface charge that is opposite in sign to the surface charge of the first layer, and so forth. The charge on the outer layer is reversed upon deposition of each sequential layer. Commonly, 5 to 10 to 25 to 50 to 100 to 200 or more layers are applied in this technique, depending on the desired thickness of the multilayer structure. LBL
techniques commonly employ charged species known as "polyelectrolytes," which are polymers having multiple charged groups. Typically, the number of charged groups is 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 charged groups, polyelectrolytes may be classified as polycations (which are generally derived from polyacids and salts thereof) or polyanions (which are generally derived from polybases and salts thereof). Specific examples of polyanions/polyacids include poly(styrene sulfonate) (PSS) (e.g., poly(sodium styrene sulfonate), polyacrylic acid, polyvinylsulfate, polyvinylsulfonate, sodium alginate, eudragit, gelatin, hyaluronic acid, carrageenan, chondroitin sulfate and carboxymethylcellulose, among many others. Specific examples of polycations/polybases include protamine sulfate, poly(allylamine) (e.g., poly(allylamine hydrochloride) (PAH)), polydiallyldimethylammonium species, polyethyleneimine (PEI), polyvinylamine, polyvinylpyridine, chitosan, gelatin, spermidine and albumin, among many others. For further information concerning the LBL process, see, e.g., US 2005/0208100 to Weber et al., and WO/2005/115496 to Chen et al.
[0047] It is also well known that ceramic regions may be formed using sol-gel processing techniques. In a typical sol-gel process, precursor materials, typically selected from inorganic metallic and semi-metallic salts, metallic and semi-metallic complexes/chelates, metallic and semi-metallic hydroxides, and organometallic and organo-semi-metallic compounds such as metal alkoxides and alkoxysilanes, are subjected to hydrolysis and condensation reactions in the formation of ceramic materials. Commonly, an alkoxide of choice (e.g., a methoxide, ethoxide, isopropoxide, tert-butoxide, etc.) of a semi-metal or metal of choice (e.g., silicon, aluminum, zirconium, titanium, tin, iron, hafnium, tantalum, molybdenum, tungsten, rhenium, iridium, etc.) is dissolved in a suitable solvent, for example, in one or more alcohols. Subsequently, water or another aqueous solution such as an acidic or basic aqueous solution (which aqueous solution can further contain organic solvent species such as alcohols) is added, causing hydrolysis and condensation to occur. The sol-gel reaction is basically understood to be a ceramic network forming process as illustrated in the following simplified scheme from G. Kickelbick, "Prog.
Polym. Sci., 28 (2003) 83-114):

~r3~r2~ka7?s~Fi~sil. _ :;i+re)F1+,., ,......... ORi 0:' 9w- ,.:.";~.....a,',~......~......~`......4~.;.=:.
,---------~- . .
..........;~.

~--...
Z~ - S. r`l#. .,. . .

in which the metal/semi-metal atoms (designated generally as M) within the ceramic phases are shown to be linked to one another via covalent linkages, such as M-O-M
linkages, although other interactions are also commonly present including, for example, hydrogen bonding due to the presence of hydroxyl groups such as residual M-OH
groups within the network. Regardless of the exact mechanism, further processing of the so-called "sol" (i.e., a suspension of solid particles within a liquid) enables solid materials to be made in a variety of different forms. For instance, wet "gel" coatings can be produced by spray coating, coating with an applicator (e.g., by roller or brush), ink-jet printing, screen printing, and so forth. The wet gel is then dried to form a ceramic region. Further information concerning sol-gel materials can be found, for example, in G.
Kickelbick supra and Viitala R. et al., "Surface properties of in vitro bioactive and non-bioactive sol-gel derived materials," Biomaterials, 2002 Aug; 23(15):3073-86, and portions of Pub. No.
US 2006/0129215 to Helmus et al.
[0048] Referring now to Figs. 5A-5F, a process for the formation of a structure in accordance with the present invention will now be described.
[0049] In a first step, a polyelectrolyte multilayer (PML) coating 512 is formed on a substrate 510 using the LBL process. In this regard, certain substrates are inherently charged and thus readily lend themselves to layer-by-layer assembly techniques. To the extent that the substrate does not have an inherent net surface charge, a surface charge may nonetheless be provided. For example, where the substrate to be coated is conductive, a surface charge may be provided by applying an electrical potential to the same. As another example, substrates, including metallic and polymeric substrates, may be chemically treated with various reagents, including reducing agents and oxidizing agents (e.g., sulfur trioxide for sulfonate formation), which modify their surfaces so as to provide them charged groups, such as amino, phosphate, sulfate, sulfonate, phosphonates and carboxylate groups, among many others. Other techniques for providing surface charge include techniques whereby a surface region is treated with a reactive plasma.
Surface modification is obtained by exposing a surface to a partially ionized gas (i.e., to a plasma). Because the plasma phase consists of a wide spectrum of reactive species (electrons, ions, etc.) these techniques have been used widely for functionalization of surfaces, including polymeric surfaces among others. Examples include glow discharge techniques (which are conducted at reduced pressure) and coronal discharge techniques (which are conducted at atmospheric pressure), with the former preferred in some cases, because the shape of the object to be treated is of minor importance during glow discharge processes. Lasers may also be used to create a localized plasma in the vicinity of the laser beam (e.g., just above the focal point of the beam). When gases like carbon monoxide (CO), carbon dioxide (C02), or oxygen (02) are used, functionalization with -COOH groups (which donate protons to form anionic groups) is commonly observed.
When gases like ammonia, a propyl amine, or Nz/Hz are employed, -NH2 groups (which accept protons to form cationic groups) are commonly formed. Functional-group-containing surfaces may also be obtained using plasma polymerization processes in which "monomers" are employed that contain functional groups. Allylamine (which produces -NHz groups) and acrylic acid (which produces -COOH groups) have been used for this purpose. By using a second feed gas (generally a non-polymerizable gas) in combination with the unsaturated monomer, it is possible to incorporate this second species in the plasma deposited layer. Examples of gas pairs include allylamine/NH3 (which leads to enhanced production of -NH2 groups) and acrylic acid/COz (which leads to enhanced production of -COOH groups). Further information on plasma processing may be found, for example, in "Functionalization of Polymer Surfaces," Europlasma Technical Paper, 05/08/04 and in Pub. No. US 2003/0236323. As another example, plasma-based techniques such as those described above may first be used to functionalize a substrate surface, followed by removal of a portion of the functional groups at the surface by exposing the surface to a laser beam, for example, in an inert atmosphere or vacuum in order to minimize deposition. As yet another example, a substrate can be provided with a charge by covalently coupling with species having functional groups with a positive charge (e.g., amine, imine or other basic groups) or a negative charge (e.g., carboxylic, phosphonic, phosphoric, sulfuric, sulfonic, or other acid groups) using methods well known in the art. Further information on covalent coupling may be found, for example, in Pub. No. US 2005/0002865. In many embodiments, a surface charge is provided on a substrate simply by adsorbing polycations or polyanions to the surface of the substrate as a first charged layer. PEI is commonly used for this purpose, as it strongly promotes adhesion to a variety of substrates. Further information can be found in Serial No.
11/322,905 to Atanasoska et al.
[0050] Regardless of the method by which a given substrate is provided with a surface charge, once a sufficient surface charge is provided, the substrate can be readily coated with a layer of an oppositely charged material. Examples of such layers include layers that contain (a) polyelectrolytes, (b) charged particles or (c) both polyelectrolytes and charged particles. Multilayer regions are formed by alternating exposure to solutions containing oppositely charged materials. The layers self-assemble by means of electrostatic layer-by-layer deposition, thus forming a multilayered region over the substrate.
[0051] Polyelectrolyte solutions (and particle containing solutions) may be applied by a variety of techniques. These techniques include, for example, full immersion techniques such as dipping techniques, spraying techniques, roll and brush coating techniques, techniques involving coating via mechanical suspension such as air suspension, ink jet techniques, spin coating techniques, web coating techniques and combinations of these processes, among others. Stamping may also be employed, for example, as described in S. Kidambi et al., "Selective Depositions on Polyelectrolyte Multilayers: Self-Assembled Monolayers of m-dPEG Acid as Molecular Templates" J. Am. Chem. Soc. 126, 4697-4703, 2004 and Park et al., "Multilayer Transfer Printing for Polyelectrolyte Multilayer Patterning: Direct Transfer of Layer-by-Layer Assembled Micropatterned Thin Films, Adv. Mater.," 2004, 16(6), 520-525.
[0052] The choice of the technique will depend on the requirements at hand.
For example, deposition or full immersion techniques may be employed where it is desired to apply the species to an entire substrate, including surfaces that are hidden from view (e.g., surfaces which cannot be reached by line-of-sight techniques, such as spray techniques).
On the other hand, spraying, roll coating, brush coating, ink jet printing and micro-polymer stamping may be employed, for instance, where it is desired to apply the species only certain portions of the substrate (e.g., on one side of a substrate, in the form of a pattern on a substrate, etc.).
[0053] Returning now to Fig. 5A, a substrate 510 is provided with a PML
coating 512 as shown, for example, by dipping in consecutive polyelectrolyte regions of opposite charge.
The surface charge of the multilayer polyelectrolyte coating 512 at the end of this process is determined by whether the last solution to which the substrate was exposed was a polycationic solution or a polyanionic solution. In some embodiments, at this point, a sol-gel-type process is carried out within the polyelectrolyte layers as described below.
[0054] In other embodiments, such as that illustrated in Figs. 5B-5C, particles of choice are adsorbed to the surface. Typically, a charged particle is used which is either inherently charged or is charged, for example, using one of the techniques described above. For example, particles may be exposed to a solution of PEI to create negatively charged particles. If desired, the charge on a particle can be reversed by exposing it to a solution containing a polyelectrolyte of opposite charge. In some embodiments, a solution of particles may be employed, in which the particles are provided with a polyelectrolyte multilayer coatings. A substrate may, for example, be exposed to a suspension of charged particles using techniques such as those above (e.g., dipping, etc.).
The result of this step is illustrated in Fig. 513, which schematically illustrates the medical device substrate 510, PML coating 512, and charged particles 515. The structure of Fig.

5B is then immersed in further polyelectrolyte solutions of alternating charge, to enclose the charged particles 515 in a PML coating 512. This process also increases the thickness of the polyelectrolyte coating that was previously applied to the substrate 510. The result of this process is illustrated in Fig. 5C.
[0055] In some embodiments, a charged therapeutic agent is used to form one or more layers of the PML coating 512. By "charged therapeutic agent" is meant a therapeutic agent that has an associated charge. For example, a therapeutic agent may have an associated charge because it is inherently charged (e.g., because it has acidic and/or or basic groups, which may be in salt form). A therapeutic agent may have an associated charge because it has been chemically modified to provide it with one or more charged functional groups.
[0056] For instance, conjugation of water insoluble or poorly soluble drugs, including anti-tumor agents such as paclitaxel, to hydrophilic polymers has recently been carried out in order to solubilize the drug (and in some cases to improve tumor targeting and reduce drug toxicity). Similarly cationic or anionic versions of water insoluble or poorly soluble drugs have also been developed. Taking paclitaxel as a specific example, various cationic forms of this drug are known, including paclitaxel N-methyl pyridinium mesylate and paclitaxel conjugated with N-2-hydroxypropyl methyl amide, as are various anionic forms of paclitaxel, including paclitaxel-poly(1-glutamic acid), paclitaxel-poly(1-glutamic acid)-PEO. See, e.g., U.S. Patent No. 6,730,699; Duncan et al., Journal of Controlled Release, 74 (2001)135; Duncan, Nature Reviews/Drug Discovery, Vol. 2, May 2003, 347;
J. G. Qasem et al, AAPS PharmSciTech 2003, 4(2) Article 21. In addition to these, U.S.
Patent No. 6,730,699, also describes paclitaxel conjugated to various other charged polymers (e.g., polyelectrolytes) including poly(d-glutamic acid), poly(dl-glutamic acid), poly(1-aspartic acid), poly(d-aspartic acid), poly(dl-aspartic acid), poly(1-lysine), poly(d-lysine), poly(dl-lysine), copolymers of the above listed polyamino acids with polyethylene glycol (e.g., paclitaxel-poly(1-glutamic acid)-PEO), as well as poly(2-hydroxyethyl 1-glutamine), chitosan, carboxymethyl dextran, hyaluronic acid, human serum albumin and alginic acid. Still other forms of paclitaxel include carboxylated forms such as 1'-malyl paclitaxel sodium salt (see, e.g. E.W. DAmen et al., "Paclitaxel esters of malic acid as prodrugs with improved water solubility," Bioorg. Med.
Chem., 2000 Feb, 8(2), pp. 427-32). Polyglutamate paclitaxel, in which paclitaxel is linked through the hydroxyl at the 2' position to the A carboxylic acid of the poly-L-glutamic acid (PGA), is produced by Cell Therapeutics, Inc., Seattle, WA, USA. (The 7 position hydroxyl is also available for esterification.) This molecule is said to be cleaved in vivo by cathepsin B to liberate diglutamyl paclitaxel. In this molecule, the paclitaxel is bound to some of the carboxyl groups along the backbone of the polymer, leading to multiple paclitaxel units per molecule. For further information, see, e.g., R. Duncan et al., "Polymer-drug conjugates, PDEPT and PELT: basic principles for design and transfer from the laboratory to clinic," Journal of Controlled Release 74 (2001) 135-146, C. Li, "Poly(L-glutamic acid)-anticancer drug conjugates," Advanced Drug Delivery Reviews 54 (2002) 695-713; Duncan, Nature Reviews/Drug Discovery, Vol. 2, May 2003, 347;
Qasem et al, AAPS PharmSciTech 2003, 4(2) Article 21; and U.S. Patent No.
5,614,549.
[0057] Using the above and other strategies, paclitaxel and innumerable other therapeutic agents may be covalently linked or otherwise associated with a variety of charged species, including charged polymer molecules (e.g., polyelectrolytes), thereby forming charged drugs and prodrugs which can be assembled in the PML process. Such charged species may be adapted for cleavage from the drug/prodrug prior to administration or upon administration (e.g., due to enzymatic cleavage, etc.).
[0058] In a next step, a sol-gel-type process is carried out within the polyelectrolyte layers. For example, the structure of Fig. 5C may be washed in an anhydrous solvent, for example, an anhydrous alcohol. This removes essentially all the water from the structure, except of the water that remains adsorbed within the PML coating 512. The structure is then immersed in a sol-gel precursor solution. For example the structure may be immersed in a solution of a semi-metal or metal alkoxide in anyhydrous alcohol solvent or in a water-alcohol solvent having a high alcohol content (i.e., a solvent in which the water concentration is too low for hydrolysis-condensation reactions to occur). Without wishing to be bound by theory of operation, the high charge density of the polyelectrolyte groups are believed to cause the PML coating 512 to have a water concentration that is higher than that of the surrounding sol-gel precursor solution (e.g., by attracting water molecules out of the sol-gel precursor solution and/or retaining water molecules during washing in anhydrous solvent). Upon diffusion into the PML coating 512, the sol-gel precursor encounters an environment of increase water concentration, in which the hydrolysis and condensation can take place. The PML coating 512 swells, due to the in-situ reaction of the sol-gel precursor within the layers. However, the charge density also decreases due to the swelling, causing a reduction in water concentration, which eventually stops the sol-gel reaction. Regardless of the exact mechanism, the resulting coating, which is a polyelectrolyte/ceramic hybrid coating, is uniformly thick, and its thickness is dependent upon the number of layers within the polyelectrolyte coating (with more layers leading to thicker coatings). The resulting structure is illustrated in Fig. 5D, which shows the substrate 510, particles 515, and polyelectrolyte/ceramic hybrid coating 514.
[0059] The structure of Fig. 5D may then heated, for example, to a temperature ranging anywhere from about 150 C to about 600 C or higher, to form a heat-treated ceramic coating 520 as shown in Figs. 5E-5G. At the higher end of the range, the ceramic coating 520 has a high proportion of ceramic species (e.g., containing 90 wt% or more ceramic species, for example, from 95 wt% to 98 wt% to 99 wt% to 99.5 wt% to 99.9 wt%
or more), with substantially all of the polyelectrolyte component of the coating having been out-gassed from the structure in a process sometimes referred to as calcination. As indicated above, the thickness of the resulting shell will generally be proportional to the number of polyelectrolyte layers that were deposited prior to sol-gel processing. For example, a thickness of about 1 nm per polyelectrolyte layer has been reported in D.
Wang and F. Caruso, Chem. Mater. 2002, 14, 1909 - 1913.
[0060] As noted above, in some embodiments, carbides and nitrides of metal and semi-metal oxides may be formed, for example, using high-temperature carbothermal reduction or nitridation processes, among others.
[0061] At the lower end of the temperature range, the ceramic coating 520 contains substantial amounts of polymeric species (polyelectrolytes) in addition to ceramic species. In such cases, however, the heat treatment will act to strengthen the ceramic coating 520.
[0062] In still other embodiments, ceramic coatings may be formed by water-vapor exposure. For example, porous titania-based (TiOX-based) anatase coatings have been formed by exposing sol-gel-derived titania thin films that contained from 0-50 mol%
silica to water vapor at 60 -180 C. H. Imai et al., J. Am. Ceram. Soc., 82(9), 1999, 2301-2304. Titanium oxide coatings have been reported to possess photocatalytic properties and a photovoltaic effect. Id. See also Margit J. Jensen et al., J.
Sol-Gel Sci.

Techn. (2006) 39:229-233 who report the preparation of nanocrystalline anatase (Ti02) films, prepared at very low temperature through a sol-gel route using titanium isopropoxide and hydrogen peroxide in ethanol. Crystallization occurred after film deposition at 35 C in an atmosphere saturated with water vapor. In the present invention, such processing can be employed in conjunction with the sol-gel-swelled PML
layers formed as described above. This would allow one, for example, to coat polymeric substrates (as the conditions would not destroy the substrate) with very flexible (as the coating is very thin) hybrid polymer-ceramic coatings.
[0063] Lower temperature post-treatment processes such as those above, among others, may also be desirable where therapeutic agents are provided in the PML
structure (see above), which therapeutic agents may be harmed at higher temperatures.
[0064] Depending upon the heat-treatment temperature and atmosphere, and upon the nature of the material forming the particles 515 of Fig. 5D, the heat-treatment process either will not result in the removal of the particle forming material (although, in some cases, resulting in a chemical modification of the particles), leaving the particles 515 encased in ceramic shells 520s as illustrated in Fig. 5E, or it will result in the partial or complete removal of the particle forming material, thereby creating ceramic shells 520s with partially or wholly hollow interiors 517 as shown in Fig. 5F.
[0065] Particle removal may also be conducted independently of heat treatment, for example, in the absence of heat treatment, prior to heat treatment, or after heat treatment (where the heat treatment does not remove the particles). For instance, particles may be removed via a dissolution process. As specific examples, polymeric particles may be removed using organic solvents (e.g., removal of polystyrene particles by tetrahydrofuran), and inorganic particles may be removed using acidic or basic aqueous solutions (e.g., removal of silica particles using HF).
[0066] In some embodiments, hybrid template particles are employed in which a portion of each particle is removed (e.g., by heat treatment, dissolution, etc.) and a portion of each particle remains within the hollow ceramic shell. One example of such a particle is a polystyrene sphere that contains one or more smaller paramagnetic particles (e.g., paramagnetic particles within a polystyrene matrix, a paramagnetic particle core with a polystyrene shell, etc.). The polystyrene portion of such a particle can be removed, for instance, by heat or by organic solvent dissolution.
[0067] Turning now to the structure of Fig. 5G, this structure is formed by a process like that used to form Fig. 5E, except that the charged particles 515 are electrostatically deposited onto the substrate 510 without first coating the substrate 510 with a polyelectrolyte multilayer coating (as is done in Fig. 5A), the result being that the particles 515 in the structure of Fig. 5G are in closer proximity to the substrate 510 than are the particles 515 of Fig. 5E.
[0068] In some embodiments, ceramic coatings in accordance with the present invention are provided over the entire surface of a substrate. In some embodiments, ceramic coatings in accordance with the present invention are provided over only a portion of the surface of a substrate (e.g., only a luminal stent surface, only an abluminal stent surface, only abluminal and side stent surfaces, etc.). Substrates may be partially coated, for example by exposing the various solutions employed (e.g., polyelectrolyte solutions, particle solutions, sol-gel solutions) to only a portion of the substrate.
Examples of techniques for doing so include the use of masking, partial dipping, roll-coating (e.g., where it is desired to apply the coating to the abluminal surface of a tubular device such as a stent) or other transfer coating technique, including the use of a suitable application device such as a brush, roller, stamp or ink jet printer, among other techniques.
[0069] Due to the straightforward nature of LBL processing and due the fact that non-charged materials may be charged using a variety of techniques, a wide range of substrate and particle materials may be employed for the practice of the present invention.
[0070] Suitable substrate materials therefore may be selected from a variety of materials, including (a) organic materials (e.g., materials containing organic species, commonly 50 wt% or more organic species) such as polymeric materials and (b) inorganic materials (e.g., materials containing inorganic species, commonly 50 wt% or more inorganic species) such as metallic materials (e.g., metals and metal alloys) and non-metallic inorganic materials (e.g., carbon, semiconductors, glasses, metal- and non-metal-oxides, metal- and non-metal-nitrides, metal- and non-metal-carbides, metal- and non-metal-borides, metal- and non-metal-phosphates, and metal- and non-metal-sulfides, among others). Suitable substrate materials include biostable materials and biodisintegrable materials (i.e., materials that, upon placement in the body, are dissolved, degraded, resorbed, and/or otherwise removed from the placement site).
[0071] Specific examples of non-metallic inorganic materials may be selected, for example, from materials containing one or more of the following: metal oxides, including aluminum oxides and transition metal oxides (e.g., oxides of titanium, zirconium, hafnium, tantalum, molybdenum, tungsten, rhenium, and iridium, as well as other metals such as those listed above as examples of ceramic species);
silicon; silicon-based materials, 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, among many others.
[0072] Specific examples of metallic inorganic materials may be selected, for example, from substantially pure biostable and biodisintegrable metals (e.g., biostable metals such as gold, platinum, palladium, iridium, osmium, rhodium, titanium, tantalum, tungsten, and ruthenium, and biodisintegrable metals such as magnesium, zinc and iron) and biostable and biodisintegrable metal alloys, for example, biostable metal alloys comprising iron and chromium (e.g., stainless steels, including platinum-enriched radiopaque stainless steel), alloys comprising nickel and titanium (e.g., Nitinol), alloys comprising cobalt and chromium, including alloys that comprise cobalt, chromium and iron (e.g., elgiloy alloys), alloys comprising nickel, cobalt and chromium (e.g., MP 35N) and alloys comprising cobalt, chromium, tungsten and nickel (e.g., L605), alloys comprising nickel and chromium (e.g., inconel alloys), and biodisintegrable metal alloys such as magnesium alloys, zinc alloys, and iron alloys (including their combinations with one another, Ce, Ca, Zn, Zr and Li, among other elements-see Pub. No. US
2002/0004060 to Heublein et al.), among many others.
[0073] Specific examples of organic materials include biostable and biodisintegrable polymers, which may be selected, for example, from the following, among others:
polycarboxylic acid polymers and copolymers including polyacrylic acids;
acetal polymers and copolymers; acrylate and methacrylate polymers and copolymers (e.g., n-butyl methacrylate); cellulosic polymers and copolymers, including cellulose acetates, cellulose nitrates, cellulose propionates, cellulose acetate butyrates, cellophanes, rayons, rayon triacetates, and cellulose ethers such as carboxymethyl celluloses and hydroxyalkyl celluloses; polyoxymethylene polymers and copolymers; polyimide polymers and copolymers such as polyether block imides, polyamidimides, polyesterimides, and polyetherimides; polysulfone polymers and copolymers including polyarylsulfones and polyethersulfones; polyamide polymers and copolymers including nylon 6,6, nylon 12, polyether-block co-polyamide polymers (e.g., Pebax resins), polycaprolactams and polyacrylamides; resins including alkyd resins, phenolic resins, urea resins, melamine resins, epoxy resins, allyl resins and epoxide resins; polycarbonates;
polyacrylonitriles;
polyvinylpyrrolidones (cross-linked and otherwise); polymers and copolymers of vinyl monomers including polyvinyl alcohols, polyvinyl halides such as polyvinyl chlorides, ethylene-vinylacetate copolymers (EVA), polyvinylidene chlorides, polyvinyl ethers such as polyvinyl methyl ethers, vinyl aromatic polymers and copolymers such as polystyrenes, styrene-maleic anhydride copolymers, vinyl aromatic-hydrocarbon copolymers including styrene-butadiene copolymers, styrene-ethylene-butylene copolymers (e.g., a polystyrene-polyethylene/butylene-polystyrene (SEBS) copolymer, available as Kraton G series polymers), styrene-isoprene copolymers (e.g., polystyrene-polyisoprene-polystyrene), acrylonitrile-styrene copolymers, acrylonitrile-butadiene-styrene copolymers, styrene-butadiene copolymers and styrene-isobutylene copolymers (e.g., polyisobutylene-polystyrene block copolymers such as SIBS), polyvinyl ketones, polyvinylcarbazoles, and polyvinyl esters such as polyvinyl acetates;
polybenzimidazoles;
ionomers; polyalkyl oxide polymers and copolymers including polyethylene oxides (PEO); polyesters including polyethylene terephthalates, polybutylene terephthalates and aliphatic polyesters such as polymers and copolymers of lactide (which includes lactic acid as well as d-,1- and meso lactide), epsilon-caprolactone, glycolide (including glycolic acid), hydroxybutyrate, hydroxyvalerate, para-dioxanone, trimethylene carbonate (and its alkyl derivatives), 1,4-dioxepan-2-one, 1,5-dioxepan-2-one, and 6,6-dimethyl-1,4-dioxan-2-one (a copolymer of polylactic acid and polycaprolactone is one specific example);
polyether polymers and copolymers including polyarylethers such as polyphenylene ethers, polyether ketones, polyether ether ketones; polyphenylene sulfides;
polyisocyanates; polyolefin polymers and copolymers, including polyalkylenes such as polypropylenes, polyethylenes (low and high density, low and high molecular weight), polybutylenes (such as polybut-l-ene and polyisobutylene), polyolefin elastomers (e.g., santoprene), ethylene propylene diene monomer (EPDM) rubbers, poly-4-methyl-pen-1-enes, ethylene-alpha-olefin copolymers, ethylene-methyl methacrylate copolymers and ethylene-vinyl acetate copolymers; fluorinated polymers and copolymers, including polytetrafluoroethylenes (PTFE), poly(tetrafluoroethylene-co-hexafluoropropene) (FEP), modified ethylene-tetrafluoroethylene copolymers (ETFE), and polyvinylidene fluorides (PVDF); silicone polymers and copolymers; polyurethanes; p-xylylene polymers;
polyiminocarbonates; copoly(ether-esters) such as polyethylene oxide-polylactic acid copolymers; polyphosphazines; polyalkylene oxalates; polyoxaamides and polyoxaesters (including those containing amines and/or amido groups); polyorthoesters;
biopolymers, such as polypeptides, proteins, polysaccharides and fatty acids (and esters thereof), including fibrin, fibrinogen, collagen, elastin, chitosan, gelatin, starch, glycosaminoglycans such as hyaluronic acid; as well as blends and further copolymers of the above.
[0074] Particles for use in the present invention varying widely in composition, size and shape (e.g., spheres, polyhedra, cylinders, tubes, fibers, ribbon-shaped particles, plate-shaped particles, and other regular and irregular particle shapes).
[0075] In general, the distance across the particles as-deposited (e.g., the diameter for spheres, cylinders and tubes, the width for other particles inclduding plates, ribbon-shaped particles, fibers, polyhedra, and other regular and irregular particles) is less thanlOO microns ( m) (the length is frequently much larger), ranging, for example, from 100 microns or more to 50 microns to 25 microns to 10 microns to 5 microns to 2 microns to 1 micron to 500 nm to 250 nm to 100 nm to 50 nm to 25 nm or less. In certain embodiments, the particles are sub-micron-particles in the sense that the distance across the particles as-deposited is less than 1000 nm, and more typically less than 100 nm.
[0076] Suitable materials for the particles can be selected from the organic and inorganic materials set forth above for use as substrate materials. Further examples of particles, which are not exclusive of those materials, may be selected from polymer microspheres, including polymethyl methacrylate (PMMA) microspheres and polystyrene microspheres, such as those available from Microparticles, Berlin, Germany _%! z_%3_ _.~.~ ._csp.~~c_~.~:_1?r~.~.~~ t~?f~~~_tt~__~~~~1), among many others, alumina particles, titanium oxide particles, tungsten oxide particles, tantalum oxide particles, zirconium oxide particles, silica particles, silicate particles such as aluminum silicate particles, synthetic or natural phyllosilicates including clays and micas (which may optionally be intercalated and/or exfoliated) such as montmorillonite, hectorite, hydrotalcite, vermiculite and laponite, and needle-like clays such as attapulgite, and further including particulate molecules such as polyhedral oligomeric silsequioxanes (POSS), including various functionalized POSS and polymerized POSS, polyoxometallates (e.g., Keggin-type, Dawson-type, Preyssler-type, etc.), fullerenes (e.g., "Buckey balls"), carbon nanofibers, single-wall carbon nanotubes and multi-wall carbon nanotubes (including so-called "few-wall" nanotubes).
[0077] In some embodiments, one or more therapeutic agents are disposed within the particles.
[0078] As noted above, in some embodiments, a polymeric coating (e.g., a therapeutic-agent-eluting coating, a lubricious coating, etc.) may be disposed over all or a portion of a ceramic coating in accordance with the invention. As used herein a polymeric coating is one that comprises a single polymer or a mixture differing polymers, for example, comprising from 50 wt% or less to 75 wt% to 90 wt% to 95 wt% to 97.5 wt% to 99 wt%
or more of one or more polymers. The polymer(s) may be biostable or biodisintegrable.
Polymers suitable for this purpose may be selected, for example, from one or more of the polymers set forth above for use as substrate materials. Further examples of polymers, which are not exclusive of those materials, include thermoplastic elastomers such as poly(styrene-co-isobutylene) block copolymers, poly(methyl methacrylate-co-butyl acrylate) block copolymers and thermoplastic polyurethanes, fluoropolymers such as PTFE, FEP, ETFE and PVDF, crosslinked hydrogels such as crosslinked thiolated chondroitin sulfate, polyacrylic acid, polyvinyl alcohol or polyvinyl pyrrolidone, polyanhydrides including aliphatic polyanhydrides such as poly(sebacic acid) or poly(adipic acid), unsaturated polyanhydrides such as poly(4, 4'-stilbenedicarboxylic acid anhydride), aromatic polyanhydrides such as poly(terephthalic acid), copolymers of the foregoing anhydrides with one another, including poly(aliphatic-aromatic anhydrides), and copolymers of the foregoing anhydrides with other monomers, including poly(ester anhydrides) and poly(ether anhydrides), fatty acid based anhydrides, terminated polyanhydrides, branched polyanhydrides, crosslinked polyanhydrides, and amino acid based polyanhydrides, see, e.g., N. Kumar et al., "Polyanhydrides: an overview,"
Advanced Drug Delivery Reviews 54 (2002) 889-910, , biodegradable polyesters such as polylactide and poly(lactide-co-glycolide), among many others, as well as blends of the foregoing.
[0079] The thickness of the therapeutic-agent-eluting polymeric coating may vary widely, typically ranging from 25 nm or less to 50 nm to 100 nm to 250 nm to 500nm to 1 m to 2.5 m to 5 m to 10 m to 25 m to 50 m to 100 m or more in thickness. As noted above, in some embodiments, the thickness of the polymeric coating is dictated by the size of the ceramic shells that are present on the surface, whereas in others it is not.
[0080] In some embodiments, the polymeric coating is a therapeutic-agent-eluting polymeric coating. As used herein, a "therapeutic-agent-eluting polymeric coating" is a coating that comprises a therapeutic agent and a polymer and from which at least a portion of the therapeutic agent is eluted, for example, upon contact with a subject, or upon implantation or insertion into a subject. The therapeutic-agent-eluting polymeric coating will typically comprise, for example, from 1 wt% or less to 2 wt% to 5 wt% to 10 wt% to 25 wt% to 50 wt% or more of a single therapeutic agent or of a mixture of therapeutic agents within the coating. Therapeutic agents may be selected, for example, from those listed below, among others.
[0081] Polymeric coatings may be applied using any suitable method. For example, where the coating contains one or more polymers having thermoplastic characteristics, the coating may be formed, for instance, by (a) providing a melt that contains polymer(s) and any other optional species such as therapeutic agent(s), as desired, and (b) subsequently cooling the melt. As another example, the coating may be formed from a curable composition (e.g., a UV curable composition), for instance, by (a) providing a curable composition that contains polymer(s), curing agents, and any other optional species such as therapeutic agent(s), as desired, and (b) curing the composition. As yet another example, a coating may be formed, for instance, by (a) providing a solution or dispersion that contains one or more solvent species, polymer(s), and any other optional species such as therapeutic agent(s), as desired, and (b) subsequently removing the solvent species.
The melt, solution or dispersion may be applied, for example, by roll-coating (e.g., where it is desired to apply the coating to the abluminal surface of a tubular device such as a stent) or other transfer coating technique, including application using a suitable application device such as a brush, roller, stamp or ink jet printer, by dipping, and by spray coating, among other methods.
[0082] A wide variety of therapeutic agents may be employed in conjunction with the present invention, including genetic therapeutic agents, non-genetic therapeutic agents and cells, which may be used for the treatment of a wide variety of diseases and conditions.
[0083] Suitable therapeutic agents for use in connection with the present invention may be selected, for example, from one or more of the following: (a) anti-thrombotic agents such as heparin, heparin derivatives, urokinase, clopidogrel, and PPack (dextrophenylalanine proline arginine chloromethylketone); (b) anti-inflammatory agents such as dexamethasone, prednisolone, corticosterone, budesonide, estrogen, sulfasalazine and mesalamine; (c) antineoplastic/antiproliferative/anti-miotic agents such as paclitaxel, 5-fluorouracil, cisplatin, vinblastine, vincristine, epothilones, endostatin, angiostatin, angiopeptin, monoclonal antibodies capable of blocking smooth muscle cell proliferation, and thymidine kinase inhibitors; (d) anesthetic agents such as lidocaine, bupivacaine and ropivacaine; (e) anti-coagulants such as D-Phe-Pro-Arg chloromethyl ketone, an RGD
peptide-containing compound, heparin, hirudin, antithrombin compounds, platelet receptor antagonists, anti-thrombin antibodies, anti-platelet receptor antibodies, aspirin, prostaglandin inhibitors, platelet inhibitors and tick antiplatelet peptides;
(f) vascular cell growth promoters such as growth factors, transcriptional activators, and translational promotors; (g) vascular cell growth inhibitors such as growth factor inhibitors, growth factor receptor antagonists, transcriptional repressors, translational repressors, replication inhibitors, inhibitory antibodies, antibodies directed against growth factors, bifunctional molecules consisting of a growth factor and a cytotoxin, bifunctional molecules consisting of an antibody and a cytotoxin; (h) protein kinase and tyrosine kinase inhibitors (e.g., tyrphostins, genistein, quinoxalines); (i) prostacyclin analogs; (j) cholesterol-lowering agents; (k) angiopoietins; (1) antimicrobial agents such as triclosan, cephalosporins, antimicrobial peptides such as magainins, aminoglycosides and nitrofurantoin; (m) cytotoxic agents, cytostatic agents and cell proliferation affectors; (n) vasodilating agents; (o)agents that interfere with endogenous vasoactive mechanisms, (p) inhibitors of leukocyte recruitment, such as monoclonal antibodies; (q) cytokines; (r) hormones; (s) inhibitors of HSP 90 protein (i.e., Heat Shock Protein, which is a molecular chaperone or housekeeping protein and is needed for the stability and function of other client proteins/signal transduction proteins responsible for growth and survival of cells) including geldanamycin, (t) beta-blockers, (u) bARKct inhibitors, (v) phospholamban inhibitors, (w) Serca 2 gene/protein, (x) immune response modifiers including aminoquizolines, for instance, imidazoquinolines such as resiquimod and imiquimod, (y) human apolioproteins (e.g., AI, All, AIII, AIV, AV, etc.), (z) selective estrogen receptor modulators (SERMs) such as raloxifene, lasofoxifene, arzoxifene, miproxifene, ospemifene, PKS 3741, MF 101 and SR 16234, (aa) PPAR agonists such as rosiglitazone, pioglitazone, netoglitazone, fenofibrate, bexaotene, metaglidasen, rivoglitazone and tesaglitazar, (bb) prostaglandin E agonists such as alprostadil or ONO 8815Ly, (cc) thrombin receptor activating peptide (TRAP), (dd) vasopeptidase inhibitors including benazepril, fosinopril, lisinopril, quinapril, ramipril, imidapril, delapril, moexipril and spirapril, (ee) thymosin beta 4.
[0084] Preferred non-genetic therapeutic agents include taxanes such as paclitaxel (including particulate forms thereof, for instance, protein-bound paclitaxel particles such as albumin-bound paclitaxel nanoparticles, e.g., ABRAXANE), sirolimus, everolimus, tacrolimus, zotarolimus, Epo D, dexamethasone, estradiol, halofuginone, cilostazole, geldanamycin, ABT-578 (Abbott Laboratories), trapidil, liprostin, Actinomcin D, Resten-NG, Ap-17, abciximab, clopidogrel, Ridogrel, beta-blockers, bARKct inhibitors, phospholamban inhibitors, Serca 2 gene/protein, imiquimod, human apolioproteins (e.g., AI-AV), growth factors (e.g., VEGF-2), as well derivatives of the forgoing, among others.
[0085] Numerous therapeutic agents, not necessarily exclusive of those listed above, have been identified as candidates for vascular and other treatment regimens, for example, as agents targeting restenosis. Such agents are useful for the practice of the present invention and suitable examples may be selected from one or more of the following: (a) Ca-channel blockers including benzothiazapines such as diltiazem and clentiazem, dihydropyridines such as nifedipine, amlodipine and nicardapine, and phenylalkylamines such as verapamil, (b) serotonin pathway modulators including: 5-HT
antagonists such as ketanserin and naftidrofuryl, as well as 5-HT uptake inhibitors such as fluoxetine, (c) cyclic nucleotide pathway agents including phosphodiesterase inhibitors such as cilostazole and dipyridamole, adenylate/Guanylate cyclase stimulants such as forskolin, as well as adenosine analogs, (d) catecholamine modulators including a-antagonists such as prazosin and bunazosine, (3-antagonists such as propranolol and a/(3-antagonists such as labetalol and carvedilol, (e) endothelin receptor antagonists, such as bosentan, sitaxsentan sodium, atrasentan, endonentan, (f) nitric oxide donors/releasing molecules including organic nitrates/nitrites such as nitroglycerin, isosorbide dinitrate and amyl nitrite, inorganic nitroso compounds such as sodium nitroprusside, sydnonimines such as molsidomine and linsidomine, nonoates such as diazenium diolates and NO
adducts of alkanediamines, S-nitroso compounds including low molecular weight compounds (e.g., S-nitroso derivatives of captopril, glutathione and N-acetyl penicillamine) and high molecular weight compounds (e.g., S-nitroso derivatives of proteins, peptides, oligosaccharides, polysaccharides, synthetic polymers/oligomers and natural polymers/oligomers), as well as C-nitroso-compounds, 0-nitroso-compounds, N-nitroso-compounds and L-arginine, (g) Angiotensin Converting Enzyme (ACE) inhibitors such as cilazapril, fosinopril and enalapril, (h) ATII-receptor antagonists such as saralasin and losartin, (i) platelet adhesion inhibitors such as albumin and polyethylene oxide, (j) platelet aggregation inhibitors including cilostazole, aspirin and thienopyridine (ticlopidine, clopidogrel) and GP IIb/IIIa inhibitors such as abciximab, epitifibatide and tirofiban, (k) coagulation pathway modulators including heparinoids such as heparin, low molecular weight heparin, dextran sulfate and (3-cyclodextrin tetradecasulfate, thrombin inhibitors such as hirudin, hirulog, PPACK(D-phe-L-propyl-L-arg-chloromethylketone) and argatroban, FXa inhibitors such as antistatin and TAP (tick anticoagulant peptide), Vitamin K inhibitors such as warfarin, as well as activated protein C, (1) cyclooxygenase pathway inhibitors such as aspirin, ibuprofen, flurbiprofen, indomethacin and sulfinpyrazone, (m) natural and synthetic corticosteroids such as dexamethasone, prednisolone, methprednisolone and hydrocortisone, (n) lipoxygenase pathway inhibitors such as nordihydroguairetic acid and caffeic acid, (o) leukotriene receptor antagonists, (p) antagonists of E- and P-selectins, (q) inhibitors of VCAM-1 and ICAM-1 interactions, (r) prostaglandins and analogs thereof including prostaglandins such as PGE1 and PGI2 and prostacyclin analogs such as ciprostene, epoprostenol, carbacyclin, iloprost and beraprost, (s) macrophage activation preventers including bisphosphonates, (t) HMG-CoA
reductase inhibitors such as lovastatin, pravastatin, atorvastatin, fluvastatin, simvastatin and cerivastatin, (u) fish oils and omega-3-fatty acids, (v) free-radical scavengers/antioxidants such as probucol, vitamins C and E, ebselen, trans-retinoic acid, SOD
(orgotein), SOD
mimics, verteporfin, rostaporfin, AGI 1067, and M 40419, (w) agents affecting various growth factors including FGF pathway agents such as bFGF antibodies and chimeric fusion proteins, PDGF receptor antagonists such as trapidil, IGF pathway agents including somatostatin analogs such as angiopeptin and ocreotide, TGF-(3 pathway agents such as polyanionic agents (heparin, fucoidin), decorin, and TGF-(3 antibodies, EGF
pathway agents such as EGF antibodies, receptor antagonists and chimeric fusion proteins, TNF-a pathway agents such as thalidomide and analogs thereof, Thromboxane A2 (TXA2) pathway modulators such as sulotroban, vapiprost, dazoxiben and ridogrel, as well as protein tyrosine kinase inhibitors such as tyrphostin, genistein and quinoxaline derivatives, (x) matrix metalloprotease (MMP) pathway inhibitors such as marimastat, ilomastat, metastat, pentosan polysulfate, rebimastat, incyclinide, apratastat, PG 116800, RO 1130830 or ABT 518, (y) cell motility inhibitors such as cytochalasin B, (z) antiproliferative/antineoplastic agents including antimetabolites such as purine analogs (e.g., 6-mercaptopurine or cladribine, which is a chlorinated purine nucleoside analog), pyrimidine analogs (e.g., cytarabine and 5-fluorouracil) and methotrexate, nitrogen mustards, alkyl sulfonates, ethylenimines, antibiotics (e.g., daunorubicin, doxorubicin), nitrosoureas, cisplatin, agents affecting microtubule dynamics (e.g., vinblastine, vincristine, colchicine, Epo D, paclitaxel and epothilone), caspase activators, proteasome inhibitors, angiogenesis inhibitors (e.g., endostatin, angiostatin and squalamine), rapamycin (sirolimus) and its analogs (e.g., everolimus, tacrolimus, zotarolimus, etc.), cerivastatin, flavopiridol and suramin, (aa) matrix deposition/organization pathway inhibitors such as halofuginone or other quinazolinone derivatives, pirfenidone and tranilast, (bb) endothelialization facilitators such as VEGF and RGD peptide, and (cc) blood rheology modulators such as pentoxifylline.
[0086] Further therapeutic agents useful for the practice of the present invention are also disclosed in U.S. Patent No. 5,733,925 to Kunz et al.
[0087] Additional embodiments will now be discussed with reference to the drawings.
[0088] The structure shown in the schematic, cross-sectional illustration of Fig. 6A is similar to those described in Figs. 4A and 4B in that it includes a substrate 610, having disposed thereon a ceramic coating 620 in accordance with the invention, which includes raised ceramic shells 620s connected by a ceramic layer 620c that is conformal with the substrate 610. A polymeric coating 630 is shown, disposed over the ceramic region 620, which in this embodiment contains a therapeutic agent. Unlike Figs. 4A and 4B, however, the hollow ceramic shells 620s of Fig. 6A contain paramagnetic particles 640.
Paramagnetic particles may be selected from various paramagnetic materials, which are typically metals, alloys or compounds of certain transition, rare earth and actinide elements (e.g., iron, iron oxides including magnetite, etc.).
[0089] Such a structure may be formed, for example, using polymeric particles (e.g., polystyrene spheres) that contain embedded paramagnetic particles as templates for the above-described LBL/sol-gel process. After removing the polystyrene component of the spheres (e.g., by heat treatment or dissolution), the paramagnetic particles remain inside of the ceramic shells 620s. The paramagnetic particles 640 are separated from the exterior environment by the ceramic shells 620s. Because they are paramagnetic, one can vibrate these particles 640 inside of their ceramic shells 620s using an external magnetic field. This will cause heat, which can, for example, increase the rate at which the therapeutic agent is released from the polymeric coating, among other effects. As an alternative embodiment, a magnetic material (e.g., one of those above) is placed on the outside of the polymeric particles (e.g., polystyrene particles may be provided, which have a magnetite coating). See, e.g., Marina Spasova et al., "Magnetic and optical tunable microspheres with a magnetite/gold nanoparticle shell," "J. Mater.
Chem., 15, (2005) 2095-2098 for more information. As above, in these embodiments, the magnetic material is embedded with the ceramic shells that are ultimately formed.
[0090] Fig. 6B is a structure like that of Fig. 6A, albeit without the polymeric coating 630. Like the structure of Fig. 6A, this structure can be heated using an external magnetic field. The high temperatures generated can be used, for example, to cause necrosis, thrombosis and other physiological effects within the body. For example, a coating like that shown in Fig. 6B may be provided on an embolic coil for the treatment of an aneurism. After implantation into an aneurism, the coil can be heated, thereby causing thrombosis within the aneurism.
[0091] As noted above, structures far more complex than those of Figs. 4A, 4B
and 6A
can be formed in accordance with the invention, which are capable of creating greater degrees of interlock between the ceramic coatings and the polymeric coatings overlying them.
[0092] In one embodiment, such a structure is produced using two sizes of charged particles. For example, with reference to Figs. 7A-7E, in a first step, a PML
coating 712a is formed on a substrate 710 using the LBL process (e.g., by dipping into polyelectrolyte solutions of alternating charge). In the embodiment shown in Fig. 7A, the top polyelectrolyte layer of the polyelectrolyte multilayer coating 712a is positively charged. In a subsequent step, spherical particles 715b, each comprising a PML
coating 712b whose top layer is negatively charged, are electrostatically assembled onto the PML
coating 712a as shown in Fig. 7B.
[0093] Next spherical particles 715c, each comprising a PML coating 712c whose top layer is positively charged, are electrostatically assembled on the structure of Fig. 7B.
The resulting structure is illustrated in Fig. 7C. Particles 715c are larger than particles 715b. Moreover, one or more paramagnetic kernels 7181ies within each particle 715c in the embodiment shown. As a specific example, polystyrene spheres 715b, 715c may be employed. For instance smaller spheres having diameters of 200 nm and larger spheres having diameters of 500 with super-paramagnetic kernels may be purchased from Microparticles, Berlin, Germany. By subjecting the kernels 718 to a magnetic field, a magnetic force is generated (illustrated by the arrow in Fig. 7C), and the coated particles 715c are urged into a closer association with the underlying coated particles 715b as shown in Fig. 7D. This improves the likelihood that the larger coated particles 715c make contact with several smaller coated particles 715b, rather than just hanging onto one sphere only. Compare Figs. 7C and 7D.
[0094] The structure of Fig. 7D can then be subjected to further polyelectrolyte deposition steps (e.g., by dipping into polyelectrolyte solution of alternating charge) to increase the thickness of the various PML coatings 712a,712b,712c as desired and to better merge them into a single continuous PML structure. The result is a structure like that of Fig. 7E. Next, a sol-gel-type process is carried out within the PML
structure, using sol-gel precursor solutions as discussed above, thereby forming a polyelectrolyte/ceramic hybrid structure 714 as shown in Fig. 7F.
[0095] The structure of Fig. 7F may then be subjected to further processing to remove the particles 715b and 715c. For example, assuming that the particles 715b and 715c are polymeric in nature (e.g., polystyrene), the structure of Fig. 7F may be heated to a temperature sufficient to substantially remove the polymeric particles 715b and 715c (and the polymeric components of the polyelectrolyte/ceramic hybrid structure 714 as well), thereby creating the ceramic coating 720 shown in Fig. 7G. The coating 720, which is a continuous structure, includes a substrate covering portion 720c and numerous ceramic shells 720s. Within the large ceramic shells 720 are found paramagnetic kernels 718, which can now be used to heat the medical device in vivo (or ex vivo), if desired.
[0096] Note that the structure of Fig. 7G contains spaces rl that are completely encapsulated/surrounded by the ceramic shells 720s as well as spaces r2 that are open to the outer environment. In the event that a polymeric coating 730 is applied as shown in Fig. 7H, the spaces r2 afford the polymeric coating 730 the opportunity to form a fully interlocking interface with the ceramic coating 720.
[0097] In another embodiment, the large spheres described in the prior embodiment can be replaced with elongated particles such as carbon nanofibers or carbon nanotubes, among many others. As with the large spheres above, the elongated particles are overcoated with PML coatings. For example, one can employ polyelectrolyte-functionalized carbon nanotubes or one can employ carbon nanotubes with PML
coatings as described in H. Kong et al. "Polyelectrolyte-functionalized multiwalled carbon nanotubes: preparation, characterization and layer-by-layer self-assembly,"
Polymer 46 (2005) 2472-2485. Following steps like those described above to create the structure of Fig. 7C (except using elongated particles rather than large spheres, and without the use of magnetic force), one ends up with a bottom layer of small spheres of a first charge, connected by elongated particles having an opposite charge. Further processing as described in Figs. 7E-7G above (polyelectrolyte deposition, exposure to a sol-gel precursor, heat treatment) results in a structure like that illustrated in Fig. 8A. Like Fig.
7G, Fig. 8A includes a substrate 810, having disposed thereon a continuous ceramic coating 820 in accordance with the invention. The region 820 includes raised ceramic hollow spherical shells 820s1 connected by a ceramic layer 820c that is conformal with the substrate 810. Unlike Figs. 7G, however, the continuous ceramic coating 820 of Fig.
8A further includes non-hollow, non-spherical ceramic shells 820s2, which contain elongated particles 815. For example, the elongated particles may be carbon fibers, carbon nanotubes or any other elongated particle that survives processing. As can be seen from Fig. 8A, these ceramic-coated fibers 815,820s2 connect the hollow ceramic spheres 820s 1 to one another. Alternatively, elongated particles may be used which are removed during the heat treatment process, in which case a structure like that in Fig.
8B would result, wherein hollow ceramic fibers 820s2 connect the hollow ceramic spheres 820s1 to one another. Because thin fibers are used to interconnect the underlying ceramic spheres (rather than larger ceramic spheres, as was the case in Fig. 7G), a structure like that of Figs. 8A and 8B should be more tolerant of bending or flexing that the structure of Fig.
7G.
[0098] As with Fig. 7G, the structures of Fig. 8A and 8B, contains spaces rl that are completely encapsulated/surrounded by ceramic shells (i.e., shells 820s1,820s2), as well as spaces r2 that are open to the outer environment. These spaces r2 afford a polymeric coating 830 the opportunity to form a fully interlocking interface with the ceramic coating 820 as seen in Fig. 8C.
[0099] In other embodiments of the invention, the use of spheres is completely eliminated. For example, for example, one could apply to a charged substrate (e.g., an LBL coated substrate) a layer of elongated particles of opposite charge (e.g., LBL
encapsulated particles), which particles may be, for example, heat-resistant particles such as a carbon nanotubes or heat-labile particles such as polystyrene fibers, among many other possibilities. After adsorbing the particles, LBL processing, sol-gel processing, and heat treatment may be conducted (see above) to produce a ceramic coating containing raised ceramic shells, which may contain the elongated particles, or which may be wholly or partially hollow.
[0100] In a variation of this embodiment, one could apply to a substrate (e.g., an LBL
coated substrate) having a given charge (e.g., a negative charge), a first layer of elongated particles (e.g., LBL coated particles) of opposite charge (e.g., a positive charge), followed by a second layer of elongated particles (e.g., LBL coated particles) of opposite charge (e.g., a negative charge), and so forth. These steps may be followed by further LBL
polyelectrolyte processing, sol gel processing, and heat treatment. Such a process would create a relatively random orientation for the elongated particles, creating a complex mesh of raised ceramic shells (which shells, again, may be filled with the elongated particles or partially or wholly hollow).
[0101] A more regular architecture may be created by using an AC electric field to orient the elongated particles within the solution at the time of deposition. For example, carbon nanotubes are known to align themselves as a result of the formation of an induced dipole in response to an electric field. A DC field will align and move the nanotubes, whereas an AC field only aligns them. In this regard, see, e.g., M. Senthil Kumar et al., "Influence of electric field type on the assembly of single walled carbon nanotubes,"
Chemical Physics Letters 383 (2004) 235-239. See also U.S. Serial No. 11/368,738. For example, using electric field alignment, the particles of the various layers may all be aligned in a single direction. As another example, electrical field alignment may be used to align the positively and negatively charged layers orthogonally with respect one another. These steps may, again, be followed by LBL polyelectrolyte processing, sol-gel processing and heat treatment, thereby forming a strongly connected ceramic network with internal reinforcement based on carbon nanotubes.
[0102] A further embodiment of the invention is illustrated in conjunction with Figs. 9A-9D. As shown in Fig. 9A, a substrate 910 having one or more depressions (e.g., blind holes 910b) is coated with a PML coating. Two layers are schematically illustrated in Fig. 9A, an inner positive polyelectrolyte layer 912p and an outer negative polyelectrolyte layer 912n, although a single layer, or three or more layers may be applied.
Moreover, the outer layer can be a positive layer, rather than a negative layer as illustrated. The substrate may be, for example, a stent within which numerous blind holes are formed (e.g., via laser ablation).
[0103] In a subsequent step, a positive polyelectrolyte layer 912p, or multiple alternating polyelectrolyte layers terminating in a positive polyelectrolyte layer, is/are selectively applied to those portions of the negative polyelectrolyte layer 912n layer over the upper substrate surface, but not those portions within the blind hole 910b, resulting in a structure like that of Fig. 9B. This structure has a negative surface charge within the blind hole 919b and a positive surface charge outside the blind hole. (In the event that the structure in Fig. 9A were to have an outer positive layer, charges for this step would be reversed, such that the surface of the blind hole would have a positive surface charge and the upper surface of the structure would have a negative surface charge.) An example of a technique by which such selective application may be achieved is described in J. Park et al., Adv. Mater.," 2004, 16(6), 520-525, which describes a technique in which a PML
coating is adsorbed onto the surface of a polymer (polydimethylsiloxane) stamp. The first layer adsorbed onto the stamp is cationic polyallylamine hydrochloride (PAH), followed by alternating layers of anionic sulfonated polystyrene (SPS) and cationic polydiallyldimethylammonium chloride (PDAC). The last layer is the cationic PDAC.
The stamp is then contacted with a substrate having a negative surface charge and the multilayer is transferred in its entirety from the stamp to the substrate. The top layer of the transferred pattern is the anionic PAH layer.
[0104] At this point, the structure of Fig. 9B is exposed to particles having a negative surface charge. In the embodiment shown in Fig. 9C, the particles are spheres 915 with PML coating layers, terminating in a positively charged polyelectrolyte layer 921p. As elsewhere herein, the structure of Fig. 9C can then be optionally provided with additional polyelectrolyte layers as desired, followed by sol-gel processing and heat treatment to produce a structure like that of Fig. 9D, which includes a substrate 910 having a ceramic coating that includes raised ceramic shells 920s (in Fig. 9D the shells are hollow, although they need not be, as note elsewhere herein) connected by a ceramic layer 920c that is conformal with the substrate. In this example, the raised ceramic shells 920s are found only in the blind holes.
[0105] In another aspect of the invention, the use of a substrate is eliminated entirely, and the resulting product is a collection of carbon nanotubes coated with a ceramic layer. For example, with reference to Fig. 10A, a carbon nanotube 1010 can be provided with a polyelectrolyte multilayer coating 1012. This structure is then exposed a sol-gel precursor, forming a polyelectrolyte/ceramic hybrid coating 1014 as shown in Fig. lOB, followed by heat treatment to create carbon nanotubes 1010 with a ceramic coating 1020 as shown in Fig. lOC. Such carbon nanotubes would have applications in many fields, for example, finding use as reinforcement particles in polymers or metals. Carbon nanotubes normally are at risk for agglomeration due to 7r-7c bonding, which is disrupted by the ceramic coating.

Example 1 [0106] A procedure for creating a coating like that illustrated in Fig. 3B
will now be described.
[0107] Solutions are prepared as follows (a) PAH solution: a solution of poly(allylamine hydrochloride) (PAH) (m.w. -70,000) (Sigma-Aldrich) was made in DI water with the following constituents: 1 g/L PAH, 0.2M NaC1, and 0.05M NaAc (sodium acetate buffer solution pH=5.6), (b) PSS solution: a solution of poly(sodium 4-styrenesulfonate) (PSS) (m.w. -70,000) (Sigma-Aldrich) was made in DI water with the following constituents:
1 g/L PSS, 0.2M NaC1, 0.05M NaAc (sodium acetate buffer solution pH=5.6), (c) polystyrene (PS) particle solution: a solution of poly(sodium 4-styrenesulfonate) particles (500 nm) (Forschungs- und Entwicklungslaboratorium, Berlin, Germany) was received as a concentrated solution (5 wt %) and diluted in deionized (DI) water to a concentration of 0.5 wt%, (d) sol-gel solution: 2g TEOS (Alfa Aesar, Johnson Matthey Catalog Company, Inc., Ward Hill, MA, USA) is combined with 100 mL Ethanol (Anhydrous, Denatured, product no. EX0285-3, EMD Chemicals, Gibstown, NJ, USA) and mixed for 10 minutes, after which are added 10 mL DI water and 1 mL ammonium hydroxide (25% in water) (Sigma-Aldrich), followed by further mixing.
[0108] Stainless stee1316L electro-polished coupons (3.5"x0.79"x0.03") are cleaned with an RF oxygen plasma in a March AP-1000 Plasma System using the following process parameters: P=200 mTorr, 300 watts, Gas 1(Argon)=250sccm, Gas2 (Oxygen)=200sccm, t=180s.
[0109] The coupon is provided with 1.5 bi-layers (PAH/PSS/PAH), followed by a PS
particle layer, followed by 1.5 bilayers (PAH/PSS/PAH). The resulting structures are analogous to those shown schematically in Figs. 5A-5C (described above). For each polyelectrolyte layer, the coupon is immersed in a beaker of PAH or PSS
solution (prepared as described above) and agitated on a shaker for 20 minutes. For the PS
particle layer, the coupon is immersed in a beaker of the PS particle solution (prepared as described above) and agitated on a shaker for 1 hour. Three DI water rinses are performed after each layer to remove non-adsorbed polyelectrolyte/particles and the coupon is placed directly into the next solution.
[0110] This structure is then submerged in a beaker of sol-gel solution (prepared as described above) for approximately 16 hours. Three DI water rinses are performed after exposure to the sol-gel solution. The resulting structure, which is analogous to that shown schematically in Fig. 5F (described above), is placed in an oven at ambient temperature and ramped to a final temperature of 540 C over a period of -1.5 hrs. After a total cycle time of 6 hrs (ramp-up and 540 C hold), the oven is turned off, and the sample is allowed to cool in the oven overnight. The final structure is analogous to that shown schematically in Fig. 5F (described above).

Example 2 [0111] A procedure for creating a coating like that illustrated in Fig. 11 will now be described.
[0112] PAH solution, PSS solution, and PS particle solution, are prepared as described in Example 1 above. For the sol gel solution, a solution was prepared in which the recipe of Example 1 was halved. Attapulgite particle solution (Atta) is prepared as follows: 50 g/L
Attapulgite Clay (ATTAGEL 50)(BASF) is provided in 25mM NaC1.
[0113] 16mm LiberteTM stainless steel stents are cleaned with an RF oxygen plasma in a March AP-1000 Plasma System using the following process parameters: P=200 mTorr, 300 watts, Gas 1(Argon)=250sccm, Gas2 (Oxygen)= 200sccm, t=180s.
[0114] The stent is provided with 3.5 bilayers (PAH/PSS/PAH/PSS/PAH/PSS/PAH), followed by 2 bilayers (Atta/PAH/Atta/PAH), followed by a PS particle layer, followed by 2 bilayers (PAH/PSS/PAH/PSS). For each polyelectrolyte layer and the attapulgite particle layers, the stent is immersed in a beaker of PAH, PSS or Atta solution (prepared as described above) and agitated on a shaker for 20 minutes. For the PS
particle layer, the stent is immersed in a beaker of the PS particle solution (prepared as described above) and agitated on a shaker for 1 hour. Three DI water rinses are performed after each layer to remove non-adsorbed polyelectrolyte/ particles and the stent placed directly into the next solution.
[0115] This structure is then submerged in a beaker of sol-gel solution (prepared as described above) for approximately 16 hours, after which three DI water rinses are performed. The resulting structure is placed in an oven at ambient temperature (-23 C) and ramped to 540 C over a period of -1.5 hrs. After a total time of 6 hrs in the oven (ramp-up and 540 C hold), the oven is turned off, and the sample allowed to cool in the oven overnight.

Example 3 [0116] Polyelectrolyte coated carbon nanotubes are prepared as an initial step. Poly(2-(N,N-dimethylaminoethyl) methacrylate (PDMAEMA) (0.15 g)( Sigma Aldrich Bornem, Belgium), NaC1(5.8 g) and 100 mL of deionized water are placed in a 250 mL
flask and stirred until the PDMAEMA and NaC1 are completely dissolved. The pH value of the solution is adjusted to 3.7 by adding 2 M HC1. Multi-wall carbon nanotubes derivatized with carboxyl groups (MWNT-COOH) (80 mg) (Cheap Tubes, Inc. 112 Mercury Drive, Brattleboro, VT, USA) are then added to the as-prepared PDMAEMA solution. The mixture is placed in an ultrasonic bath (40 kHz) for 3 min and stirred gently for 30 min.
Then the solids are separated by filtration through a 0.22 micrometer Millipore polycarbonate membrane filter and washed with DI water three times. The resulting solids are added to 100 mL of an aqueous solution of PSS (1.5 g/L) (Sigma Aldrich, Bornem, Belgium) and NaC1(1 M) in DI water, followed with the same steps as described above (ultrasonic dispersion, gentle stirring, filtration and washing). Two more bilayers of PDMAEMA and PSS are added. After the final washing step, the resulting particles are suspended in DI water at a concentration of 1 g/L. This solution is substituted for the PS solution in Example 1 above and for the Atta solution in Example 2 above.
[0117] Although various embodiments are specifically illustrated and described herein, it will be appreciated that modifications and variations of the present invention are covered by the above teachings and are within the purview of the appended claims without departing from the spirit and intended scope of the invention.

Claims (30)

1. A coated article comprising a substrate and a ceramic coating that covers at least a portion of the substrate surface, said ceramic coating comprising raised first ceramic shells connected by an underlying ceramic layer that is conformal with the substrate surface.
2. The coated article of claim 1, wherein said article is a medical article.
3. The coated article of claim 2, wherein said medical article is an implantable or insertable medical device.
4. The coated article of claim 3, wherein said medical device is selected from a stent, an electrical lead, an electrical coil, a catheter, an injection needle, a guidewire, and an embolic device.
5. The coated article of claim 1, wherein said substrate is selected from a metallic substrate and a polymeric substrate.
6. The coated article of claim 1, wherein said ceramic coating contains one or more oxides selected from oxides of silicon, titanium, zirconium, iridium, and combinations thereof.
7. The coated article of claim 1, wherein said ceramic coating contains one or more species selected from carbides and nitrides of silicon, titanium, zirconium, iridium, and combinations thereof.
8. The coated article of claim 1, wherein said first ceramic shells and said underlying ceramic layer comprise at least 90wt% metal oxide.
9. The coated article of claim 1 wherein said first ceramic shells are at least partially hollow.
10. The coated article of claim 9, wherein said at least partially hollow first ceramic shells contain paramagnetic particles.
11. The coated article of claim 1, wherein said wherein said first ceramic shells enclose a material selected from polymeric materials, metallic materials, ceramic materials and carbon.
12. The coated article of claim 1, wherein said first ceramic shells are spherical.
13. The coated article of claim 1, wherein said first ceramic shells are elongated.
14. The coated article of claim 13, wherein said elongated shells are aligned.
15. The coated article of claim 1, further comprising second ceramic shells connected to said first ceramic shells.
16. The coated article of claim 15, further comprising a polymeric coating.
17. The coated article of claim 15, wherein said first and second ceramic shells are spherical
18. The coated article of claim 15, wherein said first and second ceramic shells are elongated.
19. The coated article of claim wherein said first ceramic shells are spherical and said second ceramic shells are elongated.
20. The coated article of claim 1, further comprising a polymeric coating.
21. The coated article of claim 20, wherein said polymeric coating comprises a therapeutic agent.
22. The coated article of claim 21, wherein said wherein said medical device is a stent, wherein said therapeutic agent is an antiproliferative agent, wherein said ceramic coating is disposed over the entire stent, and wherein the polymeric coating is disposed over the abluminal surface of the stent and not over the luminal surface of the stent.
23. The coated article of claim 20, wherein said polymeric coating is selected from a lubricious coating, an electrically insulating coating, a bioresorbable coating and a protein coating.
24. The coated article of claim 20, wherein said first ceramic shells are spherical, and wherein the polymeric coating thickness is dictated by the height of the first ceramic shells
25. The coated article of claim 1, wherein said substrate comprises blind holes, through holes or both, and wherein said ceramic shells are preferentially positioned in the holes.
26. The coated article of claim 1, wherein said ceramic coating comprises a metal or semi-metal oxide and a polyelectrolyte.
27. The coated article of claim 26, wherein said ceramic coating further comprises a therapeutic agent.
28. The coated article of claim 1, wherein said ceramic shells enclose a material comprising a therapeutic agent.
29. A carbon nanotube comprising a ceramic coating.
30. A medical article comprising carbon nanotubes with ceramic coatings.
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